CN102134232B - Isotopically substituted proton pump inhibitors - Google Patents

Abstract

Translated fromChinese

本发明涉及同位素取代的质子泵抑制剂。本发明涉及式(1)苯并咪唑和包含这些化合物的药用组合物，还涉及式(2和3)中间体。

The present invention relates to isotopically substituted proton pump inhibitors. The present invention relates to benzimidazoles of formula (1) and pharmaceutical compositions comprising these compounds, as well as intermediates of formulas (2 and 3).

Description

Translated fromChinese

同位素取代的质子泵抑制剂Isotopically substituted proton pump inhibitors

本申请是申请日为2006年7月26日，申请号为200680034503.4(国际申请号为PCT/EP2006/064666)，发明名称为“同位素取代的质子泵抑制剂”的发明专利申请的分案申请。This application is a divisional application of an invention patent application with an application date of July 26, 2006, application number 200680034503.4 (international application number PCT/EP2006/064666), and an invention title of "isotope-substituted proton pump inhibitor".

发明主题Invention subject

本发明涉及同位素取代的质子泵抑制剂及其(R)-和(S)-对映体。这些化合物可用于制药工业制备药用组合物。The present invention relates to isotopically substituted proton pump inhibitors and their (R)- and (S)-enantiomers. These compounds are useful in the pharmaceutical industry for the preparation of pharmaceutical compositions.

发明背景Background of the invention

由于其H⁺/K⁺-ATP酶-抑制作用，吡啶-2-基甲基亚磺酰基-1H-苯并咪唑，例如公知的那些，如EP-A-0005129、EP-A-0166287、EP-A-0174726、EP-A-0254588和EP-A-0268956中的那些，在治疗与胃酸分泌增加有关的疾病中具有相当的重要性。Pyridin-2^{-ylmethylsulfinyl} -1H-benzimidazoles, such as those known for example from EP-A-0005129, EP-A-0166287, EP-A-0166287, EP-A-0005129, - Those of A-0174726, EP-A-0254588 and EP-A-0268956 are of considerable importance in the treatment of diseases associated with increased gastric acid secretion.

这类可买得到或处于临床开发中的活性化合物的例子有：5-甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(INN：奥美拉唑)、(S)-5-甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(INN：艾司奥美拉唑)、5-二氟甲氧基-2-[(3，4-二甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(INN：泮托拉唑)、2-[3-甲基-4-(2，2，2-三氟乙氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(INN：兰索拉唑)，2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚磺酰基}-1H-苯并咪唑(INN：雷贝拉唑)和5-甲氧基-2-((4-甲氧基-3，5-二甲基-2-吡啶基甲基)亚磺酰基)-1H-咪唑并[4，5-b]吡啶(INN：泰妥拉唑)。Examples of such active compounds that are commercially available or in clinical development are: 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfin Acyl]-1H-benzimidazole (INN: omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl) Methylsulfinyl]-1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl Sulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl Sulfinyl]-1H-benzimidazole (INN: Lansoprazole), 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylidene Sulfonyl}-1H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridylmethyl) Sulfonyl)-1H-imidazo[4,5-b]pyridine (INN: Tentoprazole).

由于其作用机制，上述亚磺酰基衍生物也称作质子泵抑制剂或者简写为PPI。Due to their mechanism of action, the aforementioned sulfinyl derivatives are also known as proton pump inhibitors or PPIs for short.

相关技术描述Related technical description

美国专利第6,818,200号公开了其中至少一个氢原子被氘原子取代的二氢吡啶化合物和抗生素。H-型化合物与氧化氘和适当催化剂的混合物在密封容器内的剧烈反应条件下反应，也就是在高温(60至80℃)下长时间反应(长达190个小时)，可以获得氘化的化合物。该专利还公开了H/D交换对这些化合物的药理性质所产生的一些影响。US Patent No. 6,818,200 discloses dihydropyridine compounds and antibiotics in which at least one hydrogen atom is replaced by a deuterium atom. The H-type compound is reacted with a mixture of deuterium oxide and a suitable catalyst under severe reaction conditions in a sealed container, that is, at a high temperature (60 to 80 ° C) for a long time (up to 190 hours), and the deuterated compound. The patent also discloses some effects of H/D exchange on the pharmacological properties of these compounds.

发明公开invention disclosure

现在令人惊讶地发现，下面详述的同位素取代化合物对抑制酸分泌产生了显著影响。It has now surprisingly been found that the isotopically substituted compounds detailed below have a significant effect on the inhibition of acid secretion.

本发明涉及通式1化合物及其药学上可接受的盐、溶剂化物(优选水合物)，以及其盐的溶剂化物(优选其盐的水合物)The present invention relates to the compound of general formula 1 and its pharmaceutically acceptable salt, solvate (preferably hydrate), and the solvate of its salt (preferably the hydrate of its salt)

其中in

R1为氢或1-4C-烷氧基R1 is hydrogen or 1-4C-alkoxy

R2为1-4C-烷基或1-4C-烷氧基R2 is 1-4C-alkyl or 1-4C-alkoxy

R3为1-4C-烷基、1-4C-烷氧基或2-8C-烷氧基烷氧基R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy

R4为氢或1-4C-烷基R4 is hydrogen or 1-4C-alkyl

Z为C-H或NZ is C-H or N

其中，R1、R2、R3、R4或者R1、R2、R3和R4的任何组合中至少一个氢原子被氘原子取代。Wherein, at least one hydrogen atom in R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is replaced by a deuterium atom.

1-4C-烷基表示具有1至4个碳原子的直链或支链烷基。可能涉及的例子有：丁基、异丁基、仲-丁基、叔-丁基、丙基、异丙基、乙基，且优选甲基。1-4C-Alkyl denotes straight-chain or branched alkyl having 1 to 4 carbon atoms. Examples which may be involved are: butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and preferably methyl.

1-4C-烷氧基表示除氧原子之外还包含上述1-4C-烷基或氟代1-4C-烷基其中之一的基团。可能涉及的1-4C-烷氧基的例子有：丁氧基、异丁氧基、仲-丁氧基、叔-丁氧基、丙氧基、异丙氧基、乙氧基，且优选甲氧基。氟代1-4C-烷基的例子有：2，2，3，3，3-五氟丙基、2，2，3，3-四氟丙基、1-(三氟甲基)-2，2，2-三氟乙基、2，2，3，3，4，4，4-七氟丁基，且优选2，2，2-三氟乙基和二氟甲基。1-4C-Alkoxy denotes a group which, in addition to an oxygen atom, also contains one of the aforementioned 1-4C-alkyl or fluoro1-4C-alkyl groups. Examples of 1-4C-alkoxy groups that may be involved are: butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy, and preferably Methoxy. Examples of fluorinated 1-4C-alkyl groups are: 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1-(trifluoromethyl)-2 , 2,2-trifluoroethyl, 2,2,3,3,4,4,4-heptafluorobutyl, and preferably 2,2,2-trifluoroethyl and difluoromethyl.

2-8C-烷氧基烷氧基表示除氧原子之外还包含内部亚烷基(包括1-4C亚烷基)和末端烷基(包括1-4C烷基，并通过氧原子与内部亚烷基相连)的基团。例子有：甲氧基甲氧基、甲氧基乙氧基、乙氧基甲氧基、乙氧基丙氧基、乙氧基异丙氧基、异丙氧基甲氧基、丙氧基甲氧基、甲氧基丁氧基、甲氧基异丁氧基、丙氧基乙氧基、异丙氧基乙氧基、丙氧基丙氧基、异丙氧基异丙氧基、异丙氧基丙氧基、丙氧基异丙氧基、乙氧基丁氧基、乙氧基异丁氧基、乙氧基-仲-丁氧基、乙氧基-叔-丁氧基，且优选甲氧基丙氧基。2-8C-alkoxyalkoxy means that in addition to oxygen atoms, it also contains internal alkylene (including 1-4C alkylene) and terminal alkyl (including 1-4C alkyl, and through the oxygen atom and internal alkylene Alkyl linked) groups. Examples are: Methoxymethoxy, Methoxyethoxy, Ethoxymethoxy, Ethoxypropoxy, Ethoxyisopropoxy, Isopropoxymethoxy, Propoxy Methoxy, Methoxybutoxy, Methoxyisobutoxy, Propoxyethoxy, Isopropoxyethoxy, Propoxypropoxy, Isopropoxyisopropoxy, Isopropoxypropoxy, propoxyisopropoxy, ethoxybutoxy, ethoxyisobutoxy, ethoxy-sec-butoxy, ethoxy-tert-butoxy , and preferably methoxypropoxy.

依照本发明，盐的意义包括所有的无机碱盐和有机碱盐，特别是碱金属盐(例如锂盐、钠盐和钾盐)，或者碱土金属盐(例如镁盐和钙盐)，以及其它药理学上相容的盐，例如铝盐或锌盐。特别优选钠盐和镁盐。According to the invention, the meaning of salt includes all salts of inorganic and organic bases, especially alkali metal salts (such as lithium salts, sodium salts and potassium salts), or alkaline earth metal salts (such as magnesium salts and calcium salts), and other Pharmacologically compatible salts, such as aluminum or zinc salts. Sodium and magnesium salts are particularly preferred.

为了药用组合物的生产，可用本领域技术人员已知的方法将药理学上不相容的盐(其最初可作为例如工业规模生产本发明化合物的过程产物(process product)获得，该过程产物也在本发明范畴之内)转化成药理学上可耐受的盐。For the production of pharmaceutical compositions, pharmacologically incompatible salts (which are initially obtainable, for example, as process products of the production of the compounds of the invention on an industrial scale, can be obtained by methods known to those skilled in the art, which process products are also within the scope of the present invention) into pharmacologically tolerable salts.

本领域技术人员周知的是，本发明化合物及其盐，例如，如果它们是以结晶形式分离得到，则可以含有不同量的溶剂。因此，本发明也包括式1化合物的所有溶剂化物(特别是所有水合物)，以及式1化合物盐的所有溶剂化物(特别是所有水合物)。溶剂化物的意义包括所有生成这种溶剂化物的药学上可接受的溶剂。It is well known to those skilled in the art that the compounds of the invention and their salts, eg if they are isolated in crystalline form, may contain different amounts of solvent. Accordingly, the present invention also includes all solvates (in particular all hydrates) of the compounds of formula 1, and all solvates (in particular all hydrates) of the salts of the compounds of formula 1. The meaning of solvates includes all pharmaceutically acceptable solvents which form such solvates.

关于本发明化合物的命名，“氘”一词应指氘原子([²H])。类似地，前面的“二”和“三”分别应指在特定基团(如，1，1-二氘化-2，2，2-三氟乙氧基或三氘化甲氧基)中出现两个或三个例如氘原子。Regarding the nomenclature of the compounds of the present invention, the term "deuterium" shall refer to a deuterium atom ([² H]). Similarly, the preceding "two" and "three" shall mean respectively in a specific group (e.g., 1,1-dideuterated-2,2,2-trifluoroethoxy or trideuterated methoxy) Two or three eg deuterium atoms are present.

在本发明范围之内，优选式1化合物，其中R3中至少一个氢原子被氘原子取代，且R3为1-2C烷氧基或2-5C烷氧基烷氧基。Within the scope of the present invention, compounds of formula 1 are preferred, wherein at least one hydrogen atom in R3 is replaced by a deuterium atom, and R3 is 1-2C alkoxy or 2-5C alkoxyalkoxy.

优选式1化合物，其中R2为1-4C烷基，且R3为2-8C烷氧基烷氧基，其中R2、R3或R2和R3中至少一个氢原子被氘原子取代。Preferred are compounds of formula 1, wherein R2 is 1-4C alkyl, and R3 is 2-8C alkoxyalkoxy, wherein R2, R3 or at least one hydrogen atom in R2 and R3 is replaced by a deuterium atom.

优选式1化合物，其中R1为1-4C烷氧基，R2和R4为1-4C烷基，且R3为1-4C-烷氧基，其中R1、R3、R4或者R1、R3和R4的任何组合中至少一个氢原子被氘原子取代。Preferred compounds of formula 1, wherein R1 is 1-4C alkoxy, R2 and R4 are 1-4C alkyl, and R3 is 1-4C-alkoxy, wherein R1, R3, R4 or any of R1, R3 and R4 At least one hydrogen atom in the combination is replaced by a deuterium atom.

还优选式1化合物，其中R1为氢、甲氧基或二氟甲氧基，R2为甲基或甲氧基，R3为甲氧基、2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢或甲基，且其中R3中至少一个氢原子被氘原子取代。Also preferred are compounds of formula 1, wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxy Propyloxy, R4 is hydrogen or methyl, and wherein at least one hydrogen atom in R3 is replaced by a deuterium atom.

还优选式1化合物，其中R2为甲基，R3为甲氧基丙氧基，且Z为C-H，其中R2、R3或R2和R3中至少一个氢原子被氘原子取代。Also preferred are compounds of formula 1, wherein R2 is methyl, R3 is methoxypropoxy, and Z is C-H, wherein R2, R3 or at least one hydrogen atom in R2 and R3 is replaced by a deuterium atom.

还优选式1化合物，其中R1为甲氧基，R2和R4为甲基，R3为甲氧基，其中R1、R3、R4或者R1、R3和R4的任何组合中至少一个氢原子被氘原子取代。可能的组合为R1和R3、R1和R4、R3和R4、R1和R3和R4。Also preferred are compounds of formula 1, wherein R1 is methoxy, R2 and R4 are methyl, R3 is methoxy, wherein at least one hydrogen atom in R1, R3, R4 or any combination of R1, R3 and R4 is replaced by a deuterium atom . Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

还优选式1化合物，其中R1为甲氧基，R2为甲基，R3为甲氧基，R4为甲基，或者其中R1为氢，R2为甲基，R3为2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢，或者其中R1为二氟甲氧基，R2为甲氧基，R3为甲氧基，R4为氢，且其中R3中至少一个氢原子被氘原子取代。Also preferred are compounds of formula 1, wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl, or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoro Ethoxy or methoxypropoxy, R4 is hydrogen, or wherein R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen, and wherein at least one hydrogen atom in R3 is replaced by Deuterium atoms are substituted.

还优选式1化合物，其中R1为甲氧基，R2为甲基，R3为甲氧基，R4为甲基，或者其中R1为氢，R2为甲基，R3为2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢，或者其中R1为二氟甲氧基，R2为甲氧基，R3为甲氧基，R4为氢，且其中R3中至少两个氢原子被氘原子取代。Also preferred are compounds of formula 1, wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl, or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoro Ethoxy or methoxypropoxy, R4 is hydrogen, or wherein R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen, and wherein R3 is at least two hydrogen atoms replaced by a deuterium atom.

更优选式1化合物，其中R2为1-4C烷基，且R3为2-8C-烷氧基烷氧基，其中R2、R3或R2和R3中所有氢原子都被氘原子取代。More preferred are compounds of formula 1, wherein R2 is 1-4C-alkyl, and R3 is 2-8C-alkoxyalkoxy, wherein R2, R3 or all hydrogen atoms in R2 and R3 are replaced by deuterium atoms.

更优选式1化合物，其中R1为1-4C烷氧基，R2和R4为1-4C烷基，且R3为1-4C-烷氧基，其中R1、R3、R4或者R1、R3和R4的任何组合中所有氢原子都被氘原子取代。可能的组合为R1和R3、R1和R4、R3和R4、R1和R3和R4。More preferred are compounds of formula 1, wherein R1 is 1-4C alkoxy, R2 and R4 are 1-4C alkyl, and R3 is 1-4C-alkoxy, wherein R1, R3, R4 or R1, R3 and R4 All hydrogen atoms in any combination are replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

更优选式1化合物，其中R3中所有氢原子都被氘原子取代，且其中R3为甲氧基、2，2，2-三氟乙氧基或甲氧基丙氧基。More preferred are compounds of formula 1, wherein all hydrogen atoms in R3 are replaced by deuterium atoms, and wherein R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.

更优选式1化合物，其中R2为甲基，R3为甲氧基丙氧基，且Z为C-H，其中R2、R3或R2和R3中所有氢原子都被氘原子取代。More preferred are compounds of formula 1, wherein R2 is methyl, R3 is methoxypropoxy, and Z is C-H, wherein R2, R3 or all hydrogen atoms in R2 and R3 are replaced by deuterium atoms.

还更优选式1化合物，其中R1为甲氧基，R2和R4为甲基，且R3为甲氧基，其中R1、R3、R4或者R1、R3和R4的任何组合中所有氢原子都被氘原子取代。可能的组合为R1和R3、R1和R4、R3和R4、R1和R3和R4。Still more preferred is a compound of formula 1, wherein R1 is methoxy, R2 and R4 are methyl, and R3 is methoxy, wherein all hydrogen atoms in R1, R3, R4 or any combination of R1, R3 and R4 are replaced by deuterium atomic substitution. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

还更优选式1化合物，其中R1为氢、甲氧基或二氟甲氧基，R2为甲基或甲氧基，R3为甲氧基、2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢或甲基，且其中R3中所有氢原子都被氘原子取代。Even more preferred are compounds of formula 1, wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methyl Oxygenoxypropoxy, R4 is hydrogen or methyl, and wherein all hydrogen atoms in R3 are replaced by deuterium atoms.

还更优选式1化合物，其中R1为甲氧基、R2为甲基，R3为甲氧基，R4为甲基，或者其中R1为氢，R2为甲基，R3为2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢，或者其中R1为二氟甲氧基、R2为甲氧基，R3为甲氧基，R4为氢，且其中R3中所有氢原子都被氘原子取代。Even more preferred are compounds of formula 1, wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl, or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-tri Fluoroethoxy or methoxypropoxy, R4 is hydrogen, or wherein R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen, and wherein all hydrogen atoms in R3 are replaced by a deuterium atom.

最优选的化合物是：5-甲氧基-2-[(4-三氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-甲氧基-2-[(4-二氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-三氘化甲氧基-2-[(4-三氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-三氘化甲氧基-2-[(4-二氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-甲氧基-2-[(3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，5-三氘化甲氧基-2-[(3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、2-[3-甲基-4-(1，1-二氘化-2，2，2-三氟乙氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-二氟甲氧基-2-[(3-三氘化甲氧基-4-甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，5-二氟甲氧基-2-[(3-二氘化甲氧基-4-甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、5-二氟甲氧基-2-[(3，4-二(二氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、2-{[4-(3-三氘化甲氧基六氘化丙氧基)-3-甲基吡啶-2-基]甲基亚磺酰基}-1H-苯并咪唑、2-{[4-(3-三氘化甲氧基六氘化丙氧基)-3-三氘化甲基吡啶-2-基]甲基亚磺酰基}-1H-苯并咪唑、5-甲氧基-2-((4-三氘化甲氧基-3，5-二甲基-2-吡啶基甲基)亚磺酰基)-1H-咪唑并[4，5-b]吡啶、5-三氘化甲氧基-2-((4-三氘化甲氧基-3，5-二甲基-2-吡啶基甲基)亚磺酰基)-1H-咪唑并[4，5-b]吡啶、5-甲氧基-2-((3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基甲基)亚磺酰基)-1H-咪唑并[4，5-b]吡啶或5-三氘化甲氧基-2-((3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基甲基)亚磺酰基)-1H-咪唑并[4，5-b]吡啶。The most preferred compound is: 5-methoxy-2-[(4-trideuteromethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole , 5-methoxy-2-[(4-dideuterated methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trideuterium Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trideuterated methoxy- 2-[(4-trideuteromethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trideuteromethoxy-2- [(4-Dideuteromethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-methoxy-2-[(3-methyl Base-4-trideuteromethoxy-5-trideuteromethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trideuteromethoxy-2-[( 3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 2-[3-methyl-4- (1,1-dideuterated-2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2- [(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methyl Oxy-4-dideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-trideuteromethoxy -4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-dideuteromethoxy-4-methoxy Base-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl )Methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(dideuteromethoxy)-2-pyridyl)methylsulfinyl ]-1H-benzimidazole, 2-{[4-(3-trideuteromethoxyhexadeuteridepropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H- Benzimidazole, 2-{[4-(3-trideuteromethoxyhexadeuteriopropoxy)-3-trideuteromethylpyridin-2-yl]methylsulfinyl}-1H-benzene and imidazole, 5-methoxy-2-((4-trideuteromethoxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl)-1H-imidazo[4,5 -b] pyridine, 5-trideuteromethoxy-2-((4-trideuteromethoxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl)-1H-imidazole And[4,5-b]pyridine, 5-methoxy-2-((3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridylmethyl)idene Sulfonyl)-1H-imidazo[4,5-b]pyridine or 5 - Trideuteromethoxy-2-((3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridylmethyl)sulfinyl)-1H-imidazo [4,5-b]pyridine.

依照本发明，术语“氢原子被氘原子取代”应理解为限定大批原料至少为80％的氘化程度，其中所有这些相应提及的氢原子被氘原子取代。例如，如果取代基R2或R3是指全部三个“氢原子被氘原子取代”的甲氧基，则根据上述定义应明白的是，大批原料中所有R2或R3甲氧基的至少80％为-OCD₃。100％以内的剩余部分包括-OCHD₂、-OCH₂D或-OCH₃。According to the invention, the term "replacement of hydrogen atoms by deuterium atoms" is understood to define a degree of deuteration of a bulk starting material of at least 80% in which all of these correspondingly mentioned hydrogen atoms are replaced by deuterium atoms. For example, if a substituent R2 or R3 refers to a methoxy group in which all three "hydrogen atoms are replaced by deuterium atoms", it should be understood from the above definition that at least 80% of all R2 or R3 methoxy groups in the bulk material are_-OCD3 . The remainder within 100% includes -OCHD₂ , -OCH₂ D or -OCH₃ .

大批原料中特定氢原子的氘化程度优选为至少90％，这意味着至少90％的所述被取代的氢原子应为氘原子。大批原料中特定氢原子的氘化程度更优选为至少92％。大批原料中特定氢原子的氘化程度进一步更优选为至少94％，大批原料中特定氢原子的氘化程度最优选为至少96％。The degree of deuteration of specific hydrogen atoms in the bulk feedstock is preferably at least 90%, which means that at least 90% of said substituted hydrogen atoms should be deuterium atoms. More preferably, the degree of deuteration of specific hydrogen atoms in the bulk feedstock is at least 92%. Even more preferably, the degree of deuteration of specific hydrogen atoms in the bulk feedstock is at least 94%, and most preferably, the degree of deuteration of specific hydrogen atoms in the bulk feedstock is at least 96%.

本发明化合物是手性化合物。因此，本发明涉及外消旋体和对映体及其任意所需比例的混合物。医学观点认为某些手性化合物以一种或另一种对映体形式给药可能是有利的，鉴于这一事实，本发明优选的主题是式1化合物的对映体，优选地，所述对映体基本不含各自相反构型的另一对映体。The compounds of the present invention are chiral compounds. Accordingly, the present invention relates to racemates and enantiomers and mixtures thereof in any desired proportions. In view of the medical point of view that it may be advantageous to administer certain chiral compounds in the form of one or the other enantiomer, preferred subjects of the present invention are the enantiomers of the compounds of formula 1, preferably, said Enantiomers are substantially free of the other enantiomer in the respective opposite configuration.

因此，一方面特别优选的是具有通式1a(S)-构型的化合物，Therefore, particular preference is given on the one hand to compounds having the (S)-configuration of the general formula 1a,

其中R1、R2、R3、R4和Z的意义如上所述。wherein the meanings of R1, R2, R3, R4 and Z are as above.

在本发明范围内，特别优选的(S)-构型化合物为：化合物(S)-5-甲氧基-2-[(4-三氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-三氘化甲氧基-2-[(4-三氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-甲氧基-2-[(4-二氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-三氘化甲氧基-2-[(4-二氘化甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-甲氧基-2-[(3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑、(S)-5-三氘化甲氧基-2-[(3-甲基-4-三氘化甲氧基-5-三氘化甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑或(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基甲基)亚磺酰基]-1H-苯并咪唑、(S)-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基甲基)亚磺酰基]-1H-苯并咪唑，以及这些化合物的溶剂化物(优选水合物)、这些化合物的盐，以及这些化合物盐的溶剂化物(优选水合物)。Within the scope of the present invention, the particularly preferred (S)-configuration compound is: compound (S)-5-methoxy-2-[(4-trideuteromethoxy-3,5-dimethyl- 2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-trideuteromethoxy-2-[(4-trideuteromethoxy-3,5-dimethyl Base-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(4-dideuteromethoxy-3,5-dimethyl -2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-trideuterated methoxy-2-[(4-dideuterated methoxy-3,5-di Methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl Base-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(3-methyl-4-trideuteromethoxy-5- Trideuteromethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-trideuteromethoxy-2-[(3-methyl-4-trideutero Methoxy-5-trideuteromethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole or (S)-5-difluoromethoxy-2-[(3-methyl Oxy-4-trideuteromethoxy-2-pyridylmethyl)sulfinyl]-1H-benzimidazole, (S)-5-difluoromethoxy-2-[(3-methoxy Base-4-dideuteromethoxy-2-pyridylmethyl)sulfinyl]-1H-benzimidazole, and solvates (preferably hydrates) of these compounds, salts of these compounds, and salts of these compounds solvates (preferably hydrates).

另一方面，特别优选通式1b(R)-构型的化合物On the other hand, compounds of the general formula 1b(R)-configuration are particularly preferred

其中，R1、R2、R3、R4和Z的意义如上所述。Wherein, the meanings of R1, R2, R3, R4 and Z are as above.

在本发明范围内，特别优选的(R)-构型化合物为：化合物(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基甲基)亚磺酰基]-1H-苯并咪唑、(R)-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基甲基)亚磺酰基]-1H-苯并咪唑，以及这些化合物的溶剂化物(优选水合物)、这些化合物的盐，以及这些化合物盐的溶剂化物(优选水合物)。Within the scope of the present invention, a particularly preferred (R)-configuration compound is: Compound (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy- 2-pyridylmethyl)sulfinyl]-1H-benzimidazole, (R)-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2 -pyridylmethyl)sulfinyl]-1H-benzimidazole, and solvates (preferably hydrates) of these compounds, salts of these compounds, and solvates (preferably hydrates) of salts of these compounds.

可用例如国际专利申请WO 92/08716中所述的各种方法，或者用柱色谱法，将式1化合物拆分成对映体。或者，可以对国际专利申请WO96/02535或WO2004/052881中所述的硫化物进行手性氧化，获得式1a和1b化合物。The compounds of formula 1 can be resolved into the enantiomers by various methods such as those described in International Patent Application WO 92/08716, or by column chromatography. Alternatively, chiral oxidation of sulfides as described in International Patent Application WO96/02535 or WO2004/052881 can be performed to obtain compounds of formulas 1a and 1b.

式1、1a和1b化合物的盐可以用已知方法来制备，使式1、1a和1b化合物(可作为弱酸)与适当的碱反应，例如与碱金属氢氧化物或醇盐(如氢氧化钠或甲醇钠)反应，或者与碱土金属醇盐(如甲醇镁)反应。举例来说，式1、1a和1b化合物的镁盐(除钠盐之外优选的盐)可以用已知方法来制备，使式1、1a和1b化合物与镁碱(例如醇镁)反应制备，或者在水或水与极性有机溶剂(例如醇，优选甲醇、乙醇或异丙醇，或者酮，优选丙酮)的混合物中，使用镁盐，由式1、1a和1b化合物的易溶盐(例如钠盐)制备。Salts of compounds of formula 1, 1a and 1b can be prepared by known methods by reacting compounds of formula 1, 1a and 1b (which can be used as weak acids) with a suitable base, for example with an alkali metal hydroxide or alkoxide (such as hydroxide sodium or sodium methoxide), or with alkaline earth metal alkoxides (such as magnesium methoxide). For example, magnesium salts (preferred salts other than sodium salts) of compounds of formula 1, 1a and 1b can be prepared by known methods by reacting compounds of formula 1, 1a and 1b with a magnesium base such as magnesium alkoxide , or in water or a mixture of water and a polar organic solvent such as an alcohol, preferably methanol, ethanol or isopropanol, or a ketone, preferably acetone, using a magnesium salt, from the lyotropic salts of compounds of formulas 1, 1a and 1b (e.g. sodium salt) preparation.

依照本发明，“(S)-构型化合物”应理解为包括“基本不含(R)-构型化合物的(S)-构型化合物”。According to the present invention, "(S)-configuration compound" is understood to include "(S)-configuration compound substantially free of (R)-configuration compound".

在本发明上下文中，“基本不含”是指(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于10％重量的(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。优选地，“基本不含”是指(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于5％重量的(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。更优选地，“基本不含”是指(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于2％重量的(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。在最优选的实施方式中，“基本不含”是指(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于1％重量的(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。In the context of the present invention, "substantially free" means that the (S)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 10% by weight of the (R)-configuration compound and / or a salt thereof, a solvate thereof, or a solvate of a salt thereof. Preferably, "substantially free" means that the (S)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 5% by weight of the (R)-configuration compound and/or its A salt, a solvate thereof, or a solvate of a salt thereof. More preferably, "substantially free" means that the (S)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 2% by weight of the (R)-configuration compound and/or A salt thereof, a solvate thereof, or a solvate of a salt thereof. In the most preferred embodiment, "substantially free" means that the (S)-configuration compound and/or its salt, its solvate or its salt's solvate contains less than 1% by weight of (R)-configuration Compounds and/or salts thereof, solvates thereof or solvates of salts thereof.

依照本发明，“(R)-构型化合物”应理解为包括“基本不含(S)-构型化合物的(R)-构型化合物”。According to the present invention, "(R)-configuration compound" is understood to include "(R)-configuration compound substantially free of (S)-configuration compound".

在本发明上下文中，“基本不含”是指(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于10％重量的(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。优选地，“基本不含”是指(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于5％重量的(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。更优选地，“基本不含”是指(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于2％重量的(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。在最优选的实施方式中，“基本不含”是指(R)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物含有少于1％重量的(S)-构型化合物和/或其盐、其溶剂化物或其盐的溶剂化物。In the context of the present invention, "substantially free" means that the (R)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 10% by weight of the (S)-configuration compound and / or a salt thereof, a solvate thereof, or a solvate of a salt thereof. Preferably, "substantially free" means that the (R)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 5% by weight of the (S)-configuration compound and/or its A salt, a solvate thereof, or a solvate of a salt thereof. More preferably, "substantially free" means that the (R)-configuration compound and/or its salt, its solvate or the solvate of its salt contains less than 2% by weight of the (S)-configuration compound and/or A salt thereof, a solvate thereof, or a solvate of a salt thereof. In the most preferred embodiment, "substantially free" means that the (R)-configuration compound and/or its salt, its solvate or its salt's solvate contains less than 1% by weight of (S)-configuration Compounds and/or salts thereof, solvates thereof or solvates of salts thereof.

本发明的另一主题是式2化合物及其盐(例如盐酸盐、硫酸盐、磷酸盐，或与其它酸的盐)，及其溶剂化物Another subject of the present invention is the compound of formula 2 and its salts (such as hydrochloride, sulfate, phosphate, or salts with other acids), and solvates thereof

其中R1、R2、R3、R4和Z的意义如上所述，且其中R1、R2、R3、R4或R1、R2、R3和R4的任何组合中至少一个氢原子被氘原子取代。这些化合物可用于生产通式1、1a或1b化合物。式2化合物特别适合作为生产式1、1a或1b化合物的氧化反应的起始原料。Wherein the meanings of R1, R2, R3, R4 and Z are as above, and wherein at least one hydrogen atom in any combination of R1, R2, R3, R4 or R1, R2, R3 and R4 is replaced by a deuterium atom. These compounds are useful in the production of compounds of general formula 1, 1a or 1b. Compounds of formula 2 are particularly suitable as starting materials for oxidation reactions to produce compounds of formula 1, 1a or 1b.

本发明的另一方面是式3化合物Another aspect of the present invention is the compound of formula 3

其中X为卤素或为醇的活化衍生物，且R2、R3和R4的意义如上所述，其中R2、R3和/或R4中至少一个氢原子被氘原子取代。Wherein X is a halogen or an activated derivative of an alcohol, and the meanings of R2, R3 and R4 are as described above, wherein at least one hydrogen atom in R2, R3 and/or R4 is replaced by a deuterium atom.

优选式3化合物，其中R2为甲基或甲氧基，R3为甲氧基、2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢或甲基，且其中R3中至少一个氢原子被氘原子取代。Preferred formula 3 compounds, wherein R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl, and wherein R3 At least one hydrogen atom in is replaced by a deuterium atom.

更优选式3化合物，其中R2为甲基，R3为甲氧基，R4为甲基，或者R2为甲氧基，R3为甲氧基，R4为氢，或者R2为甲基，R3为2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢，且其中R3中至少一个氢原子被氘原子取代。More preferred formula 3 compounds, wherein R2 is methyl, R3 is methoxyl, R4 is methyl, or R2 is methoxyl, R3 is methoxyl, R4 is hydrogen, or R2 is methyl, R3 is 2, 2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen, and wherein at least one hydrogen atom in R3 is replaced by a deuterium atom.

还更优选式3化合物，其中R2为甲基，R3为甲氧基，R4为甲基，或者R2为甲氧基，R3为甲氧基，R4为氢，或者R2为甲基，R3为2，2，2-三氟乙氧基或甲氧基丙氧基，R4为氢，且其中R3中至少两个或全部氢原子被氘原子取代。Still more preferred is a compound of formula 3, wherein R2 is methyl, R3 is methoxy, R4 is methyl, or R2 is methoxy, R3 is methoxy, R4 is hydrogen, or R2 is methyl, R3 is 2 , 2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen, and wherein at least two or all of the hydrogen atoms in R3 are replaced by deuterium atoms.

为了本发明的目的，卤素为碘、溴、氯和氟。X优选为氯。醇的活化衍生物为烷基磺酸基(例如甲磺酸基)，或芳基磺酸基(例如甲苯磺酸基或苯磺酸基)，或全氟烷烃磺酸基(例如三氟甲烷磺酸基)。For the purposes of the present invention, halogen is iodine, bromine, chlorine and fluorine. X is preferably chlorine. Activated derivatives of alcohols are alkylsulfonic acid groups (such as methanesulfonic acid groups), or arylsulfonic acid groups (such as toluenesulfonic acid groups or benzenesulfonic acid groups), or perfluoroalkanesulfonic acid groups (such as trifluoromethane sulfonic acid group).

涉及式3化合物，本发明的一个方面是式3a化合物Relating to compounds of formula 3, one aspect of the invention is a compound of formula 3a

其中，X、R2和R4的意义如上所述，R5为氯或硝基，且其中R2和/或R4中至少一个氢原子被氘原子取代。Wherein, the meanings of X, R2 and R4 are as above, R5 is chlorine or nitro, and wherein at least one hydrogen atom in R2 and/or R4 is replaced by a deuterium atom.

优选式3a化合物，其中R2为甲基或甲氧基，R4为氢或甲基，且其中R2和/或R4中至少一个氢原子被氘原子取代。Preference is given to compounds of formula 3a, wherein R2 is methyl or methoxy, R4 is hydrogen or methyl, and wherein at least one hydrogen atom in R2 and/or R4 is replaced by a deuterium atom.

更优选式3a化合物，其中R2和R4为甲基，且其中R2和/或R4中至少一个氢原子被氘原子取代。More preferred are compounds of formula 3a, wherein R2 and R4 are methyl, and wherein at least one hydrogen atom in R2 and/or R4 is replaced by a deuterium atom.

式3化合物可用于生产式1、1a或1b化合物。优选地，首先使式3化合物的氮原子季铵化，然后再与式4化合物反应Compounds of formula 3 can be used to produce compounds of formula 1, 1a or 1b. Preferably, the nitrogen atom of the compound of formula 3 is first quaternized and then reacted with the compound of formula 4

其中R1和Z的意义如上所述，从而得到如上所述的式2化合物。wherein the meanings of R1 and Z are as described above, thereby obtaining the compound of formula 2 as described above.

式3a化合物可用于生产式2a化合物Compounds of formula 3a can be used to produce compounds of formula 2a

其中，R1、R2、R5、R4和Z的意义如上所述，且其中R1、R2、R4或R1、R2和R4的任何组合中至少一个氢原子被氘原子取代。优选地，首先使式3a化合物的氮原子季铵化，然后再与式4化合物反应Wherein, the meanings of R1, R2, R5, R4 and Z are as above, and wherein at least one hydrogen atom in any combination of R1, R2, R4 or R1, R2 and R4 is replaced by a deuterium atom. Preferably, the nitrogen atom of the compound of formula 3a is first quaternized and then reacted with the compound of formula 4

其中R1和Z的意义如上所述，从而得到如上所述的式2a化合物。wherein the meanings of R1 and Z are as described above, so as to obtain the compound of formula 2a as described above.

通过用残基R3取代残基R5(两者的意义如上所述)，式2a化合物可用于生产式2化合物。在R1、R2或R4中没有一个氢原子被氘原子取代的条件下，R3中至少一个氢原子被氘原子取代。Compounds of formula 2a can be used to produce compounds of formula 2 by substituting residue R3 for residue R5 (both have meanings as described above). Under the condition that none of the hydrogen atoms in R1, R2 or R4 is replaced by a deuterium atom, at least one hydrogen atom in R3 is replaced by a deuterium atom.

本发明的另一方面是式4化合物Another aspect of the present invention is the compound of formula 4

其中R1为1-4C烷氧基，Z为C-H或N，且其中R1中至少一个氢原子被氘原子取代，优选R1为甲氧基。这些化合物可用于生产式1或2化合物。Wherein R1 is a 1-4C alkoxy group, Z is C-H or N, and wherein at least one hydrogen atom in R1 is replaced by a deuterium atom, preferably R1 is a methoxy group. These compounds are useful in the production of compounds of formula 1 or 2.

更优选其中R1为甲氧基且R1中所有氢原子被氘原子取代的化合物。More preferred are compounds wherein R1 is methoxy and all hydrogen atoms in R1 are replaced by deuterium atoms.

质子泵抑制剂以及例如R/S泮托拉唑和S-泮托拉唑的氘同系物，可以用文献(例如Kohl等人，J.Med.Chem.1992，35，1049ff.或者WO2004/052881)中的已知方法，将相应的含硫化合物氧化来制备，或者由最终三氘化甲氧基的位置(特别是吡啶基4-位)上为卤素(如氯、溴或硝基)取代基的相应的亚砜，通过将卤素置换成三氘化甲氧基进行制备。如前所述类似，用二氘化甲氧基或一氘化甲氧基置换卤素可以得到相应的氘化化合物。Proton pump inhibitors and deuterium homologues such as R/S pantoprazole and S-pantoprazole can be used in literature (such as Kohl et al., J.Med.Chem.1992, 35, 1049ff. or WO2004/052881 ) by oxidation of the corresponding sulfur-containing compound, or by substitution of a halogen (such as chlorine, bromine or nitro) at the position of the final trideuterated methoxy group (especially the 4-position of the pyridyl group) The corresponding sulfoxide of the group, prepared by displacement of the halo with a trideuteromethoxy group. Similar to that described previously, replacement of the halogen with dideuterated methoxy or mono-deuterated methoxy can afford the corresponding deuterated compound.

类似地，含硫化合物的制备，或者通过用一、二或三氘化甲氧基置换最终一、二或三氘化甲氧基-取代基位上的卤素，或者通过使5-二氟甲氧基-2-巯基苯并咪唑与相应取代的氯化2-氯甲基-3-甲氧基-4-三氘化甲氧基-吡啶偶合。Similarly, sulfur-containing compounds are prepared either by replacing the halogen at the final mono-, di- or tri-deuteromethoxy-substituent position with mono-, di- or tri-deuteromethoxy-substituents, or by making 5-difluoromethane Oxy-2-mercaptobenzimidazole with the corresponding substituted 2-chloromethyl-3-methoxy-4-trideuteromethoxy-pyridine chloride couple.

用以下反应方案可制备式1化合物：Compounds of formula 1 can be prepared using the following reaction scheme:

按照文献上的已知方法来制备亚砜与无机碱的盐，使亚砜在有机溶剂或有机溶剂与水的混合物中与相应的氢氧化物或醇盐反应。Salts of sulfoxides with inorganic bases are prepared according to methods known in the literature by reacting sulfoxides with the corresponding hydroxides or alkoxides in organic solvents or mixtures of organic solvents and water.

或者，盐的制备方法如下：亚砜与碱金属氢氧化物反应获得相应的碱金属盐(Na、K、Li)，再进一步与例如镁盐、钙盐、铝盐、锌盐反应。Alternatively, the salts can be prepared as follows: sulfoxide reacts with alkali metal hydroxides to obtain the corresponding alkali metal salts (Na, K, Li), and then further reacts with, for example, magnesium salts, calcium salts, aluminum salts, and zinc salts.

以下实施例用来更详细地举例说明本发明，而不是将其局限于所述实施例。通过使用所述方法，可以获得其它的上述化合物。The following examples serve to illustrate the invention in more detail without restricting it to said examples. By using the method, other above-mentioned compounds can be obtained.

附图说明Description of drawings

图1是由[1H]奥美拉唑以及实施例38、39和40形成5-羟基-奥美拉唑的动力学图；Fig. 1 is to form the kinetic figure of 5-hydroxyl-omeprazole by [1H] omeprazole andembodiment 38,39 and 40;

图2是在混合的冻存人肝细胞中，由(A)外消旋[¹H]泮托拉唑及对映体和(B)[²H₃]泮托拉唑(实施例19)及相应对映体(实施例27和28)形成M2的动力学图；Fig. 2 is in the cryopreservation human liver cell of mixing, by (A) racemic [¹ H] pantoprazole and enantiomer and (B) [² H₃ ] pantoprazole (embodiment 19) And corresponding enantiomer (embodiment 27 and 28) form the kinetic figure of M2;

图3是在混合的冻存人肝细胞中，由外消旋[¹H]奥美拉唑、(S)-[¹H]奥美拉唑和实施例41形成5-羟基-奥美拉唑的动力学图；Figure 3 is the formation of 5-hydroxy-omeprazole from racemic [¹ H] omeprazole, (S)-[¹ H] omeprazole and Example 41 in mixed frozen human hepatocytes Kinetic diagram of azole;

图4是在混合的冻存人肝细胞中，由外消旋[¹H]泮托拉唑和在4-甲氧基-吡啶基位上(实施例19)或3-甲氧基-吡啶基位上(实施例17)氘化的[²H₃]同类物形成M2的动力学图。Figure 4 is in the mixed cryopreserved human hepatocytes, from racemic [¹ H]pantoprazole and in 4-methoxy-pyridyl position (Example 19) or 3-methoxy-pyridine Kinetic diagram of the formation of M2 from the deuterated [² H₃ ] congener at the basal site (Example 17).

实施例Example

氘原子＞99.8％原子的甲醇-d4用作三氘化甲氧基化剂。所有制得产物中三氘化甲氧基取代基的异构纯度＞98.0％(用NMR和MS测定)。氘原子＞98.0％原子的甲醇-d2和氘原子＞98.0％原子的甲醇-d1也用作氘化剂。所得产物中二氘化甲氧基和一氘化甲氧基取代基的异构纯度＞96.0％(用NMR和MS测定)。Methanol-d4 with >99.8 atomic % of deuterium atoms was used as tripeuterated methoxylating agent. The isomeric purity of the trideuterated methoxy substituent in all the obtained products was >98.0% (determined by NMR and MS). Methanol-d2 with deuterium atoms > 98.0 atomic % and methanol-d1 with deuterium atoms > 98.0 atomic % were also used as deuterating agents. The isomeric purity of dideuterated methoxy and monodeuterated methoxy substituents in the obtained product is >96.0% (determined by NMR and MS).

实施例1Example 1

5-二氟甲氧基(R/S)2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑5-Difluoromethoxy(R/S)2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

在30至35℃搅拌下，用1至2小时向5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(1.0克，2.7毫摩尔)在水(20毫升)、2-丙醇(10毫升)和氢氧化钠(0.5毫升40％浓度的溶液，7.1毫摩尔)的浆体中，加入次氯酸钠溶液(10％浓度)(3.3mmol)。在所述温度30至60分钟之后，加入硫代硫酸钠(0.3克溶于5毫升水中)，再继续搅拌15至30分钟。Under stirring at 30 to 35°C, it takes 1 to 2 hours to prepare 5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio] -1H-benzimidazole (1.0 g, 2.7 mmol) in a slurry of water (20 mL), 2-propanol (10 mL) and sodium hydroxide (0.5 mL of a 40% strength solution, 7.1 mmol) , sodium hypochlorite solution (10% strength) (3.3 mmol) was added. After 30 to 60 minutes at said temperature, sodium thiosulfate (0.3 g dissolved in 5 mL of water) was added and stirring was continued for a further 15 to 30 minutes.

将反应混合物真空(30至40℃)浓缩至原体积的约1/3，加入水(约70毫升)。The reaction mixture was concentrated in vacuo (30 to 40° C.) to about 1/3 of the original volume, and water (about 70 mL) was added.

水相用二氯甲烷(2次，每次10毫升)萃取之后，再次加入二氯甲烷(50毫升)，搅拌下加入磷酸二氢钾水溶液，将pH调至7至8。相分离，水相再一次用二氯甲烷(20毫升)萃取，合并的有机相用水(20毫升)洗涤，用硫酸镁干燥，过滤除去干燥剂，获得粗标题化合物的溶液。After the aqueous phase was extracted with dichloromethane (twice, 10 ml each), dichloromethane (50 ml) was added again, and an aqueous solution of potassium dihydrogen phosphate was added with stirring to adjust the pH to 7-8. The phases were separated, the aqueous phase was extracted again with dichloromethane (20 mL), the combined organic phases were washed with water (20 mL), dried over magnesium sulfate, and the drying agent was removed by filtration to obtain a solution of the crude title compound.

加入石油醚(50/70；150毫升)，并在30至40℃真空旋转蒸发，浓缩至约30毫升体积，然后过滤析出的固体，用石油醚50/70清洗(20毫升)，并真空干燥(35℃，5小时)，得到类白色固体的标题化合物5-二氟甲氧基(R/S)2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，熔点：135至136℃(分解)；产量1.0克(理论值的95％)。Petroleum ether (50/70; 150 mL) was added and concentrated to a volume of about 30 mL by rotary evaporation at 30 to 40 °C under vacuum, then the precipitated solid was filtered, washed withpetroleum ether 50/70 (20 mL), and dried in vacuo (35°C, 5 hours), the title compound 5-difluoromethoxy(R/S)2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl) was obtained as an off-white solid )Methylsulfinyl]-1H-benzimidazole, melting point: 135 to 136° C. (decomposition); yield 1.0 g (95% of theory).

¹H-NMR(400MHz，DMSO d-6)：d＝3,78(s，3H，OMe)，4,68(d，1H，J(CHa，CHb)＝13Hz，S-CH2-Py)，4,73(d，1H，J(CHb，CHa)＝13Hz，S-CH2-Py)，7,10(d，1H，J(H5’，H6’)＝5Hz，H5’)7,18(bd，1H，H6)，7,24(t，1H，J(H，F)＝74Hz，OCHF2)，7，4(bs，1H，H4)，7,70(bs，1H，H7)，8,15(d，1H，J(H6’，H5’)＝5Hz，H6’)，13,7(s，1H，NH).¹ H-NMR (400MHz, DMSO d-6): d=3,78 (s, 3H, OMe), 4,68 (d, 1H, J(CHa, CHb)=13Hz, S-CH2-Py), 4,73(d,1H, J(CHb,CHa)=13Hz, S-CH2-Py),7,10(d,1H, J(H5',H6')=5Hz,H5')7,18( bd, 1H, H6), 7, 24 (t, 1H, J(H, F)=74Hz, OCHF2), 7, 4 (bs, 1H, H4), 7, 70 (bs, 1H, H7), 8 ,15(d,1H,J(H6',H5')=5Hz,H6'),13,7(s,1H,NH).

实施例2Example 2

S(-)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑S(-)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

室温下，将2.0克5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑悬浮于20毫升的甲基异丁酮中，连同(+)-L-酒石酸二-(N-吡咯烷酰胺)(2.3克)和n-丙醇锆(IV)(1.0克，70％/丙醇)在一起。将混合物在40℃加热1小时，形成几乎澄清的溶液。冷却至室温后，加入N-乙基二异丙胺(0.07毫升)和氢过氧化异丙苯(1.05毫升)。室温下搅拌该混合物直至氧化反应结束(10至24小时，用薄层色谱法TLC检视)。所述澄清溶液用10毫升甲基异丁酮稀释，并用0.08克硫代硫酸钠/14毫升饱和碳酸氢钠溶液猝灭，再搅拌2小时。相分离之后，混合物用5毫升饱和碳酸氢钠溶液洗涤两次。向甲基异丁酮相中加入15毫升水，用40％重量浓度的氢氧化钠溶液将pH调至pH＝13。相分离之后，甲基异丁酮相再用5毫升pH 13的水萃取。合并水相，并在40℃下进行减压初始蒸馏。加入作为助滤剂的Hyflo Super Cell(0.05克)，在20至25℃下搅拌1小时之后过滤。在40至45℃下，向滤液中加入10％浓度的醋酸至pH＝9.0，析出粗的标题化合物。将混合物再搅拌12小时，期间监控pH。过滤米色结晶，并用10毫升水洗涤。所得标题化合物的产量约1.6克(理论值的75％)，光学纯度＞98％。At room temperature, 2.0 g of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole was suspended in 20 mL of methyl isobutyl ketone, together with (+)-L-tartrate bis-(N-pyrrolidine amide) (2.3 g) and zirconium(IV) n-propoxide (1.0 g, 70%/propanol) together. The mixture was heated at 40°C for 1 hour, forming an almost clear solution. After cooling to room temperature, N-ethyldiisopropylamine (0.07 mL) and cumene hydroperoxide (1.05 mL) were added. The mixture was stirred at room temperature until the oxidation was complete (10 to 24 hours, as viewed by TLC). The clear solution was diluted with 10 mL of methyl isobutyl ketone and quenched with 0.08 g of sodium thiosulfate/14 mL of saturated sodium bicarbonate solution and stirred for an additional 2 hours. After phase separation, the mixture was washed twice with 5 ml of saturated sodium bicarbonate solution. 15 ml of water are added to the methyl isobutyl ketone phase and the pH is adjusted to pH=13 with 40% strength by weight sodium hydroxide solution. After phase separation, the methyl isobutyl ketone phase was extracted with 5 ml of pH 13 water. The aqueous phases were combined and subjected to an initial distillation under reduced pressure at 40°C. Hyflo Super Cell (0.05 g) was added as a filter aid, stirred at 20 to 25° C. for 1 hour and then filtered. At 40 to 45° C., 10% strength acetic acid was added to the filtrate until pH = 9.0, and the crude title compound was precipitated. The mixture was stirred for an additional 12 hours during which time the pH was monitored. The beige crystals were filtered and washed with 10 ml of water. The title compound was obtained in a yield of about 1.6 g (75% of theory) with an optical purity of >98%.

为了增加纯度，将(-)三氘化泮托拉唑溶于水/氢氧化钠水溶液中，pH为13，用醋酸(10％)在pH＝9.0时使之再次沉淀。To increase the purity, (-) trideuterated pantoprazole was dissolved in water/aqueous sodium hydroxide solution at pH 13 and reprecipitated with acetic acid (10%) at pH = 9.0.

从二氯甲烷/叔丁基甲醚中重结晶，得到类白色固体的标题化合物S(-)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，熔点：146至148℃(分解)；产量1.6克。Recrystallization from dichloromethane/tert-butyl methyl ether gave the title compound S(-)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy as an off-white solid -2-pyridyl)methylsulfinyl]-1H-benzimidazole, melting point: 146 to 148° C. (decomposition); yield 1.6 g.

实施例3Example 3

起始原料氯化2-氯甲基-3-甲氧基-4-三氘化甲氧基吡啶

的合成Starting material 2-Chloromethyl-3-methoxy-4-trideuteromethoxypyridine chloride

Synthesis

3-甲氧基-2-甲基-4-三氘化甲氧基吡啶N-氧化物的制备Preparation of 3-methoxy-2-methyl-4-trideuterated methoxypyridine N-oxide

在氘化甲醇D4(20毫升)中，回流加热4-氯-3-甲氧基-2-甲基吡啶-N-氧化物(10克)和三氘化甲醇钠(6.2克)。15小时后，真空蒸发溶剂，残余物用热的甲苯(50毫升)萃取，过滤不溶物。向滤液加入二异丙基醚，析出固体，真空干燥后得到8.1克浅棕色粉末的3-甲氧基-2-甲基-4-三氘化甲氧基吡啶N-氧化物。其随后用于以下步骤。In deuterated methanol D4 (20 mL), 4-chloro-3-methoxy-2-methylpyridine-N-oxide (10 g) and sodium trideuteromethoxide (6.2 g) were heated at reflux. After 15 hours, the solvent was evaporated in vacuo, the residue was extracted with hot toluene (50 mL), and the insoluble material was filtered. Diisopropyl ether was added to the filtrate to precipitate a solid, which was dried in vacuo to obtain 8.1 g of 3-methoxy-2-methyl-4-trideuterated methoxypyridine N-oxide as a light brown powder. It was then used in the following steps.

2-羟甲基-3-甲氧基-4-三氘化甲氧基吡啶的制备Preparation of 2-Hydroxymethyl-3-methoxy-4-trideuterated methoxypyridine

将前面步骤的产物(8.1克)溶于醋酐(50毫升)中，并在90℃加热2小时。真空蒸发之后，在80℃将黑色油状残余物与2N NaOH(20毫升)搅动2小时。冷却之后，产物经萃取进入二氯甲烷中，干燥(K₂CO₃)，真空浓缩至较小体积。加入石油醚(50/70)，过滤并真空干燥后，得到浅棕色固体(5.5克)的2-羟基-3-甲氧基-4-三氘化甲氧基吡啶，其用于以下步骤。The product from the previous step (8.1 g) was dissolved in acetic anhydride (50 ml) and heated at 90°C for 2 hours. After evaporation in vacuo, the black oily residue was stirred with 2N NaOH (20 mL) at 80 °C for 2 h. After cooling, the product was extracted into dichloromethane, dried (_K2CO3 ) and concentrated in vacuo to_a small volume. Petroleum ether (50/70) was added, filtered and vacuum dried to give 2-hydroxy-3-methoxy-4-trideuteromethoxypyridine as a light brown solid (5.5 g), which was used in the next step.

氯化2-氯甲基-3-甲氧基-4-三氘化甲氧基吡啶

的制备2-Chloromethyl-3-methoxy-4-trideuteromethoxypyridine chloride

preparation of

将前面步骤的产物(5.5克)溶于无水二氯甲烷(40毫升)中，在5至10℃搅拌下滴加亚硫酰氯(3毫升)。使混合物升温至20℃，3小时后真空蒸发至干。The product from the previous step (5.5 g) was dissolved in anhydrous dichloromethane (40 ml), and thionyl chloride (3 ml) was added dropwise with stirring at 5 to 10°C. The mixture was allowed to warm to 20°C and evaporated to dryness in vacuo after 3 hours.

加入甲苯(20毫升)，得到6.6克浅棕色固体的标题化合物氯化2-氯甲基-3-甲氧基-4-三氘化甲氧基吡啶

Toluene (20 mL) was added to give 6.6 g of the title compound 2-chloromethyl-3-methoxy-4-trideuteriomethoxypyridine chloride as a light brown solid

以这种方式合成的原料含有一些难以除去的杂质，这些杂质有可能被带入制备通式(2)化合物及其最终通式(1)化合物的下一步骤中。因此，为了制备极高纯度的通式(1)化合物，通常优选采用实施例9和35中所述的氘化烷氧化方法。The raw materials synthesized in this way contain some difficult-to-remove impurities, which may be carried into the next step of preparing the compound of general formula (2) and its final compound of general formula (1). Therefore, the deuterated alkoxylation methods described in Examples 9 and 35 are generally preferred for the preparation of compounds of general formula (1) in very high purity.

实施例4Example 4

氯化4-氯-2-氯甲基-3-甲氧基吡啶

4-Chloro-2-chloromethyl-3-methoxypyridine chloride

在85至95℃，用5至7小时向醋酐(71升)中加入4-氯-3-甲氧基-2-甲基吡啶-N-氧化物(19.2千克，111摩尔)的甲苯(148升)溶液。在约60℃的真空下，浓缩反应混合物直至蒸去约170升。加入甲苯(160升)并再次蒸去溶剂(160升)。最后一步操作重复一次。然后在35至45℃加入甲苯(14升)和40％NaOH水溶液(14.6升)，使反应混合物在此温度下保持2至3小时。如果此时pH低于13，则再加入NaOH，并继续再加热2小时。所得的两相反应混合物用甲苯(26升)和饱和碳酸氢钠水溶液(26升)稀释，进行相分离，水层用甲苯(26升和2×13升)萃取三次。最后，合并的有机相用饱和碳酸氢钠水溶液(13升)洗涤，在50至65℃真空浓缩直至蒸去约115升。用甲苯(100升)稀释后，再蒸去100升溶剂。At 85 to 95° C., 4-chloro-3-methoxyl-2-methylpyridine-N-oxide (19.2 kg, 111 mol) in toluene ( 148 liters) solution. The reaction mixture was concentrated under vacuum at about 60°C until about 170 liters had evaporated. Toluene (160 L) was added and the solvent (160 L) was distilled off again. Repeat the last step. Toluene (14 L) and 40% aqueous NaOH (14.6 L) were then added at 35 to 45°C and the reaction mixture was maintained at this temperature for 2 to 3 hours. If the pH was below 13 at this point, additional NaOH was added and heating continued for an additional 2 hours. The resulting biphasic reaction mixture was diluted with toluene (26 L) and saturated aqueous sodium bicarbonate (26 L), the phases were separated, and the aqueous layer was extracted three times with toluene (26 L and 2 x 13 L). Finally, the combined organic phases were washed with saturated aqueous sodium bicarbonate (13 liters) and concentrated in vacuo at 50 to 65° C. until about 115 liters had evaporated. After diluting with toluene (100 liters), 100 liters of solvent were distilled off.

所得的4-氯-2-羟甲基-3-甲氧基吡啶(约30％浓度)溶液用CH₂C1₂(48升)稀释。一次性加入DMF(65.5克，0.896摩尔)，然后在15至30℃，用3至5小时加入亚硫酰氯(11.1千克，93.2摩尔)。再搅拌1.5小时之后，蒸去约45升溶剂。加入甲苯(20升)，并再次蒸去20升溶剂。然后向所得稠浆中加入乙醇(1.5升)。在10至15℃过滤固体，用甲苯(17升)洗涤，真空30℃下干燥，得到类白色固体的氯化4-氯-2-氯甲基-3-甲氧基吡啶

(熔点132℃)；产量15.0千克(59％)。The resulting 4-chloro-2_- hydroxymethyl-3-methoxypyridine (about 30% strength) solution was diluted with_CH2Cl2 (48 L). DMF (65.5 g, 0.896 mol) was added in one portion, followed by thionyl chloride (11.1 kg, 93.2 mol) at 15 to 30°C over 3 to 5 hours. After stirring for a further 1.5 hours, about 45 liters of solvent were distilled off. Toluene (20 liters) was added and 20 liters of solvent were distilled off again. Ethanol (1.5 L) was then added to the resulting thick slurry. The solid was filtered at 10 to 15°C, washed with toluene (17 L) and dried under vacuum at 30°C to give 4-chloro-2-chloromethyl-3-methoxypyridine chloride as an off-white solid

(melting point 132°C); yield 15.0 kg (59%).

¹H-NMR(200MHz，CDCl₃)：δ＝4.19(s，3H)，5.14(s，2H)，7.92(d，6.0Hz，1H)，8.59(d，6.0Hz，1H)，11.64(br s，1H)；LC-MS：MH⁺＝192/194/196.¹ H-NMR (200MHz, CDCl₃ ): δ=4.19(s, 3H), 5.14(s, 2H), 7.92(d, 6.0Hz, 1H), 8.59(d, 6.0Hz, 1H), 11.64(br s, 1H); LC-MS: MH⁺ = 192/194/196.

实施例5Example 5

氯化4-氯-2-氯甲基-3-三氘化甲氧基吡啶

4-Chloro-2-chloromethyl-3-trideuteromethoxypyridine chloride

起始原料，4-氯-2-甲基-3-三氘化甲氧基吡啶-N-氧化物的制备方法见J.Med.Chem.1992，35，1049-1057中非氘化同类物的方法D：Starting material, 4-chloro-2-methyl-3-trideuterated methoxypyridine-N-oxide, see J.Med.Chem.1992, 35, 1049-1057 for non-deuterated congeners Method D:

从3-羟基-2-甲基-4-吡喃酮开始，在碳酸钾存在下在DMF中，用三氘化碘甲烷进行转化，得到2-甲基-3-三氘化甲氧基-4-吡喃酮(产率：83至96％)，其在乙醇中在150℃与氨加热，从丙酮/异丙醇4∶1中结晶后，得到4-羟基-2-甲基-三氘化甲氧基吡啶(产率：52至60％)。该原料用磷酰氯处理，形成4-氯-2-甲基-三氘化甲氧基吡啶(产率：64至81％)。然后在醋酸中用过氧化氢进行氧化，得到浅黄色固体的4-氯-2-甲基-3-三氘化甲氧基吡啶-N-氧化物(产率：87至89％)。Starting from 3-hydroxy-2-methyl-4-pyrone, transformation with trideuteuromethyl iodide in DMF in the presence of potassium carbonate gives 2-methyl-3-trideuteromethoxy- 4-Pyrone (yield: 83 to 96%), which after crystallization from acetone/isopropanol 4:1 by heating with ammonia in ethanol at 150 °C, afforded 4-hydroxy-2-methyl-tri Deuterated methoxypyridine (yield: 52 to 60%). This material was treated with phosphorous oxychloride to form 4-chloro-2-methyl-trideuteromethoxypyridine (yield: 64 to 81%). Oxidation with hydrogen peroxide in acetic acid then gave 4-chloro-2-methyl-3-trideuteromethoxypyridine-N-oxide as a pale yellow solid (yield: 87 to 89%).

最后经4-氯-2-羟甲基-3-三氘化甲氧基吡啶的转化如实施例4所述进行，得到无色晶状固体的氯化4-氯-2-氯甲基-3-三氘化甲氧基吡啶

(熔点129至130℃)；产率19.6克(42％)。Finally, the conversion of 4-chloro-2-hydroxymethyl-3-trideuteromethoxypyridine was carried out as described in Example 4 to obtain 4-chloro-2-chloromethyl-chloride as a colorless crystalline solid. 3-trideuterated methoxypyridine

(melting point 129 to 130°C); yield 19.6 g (42%).

实施例6Example 6

氯化2-氯甲基-3，4-二(三氘化甲氧基)吡啶

2-Chloromethyl-3,4-bis(trideuteromethoxy)pyridine chloride

依照实施例3所述的方法，将4-氯-2-甲基-3-三氘化甲氧基吡啶-N-氧化物(25.3克，144毫摩尔；其制备见实施例5)转化为2-甲基-3，4-二(三氘化甲氧基)吡啶-N-氧化物(产量：23.5克，96％)，再得到2-羟甲基-3，4-二(三氘化甲氧基)吡啶(产量：13.0克，56％)，最终生成类白色晶状固体氯化2-氯甲基-3，4-二(三氘化甲氧基)吡啶

(产量：15.4克，89％)。Following the procedure described in Example 3, 4-chloro-2-methyl-3-trideuteromethoxypyridine-N-oxide (25.3 g, 144 mmol; see Example 5 for its preparation) was converted to 2-Methyl-3,4-bis(trideuteromethoxy)pyridine-N-oxide (yield: 23.5 g, 96%) to give 2-hydroxymethyl-3,4-bis(trideuteromethoxy) Chloromethoxy)pyridine (yield: 13.0 g, 56%), finally generating off-white crystalline solid 2-chloromethyl-3,4-bis(trideuteromethoxy)pyridine chloride

(Yield: 15.4 g, 89%).

实施例7Example 7

5-二氟甲氧基-2-[(4-氯-3-甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H-benzimidazole

在55至65℃，用2至3小时向5-二氟甲氧基-1H-苯并咪唑-2-硫醇(8.84千克，40.9摩尔)、甲苯(43升)、水(21升)和40％NaOH水溶液(10.3千克，103摩尔)的混合物中，加入氯化4-氯-2-氯甲基-3-甲氧基吡啶

(10.0千克，43.8摩尔)的水(20升)溶液。在60℃继续搅拌2至3小时，再使反应混合物冷却至10至15℃。离心得到沉淀，用甲苯(16升)洗涤，在水(122升)中再次浆化。离心后用水(32升)清洗，在35℃下真空干燥，得到类白色固体的5-二氟甲氧基-2-[(4-氯-3-甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(KF＝4.6％)(熔点95至99℃)；产量14.2千克(92％)。5-difluoromethoxy-1H-benzimidazole-2-thiol (8.84 kg, 40.9 moles), toluene (43 liters), water (21 liters) and To a mixture of 40% aqueous NaOH (10.3 kg, 103 mol), 4-chloro-2-chloromethyl-3-methoxypyridine chloride was added

(10.0 kg, 43.8 mol) in water (20 L). Stirring was continued at 60°C for 2 to 3 hours and the reaction mixture was cooled to 10 to 15°C. A precipitate was obtained by centrifugation, washed with toluene (16 L) and reslurried in water (122 L). Wash with water (32 L) after centrifugation and dry under vacuum at 35°C to give 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylsulfide as an off-white solid ]-1H-benzimidazole monohydrate (KF=4.6%) (mp 95 to 99° C.); yield 14.2 kg (92%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.55(br s，NH+H₂O)，3.92(s，3H)，4.79(s，2H)，6.97(dd，8.6Hz，2.3Hz，1H)，7.16(t，74.8Hz，1H)，7.28(d，2.2Hz，1H)，7.47(d，8.7Hz，1H)，7.55(d，5.3Hz，1H)，8.25(d，5.2Hz，1H)；LC-MS：MH⁺＝372/374.¹ H-NMR (200MHz, DMSO-d6): δ=3.55(br s, NH+H₂ O), 3.92(s, 3H), 4.79(s, 2H), 6.97(dd, 8.6Hz, 2.3Hz, 1H), 7.16(t, 74.8Hz, 1H), 7.28(d, 2.2Hz, 1H), 7.47(d, 8.7Hz, 1H), 7.55(d, 5.3Hz, 1H), 8.25(d, 5.2Hz, 1H); LC-MS: MH⁺ = 372/374.

实施例8Example 8

5-二氟甲氧基-2-[(4-氯-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(4-chloro-3-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

从氯化4-氯-2-氯甲基-3-三氘化甲氧基吡啶

(5.00克，21.6毫摩尔)开始，依照实施例7所述的方法，获得类白色固体的5-二氟甲氧基-2-[(4-氯-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(KF＝4.7％)(熔点94至99℃)；产量7.24克(85％)。From 4-chloro-2-chloromethyl-3-trideuteromethoxypyridine chloride

(5.00 grams, 21.6 mmoles), according to the method described in Example 7, the 5-difluoromethoxy-2-[(4-chloro-3-trideuteromethoxy-2 -Pyridyl)methylthio]-1H-benzimidazole monohydrate (KF=4.7%) (mp 94 to 99° C.); yield 7.24 g (85%).

¹H-NMR(200MHz，DMSO-d6)：δ＝4.79(s，2H)，6.98(dd，8.7Hz，2.3Hz，1H)，7.16(t，74.8Hz，1H)，7.28(d，2.0Hz，1H)，7.47(d，8.6Hz，1H)，7.55(d，5.2Hz，1H)，8.25(d，5.2Hz，1H)，12.75(br s，1H)；LC-MS：MH⁺＝375/377.¹ H-NMR (200MHz, DMSO-d6): δ=4.79(s, 2H), 6.98(dd, 8.7Hz, 2.3Hz, 1H), 7.16(t, 74.8Hz, 1H), 7.28(d, 2.0Hz , 1H), 7.47(d, 8.6Hz, 1H), 7.55(d, 5.2Hz, 1H), 8.25(d, 5.2Hz, 1H), 12.75(br s, 1H); LC-MS: MH⁺ =375 /377.

实施例9Example 9

5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

在15至30℃，用30至60分钟向叔丁醇钠(6.00千克，62.4摩尔)的DMAc(27升)混合物中，加入甲醇-d4(2.26千克，62.7摩尔)。加热至57至65℃之后，用30至60分钟加入5-二氟甲氧基-2-[(4-氯-3-甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(6.08千克，15.6摩尔)的DMAc(10升)溶液。在57至65℃继续搅拌约10小时。使反应混合物冷却至20至30℃，用水(21升)稀释，然后用20％HCl水溶液(约7.5升)将pH调至7至8。用约4小时加入水(75h)，获得产物沉淀。将所得浆体加热至35至45℃1.5小时，然后冷却至10至15℃。离心(包括用水(58升)清洗)，在水(78升)中再次浆化，再次离心(包括再用水(58升)清洗)，获得5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑的水润湿的褐色固体；产量10.4千克，KF＝49.7％(91％)。To a mixture of sodium tert-butoxide (6.00 kg, 62.4 mol) in DMAc (27 L) was added methanol-d4 (2.26 kg, 62.7 mol) at 15 to 30°C over 30 to 60 minutes. After heating to 57 to 65°C, 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H-benzo A solution of imidazole monohydrate (6.08 kg, 15.6 mol) in DMAc (10 L). Stirring was continued for about 10 hours at 57 to 65°C. The reaction mixture was cooled to 20-30°C, diluted with water (21 L), and the pH was adjusted to 7-8 with 20% aqueous HCl (ca. 7.5 L). Water was added over about 4 hours (75h) and the product precipitated. The resulting slurry was heated to 35 to 45°C for 1.5 hours and then cooled to 10 to 15°C. Centrifugation (including washing with water (58 liters)), reslurry in water (78 liters), centrifugation again (including washing with water (58 liters)) gave 5-difluoromethoxy-2-[(3- Methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole as a water-wet brown solid; yield 10.4 kg, KF=49.7% (91%).

在25℃真空干燥水润湿的产物的样品(16.2克，KF＝49.7％)，得到无定型固体，其从甲苯(30毫升)中结晶，得到类白色固体的无水5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(5.80克，71％回收率，熔点＝115至116℃)。A sample (16.2 g, KF = 49.7%) of the water-wet product was dried under vacuum at 25 °C to give an amorphous solid which crystallized from toluene (30 mL) to give anhydrous 5-difluoromethoxy as an off-white solid yl-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (5.80 g, 71% recovery, mp=115 to 116 ℃).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.82(s，3H)，4.68(s，2H)，6.97(dd，8.6Hz，2.1Hz，1H)，7.08(d，5.6Hz，1H)，7.16(t，74.8Hz，1H)，7.28(brs，1H)，7.47(brd，～8.3Hz，1H)，8.16(d，5.6Hz，1H)，12.75(br s，1H)；LC-MS：MH⁺＝371.¹ H-NMR (200MHz, DMSO-d6): δ=3.82(s, 3H), 4.68(s, 2H), 6.97(dd, 8.6Hz, 2.1Hz, 1H), 7.08(d, 5.6Hz, 1H) , 7.16(t, 74.8Hz, 1H), 7.28(brs, 1H), 7.47(brd, ~8.3Hz, 1H), 8.16(d, 5.6Hz, 1H), 12.75(brs, 1H); LC-MS : MH⁺ ＝371.

实施例10Example 10

5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

从5-二氟甲氧基-2-[(4-氯-3-甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(28.6克，73.4毫摩尔)和甲醇-d2(10.0克，294毫摩尔)开始，依照实施例9所述的方法，得到水润湿的棕色固体的5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑；产量46.4克，KF＝51.6％(82％)。From 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (28.6 g, 73.4 mmol) and Starting from methanol-d2 (10.0 g, 294 mmol), following the procedure described in Example 9, 5-difluoromethoxy-2-[(3-methoxy-4- Dideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole; yield 46.4 g, KF=51.6% (82%).

¹H-NMR(400MHz，DMSO-d6)：δ＝3.81(s，3H)，3.86(s，1H)，4.67(s，2H)，6.97(dd，8.4Hz，2.0Hz，1H)，7.08(d，5.5Hz，1H)，7.16(t，74.7Hz，1H)，7.21-7.53(br m，2H)，8.16(d，5.5Hz，1H)，12.78(br s，1H)；LC-MS：MH⁺＝370.¹ H-NMR (400MHz, DMSO-d6): δ=3.81(s, 3H), 3.86(s, 1H), 4.67(s, 2H), 6.97(dd, 8.4Hz, 2.0Hz, 1H), 7.08( d, 5.5Hz, 1H), 7.16(t, 74.7Hz, 1H), 7.21-7.53(br m, 2H), 8.16(d, 5.5Hz, 1H), 12.78(br s, 1H); LC-MS: MH⁺ = 370.

实施例11Example 11

5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(3-methoxy-4-deuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

从5-二氟甲氧基-2-[(4-氯-3-甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(29.5克，75.6毫摩尔)和甲醇-d1(10.0克，303毫摩尔)开始，依照实施例9所述的方法，得到水润湿的棕色固体的5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑；产量50.3克，KF＝50.8％(89％)。From 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (29.5 g, 75.6 mmol) and Starting from methanol-d1 (10.0 g, 303 mmol), following the method described in Example 9, 5-difluoromethoxy-2-[(3-methoxy-4- Monodeuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole; yield 50.3 g, KF=50.8% (89%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.82(s，3H)，3.88(s，2H)，4.67(s，2H)，6.98(dd，8.6Hz，2.2Hz，1H)，7.08(d，5.6Hz，1H)，7.15(t，74.8Hz，1H)，7.22-7.53(brm，2H)，8.16(d，5.6Hz，1H)，12.79(brs，1H)；LC-MS：MH⁺＝369.¹ H-NMR (200MHz, DMSO-d6): δ=3.82(s, 3H), 3.88(s, 2H), 4.67(s, 2H), 6.98(dd, 8.6Hz, 2.2Hz, 1H), 7.08( d, 5.6Hz, 1H), 7.15(t, 74.8Hz, 1H), 7.22-7.53(brm, 2H), 8.16(d, 5.6Hz, 1H), 12.79(brs, 1H); LC-MS: MH⁺ =369.

实施例12Example 12

5-二氟甲氧基-2-[(4-甲氧基-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(4-methoxy-3-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

从5-二氟甲氧基-2-[(4-氯-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(6.97克，17.7毫摩尔)和甲醇(2.28克，71.2毫摩尔)开始，依照实施例9所述的方法，得到水润湿的棕色固体的5-二氟甲氧基-2-[(4-甲氧基-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑；产量7.01克，KF＝19.1％(87％)。From 5-difluoromethoxy-2-[(4-chloro-3-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (6.97 g, 17.7 mg mol) and methanol (2.28 g, 71.2 mmol), following the procedure described in Example 9, 5-difluoromethoxy-2-[(4-methoxy-3 - Trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole; yield 7.01 g, KF=19.1% (87%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.89(s，3H)，4.68(s，2H)，6.97(dd，8.6Hz，2.0Hz，1H)，7.08(d，5.5Hz，1H)，7.16(t，74.7Hz，1H)，7.18-7.47(brm，2H)，8.16(d，5.6Hz，1H)，12.76(brs，1H)；LC-MS：MH⁺＝371.¹ H-NMR (200MHz, DMSO-d6): δ=3.89(s, 3H), 4.68(s, 2H), 6.97(dd, 8.6Hz, 2.0Hz, 1H), 7.08(d, 5.5Hz, 1H) , 7.16(t, 74.7Hz, 1H), 7.18-7.47(brm, 2H), 8.16(d, 5.6Hz, 1H), 12.76(brs, 1H); LC-MS: MH⁺ =371.

实施例13Example 13

5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲硫基]-1H-苯并咪唑5-Difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl)methylthio]-1H-benzimidazole

在50至55℃，用30分钟向5-二氟甲氧基-1H-苯并咪唑-2-硫醇(14.5克，66.8毫摩尔)、乙醇(133毫升)和2M NaOH水溶液(73.5毫升，147毫摩尔)的混合物中，分次加入氯化2-氯甲基-3，4-二(三氘化甲氧基)吡啶

(15.4克，66.8毫摩尔)。在50至55℃继续搅拌1至2小时，然后在40℃真空蒸去乙醇。剩余水乳浊液用水(50毫升)稀释，并用二氯甲烷(165毫升每次)萃取三次。合并的有机相用0.1M NaOH水溶液(165毫升)洗涤，经Na₂SO₄干燥并蒸发至干，得到棕色油状的5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲硫基]-1H-苯并咪唑；产量23.8克(95％)。5-Difluoromethoxy-1H-benzimidazole-2-thiol (14.5 g, 66.8 mmol), ethanol (133 mL) and 2M aqueous NaOH (73.5 mL, 147 mmol) of the mixture, added 2-chloromethyl-3,4-bis(trideuterated methoxy)pyridine chloride in portions

(15.4 g, 66.8 mmol). Stirring was continued at 50 to 55°C for 1 to 2 hours, then the ethanol was distilled off in vacuo at 40°C. The remaining aqueous emulsion was diluted with water (50 mL) and extracted three times with dichloromethane (165 mL each)._The combined organic phases were washed with 0.1M aqueous NaOH (165 mL), dried over_Na2SO4 and evaporated to dryness to give 5-difluoromethoxy-2-[(3,4-di(trideuterium) as a brown oil (methoxy)-2-pyridyl)methylthio]-1H-benzimidazole; yield 23.8 g (95%).

实施例14Example 14

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑-大规模方法rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole-large scale method

在25至35℃，用3至4小时向5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(10.4千克，KF＝49.7％，14.2摩尔)和40％NaOH水溶液(2.84千克)在水(49升)和异丙醇(49升)混合物中的溶液内，加入次氯酸钠水溶液(10.5千克，10％浓度，14.2摩尔)。在25至35℃继续搅拌0.5至1小时，然后加入1％Na₂S₂O₃水溶液(4.3升)使反应猝灭。然后在30至45℃真空蒸去约65升溶剂。用水(55升)稀释之后，再蒸去一部分溶剂(8至10升)。使反应混合物保持在40至45℃，用1.5小时加入10％醋酸水溶液(约13升)直至pH达到8.5至9.5。一旦开始结晶，再加入10％醋酸水溶液(约0.6升)使pH缓慢调至6.8至7.2。冷却至20至25℃，过滤粗品，用水(7.5升)洗涤，再次溶于水(80升)、40％NaOH水溶液(1.6升)和Na₂S₂O₃(60克)的混合物中。所得的略混浊水溶液用MIBK(每次12升)洗涤两次，并用Hyflo处理(0.40千克)使澄清，然后在40至45℃加入10％醋酸水溶液(约8升)使pH调至9.0至9.5。一旦产物开始结晶，再加入10％醋酸以继续维持pH为9.0至9.5。最后，在20至25℃离心(包括用水(7.5升)清洗)，在约50℃真空干燥，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝134至135℃，分解)；产量3.59千克(65％)。5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H at 25 to 35°C for 3 to 4 hours - Benzimidazole (10.4 kg, KF=49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg) in a mixture of water (49 liters) and isopropanol (49 liters) were added aqueous sodium hypochlorite (10.5 kg, 10% concentration, 14.2 moles). Stirring was continued at 25 to 35 °C for 0.5 to 1 hour, then the reaction_was quenched by the addition of 1%_{aqueousNa2S2O3} (4.3 L). About 65 liters of solvent were then distilled off under vacuum at 30 to 45°C. After dilution with water (55 L), a portion of the solvent (8 to 10 L) was distilled off. The reaction mixture was maintained at 40 to 45°C, and 10% aqueous acetic acid (ca. 13 L) was added over 1.5 hours until the pH reached 8.5 to 9.5. Once crystallization started, further 10% aqueous acetic acid (ca. 0.6 L) was added to slowly adjust the pH to 6.8 to 7.2. Cooled to 20-25 °C, the crude product was filtered, washed with water (7.5 L), and_redissolved in_a mixture of water (80 L), 40% aqueous NaOH (1.6 L) and_Na2S2O3 (60 g). The resulting slightly cloudy aqueous solution was washed twice with MIBK (12 L each), clarified by treatment with Hyflo (0.40 kg), and then adjusted to pH 9.0 to 9.5 by adding 10% aqueous acetic acid (approximately 8 L) at 40 to 45°C . Once the product started to crystallize, an additional 10% acetic acid was added to continue maintaining the pH at 9.0 to 9.5. Finally, centrifugation at 20 to 25°C (including washing with water (7.5 L)) and vacuum drying at about 50°C afforded rac-5-difluoromethoxy-2-[(3-methoxy yl-4-trideuteromethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (mp=134 to 135° C., decomposition); yield 3.59 kg (65%).

¹H-NMR(400MHz，DMSO-d6)：δ＝3.78(s，3H)，4.67(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.5Hz，1H)，7.18(br d，8.7Hz，1H)，7.24(t，74.4Hz，1H)，7.44(br s，1H)，7.70(br s，1H)，8.15(d，5.5Hz，1H)，13.73(br s，1H)；LC-MS：MH⁺＝387.¹ H-NMR (400MHz, DMSO-d6): δ=3.78(s, 3H), 4.67(d, 13.1Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.10(d, 5.5Hz, 1H) , 7.18(br d, 8.7Hz, 1H), 7.24(t, 74.4Hz, 1H), 7.44(br s, 1H), 7.70(br s, 1H), 8.15(d, 5.5Hz, 1H), 13.73( br s, 1H); LC-MS: MH⁺ = 387.

实施例15Example 15

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从湿的5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(32.7克，KF＝51.6％，42.8毫摩尔)开始，依照实施例14所述的方法，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝133至135℃，分解)；产量10.8克(65％)。From wet 5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (32.7 g, KF =51.6%, 42.8 mmol) start, according to the method described in embodiment 14, obtain racemic-5-difluoromethoxyl-2-[(3-methoxyl group-4-dideuterium) of off-white solid Methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (mp=133 to 135° C., decomp.); yield 10.8 g (65%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.32(br s，NH+H₂O)，3.77(s，3H)，3.86(s，1H)，4.65(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.5Hz，1H)，7.15(dd，8.8H2，2.4Hz，1H)，7.23(t，74.4Hz，1H)，7.44(d，2.2Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)；LC-MS：MH⁺＝386.¹ H-NMR (200MHz, DMSO-d6): δ=3.32(br s, NH+H₂ O), 3.77(s, 3H), 3.86(s, 1H), 4.65(d, 13.1Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.10(d, 5.5Hz, 1H), 7.15(dd, 8.8H2, 2.4Hz, 1H), 7.23(t, 74.4Hz, 1H), 7.44(d, 2.2Hz, 1H), 7.69(d, 8.8Hz, 1H), 8.15(d, 5.5Hz, 1H); LC-MS: MH⁺ =386.

实施例16Example 16

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-difluoromethoxy-2-[(3-methoxy-4-deuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从湿的5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(34.8克，KF＝50.8％，46.5毫摩尔)开始，依照实施例14所述的方法，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝134至135℃，分解)；产量14.0克(78％)。From wet 5-difluoromethoxy-2-[(3-methoxy-4-deuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (34.8 g, KF =50.8%, 46.5 mmol) start, according to the method described in embodiment 14, obtain racemic-5-difluoromethoxyl group-2-[(3-methoxyl group-4-one deuterium) of off-white solid Methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (mp=134 to 135° C., decomposed); yield 14.0 g (78%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，3.88(s，2H)，4.66(d，13.2Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.6Hz，1H)，7.16(dd，8.8Hz，2.4Hz，1H)，7.24(t，74.4Hz，1H)，7.45(d，2.2Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)，13.77(brs，1H)；LC-MS：MH⁺＝385.¹ H-NMR (200MHz, DMSO-d6): δ=3.78(s, 3H), 3.88(s, 2H), 4.66(d, 13.2Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.10( d, 5.6Hz, 1H), 7.16(dd, 8.8Hz, 2.4Hz, 1H), 7.24(t, 74.4Hz, 1H), 7.45(d, 2.2Hz, 1H), 7.69(d, 8.8Hz, 1H) , 8.15(d, 5.5Hz, 1H), 13.77(brs, 1H); LC-MS: MH⁺ =385.

实施例17Example 17

外消旋-5-二氟甲氧基-2-[(4-甲氧基-3-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-difluoromethoxy-2-[(4-methoxy-3-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从湿的5-二氟甲氧基-2-[(4-甲氧基-3-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(3.00克，KF＝19.1％，6.55毫摩尔)开始，依照实施例38所述的方法，从TBME(10毫升)中结晶后，得到类白色固体的外消旋-5-二氟甲氧基-2-[(4-甲氧基-3-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝133至134℃，分解)；产量1.83克(72％)。From wet 5-difluoromethoxy-2-[(4-methoxy-3-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol), following the method described in Example 38, after crystallization from TBME (10 mL), rac-5-difluoromethoxy-2-[( 4-Methoxy-3-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (mp=133 to 134° C., dec.); yield 1.83 g (72%) .

¹H-NMR(200MHz，DMSO-d6)：δ＝3.90(s，3H)，4.66(d，13.1Hz，1H)，4.73(d，13.1Hz，1H)，7.10(d，5.6Hz，1H)，7.15(dd，8.9Hz，2.4Hz，1H)，7.24(t，74.4Hz，1H)，7.45(d，2.1Hz，1H)，7.69(d，8.8Hz，1H)，8.15(d，5.5Hz，1H)，13.77(brs，1H)；LC-MS：MH⁺＝387.¹ H-NMR (200MHz, DMSO-d6): δ=3.90(s, 3H), 4.66(d, 13.1Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.10(d, 5.6Hz, 1H) , 7.15(dd, 8.9Hz, 2.4Hz, 1H), 7.24(t, 74.4Hz, 1H), 7.45(d, 2.1Hz, 1H), 7.69(d, 8.8Hz, 1H), 8.15(d, 5.5Hz , 1H), 13.77 (brs, 1H); LC-MS: MH⁺ =387.

实施例18Example 18

外消旋-5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲硫基]-1H-苯并咪唑(23.8克，63.7毫摩尔)开始，依照实施例38所述的方法，从二异丙醚(700毫升)中结晶后，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑；产量20.9克(84％)。From 5-difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl)methylthio]-1H-benzimidazole (23.8 g, 63.7 mmol) Initially, following the procedure described in Example 38, rac-5-difluoromethoxy-2-[(3,4-di (Trideuteromethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole; yield 20.9 g (84%).

实施例19Example 19

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate

在15至30℃，用10至30分钟向外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(3.29千克，8.51摩尔)的丙酮(18升)溶液中，加入40％NaOH水溶液(0.85千克，8.50摩尔)。将所得悬浮液在50至55℃加热，直到获得澄清的溶液。用约12小时缓慢冷却至10至15℃，使产物结晶。过滤固体并用丙酮(1.7升)洗涤，再从丙酮/水32∶1(19升)中重结晶。最后，在50℃真空干燥，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物(熔点＝151至152℃(分解)，KF＝4.3％)；产量2.93千克(81％)。At 15 to 30°C, rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methyl To a solution of sulfinyl]-1H-benzimidazole (3.29 kg, 8.51 mol) in acetone (18 L), 40% aqueous NaOH (0.85 kg, 8.50 mol) was added. The resulting suspension was heated at 50 to 55°C until a clear solution was obtained. Slow cooling to 10 to 15°C over about 12 hours allowed the product to crystallize. The solid was filtered and washed with acetone (1.7 L) and recrystallized from acetone/water 32:1 (19 L). Finally, dry under vacuum at 50°C to obtain rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methanol as an off-white solid. sulfinyl]-1H-benzimidazole sodium salt monohydrate (mp=151 to 152° C. (dec.), KF=4.3%); yield 2.93 kg (81%).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，4.34(d，12.9Hz，1H)，4.68(d，12.9Hz，1H)，6.72(dd，8.6Hz，2.4Hz，1H)，7.02(t，75.8Hz，1H)，7.07(d，5.6Hz，1H)，7.24(d，2.2Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa⁺＝409，MH⁺＝387.¹ H-NMR (200MHz, DMSO-d6): δ=3.78(s, 3H), 4.34(d, 12.9Hz, 1H), 4.68(d, 12.9Hz, 1H), 6.72(dd, 8.6Hz, 2.4Hz , 1H), 7.02(t, 75.8Hz, 1H), 7.07(d, 5.6Hz, 1H), 7.24(d, 2.2Hz, 1H), 7.44(d, 8.6Hz, 1H), 8.22(d, 5.5Hz , 1H); LC-MS: MNa⁺ =409, MH⁺ =387.

实施例20Example 20

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate

从外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(8.10克，21.0毫摩尔)开始，依照实施例19所述的方法，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-二氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物(熔点＝150至152℃(分解)，KF＝4.8％)；产量6.05克(68％)。From rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole ( 8.10 g, 21.0 mmol), according to the method described in Example 19, to obtain racemic-5-difluoromethoxy-2-[(3-methoxy-4-dideuterated Methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate (mp=150 to 152° C. (dec.), KF=4.8%); yield 6.05 g (68%) .

¹H-NMR(200MHz，DMSO-d6)：δ＝3.77(s，3H)，3.85(s，1H)，4.36(d，12.9Hz，1H)，4.66(d，12.9Hz，1H)，6.73(dd，8.6Hz，2.4Hz，1H)，7.02(t，75.8Hz，1H)，7.07(d，5.6Hz，1H)，7.25(d，2.3Hz，1H)，7.45(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa⁺＝408，MH⁺＝386.¹ H-NMR (200MHz, DMSO-d6): δ=3.77(s, 3H), 3.85(s, 1H), 4.36(d, 12.9Hz, 1H), 4.66(d, 12.9Hz, 1H), 6.73( dd, 8.6Hz, 2.4Hz, 1H), 7.02(t, 75.8Hz, 1H), 7.07(d, 5.6Hz, 1H), 7.25(d, 2.3Hz, 1H), 7.45(d, 8.6Hz, 1H) , 8.22 (d, 5.5Hz, 1H); LC-MS: MNa⁺ =408, MH⁺ =386.

实施例21Example 21

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物rac-5-difluoromethoxy-2-[(3-methoxy-4-deuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate

从外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(10.2克，26.5毫摩尔)开始，依照实施例19所述的方法，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-一氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物(熔点＝151至152℃(分解)，KF＝4.1％)；产量8.95克(79％)。From rac-5-difluoromethoxy-2-[(3-methoxy-4-one deuteromethoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole ( 10.2 g, 26.5 mmol), and according to the method described in Example 19, rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuterated) was obtained as an off-white solid Methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate (mp=151 to 152° C. (dec.), KF=4.1%); yield 8.95 g (79%) .

¹H-NMR(200MHz，DMSO-d6)：δ＝3.78(s，3H)，3.88(s，2H)，4.34(d，12.9Hz，1H)，4.68(d，12.9Hz，1H)，6.73(dd，8.6Hz，2.4Hz，1H)，7.03(t，75.8Hz，1H)，7.08(d，5.5Hz，1H)，7.24(d，2.2Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa⁺＝407，MH⁺＝385.¹ H-NMR (200MHz, DMSO-d6): δ=3.78(s, 3H), 3.88(s, 2H), 4.34(d, 12.9Hz, 1H), 4.68(d, 12.9Hz, 1H), 6.73( dd, 8.6Hz, 2.4Hz, 1H), 7.03(t, 75.8Hz, 1H), 7.08(d, 5.5Hz, 1H), 7.24(d, 2.2Hz, 1H), 7.44(d, 8.6Hz, 1H) , 8.22 (d, 5.5Hz, 1H); LC-MS: MNa⁺ =407, MH⁺ =385.

实施例22Example 22

外消旋-5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物rac-5-difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt Hydrate

在15至25℃，用约15分钟向外消旋-5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(21.0克，53.9毫摩尔)在乙醇/二氯甲烷6∶1混合物(725毫升)的溶液中加入6M NaOH水溶液(8.92毫升，53.5毫摩尔)。室温下再搅拌10分钟，蒸去大部分溶剂。所得浓缩物(115克)用二异丙醚(1.7升)稀释。有些黑色蜡状残余物不溶，倒出黄色上清液。向该溶液中再加入一部分二异丙醚(3.4升)，生成产物沉淀。使悬浮液冷却至0℃。过滤固体，用二异丙醚(100毫升)洗涤，并在40℃真空干燥，得到类白色固体的外消旋-5-二氟甲氧基-2-[(3，4-二(三氘化甲氧基)-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物(KF＝4.0％)；产量18.9克(82％)。At 15 to 25°C, rac-5-difluoromethoxy-2-[(3,4-bis(trideuteromethoxy)-2-pyridyl)methylsulfinyl To a solution of acyl]-1H-benzimidazole (21.0 g, 53.9 mmol) in a 6:1 mixture of ethanol/dichloromethane (725 mL) was added 6M aqueous NaOH (8.92 mL, 53.5 mmol). After stirring for an additional 10 minutes at room temperature, most of the solvent was evaporated. The resulting concentrate (115 g) was diluted with diisopropyl ether (1.7 L). Some black waxy residue was insoluble and the yellow supernatant was decanted. To this solution was added a further portion of diisopropyl ether (3.4 L), resulting in the precipitation of the product. The suspension was cooled to 0 °C. The solid was filtered, washed with diisopropyl ether (100 mL), and dried under vacuum at 40 °C to give rac-5-difluoromethoxy-2-[(3,4-bis(trideuterium) as an off-white solid (Methoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt monohydrate (KF=4.0%); yield 18.9 g (82%).

¹H-NMR(400MHz，DMSO-d6)：δ＝4.32(d，12.9Hz，1H)，4.70(d，12.9Hz，1H)，6.72(dd，8.6Hz，2.4Hz，1H)，7.04(t，75.8Hz，1H)，7.08(d，5.5Hz，1H)，7.23(d，2.4Hz，1H)，7.44(d，8.6Hz，1H)，8.22(d，5.5Hz，1H)；LC-MS：MNa⁺＝412，MH⁺＝390.¹ H-NMR (400MHz, DMSO-d6): δ=4.32(d, 12.9Hz, 1H), 4.70(d, 12.9Hz, 1H), 6.72(dd, 8.6Hz, 2.4Hz, 1H), 7.04(t , 75.8Hz, 1H), 7.08(d, 5.5Hz, 1H), 7.23(d, 2.4Hz, 1H), 7.44(d, 8.6Hz, 1H), 8.22(d, 5.5Hz, 1H); LC-MS : MNa⁺ = 412, MH⁺ = 390.

实施例23Example 23

外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐倍半水合物rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt sesquihydrate

在48至55℃，将外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐一水合物(2.93千克，6.87摩尔)溶于异丙醇(12升)和水(0.50升)的混合物中。用Hyflo SuperCel(56克)处理并冷却至18至25℃，加入真实产物样品晶种后，在18至25℃搅拌40h，并在10至15℃再搅拌5小时以完成结晶。离心，在45℃真空干燥，得到白色固体的外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐倍半水合物(熔点＝140至142℃(分解)，KF＝6.6％)；产量2.28千克(78％)。At 48 to 55°C, rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]- 1H-Benzimidazole sodium salt monohydrate (2.93 kg, 6.87 mol) was dissolved in a mixture of isopropanol (12 L) and water (0.50 L). Treated with Hyflo SuperCel (56 g) and cooled to 18 to 25°C, seeded with authentic product samples, stirred at 18 to 25°C for 40 h, and at 10 to 15°C for another 5 hours to complete crystallization. Centrifugation and vacuum drying at 45 °C afforded rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methyl as a white solid Sulfinyl]-1H-benzimidazole sodium salt sesquihydrate (mp = 140 to 142° C. (dec.), KF = 6.6%); yield 2.28 kg (78%).

实施例24Example 24

双-[外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐二水合物Bis-[rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole] magnesium salt dihydrate

在40℃，将外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(500毫克，KF＝4.3％，1.17毫摩尔)的水(10.0毫升)溶液进行洁净过滤(clean filtration)。冷却至室温后，加入无水氯化镁(61.4毫克，0.644毫摩尔)的水(1.0毫升)溶液。室温下将所得悬浮液再搅拌18小时，然后冷却至0℃并过滤。在水(7.5毫升)中将滤饼再次浆化，过滤，用水(5.0毫升)清洗，并在40℃真空干燥，获得白色固体的双-[外消旋-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐二水合物(熔点＝180至182℃(分解)，KF＝4.7％；HPLC：99.5％a/a)；产量369毫克(76％)。At 40°C, racemic-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H- A solution of benzimidazole sodium salt (500 mg, KF=4.3%, 1.17 mmol) in water (10.0 mL) was subjected to clean filtration. After cooling to room temperature, a solution of anhydrous magnesium chloride (61.4 mg, 0.644 mmol) in water (1.0 mL) was added. The resulting suspension was stirred for a further 18 hours at room temperature, then cooled to 0°C and filtered. The filter cake was reslurried in water (7.5 mL), filtered, washed with water (5.0 mL), and dried under vacuum at 40 °C to obtain bis-[rac-5-difluoromethoxy-2 as a white solid -[(3-Methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole]magnesium salt dihydrate (melting point=180 to 182°C (decomposition ), KF=4.7%; HPLC: 99.5% a/a); yield 369 mg (76%).

实施例25Example 25

(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑-未干燥起始原料的大规模方法(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole-not Large-Scale Process for Drying Starting Materials

在室温，将382克湿的5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(KF＝47.6％，0.540摩尔)悬浮于2.44升甲基异丁酮中，连同(+)-L-酒石酸二-(N-吡咯烷酰胺)(55.0克)在一起。将混合物加热至40℃，真空蒸去约1.25升溶剂以除去水。然后，加入n-丙醇锆(IV)(24.0毫升，70％/n-丙醇)，并在40℃继续再搅拌1小时。冷却至30℃后，加入N-乙基二异丙胺(6.5毫升)和氢过氧化异丙苯(103毫升，约80％浓度)。在30℃搅拌约18小时之后，薄层色谱法显示没有起始原料进一步被转化。澄清的反应混合物用500毫升甲基异丁酮稀释，并用7.0克硫代硫酸钠/800毫升饱和碳酸氢钠溶液猝灭。相分离后，有机层用400毫升饱和碳酸氢钠溶液洗涤两次。向有机相中加入1.5升水，并用40％氢氧化钠水溶液将pH调至pH＝13。有机层再用400毫升pH13的水萃取。用Hyflo Super Cel(5.0克)处理后，在40至45℃加入10％醋酸水溶液将合并水相的pH调至约为9。一旦产物沉淀开始，将混合物再搅拌12小时，最后再次调pH。过滤(包括用水(200毫升)清洗)，得到光学纯度＞98％的粗品(160g，75％产率)。At room temperature, 382 grams of wet 5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (KF=47.6%, 0.540 mol) was suspended in 2.44 liters of methyl isobutyl ketone, together with (+)-L-tartrate bis-(N-pyrrolidineamide) (55.0 g). The mixture was heated to 40°C and about 1.25 liters of solvent was evaporated in vacuo to remove water. Then, zirconium(IV) n-propoxide (24.0 ml, 70%/n-propanol) was added and stirring was continued for a further 1 hour at 40°C. After cooling to 30°C, N-ethyldiisopropylamine (6.5 mL) and cumene hydroperoxide (103 mL, about 80% strength) were added. After stirring at 30°C for about 18 hours, thin layer chromatography showed no further conversion of the starting material. The clear reaction mixture was diluted with 500 mL methyl isobutyl ketone and quenched with 7.0 g sodium thiosulfate/800 mL saturated sodium bicarbonate solution. After phase separation, the organic layer was washed twice with 400 ml of saturated sodium bicarbonate solution. 1.5 liters of water were added to the organic phase and the pH was adjusted to pH=13 with 40% aqueous sodium hydroxide solution. The organic layer was extracted with 400 ml of pH 13 water. After treatment with Hyflo Super Cel (5.0 g), the pH of the combined aqueous phases was adjusted to about 9 by adding 10% aqueous acetic acid at 40-45°C. Once product precipitation started, the mixture was stirred for an additional 12 hours and finally the pH was adjusted again. Filtration (including washing with water (200 mL)) afforded the crude product (160 g, 75% yield) in >98% optical purity.

为了进一步增加纯度，将粗品溶于二氯甲烷(2.0升)中，并用水(400毫升)洗涤。用TBME通过溶剂追逐(solvent chase)进行结晶(终体积约1.1升)。在约0℃过滤晶体，用TBME(400毫升)洗涤，并在30℃真空干燥，得到类白色固体的(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点146至148℃(分解)；KF＝0.8％)；产量135克(64％)。To further increase the purity, the crude product was dissolved in dichloromethane (2.0 L) and washed with water (400 mL). Crystallization was performed by solvent chase with TBME (final volume about 1.1 L). The crystals were filtered at about 0 °C, washed with TBME (400 mL), and dried in vacuo at 30 °C to give (S)-5-difluoromethoxy-2-[(3-methoxy-4 - Trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (mp 146 to 148° C. (decomposition); KF=0.8%); yield 135 g (64%).

手性HPLC：＞98.0％ee；旋光度：[α]_D＝-98°(甲醇，c＝0.50)。Chiral HPLC: >98.0%ee; Optical rotation: [α]_D = -98° (methanol, c = 0.50).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.41(br s，NH+H₂O)，3.77(s，3H)，4.65(d，13.0Hz，1H)，4.73(d，13.1Hz，1H)，7.09(d，5.6Hz，1H)，7.15(dd，8.9Hz，2.4Hz，1H)，7.23(t，74.4Hz，1H)，7.44(d，2.1Hz，1H)，7.68(d，8.9Hz，1H)，8.14(d，5.5Hz，1H)；LC-MS：MH⁺＝387.¹ H-NMR (200MHz, DMSO-d6): δ=3.41(br s, NH+H₂ O), 3.77(s, 3H), 4.65(d, 13.0Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.09(d, 5.6Hz, 1H), 7.15(dd, 8.9Hz, 2.4Hz, 1H), 7.23(t, 74.4Hz, 1H), 7.44(d, 2.1Hz, 1H), 7.68(d, 8.9Hz, 1H), 8.14(d, 5.5Hz, 1H); LC-MS: MH⁺ =387.

实施例26Example 26

(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(70.7克，KF＝47.6％，100毫摩尔)开始，并用(-)-D-酒石酸二-(N-吡咯烷酰胺)(10.3克，40.0毫摩尔)作为手性配体，依照实施例25所述的方法，从TBME中重结晶之后，获得类白色固体的(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点：140至142℃(分解)；KF＝0.8％)；产量22.2克(57％)。From 5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (70.7 g, KF=47.6 %, 100 mmol), and use (-)-D-tartrate bis-(N-pyrrolidine amide) (10.3 g, 40.0 mmol) as the chiral ligand, according to the method described in Example 25, from TBME After recrystallization in medium, (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfin was obtained as an off-white solid Acyl]-1H-benzimidazole (melting point: 140 to 142° C. (decomposition); KF=0.8%); yield 22.2 g (57%).

手性HPLC：＞98.0％ee；旋光度：[α]_D＝+97°(甲醇，c＝0.50)。Chiral HPLC: >98.0%ee; Optical rotation: [α]_D =+97° (methanol, c=0.50).

¹H-NMR(200MHz，DMSO-d6)：δ＝3.77(s，3H)，4.65(d，13.2Hz，1H)，4.73(d，13.1Hz，1H)，7.09(d，5.5Hz，1H)，7.16(brd，～10.3Hz，1H)，7.23(t，74.4Hz，1H)，7.44(brs，1H)，7.68(brs，1H)，8.14(d，5.5Hz，1H)，13.73(brs，1H)；LC-MS：MH⁺＝387.¹ H-NMR (200MHz, DMSO-d6): δ=3.77(s, 3H), 4.65(d, 13.2Hz, 1H), 4.73(d, 13.1Hz, 1H), 7.09(d, 5.5Hz, 1H) , 7.16(brd, ~10.3Hz, 1H), 7.23(t, 74.4Hz, 1H), 7.44(brs, 1H), 7.68(brs, 1H), 8.14(d, 5.5Hz, 1H), 13.73(brs, 1H); LC-MS: MH⁺ = 387.

实施例27Example 27

(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt

在室温，向(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(100克，0.259摩尔)在甲基异丁酮(750毫升)、异丙醇(75毫升)和水(5.0毫升)混合物的悬浮液中，加入40％NaOH水溶液(18.1毫升，259毫摩尔)。加热至50℃之后获得澄清的溶液，用Hyflo Super Cel(10.0克)对该溶液进行处理。冷却至室温后，产物开始结晶，进一步冷却至0℃可使结晶完全。最后，过滤晶体，用甲基异丁酮(3份，每份40毫升)洗涤，并在35℃真空干燥，获得白色吸湿性固体的(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(熔点＝105至106℃(分解)，KF＝10.3％)；产量105克(89％)。At room temperature, to (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzene And imidazole (100 g, 0.259 mol) in the suspension of the mixture of methyl isobutyl ketone (750 ml), isopropanol (75 ml) and water (5.0 ml), add 40% NaOH aqueous solution (18.1 ml, 259 ml Moore). A clear solution obtained after heating to 50°C was treated with Hyflo Super Cel (10.0 g). After cooling to room temperature, the product began to crystallize, and further cooling to 0°C resulted in complete crystallization. Finally, the crystals were filtered, washed with methyl isobutyl ketone (3 parts, 40 mL each), and dried under vacuum at 35 °C to obtain (S)-5-difluoromethoxy-2-[ (3-Methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt (melting point=105 to 106°C (decomposition), KF=10.3% ); Yield 105 g (89%).

手性HPLC：＞99.0％ee；旋光度：[α]_D＝-94°(甲醇，c＝0.50)。Chiral HPLC: >99.0%ee; Optical rotation: [α]_D = -94° (methanol, c = 0.50).

实施例28Example 28

(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt

从(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(15.5克，40.1毫摩尔)开始，依照实施例27所述的方法，得到白色吸湿性固体的(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(熔点98至103℃(分解)；KF＝11.3％)；产量17.4克(94％)。From (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole ( 15.5 g, 40.1 mmol), and according to the method described in Example 27, (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuterium) was obtained as a white hygroscopic solid Methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt (mp 98 to 103° C. (decomposition); KF=11.3%); yield 17.4 g (94%).

手性HPLC：＞98.0％ee；旋光度：[α]_D＝+91°(甲醇，c＝0.50)。Chiral HPLC: >98.0%ee; Optical rotation: [α]_D =+91° (methanol, c=0.50).

实施例29Example 29

二-[(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐三水合物Bis-[(S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole]magnesium salt trihydrate

从(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(500毫克，KF＝10.3％，1.10毫摩尔)开始，依照实施例24所述的方法，得到白色固体的二-[(S)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐三水合物(熔点：169至175℃(分解)；KF＝6.4％)；产量350毫克(75％)。Sodium from (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole Salt (500 mg, KF=10.3%, 1.10 mmol), according to the method described in Example 24, to obtain two-[(S)-5-difluoromethoxy-2-[(3- Methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole]magnesium salt trihydrate (melting point: 169 to 175°C (decomposition); KF=6.4 %); yield 350 mg (75%).

手性HPLC：＞99.0％ee；旋光度：[α]_D＝-122°(甲醇，c＝0.50)。Chiral HPLC: >99.0%ee; Optical rotation: [α]_D = -122° (methanol, c = 0.50).

实施例30Example 30

二-[(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐三水合物Bis-[(R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole]magnesium salt trihydrate

从(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(2.30克，KF＝11.3％，5.00毫摩尔)开始，依照实施例24所述的方法，得到白色固体的二-[(R)-5-二氟甲氧基-2-[(3-甲氧基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐三水合物(熔点：141至145℃(分解)；KF＝6.9％)；产量1.23克(58％)。Sodium from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole Salt (2.30 g, KF=11.3%, 5.00 mmol), according to the method described in Example 24, to obtain bis-[(R)-5-difluoromethoxy-2-[(3- Methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole]magnesium salt trihydrate (melting point: 141 to 145°C (decomposition); KF=6.9 %); Yield 1.23 g (58%).

手性HPLC：＞99.0％ee；旋光度：[α]_D＝+120°(甲醇，c＝0.50)。Chiral HPLC: >99.0%ee; Optical rotation: [α]_D =+120° (methanol, c=0.50).

实施例31Example 31

起始原料5-三氘化甲氧基-1H-苯并咪唑-2-硫醇的合成Synthesis of starting material 5-trideuteromethoxy-1H-benzimidazole-2-thiol

4-三氘化甲氧基-硝基苯的制备Preparation of 4-trideuterated methoxy-nitrobenzene

在15至25℃，用2小时向氢氧化钠(15.6克，390毫摩尔)在甲醇-d4(47.4毫升，1.17摩尔)和THF(50毫升)混合物的溶液中，加入1-氟-4-硝基苯(50.0克，354毫摩尔)的THF(200毫升)溶液。室温下将所得悬浮液再搅拌3小时，然后加入10％HCl水溶液(100毫升)和甲苯(150毫升)。分离有机相并蒸发至干，得到棕色油的4-三氘化甲氧基-硝基苯，静置后结晶(熔点48至51℃)；产量56.6克(定量的)。1-Fluoro-4- Nitrobenzene (50.0 g, 354 mmol) in THF (200 mL). The resulting suspension was stirred for a further 3 hours at room temperature, then 10% aqueous HCl (100 mL) and toluene (150 mL) were added. The organic phase was separated and evaporated to dryness to give 4-trideuteromethoxy-nitrobenzene as a brown oil which crystallized on standing (mp 48 to 51° C.); yield 56.6 g (quantitative).

¹H-NMR(200MHz，DMSO-d6)：δ＝7.15(m，2H)，8.22(m，2H)；GC-MS：M⁺＝156.¹ H-NMR (200MHz, DMSO-d6): δ = 7.15 (m, 2H), 8.22 (m, 2H); GC-MS: M⁺ = 156.

4-三氘化甲氧基-乙酰苯胺的制备Preparation of 4-trideuterated methoxy-acetanilide

将10％Pd/C(3.6克，水湿润)、4-三氘化甲氧基-硝基苯(72.5克，464毫摩尔)和异丙醇(508毫升)装入高压锅中。用氮气彻底吹洗(4次)之后，在50至60℃氢压(3至4巴)下搅拌所得混合物，直到氢吸收停止(约2.5小时)。使反应混合物冷却至室温，加入乙酸酐(62.5毫升，580毫摩尔)。继续搅拌4个小时，然后过滤催化剂，并用热的2-丙醇(270毫升，约60℃)洗涤。合并的滤液在真空下浓缩至约150毫升，加入甲基环己烷(350毫升)，使所得浆体冷却至10℃。过滤并在45℃真空干燥，得到浅灰色固体的4-三氘化甲氧基-乙酰苯胺(熔点125至127℃)；产量67.0克(86％)。10% Pd/C (3.6 g, water wet), 4-trideuteromethoxy-nitrobenzene (72.5 g, 464 mmol) and isopropanol (508 mL) were charged into the autoclave. After purging thoroughly with nitrogen (4 times), the resulting mixture was stirred under hydrogen pressure (3 to 4 bar) at 50 to 60 °C until hydrogen uptake ceased (ca. 2.5 hours). The reaction mixture was cooled to room temperature and acetic anhydride (62.5 mL, 580 mmol) was added. Stirring was continued for 4 hours, then the catalyst was filtered and washed with hot 2-propanol (270 mL, ca. 60°C). The combined filtrates were concentrated in vacuo to about 150 mL, methylcyclohexane (350 mL) was added and the resulting slurry was cooled to 10°C. Filtration and vacuum drying at 45°C afforded 4-trideuteromethoxy-acetanilide as a light gray solid (mp 125 to 127°C); yield 67.0 g (86%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.00(s，3H)，6.85(m，2H)，7.47(m，2H)，9.74(br s，1H)；LC-MS：MH⁺＝169.¹ H-NMR (200MHz, DMSO-d6): δ = 2.00 (s, 3H), 6.85 (m, 2H), 7.47 (m, 2H), 9.74 (br s, 1H); LC-MS: MH⁺ = 169.

2-硝基-4-三氘化甲氧基-苯胺的制备Preparation of 2-nitro-4-trideuteromethoxy-aniline

在10至15℃，用1.5小时向4-三氘化甲氧基-乙酰苯胺(50.0克，297毫摩尔)的乙酸(175毫升)溶液中，加入50％硝酸水溶液(63.0毫升，654毫摩尔)。室温下继续搅拌18小时。然后，在15至20℃用约1小时加入20％NaOH水溶液(671毫升)。所得的棕色悬浮液在50℃加热20小时，然后加入20％HCl水溶液(49毫升)将pH调至约8。冷却至10℃获得粗品并过滤。在水清洗之后，使滤饼在60℃的异丙醇(200毫升)中浆化，并用1小时加入水(300毫升)。保持温度在50至60℃，蒸去190毫升溶剂。使所得悬浮液冷却至10℃，过滤并用水(60毫升)洗涤，在30℃真空干燥之后得到红色固体的2-硝基-4-三氘化甲氧基-苯胺(熔点120至122℃)；产量46.7克(92％)。To a solution of 4-trideuteromethoxy-acetanilide (50.0 g, 297 mmol) in acetic acid (175 ml) was added 50% aqueous nitric acid (63.0 ml, 654 mmol) over 1.5 hours at 10 to 15°C. ). Stirring was continued for 18 hours at room temperature. Then, 20% aqueous NaOH (671 mL) was added at 15 to 20° C. for about 1 hour. The resulting brown suspension was heated at 50°C for 20 hours, then the pH was adjusted to about 8 by the addition of 20% aqueous HCl (49 mL). Cool to 10°C to obtain crude product and filter. After washing with water, the filter cake was slurried in isopropanol (200 mL) at 60°C and water (300 mL) was added over 1 hour. Keeping the temperature at 50 to 60°C, 190 ml of solvent were distilled off. The resulting suspension was cooled to 10 °C, filtered and washed with water (60 mL) to give 2-nitro-4-trideuteromethoxy-aniline (mp 120 to 122 °C) as a red solid after drying in vacuo at 30 °C ; Yield 46.7 g (92%).

¹H-NMR(200MHz，DMSO-d6)：δ＝7.00(d，9.3Hz，1H)，7.16(dd，9.3Hz，2.9Hz，1H)，7.24(brs，2H)，7.37(d，2.9Hz，1H)；GC-MS：M⁺＝171.¹ H-NMR (200MHz, DMSO-d6): δ=7.00(d, 9.3Hz, 1H), 7.16(dd, 9.3Hz, 2.9Hz, 1H), 7.24(brs, 2H), 7.37(d, 2.9Hz , 1H); GC-MS: M⁺ = 171.

5-三氘化甲氧基-1H-苯并咪唑-2-硫醇的制备Preparation of 5-trideuterated methoxy-1H-benzimidazole-2-thiol

将10％Pd/C(2.23克，水湿润)、2-硝基-4-三氘化甲氧基-乙酰苯胺(45.6克，267毫摩尔)和异丙醇(460毫升)装入高压锅中。用氮气彻底吹洗(4次)之后，在40至50℃氢压(3至4巴)下搅拌所得混合物，直到氢吸收停止(约6小时)。然后，加入O-乙基黄原酸钾(51.2克，319毫摩尔)，回流加热反应混合物23小时。加入水(340毫升)，并用20％NaOH水溶液(10毫升)将pH调至12.5，然后蒸去约460毫升的异丙醇。所得黑色悬浮液用炭(10克)处理，过滤澄清，并用甲苯(350毫升)洗涤。加入20％HCl水溶液(53毫升)使产物沉淀，在0℃过滤分离。用水(100毫升)清洗，并在35℃真空干燥，最后得到类白色固体的5-三氘化甲氧基-1H-苯并咪唑-2-硫醇(熔点247至250℃)；产量45.5克(93％)。Charge 10% Pd/C (2.23 g, wet with water), 2-nitro-4-trideuteromethoxy-acetanilide (45.6 g, 267 mmol), and isopropanol (460 mL) into an autoclave . After purging thoroughly with nitrogen (4 times), the resulting mixture was stirred under hydrogen pressure (3 to 4 bar) at 40 to 50 °C until hydrogen uptake ceased (about 6 hours). Then, potassium O-ethylxanthate (51.2 g, 319 mmol) was added and the reaction mixture was heated at reflux for 23 hours. Water (340 mL) was added and the pH was adjusted to 12.5 with 20% aqueous NaOH (10 mL), then about 460 mL of isopropanol was distilled off. The resulting black suspension was treated with charcoal (10 g), clarified by filtration and washed with toluene (350 mL). The product was precipitated by the addition of 20% aqueous HCl (53 mL) and isolated by filtration at 0°C. Rinse with water (100 ml) and dry under vacuum at 35°C to finally give 5-trideuteromethoxy-1H-benzimidazole-2-thiol (mp 247 to 250°C) as an off-white solid; yield 45.5 g (93%).

¹H-NMR(400MHz，DMSO-d6)：δ＝6.67(d，2.3Hz，1H)，6.72(dd，8.7Hz，2.4Hz，1H)，7.03(d，8.6Hz，1H)，12.36(brs，1H)，12.40(brs，1H)；LC-MS：MH⁺＝184.¹ H-NMR (400MHz, DMSO-d6): δ=6.67(d, 2.3Hz, 1H), 6.72(dd, 8.7Hz, 2.4Hz, 1H), 7.03(d, 8.6Hz, 1H), 12.36(brs , 1H), 12.40 (brs, 1H); LC-MS: MH⁺ =184.

实施例32Example 32

起始原料氯化4-氯-2-氯甲基-3，5-二甲基吡啶

的合成Starting material 4-Chloro-2-chloromethyl-3,5-lutidine chloride

Synthesis

4-氯-2-羟甲基-3，5-二甲基吡啶的制备Preparation of 4-chloro-2-hydroxymethyl-3,5-lutidine

在90至95℃，用7小时向乙酸酐(232毫升)中加入保持在约60℃的4-氯-2，3，5-三甲基吡啶-N-氧化物(60.0克，350毫摩尔)的甲苯(920毫升)溶液。在约60℃下，真空浓缩反应混合物直至蒸去820毫升。加入甲苯(840毫升)，再次蒸去溶剂(940毫升)。然后，加入甲苯(180毫升)和40％NaOH水溶液(80毫升)，然后在50℃加热反应混合物约15小时。加入饱和碳酸氢钠水溶液(120毫升)，相分离，水层用甲苯(80毫升)再萃取一次。最后，合并的有机相用饱和碳酸氢钠溶液(120毫升)洗涤，并蒸发至干，得到带棕色的油4-氯-2-羟甲基-3，5-二甲基吡啶，静置后凝固；产量61.8克(定量的)。To acetic anhydride (232 ml) was added 4-chloro-2,3,5-collidine-N-oxide (60.0 g, 350 mmol ) in toluene (920 ml). At about 60°C, the reaction mixture was concentrated in vacuo until 820 mL had evaporated. Toluene (840 ml) was added, and the solvent (940 ml) was distilled off again. Then, toluene (180 mL) and 40% aqueous NaOH (80 mL) were added, and the reaction mixture was heated at 50° C. for about 15 hours. Saturated aqueous sodium bicarbonate (120 mL) was added, the phases were separated, and the aqueous layer was extracted once more with toluene (80 mL). Finally, the combined organic phases were washed with saturated sodium bicarbonate solution (120 mL) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-lutidine as a brownish oil which, after standing Solidified; yield 61.8 g (quantitative).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.30(s，3H)，2.36(s，3H)，4.58(br s，2H)，5.11(br s，1H)，8.27(s，1H)；LC-MS：MH⁺＝172/174.¹ H-NMR (200MHz, DMSO-d6): δ=2.30(s, 3H), 2.36(s, 3H), 4.58(br s, 2H), 5.11(br s, 1H), 8.27(s, 1H) ; LC-MS: MH⁺ = 172/174.

氯化4-氯-2-氯甲基-3，5-二甲基吡啶

的制备4-Chloro-2-chloromethyl-3,5-lutidine chloride

preparation of

在15至30℃，用2小时向4-氯-2-羟甲基-3，5-二甲基吡啶(60.7克，354毫摩尔)和DMF(0.25毫升，3.54毫摩尔)的甲苯(200毫升)溶液中，加入亚硫酰氯(26.9毫升，371毫摩尔)。室温下再搅拌2小时后，向稠的浆体中加入乙醇(6毫升)。在约10℃下过滤除去固体，用甲苯(80毫升)洗涤，并在40℃真空干燥，得到类白色固体的氯化4-氯-2-氯甲基-3，5-二甲基吡啶(熔点＝195至196℃)；产量66.5克(84％)。4-Chloro-2-hydroxymethyl-3,5-lutidine (60.7 g, 354 mmol) and DMF (0.25 mL, 3.54 mmol) in toluene (200 mL) solution, was added thionyl chloride (26.9 mL, 371 mmol). After stirring for an additional 2 hours at room temperature, ethanol (6 mL) was added to the thick slurry. The solid was removed by filtration at about 10°C, washed with toluene (80 mL), and dried under vacuum at 40°C to give 4-chloro-2-chloromethyl-3,5-lutidine chloride as an off-white solid (melting point = 195 to 196°C); yield 66.5 g (84%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.36(s，3H)，2.46(s，3H)，4.93(s，2H)，8.44(s，1H)，8.79(br s，1H)：LC-MS：MH⁺＝190/192/194.¹ H-NMR (200MHz, DMSO-d6): δ=2.36(s, 3H), 2.46(s, 3H), 4.93(s, 2H), 8.44(s, 1H), 8.79(br s, 1H): LC-MS: MH⁺ = 190/192/194.

实施例33Example 33

5-三氘化甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑5-trideuteromethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole

在55至65℃，用2小时向5-三氘化甲氧基-1H-苯并咪唑-2-硫醇(9.50克，51.8毫摩尔)、甲苯(47毫升)、水(23毫升)和40％NaOH水溶液(14毫升)的混合物中，加入氯化4-氯-2-氯甲基-3，5-二甲基吡啶

(12.6克，55.6毫摩尔)的水(21毫升)溶液。在60℃继续搅拌16小时，然后使反应混合物冷却至约10℃。过滤沉淀，用甲苯(17毫升)洗涤，并在水(132毫升)中再次浆化。过滤后用水(70毫升)清洗，并在35℃真空干燥，得到类白色固体的5-三氘化甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(KF＝5.0％)(熔点＝99至102℃)；产量15.1克(82％)。At 55 to 65°C, 5-trideuteromethoxy-1H-benzimidazole-2-thiol (9.50 g, 51.8 mmol), toluene (47 ml), water (23 ml) and To a mixture of 40% aqueous NaOH (14 mL), was added 4-chloro-2-chloromethyl-3,5-lutidine chloride

(12.6 g, 55.6 mmol) in water (21 mL). Stirring was continued at 60°C for 16 hours, then the reaction mixture was cooled to about 10°C. The precipitate was filtered, washed with toluene (17 mL) and reslurried in water (132 mL). After filtering, washing with water (70 ml) and drying in vacuo at 35°C, 5-trideuteromethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl) was obtained as an off-white solid )methylthio]-1H-benzimidazole monohydrate (KF=5.0%) (melting point=99 to 102° C.); yield 15.1 g (82%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.30(s，3H)，2.43(s，3H)，4.72(s，2H)，6.76(dd，8.7Hz，2.5Hz，1H)，6.97(brs，1H)，7.35(d，8.7Hz，1H)，8.28(s，1H)，12.47(br s，1H)；LC-MS：MH⁺＝337/339.¹ H-NMR (200MHz, DMSO-d6): δ=2.30(s, 3H), 2.43(s, 3H), 4.72(s, 2H), 6.76(dd, 8.7Hz, 2.5Hz, 1H), 6.97( brs, 1H), 7.35(d, 8.7Hz, 1H), 8.28(s, 1H), 12.47(br s, 1H); LC-MS: MH⁺ =337/339.

实施例34Example 34

5-甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole

从5-甲氧基-1H-苯并咪唑-2-硫醇(24.0克，111毫摩尔)开始，依照实施例33所述的方法，得到类白色固体的5-甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(KF＝5.2％)(熔点＝100至102℃)；产量34.8克(89％)。Starting from 5-methoxy-1H-benzimidazole-2-thiol (24.0 g, 111 mmol), following the procedure described in Example 33, 5-methoxy-2-[ (4-Chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (KF=5.2%) (melting point=100 to 102° C.); yield 34.8 g ( 89%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.30(s，3H)，2.43(s，3H)，4.72(s，2H)，6.76(dd，8.7Hz，2.5Hz，1H)，6.98(br s，1H)，7.35(d，8.7Hz，1H)，8.28(s，1H)，12.41(br s，1H)；LC-MS：MH⁺＝334/336.¹ H-NMR (200MHz, DMSO-d6): δ=2.30(s, 3H), 2.43(s, 3H), 4.72(s, 2H), 6.76(dd, 8.7Hz, 2.5Hz, 1H), 6.98( br s, 1H), 7.35(d, 8.7Hz, 1H), 8.28(s, 1H), 12.41(br s, 1H); LC-MS: MH⁺ =334/336.

实施例35Example 35

5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole

在60至65℃，用1.5小时向5-三氘化甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(5.20克，14.7毫摩尔)的NMP(30毫升)溶液中，加入约10等份的固体甲醇钠(5.80克，104毫摩尔)。在60℃继续搅拌16小时，然后在70℃加热反应混合物24小时，最后在80℃加热4小时。用水(200毫升)稀释，加入10％HCl水溶液(10毫升)后，所得咖啡色溶液用甲苯萃取两次(100+40毫升)。合并的有机相先后用5％NaOH水溶液(2×200毫升)和水(100毫升)洗涤，然后蒸发至干。残余物置于热的甲苯(50毫升)中，洁净过滤，并再次蒸发至干。最后，从TBME/甲苯10∶1(33毫升)中结晶，得到白色固体的5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑(熔点＝120至121℃)；产量2.27克(46％)。At 60 to 65°C, 5-trideuteromethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole was prepared in 1.5 hours To a solution of the monohydrate (5.20 g, 14.7 mmol) in NMP (30 mL) was added about 10 equal parts of solid sodium methoxide (5.80 g, 104 mmol). Stirring was continued at 60°C for 16 hours, then the reaction mixture was heated at 70°C for 24 hours and finally at 80°C for 4 hours. After dilution with water (200 mL) and addition of 10% aqueous HCl (10 mL), the resulting brown solution was extracted twice with toluene (100+40 mL). The combined organic phases were washed successively with 5% aqueous NaOH (2 x 200 mL) and water (100 mL), then evaporated to dryness. The residue was taken up in hot toluene (50 mL), filtered clean and evaporated to dryness again. Finally, crystallization from TBME/toluene 10:1 (33 mL) gave 5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridine as a white solid yl)methylthio]-1H-benzimidazole (mp=120 to 121° C.); yield 2.27 g (46%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.20(s，3H)，2.27(s，3H)，3.73(s，3H)，4.65(s，2H)，6.75(dd，8.7Hz，2.5Hz，1H)，6.97(br s，1H)，7.35(d，8.7Hz，1H)，8.17(s，1H)，12.44(br s，1H)；LC-MS：MH⁺＝333.¹ H-NMR (200MHz, DMSO-d6): δ=2.20(s, 3H), 2.27(s, 3H), 3.73(s, 3H), 4.65(s, 2H), 6.75(dd, 8.7Hz, 2.5 Hz, 1H), 6.97(br s, 1H), 7.35(d, 8.7Hz, 1H), 8.17(s, 1H), 12.44(br s, 1H); LC-MS: MH⁺ =333.

实施例36Example 36

5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

在约50℃，用30分钟向氢化钠(60％/矿物油，1.70克，41.5毫摩尔)的NMP(12毫升)悬浮液中，加入甲醇-d4(1.70毫升，41.5毫摩尔)，制得三氘化甲醇钠溶液。加热至60℃之后，加入5-三氘化甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(2.10克，5.92毫摩尔)的NMP(4毫升)溶液。继续搅拌，先在70℃下24小时，然后在85℃下5小时。依照实施例35所述的后处理方法，得到白色固体的5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(熔点＝120至121℃)；产量0.55克(28％)。To a suspension of sodium hydride (60%/mineral oil, 1.70 g, 41.5 mmol) in NMP (12 mL) was added methanol-d4 (1.70 mL, 41.5 mmol) over 30 minutes at about 50 °C to obtain Sodium trideuteride methoxide solution. After heating to 60°C, add 5-trideuteromethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (2.10 g, 5.92 mmol) in NMP (4 mL). Stirring was continued, first at 70°C for 24 hours, then at 85°C for 5 hours. According to the post-treatment method described in Example 35, 5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl) was obtained as a white solid Methylthio]-1H-benzimidazole (melting point = 120 to 121° C.); yield 0.55 g (28%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.20(s，3H)，2.27(s，3H)，4.64(s，2H)，6.75(dd，8.7Hz，2.4Hz，1H)，6.89-7.38(br m，2H)，8.17(s，1H)，12.42(br s，1H)；LC-MS：MH⁺＝336.¹ H-NMR (200MHz, DMSO-d6): δ=2.20(s, 3H), 2.27(s, 3H), 4.64(s, 2H), 6.75(dd, 8.7Hz, 2.4Hz, 1H), 6.89- 7.38 (br m, 2H), 8.17 (s, 1H), 12.42 (br s, 1H); LC-MS: MH⁺ =336.

实施例37Example 37

5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole

从5-甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑一水合物(24.0克，68.2毫摩尔)开始，依照实施例36所述的方法，得到白色固体的5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(熔点＝119至121℃)；产量8.72克(38％)。Starting with 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole monohydrate (24.0 g, 68.2 mmol) According to the method described in Example 36, 5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio] was obtained as a white solid - 1H-benzimidazole (melting point = 119 to 121° C.); yield 8.72 g (38%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.20(s，3H)，2.27(s，3H)，3.77(s，3H)，4.64(s，2H)，6.75(dd，8.7Hz，2.5Hz，1H)，6.98(br s，1H)，7.35(br d，8.6Hz，1H)，8.17(s，1H)，12.43(br s，1H)；LC-MS：MH⁺＝333.¹ H-NMR (200MHz, DMSO-d6): δ=2.20(s, 3H), 2.27(s, 3H), 3.77(s, 3H), 4.64(s, 2H), 6.75(dd, 8.7Hz, 2.5 Hz, 1H), 6.98(br s, 1H), 7.35(br d, 8.6Hz, 1H), 8.17(s, 1H), 12.43(br s, 1H); LC-MS: MH⁺ =333.

实施例38Example 38

外消旋-5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole

将5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲硫基]-1H-苯并咪唑(1.50克，4.51毫摩尔)溶于CH₂Cl₂(15毫升)中，并冷却至-55至-40℃。在此温度下，用1.5小时缓慢加入3-氯过氧苯甲酸(湿，77％浓度，1.12克，5.00毫摩尔)的CH₂Cl₂(8毫升)溶液。在-55至-40℃下再1小时后，先后加入三乙胺(0.87毫升，6.28毫摩尔)以及6％Na₂CO₃水溶液和2％Na₂S₂O₃水溶液的1∶1混合物(10毫升)，同时使混合物加热至约0℃。室温下继续搅拌1小时。相分离，有机层用6％Na₂CO₃水溶液和2％Na₂S₂O₃水溶液的1∶1混合物洗涤两次，用水洗涤一次(每次10毫升)，然后蒸发至干。所得残余物用乙酸乙酯(6.0毫升)结晶，得到白色固体的外消旋-5-三氘化甲氧基-2-[(4-甲氧基-3，5-二甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝150至152℃，分解)；产量1.27克(81％)。5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole (1.50 g, 4.51 mmol ) was dissolved in_CH2Cl2 (15 mL) and cooled to -55 to -40 °C_. At this temperature, a solution of 3-chloroperoxybenzoic acid (wet, 77% strength, 1.12 g, 5.00 mmol) in_CH2Cl2 (8 mL) was slowly added over_1.5 h. After another 1 h at -55 to -40 °C, triethylamine (0.87 mL, 6.28 mmol) was added followed by_a 1_: 1 mixture of 6% aqueous_Na2CO3 and₂ % aqueous_Na2S2O3 ( 10 mL), while warming the mixture to about 0°C. Stirring was continued for 1 hour at room temperature. The phases were separated and_the organic layer was washed twice with_a 1:1 mixture of 6% aqueous_Na2CO3 and 2%_{aqueousNa2S2O3} , once with water (10 mL each), and evaporated to dryness. The resulting residue was crystallized from ethyl acetate (6.0 mL) to give rac-5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2- Pyridyl)methylsulfinyl]-1H-benzimidazole (mp=150 to 152° C., decomp.); yield 1.27 g (81%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.17(s，3H)，2.20(s，3H)，3.69(s，3H)，4.67(d，13.6Hz，1H)，4.77(d，13.5Hz，1H)，6.92(dd，8.9Hz，2.4Hz，1H)，7.09(brs，1H)，7,54(brd，8.9Hz，1H)，8.18(s，1H)，13.39(br s，1H)；LC-MS：MH⁺＝349.¹ H-NMR (200MHz, DMSO-d6): δ=2.17(s, 3H), 2.20(s, 3H), 3.69(s, 3H), 4.67(d, 13.6Hz, 1H), 4.77(d, 13.5 Hz, 1H), 6.92(dd, 8.9Hz, 2.4Hz, 1H), 7.09(brs, 1H), 7,54(brd, 8.9Hz, 1H), 8.18(s, 1H), 13.39(brs, 1H ); LC-MS: MH⁺ = 349.

实施例39Example 39

外消旋-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzo imidazole

从5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(1.20克，3.57毫摩尔)开始，依照实施例38所述的方法，得到白色固体的外消旋-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝147至148℃，分解)；产量0.90克(72％)。From 5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (1.20 g, 3.57 mmol), according to the method described in Example 38, to obtain rac-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy) as a white solid Oxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (mp=147 to 148° C., decomposed); yield 0.90 g (72%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.16(s，3H)，2.20(s，3H)，4.67(d，13.5Hz，1H)，4.77(d，13.5Hz，1H)，6.90-7.55(br m，3H)，8.18(s，1H)，13.39(br s，1H)；LC-MS：MH⁺＝352.¹ H-NMR (200MHz, DMSO-d6): δ=2.16(s, 3H), 2.20(s, 3H), 4.67(d, 13.5Hz, 1H), 4.77(d, 13.5Hz, 1H), 6.90- 7.55 (br m, 3H), 8.18 (s, 1H), 13.39 (br s, 1H); LC-MS: MH⁺ =352.

实施例40Example 40

外消旋-5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑rac-5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole

从5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(1.00克，3.01毫摩尔)开始，依照实施例38所述的方法，得到白色固体的外消旋-5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑(熔点＝143至144℃，分解)；产量0.86克(82％)。From 5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole (1.00 g, 3.01 mmol ), according to the method described in Example 38, the racemic-5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridine of white solid was obtained yl)methylsulfinyl]-1H-benzimidazole (mp=143 to 144° C., decomposed); yield 0.86 g (82%).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.17(s，3H)，2.20(s，3H)，3.81(s，3H)，4.67(d，13.6Hz，1H)，4.77(d，13.5Hz，1H)，6.90-7.55(brm，3H)，8.18(s，1H)，13.40(brs，1H)；LC-MS：MH⁺＝349.¹ H-NMR (200MHz, DMSO-d6): δ=2.17(s, 3H), 2.20(s, 3H), 3.81(s, 3H), 4.67(d, 13.6Hz, 1H), 4.77(d, 13.5 Hz, 1H), 6.90-7.55(brm, 3H), 8.18(s, 1H), 13.40(brs, 1H); LC-MS: MH⁺ =349.

实施例41Example 41

(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(S)-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole Sodium Salt

在室温，将5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-苯并咪唑(3.02克，9.00毫摩尔)和(+)-L-酒石酸二-(N-吡咯烷酰胺)(0.92克，3.60毫摩尔)悬浮于35毫升甲基异丁酮中。将混合物加热至40℃，真空蒸去约8毫升溶剂以除去水。然后，加入n-丙醇锆(IV)(0.40毫升，70％/丙醇，0.90毫摩尔)，在40℃再继续搅拌1小时。冷却至30℃之后，加入N-乙基二异丙胺(0.11毫升，0.63毫摩尔)和氢过氧化异丙苯(1.52毫升，约80％浓度，8.55毫摩尔)。在30℃搅拌约20小时后，澄清的反应混合物用甲基异丁酮(8.5毫升)稀释，并用硫代硫酸钠(0.11克)/饱和碳酸氢钠溶液(15毫升)猝灭。相分离之后，有机层用饱和碳酸氢钠溶液洗涤两次(每次7.5毫升)。向有机相加入水(25毫升)，用40％NaOH水溶液(0.71毫升)将pH调至pH＝12.5至13。有机层再用pH12.5至13(通过加入必要量的40％NaOH水溶液)的水(7.5毫升)萃取两次。合并的有机相用二氯甲烷(15毫升)洗涤。然后，用磷酸二氢钾将pH调至约10，水溶液用二氯甲烷萃取(一次40毫升，两次10毫升)。将有机相蒸发至干，得到褐色油的(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，通过形成相应的钠盐获得进一步的纯化。At room temperature, 5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole ( 3.02 g, 9.00 mmol) and (+)-L-tartrate bis-(N-pyrrolidineamide) (0.92 g, 3.60 mmol) were suspended in 35 mL of methyl isobutyl ketone. The mixture was heated to 40°C and about 8 mL of solvent was evaporated in vacuo to remove water. Then, zirconium(IV) n-propoxide (0.40 ml, 70%/propanol, 0.90 mmol) was added and stirring was continued for a further 1 hour at 40°C. After cooling to 30° C., N-ethyldiisopropylamine (0.11 mL, 0.63 mmol) and cumene hydroperoxide (1.52 mL, about 80% strength, 8.55 mmol) were added. After stirring at 30°C for about 20 hours, the clear reaction mixture was diluted with methyl isobutyl ketone (8.5 mL) and quenched with sodium thiosulfate (0.11 g)/saturated sodium bicarbonate solution (15 mL). After phase separation, the organic layer was washed twice with saturated sodium bicarbonate solution (7.5 mL each). Water (25 mL) was added to the organic phase and the pH was adjusted to pH=12.5-13 with 40% aqueous NaOH (0.71 mL). The organic layer was extracted twice more with water (7.5 mL) at pH 12.5 to 13 (by adding the necessary amount of 40% aqueous NaOH). The combined organic phases were washed with dichloromethane (15 mL). Then, the pH was adjusted to about 10 with potassium dihydrogen phosphate, and the aqueous solution was extracted with dichloromethane (once 40 mL, twice 10 mL). The organic phase was evaporated to dryness to give (S)-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl) as a brown oil Methylsulfinyl]-1H-benzimidazole, further purification was obtained by formation of the corresponding sodium salt.

到最后，将粗品置于甲基异丁酮(15毫升)和异丙醇(1.5毫升)中。然后，加入40％NaOH水溶液(0.63毫升)，使所得悬浮液冷却至0℃。过滤固体，用甲基异丁酮洗涤(两次2.0毫升)，并在45℃真空干燥，得到类白色固体的(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(熔点＝224至225℃(分解)，KF＝1.5％)；产量2.05克(61％)。At the end, the crude product was taken up in methyl isobutyl ketone (15 mL) and isopropanol (1.5 mL). Then, 40% aqueous NaOH (0.63 mL) was added and the resulting suspension was cooled to 0°C. The solid was filtered, washed with methyl isobutyl ketone (twice 2.0 mL), and dried under vacuum at 45 °C to give (S)-5-trideuteromethoxy-2-[(3,5- Dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt (mp=224 to 225° C. (decomposition), KF=1.5%); yield 2.05 grams (61%).

手性HPLC：＞97.0％ee；旋光度：[α]_D＝-44°(甲醇，c＝0.53)，[α]_D＝+39°(水，c＝0.39)。Chiral HPLC: >97.0%ee; Optical rotation: [α]_D = -44° (methanol, c = 0.53), [α]_D = +39° (water, c = 0.39).

¹H-NMR(200MHz，DMSO-d6)：δ＝2.18(s，3H)，2.21(s，3H)，4.39(d，12.9Hz，1H)，4.63(d，12.9Hz，1H)，6.54(dd，8.7Hz，2.5Hz，1H)，6.98(d，2.5Hz，1H)，7,32(br d，8.6Hz，1H)，8.23(s，1H).¹ H-NMR (200MHz, DMSO-d6): δ=2.18(s, 3H), 2.21(s, 3H), 4.39(d, 12.9Hz, 1H), 4.63(d, 12.9Hz, 1H), 6.54( dd, 8.7Hz, 2.5Hz, 1H), 6.98(d, 2.5Hz, 1H), 7, 32(br d, 8.6Hz, 1H), 8.23(s, 1H).

实施例42Example 42

二-[(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐Bis-[(S)-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole]magnesium salt

从(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑钠盐(200毫克，KF＝1.5％，0.528毫摩尔)开始，依照实施例24所述的方法，得到白色固体的二-[(S)-5-三氘化甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑]镁盐(熔点＝161至162℃(分解)，KF＝1.5％)；产量132mg(68％)。From (S)-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzene Starting with imidazole sodium salt (200 mg, KF=1.5%, 0.528 mmol), according to the method described in Example 24, bis-[(S)-5-trideuteromethoxy-2- [(3,5-Dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole]magnesium salt (melting point=161 to 162°C (decomposition), KF = 1.5%); yield 132 mg (68%).

手性HPLC：＞97.0％ee；旋光度：[α]_D＝-120°(甲醇，c＝0.50)。Chiral HPLC: >97.0%ee; Optical rotation: [α]_D = -120° (methanol, c = 0.50).

通过上述步骤的适当组合，还可获得通式(1)的其它化合物：Through the appropriate combination of the above steps, other compounds of general formula (1) can also be obtained:

例如，依照实施例7所述的方法，使氯化4-氯-2-氯甲基-3-甲基吡啶与1H-苯并咪唑-2-硫醇反应，得到2-[(4-氯-3-甲基-2-吡啶基)甲硫基]-1H-苯并咪唑。然后，依照实施例9所述的方法，使用例如1，1-二氘化-3-甲氧基-1-丙醇或1，1-二氘化-2，2，2-三氟乙醇，可将该产物转化，分别形成2-[(4-(1，1-二氘化-3-甲氧基丙-1-氧基)-3-甲基-2-吡啶基)甲硫基]-1H-苯并咪唑和2-[(4-(1，1-二氘化-2，2，2-三氟乙氧基)-3-甲基-2-吡啶基)甲硫基]-1H-苯并咪唑。最后，依照实施例38所述的方法将这些化合物氧化，分别得到都是代表式(1)化合物的外消旋2-[(4-(1，1-二氘化-3-甲氧基丙-1-氧基)-3-甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑和外消旋2-[(4-(1，1-二氘化-2，2，2-三氟乙氧基)-3-甲基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑。For example, according to the method described in Example 7, the chloride 4-chloro-2-chloromethyl-3-picoline Reaction with 1H-benzimidazole-2-thiol affords 2-[(4-chloro-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole. Then, according to the method described in Example 9, using, for example, 1,1-dideuterated-3-methoxy-1-propanol or 1,1-dideuterated-2,2,2-trifluoroethanol, This product can be transformed to form 2-[(4-(1,1-dideuterated-3-methoxyprop-1-oxy)-3-methyl-2-pyridyl)methylthio], respectively -1H-benzimidazole and 2-[(4-(1,1-dideuterated-2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl)methylthio]- 1H-benzimidazole. Finally, these compounds were oxidized according to the method described in Example 38 to obtain racemic 2-[(4-(1,1-dideuterated-3-methoxypropane, respectively) representing compounds of formula (1). -1-oxyl)-3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole and racemic 2-[(4-(1,1-dideuterated-2, 2,2-trifluoroethoxy)-3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole.

另一个实施例，依照实施例33所述的方法，使氯化4-氯-2-氯甲基-3，5-二甲基吡啶

与5-甲氧基-1H-咪唑并[4，5-b]吡啶-2-硫醇反应，得到5-甲氧基-2-[(4-氯-3，5-二甲基-2-吡啶基)甲硫基]-1H-咪唑并[4，5-b]吡啶。依照实施例36所述的方法，用甲醇-d4可将该产物转化，形成5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲硫基]-1H-咪唑并[4，5-b]吡啶，该化合物又可依照实施例38中所用的方法，被氧化为外消旋-5-甲氧基-2-[(3，5-二甲基-4-三氘化甲氧基-2-吡啶基)甲基亚磺酰基]-1H-咪唑并[4，5-b]吡啶，即另一种式(1)化合物。In another embodiment, according to the method described in embodiment 33, chlorinated 4-chloro-2-chloromethyl-3,5-lutidine

Reaction with 5-methoxy-1H-imidazo[4,5-b]pyridine-2-thiol affords 5-methoxy-2-[(4-chloro-3,5-dimethyl-2 -pyridyl)methylthio]-1H-imidazo[4,5-b]pyridine. Following the procedure described in Example 36, this product can be converted with methanol-d4 to form 5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridine base)methylthio]-1H-imidazo[4,5-b]pyridine, which can be oxidized to racemic-5-methoxy-2-[( 3,5-Dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine, another formula (1) compound.

商业用途business use

通式1化合物及其盐和溶剂化物(优选水合物)，以及其盐的溶剂化物(优选水合物)(下文称为“本发明化合物”)有用的药理学性质使其具有商业用途。特别地，它们对胃酸分泌有显著的抑制作用，且对温血动物(特别是人类)的胃肠有极好的保护作用。这里，本发明化合物的特征是：选择性高、有利的作用持续时间、生物利用度特别高，不同个体间的代谢概况一致、没有明显副作用，且治疗谱宽。The useful pharmacological properties of the compounds of general formula 1 and their salts and solvates (preferably hydrates), and solvates of their salts (preferably hydrates) (hereinafter referred to as "compounds of the invention") lend themselves to commercial use. In particular, they have a marked inhibitory effect on gastric acid secretion and an excellent protective effect on the gastrointestinal tract of warm-blooded animals, especially humans. Here, the compounds according to the invention are characterized by a high selectivity, an advantageous duration of action, a particularly high bioavailability, a uniform metabolic profile among different individuals, the absence of significant side effects, and a broad therapeutic spectrum.

在本上下文中，“胃肠保护”应理解为预防和治疗胃肠疾病，特别是胃肠炎症疾病和损伤(例如，胃溃疡、十二指肠溃疡、胃炎、由于产酸增加或药物作用引起的易激肠、GERD、局限性回肠炎、IBD)，引起这些疾病的原因可以是例如微生物(例如幽门螺杆菌)、细菌毒素、药用组合物(例如某些消炎剂和治疗风湿药剂)、化学品(例如乙醇)、胃酸或压力。In this context, "gastrointestinal protection" is understood as the prevention and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and injuries (for example, gastric ulcer, duodenal ulcer, gastritis, irritable bowel, GERD, Crohn's disease, IBD), which can be caused by, for example, microorganisms (such as Helicobacter pylori), bacterial toxins, pharmaceutical compositions (such as certain anti-inflammatory agents and rheumatic agents), Chemicals (such as alcohol), stomach acid, or stress.

在测定抗溃疡和抗分泌性质的各种模型中，令人惊讶地发现，本发明化合物具有优良性质，明显优于现有技术化合物，特别是其药动学性质。这些改善的药动学性质，可以例如减少本发明化合物用于治疗或预防的剂量。或者通过使用与现有技术化合物相同剂量的本发明化合物，可以获得较长的有效时间。与这些性质相关的是有关患者安全性或经济方面(例如，药价等等)的优势。由于这些性质，本发明化合物非常适用于在人用药和兽用药中使用，特别适用于治疗和/或预防胃肠疾病。In various models for determining the antiulcer and antisecretory properties, it was surprisingly found that the compounds of the present invention possess superior properties, significantly superior to those of the prior art, especially their pharmacokinetic properties. These improved pharmacokinetic properties allow, for example, to reduce the therapeutic or prophylactic dosage of the compounds of the invention. Alternatively, a longer effective time can be obtained by using the same dosage of the compounds of the present invention as the compounds of the prior art. Associated with these properties are advantages with regard to patient safety or economic aspects (eg, drug prices, etc.). Due to these properties, the compounds according to the invention are very suitable for use in human and veterinary medicine, especially for the treatment and/or prophylaxis of gastrointestinal diseases.

因此，本发明还提供了本发明化合物用于治疗和/或预防上述疾病的用途。Therefore, the present invention also provides the use of the compounds of the present invention for the treatment and/or prevention of the diseases mentioned above.

本发明还包括本发明化合物制备用于治疗和/或预防上述疾病的药用组合物的用途。The present invention also includes the use of the compounds of the present invention for the preparation of pharmaceutical compositions for the treatment and/or prevention of the above-mentioned diseases.

本发明还提供了含有本发明化合物的药用组合物。特别地，本发明提供了含有其盐形式(特别是钠盐或镁盐形式)，和/或这些盐的水合物形式的式1、1a或1b化合物的口服固体剂型药用组合物。The invention also provides pharmaceutical compositions comprising compounds of the invention. In particular, the present invention provides pharmaceutical compositions in oral solid dosage form comprising compounds of formula 1, 1a or 1b in the form of their salts, especially in the form of sodium or magnesium salts, and/or in the form of hydrates of these salts.

所述药用组合物可以用本领域技术人员熟悉的已知方法来制备。作为药用组合物，本发明化合物可以直接使用，或者优选与适当的药用辅料或载体组合使用，剂型有片剂、包衣片剂、胶囊、栓剂、膏剂(例如作为TTS)、乳剂、悬浮液或溶液，其中活性化合物的含量有利的为约0.1％至约95％，而且通过选择适当的辅料和载体，可以制成适合于活性化合物和/或所需起效时间和/或作用持续时间的药用剂型(例如缓释型或肠溶型)。Said pharmaceutical compositions can be prepared by known methods familiar to those skilled in the art. As a pharmaceutical composition, the compounds of the present invention can be used directly or preferably in combination with suitable pharmaceutical excipients or carriers in the form of tablets, coated tablets, capsules, suppositories, ointments (e.g. as TTS), emulsions, suspensions Liquid or solution, wherein the active compound content is advantageously about 0.1% to about 95%, and by selecting appropriate adjuvants and carriers, it can be made suitable for the active compound and/or the desired onset time and/or duration of action pharmaceutical dosage forms (such as sustained-release or enteric-coated).

适用于所需药用制剂的辅料或载体是本领域技术人员已知的。除了溶剂、凝胶成型剂、栓剂基质、压片辅料及其它用于活性化合物的载体之外，还可以使用例如抗氧剂、分散剂、乳化剂、防沫剂、气味掩盖剂(flavour-masking agents)、防腐剂、增溶剂、着色剂，或者特别地，渗透促进剂和复合物形成剂(例如环糊精)。Adjuvants or carriers suitable for the desired pharmaceutical formulations are known to those skilled in the art. In addition to solvents, gel formers, suppository bases, tableting auxiliaries and other carriers for the active compound, for example antioxidants, dispersants, emulsifiers, antifoams, flavor-masking agents), preservatives, solubilizers, colorants or, in particular, penetration enhancers and complex formers (eg cyclodextrins).

本发明化合物可以口服给药、肠胃外给药或经皮给药。The compounds of the present invention can be administered orally, parenterally or transdermally.

在人用药中，通常已发现，有利的是，本发明化合物口服给药时，日用剂量约0.01至约1毫克/千克体重，优选约0.02至约0.5毫克/千克体重，特别优选约0.04至约0.3毫克/千克体重[以本发明化合物的游离态(即不是盐的形式，＝“游离化合物”)为基础计算]，如果合适，以多个，优选1至4个单剂量的形式给药，以获得所需的效果。对于肠胃外治疗，可以使用相似剂量或者通常更低的剂量(特别当静脉给予活性化合物时)。每种情况下所需的最佳剂量和活性化合物的给药方式，本领域技术人员可容易确定。In human administration, it has generally been found that advantageously, when the compounds of the present invention are administered orally, the daily dose is from about 0.01 to about 1 mg/kg body weight, preferably from about 0.02 to about 0.5 mg/kg body weight, particularly preferably from about 0.04 to about 0.04 mg/kg body weight. About 0.3 mg/kg body weight [calculated on the basis of the compound of the invention in its free state (i.e. not in the form of a salt, = "free compound")], if appropriate, in the form of multiple, preferably 1 to 4, single doses, to get the desired effect. For parenteral treatment, similar dosages or generally lower dosages (particularly when the active compound is administered intravenously) may be used. The optimum dosage and mode of administration of the active compound required in each case can readily be determined by a person skilled in the art.

因此，本发明的另一方面是包含一种或多种本发明化合物和一种或多种常规辅料的药用组合物，其中单剂量包含约2至约60毫克的游离化合物。Accordingly, another aspect of the invention are pharmaceutical compositions comprising one or more compounds of the invention together with one or more conventional excipients, wherein a single dose contains from about 2 to about 60 mg of free compound.

本发明的另一方面是包含一种或多种本发明化合物和一种或多种常规辅料的药用组合物，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the invention are pharmaceutical compositions comprising one or more compounds of the invention together with one or more conventional excipients, wherein a single dose contains from about 4 to about 40 mg of free compound.

本发明的另一方面是本发明化合物用于治疗胃肠疾病的用途。Another aspect of the invention is the use of compounds of the invention for the treatment of gastrointestinal disorders.

本发明的另一方面是本发明化合物治疗为慢代谢者的患者胃肠疾病的用途。Another aspect of the invention is the use of the compounds of the invention for the treatment of gastrointestinal disorders in patients who are poor metabolizers.

本发明的另一方面是本发明化合物治疗有药物相互作用风险的患者胃肠疾病的用途。Another aspect of the invention is the use of compounds of the invention for the treatment of gastrointestinal disorders in patients at risk of drug interactions.

本发明的另一方面是本发明化合物治疗需要长时间抑制酸分泌的患者胃肠疾病的用途。Another aspect of the invention is the use of the compounds of the invention for the treatment of gastrointestinal disorders in patients requiring prolonged suppression of acid secretion.

本发明的另一方面是用于治疗为慢代谢者的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients who are poor metabolizers, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose contains about 2 to about 60 mg of free compound.

本发明的另一方面是用于治疗为慢代谢者的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients who are poor metabolizers, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose contains about 4 to about 40 mg of free compound.

本发明的另一方面是用于治疗有药物相互作用风险的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients at risk of drug interactions, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose contains about 2 to about 60 mg of free compound.

本发明的另一方面是用于治疗有药物相互作用风险的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients at risk of drug interactions, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose contains about 4 to about 40 mg of free compound.

本发明的另一方面是用于治疗需要长时间抑制酸分泌的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients requiring prolonged suppression of acid secretion, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose comprises From about 2 to about 60 mg of free compound.

本发明的另一方面是用于治疗需要长时间抑制酸分泌的患者胃肠疾病的药用组合物，其包含一种或多种本发明化合物和一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients requiring prolonged suppression of acid secretion, comprising one or more compounds of the present invention and one or more conventional excipients, wherein a single dose comprises From about 4 to about 40 mg of free compound.

本发明的另一方面是用于治疗为慢代谢者的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients who are slow metabolizers, comprising one or more salts of the present invention or their hydrates and one or more A conventional excipient, wherein a single dose contains from about 2 to about 60 mg of the free compound.

本发明的另一方面是用于治疗为慢代谢者的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for the treatment of gastrointestinal diseases in patients who are slow metabolizers, comprising one or more salts of the present invention or their hydrates and one or more A conventional excipient, wherein a single dose contains from about 4 to about 40 mg of free compound.

本发明的另一方面是用于治疗有药物相互作用风险的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for treating gastrointestinal diseases in patients at risk of drug interaction, comprising one or more salts or hydrates thereof of the present invention and one or more Various conventional excipients, wherein a single dose contains from about 2 to about 60 mg of free compound.

本发明的另一方面是用于治疗有药物相互作用风险的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for treating gastrointestinal diseases in patients at risk of drug interaction, comprising one or more salts or hydrates thereof of the present invention and one or more Various conventional excipients, wherein a single dose contains from about 4 to about 40 mg of free compound.

本发明的另一方面是用于治疗需要长时间抑制酸分泌的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约2至约60毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for treating gastrointestinal diseases of patients requiring long-term suppression of acid secretion, which comprises one or more salts or hydrates of the present invention and a or various conventional excipients, wherein a single dose contains from about 2 to about 60 mg of the free compound.

本发明的另一方面是用于治疗需要长时间抑制酸分泌的患者胃肠疾病的药用组合物，其口服固体应用剂型中包含一种或多种本发明的盐或其水合物以及一种或多种常规辅料，其中单剂量包含约4至约40毫克的游离化合物。Another aspect of the present invention is a pharmaceutical composition for treating gastrointestinal diseases of patients requiring long-term suppression of acid secretion, which comprises one or more salts or hydrates thereof of the present invention and a or various conventional excipients, wherein a single dose contains from about 4 to about 40 mg of the free compound.

如果本发明化合物用于治疗上述疾病，则药用制剂还可以包含一种或多种来自其它类别药用组合物的药理活性成分。可提及的例子包括镇定剂(例如苯并二氮

类，如安定)、解痉药(例如比坦维林(bietamiverine)或卡米罗芬(camylofine))、抗胆碱能药(例如，羟苄利明或芬卡米特)、局部麻醉剂(例如，丁卡因或普鲁卡因)，任选还包括酶、维生素或氨基酸。If the compounds according to the invention are used in the treatment of the diseases mentioned above, the pharmaceutical preparations may also contain one or more pharmacologically active ingredients from other classes of pharmaceutical compositions. Examples that may be mentioned include tranquilizers (such as benzodiazepines

antispasmodics (such as diazepam), antispasmodics (such as bietamiverine or camylofine), anticholinergics (such as oxybenzidine or fencamid), local anesthetics (such as , tetracaine or procaine), optionally further comprising enzymes, vitamins or amino acids.

在本上下文中，特别强调本发明化合物与起到缓冲或中和胃酸或者抑制酸分泌作用的其它药品的组合，例如抗酸剂(如氢氧化镁铝)或H2阻断剂(如西咪替丁、雷尼替丁)，以及与胃泌素拮抗剂的组合，以附加或超加地增强主要作用和/或消除或减少副作用或者起效更快。还有与NSAID(例如，依托芬那酯、双氯芬酸、吲哚美辛、布洛芬或吡罗昔康)的固定或自由组合，以防止由NSAID引起的胃肠损伤，或者与改变胃肠动力的化合物固定或自由组合，或者与降低一过性下食管括约肌松弛(TLOSR)发生率的化合物固定或自由组合，或者与抗菌药(例如头孢菌素、四环素、青霉素、大环内酯类、硝基咪唑或铋盐)固定或自由组合以控制幽门杆菌。可作为抗菌组合部分的包括，例如美洛西林、氨苄西林、阿莫西林、头孢噻吩、头孢西丁、头孢噻肟、亚胺培南、庆大霉素、阿米卡星、红霉素、环丙沙星、甲硝唑、克拉霉素、阿奇霉素及其组合物(例如克拉霉素+甲硝唑或者阿莫西林+克拉霉素)。In this context, particular emphasis is given to combinations of the compounds of the invention with other medicinal products that buffer or neutralize gastric acid or inhibit acid secretion, such as antacids (such as magnesium aluminum hydroxide) or H2 blockers (such as cimetidine dinidine, ranitidine), and combinations with gastrin antagonists to additionally or superadditively enhance the main effect and/or eliminate or reduce side effects or have a faster onset of action. There is also fixed or liberal combination with NSAIDs (eg, etofenamate, diclofenac, indomethacin, ibuprofen, or piroxicam) to prevent gastrointestinal injury caused by NSAIDs, or with compounds that alter gastrointestinal motility Fixed or free combination, or fixed or free combination with compounds that reduce the incidence of transient lower esophageal sphincter relaxation (TLOSR), or with antimicrobials (eg, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or bismuth salts) fixed or free combination to control pylori. Examples that may be part of antimicrobial combinations include, for example, mezlocillin, ampicillin, amoxicillin, cefalotin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, Ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof (eg, clarithromycin + metronidazole or amoxicillin + clarithromycin).

实施本发明时，在组合治疗中，本发明化合物可与上述一种或多种标准治疗药物分开、连续、同时或按时间顺序交错地给予(例如，作为组合的单位剂型、作为分开的单位剂型、作为邻近的不连续的单位剂型、作为固定或非固定的组合、作为组成的药盒(kit-of-parts)或者作为混合物)。In practicing the present invention, in combination therapy, the compounds of the present invention may be administered separately, sequentially, simultaneously or chronologically staggered with one or more of the aforementioned standard therapeutic agents (e.g., as a combined unit dosage form, as a separate unit dosage form , as contiguous discrete unit dosage forms, as a fixed or non-fixed combination, as a kit-of-parts or as a mixture).

本发明的术语“组合”可以是固定组合、非固定组合或组成的药盒(kit-of-parts)。The term "combination" of the present invention may be a fixed combination, a non-fixed combination or a kit-of-parts.

“固定组合”被定义为一种组合，其中第一活性成分和第二活性成分一起存在于一个单位制剂或单个实体中。“固定组合”的一个例子是一种药用组合物，其中所述第一活性成分和所述第二活性成分存在于同时给药的混合物(如制剂)中。“固定组合”的另一个例子是一种药用组合物，其中所述第一活性成分和所述第二活性成分存在于一个单位中但不混合。A "fixed combination" is defined as a combination wherein a first active ingredient and a second active ingredient are present together in a unit formulation or single entity. An example of a "fixed combination" is a pharmaceutical composition wherein said first active ingredient and said second active ingredient are present in admixture (eg, formulation) administered simultaneously. Another example of a "fixed combination" is a pharmaceutical composition wherein said first active ingredient and said second active ingredient are present in one unit but not mixed.

“组成的药盒”被定义为一种组合，其中所述第一活性成分和所述第二活性成分存在于一个以上单位中。“组成的药盒”的一个例子是一种组合，其中所述第一活性成分和所述第二活性成分分开存在。组成的药盒的组份可以分开、连续、同时或按时间顺序交错地给予。A "kit of parts" is defined as a combination wherein said first active ingredient and said second active ingredient are present in more than one unit. An example of a "kit of parts" is a combination wherein said first active ingredient and said second active ingredient are present separately. The components of the kit of parts may be administered separately, serially, simultaneously or chronologically staggered.

药理学Pharmacology

肝微粒体中的代谢Metabolism in liver microsomes

材料和方法Materials and methods

将泮托拉唑或实施例1或2(各10μM)与肝微粒体(来源：除迷你猪(Mini Pig)来自TEBU之外，都来自GenTest)保温，在1毫克/毫升蛋白、100mM Tris-HCl、pH7.4、1mM NADPH₂的条件下保温。90分钟后用液氮终止反应，用HPLC检测母体化合物(10mM KH₂PO₄，pH 7.4，乙腈梯度20至44％)。Pantoprazole or Example 1 or 2 (10 μ M each) was incubated with liver microsomes (source: all from GenTest except that Mini Pig (Mini Pig) was from TEBU) at 1 mg/ml protein, 100 mM Tris- Incubate under the conditions of HCl, pH7.4, 1mM NADPH₂ . After 90 minutes the reaction was stopped with liquid nitrogen and the parent compound was detected by HPLC (10 mM_KH2PO4 , pH_7.4 ,acetonitrile gradient 20 to 44%).

表1：Table 1:

保温90分钟后，微粒体代谢H-泮托拉唑和代谢氘化化合物(实施例1或2)的比较(种属依赖性)After incubation for 90 minutes, the comparison (species dependence) of microsome metabolism H-pantoprazole and metabolism deuterated compound (embodiment 1 or 2)

代谢清除率metabolic clearance

为了评估本发明化合物的性质，测定了重组人细胞色素P450(CYP)同工酶CYP1A2、CYP2C8、CYP2C19、CYP2D6、CYP3A4和CYP3A5中化合物的内在清除率。In order to evaluate the properties of the compounds of the invention, the intrinsic clearance of the compounds in the recombinant human cytochrome P450 (CYP) isozymes CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 was determined.

材料和方法Materials and methods

在37℃下，将实施例17、19、20、21、27、28、38、39、40和41中所述化合物、非氘化的外消旋奥美拉唑及其(S)-对映体和非氘化的泮托拉唑及其对映体在含有1nmol/mL重组P450(Cypex，Dundee，UK)、4mg/mL微粒体蛋白、100mMol/L Tris-HCl(pH7.4)和1mMol/LNADPH的缓冲液中保温0、3、6、12和15或30分钟。保温一式三份。对于与CYP2C19的保温，P450浓度降低至0.5nmol/mL，且保温间隔改为0、1、2、3、4和5分钟。基于母体化合物的消失速率来测定内在清除率。用HPLC-UV测定奥美拉唑和氘化同类物。基于试验变异性的检测分辨率(resolution)的低限为17.6μl/min/nmol P450。At 37°C, the compounds described in Examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41, non-deuterated racemic omeprazole and their (S)-pair Enantiomers and non-deuterated pantoprazole and its enantiomers in the presence of 1nmol/mL recombinant P450 (Cypex, Dundee, UK), 4mg/mL microsomal protein, 100mMol/L Tris-HCl (pH7.4) and 1mMol/LNADPH buffer for 0, 3, 6, 12 and 15 or 30 minutes. Insulate in triplicate. For incubations with CYP2C19, the P450 concentration was reduced to 0.5 nmol/mL, and the incubation intervals were changed to 0, 1, 2, 3, 4, and 5 minutes. Intrinsic clearance was determined based on the rate of disappearance of the parent compound. Determination of omeprazole and deuterated congeners by HPLC-UV. The lower limit of detection resolution based on assay variability was 17.6 μl/min/nmol P450.

结果result

发现CYP2C19和CYP3A4有助于奥美拉唑、泮托拉唑及其氘化同类物的氧化代谢。其它所有细胞色素P450同工酶(CYP1A2、CYP2C8、CYP2C9、CYP2D6、CYP3A5)对高于检测分辨率低限的任何研究化合物的代谢没有帮助。CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of omeprazole, pantoprazole, and their deuterated congeners. All other cytochrome P450 isozymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the investigated compounds above the lower limit of detection resolution.

奥美拉唑5-羟基-奥美拉唑和5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫Omeprazole 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-thio酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑)的形成动力学Formation Kinetics of Acidyl-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole)

在用P450酶评估本发明化合物的代谢清除率后，测定在人体中确定的主要代谢物的形成动力学，即对于奥美拉唑，测定5-羟基-奥美拉唑(5-甲氧基)-2-[[(4-甲氧基-3-甲基-5-羟基甲基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑)，而对于泮托拉唑，测定5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑。主要通过CYP2C19形成5-羟基-奥美拉唑和5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑)。我们选择混合的(pooled)冻存人肝细胞作为比人肝微粒体更高级的体外系统，因为所有的主要药物代谢酶(第I阶段、第II阶段、水解酶)在这个体外系统中都是起作用的。After assessing the metabolic clearance of the compounds of the invention with P450 enzymes, the kinetics of formation of the major metabolites identified in humans were determined, i.e. for omeprazole, 5-hydroxy-omeprazole (5-methoxy )-2-[[(4-methoxy-3-methyl-5-hydroxymethyl-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole), and for pantolar Azole, determination of 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole. Formation of 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfato-2-pyridyl)-methyl]sulfinyl mainly via CYP2C19 Acyl]-1H-benzimidazole). We chose pooled cryopreserved human hepatocytes as a higher-order in vitro system than human liver microsomes because all major drug-metabolizing enzymes (phase I, phase II, hydrolytic enzymes) are effective.

材料和方法Materials and methods

将实施例17、19、20、21、27、28、38、39、40和41中所述化合物、非氘化的外消旋奥美拉唑及其(S)-对映体和非氘化的泮托拉唑及其对映体在含有84μg/mL阿米卡星、1mMol/L氯化钙、20mMol/LHepes、4.2μMol/L hepatonic酸(hepatonic acid)、28.5mMol/L碳酸氢钠和浓度为10⁶细胞/mL的人冻存肝细胞(10供者库(donor pool)，InVitro Technologies，Baltimore，MD USA)的Krebs HenseleitPuffer(KHB)中保温。在这些条件下5-羟基-奥美拉唑和5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑(M2)的形成速率成线性直至60分钟。测定了在37℃一式两份保温60分钟的10个不同化合物浓度(0、1.0、2.5、5.0、10.0、25.0、50.0、100、200和2500μMol/L)下的5-羟基-奥美拉唑形成速率。测定了在37℃一式两份保温60分钟的9个不同化合物浓度(0、0.5、1.0、2.5、5.0、10.0、25.0、50.0和100μMol/L)下的5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑(M2)形成速率。用LC-MS/MS对5-羟基-奥美拉唑进行定量。5-羟基-奥美拉唑由Ramidius AB，Lund，Sweden获得，从人尿中分离出的5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑(M2)用作外标。用Michaelis-Menten方程通过非线性回归分析，获得达半数最大形成速率的浓度(K_M-值)和最大形成速率(V_max)。用V_max除以K_M得到内在清除率(Cl_int)。Compounds described in Examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41, non-deuterated racemic omeprazole and its (S)-enantiomer and non-deuterated The pantoprazole and its enantiomers containing 84μg/mL amikacin, 1mMol/L calcium chloride, 20mMol/LHepes, 4.2μMol/L hepatonic acid (hepatonic acid), 28.5mMol/L sodium bicarbonate It was incubated with Krebs Henseleit Puffer (KHB) of human cryopreserved hepatocytes (donor pool, InVitro Technologies, Baltimore, MD USA) at a concentration of 10⁶ cells/mL. Under these conditions 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfato-2-pyridyl)-methyl]sulfin The rate of formation of acyl]-1H-benzimidazole (M2) was linear up to 60 min. 5-Hydroxy-omeprazole was determined at 10 different compound concentrations (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100, 200 and 2500 μMol/L) incubated in duplicate at 37°C for 60 minutes. rate of formation. The 5-(difluoromethoxy)- 2-[[(3-Methoxy-4-sulfato-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2) formation rate. 5-Hydroxy-omeprazole was quantified by LC-MS/MS. 5-Hydroxy-omeprazole was obtained from Ramidius AB, Lund, Sweden, 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfatyl- 2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2) was used as external standard. The concentration up to the half-maximal formation rate (K_M -value) and the maximum formation rate (V_max ) were obtained by nonlinear regression analysis using the Michaelis-Menten equation. Intrinsic clearance (Cl_int ) was obtained by dividing V_max by K_M .

结果result

与非氘化奥美拉唑相比，实施例39和40(两者在4-甲氧基-吡啶基位上都被氘化)形成速率降低了约1.5倍。外消旋[¹H]、[²H₃]和[²H₆]奥美拉唑同类物的K_M值之间没有超过实验变异性的差异(图1)。实施例40观察到5-羟基-奥美拉唑的形成速率降低，但令人惊讶的是实施例38没有观察到(图1)。而且，在4-甲氧基-吡啶基位上氘化的[²H₃]奥美拉唑(实施例40)和另外在5-甲氧基-苯并咪唑位上氘化的[²H₆]奥美拉唑(实施例41，图3)的形成速率之间没有差别。由外消旋[¹H]奥美拉唑和由其(S)-对映体形成5-羟基-奥美拉唑，显示有立体特异性差异，这是由于外消旋和(S)-奥美拉唑的K_M和V_max值之间的差异超过了实验变异性。(S)-奥美拉唑的4-甲氧基-吡啶基和5-甲氧基-苯并咪唑位上6个[¹H]原子被[²H]原子取代(实施例41)，并没有改变5-羟基-奥美拉唑的内在清除率(Cl_int)(图3)。The rate of formation of Examples 39 and 40 (both deuterated at the 4-methoxy-pyridyl position) was reduced by about 1.5 times compared to non-deuterated omeprazole. The_KM values for the racemic [¹ H], [² H₃ ], and [² H₆ ] omeprazole congeners did not differ beyond experimental variability (Figure 1). A reduced rate of formation of 5-hydroxy-omeprazole was observed for Example 40, but surprisingly not for Example 38 (Figure 1). Furthermore, [² H₃ ]omeprazole deuterated at the 4-methoxy-pyridyl position (Example 40) and [² H₆ ] There was no difference between the formation rates of omeprazole (Example 41, Figure 3). The formation of 5-hydroxy-omeprazole from racemic [¹ H]omeprazole and from its (S)-enantiomer showed stereospecific differences due to racemic and (S)- The difference between the_KM and_Vmax values of omeprazole exceeds the experimental variability. 6^{[ 1 H] atoms on the 4-methoxy-pyridyl and 5-methoxy-benzimidazole positions of (S)-omeprazole are replaced by [ 2H} ] atoms (Example 41), and The intrinsic clearance (Cl_int ) of 5-hydroxy-omeprazole was not altered (Figure 3).

由泮托拉唑、其对映体和实施例17、19、20、21、27和28中所述化合物形成5-(二氟甲氧基)-2-[[(3-甲氧基-4-硫酸基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑(M2)，显示出受到高于100μM底物浓度的抑制。因此，将100和250μM底物浓度的保温数据排除在K_m和V_max的计算之外。由外消旋[¹H]泮托拉唑和对映体形成M2，显示有立体特异性差异(图2A)。与其非氘化的对应物相比，在4-甲氧基-吡啶基位上氘化的外消旋、(R)和(S)-同类物(实施例19、27和28)显示形成速率至少减少至2.5分之一(图2B)。与其非氘化的对应物相比，在4-甲氧基-吡啶基位上氘化的外消旋、(R)和(S)-同类物(实施例19、27和28)的内在清除率至少减少至4.7分之一(表2)。从[¹H]泮托拉唑同类物观察到的M2形成速率的立体特异性差异没有4-甲氧基-吡啶基位上氘化的同类物显著(图2B)。令人惊讶的是，与非氘化化合物相比，M2形成速率的降低显示出依赖于三氘化甲氧基在分子吡啶基部分中的位置(图4)。增加分子中4-甲氧基-吡啶基位上被[²H]原子取代的[¹H]原子数目([¹H]、[²H₁]实施例21，[²H₂]实施例20以及[²H₃]实施例19)，可降低M2的形成速率。Formation of 5-(difluoromethoxy)-2-[[(3-methoxy- 4-Sulfato-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2), showed inhibition by substrate concentrations above 100 μM. Therefore, the incubation data for 100 and 250 μM substrate concentrations were excluded from the calculation of_Km and_Vmax . Formation of M2 from racemic [¹ H]pantoprazole and the enantiomers showed stereospecific differences (Fig. 2A). The racemic, (R) and (S)-congeners deuterated at the 4-methoxy-pyridyl position (Examples 19, 27 and 28) show rates of formation compared to their non-deuterated counterparts At least to a factor of 2.5 (Fig. 2B). Intrinsic clearance of racemic, (R) and (S)-congeners (Examples 19, 27 and 28) deuterated at the 4-methoxy-pyridyl position compared to their non-deuterated counterparts rate was reduced to at least one in 4.7 (Table 2). The stereospecific difference in the rate of M2 formation observed from the [¹ H]pantoprazole congeners was less significant than that of the deuterated congeners at the 4-methoxy-pyridyl position ( FIG. 2B ). Surprisingly, the reduction in the rate of M2 formation was shown to be dependent on the position of the trideuterated methoxy group in the pyridyl portion of the molecule compared to non-deuterated compounds (Figure 4). Increase the number of [¹ H] atoms replaced by [ 2 H] atoms on the 4-methoxy-pyridyl position in the molecule^{([ 1 H], [ 2 H 1 ] Example 21, [ 2H2}_]^Example₂₀ and [² H₃ ] (Example 19), can reduce the formation rate of M2.

表2：Table 2:

与泮托拉唑和本发明化合物保温而获得的混合(pooled)人肝细胞中的内在清除率(Cl_int)。Intrinsic clearance (Cl_int ) in pooled human hepatocytes obtained from incubation with pantoprazole and compounds of the invention.

Claims (13)

1. method of producing general formula 1 compound and pharmacy acceptable salt thereof,

Wherein

R1 is hydrogen or 1-4C-alkoxyl group

R2 is the 1-4C-alkyl

R3 is 1-4C-alkyl, 1-4C-alkoxyl group or 2-8C-alkoxyl group alkoxyl group

R4 is hydrogen or 1-4C-alkyl

Z is C-H or N

Wherein, at least one Wasserstoffatoms is replaced by D atom in any combination of R1, R2, R3, R4 or R1, R2, R3 and R4,

Said method comprises the step of oxidation general formula 2 compounds,

Wherein, R1, R2, R3, R4 and Z as stated, and

The 1-4C-alkoxyl group representes except that Sauerstoffatom, also to comprise one of them group of 1-4C-alkyl or fluoro 1-4C-alkyl.

2. the process of claim 1 wherein that the preparation method of general formula 2 compounds is following: general formula 3 compounds are quaternized,

Wherein

X is halogen or is pure activated derivatives

R2 is the 1-4C-alkyl

R3 is 1-4C-alkyl, 1-4C-alkoxyl group or 2-8C-alkoxyl group alkoxyl group

R4 is hydrogen or 1-4C-alkyl

Wherein at least one Wasserstoffatoms is replaced by D atom in any combination of R2, R3, R4 or R2, R3 and R4,

Make quaternized general formula 3 compounds and the reaction of general formula 4 compounds of gained then

Wherein R1 and Z in the claim 1 definition.

3. the method for claim 2, wherein X is iodine, bromine, fluorine or chlorine.

4. the method for claim 2, wherein X is a chlorine.

5. the method for claim 2, wherein X is the activated derivatives that is selected from the alcohol of alkylsulphonic acid base, aryl sulfonic acid groups or perfluoroalkane sulfonate base.

6. claim 1 or 2 method, wherein R3 is three deuterate methoxyl groups.

7. claim 1 or 2 method, wherein R3 is two deuterate methoxyl groups.

8. each method in the claim 1 to 5, wherein R2 is a methyl, R3 is a methoxyl group, 2,2,2-trifluoro ethoxy or methoxy propoxy, R4 is hydrogen or methyl, and wherein among the R3 at least one Wasserstoffatoms replaced by D atom.

9. the method for claim 5, wherein all Wasserstoffatomss are replaced by D atom among the R3.

10. each method in the claim 1 to 5, wherein at least one Wasserstoffatoms is replaced by D atom among the R3, and R3 is 1-2C alkoxyl group or 2-5C-alkoxyl group alkoxyl group.

11. the process of claim 1 wherein that R1 is hydrogen or methoxyl group, R2 is a methyl, R3 is a methoxyl group, 2,2,2-trifluoro ethoxy or methoxy propoxy, R4 is hydrogen or methyl, and wherein among the R3 at least one Wasserstoffatoms replaced by D atom.

12. the method for claim 5, wherein R3 is a methoxyl group, 2,2,2-trifluoro ethoxy or methoxy propoxy, and wherein among the R3 all Wasserstoffatomss replaced by D atom.

13. the process of claim 1 wherein that R1 is hydrogen or methoxyl group, R2 is a methyl, R3 is a methoxyl group, 2,2,2-trifluoro ethoxy or methoxy propoxy, R4 is hydrogen or methyl, and wherein among the R3 all Wasserstoffatomss replaced by D atom.

Images