本發明係關於同位素取代之質子泵抑制劑及其(R)－與(S)－對映異構體。該等化合物可用於醫藥工業中用於製備醫藥組合物。This 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.
吡啶－2－基甲基亞磺醯基－1H－苯并咪唑(例如彼等自例如歐洲專利第EP－A－0005129號、歐洲專利第EP－A－0166287號、歐洲專利第EP－A－0174726號、歐洲專利第EP－A－0254588號及歐洲專利第EP－A－0268956號中熟知者)之H＋/K＋－腺苷三磷酸酶(ATPase)抑制作用使得其在治療與胃酸分泌增加有關之疾病方面佔有相當重要的地位。Pyridin-2-ylmethylsulfinyl-1H-benzimidazole (for example, from, for example, European Patent No. EP-A-0005129, European Patent No. EP-A-0166287, European Patent No. EP-A- The inhibition of H+ /K+ -adenosine triphosphatase (ATPase) in the treatment and gastric acid secretion is known from the European Patent No. EP-A-0254588 and the European Patent No. EP-A-0268956. It has a very important position in increasing the related diseases.
已市售或處於臨床研製階段的該類化合物中的活性化合物實例係5－甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(INN：奧美派唑(omeprazole))、(S)－5－甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(INN：伊索派唑(esomeprazole))、5－二氟甲氧基－2－[(3,4－二甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(INN：泛託派唑(pantoprazole))、2－[3－甲基－4－(2,2,2－三氟乙氧基)－2－吡啶基]甲基亞磺醯基]－1H－苯并咪唑(INN：南索派唑(lansoprazole))、2－{[4－(3－甲氧基丙氧基)－3－甲基吡啶－2－基]甲基亞磺醯基}－1H－苯并咪唑(INN：雷貝派唑(rabeprazole))及5－甲氧基－2－((4－甲氧基－3,5－二甲基－2－吡啶基甲基)亞磺醯基)－1H－咪唑并[4,5－b]吡啶(INN：替那派唑(tenatoprazole))。Examples of active compounds in such compounds which are commercially available or in clinical development are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl Sulfhydryl]-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)methylsulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoro) Ethoxy)-2-pyridyl]methylsulfinyl]-1H-benzimidazole (INN: lansoprazole), 2-{[4-(3-methoxypropoxy) )-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-A) Oxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl)-1H-imidazo[4,5-b]pyridine (INN: tenatoprazole).
上述亞磺醯基衍生物由於其作用機理亦稱為質子泵抑制劑或簡稱為PPI。The above sulfinamide derivatives are also referred to as proton pump inhibitors or simply PPIs due to their mechanism of action.
美國專利第6,818,200號揭示二氫吡啶化合物及抗生素，其中至少一個氫原子被一氘原子取代。該等氘代化合物係藉由H－形式與氧化氘與一適宜觸媒之混合物在密封容器中在苛刻的反應條件(即高溫(60－80℃)下且長反應時間(長達190小時)下反應來獲得。其進一步揭示因H/D交換對該等化合物之醫藥性質的一些影響。U.S. Patent No. 6,818,200 discloses dihydropyridine compounds and antibiotics in which at least one hydrogen atom is replaced by a ruthenium atom. The deuterated compounds are subjected to harsh reaction conditions (ie, high temperature (60-80 ° C) and long reaction time (up to 190 hours) in a sealed vessel by a mixture of H-form and cerium oxide and a suitable catalyst. The next reaction is obtained, which further reveals some of the effects of the H/D exchange on the pharmaceutical properties of the compounds.
現在，令人驚奇地發現，同位素取代之化合物(如下文詳細闡述者)明顯影響胃酸分泌的抑制。It has now surprisingly been found that isotopically substituted compounds (as detailed below) significantly affect the inhibition of gastric acid secretion.
本發明係關於式1化合物，
1－4C－烷基代表具有1至4個碳原子的直鏈或具支鏈烷基。其可提及實例係丁基、異丁基、第二丁基、第三丁基、丙基、異丙基、乙基且較佳甲基。1-4C-alkyl represents a straight or branched alkyl group having 1 to 4 carbon atoms. Mention may be made, by way of example, of butyl, isobutyl, tert-butyl, tert-butyl, propyl, isopropyl, ethyl and preferably methyl.
1－4C－烷氧基代表一個基團，其除氧原子外還包含以上提及之1－4C－烷基基團或氟代1－4C－烷基中之一。可提及之1－4C－烷氧基實例係丁氧基、異丁氧基、第二丁氧基、第三丁氧基、丙氧基、異丙氧基、乙氧基且較佳係甲氧基。氟代1－4C－烷基之實例係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、且較佳係2,2,2－三氟乙基及二氟甲基。The 1-4C-alkoxy group represents a group which, in addition to the oxygen atom, further comprises one of the above-mentioned 1-4C-alkyl group or fluoro1-4C-alkyl group. Examples of 1-4C-alkoxy groups which may be mentioned are butoxy, isobutoxy, second butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and preferably Methoxy. Examples of fluoro-4-C-alkyl 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－烷氧基烷氧基代表一個基團，其除氧原子外還包含一個含1－4C伸烷基之內部伸烷基及一個末端烷基，末該端烷基包含1－4C烷基且係藉由一氧原子連接至該內部伸烷基基團。實例係甲氧基甲氧基、甲氧基乙氧基、乙氧基甲氧基、乙氧基丙氧基、乙氧基異丙氧基、異丙氧基甲氧基、丙氧基甲氧基、甲氧基丁氧基、甲氧基異丁氧基、丙氧基乙氧基、異丙氧基乙氧基、丙氧基丙氧基、異丙氧基異丙氧基、異丙氧基丙氧基、丙氧基異丙氧基、乙氧基丁氧基、乙氧基異丁氧基、乙氧基－第二－丁氧基、乙氧基－第三－丁氧基且較佳甲氧基丙氧基。2-8C-Alkoxyalkoxy represents a group which, in addition to the oxygen atom, further comprises an internal alkyl group having a 1-4C alkylene group and a terminal alkyl group, and the terminal alkyl group comprises 1-4C. The alkyl group is attached to the internal alkyl group by an oxygen atom. Examples are methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy, propoxy Oxyl, methoxybutoxy, methoxyisobutoxy, propoxyethoxy, isopropoxyethoxy, propoxypropoxy, isopropoxyisopropoxy, iso Propoxypropoxy, propoxyisopropoxy, ethoxybutoxy, ethoxyisobutoxy, ethoxy-second-butoxy, ethoxy-third-butoxy More preferably, it is a methoxypropoxy group.
根據本發明，所有與無機及有機鹼形成之鹽皆涵蓋於鹽含義之範圍內，尤其是具有鹼金屬之鹽(例如，鋰、鈉及鉀鹽)或鹼土金屬鹽(例如，鎂及鈣鹽)，但亦包括其他藥理學上可接受的鹽(例如鋁或鋅鹽)。尤其較佳者係鈉及鎂鹽。According to the invention, all salts formed with inorganic and organic bases are encompassed within the meaning of the salt, especially those having an alkali metal (for example, lithium, sodium and potassium salts) or alkaline earth metal salts (for example, magnesium and calcium salts). ), but also includes other pharmacologically acceptable salts (such as aluminum or zinc salts). Particularly preferred are sodium and magnesium salts.
最初可作為(例如)以工業規模生產本發明化合物中的過程產物獲得的藥理學上不可接受的鹽亦屬於本發明之範圍，該等鹽可藉由熟習此項技術者已知的方法轉變成藥理學上可接受的鹽用於生產醫藥。Pharmacologically unacceptable salts which are initially obtainable, for example, as a process product in the production of a compound of the invention on an industrial scale, are also within the scope of the invention, which salts can be converted into a medicament by methods known to those skilled in the art. A physiologically acceptable salt is used in the manufacture of medicine.
熟諳此項技術者知道，若本發明化合物及其鹽係以(例如)晶體形式分離，則其可包含不同量的溶劑。因此，本發明亦涵蓋式1化合物之所有溶合物且尤其所有水合物，並亦涵蓋式1化合物鹽的所有溶合物且尤其所有水合物。所有獲得該等溶合物之醫藥上可接受之溶劑皆涵蓋於溶合物含義之範圍內。Those skilled in the art will recognize that if the compounds of the invention and their salts are separated, for example, in crystalline form, they may contain varying amounts of solvent. Accordingly, the invention also encompasses all solvates of the compounds of formula 1 and especially all hydrates, and also covers all solvates of the salts of the compounds of formula 1 and especially all hydrates. All pharmaceutically acceptable solvents for obtaining such solvates are encompassed within the meaning of the lysate.
提及該等化合物之命名時，本發明術語「氘(deutero)或氘代(deuterio)」係指一個氘原子([2H])。同樣，前置詞語「雙」或「二」及「三」或「叁」分別表示在一個給定基團中存在二或三個(例如)氘原子，即，1,1－二氘代－2,2,2－三氟乙氧基或三氘代甲氧基。Naming reference to such compounds, of the present invention, the term "deuterium (the deutero) or deuterated (deuterio)" means a deuterium atom([2 H]). Similarly, the prefixes "double" or "two" and "three" or "叁" mean that there are two or three (for example) germanium atoms in a given group, ie, 1,1-diode-2. 2,2-Trifluoroethoxy or tridecyl methoxy.
在本發明之範圍內較佳者係式1其中R3的至少一個氫原子被一個氘原子取代且R3係1－2C烷氧基基團或2－5C－烷氧基烷氧基基團之化合物。Preferred among the scope of the present invention are those wherein at least one hydrogen atom of R3 is substituted by one deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C-alkoxy alkoxy group. .
較佳者係式1其中R2為1－4C烷基基團且R3為2－8C－烷氧基烷氧基之化合物，其中R2、R3或R2與R3的至少一個氫原子被一個氘原子取代。Preferred is a compound wherein R 2 is a 1-4C alkyl group and R 3 is a 2-8C-alkoxy alkoxy group, wherein at least one hydrogen atom of R 2 , R 3 or R 2 and R 3 is substituted by a halogen atom .
較佳者係式1其中R1為1－4C烷氧基基團、R2與R4係1－4C烷基基團且R3為1－4C－烷氧基基團之化合物，其中R1、R3、R4或R1、R3與R4的任一組合的至少一個氫原子被一個氘原子取代。Preferred are compounds wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl group and R3 is a 1-4C-alkoxy group, wherein R1, R3, R4 Or at least one hydrogen atom of any combination of R1, R3 and R4 is substituted by one deuterium atom.
較佳者亦係式1其中R1為氫、甲氧基或二氟甲氧基、R2為甲基或甲氧基、R3為甲氧基、2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或甲基且其中R3的至少一個氫原子被一個氘原子取代之化合物。Preferred is also Formula 1 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or A A oxypropoxy group, a compound wherein R4 is hydrogen or methyl and wherein at least one hydrogen atom of R3 is substituted by a deuterium atom.
較佳者進一步係式1其中R2為甲基、R3為甲氧基丙氧基且Z係C－H之化合物，其中R2、R3或R2及R3的至少一個氫原子被一個氘原子取代。Further preferred are compounds of the formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is C-H, wherein at least one hydrogen atom of R2, R3 or R2 and R3 is substituted by a deuterium atom.
較佳者進一步係式1其中R1為甲氧基，R2與R4為甲基且R3為甲氧基之化合物，其中R1、R3、R4或R1、R3及R4的任一組合的至少一個氫原子被一個氘原子取代。可能組合係R1與R3、R1與R4、R3與R4、R1與R3及R4。Further preferred is a compound wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy, wherein R1, R3, R4 or at least one hydrogen atom of any combination of R1, R3 and R4 Replaced by a helium atom. It is possible to combine R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
較佳者亦係式1其中R1為甲氧基、R2為甲基、R3為甲氧基、R4為甲基或其中R1為氫、R2為甲基、R3為2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或其中R1為二氟甲氧基、R2為甲氧基、R3為甲氧基、R4為氫且其中R3的至少一個氫原子被一個氘原子取代之化合物。Preferably, R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, and 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 of R3 is a hydrazine Atom-substituted compound.
較佳者進一步係式1其中R1為甲氧基、R2為甲基、R3為甲氧基、R4為甲基或其中R1為氫、R2為甲基、R3為2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或其中R1為二氟甲氧基、R2為甲氧基、R3為甲氧基、R4為氫且其中R3的至少兩個氫原子被一個氘原子取代之化合物。Preferred is further wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, and 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 two hydrogen atoms of R3 are A compound substituted with a halogen atom.
更佳者係式1其中R2為1－4C烷基基團且R3為2－8C－烷氧基烷氧基基團之化合物，其中R2、R3或R2與R3的所有氫原子皆被氘原子取代。More preferably, the compound of formula 1 wherein R 2 is a 1-4C alkyl group and R 3 is a 2-8C-alkoxy alkoxy group, wherein all hydrogen atoms of R 2 , R 3 or R 2 and R 3 are deuterated atoms Replace.
更佳者係式1其中R1為1－4C烷氧基基團、R2與R4為1－4C烷基基團且R3為1－4C－烷氧基基團之化合物，其中R1、R3、R4或R1、R3及R4的任一組合的所有氫原子皆被氘原子取代。可能組合係R1與R3、R1與R4、R3與R4、R1與R3及R4。More preferably, the compound of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl group and R3 is a 1-4C-alkoxy group, wherein R1, R3, R4 Or all hydrogen atoms of any combination of R1, R3 and R4 are replaced by deuterium atoms. It is possible to combine R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
更佳者係式1其中R3的所有氫原子皆被氘原子取代且其中R3為甲氧基、2,2,2－三氟乙氧基或甲氧基丙氧基之化合物。More preferred are compounds wherein all of the hydrogen atoms of R3 are replaced by deuterium atoms and wherein R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.
更佳者進一步係式1其中R2為甲基、R3為甲氧基丙氧基且Z係C－H之化合物，其中R2、R3或R2與R3的所有氫原子皆被氘原子取代。More preferably, the compound of formula 1 wherein R2 is methyl, R3 is methoxypropoxy, and Z is C-H, wherein all of the hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
更佳者進一步係式1其中R1為甲氧基、R2與R4為甲基且R3為甲氧基之化合物，其中R1、R3、R4或R1、R3及R4的任一組合的所有氫原子皆被氘原子取代。可能組合係R1與R3、R1與R4、R3與R4、R1與R3及R4。More preferably further compounds of the formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy, wherein all of the hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and R4 are Replaced by helium atoms. It is possible to combine R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
更佳者亦係式1其中R1為氫、甲氧基或二氟甲氧基、R2為甲基或甲氧基、R3為甲氧基、2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或甲基且其中R3的所有氫原子皆被氘原子取代之化合物。More preferably, R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or A A compound which is oxypropoxy, R4 is hydrogen or methyl and wherein all of the hydrogen atoms of R3 are replaced by deuterium atoms.
更佳者亦係式1其中R1為甲氧基、R2為甲基、R3為甲氧基、R4為甲基或其中R1為氫、R2為甲基、R3為2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或其中R1為二氟甲氧基、R2為甲氧基、R3為甲氧基、R4為氫且其中R3的所有氫原子被氘原子取代之化合物。More preferably, R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, and 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 all hydrogen atoms of R3 are replaced by deuterium atoms Compound.
最佳者係以下化合物：5－甲氧基－2－[(4－三氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－甲氧基－2－[(4－二氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－三氘代甲氧基－2－[(4－三氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－三氘代甲氧基－2－[(4－二氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－甲氧基－2－[(3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－三氘代甲氧基－2－[(3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、2－[3－甲基－4－(1，1－二氘代－2，2，2－三氟乙氧基)－2－吡啶基]甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3－三氘代甲氧基－4－甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3－二氘代甲氧基－4－甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、5－二氟甲氧基－2－[(3,4－雙(二氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、2－{[4－(3－三氘代甲氧基六氘代丙氧基)－3－甲基吡啶－2－基]甲基亞磺醯基}－1H－苯并咪唑、2－{[4－(3－三氘代甲氧基六氘代丙氧基)－3－三氘代甲基吡啶－2－基]甲基亞磺醯基}－1H－苯并咪唑、5－甲氧基－2－((4－三氘代甲氧基－3,5－二甲基－2－吡啶基甲基)亞磺醯基)－1H－咪唑并[4,5－b]吡啶、5－三氘代甲氧基－2－((4－三氘代甲氧基－3,5－二甲基－2－吡啶基甲基)亞磺醯基)－1H－咪唑并[4,5－b]吡啶、5－甲氧基－2－((3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基甲基)亞磺醯基)－1H－咪唑并[4,5－b]吡啶或5－三氘代甲氧基－2－((3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基甲基)亞磺醯基)－1H－咪唑并[4,5－b]吡啶。The best compound is the following compound: 5-methoxy-2-[(4-tridecylmethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzene Imidazole, 5-methoxy-2-[(4-didecylmethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5 -Trisedylmethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-triantane Methoxy-2-[(4-tridecylmethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trimyl Oxy-2-[(4-didecylmethoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-methoxy-2 -[(3-Methyl-4-tridecylmethoxy-5-tridemethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-trimethyl Oxy-2-[(3-methyl-4-trideuteromethoxy-5-tridemethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 2- [3-Methyl-4-(1,1-dioxo-2,2,2-trifluoro) Oxy)-2-pyridyl]methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-tridemethoxy)- 2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-didecylmethoxy-2-pyridyl) )methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-tridecylmethoxy-4-methoxy-2-pyridyl)methyl Sulfhydryl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-dioxomethoxy-4-methoxy-2-pyridyl)methylsulfinyl] -1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(tridemethoxy)-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole, 5-difluoromethoxy-2-[(3,4-bis(di-decyloxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 2-{ [4-(3-tridesylmethoxyhexafluoropropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole, 2-{[4- (3-tridesy methoxy hexafluoropropoxy)-3-tris-methyl Pyridin-2-yl]methylsulfinyl}-1H-benzimidazole, 5-methoxy-2-((4-tridecylmethoxy-3,5-dimethyl-2-pyridine) Methyl)sulfinyl)-1H-imidazo[4,5-b]pyridine, 5-trioxomethoxy-2-((4-tridemethoxy)-3,5-di Methyl-2-pyridylmethyl)sulfinyl)-1H-imidazo[4,5-b]pyridine, 5-methoxy-2-((3-methyl-4-trimethyl) Oxy-5-tridecylmethyl-2-pyridylmethyl)sulfinyl)-1H-imidazo[4,5-b]pyridine or 5-trioxomethoxy-2-(( 3-Methyl-4-trideuteromethoxy-5-tridemethyl-3-pyridylmethyl)sulfinyl)-1H-imidazo[4,5-b]pyridine.
根據本發明，術語「被一氘原子取代之氫原子」應理解成界定本體材料的氘化程度為至少80%，其中所有該等相應提及之氫原子皆被氘原子取代。舉例而言，若取代基R2或R3係指一個所有三個「氫原子皆被氘原子取代」之甲氧基，則根據以上定義，應理解為本體材料中所有R2或R3甲氧基基團的至少80%係－OCD3。其餘補足至100%之部分包括－OCHD2、－OCH2D或－OCH3。According to the invention, the term "a hydrogen atom substituted by a halogen atom" is understood to mean that the degree of deuteration of the bulk material is at least 80%, wherein all of the correspondingly mentioned hydrogen atoms are replaced by deuterium atoms. For example, if the substituent R2 or R3 refers to a methoxy group in which all three "hydrogen atoms are replaced by deuterium atoms", it is understood that all R2 or R3 methoxy groups in the bulk material are understood according to the above definition. At least 80% of the lines are -OCD3 . The remaining portion that complements 100% includes -OCHD2 , -OCH2 D or -OCH3 .
較佳地，該本體材料中特定氫原子至少90%的氘化程度係指至少90%之經取代氫原子係氘原子。更佳者係該本體材料中特定氫原子的氘化程度為至少92%。甚至更佳者係該本體材料中特定氫原子之氘化程度為至少94%且最佳者係該本體材料中特定氫原子之氘化程度為至少96%。Preferably, at least 90% of the degree of deuteration of a particular hydrogen atom in the bulk material refers to at least 90% of the substituted hydrogen atom system helium atoms. More preferably, the degree of deuteration of a particular hydrogen atom in the bulk material is at least 92%. Even more preferably, the degree of deuteration of a particular hydrogen atom in the bulk material is at least 94% and preferably the degree of deuteration of a particular hydrogen atom in the bulk material is at least 96%.
本發明化合物係對掌性化合物。因此，本發明係關於外消旋異構體以及對映異構體及其任何期望比例之混合物。就醫學觀點而言，鑒於某些對掌性化合物可以一或另一種對映異構體形式有利地投與這一事實，本發明之較佳標題物質係式1化合物之對映異構體，較佳該等對映異構體實質上不含具有相反構型之相應另一對映異構體。The compounds of the invention are antagonistic to palm compounds. Accordingly, the present invention is directed to racemic isomers as well as enantiomers and mixtures thereof in any desired ratio. From a medical point of view, in view of the fact that certain palm compounds may be advantageously administered in one or the other enantiomeric form, the preferred subject matter of the invention is the enantiomer of the compound of formula 1, Preferably, the enantiomers are substantially free of the corresponding other enantiomer having the opposite configuration.
因此，一方面，尤其較佳者係具有通式1a之(S)－構型之化合物，
在本發明之範圍內具有(S)－構型的尤其較佳化合物係以下化合物：(S)－5－甲氧基－2－[(4－三氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－三氘代甲氧基－2－[(4－三氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－甲氧基－2－[(4－二氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－三氘代甲氧基－2－[(4－二氘代甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－甲氧基－2－[(3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑、(S)－5－三氘代甲氧基－2－[(3－甲基－4－三氘代甲氧基－5－三氘代甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑或(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基甲基)亞磺醯基]－1H－苯并咪唑(S)－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基甲基)亞磺醯基]－1H－苯并咪唑及該等化合物之溶合物(較佳水合物)、該等化合物之鹽及該等化合物鹽之溶合物(較佳水合物)。Particularly preferred compounds having the (S)-configuration within the scope of the present invention are the following compounds: (S)-5-methoxy-2-[(4-tridecylmethoxy-3,5-di) Methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-tris-methoxy-2-[(4-tridemethoxy--3, 5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(4-didecylmethoxy-3, 5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-tris-methoxy-2-[(4-didecylmethoxy) -3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-trideuteromethoxy-2-[(4-methoxy) -3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-methoxy-2-[(3-methyl-4-tris) Deuterated methoxy-5-tridemethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, (S)-5-tridecylmethoxy-2-[( 3-methyl-4-tridemethoxy--5-tridemethyl-2-pyridyl) Sulfosyl]-1H-benzimidazole or (S)-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridylmethyl) Sulfo]1H-benzimidazole (S)-5-difluoromethoxy-2-[(3-methoxy-4-didecylmethoxy-2-pyridylmethyl) Sulfosyl]-1H-benzimidazole and solvates of such compounds (preferably hydrates), salts of such compounds, and solvates of such compounds (preferably hydrates).
另一方面，尤其較佳者係具有通式1b之(R)－構型之化合物，
在本發明之範圍內，具有(R)－構型之尤其較佳化合物係化合物(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基甲基)亞磺醯基]－1H－苯并咪唑、(R)－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基甲基)亞磺醯基]－1H－苯并咪唑及該等化合物之溶合物(較佳水合物)、該等化合物之鹽及該等化合物鹽之溶合物(較佳水合物)。Particularly preferred compounds having the (R)-configuration are compounds (R)-5-difluoromethoxy-2-[(3-methoxy-4-trioxomethoxy) within the scope of the present invention. Benzyl-2-pyridylmethyl)sulfinyl]-1H-benzimidazole, (R)-5-difluoromethoxy-2-[(3-methoxy-4-diindole methoxy) Alkyl-2-pyridylmethyl)sulfinyl]-1H-benzimidazole and a solvate thereof (preferably a hydrate), a salt of such a compound, and a salt of such a compound ( Preferred hydrates).
可根據各種方法(例如闡述於國際專利申請案WO 92/08716中者或藉由管柱層析)將式1之化合物分離成對映異構體。或者，可藉由硫化物之對掌性氧化(如闡述於國際專利申請案WO 96/02535或WO 2004/052881中者)獲得式1a與1b之化合物。The compound of formula 1 can be separated into the enantiomers according to various methods, such as those described in International Patent Application WO 92/08716 or by column chromatography. Alternatively, the compounds of formulae 1a and 1b can be obtained by the palmitic oxidation of the sulfides, as described in International Patent Application WO 96/02535 or WO 2004/052881.
藉由自身已習知之方法藉由式1、1a及1b之化合物(其可認為係弱酸)與適宜鹼、例如與鹼金屬氫氧化物或醇鹽(例如，氫氧化鈉或甲醇鈉)或與鹼土金屬醇鹽(例如甲醇鎂)反應製備式1、1a及1b化合物之鹽。舉例而言，式1、1a及1b化合物之鎂鹽係除鈉鹽以外之較佳鹽，其係以自身習知方式藉由式1、1a及1b之化合物與鎂鹼(例如，烷醇鎂)反應或自式1、1a及1b化合物之易溶鹽(例如鈉鹽)使用一鎂鹽在水或水與極性有機溶劑(例如醇(較佳甲醇、乙醇或異丙醇)、或酮(較佳丙酮))中反應來製備。By a method known per se by a compound of the formulae 1, 1a and 1b (which may be considered to be a weak acid) and a suitable base, for example with an alkali metal hydroxide or alkoxide (for example sodium hydroxide or sodium methoxide) or The alkaline earth metal alkoxide (e.g., magnesium methoxide) is reacted to prepare a salt of the compound of formula 1, 1a and 1b. For example, the magnesium salt of the compound of the formulae 1, 1a and 1b is a preferred salt other than the sodium salt, which is a compound of the formula 1, 1a and 1b and a magnesium base (for example, magnesium alkoxide) in a conventional manner. The reaction or a readily soluble salt of a compound of formula 1, 1a and 1b (for example a sodium salt) using a magnesium salt in water or water with a polar organic solvent such as an alcohol (preferably methanol, ethanol or isopropanol), or a ketone ( It is preferably prepared by reacting in acetone)).
根據本發明，「具有(S)－構型之化合物」應理解為包括「具有(S)－構型之化合物實質上不含具有(R)－構型之化合物」。According to the present invention, "a compound having the (S)-configuration" is understood to include "a compound having the (S)-configuration substantially free of a compound having the (R)-configuration".
在本發明上下文中，「實質上不含」係指具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小610重量%的具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。較佳地，「實質上不含」係指具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於5重量%的具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。更佳地，「實質上不含」係指具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於2重量%的具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。在最佳實施例中，「實質上不含」係指具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於1重量%的具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。In the context of the present invention, "substantially free" means that the compound having the (S)-configuration and/or its salt, solvate or salt solvate comprises 610% by weight of (R)-structure. A compound of the type and/or a salt, a solvate or a salt thereof. Preferably, "substantially free" means that the compound having the (S)-configuration and/or its salt, solvate or salt comprises less than 5% by weight of the (R)-configuration. A compound and/or a salt, a solvate or a salt thereof. More preferably, "substantially free" means that the compound having the (S)-configuration and/or a salt, a solvate or a salt thereof contains less than 2% by weight of the (R)-configuration. A compound and/or a salt, a solvate or a salt thereof. In a preferred embodiment, "substantially free" means that the compound having the (S)-configuration and/or a salt, solvate or salt thereof contains less than 1% by weight of (R)- A compound of the configuration and/or a salt, a solvate or a salt thereof.
根據本發明，「具有(R)－構型之化合物」應理解為包括「具有(R)－構型之化合物實質上不含具有(S)－構型之化合物」。According to the invention, "a compound having the (R)-configuration" is understood to include "a compound having the (R)-configuration substantially free of a compound having the (S)-configuration".
在本發明上下文中，「實質上不含」係指具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於10重量%的具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。較佳地，「實質上不含」係指具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於5重量%的具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。更佳地，「實質上不含」係指具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於2重量%的具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。在最佳實施例中，「實質上不含」係指具有(R)－構型之化合物及/或其鹽、溶合物或鹽之溶合物包含小於1重量%的具有(S)－構型之化合物及/或其鹽、溶合物或鹽之溶合物。In the context of the present invention, "substantially free" means that the compound having the (R)-configuration and/or its salt, solvate or salt solvate comprises less than 10% by weight of (S)-form A compound of the type and/or a salt, a solvate or a salt thereof. Preferably, "substantially free" means that the compound having the (R)-configuration and/or its salt, solvate or salt solvate comprises less than 5% by weight of the (S)-configuration. A compound and/or a salt, a solvate or a salt thereof. More preferably, "substantially free" means that the compound having the (R)-configuration and/or a salt, a solvate or a salt thereof contains less than 2% by weight of the (S)-configuration. A compound and/or a salt, a solvate or a salt thereof. In a preferred embodiment, "substantially free" means that the compound having the (R)-configuration and/or a salt, solvate or salt thereof contains less than 1% by weight of (S)- A compound of the configuration and/or a salt, a solvate or a salt thereof.
本發明之附加標題物質係式2之化合物，
本發明另一態樣係式3之化合物，
較佳者係式3其中R2為甲基或甲氧基、R3為甲氧基、2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫或甲基且其中其中R3的至少一個氫原子被氘原子取代之化合物。Preferred is 3 wherein R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R 4 is hydrogen or methyl and wherein A compound in which at least one hydrogen atom of R3 is replaced by a deuterium atom.
更佳者係式3其中R2為甲基、R3為甲氧基、R4為甲基或R2為甲氧基、R3為甲氧基、R4為氫或R2為甲基、R3為2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫且其中R3的至少一個氫原子被氘原子取代之化合物。More preferably, wherein R 2 is methyl, R 3 is methoxy, R 4 is methyl or R 2 is methoxy, R 3 is methoxy, R 4 is hydrogen or R 2 is methyl, and R 3 is 2, 2. A compound of 2-trifluoroethoxy or methoxypropoxy, wherein R4 is hydrogen and wherein at least one hydrogen atom of R3 is replaced by a deuterium atom.
亦更佳者係式3其中R2為甲基、R3為甲氧基、R4為甲基或R2為甲氧基、R3為甲氧基、R4為氫或R2為甲基、R3為2,2,2－三氟乙氧基或甲氧基丙氧基、R4為氫且其中R3的至少兩個或所有氫原子被氘原子取代。Further preferred is a formula 3 wherein R 2 is methyl, R 3 is methoxy, R 4 is methyl or R 2 is methoxy, R 3 is methoxy, R 4 is hydrogen or R 2 is methyl, and R 3 is 2, 2. , 2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen and wherein at least two or all of the hydrogen atoms of R3 are replaced by deuterium atoms.
出於本發明之目的，鹵素係碘、溴、氯及氟。X較佳為氯。一醇之活性衍生物係一烷基磺酸根基團(例如甲磺酸根)或芳基磺酸根基團(例如甲苯磺酸根或苯磺酸根)、或一全氟烷烴磺酸根基團(例如三氟甲烷磺酸根)。For the purposes of the present invention, halogen is iodine, bromine, chlorine and fluorine. X is preferably chlorine. The active derivative of the monohydric alcohol is a monoalkylsulfonate group (for example, mesylate) or an arylsulfonate group (for example, tosylate or benzenesulfonate), or a perfluoroalkanesulfonate group (for example, three). Fluoromethanesulfonate).
本發明係關於式3之化合物且因此本發明之一態樣係下式3a之化合物，
較佳者係式3a其中R2為甲基或甲氧基、R4為氫或甲基且其中R2及/或R4的至少一個氫原子被一個氘原子取代之化合物。Preferred are compounds of the formula 3a wherein R2 is methyl or methoxy, R4 is hydrogen or methyl and at least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom.
更佳者係式3a其中R2與R4為甲基且其中R2及/或R4的至少一個氫原子被一個氘原子取代之化合物。More preferred are compounds of the formula 3a wherein R2 and R4 are methyl and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom.
式3之化合物可用於製備式1、1a或1b之化合物。較佳地，首先將式3化合物之氮原子加以四級銨化並然後與式4之化合物反應
式3a之化合物可用於製備式2a之化合物，
較佳地，首先將式3a化合物之氮原子加以四級銨化並然後與式4之化合物反應
式2a之化合物可藉由用一殘基R3取代殘基R5(二者皆具有上述意義)用於製備式2之化合物。但須R1、R2或R4的氫原子皆為未經氘原子取代，R3的至少一個氫原子被一個氘原子取代。The compound of formula 2a can be used to prepare a compound of formula 2 by substituting a residue R3 for a residue R5, both of which have the above meanings. However, the hydrogen atom of R1, R2 or R4 is substituted by a non-deuterium atom, and at least one hydrogen atom of R3 is substituted by a deuterium atom.
本發明另一態樣係式4之化合物，
更佳者係其中R1為甲氧基且其中R1的所有氫原子皆被氘原子取代之化合物。More preferred are compounds wherein R1 is methoxy and wherein all of the hydrogen atoms of R1 are replaced by deuterium atoms.
質子泵抑制劑及(例如)R/S潘托拉唑(pantoprazole)及S－潘托拉唑之氘同系物可根據自文獻中得知之方法(例如Kohl等人，J.Med.Chem.1992，35，1049及其後或WO 2004/052881)藉由氧化相應硫代化合物來製備，或藉由在最終三氘代甲氧基基團之位置(尤其在吡啶基團之4－位)上將具有鹵素(例如，氯、溴或硝基)取代基的相應亞碸之鹵素替換成三氘代甲氧基來製備。與上述類似，將一鹵素替換成二氘代甲氧基或單氘代甲氧基將獲得相應的氘代化合物。Proton pump inhibitors and, for example, R/S pantoprazole and S-pantoprazole ruthenium homologues can be obtained according to methods known in the literature (e.g., Kohl et al., J. Med. Chem. 1992). , 35, 1049 and thereafter or WO 2004/052881) by oxidation of the corresponding thio compound, or by the position of the final trideuteromethoxy group (especially at the 4-position of the pyridine group) It is prepared by replacing a halogen of the corresponding fluorene having a halogen (e.g., chlorine, bromine or nitro) substituent with a tri-deuterated methoxy group. Similar to the above, the replacement of a halogen with a di-deuterated methoxy group or a mono-deuterated methoxy group will give the corresponding deuterated compound.
類似地，該等硫代化合物係藉由在最終單、二或三氘代甲氧基－取代基位置上將鹵素替換成單、二或三氘代甲氧基或藉由使5－二氟甲氧基－2－巰基苯并咪唑與相應經取代之氯化2－氯甲基－3－甲氧基－4－三氘代甲氧基－吡啶鎓偶合來製備。Similarly, the thio compounds are substituted by a halogen at the final mono-, di- or tri-deuterated methoxy-substituent position with a mono-, di- or tri-deuterated methoxy group or by a 5-difluoro group. Methoxy-2-mercaptobenzimidazole is prepared by coupling with the corresponding substituted 2-chloromethyl-3-methoxy-4-tridemethoxy-pyridinium chloride.
式1化合物可根據以下反應示意圖製備：
亞碸與無機鹼之鹽係根據自文獻得知之方法藉由亞碸與相應氫氧化物或醇鹽在有機溶劑或有機溶劑與水之混合物中反應來製備。The salts of the hydrazine and the inorganic base are prepared by reacting the hydrazine with the corresponding hydroxide or alkoxide in an organic solvent or a mixture of an organic solvent and water according to a method known from the literature.
或者，藉由亞碸與鹼金屬氫氧化物反應獲得相應鹼金屬鹽(Na、K、Li)並進一步與(例如)鎂、鈣、鋁、鋅鹽反應來製備鹽。Alternatively, a salt can be prepared by reacting an anthraquinone with an alkali metal hydroxide to obtain a corresponding alkali metal salt (Na, K, Li) and further reacting with, for example, magnesium, calcium, aluminum, or a zinc salt.
下述實例用於更詳細地闡釋本發明，而非將其限於所闡述之實例。其他上述之化合物可藉由使用所闡述之方法獲得。The following examples are intended to illustrate the invention in more detail, and are not intended to limit the examples. Other such compounds can be obtained by using the methods set forth.
使用具有>99.8原子%D之d4－甲醇作為三氘代甲氧基化試劑。在所有所得產物中三氘代甲氧基取代基之異構純度係>98.0%，如藉由NMR與MS所量測者。使用具有>98.0原子%D之d2－甲醇及具有>98.0原子%D之d1－甲醇作為另一氘代試劑。在所得產物中二氘代甲氧基與單氘代甲氧基取代基之異構純度係>96.0%，如藉由NMR與MS所量測者。D4-methanol having >99.8 atomic % D was used as the trideuterated methoxylation reagent. The isomer purity of the trideuterated methoxy substituent in all of the resulting products was >98.0% as measured by NMR and MS. As the deuterated reagent, d2-methanol having >98.0 atomic % D and d1-methanol having >98.0 atomic % D were used. The isomeric purity of the di-deuterated methoxy group and the mono-deuterated methoxy substituent in the resulting product was >96.0% as measured by NMR and MS.
5－二氟甲氧基(R/S)2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑於30－35℃下攪拌的同時將次氯酸鈉(10%濃度)(3.3毫莫耳)溶液在1至2小時內添加於5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(1.0克，2.7毫莫耳)於水(20毫升)、2－丙醇(10毫升)及氫氧化鈉(0.5毫升濃度40%的溶液，7.1毫莫耳)中之漿液中。在所述溫度下30－60分鐘後，添加硫代硫酸鈉(0.3克溶於5毫升水中)並再繼續攪拌15－30分鐘。5-difluoromethoxy (R/S) 2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole A solution of sodium hypochlorite (10% strength) (3.3 mmol) was added to 5-difluoromethoxy-2-[(3-methoxy-4-) over 1 to 2 hours while stirring at 30-35 °C. Trioxomethoxy-2-pyridyl)methylthio]-1H-benzimidazole (1.0 g, 2.7 mmol) in water (20 mL), 2-propanol (10 mL) and sodium hydroxide (0.5 ml of a 40% solution, 7.1 mmol) in the slurry. After 30-60 minutes at the temperature, sodium thiosulfate (0.3 g dissolved in 5 ml of water) was added and stirring was continued for a further 15-30 minutes.
將反應混合物在真空中(30至40℃)濃縮至約初始體積的三分之一併添加水(約70毫升)。The reaction mixture was concentrated in vacuo (30 to 40 ° C) to about one third 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)萃取後，再添加二氯甲烷(50毫升)並藉由添加磷酸二氫鉀水溶液同時攪拌將pH調節至7－8。產生相分離，水相進一步用二氯甲烷(20毫升)萃取，合併的有機相用水(20毫升)洗滌亁燥、硫酸鎂亁燥並濾除亁燥試劑，獲得一粗標題化合物之溶液。The aqueous phase was extracted with dichloromethane (2 times, 10 mL each time) and then dichloromethane (50 ml) was added and the pH was adjusted to 7-8 by adding aqueous potassium dihydrogen phosphate solution while stirring. The phases were separated and the aqueous phase was extracted with EtOAc (EtOAc)EtOAc.
添加石油醚(50/70；150毫升)並在旋轉蒸發器中於真空中在30－40℃下濃縮至約30毫升體積，隨後過濾所沉澱固體，用石油醚50/70(20毫升)洗滌並在真空中(35℃，5小時)亁燥，獲得灰白色固體狀標題化合物5－二氟甲氧基(R/S)2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑，熔點135－136℃(分解)；產量1.0克(理論值的95%)。Petroleum ether (50/70; 150 ml) was added and concentrated in a rotary evaporator at 30-40 ° C to a volume of ca. 30 mL, then the precipitated solid was filtered and washed with petroleum ether 50/70 (20 mL) Drying in vacuo (35 ° C, 5 hr) to give the title compound 5-difluoromethoxy (R/S) 2-[(3-methoxy-4-tridecylmethoxy) 2-pyridyl)methylsulfinyl]-1H-benzimidazole, melting point 135-136 ° C (decomposition); yield 1.0 g (95% of theory).
1H－NMR(400 MHz，DMSO d－6)：δ＝3.78(s,3 H,OMe),4.68(d,1H,J(CHa,CHb)＝13 Hz,S－CH2－Py),4.73(d,1H,J(CHb,CHa)＝13 Hz,S－CH2－Py),7.10(d,1H,J(H5',H6')＝5 Hz,H5'),7.18(bd,1H,H6),7.24(t,1H,J(H,F)＝74 Hz,OCHF2),7.4(bs,1H,H4),7.70(bs,1H,H7),8.15(d,1H,J(H6',H5')＝5 Hz)H6'),13.7(s,1H,NH)。1 H-NMR (400 MHz, DMSO d-6): δ = 3.78 (s, 3 H, OMe), 4.68 (d, 1H, J (CHa, CHb) = 13 Hz, S-CH2-Py), 4.73 (d, 1H, J(CHb, CHa) = 13 Hz, S-CH2-Py), 7.10 (d, 1H, J(H5', H6') = 5 Hz, H5'), 7.18 (bd, 1H, H6), 7.24 (t, 1H, J (H, F) = 74 Hz, OCHF2), 7.4 (bs, 1H, H4), 7.70 (bs, 1H, H7), 8.15 (d, 1H, J (H6') , H5') = 5 Hz) H6'), 13.7 (s, 1H, NH).
S(－)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑於室溫下，將2.0克5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑與(＋)－L－酒石酸雙－(N－吡咯啶醯胺)(2.3克)及正丙醇鋯(IV)(1.0克，70%於丙醇中)一起懸浮於20毫升甲基異丁基酮中。於40℃下加熱該混合物1小時，形成一幾乎透明之溶液。冷卻至室溫後，添加N－乙基二異丙基胺(0.07毫升)及異丙基苯過氧化氫(1.05毫升)。於室溫下攪拌該混合物直至氧化結束為止(10至24小時，藉由TLC監測)。用10毫升甲基異丁基酮稀釋該透明溶液，並用0.08克存於14毫升飽和碳酸氫鈉溶液中之硫代硫酸鈉中止反應並再攪拌2小時。相分離後，用5毫升飽和碳酸氫鈉溶液將該混合物洗滌兩次。向甲基異丁基酮相中添加15毫升水，並用40重量%濃度之氫氧化鈉溶液將pH值調節為pH＝13。相分離後，另用5毫升水於pH＝13時萃取甲基異丁基酮相。合併該等水相並於40℃及低壓下對其實施初始蒸餾。添加Hyflo Super Cell作為過濾助劑(0.05克)，並於20－25℃下攪拌1小時後濾除。在40－45℃下，藉由將10%濃度的乙酸添加於濾液中至pH＝9.0來沉澱粗標題化合物。將該混合物再攪拌12小時，在此期間對pH值實施監測。過濾出淺褐色晶體並用10毫升水洗滌。獲得產量約1.6克(理論值的75%)且光學純度大於98%之標題化合物。S(-)-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole 2.0 g of 5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylthio]-1H-benzimidazole at room temperature Suspended in 20 ml of methyl isobutyl with (+)-L-bis-(N-pyrrolidinium tarta) (2.3 g) and zirconium (IV) n-propoxide (1.0 g, 70% in propanol) Ketone. The mixture was heated at 40 ° C for 1 hour to form an almost transparent solution. After cooling to room temperature, N-ethyldiisopropylamine (0.07 mL) and isopropylbenzene hydrogen peroxide (1.05 mL) were added. The mixture was stirred at room temperature until the end of oxidation (10 to 24 hours, monitored by TLC). The clear solution was diluted with 10 ml of methyl isobutyl ketone and quenched with 0.08 g of sodium thiosulfate in 14 ml of saturated sodium bicarbonate and stirred for a further 2 hr. After phase separation, the mixture was washed twice with 5 mL of saturated sodium bicarbonate solution. 15 ml of water was added to the methyl isobutyl ketone phase, and the pH was adjusted to pH = 13 with a 40% by weight sodium hydroxide solution. After phase separation, the methyl isobutyl ketone phase was extracted with another 5 ml of water at pH = 13. The aqueous phases were combined and subjected to initial distillation at 40 ° C and low pressure. Hyflo Super Cell was added as a filter aid (0.05 g), and stirred at 20-25 ° C for 1 hour and then filtered off. The crude title compound was precipitated by adding 10% strength acetic acid to the filtrate to pH = 9.0 at 40-45 °C. The mixture was stirred for a further 12 hours during which time the pH was monitored. The light brown crystals were filtered off and washed with 10 ml of water. The title compound was obtained in an amount of about 1.6 g (75% of theory) and optical purity greater than 98%.
為提高純度，於pH＝13時將(－)三氘代潘托拉唑溶於水/氫氧化鈉水溶液中，並於pH＝9.0時用乙酸(10%)再沉澱。To increase the purity, (-) triterpene pantoprazole was dissolved in water/aqueous sodium hydroxide solution at pH = 13 and reprecipitated with acetic acid (10%) at pH = 9.0.
自二氯甲烷/第三丁基甲基醚再結晶，獲得灰白色固體狀標題化合物S(－)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑，m.p.146－148℃(分解)；產量1.6克。Recrystallization from dichloromethane/t-butylmethylether afforded the title compound S (-)-5-difluoromethoxy-2-[(3-methoxy-4-tridecyloxy) 2-pyridyl)methylsulfinyl]-1H-benzimidazole, mp 146-148 ° C (decomposition); yield 1.6 g.
起始材料氯化2－氯甲基－3－甲氧基－4－三氘代甲氧基吡啶鎓之合成3－甲氧基－2－甲基－4－三氘代甲氧基吡啶N－氧化物之製備將4－氯－3－甲氧基－2－甲基吡啶N－氧化物(10克)與存於D4氘代甲醇(20毫升)中之三氘代甲醇鈉(6.2克)加熱回流。15小時後，在真空中蒸發溶劑，殘餘物用熱甲苯(50毫升)萃取並濾除不溶物。添加異丙醚於濾液中以沉澱一固體，該固體在真空中亁燥後獲得8.1克淺褐色粉末狀3－甲氧基－2－甲基－4－三氘代甲氧基吡啶N－氧化物。其隨後用於下一步驟中。Synthesis of 2-Chloromethyl-3-methoxy-4-tridemethoxymethoxypyridinium as starting material 3-methoxy-2-methyl-4-tridemethoxyphenyl N - Preparation of Oxide 4-Chloro-3-methoxy-2-methylpyridine N-oxide (10 g) and trisodium methoxide (6.2 g) in D4 deuterated methanol (20 ml) ) Heating back. After 15 hours, the solvent was evaporated in vacuo. Isopropyl ether was added to the filtrate to precipitate a solid, which was dried in vacuo to give 8.1 g of light brown powdery 3-methoxy-2-methyl-4-tridecylmethoxypyridine N-oxidation Things. It is then used in the next step.
2－羥甲基－3－甲氧基－4－三氘代甲氧基吡啶之製備將前述步驟之產物(8.1克)溶於乙酸酐(50毫升)並在90℃下加熱2小時。在真空中蒸發後，於80℃下將黑色油狀殘餘物與2 N NaOH(20毫升)一起攪拌2小時。冷卻後，將該產物萃取至二氯甲烷中、亁燥(K2CO3)並在真空中濃縮以減少體積。添加石油醚(50/70)、過濾並在真空中亁燥後獲得淺褐色固體狀2－羥基－3－甲氧基－4－三氘代甲氧基吡啶(5.5克)，其用於隨後步驟。Preparation of 2-Hydroxymethyl-3-methoxy-4-trideuteromethoxypyridine The product of the previous step (8.1 g) was dissolved in acetic acid (50 ml) and warmed at 90 ° C for 2 hr. After evaporation in vacuo, aq. EtOAc m. After cooling, the product was extracted into dichloromethane, Gan dry (K2 CO3) and concentrated in vacuo to reduce the volume. Add petroleum ether (50/70), filter and dry in vacuo to give 2-hydroxy-3-methoxy-4-tridecylmethoxypyridine (5.5 g) as a light brown solid. step.
氯化2－氯甲基－3－甲氧基－4－三氘代甲氧基吡啶鎓之製備將上述步驟之產物(5.5克)溶於無水二氯甲烷(40毫升)中並於5至10℃下逐滴滴加亞硫醯氯(3毫升)同時攪拌。將該混合物加熱至最高20℃且3小時後蒸發以在真空中亁燥。Preparation of 2-chloromethyl-3-methoxy-4-trideoxymethoxypyridinium chloride The product of the above step (5.5 g) was dissolved in anhydrous dichloromethane (40 ml) Thyrene chloride (3 ml) was added dropwise at 10 ° C while stirring. The mixture was heated to a maximum of 20 ° C and evaporated for 3 hours to dry in vacuo.
添加甲苯(20毫升)，獲得6.6克淺褐色固體狀標題化合物氯化2－氯甲基－3－甲氧基－4－三氘代甲氧吡啶鎓。Addition of toluene (20 ml) gave 6.6 g (yield: EtOAc)
以此方法合成之材料包含一些難以去除之雜質，此顯示需實施後續步驟的傾向以獲得通式(2)之化合物且最終獲得通式(1)之化合物。因此，為製備具有尤其高純度之通式(1)之化合物，通常較佳採取實例9及35中所述之氘代烷氧基化方法。The material synthesized in this way contains some impurities which are difficult to remove, which shows a tendency to carry out a subsequent step to obtain a compound of the formula (2) and finally obtain a compound of the formula (1). Therefore, in order to prepare a compound of the formula (1) having particularly high purity, it is generally preferred to employ the deuteration alkoxylation process as described in Examples 9 and 35.
氯化4－氯－2－氯甲基－3－甲氧基吡啶鎓於85－95℃下，在5至7小時內將4－氯－3－甲氧基－2－甲基吡啶－N－氧化物(19.2公斤，111莫耳)存於甲苯(148公升)之溶液添加於乙酸酐(71公升)中。在真空下在約60℃下，將反應混合物濃縮直至蒸餾出約170公升為止。添加甲苯(160公升)並再次蒸餾出溶劑(160公升)。將此最後作業再重複一次。然後，於35－45℃下添加甲苯(14公升)及40% NaOH水溶液(14.6公升)並於此溫度下將該反應混合物保持2－3小時。若此時pH低於13，則添加更多NaOH並持續加熱2小時以上。所得兩相反應混合物用甲苯(26公升)及飽和碳酸氫鈉水溶液(26公升)稀釋，相分離且水層用甲苯(26公升及2×13公升)萃取三次。最後，將合併的有機相用飽和碳酸氫鈉水溶液(13公升)洗滌並在真空下於50－65℃下濃縮直至蒸餾出約115公升為止。用甲苯(100公升)稀釋後，再蒸餾出100公升溶劑。4-Chloro-2-chloromethyl-3-methoxypyridinium chloride 4-chloro-3-methoxy-2-methylpyridine-N in 5 to 7 hours at 85-95 ° C A solution of the oxide (19.2 kg, 111 mol) in toluene (148 liters) was added to acetic anhydride (71 liters). The reaction mixture was concentrated under vacuum at about 60 ° C until about 170 liters of distillation. Toluene (160 liters) was added and the solvent (160 liters) was again distilled off. Repeat this last job again. Then, toluene (14 liters) and 40% aqueous NaOH (14.6 liters) were added at 35-45 ° C and the reaction mixture was maintained at this temperature for 2-3 hours. If the pH is below 13 at this time, more NaOH is added and heating is continued for more than 2 hours. The resulting two-phase reaction mixture was diluted with toluene (26 liters) and saturated aqueous sodium bicarbonate (26 liters), phase separated and the aqueous layer was extracted three times with toluene (26 liters and 2 x 13 liters). Finally, the combined organic phases were washed with saturated aqueous sodium bicarbonate (13 liters) and concentrated under vacuum at 50-65 ° C until about 115 liters. After diluting with toluene (100 liters), 100 liters of solvent was distilled off.
所得4－氯－2－羥甲基－3－甲氧基吡啶溶液(約30%濃度)用CH2Cl2(48公升)稀釋。一次性添加DMF(65.5克，0.896莫耳)，並然後於15－30℃下在3至5小時內添加亞硫醯氯(11.1公斤，93.2莫耳)。再攪拌1.5小時後，蒸餾出約45公升溶劑。添加甲苯(20公升)並再次藉由蒸餾去除20公升溶劑。然後，添加乙醇(1.5公升)以獲得稠漿液。於10－15℃下將固體濾出、用甲苯(17公升)洗滌並在真空中於30℃下亁燥，獲得灰白色固體狀氯化4－氯－2－氯甲基－3－甲氧基吡啶鎓(m.p.132℃)；產量15.0公斤(59%)。The resulting 4-chloro-2-hydroxymethyl-3-methoxy-pyridine solution (about 30% strength) was diluted with CH2 Cl2 (48 liters). DMF (65.5 g, 0.896 mol) was added in one portion and then sulphur sulphide chloride (11.1 kg, 93.2 mol) was added over 3 to 5 hours at 15-30 °C. After stirring for an additional 1.5 hours, about 45 liters of solvent was distilled off. Toluene (20 liters) was added and 20 liters of solvent was again removed by distillation. Then, ethanol (1.5 liters) was added to obtain a thick slurry. The solid was filtered off at 10-15 ° C, washed with toluene (17 liters) and dried at 30 ° C in vacuo to give 4-chloro-2-chloromethyl-3-methoxy Pyridinium (mp 132 ° C); yield 15.0 kg (59%).
1H－NMR(200 MHz，CDCl3)：δ＝4.19(s,3H),5.14(s,2H),7.92(d,6.0 Hz,1H),8.59(d,6.0 Hz,1H),11.64(br s,1H)；LC－MS：MH＋＝192/194/196。1 H-NMR (200 MHz, CDCl3 ): δ = 4.19 (s, 3H), 5.14 (s, 2H), 7.92 (d, 6.0 Hz, 1H), 8.59 (d, 6.0 Hz, 1H), 11.64 ( Br s, 1H); LC-MS: MH+ = 192 / 194 / 196.
氯化4－氯－2－氯甲基－3－三氘代甲氧基吡啶鎓根據J.Med.Chem.(1992，35，1049－1057)中用於未經氘代類似物之方法D製備起始材料4－氯－2－甲基－3－三氘代甲氧基吡啶－N－氧化物：自3－羥基－2－甲基－4－吡喃酮起始，使用三氘代－碘甲烷在碳酸鉀之存在下在DMF中轉化，獲得2－甲基－3－三氘代甲氧基－4－吡喃酮(產率：83－96%)，加熱時其與氨於150℃下在乙醇中反應自丙酮/異丙醇4：1結晶後獲得4－羥基－2－甲基－三氘代甲氧基吡啶(產率：52－60%)。用磷醯氯處理此材料導致形成4－氯－2－甲基－三氘代甲氧基吡啶(產率：64－81%)。隨後用過氧化氫在乙酸中氧化，獲得淺黃色固體狀4－氯－2－甲基－3－三氘代甲氧基吡啶－N－氧化物(產率：87－89%)。4-Chloro-2-chloromethyl-3-tridemethoxymethoxypyridinium chloride according to Method D for non-deuterated analogs inJ. Med. Chem. (1992,35 , 1049-1057) Preparation of starting material 4-chloro-2-methyl-3-tridemethoxy methoxypyridine-N -oxide: starting from 3-hydroxy-2-methyl-4-pyranone, using three generations -Methyl iodide is converted in DMF in the presence of potassium carbonate to obtain 2-methyl-3-tridemethoxymethoxypyranone (yield: 83-96%), which is combined with ammonia upon heating. 4-Hydroxy-2-methyl-tridecylmethoxypyridine (yield: 52-60%) was obtained by crystallizing from acetone/isopropanol 4:1 at 150 ° C in ethanol. Treatment of this material with phosphonium chloride resulted in the formation of 4-chloro-2-methyl-tridecylmethoxypyridine (yield: 64-81%). Subsequently, it was oxidized with hydrogen peroxide in acetic acid to obtain 4-chloro-2-methyl-3-tridecylmethoxypyridine-N -oxide as a pale yellow solid (yield: 87-89%).
根據實例4所述藉由4－氯－2－羥甲基－3－三氘代甲氧基吡啶進行最終轉化，獲得無色晶狀固體氯化4－氯－2－氯甲基－3－三氘代甲氧基吡啶鎓(m.p.129－130℃)；產量19.6克(42%)。Final conversion by 4-chloro-2-hydroxymethyl-3-tridemethoxy pyridine as described in Example 4 gave 4-chromo-2-chloromethyl-3- Deuterated methoxypyridinium (mp 129-130 ° C); yield 19.6 g (42%).
氯化2－氯甲基－3,4－雙(三氘代甲氧基)吡啶鎓根據以上實例3中所闡述之程序，將4－氯－2－甲基－3－三氘代甲氧基吡啶－N－氧化物(25.3克，144毫莫耳；製備參見實例5)轉化為2－甲基－3,4－雙(三氘代甲氧基)吡啶－N－氧化物(產量：23.5克，96%)，其進而獲得2－羥甲基－3,4－雙(三氘代甲氧基)吡啶(產量：13.0克，56%)，且最終獲得灰白色晶狀固體氯化2－氯甲基－3,4－雙(三氘代甲氧基)吡啶鎓(產量：15.4克，89%)。2-Chloromethyl-3,4-bis(tridemethoxymethoxy)pyridinium chloride 4-chloro-2-methyl-3-trioxomethoxy by the procedure set forth in Example 3 above Pyridine-N -oxide (25.3 g, 144 mmol; prepared see Example 5) was converted to 2-methyl-3,4-bis(tridemethoxy)pyridine-N -oxide (yield: 23.5 g, 96%), which in turn obtained 2-hydroxymethyl-3,4-bis(tridemethoxy)pyridine (yield: 13.0 g, 56%), and finally obtained as an off-white crystalline solid. -Chloromethyl-3,4-bis(tridemethoxy)pyridinium (yield: 15.4 g, 89%).
5－二氟甲氧基－2－[(4－氯－3－甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑於55－65℃下在2－3小時內，將氯化4－氯－2－氯甲基－3－甲氧基吡啶鎓(10.0公斤，43.8莫耳)存於水(20公升)中之溶液添加於5－三氘代甲氧基－1H－苯并咪唑－2－硫醇(8.84公斤，40.9莫耳)、甲苯(43公升)、水(21公升)及40% NaOH水溶液(10.3公斤，103莫耳)之混合物中。於60℃下持續攪拌2－－3小時，然後將該反應混合物冷卻至10－15℃。將沉澱物離心分離出、用甲苯(16公升)洗滌並在水(122公升)中重新製成漿液。離心分離，隨後用一水漂洗(32公升)並於35℃下在真空中亁燥，獲得灰白色固體狀5－二氟甲氧基－2－[(4－氯－3－甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(KF＝4.6%)(m.p.95－99℃)；產量14.2公斤(92%)。5-Difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H -benzimidazole at 55-65 ° C for 2-3 hours Adding a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mol) in water (20 liters) to 5-tris-methoxy- A mixture of 1H -benzimidazole-2-thiol (8.84 kg, 40.9 mol), toluene (43 liters), water (21 liters) and 40% aqueous NaOH (10.3 kg, 103 moles). Stirring was continued at 60 °C for 2 - 3 hours and then the reaction mixture was cooled to 10-15 °C. The precipitate was centrifuged, washed with toluene (16 liters) and re-slurried in water (122 liters). After centrifugation, it was rinsed with water (32 liters) and dried in vacuo at 35 ° C to give 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2) as an off white solid. -pyridyl)methylthio]-1H -benzimidazole monohydrate (KF = 4.6%) (mp 95-99 ° C); yield 14.2 kg (92%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.55(br s,NH＋H2O),3.92(s,3H),4.79(s,2H),6.97(dd,8.6 Hz,2.3 Hz,1H),7.16(t,74.8 Hz,1H),7.28(d,2.2 Hz,1H),7.47(d,8.7 Hz,1H),7.55(d,5.3 Hz,1H),8.25(d,5.2 Hz,1H)；LC－MS：MH＋＝372/374。1 H-NMR (200 MHz, DMSO-d6): δ = 3.55 (br s, NH + H2 O), 3.92 (s, 3H), 4.79 (s, 2H), 6.97 (dd, 8.6 Hz, 2.3 Hz, 1H ), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.2 Hz, 1H), 7.47 (d, 8.7 Hz, 1H), 7.55 (d, 5.3 Hz, 1H), 8.25 (d, 5.2 Hz, 1H) ); LC-MS: MH+ = 372/374.
5－二氟甲氧基－2－[(4－氯－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑自氯化4－氯－2－氯甲基－3－三氘代甲氧基吡啶鎓(5.00克，21.6毫莫耳)起始並根據實例7中闡述之程序，獲得灰白色固體狀5－二氟甲氧基－2－[(4－氯－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(KF＝4.7%)(m.p.94－99℃)；產量7.24克(85%)。5-Difluoromethoxy-2-[(4-chloro-3-tridecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole from 4-chloro-2-chloride Starting with chloromethyl-3-tridemethoxy methoxypyridinium (5.00 g, 21.6 mmol) and according to the procedure given in Example 7 afforded 5-difluoromethoxy-2-[ 4-chloro-3-trideuteromethoxy-2-pyridyl)methylthio]-1H -benzimidazole monohydrate (KF=4.7%) (mp 94-99 ° C); yield 7.24 g (85 %).
1H－NMR(200 MHz，DMSO－d6)：δ＝4.79(s,2H),6.98(dd,8.7 Hz,2.3 Hz,1H),7.16(t,74.8 Hz,1H),7.28(d,2.0 Hz,1H),7.47(d,8.6 Hz,1H),7.55(d,5.2 Hz,1H),8.25(d,5.2 Hz,1H),12.75(br s,1H)；LC－MS：MH＋＝375/377。1 H-NMR (200 MHz, DMSO-d6): δ = 4.79 (s, 2H), 6.98 (dd, 8.7 Hz, 2.3 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.0) Hz, 1H), 7.47 (d, 8.6 Hz, 1H), 7.55 (d, 5.2 Hz, 1H), 8.25 (d, 5.2 Hz, 1H), 12.75 (br s, 1H); LC-MS: MH+ = 375/377.
5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑於15－30℃下在30至60分鐘內將d4－甲醇(2.26公斤，62.7莫耳)添加於第三丁醇鈉(6.00公斤，62.4莫耳)存於DMAc(27公升)中之混合物中。加熱至57－65℃後，在30至60分鐘內添加5－二氟甲氧基－2－[(4－氯－3－甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(6.08公斤，15.6莫耳)存於DMAc(10公升)中之溶液。於57－65℃下繼續攪拌約10小時。將該反應混合物冷卻至20－30℃用水(21公升)稀釋，之後用20%HCl水溶液(約7.5公升)將pH調節至7－8。藉由在約4小時內添加水(75 h)來達成該產物之沉澱。將所得漿液在35－45℃下加熱1.5小時，之後冷卻至10－15℃。藉由離心(包括一用水漂洗(58公升))、在水(78公升)中重新製成漿液並再次離心(包括又一次用水漂洗(58公升))獲得含水褐色固體狀5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑；產量10.4公斤，KF＝49.7%(91%)。5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylthio]-1H-benzimidazole at 15-30 ° C at 30 D4-Methanol (2.26 kg, 62.7 mol) was added to a mixture of sodium t-butoxide (6.00 kg, 62.4 mol) in DMAc (27 liters) over 60 minutes. After heating to 57-65 ° C, 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridyl)methylthio]-1H - was added over 30 to 60 minutes. Benzimidazole monohydrate (6.08 kg, 15.6 mol) was stored in DMAc (10 liters). Stirring was continued at 57-65 ° C for about 10 hours. The reaction mixture was cooled to 20-30 ° C and diluted with water (21 liters), then the pH was adjusted to 7-8 with 20% aqueous HCl (about 7.5 liters). Precipitation of the product was achieved by the addition of water (75 h) over about 4 hours. The resulting slurry was heated at 35-45 °C for 1.5 hours and then cooled to 10-15 °C. Aqueous brown solid 5-pentamethoxymethoxy obtained by centrifugation (including a water rinse (58 liters)), re-slurry in water (78 liters) and re-centrifugation (including another water rinse (58 liters)) Benzyl-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole; yield 10.4 kg, KF=49.7% (91%) .
於25℃下在真空中亁燥含水產物之樣品(16.2克，KF＝49.7%)，獲得一非晶形固體，其自甲苯(30毫升)結晶後獲得灰白色固體狀無水5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(5.80克，71%回收率，m.p.＝115－116℃)。A sample of the aqueous product (16.2 g, KF = 49.7%) was obtained in vacuo to give an amorphous solid which crystallised from toluene (30 ml) to afford an anhydrous 5-difluoromethoxy -2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylthio]-1H -benzimidazole (5.80 g, 71% recovery, mp=115-116 °C).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.82(s,3H),4.68(s,2H),6.97(dd,8.6 Hz,2.1 Hz,1H),7.08(d,5.6 Hz,1H),7.16(t,74.8 Hz,1H),7.28(br s,1H),7.47(br d,~8.3 Hz,1H),8.16(d,5.6 Hz,1H),12.75(br s,1 H)；LC－MS：MH＋＝371。1 H-NMR (200 MHz, DMSO-d6): δ = 3.82 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.1 Hz, 1H), 7.08 (d, 5.6 Hz, 1H) ), 7.16 (t, 74.8 Hz, 1H), 7.28 (br s, 1H), 7.47 (br d, ~8.3 Hz, 1H), 8.16 (d, 5.6 Hz, 1H), 12.75 (br s, 1 H) ; LC-MS: MH+ = 371.
5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑自5－二氟甲氧基－2－[(4－氯－3－甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(28.6克，73.4毫莫耳)及d2－甲醇(10.0克，294毫莫耳)起始，根據實例9中闡述之程序獲得含水褐色固體狀5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑；產量46.4克，KF＝51.6%(82%)。5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylthio]-1H -benzimidazole from 5-difluoromethoxy Benzyl-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1H -benzimidazole monohydrate (28.6 g, 73.4 mmol) and d2-methanol (10.0 </RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; -pyridyl)methylthio]-1H -benzimidazole; yield 46.4 g, KF = 51.6% (82%).
1H－NMR(400 MHz，DMSO－d6)：δ＝3.81(s,3H),3.86(s,1H),4.67(s,2H),6.97(dd,8.4 Hz,2.0 Hz,1H),7.08(d,5.5 Hz,1H),7.16(t,74.7 Hz,1H),7.21－7.53(br m,2H),8.16(d,5.5 Hz,1H),12.78(br s,1 H)；LC－MS：MH＋＝370。1 H-NMR (400 MHz, DMSO-d6): δ = 3.81 (s, 3H), 3.86 (s, 1H), 4.67 (s, 2H), 6.97 (dd, 8.4 Hz, 2.0 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.16 (t, 74.7 Hz, 1H), 7.21-7.53 (br m, 2H), 8.16 (d, 5.5 Hz, 1H), 12.78 (br s, 1 H); LC- MS: MH+ = 370.
5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑自5－二氟甲氧基－2－[(4－氯－3－甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(29.5克，75.6毫莫耳)與d1－甲醇(10.0克，303毫莫耳)起始，根據實例9闡述之程序獲得含水褐色固體狀5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑；產量50.3克，KF＝50.8%(89%)。5-Difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole from 5-difluoromethoxy Benzyl-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1H -benzimidazole monohydrate (29.5 g, 75.6 mmol) with d1-methanol (10.0 </ RTI></RTI><RTIgt;</RTI> 303 <RTIgt;</RTI><RTIgt;</RTI><RTIgt; Pyridyl)methylthio]-1H -benzimidazole; yield 50.3 g, KF = 50.8% (89%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.82(s,3H),3.88(s,2H),4.67(s,2H),6.98(dd,8.6 Hz,2.2 Hz,1H),7.08(d,5.6 Hz,1H),7.15(t,74.8 Hz,1H),7.22－7.53(br m,2H),8.16(d,5.6 Hz,1H),12.79(br s,1 H)；LC－MS：MH＋＝369。1 H-NMR (200 MHz, DMSO-d6): δ = 3.82 (s, 3H), 3.88 (s, 2H), 4.67 (s, 2H), 6.98 (dd, 8.6 Hz, 2.2 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 7.15 (t, 74.8 Hz, 1H), 7.22-7.53 (br m, 2H), 8.16 (d, 5.6 Hz, 1H), 12.79 (br s, 1 H); LC- MS: MH+ = 369.
5－二氟甲氧基－2－[(4－甲氧基－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑自5－二氟甲氧基－2－[(4－氯－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(6.97克，17.7毫莫耳)與甲醇(2.28克，71.2毫莫耳)起始，根據實例9闡述之程序獲得含水褐色固體狀5－二氟甲氧基－2－[(4－甲氧基－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑；產量7.01克，KF＝19.1%(87%)。5-difluoromethoxy-2-[(4-methoxy-3-tridemethoxymethoxy-2-pyridyl)methylthio]-1H -benzimidazole from 5-difluoromethoxy Benzyl-2-[(4-chloro-3-tridecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole monohydrate (6.97 g, 17.7 mmol) and methanol ( 2.28 g, 71.2 mmol, starting from the procedure described in Example 9 to give 5-difluoromethoxy-2-[(4-methoxy-3-tridecylmethoxy-2) as a brown solid. -pyridyl)methylthio]-1H -benzimidazole; yield 7.01 g, KF = 19.1% (87%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.89(s,3H),4.68(s,2H),6.97(dd,8.6 Hz,2.0 Hz,1H),7.08(d,5.5 Hz,1H),7.16(t,74.7 Hz,1H),7.18－7.47(br m,2H),8.16(d,5.6 Hz,1H),12.76(br s,1 H)；LC－MS：MH＋＝371。1 H-NMR (200 MHz, DMSO-d6): δ = 3.89 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.0 Hz, 1H), 7.08 (d, 5.5 Hz, 1H) ), 7.16 (t, 74.7 Hz, 1H), 7.18-7.47 (br m, 2H), 8.16 (d, 5.6 Hz, 1H), 12.76 (br s, 1 H); LC-MS: MH+ = 371.
5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲硫基]－1H－苯并咪唑於50－55℃下在30分鐘內將氯化2－氯甲基－3,4－雙(三氘代甲氧基)吡啶鎓(15.4克，66.8毫莫耳)逐滴添加於5－二氟甲氧基－1H－苯并咪唑－2－硫醇(14.5克，66.8毫莫耳)、乙醇(133毫升)及2 M NaOH水溶液(73.5毫升，147毫莫耳)之混合物中。於50－55℃下持續攪拌1－2小時，之後藉由在真空中於40℃下蒸餾去除乙醇。剩餘水性乳液用水(50毫升)稀釋並用二氯甲烷(165毫升/份)萃取三次。合併的有機相用0.1 M NaOH水溶液(165毫升)洗滌，經Na2SO4亁燥，並蒸發亁燥，獲得褐色油狀5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲硫基]－1H－苯并咪唑；產量23.8克(95%)。5-Difluoromethoxy-2-[(3,4-bis(tridemethoxy)-2-pyridyl)methylthio]-1H -benzimidazole at 50-55 ° C at 30 2-Chloromethyl-3,4-bis(trioxomethoxy)pyridinium chloride (15.4 g, 66.8 mmol) was added dropwise to 5-difluoromethoxy-1H in minutes. A mixture of benzimidazole-2-thiol (14.5 g, 66.8 mmol), ethanol (133 mL) and 2 M aqueous NaOH (73.5 mL, 147 mmol). Stirring was continued at 50-55 ° C for 1-2 hours, after which the ethanol was removed by distillation at 40 ° C in vacuo. The remaining aqueous emulsion was diluted with water (50 mL) and extracted thrice with dichloromethane (165 ml / portion). The combined organic phases were washed with aqueous 0.1 M NaOH (165 mL), dried over dry Na2 SO4 Gan, Gan and evaporated to dryness to give a brown oil 5-difluoromethoxy-2 - [(3,4-bis ( Triterpene methoxy)-2-pyridyl)methylthio]-1H -benzimidazole; yield 23.8 g (95%).
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑－大規模程序於25－35℃下在3至4小時內將次氯酸鈉水溶液(10.5公斤，10%濃度，14.2莫耳)添加於5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(10.4公斤，KF＝49.7%，14.2莫耳)與40% NaOH水溶液(2.84公斤)於水(49公升)與異丙醇(49公升)中之溶液中。於25－35℃下持續攪拌0.5－1小時，之後藉由添加1% Na2S2O3水溶液(4.3公升)使反應中止。然後，於30－45℃下在真空中蒸餾出約65公升溶劑。用水(55公升)稀釋後，藉由蒸餾去除另一部分溶劑(8－10公升)。在保持反應混合物於40－45℃下的同時，在1.5小時內添加10%乙酸水溶液(約13公升)直至達到pH 8.5－9.5為止。一旦開始結晶，則藉由添加更多10%乙酸水溶液(約0.6公升)來緩慢調節pH至6.8－7.2。冷卻至20－25℃後，濾出粗產物並用水(7.5公升)洗滌並重新溶解於水(80公升)、40% NaOH水溶液(1.6公升)及Na2S2O3(60克)之混合物中。將所得稍微渾濁的水溶液用MIBK(每次12公升)洗滌兩次並藉由Hyflo處理劑(0.40公斤)澄清，之後於40－45℃下藉由添加10%乙酸水溶液(約8公升)將pH調節至9.0－9.5。一旦產物開始結晶，添加更多10%乙酸以便持續維持pH 9.0－9.5。最後，於20－25℃下離心分離(包括用水漂洗(7.5公升))並在真空中於約50℃下亁燥，獲得灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.＝134－135℃，分解)；產量3.59公斤(65%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole - Large scale procedure to add sodium hypochlorite aqueous solution (10.5 kg, 10% strength, 14.2 mol) to 5-difluoromethoxy-2-[(3-methoxy) over a period of 3 to 4 hours at 25-35 °C -4-tridecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole (10.4 kg, KF = 49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg) in water (49 liters) in solution with isopropanol (49 liters). Stirring was continued at 25-35 ° C for 0.5-1 hour, after which the reaction was quenched by the addition of 1% aqueous Na2 S2 O3 (4.3 liters). Then, about 65 liters of solvent was distilled off in vacuo at 30-45 °C. After dilution with water (55 liters), another portion of the solvent (8-10 liters) was removed by distillation. While maintaining the reaction mixture at 40-45 ° C, 10% aqueous acetic acid (about 13 liters) was added over 1.5 hours until a pH of 8.5-9.5 was reached. Once crystallization started, the pH was slowly adjusted to 6.8-7.2 by adding more 10% aqueous acetic acid (about 0.6 liters). After cooling to 20-25 ° C, the crude product was filtered off and washed with water (7.5 liters) and redissolved in water (80 liters), 40% aqueous NaOH (1.6 liters) and Na2 S2 O3 (60 g) in. The slightly turbid aqueous solution obtained was washed twice with MIBK (12 liters each time) and clarified by Hyflo treatment (0.40 kg), followed by pH at 40-45 ° C by adding 10% aqueous acetic acid (about 8 liters). Adjust to 9.0-9.5. Once the product began to crystallize, more 10% acetic acid was added to maintain pH 9.0-9.5. Finally, it was centrifuged at 20-25 ° C (including rinsing with water (7.5 liters)) and dried in vacuo at about 50 ° C to give racemic-5-difluoromethoxy-2-[ (3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole (mp=134-135 ° C, decomposition); yield 3.59 kg ( 65%).
1H－NMR(400 MHz，DMSO－d6)：δ＝3.78(s,3H),4.67(d,13.1 Hz,1H),4.73(d,13.1 Hz,1H),7.10(d,5.5 Hz,1H),7.18(br d,8.7 Hz,1H),7.24(t,74.4 Hz,1H),7.44(br s,1H),7.70(br s,1H),8.15(d,5.5 Hz,1H),13.73(br s,1H)；LC－MS：MH＋＝387。1 H-NMR (400 MHz, DMSO-d6): δ = 3.78 (s, 3H), 4.67 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1H) ), 7.18 (br d, 8.7 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.44 (br s, 1H), 7.70 (br s, 1H), 8.15 (d, 5.5 Hz, 1H), 13.73 (br s, 1H); LC-MS: MH+ = 387.
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自濕5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(32.7克，KF＝51.6%，42.8毫莫耳)起始並根據實例14闡述之程序獲得一灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.＝133－135℃，分解)；產量10.8克(65%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-dioxomethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Self-wetting 5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridyl)methylthio]-1H -benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol, starting and according to the procedure set forth in Example 14 to give EtOAc---difluoromethoxy-2-[(3-methoxy-4-diode) as an off-white solid. Methoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole (mp = 133-135 ° C, decomposition); yield 10.8 g (65%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.32(br s,NH＋H2O),3.77(s,3H),3.86(s,1H),4.65(d,13.1 Hz,1H),4.73(d,13.1 Hz,1H),7.10(d,5.5 Hz,1H),7.15(dd,8.8 Hz,2.4 Hz,1H),7.23(t,74.4 Hz,1H),7.44(d,2.2 Hz,1H),7.69(d,8.8 Hz,1H),8.15(d,5.5 Hz,1H)；LC－MS：MH＋＝386。1 H-NMR (200 MHz, DMSO-d6): δ = 3.32 (br s, NH + H2 O), 3.77 (s, 3H), 3.86 (s, 1H), 4.65 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1H), 7.15 (dd, 8.8 Hz, 2.4 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.2 Hz, 1H) ), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5 Hz, 1H); LC-MS: MH+ = 386.
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自濕5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(34.8克，KF＝50.8%，46.5毫莫耳)起始並根據實例14闡述之程序，獲得一灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.＝134－135℃，分解)；產量14.0克(78%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Self-wetting 5-difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylthio]-1H -benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol, starting and according to the procedure as described in Example 14 to give sd.sup.5-difluoromethoxy-2-[(3-methoxy-4-monoindole) as an off white solid. Methoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole (mp = 134-135 ° C, decomposition); yield 14.0 g (78%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.78(s,3H),3.88(s,2H),4.66(d,13.2 Hz,1H),4.73(d,13.1 Hz,1H),7.10(d,5.6 Hz,1H),7.16(dd,8.8 Hz,2.4 Hz,1H),7.24(t,74.4 Hz,1H),7.45(d,2.2 Hz,1H),7.69(d,8.8 Hz,1H),8.15(d,5.5 Hz,1H),13.77(br s,1H)；LC－MS：MH＋＝385。1 H-NMR (200 MHz, DMSO-d6): δ = 3.78 (s, 3H), 3.88 (s, 2H), 4.66 (d, 13.2 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.6 Hz, 1H), 7.16 (dd, 8.8 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.45 (d, 2.2 Hz, 1H), 7.69 (d, 8.8 Hz, 1H) ), 8.15 (d, 5.5 Hz, 1H), 13.77 (br s, 1H); LC-MS: MH+ = 385.
外消旋－5－二氟甲氧基－2－[(4－甲氧基－3－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自濕5－二氟甲氧基－2－[(4－甲氧基－3－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(3.00克，KF＝19.1%，6.55毫莫耳)起始並根據實例38闡述之程序，自TBME(10毫升)結晶後獲得外消旋－5－二氟甲氧基－2－[(4－甲氧基－3－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑；一灰白色固體(m.p.＝133－134℃，分解)；產量1.83克(72%)。Racemic-5-difluoromethoxy-2-[(4-methoxy-3-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Self-wetting 5-difluoromethoxy-2-[(4-methoxy-3-tridemethoxymethoxy-2-pyridyl)methylthio]-1H -benzimidazole (3.00 g, KF) =19.1%, 6.55 mmoles starting and crystallization from TBME (10 mL) afforded racemic-5-difluoromethoxy-2-[(4-methoxy-) 3-tridemethoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole; an off-white solid (mp = 133-134 ° C, decomposed); yield 1.83 g (72%) .
1H－NMR(200 MHz，DMSO－d6)：δ＝3.90(s,3H),4.66(d,13.1 Hz,1H),4.73(d,13.1 Hz,1H),7.10(d,5.6 Hz,1H),7.15(dd,8.9 Hz,2.4 Hz,1H),7.24(t,74.4 Hz,1H),7.45(d,2.1 Hz,1H),7.69(d,8.8 Hz,1H),8.15(d,5.5 Hz,1H),13.77(br s,1H)；LC－MS：MH＋＝387。1 H-NMR (200 MHz, DMSO-d6): δ = 3.90 (s, 3H), 4.66 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.6 Hz, 1H) ), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.45 (d, 2.1 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5) Hz, 1H), 13.77 (br s, 1H); LC-MS: MH+ = 387.
外消旋－5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲硫基]－1H－苯并咪唑(23.8克，63.7毫莫耳)起始並根據以下實例38中所闡述之程序，自異丙醚(700毫升)結晶後獲得灰白色固體狀外消旋－5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑；產量20.9克(84%)。Racemic-5-difluoromethoxy-2-[(3,4-bis(tridemethoxy)-2-pyridyl)methylsulfinyl]-1H -benzimidazole 5-difluoromethoxy-2-[(3,4-bis(tridemethoxy)-2-pyridyl)methylthio]-1H -benzimidazole (23.8 g, 63.7 mmol) Starting and crystallization from isopropyl ether (700 mL) afforded EtOAc (EtOAc, m. Triterpene methoxy)-2-pyridyl)methylsulfinyl]-1H -benzimidazole; yield 20.9 g (84%).
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物於15－30℃下在10至30分鐘內將40% NaOH水溶液(0.85公斤，8.50莫耳)添加於外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(3.29公斤，8.51莫耳)存於丙酮(18公升)中之溶液中。將所得懸浮液於50－55℃下加熱直至獲得一透明溶液為止。藉由在約12小時內緩慢冷卻至10－15℃達成產物之結晶。將固體濾出並用丙酮(1.7公升)洗滌，之後自丙酮/水32：1(19公升)再結晶。最後，於50℃下在真空中亁燥，獲得灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物(m.p.＝151－152℃(分解)，KF＝4.3%)；產量2.93公斤(81%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole The sodium salt monohydrate was added to the racemic-5-difluoromethoxy-2-[(3-) at 15-30 ° C for 10 to 30 minutes in 40% aqueous NaOH (0.85 kg, 8.50 mol). a solution of methoxy-4-tridemethoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole (3.29 kg, 8.51 mol) in acetone (18 liters) in. The resulting suspension was heated at 50-55 ° C until a clear solution was obtained. Crystallization of the product was achieved by slow cooling to 10-15 °C over about 12 hours. The solid was filtered off and washed with acetone (1.7 liter) then recrystallised from acetone/water 32:1 (19 liters). Finally, it was dried in vacuo at 50 ° C to give racemic-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridine as an off white solid. Methylsulfinyl]-1H -benzimidazole sodium salt monohydrate (mp = 151-152 ° C (decomposition), KF = 4.3%); yield: 2.93 kg (81%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.78(s,3H),4.34(d,12.9 Hz,1H),4.68(d,12.9 Hz,1H),6.72(dd,8.6 Hz,2.4 Hz,1H),7.02(t,75.8 Hz,1H),7.07(d,5.6 Hz,1H),7.24(d,2.2 Hz,1H),7.44(d,8.6 Hz,1H),8.22(d,5.5 Hz,1H)；LC－MS：MNa＋＝409,MH＋＝387。1 H-NMR (200 MHz, DMSO-d6): δ = 3.78 (s, 3H), 4.34 (d, 12.9 Hz, 1H), 4.68 (d, 12.9 Hz, 1H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.02 (t, 75.8 Hz, 1H), 7.07 (d, 5.6 Hz, 1H), 7.24 (d, 2.2 Hz, 1H), 7.44 (d, 8.6 Hz, 1H), 8.22 (d, 5.5) Hz, 1H); LC-MS: MNa+ = 409, MH+ = 387.
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物自外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(8.10克，21.0毫莫耳)起始，根據實例19闡述之程序，獲得一灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－二氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物(m.p.＝150－152℃(分解)，KF＝4.8%)；產量6.05克(68%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-dioxomethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Sodium salt monohydrate from racemic-5-difluoromethoxy-2-[(3-methoxy-4-didecylmethoxy-2-pyridyl)methylsulfinyl]- Starting with 1H -benzimidazole (8.10 g, 21.0 mmol), mp. Base-4-di-deuterated methoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole sodium salt monohydrate (mp=150-152°C (decomposition), KF=4.8% ); Yield 6.05 g (68%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.77(s,3H),3.85(s,1H),4.36(d,12.9 Hz,1H),4.66(d,12.9 Hz,1H),6.73(dd,8.6 Hz,2.4 Hz,1H),7.02(t,75.8 Hz,1H),7.07(d,5.6 Hz,1H),7.25(d,2.3 Hz,1H),7.45(d,8.6 Hz,1H),8.22(d,5.5 Hz,1H)；LC－MS：MNa＋＝408,MH＋＝386。1 H-NMR (200 MHz, DMSO-d6): δ = 3.77 (s, 3H), 3.85 (s, 1H), 4.36 (d, 12.9 Hz, 1H), 4.66 (d, 12.9 Hz, 1H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.02 (t, 75.8 Hz, 1H), 7.07 (d, 5.6 Hz, 1H), 7.25 (d, 2.3 Hz, 1H), 7.45 (d, 8.6 Hz, 1H) ), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa+ = 408, MH+ = 386.
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物自外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(10.2克，26.5毫莫耳)起始，根據實例19闡述之程序，獲得一灰白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－單氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物(m.p.＝151－152℃(分解)，KF＝4.1%)；產量8.95克(79%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Sodium salt monohydrate from racemic-5-difluoromethoxy-2-[(3-methoxy-4-monodecylmethoxy-2-pyridyl)methylsulfinyl]- Starting with 1H -benzimidazole (10.2 g, 26.5 mmol), according to the procedure as described in Example 19, m. m. m. Base-4-monodeuteromethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole sodium salt monohydrate (mp=151-152°C (decomposition), KF=4.1% ); yield 8.95 g (79%).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.78(s,3H),3.88(s,2H),4.34(d,12.9 Hz,1H),4.68(d,12.9 Hz,1H),6.73(dd,8.6 Hz,2.4 Hz,1H),7.03(t,75.8 Hz,1H),7.08(d,5.5 Hz,1H),7.24(d,2.2 Hz,1H),7.44(d,8.6 Hz,1H),8.22(d,5.5 Hz,1H)；LC－MS：MNa＋＝407,MH＋＝385。1 H-NMR (200 MHz, DMSO-d6): δ = 3.78 (s, 3H), 3.88 (s, 2H), 4.34 (d, 12.9 Hz, 1H), 4.68 (d, 12.9 Hz, 1H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.03 (t, 75.8 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.24 (d, 2.2 Hz, 1H), 7.44 (d, 8.6 Hz, 1H) ), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa+ = 407, MH+ = 385.
外消旋－5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物於15－25℃下在約15分鐘內，將6 M NaOH水溶液(8.92毫升，53.5毫莫耳)添加於外消旋－5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(21.0克，53.9毫莫耳)於乙醇/二氯甲烷之6：1混合物(725毫升)中之溶液中。於室溫下再攪拌10分鐘後，蒸餾出大多數溶劑。將所得濃縮物(115克)用異丙醚(1.7公升)稀釋。剩餘一些未溶解的黑色蠟狀殘餘物，並輕輕倒出上層透明黃色溶液。向該溶液中添加另一份異丙醚(3.4公升)以使產物沉澱。將該懸浮液冷卻至0℃，並將固體濾出，用異丙醚(100毫升)洗滌並於40℃下在真空中亁燥，獲得一灰白色固體狀外消旋－5－二氟甲氧基－2－[(3,4－雙(三氘代甲氧基)－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物(KF＝4.0%)；產量18.9克(82%)。Racemic-5-difluoromethoxy-2-[(3,4-bis(tris-methoxy)-2-pyridyl)methylsulfinyl]-1H -benzimidazole sodium The salt monohydrate was added to the racemic-5-difluoromethoxy-2-[3, a 6 M aqueous NaOH solution (8.92 mL, 53.5 mmol) at 15-25 ° C for about 15 minutes. 4-bis(tridemethoxy)-2-pyridyl)methylsulfinyl]-1H -benzimidazole (21.0 g, 53.9 mmol) 6:1 in ethanol/dichloromethane In a solution of the mixture (725 ml). After stirring for an additional 10 minutes at room temperature, most of the solvent was distilled off. The resulting concentrate (115 g) was diluted with isopropyl ether (1.7 liter). Some undissolved black waxy residue remained and the upper clear yellow solution was decanted. Another portion of isopropyl ether (3.4 liters) was added to the solution to precipitate the product. The suspension was cooled to 0 ° C, and the solid was filtered, washed with EtOAc EtOAc (EtOAc) Benzyl-2-[(3,4-bis(tridemethoxy)-2-pyridyl)methylsulfinyl]-1H -benzimidazole sodium salt monohydrate (KF=4.0%) The yield was 18.9 g (82%).
1H－NMR(400 MHz，DMSO－d6)：δ＝4.32(d,12.9 Hz,1H),4.70(d,12.9 Hz,1H),6.72(dd,8.6 Hz,2.4 Hz,1H),7.04(t,75.8 Hz,1H),7.08(d,5.5 Hz,1H),7.23(d,2.4 Hz,1H),7.44(d,8.6 Hz,1H),8.22(d,5.5 Hz,1H)；LC－MS：MNa＋＝412,MH＋＝390。1 H-NMR (400 MHz, DMSO-d6): δ = 4.32 (d, 12.9 Hz, 1H), 4.70 (d, 12.9 Hz, 1H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.04 ( t,75.8 Hz,1H),7.08 (d,5.5 Hz,1H), 7.23 (d, 2.4 Hz, 1H), 7.44 (d, 8.6 Hz, 1H), 8.22 (d, 5.5 Hz, 1H); LC- MS: MNa+ = 412, MH+ = 390.
外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽倍半水合物於48－55℃將外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽單水合物(2.93公斤，6.87莫耳)溶於異丙醇(12公升)與水(0.50公升)之混合物中。用Hyflo Super Cel(56克)處理並冷卻至18－25℃後，藉由用產物之基準試樣加晶種、隨後於18－25℃下攪拌40小時並再於10－15℃下5小時完成結晶。離心分離並於45℃下在真空中亁燥，獲得一白色固體狀外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽倍半水合物(m.p.＝140－142℃(分解)，KF＝6.6%)；產量2.28公斤(78%)。Racemic-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole Sodium salt sesquihydrate to racemic-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methyl at 48-55 ° C Sulfosyl]-1H -benzimidazole sodium salt monohydrate (2.93 kg, 6.87 mol) was dissolved in a mixture of isopropanol (12 liters) and water (0.50 liters). After treatment with Hyflo Super Cel (56 g) and cooling to 18-25 ° C, seeding with the reference sample of the product, followed by stirring at 18-25 ° C for 40 hours and then at 10-15 ° C for 5 hours Crystallization is completed. The mixture was separated by centrifugation and dried in vacuo to give a white solid as a white solid as a racemic-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2) -pyridyl)methylsulfinyl]-1H -benzimidazole sodium salt sesquihydrate (mp = 140-142 ° C (decomposition), KF = 6.6%); yield 2.28 kg (78%).
雙－[外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽二水合物於40℃下將外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(500毫克，KF＝4.3%，1.17毫莫耳)存於水(10.0毫升)中之溶液進行澄清過濾。冷卻至室溫後，添加無水氯化鎂(61.4毫克，0.644毫莫耳)存於1.0毫升水中之溶液。將所得懸浮液再於室溫下攪拌18小時，之後冷卻至0℃並過濾。將濾餅在水(7.5毫升)中重新製成漿液、過濾並用水(5.0毫升)沖洗並於40℃下在真空中亁燥，獲得白色固體狀雙－[外消旋－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽二水合物(m.p.＝180－182℃(分解)；KF＝4.7%；HPLC：99.5% a/a)；產量369毫克(76%)。Bis-[racemic-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzene And imidazole]magnesium salt dihydrate will be racemic-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl) A at 40 ° C A solution of the sulfinyl]-1H-benzimidazole sodium salt (500 mg, KF = 4.3%, 1.17 mmol) in water (10.0 mL) was clarified. After cooling to room temperature, a solution of anhydrous magnesium chloride (61.4 mg, 0.644 mmol) in 1.0 ml of water was added. The resulting suspension was stirred at room temperature for additional 18 hours then cooled to 0 ° C and filtered. The filter cake was reslurried in water (7.5 ml), filtered and washed with water (5 mL) and dried in vacuo to give a white solid bis-[race--5-difluoro- Oxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole] magnesium salt dihydrate (mp=180 -182 ° C (decomposition); KF = 4.7%; HPLC: 99.5% a / a); yield 369 mg (76%).
(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑－用於未經亁燥起始材料之大規模程序於室溫下將382克濕5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(KF＝47.6%，0.540莫耳)連同(＋)－L－酒石酸雙－(N－吡咯啶醯胺)(55.0克)一起懸浮於2.44公升甲基異丁基酮中。將該混合物加熱至40℃並在真空下蒸餾出約1.25公升溶劑以去除水。然後，添加正－丙醇鋯(IV)(24.0毫升，70%存於正丙醇中)並於40℃下持續攪拌1小時以上。冷卻至30℃後，添加N－乙基異丙基胺(6.5毫升)及異丙基苯過氧化氫(103毫升，約80%濃度)。於30℃下攪拌約18小時後，TLC表明起始材料無其他轉化。將該透明反應混合物用500毫升甲基異丁基酮稀釋並用7.0克於800毫升飽和碳酸氫鈉溶液中之硫代硫酸鈉中止反應。經相分離後，用400毫升飽和碳酸氫鈉溶液將有機層洗滌兩次。向該有機相中添加1.5公升水並然後使用40%氫氧化鈉水溶液將pH調節至pH＝13。於pH 13下再用400毫升水萃取有機層。用Hyflo Super Cel(5.0克)處理後，藉由添加10%於40－45℃下之乙酸水溶液將合併水相之pH調節至約9。一旦產物開始結晶，將該混合物再攪拌12小時同時最後重新調節pH。藉由過濾(包括一水漂洗(200毫升))獲得光學純度>98%之粗產物(160克，75%產率)。(S )-5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole- 382 g of wet 5-difluoromethoxy-2-[(3-methoxy-4-tridemethoxy--2-) at room temperature for large-scale procedures without drying the starting material Pyridyl)methylthio]-1H-benzimidazole (KF = 47.6%, 0.540 mol) was suspended in 2.44 liters together with (+)-L-tartrate bis-(N-pyrrolidinium) (55.0 g) In methyl isobutyl ketone. The mixture was heated to 40 ° C and about 1.25 liters of solvent was distilled off under vacuum to remove water. Then, zirconium (IV) n-propoxide (24.0 ml, 70% in n-propanol) was added and stirring was continued at 40 ° C for 1 hour or more. After cooling to 30 ° C, N-ethylisopropylamine (6.5 ml) and cumene hydroperoxide (103 ml, about 80% concentration) were added. After stirring at 30 ° C for about 18 hours, TLC indicated no further conversion of starting material. The clear reaction mixture was diluted with 500 ml of methyl isobutyl ketone and quenched with 7.0 g of sodium thiosulfate in 800 ml of saturated sodium bicarbonate. After phase separation, the organic layer was washed twice with 400 mL of saturated sodium bicarbonate. To the organic phase was added 1.5 liters of water and then the pH was adjusted to pH = 13 using a 40% aqueous sodium hydroxide solution. The organic layer was extracted with 400 ml of water at pH 13. After treatment with Hyflo Super Cel (5.0 g), the pH of the combined aqueous phase was adjusted to about 9 by the addition of 10% aqueous acetic acid at 40-45 °C. Once the product began to crystallize, the mixture was stirred for a further 12 hours while finally re-adjusting the pH. A crude product (160 g, 75% yield) of optical purity > 98% was obtained by filtration (yield one water rinse (200 mL)).
為進一步提高純度，將粗產物溶於二氯甲烷(2.0公升)中並用水(400毫升)洗滌。藉由一含有TBME之溶劑(最終體積約1.1公升)達成結晶。將該等晶體於約0℃下濾出，用TBME(400毫升)洗滌，並於30℃下在真空中亁燥，獲得灰白色固體狀(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.＝146－148℃(分解)；KF＝0.8%)；產量135克(64%)。To further increase the purity, the crude product was dissolved in dichloromethane (2.0 liter) and washed with water (400 mL). Crystallization was achieved by a solvent containing TBME (final volume of about 1.1 liters). The other crystals were filtered off at about 0 ℃, washed with TBME (400 ml), and at 30 deg.] C Gan dryness in vacuo to give an off-white solid(S) -5- difluoromethoxy-2- [ (3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (mp=146-148°C (decomposition); KF=0.8%) The yield was 135 g (64%).
對掌性HPLC：>98.0%ee；旋光度：[α]D＝－98°(MeOH，c＝0.50)。For palmar HPLC: >98.0% ee; optical rotation: [α ]D = -98° (MeOH, c = 0.50).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.41(br s,NH＋H2O),3.77(s,3H),4.65(d,13.0 Hz,1H),4.73(d,13.1 Hz,1H),7.09(d,5.6 Hz,1H),7.15(dd,8.9 Hz,2.4 Hz,1H),7.23(t,74.4 Hz,1H),7.44(d,2.1 Hz,1H),7.68(d,8.9 Hz,1H),8.14(d,5.5 Hz,1H)；LC－MS：MH＋＝387。1 H-NMR (200 MHz, DMSO-d6): δ = 3.41 (br s, NH + H2 O), 3.77 (s, 3H), 4.65 (d, 13.0 Hz, 1H), 4.73 (d, 13.1 Hz, 1H) ), 7.09 (d, 5.6 Hz, 1H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.68 (d, 8.9) Hz, 1H), 8.14 (d, 5.5 Hz, 1H); LC-MS: MH+ = 387.
(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(70.7克，KF＝47.6%，100毫莫耳)起始並使用(－)－D－酒石酸雙－(N－吡咯啶醯胺)(10.3克，40.0毫莫耳)作為對掌性配體，根據實例25闡述之程序自TBME再結晶後獲得灰白色固體狀(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.140－142℃(分解)；KF＝0.8%)；產量22.2克(57%)。(R )-5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole 5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylthio]-1H-benzimidazole (70.7 g, KF = 47.6%) , 100 millimoles starting and using (-)-D-tartrate bis-(N-pyrrolidine) (10.3 g, 40.0 mmol) as the palmitic ligand, according to the procedure illustrated in Example 25 After recrystallization from TBME, (R )-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylsulfinyl group was obtained as an off-white solid. -1H-benzimidazole (mp 140-142 ° C (decomposition); KF = 0.8%); yield 22.2 g (57%).
對掌性HPLC：>98.0%ee；旋光度：[α]D＝＋97°(MeOH，c＝0.50)。For palmar HPLC: >98.0% ee; optical rotation: [α ]D = +97° (MeOH, c = 0.50).
1H－NMR(200 MHz，DMSO－d6)：δ＝3.77(s,3H),4.65(d,13.2 Hz,1H),4.73(d,13.1 Hz,1H),7.09(d,5.5 Hz,1H),7.16(br d,~10.3 Hz,1H),7.23(t,74.4 Hz,1H),7.44(br s,1H),7.68(br s,1H),8.14(d,5.5 Hz,1H),13.73(br s,1H)；LC－MS：MH＋＝387。1 H-NMR (200 MHz, DMSO-d6): δ=3.77 (s, 3H), 4.65 (d, 13.2 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.09 (d, 5.5 Hz, 1H) ), 7.16 (br d, ~10.3 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (br s, 1H), 7.68 (br s, 1H), 8.14 (d, 5.5 Hz, 1H), 13.73 (br s, 1H); LC-MS: MH+ = 387.
(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽於室溫下向(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(100克，0.259莫耳)存於甲基異丁基酮(750毫升)、異丙醇(75毫升)及水(5.0毫升)之混合物中之懸浮液添加40% NaOH水溶液(18.1毫升，259毫莫耳)。加熱至50℃時獲得一透明溶液，使用Hyflo Super Cel(10.0克)對其進行處理。冷卻至室溫後產物開始結晶並藉由進一步冷卻至0℃驅使結晶完成。最後，將該等晶體濾出，用甲基異丁基酮(3份，每份40毫升)洗滌並於35℃下在真空中亁燥，獲得白色吸濕固體(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(m.p.105－106℃(分解)；KF＝10.3%)；產量105克(89%)。(S )-5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium The salt is (S )-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylsulfinyl]- at room temperature a suspension of 1H-benzimidazole (100 g, 0.259 mol) in a mixture of methyl isobutyl ketone (750 ml), isopropanol (75 ml) and water (5.0 ml) was added 40% aqueous NaOH (18.1 ml, 259 mmol). A clear solution was obtained upon heating to 50 ° C and treated with Hyflo Super Cel (10.0 g). After cooling to room temperature the product began to crystallize and was driven to completion by further cooling to 0 °C. Finally, the crystals were filtered off, washed with methyl isobutyl ketone (3 parts, 40 ml portions) and dried in vacuo at 35 ° C to give a white hygroscopic solid (S )-5-difluoro Methoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt (mp 105-106 ° C (decomposition) ); KF = 10.3%); yield 105 g (89%).
對掌性HPLC：>99.0%ee；旋光度：[α]D＝－94°(MeOH，c＝0.50)。For palmar HPLC: >99.0% ee; optical rotation: [α ]D = -94° (MeOH, c = 0.50).
(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽自(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(15.5克，40.1毫莫耳)起始並根據實例27闡述之程序，獲得一白色吸濕固體(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(m.p.98－103℃(分解)；KF＝11.3%)；產量17.4克(94%)。(R )-5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium Salt from (R )-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzo Imidazole (15.5 g, 40.1 mmol) was started and obtained according to the procedure described in Example 27 to give a white hygroscopic solid (R )-5-difluoromethoxy-2-[(3-methoxy-4-) Trioxomethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium salt (mp 98-103 ° C (decomposition); KF = 11.3%); yield 17.4 g (94%).
對掌性HPLC：>98.0%ee；旋光度：[α]D＝＋91°(MeOH，c＝0.50)。For palmar HPLC: >98.0% ee; optical rotation: [α ]D = +91° (MeOH, c = 0.50).
雙－[(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽三水合物自(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(500毫克，KF＝10.3%，1.10毫莫耳)起始並根據實例24闡述之程序，獲得白色固體狀雙－[(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽三水合物(m.p.169－175℃(分解)；KF＝6.4%)；產量350毫克(75%)。Bis-[(S )-5-difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzene And imidazole]magnesium salt trihydrate from (S )-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylsulfinium Starting from the group -1H-benzimidazole sodium salt (500 mg, KF = 10.3%, 1.10 mmol) and obtained as a white solid, bis-[(S )-5-difluoro- Oxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole] magnesium salt trihydrate (mp169-175 °C (decomposition); KF = 6.4%); yield 350 mg (75%).
對掌性HPLC：>99.0%ee；旋光度：[α]D＝－122°(MeOH，c＝0.50)。For palmar HPLC: >99.0% ee; optical rotation: [α ]D = -122° (MeOH, c = 0.50).
雙－[(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽三水合物自(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(2.30克，KF＝11.3%，5.00毫莫耳)起始並根據實例24闡述之程序，獲得白色固體狀雙－[(R)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽三水合物(m.p.141－145℃(分解)；KF＝6.9%)；產量1.23克(58%)。Bis-[(R )-5-difluoromethoxy-2-[(3-methoxy-4-tridemethoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzene And imidazole]magnesium salt trihydrate from (R )-5-difluoromethoxy-2-[(3-methoxy-4-tridecylmethoxy-2-pyridyl)methylsulfinium Starting from the group -1H-benzimidazole sodium salt (2.30 g, KF = 11.3%, 5.00 mmol) and obtained the white solid as bis-[(R )-5-difluoromethyl. Oxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole] magnesium salt trihydrate (mp141-145 °C (decomposition); KF = 6.9%); yield 1.23 g (58%).
對掌性HPLC：>99.0%ee；旋光度：[α]D＝＋120°(MeOH，c＝0.50)。For palmar HPLC: >99.0% ee; optical rotation: [α ]D = +120° (MeOH, c = 0.50).
起始材料5－三氘代甲氧基－1H－苯并咪唑－2－硫醇之合成製備4－三氘代甲氧基－硝基苯於15－25℃下在2小時內向氫氧化鈉(15.6克，390毫莫耳)存於d4－甲醇(47.4毫升，1.17莫耳)與THF(50毫升)之混合物之溶液中添加1－氟－4－硝基苯(50.0克，354毫莫耳)於THF(200毫升)中之溶液。將所得懸浮液於室溫下攪拌3小時以上，之後添加10%HCl水溶液(100毫升)及甲苯(150毫升)。將有機相分離並蒸發亁燥，獲得褐色油狀4－三氘代甲氧基－硝基苯，將其靜置後結晶(m.p.48－51℃)；產量56.6克(定量)。Preparation of starting material 5-trioxomethoxy-1H -benzimidazole-2-thiol 4-Dimercaptomethoxy-nitrobenzene was oxidized at 15-25 ° C for 2 hours Add sodium 1-fluoro-4-nitrobenzene (50.0 g, 354 mil) to a solution of a mixture of d4-methanol (47.4 mL, 1.17 mol) and THF (50 mL). Mole) in THF (200 mL). The resulting suspension was stirred at room temperature for more than 3 hours, then 10% aqueous HCl (100 mL) and toluene (150 mL). The organic phase was separated and evaporated to dryness to give 4-tris-yt-methoxy-nitrobenzene as a brown oil, which was crystallised (mp 48-51 ° C); yield 56.6 g (quant.).
1H－NMR(200 MHz，DMSO－d6)：δ＝7.15(m,2H),8.22(m,2H)；GC－MS：M＋＝156。1 H-NMR (200 MHz, DMSO-d6): δ = 7.15 (m, 2H), 8.22 (m, 2H); GC-MS: M + = 156.
製備4－三氘代甲氧基－乙醯苯胺向一高壓釜中填充10%Pd/C(3.6克，水潤濕)、4－三氘代甲氧基－硝基苯(72.5克，464毫莫耳)及異丙醇(508毫升)。使用氮氣(4次)徹底吹掃後，在氫壓力(3－4巴)於50－60℃下將所得混合物攪拌直至停止吸收氫為止(約2.5小時)。將反應混合物冷卻至室溫並添加乙酸酐(62.5毫升，580毫莫耳)。持續攪拌4小時以上，然後濾出晶體並用熱2－丙醇(270毫升，約60℃)洗滌。將合併的濾液於真空中濃縮至約150毫升，添加甲基環己烷(350毫升)，並將所得漿液冷卻至10℃。過濾並於45℃在真空中亁燥，獲得淺灰色固體狀4－三氘代甲氧基－乙醯苯胺(m.p.125－127℃)；產量67.0克(86%)。Preparation of 4-tridemethoxy-acetanilide An autoclave was filled with 10% Pd/C (3.6 g, water wet), 4-tris-methoxy-nitrobenzene (72.5 g, 464). Millol) and isopropanol (508 ml). After thoroughly purging with nitrogen (4 times), the resulting mixture was stirred under hydrogen pressure (3-4 bar) at 50-60 ° C until hydrogen absorption ceased (about 2.5 hours). The reaction mixture was cooled to room temperature and acetic anhydride (62.5 mL, 580 m. Stirring was continued for more than 4 hours, then the crystals were filtered off and washed with hot 2-propanol (270 mL, ca. 60 ° C). The combined filtrate was concentrated in vacuo to ca. 150 mL, methyl cyclohexane (350 mL). Filtration and drying in vacuo at 45 ° C afforded 4-tris- methoxy-acetanilide (m.p. 125-127 ° C)
1H－NMR(200 MHz，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 (200 MHz, DMSO-d6): δ = 2.00 (s, 3H), 6.85 (m, 2H), 7.47 (m, 2H), 9.74 (br s, 1H); LC-MS: MH + =169.
製備2－硝基－4－三氘代甲氧基－苯胺於10－15℃下於1.5小時內將50%硝酸水溶液(63.0毫升，654毫莫耳)添加於4－三氘代甲氧基－乙醯苯胺(50.0克，297毫莫耳)存於乙酸(175毫升)中之溶液中。於室溫下持續攪拌18小時。然後，於15－20℃下於約1小時內添加20% NaOH水溶液(671毫升)。將所得褐色懸浮液於50℃下加熱20小時，然後藉由添加20%HCl水溶液(49毫升)調節pH至約8。藉由冷卻至10℃並過濾獲得粗產物。水漂洗一次後，於60℃下將該濾餅在異丙醇(200毫升)中製成漿液並於1小時內添加水(300毫升)。維持溫度介於50與60℃之間的同時，濾除190毫升溶劑。將所得懸浮液冷卻至10℃、過濾並用水(60毫升)洗滌，於30℃下在真空中亁燥後獲得紅色固體2－硝基－4－三氘代甲氧基－苯胺(m.p.120－122℃)；產量46.7克(92%)。Preparation of 2-nitro-4-trideuteromethoxy-phenylamine A 50% aqueous solution of nitric acid (63.0 ml, 654 mmol) was added to 4-trioxomethoxy at 1.5-15 ° C over a period of 1.5 hours. -Acetylaniline (50.0 g, 297 mmol) in solution in acetic acid (175 mL). Stirring was continued for 18 hours at room temperature. Then, 20% aqueous NaOH (671 ml) was added over 15 hours at 15-20 °C. The resulting brown suspension was heated at 50 <0>C for 20 h then the pH was adjusted to ca. The crude product was obtained by cooling to 10 ° C and filtration. After rinsing once with water, the filter cake was slurried in isopropanol (200 ml) at 60 ° C and water (300 ml) was added over 1 hour. While maintaining the temperature between 50 and 60 ° C, 190 ml of solvent was filtered off. The resulting suspension was cooled to 10 ° C, filtered and washed with water (60 ml) and dried in vacuo to give a red solid 2-nitro-4-tris- methoxy-aniline (mp 120- 122 ° C); yield 46.7 g (92%).
1H－NMR(200 MHz，DMSO－d6)：δ＝7.00(d,9.3 Hz,1H),7.16(dd,9.3 Hz,2.9 Hz,1H),7.24(br s,2H),7.37(d,2.9 Hz,1H)；GC－MS：M＋＝171。1 H-NMR (200 MHz, DMSO-d6): δ=7.00 (d, 9.3 Hz, 1H), 7.16 (dd, 9.3 Hz, 2.9 Hz, 1H), 7.24 (br s, 2H), 7.37 (d, 2.9 Hz, 1H); GC-MS: M+ = 171.
製備5－三氘代甲氧基－1H－苯并咪唑－2－硫醇向一高壓釜中填充10%Pd/C(2.23克，水潤濕)、2－硝基－4－三氘代甲氧基－乙醯苯胺(45.6克，267毫莫耳)及異丙醇(460毫升)。用氮氣(4次)徹底吹掃後，於氫壓力(3－4巴)下於40－50℃下攪拌所得混合物直至停止吸收氫為止(約6小時)。然後，添加O－乙烯基黃原酸鉀鹽(51.2克，319毫莫耳)並於回流下將反應混合物加熱23小時。添加水(340毫升)並用20% NaOH水溶液(10毫升)將pH調節至12.5，然後蒸餾出大致量的異丙醇(460毫升)。將所得黑色懸浮液用活性炭(10克)處理，藉由過濾澄清並用甲苯(350毫升)洗滌。藉由添加20%HCl水溶液(53毫升)來沉澱產物並藉由於0℃下過濾來分離。用水(100毫升)沖洗並於35℃下在陣列中亁燥，最終獲得灰白色固體狀5－三氘代甲氧基－1H－苯并咪唑－2－硫醇(m.p.247－250℃)；產量45.5克(93%)。Preparation of 5-trihalomethoxy-1H -benzimidazole-2-thiol An autoclave was filled with 10% Pd/C (2.23 g, water wet), 2-nitro-4-triterpene Methoxy-acetanilide (45.6 g, 267 mmol) and isopropanol (460 mL). After thoroughly purging with nitrogen (4 times), the resulting mixture was stirred at 40-50 ° C under hydrogen pressure (3-4 bar) until hydrogen evolution ceased (about 6 hours). Then, potassium salt ofO -vinylxanthate (51.2 g, 319 mmol) was added and the reaction mixture was heated under reflux for 23 hours. Water (340 ml) was added and the pH was adjusted to 12.5 with 20% aqueous NaOH (10 mL) and then evaporated and evaporated. The resulting black suspension was treated with EtOAc (EtOAc) (EtOAc) The product was precipitated by the addition of a 20% aqueous HCl solution (53 mL) and separated by filtration at 0 °C. Rinse with water (100 ml) and dry in an array at 35 ° C to give a 5-white methoxy-1H -benzimidazole-2-thiol (mp 247-250 ° C) as an off-white solid; 45.5 grams (93%).
1H－NMR(400 MHz，DMSO－d6)：δ＝6.67(d,2.3 Hz,1H),6.72(dd,8.7 Hz,2.4 Hz,1H),7.03(d,8.6 Hz,1H),12.36(br s,1H),12.40(br s,1H)；LC－MS：MH＋＝184。1 H-NMR (400 MHz, DMSO-d6): δ = 6.67 (d, 2.3 Hz, 1H), 6.72 (dd, 8.7 Hz, 2.4 Hz, 1H), 7.03 (d, 8.6 Hz, 1H), 12.36 ( Br s, 1H), 12.40 (br s, 1H); LC-MS: MH+ = 184.
起始材料氯化4－氯－2－氯甲基－3,5－二甲基吡啶鎓製備4－氯－2－羥甲基－3,5－二甲基吡啶於90－95℃下於7小時內將保持於約60℃的4－氯－2,3,5－三甲基吡啶－N－氧化物(60.0克，350毫莫耳)於甲苯(920毫升)中之溶液添加於乙酸酐(232毫升)中。在真空下在約60℃下，將反應混合物濃縮直至蒸餾出約820毫升為止。添加甲苯(840毫升)並再次蒸餾出溶劑(940毫升)。然後，添加甲苯(180毫升)與40% NaOH水溶液(80毫升)，然後將反應混合物於50℃下加熱約15小時。添加飽和碳酸氫鈉水溶液(120毫升)後，相分離且將水層用甲苯(80毫升)再次萃取。最後，將合併的有機相用飽和碳酸氫鈉水溶液(120毫升)洗滌並蒸發亁燥，獲得褐色油狀4－氯－2－羥甲基－3,5－二甲基吡啶，將其靜止固化；產量61.8克(定量)。Starting material 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine at 90-95 ° C A solution of 4-chloro-2,3,5-trimethylpyridine-N -oxide (60.0 g, 350 mmol) in toluene (920 ml) maintained at about 60 ° C over 7 hours was added to B. In the anhydride (232 ml). The reaction mixture was concentrated under vacuum at about 60 ° C until about 820 mL was distilled. Toluene (840 mL) was added and the solvent (940 mL) was distilled again. Then, toluene (180 ml) and 40% aqueous NaOH (80 ml) were added, and then the reaction mixture was heated at 50 ° C for about 15 hours. After a saturated aqueous solution of sodium hydrogencarbonate (120 ml) was added, the mixture was separated and evaporated. Finally, the combined organic phases were washed with aq. aq. The yield was 61.8 g (quantitative).
1H－NMR(200 MHz，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 (200 MHz, 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.
製備氯化4－氯－2－氯甲基－3,5－二甲基吡啶鎓於15－30℃下在2小時內向4－氯－2－羥甲基－3,5－二甲基吡啶(60.7克，354毫莫耳)及DMF(0.25毫升，3.54毫莫耳)存於甲苯(200毫升)的溶液中添加亞硫醯氯(26.9毫升，371毫莫耳)。於環境溫度下攪拌2小時以上後，向該稠漿液中添加乙醇(6毫升)。於約10℃下將固體濾出、用甲苯(80毫升)洗滌並於40℃下在真空中亁燥，獲得灰白色固體狀氯化4－氯－2－氯甲基－3,5－二甲基吡啶鎓(m.p.195－196℃)；產量66.5克(84%)。Preparation of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride to 4-chloro-2-hydroxymethyl-3,5-lutidine at 15-30 ° C for 2 hours (60.7 g, 354 mmol) and DMF (0.25 mL, 3.54 mmol) in toluene (200 mL). After stirring at ambient temperature for 2 hours or more, ethanol (6 ml) was added to the thick slurry. The solid was filtered, washed with EtOAc (EtOAc) (EtOAc) Pyridinium (mp 195-196 ° C); yield 66.5 g (84%).
1H－NMR(200 MHz，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 (200 MHz, 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.
5－三氘代甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑於55－65℃下在2小時內將氯化4－氯－2－氯甲基－3,5－二甲基吡啶鎓(12.6克，55.6毫莫耳)於水(21毫升)中之溶液添加於5－三氘代甲氧基－1H－苯并咪唑－2－硫醇(9.50克，51.8毫莫耳)、甲苯(47毫升)、水(23毫升)及40% NaOH水溶液(14毫升)之混合物中。於60℃下持續攪拌16小時，然後將該反應混合物冷卻至約10℃。將沉澱物離心分離出、用甲苯(17毫升)洗滌並在水(132毫升)中重新製成漿液。離心分離，隨後用一水漂洗(70毫升)並於35℃下在真空中亁燥，獲得灰白色固體狀5－三氘代甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(KF＝5.0%)(m.p.99－102℃)；產量15.1克(82%)。5-trideuteromethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole at 55-65 ° C for 2 hours A solution of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride (12.6 g, 55.6 mmol) in water (21 ml) was added to 5-trioxane methoxy A mixture of benzyl-1H -benzimidazole-2-thiol (9.50 g, 51.8 mmol), toluene (47 mL), water (23 mL) and 40% aqueous NaOH (14 mL). Stirring was continued at 60 ° C for 16 hours and then the reaction mixture was cooled to about 10 °C. The precipitate was separated by centrifugation, washed with toluene (17 mL) and re-sluded in water (132 ml). After centrifugation, it was rinsed with water (70 ml) and dried in vacuo at 35 ° C to give 5-tris-methoxy-2-[(4-chloro-3,5-dimethyl Benzyl-2-pyridyl)methylthio]-1H -benzimidazole monohydrate (KF = 5.0%) (mp 99-102 ° C); yield 15.1 g (82%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.30(s,3H),2.43(s,3H),4.72(s,2H),6.76(dd,8.7 Hz,2.5 Hz,1H),6.97(br s,1H),7.35(d,8.7 Hz,1H),8.28(s,1H),12.47(br s,1H)；LC－MS：MH＋＝337/339。1 H-NMR (200 MHz, DMSO-d6): δ = 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.97 (br s, 1H), 7.35 (d, 8.7 Hz, 1H), 8.28 (s, 1H), 12.47 (br s, 1H); LC-MS: MH+ = 337 / 339.
5－甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑自5－甲氧基－1H－苯并咪唑－2－硫醇(24.0克，111毫莫耳)起始並根據實例33闡述之程序，獲得白色固體狀5－甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(KF＝5.2%)(m.p.100－102℃)；產量34.8克(89%)。5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole from 5-methoxy-1H -benzo Imidazole-2-thiol (24.0 g, 111 mmol) was started and obtained according to the procedure of Example 33 to give 5-methoxy-2-[(4-chloro-3,5-dimethyl) as a white solid. 2-pyridyl)methylthio]-1H -benzimidazole monohydrate (KF = 5.2%) (mp 100-102 ° C); yield: 34.8 g (89%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.30(s,3H),2.43(s,3H),4.72(s,2H),6.76(dd,8.7 Hz,2,5 Hz,1H),6.98(br s,1H),7.35(d,8.7 Hz,1H),8.28(s,1 H),12.41(br s,1H)；LC－MS：MH＋＝334/336。1 H-NMR (200 MHz, DMSO-d6): δ=2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz, 2,5 Hz, 1H) , 6.98 (br s, 1H), 7.35 (d, 8.7 Hz, 1H), 8.28 (s, 1 H), 12.41 (br s, 1H); LC-MS: MH+ = 334 / 336.
5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑於60－65℃下在1.5小時內向5－三氘代甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(5.20克，14.7毫莫耳)於NMP(30毫升)之溶液中分約10等份添加固體甲醇鈉(5.80克，104毫莫耳)。於60℃下持續攪拌16小時，然後於70℃下將反應混合物加熱24小時，且最後於80℃下4小時。用水(200毫升)稀釋並添加10%HCl水溶液(10毫升)後，將所得黑褐色溶液用甲苯(100＋40毫升)萃取兩次。將合併的有機相相繼用5% NaOH水溶液(2 x 200毫升)及水(100毫升)洗滌，然後蒸發至亁。將殘餘物溶解於熱甲苯(50毫升)中，進行澄清過濾並再次蒸發至亁。最後，自TBME/甲苯10：1(33毫升)結晶，獲得白色固體狀5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑(m.p.120－121℃)；產量2.27克(46%)。5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole at 60-65 ° C 5-tridecylidene methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole monohydrate (5.20 g) over 1.5 hours Solid sodium methoxide (5.80 g, 104 mmol) was added to a solution of NMP (30 mL) in 10 portions. 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 diluting with water (200 ml) and aq. EtOAc (10 mL). The combined organic phases were washed successively with 5% aqueous NaOH solution (2 x 200 mL) and water (100 mL) and evaporated. The residue was dissolved in hot toluene (50 mL), filtered and evaporated and evaporated. Finally, it was crystallized from TBME / toluene 10:1 (33 ml) to give 5-tris-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl) as a white solid. Methylthio]-1H -benzimidazole (mp 120-121 ° C); yield 2.27 g (46%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.20(s,3H),2.27(s,3H),3.73(s,3H),4.65(s,2H),6.75(dd,8.7 Hz,2.5 Hz,1H),6.97(br s,1H),7.35(d,8.7 Hz,1H),8.17(s,1H),12.44(br s,1H)；LC－MS：MH＋＝333。1 H-NMR (200 MHz, DMSO-d6): δ=2.20 (s, 3H), 2.27 (s, 3H), 3.73 (s, 3H), 4.65 (s, 2H), 6.75 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.97 (br s, 1H), 7.35 (d, 8.7 Hz, 1H), 8.17 (s, 1H), 12.44 (br s, 1H); LC-MS: MH+ = 333.
5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑藉由以下步驟製備三氘代甲醇鈉溶液：於約50℃下在30分鐘內將d4－甲醇(1.70毫升，41.5毫莫耳)添加於氫化鈉(60%存於礦物油中，1.70克，41.5毫莫耳)存於NMP(12毫升)中之懸浮液中。加熱至60℃後，添加5－三氘代甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(2.10克，5.92毫莫耳)於NMP(4毫升)中之溶液。持續攪拌，首先於70℃下24小時，然後於85℃下5小時。隨後根據實例35所述之處理程序，獲得白色固體狀5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(m.p.120－121℃)；產量0.55克(28%)。5-trideuteromethoxy-2-[(3,5-dimethyl-4-tridemethoxymethoxy-2-pyridyl)methylthio]-1H-benzimidazole was prepared by the following procedure Triterpene sodium methoxide solution: D4-methanol (1.70 ml, 41.5 mmol) was added to sodium hydride (60% in mineral oil, 1.70 g, 41.5 mmol) in 30 min at about 50 °C. Store in a suspension in NMP (12 mL). After heating to 60 ° C, 5-trioxomethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole monohydrate was added. A solution of (2.10 g, 5.92 mmol) in NMP (4 mL). Stirring was continued, first at 70 ° C for 24 hours and then at 85 ° C for 5 hours. Subsequent to the procedure described in Example 35, 5-tris-methoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl) A was obtained as a white solid. Thio]-1H -benzimidazole (mp 120-121 ° C); yield 0.55 g (28%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.20(s,3H),2.27(s,3H),4.64(s,2H),6.75(dd,8.7 Hz,2.4 Hz,1H),6.89－7.38(br m,2H),8.17(s,1H),12.42(br s,1H)；LC－MS：MH＋＝336。1 H-NMR (200 MHz, DMSO-d6): δ=2.20 (s, 3H), 2.27 (s, 3H), 4.64 (s, 2H), 6.75 (dd, 8.7 Hz, 2.4 Hz, 1H), 6.89 -7.38 (br m, 2H), 8.17 (s, 1H), 12.42 (br s, 1H); LC-MS: MH+ = 336.
5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑自5－甲氧基－2－[(4－氯－3,5－二甲基－2－吡啶基)甲硫基]－1H－苯并咪唑單水合物(24.0克，68.2毫莫耳)起始並根據實例36所闡述之程序，獲得白色固體狀5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(m.p.119－121℃)；產量8.72克(38%)。5-methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylthio]-1H-benzimidazole from 5-methoxy-2 -[(4-Chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole monohydrate (24.0 g, 68.2 mmol) starting from Example 36 The procedure was carried out to give 5-methoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl)methylthio]-1H -benzene as a white solid. Imidazole (mp 119-121 ° C); yield 8.72 g (38%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.20(s,3H),2.27(s,3H),3.77(s,3H),4.64(s,2H),6.75(dd,8.7 Hz,2.5 Hz,1H),6.98(br s,1H),7.35(br d,8.6 Hz,1H),8.17(s,1H),12.43(br s,1H)；LC－MS：MH＋＝333。1 H-NMR (200 MHz, DMSO-d6): δ=2.20 (s, 3H), 2.27 (s, 3H), 3.77 (s, 3H), 4.64 (s, 2H), 6.75 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.98 (br s, 1H), 7.35 (br d, 8.6 Hz, 1H), 8.17 (s, 1H), 12.43 (br s, 1H); LC-MS: MH+ = 333.
外消旋－5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑將5－三氘代甲氧基－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毫莫耳)溶於CH2Cl2(15毫升)中並冷卻至－55至－40℃。於此溫度下在1.5小時內緩慢添加3－氯過氧化苯甲酸(濕，77%濃度，1.12克，5.00毫莫耳)存於CH2Cl2(8毫升)中之溶液。於－55至－40℃下1小時以上後，相繼添加三乙胺(0.87毫升，6.28毫莫耳)及6% Na2CO3水溶液與2% Na2S2O3水溶液之1：1混合物(10毫升)，同時將混合物加熱至約0℃。於環境溫度下持續攪拌1小時。相分離，且有機層用6% Na2CO3水溶液與2% Na2S2O3水溶液之1：1混合物洗滌兩次且用水(每次10毫升)洗滌一次，之後蒸發亁燥。自乙酸乙酯(6.0毫升)結晶所得殘餘物，獲得白色固體外消旋－5－三氘代甲氧基－2－[(4－甲氧基－3,5－二甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.150－152℃，分解)；產量1.27克(81%)。Racemic-5-trideuteromethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H -benzimidazole 5-Tridecyl methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H -benzimidazole (1.50 g, 4.51 m) in mole) was dissolved in CH2 Cl2 (15 mL) and cooled to -55 to -40 ℃. A solution of 3-chloroperoxybenzoic acid (wet, 77% strength, 1.12 g, 5.00 mmol) in CH2 Cl2 (8 mL) was slowly added at this temperature over 1.5 hr. After 1 hour or more at -55 to -40 ° C, a 1:1 mixture of triethylamine (0.87 ml, 6.28 mmol) and a 6% aqueous solution of Na2 CO3 and 2% Na2 S2 O3 was added . (10 ml) while heating the mixture to about 0 °C. Stirring was continued for 1 hour at ambient temperature. Phases were separated, and the organic layer was washed with 6% Na2 CO3 solution and1 2% Na 2 S 2 O 3 aqueous solution of: 1 and the mixture was washed twice with water (10 ml each), washed once, then evaporated to dryness Gan. The residue obtained was crystallized from ethyl acetate (EtOAc) (EtOAcjjjjjj Methylsulfinyl]-1H -benzimidazole (mp 150-152 ° C, decomposition); yield 1.27 g (81%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.17(s,3H),2.20(s,3H),3.69(s,3H),4.67(d,13.6 Hz,1H),4.77(d,13.5 Hz,1H),6.92(dd,8.9 Hz,2.4 Hz,1H),7.09(br s,1H),7,54(br d,8.9 Hz,1H),8.18(s,1H),13.39(br s,1H)；LC－MS：MH＋＝349。1 H-NMR (200 MHz, DMSO-d6): δ = 2.17 (s, 3H), 2.20 (s, 3H), 3.69 (s, 3H), 4.67 (d, 13.6 Hz, 1H), 4.77 (d, 13.5 Hz, 1H), 6.92 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.09 (br s, 1H), 7, 54 (br d, 8.9 Hz, 1H), 8.18 (s, 1H), 13.39 (br s, 1H); LC-MS: MH+ = 349.
外消旋－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(1.20克，3.57毫莫耳)起始並根據實例38闡述之程序，獲得一白色固體狀外消旋－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.＝147－148℃，分解)；產量0.90克(72%)。Racemic-5-trideuteromethoxy-2-[(3,5-dimethyl-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H - Benzimidazole from 5-trioxomethoxy-2-[(3,5-dimethyl-4-trideoxymethoxy-2-pyridyl)methylthio]-1H -benzimidazole (1.20 g, 3.57 mmol) starting and according to the procedure as described in Example 38, m. m. -Trisylmethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole (mp = 147-148 ° C, decomposition); yield 0.90 g (72%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.16(s,3H),2.20(s,3H),4.67(d,13.5 Hz,1H),4.77(d,13.5 Hz,1H),6.90－7.55(br m,3H),8.18(s,1H),13.39(br s,1H)；LC－MS：MH＋＝352。1 H-NMR (200 MHz, DMSO-d6): δ = 2.16 (s, 3H), 2.20 (s, 3H), 4.67 (d, 13.5 Hz, 1H), 4.77 (d, 13.5 Hz, 1H), 6.90 -7.55 (br m, 3H), 8.18 (s, 1H), 13.39 (br s, 1H); LC-MS: MH+ =352.
外消旋－5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑自5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(1.00克，3.01毫莫耳)起始並根據實例38所闡述之程序，獲得白色固體狀外消旋－5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑(m.p.143－144℃，分解)；產量0.86克(82%)。Racemic-5-methoxy-2-[(3,5-dimethyl-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole From 5-methoxy-2-[(3,5-dimethyl-4-trideoxymethoxy-2-pyridyl)methylthio]-1H -benzimidazole (1.00 g, 3.01 m) Starting and following the procedure as described in Example 38 to give racemic-5-methoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2) as a white solid. -pyridyl)methylsulfinyl]-1H -benzimidazole (mp 143-144 ° C, decomposition); yield 0.86 g (82%).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.17(s,3H),2.20(s,3H),3.81(s,3H),4.67(d,13.6 Hz,1H),4.77(d,13.5 Hz,1H),6.90－7.55(br m,3H),8.18(s,1H),13.40(br s,1H)；LC－MS：MH＋＝349。1 H-NMR (200 MHz, DMSO-d6): δ = 2.17 (s, 3H), 2.20 (s, 3H), 3.81 (s, 3H), 4.67 (d, 13.6 Hz, 1H), 4.77 (d, 13.5 Hz, 1H), 6.90-7.55 (br m, 3H), 8.18 (s, 1H), 13.40 (br s, 1H); LC-MS: MH+ = 349.
(S)－5－二氟甲氧基－2－[(3－甲氧基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽三水合物於室溫下，將5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－苯并咪唑(3.02克，9.00毫莫耳)與(＋)－L－酒石酸雙－(N－吡咯啶醯胺)(0.92克，3.60毫莫耳)懸浮於35毫升甲基異丁基酮中。將該混合物加熱至40℃並在真空下蒸餾出約8毫升溶劑以去除水。然後，添加正丙醇鋯(IV)(0.40毫升，70%存於正丙醇中，0.90毫莫耳)並於40℃下持續攪拌1小時以上。冷卻至30℃後，添加N－乙基異丙基胺(0.11毫升，0.63毫莫耳)及異丙基苯過氧化氫(1.52毫升，約80%濃度，8.55毫莫耳)。於30℃下攪拌約20小時後，將該透明反應混合物用甲基異丁基酮(8.5毫升)稀釋並用硫代硫酸鈉(0.11克)之飽和碳酸氫鈉溶液(15毫升)中止反應。相分離後，用飽和碳酸氫鈉溶液(每次7.5毫升)將有機層洗滌兩次。向該有機相中添加水(25毫升)，並用40% NaOH水溶液(0.71毫升)將pH調節至pH＝12.5－13。於pH 12.5－13(藉助添加必要量的40% NaOH水溶液)下將有機層用水(7.5毫升)萃取兩次以上。合併的有機相用二氯甲烷(15毫升)洗滌。然後，使用磷酸二氫鉀將pH調節至約10並用二氯甲烷(40毫升一次且10毫升兩次)萃取該水性溶液。蒸發有機相至亁燥，獲得褐色油狀(S)－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑，其可藉由形成相應地鈉鹽進一步純化。(S )-5-Difluoromethoxy-2-[(3-methoxy-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole sodium Salt trihydrate at room temperature, 5-trioxomethoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl)methylthio]- 1H -benzimidazole (3.02 g, 9.00 mmol) and (+)-L-tartrate bis-(N-pyrrolidinium) (0.92 g, 3.60 mmol) suspended in 35 ml of methyl isobutyl Ketone. The mixture was heated to 40 ° C and about 8 mL of solvent was distilled off under vacuum to remove water. Then, zirconium (IV) n-propoxide (0.40 ml, 70% in n-propanol, 0.90 mmol) was added and stirring was continued at 40 ° C for 1 hour or more. After cooling to 30 ° C, N-ethylisopropylamine (0.11 mL, 0.63 mmol) and isopropylbenzene hydrogen peroxide (1.52 mL, approximately 80% concentration, 8.55 mmol). After stirring at 30 ° C for about 20 hours, the reaction mixture was diluted with EtOAc EtOAc (EtOAc) After phase separation, the organic layer was washed twice with saturated sodium bicarbonate solution (7.5 mL each time). 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 12.5-13 (with the addition of 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 using potassium dihydrogen phosphate and the aqueous solution was extracted with dichloromethane (40 ml once and 10 ml twice). The organic phase was evaporated to dryness to give (S )-5-tris- methoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl) as a brown oil. Methylsulfinyl]-1H -benzimidazole, which can be further purified by formation of the corresponding sodium salt.
為此，將粗產物溶解於甲基異丁基酮(15毫升)及異丙醇(1.5毫升)中。然後，添加40% NaOH水溶液(0.63毫升)並將所得懸浮液冷卻至0℃。將固體濾出、用甲基異丁基酮(2.0毫升兩次)洗滌並於45℃下在真空中亁燥，獲得灰白色固體狀(S)－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(m.p.224－225℃(分解)，KF＝1.5%)；產量2.05克(61%)。For this, the crude product was dissolved in methyl isobutyl ketone (15 ml) and isopropyl alcohol (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 off, washed with water (2.0 ml twice) and with methyl isobutyl ketone at 45 ℃ Gan dryness in vacuo to give an off-white solid(S) -5- trideuteriomethoxy-2- [ (3,5-Dimethyl-4-trideoxymethoxy-2-pyridyl)methylsulfinyl]-1H -benzimidazole sodium salt (mp224-225 ° C (decomposition), KF= 1.5%); yield 2.05 g (61%).
對掌性HPLC：>97.0% ee；旋光度：[α]D＝－44°(MeOH，c＝0.53)、[α]D＝＋39°(H2O、c＝0.39)。For palmar HPLC: >97.0% ee; optical rotation: [α]D = -44° (MeOH, c = 0.53), [α]D = +39° (H2 O, c = 0.39).
1H－NMR(200 MHz，DMSO－d6)：δ＝2.18(s,3H),2.21(s,3H),4.39(d,12.9 Hz,1H),4.63(d,12.9 Hz,1H),6.54(dd,8.7 Hz,2.5 Hz,1H),6.98(d,2.5 Hz,1H),7,32(br d,8.6 Hz,1H),8.23(s,1H)。1 H-NMR (200 MHz, DMSO-d6): δ = 2.18 (s, 3H), 2.21. (s, 3H), 4.39 (d, 12.9 Hz, 1H), 4.63 (d, 12.9 Hz, 1H), 6.54 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.98 (d, 2.5 Hz, 1H), 7, 32 (br d, 8.6 Hz, 1H), 8.23 (s, 1H).
雙－[(S)－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽自(S)－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑鈉鹽(200毫克，KF＝1.5%，0.528毫莫耳)起始並根據實例24闡述之程序，獲得白色固體狀雙－[(S)－5－三氘代甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑]鎂鹽三水合物(m.p.161－162℃(分解)；KF＝1.5%)；產量132毫克(68%)。Bis-[(S )-5-trideuteromethoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl)methylsulfinyl]- 1H-benzimidazole]magnesium salt from (S )-5-tridecylmethoxy-2-[(3,5-dimethyl-4-tridemethoxymethoxy-2-pyridyl)methyl Sulfosyl]-1H-benzimidazole sodium salt (200 mg, KF = 1.5%, 0.528 mmol) was started and obtained from the procedure of Example 24 to give bis-[(S )-5- as a white solid. Triterpene methoxy-2-[(3,5-dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole] magnesium salt Hydrate (mp 161-162 ° C (decomposition); KF = 1.5%); yield 132 mg (68%).
對掌性HPLC：>97.0%ee；旋光度：[α]D＝－120°(MeOH，c＝0.50)。For palmar HPLC: >97.0% ee; optical rotation: [α ]D = -120° (MeOH, c = 0.50).
藉由適當組合上述之程序，亦可獲得通式(1)之其他化合物：舉例而言，可根據根據實例7所闡述之程序使氯化4－氯－2－氯甲基－3－甲基吡啶鎓與1H－苯并咪唑－2－硫醇反應獲得2－[(4－氯－3－甲基－2－吡啶基)甲硫基]－1H－苯并咪唑。然後根據實例9所闡述之規定使用(例如)1,1－二氘代－3－甲氧基－1－丙醇或1,1－二氘代－2,2,2－三氟乙醇將此產物轉化，導致分別形成2－[(4－(1,1－二氘代－3－甲氧基丙－1－氧基)－3－甲基－2－吡啶基)甲硫基]－1H－苯并咪唑及2－[(4－(1,1－二氘代－2,2,2－三氟乙氧基)－3－甲基－2－吡啶基)甲硫基]－1H－苯并咪唑。最後，根據實例38中所用之程序氧化該等化合物將分別獲得外消旋－2－[(4－(1,1－二氘代－3－甲氧基丙－1－氧基)－3－甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑及外消旋－2－[(4－(1,1－二氘代－2,2,2－三氟乙氧基)－3－甲基－2－吡啶基)甲基亞磺醯基]－1H－苯并咪唑，該等兩種化合物皆代表式(1)之化合物。Other compounds of the general formula (1) can also be obtained by appropriate combination of the above procedures: for example, 4-chloro-2-chloromethyl-3-methyl chloride can be obtained according to the procedure as described in Example 7. Pyridinium is reacted with 1H -benzimidazole-2-thiol to give 2-[(4-chloro-3-methyl-2-pyridyl)methylthio]-1H -benzimidazole. This was then carried out according to the procedure set forth in Example 9 using, for example, 1,1-diindole-3-methoxy-1-propanol or 1,1-dideutero-2,2,2-trifluoroethanol. Conversion of the product results in the formation of 2-[(4-(1,1-dioxo-3-methoxyprop-1-yloxy)-3-methyl-2-pyridyl)methylthio]-1, respectivelyH -benzimidazole and 2-[(4-(1,1-dioxo-2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl)methylthio]-1H -benzimidazole. Finally, oxidation of the compounds according to the procedure used in Example 38 gave the racemic-2-[(4-(1,1-diindole-3-methoxyprop-1-yloxy)-3-, respectively. Methyl-2-pyridyl)methylsulfinyl]-1H -benzimidazole and racemic-2-[(4-(1,1-dioxo-2,2,2-trifluoro) Ethoxy)-3-methyl-2-pyridyl)methylsulfinyl]-1H -benzimidazole, both of which represent a compound of formula (1).
另一實例，可根據實例33所闡述之程序使氯化4－氯－2－氯甲基－3,5－二甲基吡啶鎓與5－甲氧基－1H－咪唑并[4,5－b]吡啶－2－硫醇反應，獲得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。然後根據實例36所闡述之規定使用d4－甲醇將此產物轉化，導致形成5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲硫基]－1H－咪唑并[4,5－b]吡啶，其進而可根據實例38中所用之程序氧化成外消旋－5－甲氧基－2－[(3,5－二甲基－4－三氘代甲氧基－2－吡啶基)甲基亞磺醯基]－1H－咪唑并[4,5－b]吡啶，即，式(1)之另一化合物。In another example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride can be combined with 5-methoxy-1H -imidazolium [4,5] according to the procedure set forth in Example 33. -b ] Pyridine-2-thiol reaction to obtain 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridyl)methylthio]-1H -imidazo[ 4,5-b ]pyridine. This product was then converted using d4-methanol according to the procedure set forth in Example 36, resulting in the formation of 5-methoxy-2-[(3,5-dimethyl-4-tridecylmethoxy-2-pyridyl) Methylthio]-1H -imidazo[4,5-b ]pyridine, which in turn can be oxidized to racemic-5-methoxy-2-[(3,5-) according to the procedure used in Example 38. Dimethyl-4-trideuteromethoxy-2-pyridyl)methylsulfinyl]-1H -imidazo[4,5-b ]pyridine, ie, another compound of formula (1) .
通式1之化合物及其鹽及溶合物(較佳水合物)、及該等鹽之溶合物(較佳水合物)(下文稱為「本發明化合物」)具有有用之藥理學性質，此使得其具有商業利用性。特定而言，其在恒溫動物(尤其是人類)中對胃酸分泌具有顯著的抑制效果且具有極佳的胃腸保護作用。此處，本發明化合物的特徵為：作用選擇性高、作用持續時間有利、生物利用率特別高、在不同個體中代謝曲線一致、無明顯副作用以及治療範圍寬。The compound of the formula 1 and salts and solvates thereof (preferably hydrates), and the salts of the salts (preferably hydrates) (hereinafter referred to as "the compounds of the invention") have useful pharmacological properties. This makes it commercially viable. In particular, it has a significant inhibitory effect on gastric acid secretion in a warm-blooded animal, especially a human, and has an excellent gastrointestinal protective effect. Here, the compounds of the present invention are characterized by high selectivity of action, favorable duration of action, particularly high bioavailability, consistent metabolic profiles in different individuals, no significant side effects, and a wide therapeutic range.
在這裏，「胃腸保護」應理解為胃腸病的預防與治療，尤其是由(例如)微生物(例如，幽門螺旋桿菌(Helicobacter pylori))、細菌毒素、醫藥組合物(例如，某些消炎藥及抗風濕藥)、化學品(例如，乙醇)、胃酸或緊張引起的胃腸炎症及損傷(例如，胃潰瘍、十二指腸潰瘍、胃炎、因酸性產物增加或由醫藥組合物導致的易感性腸、GERD、克隆氏病(Crohn's disease)、IBD)。Here, "gastrointestinal protection" is to be understood as prevention and treatment of gastrointestinal diseases, in particular, for example, by microorganisms (for example, Helicobacter pylori), bacterial toxins, pharmaceutical compositions (for example, certain anti-inflammatory drugs and Gastrointestinal inflammation and damage caused by anti-rheumatic drugs, chemicals (eg, ethanol), stomach acid or stress (eg, gastric ulcer, duodenal ulcer, gastritis, increased intestinal acid, or susceptibility to intestinal GERD, cloning due to pharmaceutical composition) Crohn's disease, IBD).
由於本發明化合物在各種用於確定抗潰瘍與抗痙攣性質之模型中的優良性質，其令人驚奇的證明明顯優於先前技術化合物，尤其在其代謝性質方面。該等經改良之代謝性質允許(例如)減少一治療或預防所需本發明化合物之量。或藉由使用與先前技術化合物所用相同量之本發明化合物可達成更長之作用持續時間。與該等性質相關的優點涉及患者安全或經濟方面(例如，相同的藥費等)。由於該些性質，本發明之化合物非常適用於人類藥物及獸藥，其中該些化合物尤其用於胃腸病的治療及/或預防。Due to the excellent properties of the compounds of the invention in various models for determining anti-ulcer and anti-caries properties, their surprising evidence is clearly superior to prior art compounds, especially in terms of their metabolic properties. Such improved metabolic properties allow, for example, a reduction in the amount of a compound of the invention required to treat or prevent. A longer duration of action can be achieved by using the same amount of the compound of the invention as used in the prior art compounds. Advantages associated with such properties relate to patient safety or economic aspects (eg, the same medication fee, etc.). Due to these properties, the compounds of the present invention are highly suitable for use in human pharmaceuticals and veterinary medicines, among which these compounds are especially useful for the treatment and/or prevention of gastrointestinal diseases.
因此，本發明另外提供本發明化合物用於治療及/或預防上述疾病的用途。Accordingly, the invention further provides the use of a compound of the invention for the treatment and/or prophylaxis of the above mentioned diseases.
本發明亦涵蓋本發明化合物用於製備醫藥組合物之用途，該等組合物係用於治療及/或預防上述疾病。The invention also encompasses the use of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of the above mentioned diseases.
本發明亦提供包含本發明化合物之醫藥組合物。特定而言，本發明提供包含式1、1a或1b化合物以固體形式口服使用之醫藥組合物，該等化合物呈其鹽(尤其呈鈉或鎂鹽形式)及/或呈該鹽之水合物形式。The invention also provides pharmaceutical compositions comprising a compound of the invention. In particular, the present invention provides a pharmaceutical composition comprising a compound of formula 1, 1a or 1b for oral use in solid form, the compound being in the form of a salt thereof, especially in the form of a sodium or magnesium salt, and/or in the form of a hydrate of the salt .
該等醫藥組合物可以其自身已為熟習該項技術者習知之方法製備。作為醫藥組合物，本發明化合物可以本身形式使用或較佳與適宜醫藥助劑或載劑結合以錠劑、包衣錠劑、膠囊、栓劑、藥膏(例如作為TTS)、乳劑、懸浮液或溶液形式使用，其中活性化合物的含量較佳自約0.1至約95%且其可藉由適當選擇助劑及載劑製成適合於該活性化合物及/或期望作用開始時間及/或作用持續時間的醫藥劑型(例如，流動釋放型或經腸型)。Such pharmaceutical compositions can be prepared by themselves in a manner known to those skilled in the art. As a pharmaceutical composition, the compound of the present invention may be used as it is or preferably in combination with a suitable pharmaceutical adjuvant or carrier in the form of a troche, a lozenge, a capsule, a suppository, an ointment (for example as a TTS), an emulsion, a suspension or a solution. The form is used in which the active compound is preferably present in an amount of from about 0.1 to about 95% and can be prepared by suitable selection of adjuvants and carriers for the active compound and/or the desired duration of action and/or duration of action. A pharmaceutical dosage form (eg, a fluid release or enteral type).
適用於期望醫藥調配物之助劑或載劑已為熟習該項技術者習知。除溶劑、凝膠成型劑、栓劑基質、壓片助劑及其他適合於活性化合物的載劑以外，可使用(例如)抗氧化劑、分散劑、乳化劑、消泡劑、氣味掩蔽劑、防腐劑、增溶劑、著色劑或(特定而言)滲透促進劑及錯合物形成劑(例如，環糊精)。Auxiliaries or carriers suitable for the desired pharmaceutical formulation are well known to those skilled in the art. In addition to solvents, gel forming agents, suppository bases, tableting aids and other carriers suitable for the active compound, for example, antioxidants, dispersants, emulsifiers, defoamers, odor masking agents, preservatives can be used. , solubilizers, colorants or (particularly) penetration enhancers and complex forming agents (eg, cyclodextrins).
本發明化合物可經口、非經腸或經皮投與。The compounds of the invention may be administered orally, parenterally or transdermally.
在人類藥物中，已發現，當經口投與時，若期望複數個、較佳1至4個單獨劑量形式，則通常較佳以約0.01至約1、較佳約0.02至約0.5且尤其約0.04至約0.3毫克/公斤體重[根據本發明化合物之游離形式計算，即非鹽形式(＝「游離化合物」)]之日劑量投與本發明化合物以獲得期望結果。對於非經腸治療而言，可使用類似或(尤其當活性化合物靜脈內投與時)通常較低的劑量。所屬領域的技術人員可容易地確定所有情況下所需活性化合物的最佳劑量及投與形式。In human pharmaceuticals, it has been found that when administered orally, if a plurality, preferably from 1 to 4, of individual dosage forms are desired, it is usually preferably from about 0.01 to about 1, preferably from about 0.02 to about 0.5, and especially A daily dose of from about 0.04 to about 0.3 mg/kg body weight [calculated according to the free form of the compound of the invention, i.e., the non-salt form (= "free compound"), is administered to the compound of the invention to achieve the desired result. For parenteral treatment, a dose that is similar or (especially when the active compound is administered intravenously) is generally used. One of ordinary skill in the art can readily determine the optimal dosage and form of administration of the active compound desired in all circumstances.
因此，本發明另一態樣係一種醫藥組合物，其包含一或多種本發明化合物連同一或多種常用助劑，其中該單一劑量包含約2至約60毫克之游離化合物。Accordingly, another aspect of the invention is a pharmaceutical composition comprising one or more compounds of the invention in association with one or more conventional adjuvants, wherein the single dose comprises from about 2 to about 60 mg of free compound.
本發明再一態樣係一種醫藥組合物，其包含一或多種本發明化合物連同一或多種常用助劑，其中該單一劑量包含約4至約40毫克的游離化合物。A further aspect of the invention is a pharmaceutical composition comprising one or more compounds of the invention in association with one or more conventional adjuvants, wherein the single dose comprises from about 4 to about 40 mg of free compound.
本發明又一態樣係本發明化合物用於治療胃腸病之用途。A further aspect of the invention is the use of a compound of the invention for the treatment of a gastrointestinal disorder.
本發明另一態樣係本發明化合物用於治療代謝緩慢患者的胃腸病之用途。Another aspect of the invention is the use of a compound of the invention for the treatment of gastrointestinal disorders in patients with slow metabolism.
本發明再一態樣係本發明化合物用於治療有藥物相互作用危險患者的胃腸病的用途。A further aspect of the invention is the use of a compound of the invention for the treatment of a gastrointestinal disorder in a patient at risk of drug interaction.
本發明又一態樣係本發明化合物用於治療需要長時間抑制胃酸分泌的患者的胃腸病的用途。A further aspect of the invention is the use of a compound of the invention for the treatment of a gastrointestinal disorder in a patient in need of prolonged inhibition of gastric acid secretion.
本發明再一態樣係一種用於治療代謝緩慢患者的胃腸病之醫藥組合物，其包括一或多種本發明之化合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克的游離化合物。A further aspect of the invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient with slow metabolism comprising one or more compounds of the invention in association with one or more conventional auxiliaries, wherein a single dose comprises from about 2 to about 60 mg. Free compound.
本發明再一態樣係一種用於治療代謝緩慢患者的胃腸病之醫藥組合物，其包括一或多種本發明之化合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克的游離化合物。A further aspect of the invention is a pharmaceutical composition for the treatment of gastrointestinal disorders in patients with slow metabolism comprising one or more compounds of the invention in association with one or more conventional auxiliaries, wherein a single dose comprises from about 4 to about 40 mg. Free compound.
本發明再一態樣係一種用於治療有藥物相互作用危險患者的胃腸病之醫藥組合物，其包括一或多種本發明之化合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克的游離化合物。A further aspect of the invention is a pharmaceutical composition for the treatment of a gastrointestinal disorder in a patient at risk of drug interaction, comprising one or more compounds of the invention in association with one or more conventional auxiliaries, wherein a single dose comprises from about 2 to about 60 mg of free compound.
本發明再一態樣係一種用於治療有藥物相互作用危險患者的胃腸病之醫藥組合物，其包括一或多種本發明之化合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克的游離化合物。A further aspect of the invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient at risk of drug interaction, comprising one or more compounds of the invention in association with one or more conventional auxiliaries, wherein a single dose comprises from about 4 to about 40 mg of free compound.
本發明另一態樣係一種用於治療需要長時間抑制胃酸分泌的患者的醫藥組合物，其包括一或多種本發明化合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克的游離化合物。Another aspect of the invention is a pharmaceutical composition for treating a patient in need of prolonged inhibition of gastric acid secretion comprising one or more compounds of the invention in association with one or more conventional adjuvants, wherein a single dose comprises from about 2 to about 60 mg Free compound.
本發明另一態樣係一種用於治療需要長時間抑制胃酸分泌的患者的醫藥組合物，其包括一或多種本發明之化合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克的游離化合物。Another aspect of the invention is a pharmaceutical composition for treating a patient in need of prolonged inhibition of gastric acid secretion comprising one or more compounds of the invention in association with one or more conventional adjuvants, wherein a single dose comprises from about 4 to about 40 Millions of free compound.
本發明再一態樣係一種用於治療代謝緩慢患者的胃腸病的醫藥組合物，其包括呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克游離化合物。A further pharmaceutical composition for treating a gastrointestinal disorder in a patient with slow metabolism, comprising one or more salts of the invention or a hydrate thereof in an oral solid form, together with one or more conventional adjuvants, wherein A single dose will contain from about 2 to about 60 mg of free compound.
本發明另一態樣係一種用於治療代謝緩慢患者的胃腸病的醫藥組合物，其包含呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克游離化合物。Another aspect of the invention is a pharmaceutical composition for treating a gastro-intestinal disease in a patient with slow metabolism, comprising one or more salts of the invention or a hydrate thereof in an oral solid form, together with one or more conventional adjuvants, wherein A single dose will contain from about 4 to about 40 mg of free compound.
本發明另一態樣係一種用於治療有藥物相互作用危險患者的胃腸病的醫藥組合物，其包含呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克游離化合物。Another aspect of the invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient at risk of drug interaction, comprising one or more salts of the invention or a hydrate thereof in an oral solid form, together with one or more common auxiliaries A single dose comprising from about 2 to about 60 mg of free compound.
本發明另一態樣係一種用於治療有藥物相互作用危險患者的胃腸病的醫藥組合物，其包含呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克游離化合物。Another aspect of the invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient at risk of drug interaction, comprising one or more salts of the invention or a hydrate thereof in an oral solid form, together with one or more common auxiliaries A single dose comprising from about 4 to about 40 mg of free compound.
本發明另一態樣係用於治療需要長時間抑制胃酸分泌患者的腸胃病的醫藥組合物，其包括呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約2至約60毫克的游離化合物。Another aspect of the present invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient in need of prolonged inhibition of gastric acid secretion, comprising one or more salts of the present invention or a hydrate thereof in an orally administered form, together with one or more common auxiliaries A single dose comprising from about 2 to about 60 mg of free compound.
本發明另一態樣係用於治療需要長時間抑制胃酸分泌患者的腸胃病的醫藥組合物，其包括呈口服固體施用形式的一或多種本發明之鹽或其水合物連同一或多種常用助劑，其中單一劑量包含約4至約40毫克的游離化合物。Another aspect of the present invention is a pharmaceutical composition for treating a gastrointestinal disorder in a patient in need of prolonged inhibition of gastric acid secretion, comprising one or more salts of the present invention or a hydrate thereof in an orally administered form, together with one or more common auxiliaries A single dose comprising from about 4 to about 40 mg of free compound.
若使用本發明化合物治療上述疾病，則該等醫藥製劑亦可包括一或多種來自其他類醫藥組合物的醫藥活性成份。可提及的實例包括鎮靜劑(例如，來自苯并二氮呯類，例如，二氮呯(diazepam))、抗痙攣藥(例如，苯哌乙胺酯(bietamiverine)或胺苯戊酯(camylofine))、抗膽鹼藥(例如，羥苄利明(oxyphencyclimine)或苯卡巴胺(phencarbamide))、局部麻醉劑(例如，丁卡因(tetracaine)或普魯卡因(procaine))，且視情況亦包括酶、維生素或氨基酸。If a compound of the invention is used to treat the above mentioned conditions, the pharmaceutical preparations may also include one or more pharmaceutically active ingredients from other pharmaceutical compositions. Examples which may be mentioned include sedatives (for example, from benzodiazepines, for example, diazepam), antispasmodics (for example, bietamiverine or camyllofine). ), an anticholinergic agent (eg, oxyphencyclimine or phencarbamide), a local anesthetic (eg, tetracaine or procaine), and optionally enzymes, vitamins Or an amino acid.
在這裏，著重闡述本發明化合物與其他可緩衝或中和胃酸或抑制胃酸分泌的藥物(例如，抗酸劑(例如，鎂加鋁(magaldrate))或H2阻斷劑(例如，西眯替丁(cimetidine)、雷尼替丁(ranitidine))及與胃泌激素拮抗劑之組合，其目的係以相加或超加和程度增強主要作用及/或消除或緩解副作用或使作用更快速地開始。亦應提及與以下物質的固定或自由組合：NSAID(例如，依託芬那酯(etofenamate)、雙氯芬酸(diclofenac)、吲哚美辛(indometacin)、布洛芬(ibuprofen)或吡羅昔康(piroxicam))，以預防由NSAID造成的胃腸損害；或緩和胃腸蠕動的化合物；或減少瞬時下食管括約肌鬆弛(TLOSR)發病率的化合物；或抗菌物質(例如，頭孢菌素(cephalosporin)、四環素(tetracyclin)、青黴素(penicillin)、大環內酯類、硝基咪唑或其他鉍鹽)，以控制幽門螺旋桿菌。可提及之抗菌組合搭配劑包括(例如)美洛西林(mezlocillin)、氨苄西林(ampicillin)、阿莫西林(amoxicillin)、頭孢噻吩(cefalothin)、頭孢西丁(cefoxitin)、頭孢噻肟(cefotaxim)、亞胺培南(imipenem)、慶大黴素(gentamycin)、丁胺黴素(amicacin)、紅黴素(erythromycin)、環丙沙星(ciprofloxadin)、甲硝唑(metronidazole)、克拉黴素(clarithromycin)、阿爾奇毒素(azithromycin)及其組合(例如，克拉黴素＋甲硝唑或阿莫西林＋克拉黴素)。Here, the compounds of the present invention are highlighted with other drugs that can buffer or neutralize gastric acid or inhibit gastric acid secretion (for example, antacids (for example, magnesium plus magnesium) or H2 blockers (for example, cichreidine) Cimetidine, ranitidine, and a combination with a gastrin antagonist, the purpose of which is to increase the primary effect and/or eliminate or alleviate side effects or to make the effect faster by adding or superadding Beginning. Reference should also be made to fixed or free combinations with NSAIDs (eg, etofenamate, diclofenac, indometacin, ibuprofen or piroxicam). Piroxicam) to prevent gastrointestinal damage caused by NSAIDs; or compounds that alleviate gastrointestinal motility; or compounds that reduce the incidence of transient lower esophageal sphincter relaxation (TLOSR); or antibacterial substances (eg, cephalosporin, Tetracyclin, penicillin, macrolide, nitroimidazole or other guanidinium salts to control H. pylori. Antibacterial combination collocations may include, for example, mezlocillin , ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxim, imipenem, gentamycin, Amicacin, erythromycin, ciprofloxadin, metronidazole, clarithromycin, azithromycin, and combinations thereof (eg, carat Neomycin + metronidazole or amoxicillin + clarithromycin).
在本發明實踐中，本發明化合物可在組合治療中與一或多種彼等上述標準治療劑單獨、相繼、同時或時間交錯(例如，作為組合單位劑型、作為單獨單位劑型、作為相鄰離散單位劑型、作為固定或不固定組合、作為成份套組或作為混合物)投與。In the practice of the invention, the compounds of the invention may be staggered, in combination, with one or more of the above standard therapeutic agents, alone, sequentially, simultaneously or in time (eg, as a combined unit dosage form, as a separate unit dosage form, as an adjacent discrete unit). The dosage form, as a fixed or unfixed combination, as a component kit or as a mixture, is administered.
本發明之術語「組合」可作為一固定組合、不固定組合或成份套組存在。The term "combination" of the present invention may exist as a fixed combination, an unfixed combination, or a kit of ingredients.
「固定組合」係定義成其中第一活性成份與第二活性成份一起存在於一單位劑量或一單一實體中之組合。「固定組合」之一實例係一種醫藥組合物，其中該第一活性成份與該第二活性成份係存在於一同時投與之混合物(例如，調配物)中。「固定組合」之另一實例係一種醫藥組合物，其中該第一活性成份與該第二活性成份係存在於一個單位而不在一混合物中。A "fixed combination" is defined as a combination in which a first active ingredient is present in a unit dose or a single entity together with a second active ingredient. An example of a "fixed combination" is a pharmaceutical composition wherein the first active ingredient and the second active ingredient are present in a simultaneously administered mixture (e.g., a formulation). Another example of a "fixed combination" is a pharmaceutical composition wherein the first active ingredient and the second active ingredient are present in one unit and not in a mixture.
「成份套組」係定義成一種其中該第一活性成份與該第二活性成份存在於一個以上單位中之組合。「成份套組」之一實例係一其中該第一活性成份與該第二活性成份分別存在之組合。該成份套組之組份可分別、相繼、同時或時間交錯投與。A "component set" is defined as a combination wherein the first active ingredient and the second active ingredient are present in more than one unit. An example of a "component set" is a combination wherein the first active ingredient and the second active ingredient are separately present. The components of the component kit can be administered separately, sequentially, simultaneously or in time.
潘托拉唑或實例1或2(每一個10 μM)用肝微粒體(來源：除Mini Pig自TEBU購得以外，所有皆自GenTest購得)培育，在1毫克/毫升蛋白質、100 mM Tris－HCl(pH 7.4)、1 mM NADPH2中進行培育。90分鐘後用液態氮終止反應，然後用HPLC(10 mM KH2PO4，pH 7.4，乙腈梯度20－44%)檢測母體化合物。Pantoprazole or Example 1 or 2 (each 10 μM) was incubated with liver microsomes (source: all purchased from GenTest except for Mini Pig from TEBU) at 1 mg/ml protein, 100 mM Tris Incubation was carried out in -HCl (pH 7.4), 1 mM NADPH2 . After 90 minutes, the reaction was quenched with liquid nitrogen, and then the title compound was detected by HPLC (10 mM KH2 PO4 , pH 7.4, acetonitrile gradient 20-44%).
為評價本發明化合物之性質，確定該等化合物在重組人油胞色素P450(CYP)同工酶CYP1A2、CYP2C8、CYP2C19、CYP2D6、CYP3A4及CYP3A5中之固有清除率。To assess the nature of the compounds of the invention, the intrinsic clearance of these compounds in recombinant human oil cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 was determined.
於37℃下將闡述於實例17、19、20、21、27、28、38、39、40及41中之化合物及未經氘代之外消旋奧美派唑、其(S)－對映異構體及未經氘代之潘托拉唑及其對映異構體在緩衝液中培養0、3、6、12及15或30分鐘，該緩衝液包含1奈莫耳/毫升重組P450(Cypex，Dundee，UK)、4毫克/毫升微粒體蛋白質、100毫莫耳/公升Tris－HCl(pH 7.4)及1毫莫耳/公升NADPH。一式三份進行培養。為使用CYP2C19進行培養，將P450濃度降低至0.5奈莫耳/毫升且培養間隔變成0、1、2、3、4及5分鐘。根據母體化合物之消失速率測定固有清除率。藉由HPLC－UV測定奧美派唑及該等氘代類似物。基於實驗差異性之分析解析度下限係17.6微升/分鐘/奈莫耳P450。The compounds described in Examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41 and the non-deuterated racemic Omeprazole, (S)-pair thereof at 37 °C Peptone and undeuterated pantoprazole and its enantiomers were incubated in buffer for 0, 3, 6, 12 and 15 or 30 minutes. The buffer contained 1 nanomol/ml recombination. P450 (Cypex, Dundee, UK), 4 mg/ml microsomal protein, 100 millimoles/liter Tris-HCl (pH 7.4) and 1 millimol/liter NADPH. Culture was carried out in triplicate. For culturing using CYP2C19, the P450 concentration was lowered to 0.5 NM/ml and the culture interval was changed to 0, 1, 2, 3, 4 and 5 minutes. The intrinsic clearance is determined based on the rate of disappearance of the parent compound. Omeprazole and the deuterated analogs were determined by HPLC-UV. The analytical lower limit based on experimental differences was 17.6 μl/min/Nemo P450.
發現CYP2C19與CYP3A4有助於奧美派唑、潘托拉唑與其氘代類似物之氧化代謝。所有其他細胞色素P450同工酶(CYP1A2、CYP2C8、CYP2C9、CYP2D6、CYP3A5)在分析分辨率下限以上對所研究任何化合物之代謝皆無幫助。It was found that CYP2C19 and CYP3A4 contribute to the oxidative metabolism of omeprazole, pantoprazole and its progeny analogs. All other cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the compounds studied above the lower limit of analytical resolution.
經由P450酵素評價本發明化合物之代謝清除率後，確定在人類中所鑑別之主要代謝物(即，對於奧美派唑5－羥基－奧美派唑(5－甲氧基－2[[(4－甲氧基－3－甲基－5－羥甲基－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑)及對於潘托拉唑5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑)的形成動力學。5－羥基－奧美派唑與5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑之產生主要係由CYP2C19實施。我們選擇混合人類經冷藏肝細胞作為比人類肝微粒體更佳的活體外體系，此乃因所有主要藥物代謝酵素(階段I、階段II水解酶)在該活體外體系中皆起作用。After assessing the metabolic clearance of the compounds of the invention via P450 enzymes, the major metabolites identified in humans were identified (ie, for Omeprazole 5-hydroxy-omeprazole (5-methoxy-2[[( 4-methoxy-3-methyl-5-hydroxymethyl-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole) and pantoprazole 5-(difluoromethyl) Formation kinetics of oxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole). 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]- The production of 1H-benzimidazole is mainly carried out by CYP2C19. We chose to mix human chilled hepatocytes as a better in vitro system than human liver microsomes, since all major drug metabolizing enzymes (stage I, phase II hydrolase) play a role in this in vitro system.
將闡述於實例17、19、20、21、27、28、38、39、40及41中之化合物及未經氘代之外消旋奧美派唑、其(S)－對映異構體及未經氘代之潘托拉唑及其對映異構體培養於Krebs Henseleit Puffer(KHB)中，其包含84微克/毫升阿米卡星(amikacin)、1毫莫耳/公升氯化鈣、20毫莫耳/公升Hepes、4.2微莫耳/公升益甘陀酸(hepatdnic acid)、28.5毫莫耳/公升碳酸氫鈉及濃度為106個細胞/毫升之人類經冷藏肝細胞(10個捐贈者庫，InVitro Technologies，Baltimore，MD USA)。在該等條件下5－羥基－奧美派唑及5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑(M2)形成速率在60分鐘之前呈線性變化。於37℃下一式兩份培養60分鐘，在9個不同化合物濃度(0、1.0、2.5、5.0、10.0、25.0、50.0、100、200及2500微莫耳/公升)下測定5－羥基－奧美派唑之形成速率。於37℃下一式兩份培養60分鐘，在9個不同化合物濃度(0、0.5、1.0、2.5、5.0、10.0、25.0、50.0及100微莫耳/公升)下測定5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑(M2)之形成速率。使用LC－MS/MS確定5－羥基－奧美派唑之數量。使用自Ramidius AB(Lund，Sweden)獲得之5－羥基－奧美派唑及自人類尿中分離出之5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑(M2)作為外標準。使用米－曼氏方程(Michaelis－Menten equation)藉由非線性回歸分析獲得達到最大形成速率一半(KM－值)及最大形成速率(Vmax)之濃度。Vmax除以KM獲得固有清除率(Clint)。The compounds described in Examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41 and the non-deuterated racemic Omeprazole, its (S)-enantiomer And non-deuterated pantoprazole and its enantiomers were cultured in Krebs Henseleit Puffer (KHB) containing 84 μg/ml amikacin, 1 mmol/L of calcium chloride , 20 mmol / L Hepes, 4.2 micromolar / liter Yi Gan tuo acid (hepatdnic acid), 28.5 mmol / liter concentration sodium bicarbonate and human106 cells / ml of hepatocytes was refrigerated (10 A pool of donors, InVitro Technologies, Baltimore, MD USA). Under these conditions 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl] The rate of formation of sulfonyl]-1H-benzimidazole (M2) varied linearly up to 60 minutes. The mixture was cultured in two portions at 37 ° C for 60 minutes, and the 5-hydroxy-Ou was measured at 9 different compound concentrations (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100, 200, and 2500 micromoles/liter). The rate of formation of mexazole. The mixture was cultured in two portions at 37 ° C for 60 minutes, and 5-(difluoromethoxy) was measured at 9 different compound concentrations (0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, and 100 micromoles/liter). Rate of formation of 2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2). The amount of 5-hydroxy-omeprazole was determined using LC-MS/MS. 5-hydroxy-omeprazole obtained from Ramidius AB (Lund, Sweden) and 5-(difluoromethoxy)-2-[[(3-methoxy-4-) isolated from human urine Sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2) was used as an external standard. The concentration reaching the maximum formation rate of half (KM -value) and the maximum formation rate (Vmax ) was obtained by nonlinear regression analysis using the Michaelis-Menten equation. The intrinsic scavenging rate (Clint ) is obtained by dividing Vmax by KM .
皆在4－甲氧基－吡啶基位置上經氘代之實例39及40二者所展示之形成速率較未經氘代之奧美派唑降低約1.5倍。外消旋[1H]、[2H3]及[2H6]奧美派唑類似物之KM－值之間沒有超過實驗差異性之差異(圖1)。觀察到實例40的5－羥基－奧美派唑之形成速率降低，但令人驚奇的是，實例38未發現降低(圖1)。而且，在4－甲氧基－吡啶基位置上經氘代之[2H3]奧美派唑(實例40)與另外在5－甲氧基－苯并咪唑位置上經氘代之[2H6]奧美派唑(實例41，圖3)之間之形成速率無差異。自外消旋[1H]奧美派唑及其(S)－對映異構體之5－羥基－奧美派唑形成展示立體特異性差異，此乃因外消旋及(S)－奧美派唑之KM與Vmax值間之差異已超過實驗差異。在(S)－奧美派唑的4－甲氧基－吡啶基及5－甲氧基－苯并咪唑位置上六個[1H]原子被[2H]原子取代(實例41)並未改變5－羥基－奧美派唑之固有清除率(Clint)(圖3)。Both of the examples 39 and 40, which were deuterated at the 4-methoxy-pyridyl position, exhibited a formation rate that was about 1.5 times lower than that of the undeuterated omeprazole. There was no difference in the KM -value between the racemic [1 H], [2 H3 ] and [2 H6 ] Omeprazole analogs (Fig. 1). The rate of formation of 5-hydroxy-omeprazole of Example 40 was observed to decrease, but surprisingly, no decrease was observed for Example 38 (Figure 1). Moreover, [2 H3 ] Omeprazole (Example 40) was deuterated at the 4-methoxy-pyridyl position and was additionally deuterated at the 5-methoxy-benzimidazole position [2 There was no difference in the rate of formation between H6 ] Omeprazole (Example 41, Figure 3). The formation of stereospecific differences from racemic [1 H]Omeprazole and its (S)-enantiomer 5-hydroxy-omeprazole formation due to racemic and (S)- The difference between the KM and Vmax values of omeprazole has exceeded the experimental difference. The six [1 H] atoms at the 4-methoxy-pyridyl and 5-methoxy-benzimidazole positions of (S)-omeprazole were replaced by [2 H] atoms (Example 41). The intrinsic clearance (Clint ) of 5-hydroxy-omeprazole was changed (Fig. 3).
自潘托拉唑、其對映異構體及闡述於實例17、19、20、21、27及28中之化合物之5－(二氟甲氧基)－2－[[(3－甲氧基－4－硫酸根－2－吡啶基)－甲基]亞磺醯基]－1H－苯并咪唑(M2)形成似乎受高於100 μM之基質濃度的抑制。因此，用100與250 μM基質濃度培養之數據不考慮在Km與Vmax之計算之內。自外消旋[1H]潘托拉唑及對映異構體之M2形成展示立體特異性差異(圖2A)。在4－甲氧基－吡啶基位置經氘代之外消旋、(R)及(S)－類似物(實例19、27及28)所展示之形成速率較其未經氘代配對物(圖2B)降低至少2.5倍。在4－甲氧基－吡啶基位置經氘代之外消旋、(R)及(S)－類似物(實例19、27及28)之固有清除率較其未經氘代配對物降低至少4.7倍(表2)。對於在4－甲氧基－吡啶基位置經氘代之類似物而言，[1H]潘托拉唑類似物中所觀察的M2形成速率之立體特異性差異明顯減少(圖2B)。令人驚訝的是，與未經氘代之化合物相比M2形成速率之降低似乎取決於三氘代甲氧基－基團在該分子之吡啶基部分中之位置(圖4)。在該分子之4－甲氧基－吡啶基位置上被[2H]原子取代之[1H]原子數量的增加([1H]、[2H1]實例21、[2H2]實例20及[2H3]實例19)使M2形成速率降低。5-(Difluoromethoxy)-2-[[(3-methoxy) from pantoprazole, its enantiomers and the compounds described in Examples 17, 19, 20, 21, 27 and 28. The formation of the base-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole (M2) appears to be inhibited by a substrate concentration above 100 μM. Therefore, data cultured at a substrate concentration of 100 and 250 μM is not considered to be within the calculation of Km and Vmax . M2 formation from racemic [1 H] pantoprazole and enantiomers exhibited stereospecific differences (Fig. 2A). Racemic, (R) and (S)-analogs at the 4-methoxy-pyridyl position, (R) and (S)-analogs (Examples 19, 27 and 28) exhibited a rate of formation compared to their undeuterated counterparts ( Figure 2B) is reduced by at least 2.5 times. The intrinsic clearance of the racemic, (R) and (S)-analogs (Examples 19, 27 and 28) at the 4-methoxy-pyridyl position by deuteration is at least lower than that of the non-deuterated counterpart. 4.7 times (Table 2). For the analogs deuterated at the 4-methoxy-pyridyl position, the stereospecific difference in the rate of M2 formation observed in the [1 H] pantoprazole analog was significantly reduced (Fig. 2B). Surprisingly, the decrease in the rate of M2 formation compared to the undeuterated compound appears to depend on the position of the triterpene methoxy-group in the pyridyl moiety of the molecule (Figure 4). An increase in the number of [1 H] atoms substituted by a [2 H] atom at the 4-methoxy-pyridyl position of the molecule ([1 H], [2 H1 ] Example 21, [2 H2 ] Examples 20 and [2 H3 ] Example 19) Reduced the rate of formation of M2.
表2：用潘托拉唑及本發明化合物培養後獲得混合人類肝細胞中之固有清除率(Clint)。
圖1：自[1H]奧美派唑及實例38、39及40之5－羥基－奧美派唑形成動力學。Figure 1: Kinetics of formation of 5-hydroxy-omeprazole from [1H] Omeprazole and Examples 38, 39 and 40.
圖2：在混合經冷藏人類肝細胞中(A)外消旋[1H]潘托拉唑及對映異構體及(B)[2H3]潘托拉唑(實例19)及相應對映異構體(實例27與28)之M2形成動力學。Figure 2: Racemic [1 H] pantoprazole and enantiomers and (B) [2 H3 ] pantoprazole (Example 19) and phase in mixed human liver cells The M2 formation kinetics of the enantiomers (Examples 27 and 28).
圖3：在混合經冷藏人類肝細胞中消旋[1H]奧美派唑、(S)－[1H]奧美派唑及實例41之5－羥基－奧美派唑形成速率動力學。Figure 3: Rate of kinetics of racemic [1 H]Omeprazole, (S)-[1 H] Omeprazole, and 5-hydroxy-omeprazole in Example 41 in mixed chilled human hepatocytes .
圖4：在混合經冷藏的人類肝細胞中在4－甲氧基－吡啶基(實例19)或3－甲氧基－吡啶基位置(實例17)上經氘代之外消旋[1H]潘托拉唑及[2H3]類似物之M2形成速率動力學。Figure 4: Racemic racemic [1 H on a 4-methoxy-pyridyl (Example 19) or 3-methoxy-pyridyl position (Example 17) in mixed chilled human hepatocytes M2 formation rate kinetics of pantoprazole and [2 H3 ] analogues.
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