技术领域technical field
本发明属于医药化工领域，具体而言涉及一种Baricitinib中间体的制备方法。The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a baricitinib intermediate.
背景技术Background technique
Baricitinib，化学名为{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈，是由Eli Lilly和Incyte公司开发的小分子JAK-1和JAK2激酶抑制剂，用于口服治疗类风湿关节炎、牛皮癣和其它炎症性疾病，以及糖尿病肾病。Baricitinib, chemical name {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azepine Cyclobutan-3-yl}acetonitrile is a small molecule JAK-1 and JAK2 kinase inhibitor developed by Eli Lilly and Incyte for oral treatment of rheumatoid arthritis, psoriasis and other inflammatory diseases, as well as diabetic nephropathy.
CN102026999A公开了Baricitinib及其中间体2-[1-乙磺酰基-3-[4-(7-[(2-(三甲基甲硅烷基)乙氧基)甲基]-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基]乙腈(式Ⅰ)的制备方法，该中间体制备方法如下：CN102026999A discloses Baricitinib and its intermediate 2-[1-ethanesulfonyl-3-[4-(7-[(2-(trimethylsilyl) ethoxy) methyl]-7H-pyrrolo[ 2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl] azetidin-3-yl] the preparation method of acetonitrile (formula I), the intermediate preparation method is as follows:
方法1：method 1:
方法2：Method 2:
方法1和方法2均需要先将化合物2与化合物3在Pd(PPh3)4存在下反应制备中间体4-(1-(1-乙氧基乙基)-1H-吡唑-4-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(化合物6)，然后脱去1-乙氧基乙基保护基得到中间体4-(1H-吡唑-4-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(化合物5)，再通过该中间体进行后续反应；由于化合物3是通过在1H-吡唑的结构的相应位置上分别连接“1-乙氧基乙基”和“4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基”结构片段制备而来(例如Qiyan Lin等，EnantioselectiveSynthesis of Janus Kinase Inhibitor INCB018424via an Organocatalytic Aza-Michael Reaction,Organic Letters,2009,11(9),pp 1999-2002)，因此方法1和方法2的反应路线具有“1-乙氧基乙基”保护基的连接和脱去两个步骤，反应路线长，生产成本高，不适和工业化生产，因此仍需要新的制备方法，以适应工业化生产的需求。Both method 1 and method 2 need to react compound 2 and compound 3 in the presence of Pd(PPh3 )4 to prepare intermediate 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl )-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 6), and then remove 1-ethoxyethyl The protecting group gives the intermediate 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d] pyrimidine (compound 5), and then carry out follow-up reaction through this intermediate; Since compound 3 is by connecting "1-ethoxyethyl" and "4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl"fragment (for example, Qiyan Lin et al., EnantioselectiveSynthesis of Janus Kinase Inhibitor INCB018424via an Organocatalytic Aza-Michael Reaction , Organic Letters, 2009,11(9), pp 1999-2002), so the reaction route of method 1 and method 2 has two steps of connection and removal of "1-ethoxyethyl" protecting group, and the reaction route is long , high production cost, unsuitable for industrialized production, so new preparation methods are still needed to meet the needs of industrialized production.
发明内容Contents of the invention
一方面，本发明提供一种式Ⅰ化合物的制备方法，包括：式Ⅱ化合物与式Ⅲ化合物在催化剂的存在下进行反应制备式Ⅰ化合物，In one aspect, the present invention provides a method for preparing a compound of formula I, comprising: reacting a compound of formula II and a compound of formula III in the presence of a catalyst to prepare a compound of formula I,
其中R1和R2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基，其中上述基团任选地被一种或多种下述取代基取代：卤素、羟基、硝基、亚硝基、羧基、氨基、烷基、卤素取代的烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个卤素、羟基、硝基、亚硝基、羧基、氨基、低级烷基、低级烷氧基、低级烷硫基取代的芳基或杂芳基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-12元杂环，所述杂环未取代或者任选被1-20个选自取代或未取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基取代；wherein R and R are each independently selected fromhydrogen , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the above groups are optionally replaced byone or more The following substituents are substituted: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, alkyl, halogen-substituted alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted Lower alkoxy, lower alkylthio, lower alkylthio substituted by halogen, mono-alkylamino, di-alkylamino, cycloalkylamino and optionally replaced by one or more halogen, hydroxy, nitro, ethylene nitro, carboxyl, amino, lower alkyl, lower alkoxy, lower alkylthio substituted aryl or heteroaryl; or R and R together form5-12 with the oxygen atom to which they are attached and the boron atom A membered heterocyclic ring, which is unsubstituted or optionally substituted by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-8元杂环，所述杂环未取代或者任选被1-10个C1-6烷基取代；Preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-8 membered heterocycle together with the oxygen atom and boron atom they are connected to, and the heterocycle The ring is unsubstituted or optionally substituted by 1-10 C1-6 alkyl groups;
更优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-6元杂环，所述杂环未取代或者任选被1-6个C1-6烷基取代；More preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-6 membered heterocyclic ring together with the oxygen atom and boron atom they are connected to, said The heterocyclic ring is unsubstituted or optionally substituted by 1-6 C1-6 alkyl groups;
最优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成如下结构部分，Most preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form the following structural part together with the oxygen atom and boron atom they are connected to,
其中R11、R12、R13、R14、R21、R22、R23、R24、R25和R26各自独立的选自C1-6烷基；wherein R11 , R12 , R13 , R14 , R21 , R22 , R23 , R24 , R25 and R26 are each independently selected from C1-6 alkyl groups;
在本发明的一些具体实施方案中，R1和R2与它们所连接的氧原子以及硼原子一起形成以下结构部分，In some specific embodimentsof the invention, R and R together with the oxygen atom and the boron atom to which they are attached form the following moiety,
在本发明的一些更加具体实施方案中，式Ⅱ化合物的结构为式Ⅳ化合物，相应的，式Ⅰ化合物结构为式Ⅴ化合物，In some more specific embodiments of the present invention, the structure of the compound of formula II is the compound of formula IV, and correspondingly, the structure of the compound of formula I is the compound of formula V,
应当理解，式Ⅱ化合物也可以是式Ⅱ化合物药学上可接受的盐或硼酸酐，只要上述反应能够进行即可；式Ⅱ化合物和式Ⅰ化合物与硼原子相连的氧也可以是其它原子，只要上述反应能够进行即可。It should be understood that the compound of formula II can also be a pharmaceutically acceptable salt or boric anhydride of the compound of formula II, as long as the above-mentioned reaction can be carried out; the oxygen connected to the boron atom of the compound of formula II and the compound of formula I can also be other atoms, as long as It is sufficient that the above reaction can proceed.
式Ⅱ化合物可以通过市售获得或者通过现有技术的方法制备，例如式Ⅱ化合物可以通过吡唑与适当的含硼的试剂反应制备而来，具体的例子，例如式Ⅳ化合物可以通过吡唑与联硼酸频那醇酯反应制备而来。Compounds of formula II can be commercially available or prepared by methods in the prior art. For example, compounds of formula II can be prepared by reacting pyrazole with a suitable boron-containing reagent. For example, compounds of formula IV can be prepared by reacting pyrazole with a suitable boron-containing reagent. It is prepared by the reaction of pinacol ester of borate.
其中所述催化剂选自四甲基胍、1,8-二氮杂双环(5.4.0)十一碳-7-烯(DBU)、1,5-二氮杂双环(4.3.0)壬-5-烯、1,4-二氮杂双环(2.2.2)辛烷、叔丁基氢氧化铵、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、磷酸三钾、硅酸钠、氧化钙、三乙胺、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸氢钾、三苯膦、三乙基磷、乙酸钾或丙烯酸钾中的一种或几种，优选为1,8-二氮杂双环(5.4.0)十一碳-7-烯。Wherein the catalyst is selected from tetramethylguanidine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nonane- 5-ene, 1,4-diazabicyclo(2.2.2) octane, tert-butylammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, One or more of triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenylphosphine, triethylphosphine, potassium acetate or potassium acrylate, preferably 1,8- Diazabicyclo(5.4.0)undec-7-ene.
应当理解，本发明制备式Ⅰ化合物的催化剂还包括上述未列举的各种可以促进反应进行的试剂，只要所述反应能够进行即可。It should be understood that the catalyst for preparing the compound of formula I in the present invention also includes various reagents not listed above that can promote the reaction, as long as the reaction can be carried out.
其中式Ⅰ化合物的制备根据需要选择合适的溶剂进行反应，所述溶剂选自乙腈、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、苯、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜的一种或几种，优选为乙腈、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺的一种或几种，最优选为乙腈。Wherein the preparation of the compound of formula I selects suitable solvent to carry out reaction according to need, and described solvent is selected from acetonitrile, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-di Oxyhexane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, benzene, toluene, di One or more of toluene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably acetonitrile, N,N-dimethylformamide or N,N -one or more of dimethylacetamides, most preferably acetonitrile.
其中式Ⅰ化合物的制备可以根据需要选择合适的反应温度，例如反应温度可为从0℃至反应系统的沸点，在本发明的一些具体实施方案中，所述反应温度为25℃。For the preparation of the compound of formula I, an appropriate reaction temperature can be selected according to needs, for example, the reaction temperature can be from 0°C to the boiling point of the reaction system, and in some specific embodiments of the present invention, the reaction temperature is 25°C.
其中所述反应可以根据需要选择合适的反应时间，例如反应时间可以为0-48小时，也可以为2-12小时，在本发明的一些具体实施方案中，反应时间为2小时。Wherein the reaction can select a suitable reaction time according to needs, for example, the reaction time can be 0-48 hours, or 2-12 hours, and in some specific embodiments of the present invention, the reaction time is 2 hours.
其中式Ⅲ化合物与式Ⅱ化合物的摩尔比可以是1，也可以大于1或者小于1；例如式Ⅲ化合物与式Ⅱ化合物的摩尔比可以是约0.1-10，或者约0.8-1.5；在本发明的一些具体实施方案中，式Ⅲ化合物与式Ⅱ化合物的摩尔比是约1.34。Wherein the molar ratio of the compound of formula III to the compound of formula II can be 1, or greater than 1 or less than 1; for example, the molar ratio of the compound of formula III to the compound of formula II can be about 0.1-10, or about 0.8-1.5; in the present invention In some embodiments, the molar ratio of the compound of formula III to the compound of formula II is about 1.34.
任选地，式Ⅰ化合物的制备可以在氮气或氩气的保护下进行。Optionally, the preparation of the compound of formula I can be carried out under the protection of nitrogen or argon.
任选地，式Ⅰ化合物还可以进一步包括如下步骤：Optionally, the compound of formula I may further comprise the following steps:
i.反应结束后向反应液中加入与水不混溶的有机溶剂萃取，i. After the reaction finishes, add a water-immiscible organic solvent to the reaction solution for extraction,
ii.浓缩，ii. to concentrate,
其中所述与水不混溶的有机溶剂包括但不限于乙酸乙酯、乙酸丁酯、二氯甲烷、三氯甲烷或乙醚等，在本发明的一个具体实施方案中，所述与水不混溶的有机溶剂为乙酸乙酯。Wherein said water immiscible organic solvent includes but not limited to ethyl acetate, butyl acetate, dichloromethane, chloroform or ether etc., in a specific embodiment of the present invention, said water immiscible The soluble organic solvent is ethyl acetate.
另一方面，本发明提供了一种式Ⅶ化合物的制备方法，包括：式Ⅰ化合物和式Ⅵ化合物在钯催化剂和碱的存在下进行反应制备式Ⅶ化合物，In another aspect, the present invention provides a method for preparing a compound of formula VII, comprising: reacting a compound of formula I and a compound of formula VI in the presence of a palladium catalyst and a base to prepare a compound of formula VII,
其中R1和R2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基，其中上述基团任选地被一种或多种下述取代基取代：卤素、羟基、硝基、亚硝基、羧基、氨基、烷基、卤素取代的烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个卤素、羟基、硝基、亚硝基、羧基、氨基、低级烷基、低级烷氧基、低级烷硫基取代的芳基或杂芳基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-12元杂环，所述杂环未取代或者任选被1-20个选自取代或未取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基取代；wherein R and R are each independently selected fromhydrogen , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the above groups are optionally replaced byone or more The following substituents are substituted: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, alkyl, halogen-substituted alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted Lower alkoxy, lower alkylthio, lower alkylthio substituted by halogen, mono-alkylamino, di-alkylamino, cycloalkylamino and optionally replaced by one or more halogen, hydroxy, nitro, ethylene nitro, carboxyl, amino, lower alkyl, lower alkoxy, lower alkylthio substituted aryl or heteroaryl; or R and R together form5-12 with the oxygen atom to which they are attached and the boron atom A membered heterocyclic ring, which is unsubstituted or optionally substituted by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-8元杂环，所述杂环未取代或者任选被1-10个C1-6烷基取代；Preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-8 membered heterocycle together with the oxygen atom and boron atom they are connected to, and the heterocycle The ring is unsubstituted or optionally substituted by 1-10 C1-6 alkyl groups;
更优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-6元杂环，所述杂环未取代或者任选被1-6个C1-6烷基取代；More preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-6 membered heterocyclic ring together with the oxygen atom and boron atom they are connected to, said The heterocyclic ring is unsubstituted or optionally substituted by 1-6 C1-6 alkyl groups;
最优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成如下结构部分，Most preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form the following structural part together with the oxygen atom and boron atom they are connected to,
其中R11、R12、R13、R14、R21、R22、R23、R24、R25和R26各自独立的选自C1-6烷基；wherein R11 , R12 , R13 , R14 , R21 , R22 , R23 , R24 , R25 and R26 are each independently selected from C1-6 alkyl groups;
在本发明的一些具体实施方案中，R1和R2与它们所连接的氧原子以及硼原子一起形成以下结构部分，In some specific embodimentsof the invention, R and R together with the oxygen atom and the boron atom to which they are attached form the following moiety,
在本发明的一些更加具体实施方案中，式Ⅰ化合物结构为式Ⅴ化合物，In some more specific embodiments of the present invention, the compound of formula I is a compound of formula V,
其中X选自氟、氯、溴、碘、甲苯磺酸根基团或三氟甲磺酸根基团，优选为氯、溴或碘，最优选为氯。Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate or triflate, preferably chlorine, bromine or iodine, most preferably chlorine.
其中P是保护基团，所述保护基团包括但不限于2-(三甲基硅烷基)乙氧基甲基(SEM)、N-戊酰氧基甲基(POM)、苄氧基羰基(Cbz)、2,2,2-三氯乙氧基羰基(Troc)、2-(三甲基硅烷基)乙氧基羰基(Teoc)、2-(4-三氟甲基苯基磺酰基)乙氧基羰基(Tsc)、叔丁氧基羰基(BOC)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧基羰基(TcBOC)、乙烯基、2-氯乙基、2-苯基磺酰基乙基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧基甲基(Bum)、苄氧基甲基(BOM)或2-四氢吡喃基(THP)，优选为2-(三甲基硅烷基)乙氧基甲基或者N-戊酰氧基甲基，最优选为2-(三甲基硅烷基)乙氧基甲基。Wherein P is a protecting group, said protecting group includes but not limited to 2-(trimethylsilyl)ethoxymethyl (SEM), N-pentanoyloxymethyl (POM), benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl ) ethoxycarbonyl (Tsc), tert-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpentyl -3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloro Ethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'- Dimethylhydrazino, methoxymethyl, tert-butoxymethyl (Bum), benzyloxymethyl (BOM) or 2-tetrahydropyranyl (THP), preferably 2-(trimethyl silyl)ethoxymethyl or N-pentanoyloxymethyl, most preferably 2-(trimethylsilyl)ethoxymethyl.
在本发明的一些具体实施方案中，式Ⅵ化合物为式Ⅷ化合物，优选为式Ⅸ化合物，相应的，式Ⅶ化合物为式Ⅺ化合物，In some specific embodiments of the present invention, the compound of formula VI is a compound of formula VIII, preferably a compound of formula IX, and correspondingly, the compound of formula VII is a compound of formula XI,
其中所述钯催化剂可以是钯(0)和钯(II)催化剂，包括但不限于Pd(PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3、Pd(dba)2或Pd(dppf)2Cl2，在本发明的一些具体实施方案中，钯催化剂为Pd(PPh3)4。Wherein the palladium catalyst can be palladium (0) and palladium (II) catalyst, including but not limited to Pd(PPh3 )4 , Pd(OAc)2 , PdCl2 (dppf), Pd2 (dba)3 , Pd( dba)2 or Pd(dppf)2 Cl2 , in some embodiments of the invention the palladium catalyst is Pd(PPh3 )4 .
应当理解，本发明的钯催化剂还可以是各种钯催化剂与配体制备的各种钯配合物化合物，所述配体包括但不限于PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe)或Ph2P(CH2)3PPh2(dppp)。It should be understood that the palladium catalyst of the present invention can also be various palladium complex compounds prepared by various palladium catalysts and ligands, and the ligands include but not limited to PCy3 , AsPh3 , n-Bu3 P, (MeO)3 P, Ph2 P(CH2 )2 PPh2 (dppe), or Ph2 P(CH2 )3 PPh2 (dppp).
其中所述碱选自N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、碳酸铯、碳酸锂、氢化钠、氨基钠、丁基锂、叔丁醇锂、二异丙基氨基锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾的一种或几种，优选为碳酸钾、碳酸钠、碳酸氢钠或碳酸氢钾的一种或几种，最优选为碳酸钾。Wherein the base is selected from N,N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, sodium methylate, sodium ethylate, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, Sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyllithium, lithium tert-butoxide, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, One or more of potassium acetate, sodium bicarbonate or potassium bicarbonate, preferably one or more of potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate, most preferably potassium carbonate.
其中式Ⅲ化合物的制备可以根据需要选择合适的溶剂进行反应，所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、1,2-二甲氧基乙烷、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜的一种或几种，优选为正丁醇或1,2-二甲氧基乙烷中的一种或两种，最优选为正丁醇。Wherein the preparation of formula III compound can select suitable solvent to carry out reaction according to need, and described solvent is selected from water, methanol, ethanol, propanol, isopropanol, 1,2-dimethoxyethane, n-butanol, isopropanol Butanol, tert-butanol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate , butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably n- One or both of butanol or 1,2-dimethoxyethane, most preferably n-butanol.
其中所述反应可以根据需要选择合适的反应温度进行，例如反应温度可为从0℃至反应系统的沸点，优选在本发明的一些具体实施方案中，所述反应温度为反应系统的沸点。The reaction can be carried out at an appropriate reaction temperature as required, for example, the reaction temperature can be from 0°C to the boiling point of the reaction system, preferably in some embodiments of the present invention, the reaction temperature is the boiling point of the reaction system.
其中所述反应可以根据需要选择合适的反应时间，例如反应时间可以为0-48小时，也可以为2-12小时，在本发明的一些具体实施方案中，反应时间为2小时。Wherein the reaction can select a suitable reaction time according to needs, for example, the reaction time can be 0-48 hours, or 2-12 hours, and in some specific embodiments of the present invention, the reaction time is 2 hours.
其中式Ⅵ化合物与式Ⅰ化合物的摩尔比可以是1，也可以大于1或者小于1；例如式Ⅵ化合物与式Ⅰ化合物的摩尔比可以是约0.1-10，或者约1-3；在本发明的一些具体实施方案中，式Ⅵ化合物与式Ⅰ化合物的摩尔比是约2。Wherein the molar ratio of the compound of formula VI to the compound of formula I can be 1, or greater than 1 or less than 1; for example, the molar ratio of the compound of formula VI to the compound of formula I can be about 0.1-10, or about 1-3; In some embodiments, the molar ratio of the compound of formula VI to the compound of formula I is about 2.
其中式Ⅰ化合物与钯催化剂的质量比不特别限定，在本发明的一些实施方案中，式Ⅰ化合物与钯催化剂的质量比可以是约0.0001-10，或者约0.05-0.5；在本发明的一些具体实施方案中，式Ⅰ化合物与钯催化剂的质量比是约0.2。Wherein the mass ratio of formula I compound and palladium catalyst is not particularly limited, in some embodiments of the present invention, the mass ratio of formula I compound and palladium catalyst can be about 0.0001-10, or about 0.05-0.5; In a specific embodiment, the mass ratio of the compound of formula I to the palladium catalyst is about 0.2.
任选地，式Ⅶ化合物的制备还可以进一步包括如下步骤：Optionally, the preparation of the compound of formula VII may further comprise the following steps:
i.反应结束后向反应液中加入与水不混溶的有机溶剂萃取，i. After the reaction finishes, add a water-immiscible organic solvent to the reaction solution for extraction,
ii.浓缩，ii. to concentrate,
其中所述与水不混溶的有机溶剂包括但不限于乙酸乙酯、乙酸丁酯、二氯甲烷、三氯甲烷或乙醚等，在本发明的一个具体实施方案中，所述与水不混溶的有机溶剂为乙酸乙酯。Wherein said water immiscible organic solvent includes but not limited to ethyl acetate, butyl acetate, dichloromethane, chloroform or ether etc., in a specific embodiment of the present invention, said water immiscible The soluble organic solvent is ethyl acetate.
本发明的式Ⅵ化合物可以通过市售获得，也可以通过现有技术的方法制备，例如CN102026999A公开的方法，式Ⅵ化合物通过用P保护基团保护式Ⅻ化合物来形成，The compound of formula VI of the present invention can be obtained commercially, or can be prepared by methods of the prior art, such as the method disclosed in CN102026999A, the compound of formula VI is formed by protecting the compound of formula XII with a P protecting group,
其中P保护基团如上所述，在本发明的一些具体实施方式中，所述P保护基团为2-(三甲基硅烷基)乙氧基甲基或者N-戊酰氧基甲基，优选为2-(三甲基硅烷基)乙氧基甲基。Wherein the P protecting group is as described above, in some embodiments of the present invention, the P protecting group is 2-(trimethylsilyl)ethoxymethyl or N-pentanoyloxymethyl, Preferred is 2-(trimethylsilyl)ethoxymethyl.
在本发明的一些具体实施方案中，式Ⅵ化合物为式Ⅷ化合物，式Ⅷ化合物通过如下方法制备，In some specific embodiments of the present invention, the compound of formula VI is a compound of formula VIII, and the compound of formula VIII is prepared by the following method,
其中X选自氟、氯、溴、碘、甲苯磺酸根基团或三氟甲磺酸根基团，优选为氯、溴或碘，最优选为氯。Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate or triflate, preferably chlorine, bromine or iodine, most preferably chlorine.
其中Y选自氟、氯、溴或碘，优选为氯、溴或碘，最优选为氯。wherein Y is selected from fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, most preferably chlorine.
式Ⅷ化合物的制备可以根据需要选择合适的碱，例如氢化钠(NaH)。For the preparation of the compound of formula VIII, an appropriate base, such as sodium hydride (NaH), can be selected as needed.
式Ⅷ化合物的制备可以根据需要选择合适的溶剂，例如N,N-二甲基乙酰胺、四氢呋喃、1,2-二甲氧基乙烷或1,4-二氧六环等。For the preparation of the compound of formula VIII, an appropriate solvent can be selected according to needs, such as N,N-dimethylacetamide, tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane and the like.
在一方面，本发明提供了一种式Ⅶ化合物的制备方法，包括：In one aspect, the present invention provides a method for preparing a compound of formula VII, comprising:
(1)式Ⅱ化合物与式Ⅲ化合物在催化剂的存在下进行反应制备式Ⅰ化合物，(1) the compound of formula II and the compound of formula III react in the presence of a catalyst to prepare the compound of formula I,
(2)式Ⅰ化合物和式Ⅵ化合物在钯催化剂和碱的存在下进行反应制备式Ⅶ化合物，(2) the compound of formula I and the compound of formula VI are reacted to prepare the compound of formula VII in the presence of palladium catalyst and alkali,
其中R1和R2的定义如上所述，在本发明的一些具体实施方案中，R1和R2与它们所连接的氧原子以及硼原子一起形成以下结构部分，Wherein R1 and R2 are defined as above, in some embodiments of the present invention, R1 and R2 form the following structural moiety together with the oxygen atom and boron atom they are connected to,
其中X选自氟、氯、溴、碘、甲苯磺酸根基团或三氟甲磺酸根基团，优选为氯、溴或碘，最优选为氯。Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate or triflate, preferably chlorine, bromine or iodine, most preferably chlorine.
其中P保护基团如上所述，在本发明的一些具体实施方式中，所述P保护基团为2-(三甲基硅烷基)乙氧基甲基或者N-戊酰氧基甲基，优选为2-(三甲基硅烷基)乙氧基甲基。Wherein the P protecting group is as described above, in some embodiments of the present invention, the P protecting group is 2-(trimethylsilyl)ethoxymethyl or N-pentanoyloxymethyl, Preferred is 2-(trimethylsilyl)ethoxymethyl.
其中步骤(1)所述的催化剂选自四甲基胍、1,8-二氮杂双环(5.4.0)十一碳-7-烯、1,5-二氮杂双环(4.3.0)壬-5-烯、1,4-二氮杂双环(2.2.2)辛烷、叔丁基氢氧化铵、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、磷酸三钾、硅酸钠、氧化钙、三乙胺、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸氢钾、三苯膦、三乙基磷、乙酸钾或丙烯酸钾中的一种或几种，优选为1,8-二氮杂双环(5.4.0)十一碳-7-烯。Wherein the catalyst described in step (1) is selected from tetramethylguanidine, 1,8-diazabicyclo (5.4.0) undec-7-ene, 1,5-diazabicyclo (4.3.0) Non-5-ene, 1,4-diazabicyclo(2.2.2)octane, tert-butylammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, oxide One or more of calcium, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogenphosphate, triphenylphosphine, triethylphosphine, potassium acetate or potassium acrylate, preferably 1, 8-Diazabicyclo(5.4.0)undec-7-ene.
其中步骤(2)所述的钯催化剂可以是钯(0)和钯(II)催化剂，包括但不限于Pd(PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3、Pd(dba)2或Pd(dppf)2Cl2，在本发明的一些具体实施方案中，钯催化剂为Pd(PPh3)4。Wherein the palladium catalyst described in step (2) can be palladium (0) and palladium (II) catalyst, including but not limited to Pd(PPh3 )4 , Pd(OAc)2 , PdCl2 (dppf), Pd2 (dba )3 , Pd(dba)2 or Pd(dppf)2 Cl2 , in some embodiments of the invention, the palladium catalyst is Pd(PPh3 )4 .
其中步骤(2)所述碱选自N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、碳酸铯、碳酸锂、氢化钠、氨基钠、丁基锂、叔丁醇锂、二异丙基氨基锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾的一种或几种，优选为碳酸钾、碳酸钠、碳酸氢钠或碳酸氢钾的一种或几种，最优选为碳酸钾。Wherein the base in step (2) is selected from N,N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, sodium methylate, sodium ethylate, sodium n-propoxide, sodium isopropoxide, n- Sodium butoxide, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyllithium, lithium tert-butoxide, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate , one or more of sodium acetate, potassium acetate, sodium bicarbonate or potassium bicarbonate, preferably one or more of potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate, most preferably potassium carbonate.
又一方面，本发明提供了式Ⅰ化合物或其药学上可接受的盐，In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,
其中R1和R2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基，其中上述基团任选地被一种或多种下述取代基取代：卤素、羟基、硝基、亚硝基、羧基、氨基、烷基、卤素取代的烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个卤素、羟基、硝基、亚硝基、羧基、氨基、低级烷基、低级烷氧基、低级烷硫基取代的芳基或杂芳基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-12元杂环，所述杂环未取代或者任选被1-20个选自取代或未取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基取代；wherein R and R are each independently selected fromhydrogen , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the above groups are optionally replaced byone or more The following substituents are substituted: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, alkyl, halogen-substituted alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted Lower alkoxy, lower alkylthio, lower alkylthio substituted by halogen, mono-alkylamino, di-alkylamino, cycloalkylamino and optionally replaced by one or more halogen, hydroxy, nitro, ethylene nitro, carboxyl, amino, lower alkyl, lower alkoxy, lower alkylthio substituted aryl or heteroaryl; or R and R together form5-12 with the oxygen atom to which they are attached and the boron atom A membered heterocyclic ring, which is unsubstituted or optionally substituted by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-8元杂环，所述杂环未取代或者任选被1-10个C1-6烷基取代；Preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-8 membered heterocycle together with the oxygen atom and boron atom they are connected to, and the heterocycle The ring is unsubstituted or optionally substituted by 1-10 C1-6 alkyl groups;
更优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成5-6元杂环，所述杂环未取代或者任选被1-6个C1-6烷基取代；More preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form a 5-6 membered heterocyclic ring together with the oxygen atom and boron atom they are connected to, said The heterocyclic ring is unsubstituted or optionally substituted by 1-6 C1-6 alkyl groups;
最优选的，R1和R2各自独立地选自氢或C1-6烷基；或者R1和R2与它们所连接的氧原子以及硼原子一起形成如下结构部分，Most preferably, R1 and R2 are each independently selected from hydrogen or C1-6 alkyl; or R1 and R2 form the following structural part together with the oxygen atom and boron atom they are connected to,
其中R11、R12、R13、R14、R21、R22、R23、R24、R25和R26各自独立的选自C1-6烷基；wherein R11 , R12 , R13 , R14 , R21 , R22 , R23 , R24 , R25 and R26 are each independently selected from C1-6 alkyl groups;
在本发明的一些具体实施方案中，R1和R2与它们所连接的氧原子以及硼原子一起形成以下结构部分，In some specific embodimentsof the invention, R and R together with the oxygen atom and the boron atom to which they are attached form the following moiety,
在本发明的一些更加具体实施方案中，式Ⅰ化合物结构为式Ⅴ化合物，In some more specific embodiments of the present invention, the compound of formula I is a compound of formula V,
又一方面，本发明提供了式Ⅰ化合物或其药学上可接受的盐在制备式Ⅶ化合物的用途。In another aspect, the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of the compound of formula VII.
还一方面，本发明提供了式Ⅰ化合物或其药学上可接受的盐在制备2-[1-乙磺酰基-3-[4-(7-[(2-(三甲基甲硅烷基)乙氧基)甲基]-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基]乙腈的用途。In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of 2-[1-ethanesulfonyl-3-[4-(7-[(2-(trimethylsilyl) Use of ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile.
除非另有说明，否则所用的通用化学术语，例如但不限于，“烷基”、“胺”、“芳基”等同于其任选取代的形式。例如，本文所用的“烷基”包括取代的和未取代的烷基。Unless otherwise indicated, common chemical terms such as, but not limited to, "alkyl", "amine", "aryl" are used to identify the optionally substituted versions thereof. For example, "alkyl" as used herein includes substituted and unsubstituted alkyl groups.
本文所用术语“基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The term "group" as used herein refers to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not.
本文单独或组合使用的术语“烃”是指仅包含碳原子和氢原子的化合物或化学基团。The term "hydrocarbon" as used herein alone or in combination refers to a compound or chemical group comprising only carbon and hydrogen atoms.
本文单独或组合使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自硼、氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。The term "heteroatom" or "hetero" as used herein, alone or in combination, means an atom other than carbon and hydrogen. The heteroatoms are independently selected from boron, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
本文单独或组合使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃。本文的“烷基”可具有1-约18个碳原子，或具有1-约10个碳原子，优选1-6个碳原子。本文的烷基实例包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基和己基，以及更长的烷基基团，如庚基和辛基等。本文中出现数字范围时，例如“C1-6烷基”是指可由1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烷基，“C1-6烷基”包括“C1-2烷基”、“C1-3烷基”、“C1-4烷基”或“C1-5烷基”，本文的烷基也包含未指定数字范围的情况。The term "alkyl" as used herein alone or in combination refers to an optionally substituted linear or optionally substituted branched monovalent saturated hydrocarbon. "Alkyl" herein may have 1 to about 18 carbon atoms, or 1 to about 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- Butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl -1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- Dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl radical, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl and octyl, etc. When a numerical range appears herein, for example, "C1-6 alkyl" refers to a group consisting of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms Alkyl, "C1-6 alkyl" includes "C1-2 alkyl", "C1-3 alkyl", "C1-4 alkyl" or "C1-5 alkyl", herein Alkyl also includes cases where no numerical range is specified.
本文组合使用的“烷基”包括但不限于包含在“烷氧基”、“烷硫基”、“单-烷基氨基”和“二-烷基氨基”等中的“烷基”。"Alkyl" used in combination herein includes, but is not limited to, "alkyl" contained in "alkoxy", "alkylthio", "mono-alkylamino", and "di-alkylamino" and the like.
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳双键。所述烯基例如具有2-约18个碳原子，或具有2-约10个碳原子，更优选2-约6个碳原子。这些基团中的双键可以为顺式或反式构型，并应被理解为包含所述两种异构体。实例包括但不限于乙烯基(-CH＝CH2)、1-丙烯基(-CH2CH＝CH2)、异丙烯基(-C(CH3)＝CH2)、丁烯基和1,3-丁二烯基等。The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent hydrocarbon having one or more carbon-carbon double bonds. The alkenyl group has, for example, 2 to about 18 carbon atoms, or 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans configuration and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2 ), 1-propenyl (-CH2CH=CH2 ), isopropenyl (-C(CH3 )=CH2) , butenyl, and 1, 3-butadienyl, etc.
本文单独或组合使用的术语“炔基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳三键。例如所述炔基具有2-约18个碳原子或2-约10个碳原子，更优选2-约6个碳原子。本文的炔基实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent hydrocarbon having one or more carbon-carbon triple bonds. For example, the alkynyl group has 2 to about 18 carbon atoms or 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples of alkynyl herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
本文单独或组合使用的术语“卤素取代的烷基”是指任选取代的烷基基团，如上定义的，其中一个或多个氢原子被替换成氟、氯、溴或碘原子或其组合。在一些实施方式中，使用彼此相同的卤素原子替换两个或多个氢原子(例如二氟甲基、三氟甲基)；在其它实施方式中使用彼此并不完全相同的卤素原子替换两个或多个氢原子(例如1-氯-1-氟-1-碘乙基)。卤素取代的烷基的非限定性实例为氟甲基和溴乙基。The term "halo-substituted alkyl" as used herein alone or in combination refers to an optionally substituted alkyl group, as defined above, in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or combinations thereof . In some embodiments, two or more hydrogen atoms are replaced with halogen atoms that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not identical to each other. or multiple hydrogen atoms (eg 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of halo-substituted alkyl are fluoromethyl and bromoethyl.
本文单独或组合使用的术语“环”以及“……元环”是指如本文所述的任意共价闭合的结构，其包括脂环、杂环、芳环、杂芳环和多环稠合环系或多环非稠合环系。环可被任意取代。环可形成稠合环系部分。术语“元”是指组成环的骨架原子的数目。因此，举例而言，环己烷、吡啶、吡喃和嘧啶为六元环，而环戊烷、吡咯、四氢呋喃和噻吩为五元环。The terms "ring" and "membered ring" as used herein, alone or in combination, refer to any covalently closed structure as described herein, including alicyclic rings, heterocyclic rings, aromatic rings, heteroaryl rings and polycyclic fused rings ring system or polycyclic non-fused ring system. Rings can be optionally substituted. Rings may form part of fused ring systems. The term "member" refers to the number of skeletal atoms making up the ring. Thus, for example, cyclohexane, pyridine, pyran, and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran, and thiophene are five-membered rings.
本文单独或组合使用的术语“环烷基”是指任选取代的一价饱和烃环，其包含3-约15个成环碳原子或3-约10个成环碳原子，也可包括作为取代基的其它非成环碳原子(例如甲基环丙基)。环烷基可具有3至约10个或3-约8个或3-约6个或3-5个成环原子，环烷基的实例包括但不限于环丙烷、环丁烷、环戊烷和环己烷。The term "cycloalkyl" used herein alone or in combination refers to an optionally substituted monovalent saturated hydrocarbon ring containing 3 to about 15 ring-forming carbon atoms or 3 to about 10 ring-forming carbon atoms, and may also include Other non-ring-forming carbon atoms of substituents (eg methylcyclopropyl). Cycloalkyl groups can have from 3 to about 10 or 3 to about 8 or 3 to about 6 or 3 to 5 ring-forming atoms, examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane and cyclohexane.
本文单独或组合使用的术语“杂环烷基”的非限制性实例包括吖嗪基(azinyl)、氮杂环丁烷基(azetidinyl)、氧杂环丁基(oxetanyl)、硫杂环丁基(thietanyl)、高哌啶基(homopiperidinyl)、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、氮杂氧杂环庚三烯基(oxazepinyl)、二氮杂环庚三烯(diazepinyl)、氮杂硫杂环庚三烯(thiazepinyl)、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基(dioxanyl)、1,3-二氧戊环基(1,3-dioxolanyl)、吡唑啉基、二硫环己基(dithianyl)、二硫环戊基(dithiolanyl)、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基(imidazolidinyl)、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基和喹嗪基等。该术语还包括糖类的所有环状形式，包括但不限于单糖、二糖和寡糖。Non-limiting examples of the term "heterocycloalkyl" as used herein, alone or in combination, include azinyl, azetidinyl, oxetanyl, thietanyl (thietanyl), homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepine (diazepinyl), thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyridine Pyranyl, 4H-pyranyl, dioxanyl (dioxanyl), 1,3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl, dithianyl (dithianyl), disulfide Cyclopentyl (dithiolanyl), dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl , 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinozinyl, etc. The term also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.
本文单独或组合使用的术语“芳基”是指任选取代的芳香烃基，其具有6-约20个成环碳原子，并包括稠合环和非稠合芳基环。稠合芳基包含2-4个稠合的环，其中连接环是芳环，其它每个环可以为脂环、杂环、芳环、杂芳环或其任意组合。进一步的，术语芳基包括稠合和非稠合环。此外，术语芳基包括但不限于单环、双环、三环或更多环。芳基(例如单环芳基)包括例如6至约12个、6至约10个或6至约8个成环碳原子。单环芳基的非限制性实例包括苯基，稠合环芳基包括萘基、菲基、蒽基、薁基(azulenyl)，非稠合的双-芳基包括联苯基。The term "aryl" as used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having from 6 to about 20 ring carbon atoms and including fused and non-fused aryl rings. The fused aryl group contains 2-4 fused rings, wherein the linking ring is an aromatic ring, and each of the other rings can be an alicyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring or any combination thereof. Further, the term aryl includes fused and non-fused rings. Furthermore, the term aryl includes, but is not limited to, monocyclic, bicyclic, tricyclic or more rings. Aryl groups (eg, monocyclic aryl groups) include, for example, 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms. Non-limiting examples of monocyclic aryl groups include phenyl, fused ring aryl groups include naphthyl, phenanthrenyl, anthracenyl, azulenyl, and non-fused bis-aryl groups include biphenyl.
本文单独或组合使用的术语“杂芳基”是指任意取代的一价芳基，其包含约5至约20个骨架成环原子，其中一个或多个成环原子为杂原子，所述杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于此；其前提是所述基团的环不包含两个相邻的O或S原子。在环中出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。术语杂芳基包括任选取代的具有至少一个杂原子的稠合的或非稠合的杂芳基。术语杂芳基还包括含5至约12个骨架成环原子的稠合的和非稠合的杂芳基，以及含5至约10个骨架成环原子的稠合的和非稠合的杂芳基。可通过碳原子或杂原子与杂芳基结合。因此，非限制性的举例，咪唑基可通过其任一碳原子(咪唑-2-基、咪唑-4-基或咪唑-5-基)或其氮原子(咪唑-1-基或咪唑-3-基)与母体分子相连。类似地，杂芳基可通过其任意或全部碳原子和/或任意或全部杂原子被进一步取代。稠合的杂芳基可包含2-4个稠合环，其中连接环是杂芳环，其它每个环可以为脂环、杂环、芳环、杂芳环或其任意组合。单环杂芳基包括但不限于具有5至约12个、5至约10个、5至约7个或6个成环原子的单环杂芳基。单环杂芳基的非限定性实例包括吡啶基，稠合环杂芳基包括苯并咪唑基、喹啉基、吖啶基，非稠合的双-杂芳基包括二吡啶基。杂芳基的其它实例包括但不限于：呋喃基、噻吩基、噁唑基、吖啶基、吩嗪基、苯并咪唑基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基(benzothiadiazolyl)、苯并噻吩基(benzothiophenyl)、苯并噁二唑基、苯并三唑基、咪唑基、吲哚基、异噁唑基、异喹啉基、吲嗪基(indolizinyl)、异噻唑基、异吲哚基噁二唑基、吲唑基、吡啶基、哒嗪基(pyridazyl)、嘧啶基、吡嗪基、吡咯基、吡唑基、嘌呤基、酞嗪基、蝶啶基(pteridinyl)、喹啉基、喹唑啉基、喹噁啉基(quinoxalinyl)、三唑基、四唑基、噻唑基、三嗪基和噻二唑基(thiadiazolyl)等，及其氧化物，例如吡啶基-N-氧化物等。The term "heteroaryl" as used herein, alone or in combination, refers to an optionally substituted monovalent aryl group comprising from about 5 to about 20 skeletal ring atoms, one or more of which is a heteroatom, the heteroatom The atoms are independently selected from, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin; provided that the ring of the group does not contain two adjacent O or S atoms. In embodiments where two or more heteroatoms are present in a ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted fused or non-fused heteroaryl groups having at least one heteroatom. The term heteroaryl also includes fused and non-fused heteroaryl groups containing 5 to about 12 skeletal ring atoms, and fused and non-fused heteroaryl groups containing 5 to about 10 skeletal ring atoms. Aryl. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom. Thus, by way of non-limiting example, an imidazolyl group can be converted through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3 -group) is linked to the parent molecule. Similarly, a heteroaryl group may be further substituted via any or all of its carbon atoms and/or any or all of its heteroatoms. A fused heteroaryl group can contain 2-4 fused rings, wherein the linking ring is a heteroaryl ring, and each of the other rings can be an alicyclic ring, a heterocyclic ring, an aromatic ring, a heteroaryl ring, or any combination thereof. Monocyclic heteroaryl groups include, but are not limited to, monocyclic heteroaryl groups having 5 to about 12, 5 to about 10, 5 to about 7, or 6 ring-forming atoms. Non-limiting examples of monocyclic heteroaryls include pyridyl, fused ring heteroaryls include benzimidazolyl, quinolinyl, acridinyl, and non-fused bis-heteroaryls include dipyridyl. Other examples of heteroaryl include, but are not limited to: furyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuryl, benzoxazolyl, benzothiazolyl, Benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolyl, indazine Indolizinyl, isothiazolyl, isoindolyl oxadiazolyl, indazolyl, pyridyl, pyridazyl (pyridazyl), pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, purinyl, phthalo Azinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl and thiadiazolyl, etc. , and its oxides, such as pyridyl-N-oxide, etc.
本文单独或组合使用的术语“杂环”是指杂脂环或杂芳环，所述环中必然存在至少一个非碳原子(杂原子)。如“5-n元杂环”的命名是指环中所含的原子总数(即五或n元环，其中至少一个原子为碳原子，至少一个原子为杂原子，且剩余的3-(n减2)个原子为碳原子或杂原子，所述n大于5，例如可以为6、8或12)；若“杂环”中环上的原子已有一个或多个原子固定，且至少含有一个杂原子，那么剩余的环上的原子为碳原子或杂原子。对于具有两个或更多杂原子的杂环而言，所述两个或更多杂原子可以彼此相同或不同。The term "heterocycle" as used herein alone or in combination refers to a heteroalicyclic or heteroaromatic ring in which at least one non-carbon atom (heteroatom) is necessarily present. Such as "5-n membered heterocyclic ring" designation refers to the total number of atoms contained in the ring (i.e. five or n membered ring, wherein at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 3-(n minus 2) the atoms are carbon atoms or heteroatoms, the n is greater than 5, such as 6, 8 or 12); if the atoms on the ring in the "heterocyclic ring" have one or more atoms fixed, and contain at least one heteroatom atoms, then the remaining ring atoms are carbon atoms or heteroatoms. For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same or different from each other.
本文单独或组合使用的术语“烷氧基”是指烷基醚基，O-烷基，其包括O-脂基和O-碳环基，其中烷基、脂基和碳环基可被任选地取代，并且其中的术语烷基、脂基和碳环基如上文的定义。烷氧基的非限定性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。The term "alkoxy" used herein alone or in combination refers to alkyl ether groups, O-alkyl groups, including O-aliphatic and O-carbocyclic groups, wherein alkyl, aliphatic and carbocyclic groups can be optionally is optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, and the like.
本文单独或组合使用的术语“卤素”、“卤代”或“卤化物”是指氟、氯、溴和碘。The terms "halogen", "halo" or "halide" as used herein, alone or in combination, refer to fluorine, chlorine, bromine and iodine.
本文单独或组合使用的术语“烷硫基”是指“-S-烷基”，其包括-S-脂基和-S-碳环基。其中的烷基、脂基和碳环基如上文的定义。烷硫基的非限定性实例包括甲硫基、乙硫基、丙硫基和丁硫基等。The term "alkylthio" as used herein alone or in combination refers to "-S-alkyl", which includes -S-aliphatic and -S-carbocyclyl. The alkyl group, aliphatic group and carbocyclic group are as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, and the like.
本文单独或组合使用的术语“dppf”为1,1'-双(二苯基膦)二茂铁。The term "dppf" as used herein, alone or in combination, is 1,1'-bis(diphenylphosphino)ferrocene.
本文单独或组合使用的术语“dba”为二亚苄基丙酮。The term "dba" as used herein, alone or in combination, means dibenzylideneacetone.
本文单独或组合使用的术语“PCy3”为三环己基膦。The term "PCy3" as used herein, alone or in combination, is tricyclohexylphosphine.
本文单独或组合使用的术语“dppe”为1,2-双(二苯基膦)乙烷。The term "dppe" as used herein, alone or in combination, is 1,2-bis(diphenylphosphine)ethane.
本文单独或组合使用的术语“dppp”为1,3-双(二苯基膦)丙烷。The term "dppp" as used herein, alone or in combination, means 1,3-bis(diphenylphosphino)propane.
本发明的制备方法，以式Ⅱ化合物所示的4-吡唑硼化物为原料，与2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈反应制备关键中间体2-[1-乙磺酰基-3-[4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)-1H-吡唑-1-基]氮杂环丁-3-基]乙腈，无需对式Ⅱ化合物吡唑环上的氮进行保护，从而后续也没有脱去该相应保护基步骤，因此整个反应路线短，原料更易获得，生产成本低，同时，采用本发明的制备方法反应时间短，反应条件温和，避免使用有毒、有刺激性和强腐蚀性试剂，绿色环保，制备简单易操作，所得产品具有高收率和高纯度，能够直接用于进一步制备Baricitinib，特别适合工业化生产。The preparation method of the present invention uses the 4-pyrazole boride represented by the compound of formula II as a raw material, and reacts with 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile to prepare the key intermediate 2- [1-Ethylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazole-1- base] azetidin-3-yl] acetonitrile, without the need to protect the nitrogen on the pyrazole ring of the compound of formula II, so that there is no subsequent step of removing the corresponding protecting group, so the entire reaction route is short, and the raw materials are easier to obtain. Production The cost is low, and at the same time, the preparation method of the present invention has short reaction time, mild reaction conditions, avoids the use of toxic, irritating and strong corrosive reagents, is green and environmentally friendly, and is easy to prepare and operate. The obtained product has high yield and high purity, It can be directly used for further preparation of baricitinib, and is especially suitable for industrial production.
具体实施方式detailed description
本发明通过以下实施例，它们仅仅是实施例，并不限制本发明，凡是基于本发明所实现的技术，均属于本发明的范围。The present invention adopts the following examples, which are only examples and do not limit the present invention, and all technologies realized based on the present invention all belong to the scope of the present invention.
实施例1 4-氯-7-[(2-(三甲基硅烷基)乙氧基)甲基]-7H-吡咯[2,3-d]嘧啶(式Ⅸ化合物)的制备Example 1 Preparation of 4-chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrole[2,3-d]pyrimidine (compound of formula IX)
2升三口瓶中，加入4-氯吡咯并嘧啶(280g,1.83mol)和N,N-二甲基乙酰胺(500mL)，降温至-10℃，分三次加入NaH(84g)，加毕，保温搅拌0.5小时。加入2-(三甲基硅)乙氧基甲基氯(385mL,1.98mol)，加毕，室温反应2小时后，将反应液倒入1L水中，加入500mL乙酸乙酯，搅拌萃取分出酯层，用300mL饱和氯化钠洗一次，无水硫酸钠干燥，过滤，减压浓缩得到红色产物390g，收率75％。In a 2-liter three-necked flask, add 4-chloropyrrolopyrimidine (280g, 1.83mol) and N,N-dimethylacetamide (500mL), cool down to -10°C, add NaH (84g) three times, and the addition is complete. Keep stirring for 0.5 hours. Add 2-(trimethylsilyl)ethoxymethyl chloride (385mL, 1.98mol). After the addition is complete, react at room temperature for 2 hours, pour the reaction solution into 1L of water, add 500mL of ethyl acetate, stir and extract to separate the ester layer, washed once with 300 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 390 g of a red product with a yield of 75%.
实施例2 2-[1-乙磺酰基-3-[4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)-1H-吡唑-1-基]氮杂环丁-3-基]乙腈(式Ⅴ化合物)的制备Example 2 2-[1-Ethylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H- Preparation of pyrazol-1-yl]azetidin-3-yl]acetonitrile (compound of formula V)
室温下将4-吡唑硼酸频哪醇酯(14g,72.1mmol)加入到100mL乙腈中，加入2-[1-(乙基磺酰基)-3-氮杂环丁亚基]乙腈(18g,96.7mmol)和DBU(20mL)，室温搅拌反应2小时后，加入乙酸乙酯(500mL)和水(500mL)，萃取分液，水层用50mL乙酸乙酯萃取一次，合并有机层，再用50mL饱和氯化钠洗一次，无水硫酸钠干燥，过滤，减压浓缩得到黄色固体23g。收率85％。1H-NMR(300MHz,CDCl3),δ(ppm):1.32(12H,s,4×CH3),1.37～1.41(3H,t,J＝7.4Hz,CH3),3.02～3.09(2H,q,J＝7.3Hz,CH2),3.33(2H,s,CNCH2),4.15～4.18(2H,d,J＝9.1Hz,NCH2),4.50～4.53(2H,d,J＝9.2Hz,NCH2),7.87(1H,s,N＝CH-C),7.91(1H,s,N-CH＝C).MS(ESI,m/z):381.1([M+H]+,base peak).Add 4-pyrazoleboronic acid pinacol ester (14g, 72.1mmol) to 100mL acetonitrile at room temperature, add 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (18g, 96.7mmol ) and DBU (20mL), stirred and reacted at room temperature for 2 hours, added ethyl acetate (500mL) and water (500mL), extracted and separated, the aqueous layer was extracted once with 50mL ethyl acetate, the organic layer was combined, and then washed with 50mL saturated chlorine Wash once with sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 23 g of a yellow solid. Yield 85%.1 H-NMR (300MHz, CDCl3 ), δ (ppm): 1.32 (12H, s, 4×CH3 ), 1.37～1.41 (3H, t, J＝7.4Hz, CH3 ), 3.02～3.09 (2H ,q,J=7.3Hz,CH2 ),3.33(2H,s,CNCH2 ),4.15～4.18(2H,d,J=9.1Hz,NCH2 ),4.50～4.53(2H,d,J=9.2 Hz,NCH2 ),7.87(1H,s,N=CH-C),7.91(1H,s,N-CH=C).MS(ESI,m/z):381.1([M+H]+ , base peak).
实施例3 2-[1-乙磺酰基-3-[4-(7-[(2-(三甲基甲硅烷基)乙氧基)甲基]-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基]乙腈(式Ⅺ化合物)的制备Example 3 2-[1-Ethylsulfonyl-3-[4-(7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile (compound of formula XI)
室温下将4-氯-7-[(2-(三甲基硅烷基)乙氧基)甲基]-7H-吡咯[2,3-d]嘧啶(50g，0.176mol)和2-[1-乙磺酰基-3-[4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)-1H-吡唑-1-基]氮杂环丁-3-基]乙腈(67g，0.176mol)加入到2L茄型瓶中，依次加入正丁醇(500mL)、碳酸钾(50g，0.352mol)、四(三苯基膦)钯(0)(Pd(PPh3)4,10g)和水(100mL)后，升温至回流反应2小时，往反应液中加入500mL乙酸乙酯和500mL水，萃取分液，分出有机层，再用200mL饱和氯化钠溶液洗一次，无水硫酸钠干燥，过滤，减压浓缩得到淡黄色固体78g，收率95％。1H-NMR(300MHz,DMSO-d6),δ(ppm):0.00(9H,s,3×CH3)，0.90～0.96(2H,t,J＝8.1Hz,CH2),1.32～1.37(3H,t,J＝7.4Hz,CH3),3.30～3.37(2H,q,J＝7.4Hz,CH2),3.61～3.66(2H,t,J＝7.9Hz,CH3),3.80(2H,s,CH2),4.36～4.33(2H,d,J＝9.1Hz,CH2),4.69～4.72(2H,d,J＝9.1Hz,CH2),5.74(2H,s,CH2),7.29～7.30(1H,d,J＝3.5Hz,ArH),7.90～7.91(1H,d,J＝3.6Hz,ArH),8.60(1H,s,ArH)，8.89(1H,s,ArH),9.06(s,1H,ArH).MS(ESI,m/z):502.2([M+H]+,base peak).4-Chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrole[2,3-d]pyrimidine (50g, 0.176mol) and 2-[1 -Ethylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazol-1-yl] Azetidin-3-yl]acetonitrile (67g, 0.176mol) was added to a 2L eggplant-shaped bottle, and n-butanol (500mL), potassium carbonate (50g, 0.352mol), and tetrakis(triphenylphosphine)palladium were added successively (0) (Pd(PPh3 )4 , 10g) and water (100mL), heat up to reflux for 2 hours, add 500mL ethyl acetate and 500mL water to the reaction solution, extract and separate the liquid, separate the organic layer, and then Wash once with 200 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 78 g of a light yellow solid with a yield of 95%.1 H-NMR (300MHz, DMSO-d6 ), δ(ppm): 0.00 (9H, s, 3×CH3 ), 0.90～0.96 (2H, t, J＝8.1Hz, CH2 ), 1.32～1.37 (3H,t,J=7.4Hz,CH3 ),3.30～3.37(2H,q,J=7.4Hz,CH2 ),3.61～3.66(2H,t,J=7.9Hz,CH3 ),3.80( 2H, s, CH2 ), 4.36～4.33 (2H, d, J＝9.1Hz, CH2 ), 4.69～4.72 (2H, d, J＝9.1Hz, CH2 ), 5.74 (2H, s, CH2 ),7.29～7.30(1H,d,J＝3.5Hz,ArH),7.90～7.91(1H,d,J＝3.6Hz,ArH),8.60(1H,s,ArH),8.89(1H,s,ArH ),9.06(s,1H,ArH).MS(ESI,m/z):502.2([M+H]+ ,base peak).
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| CN201510628431.7ACN106554363B (en) | 2015-09-28 | 2015-09-28 | A kind of preparation method of Baricitinib intermediate |
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| US10766900B2 (en) | 2017-12-29 | 2020-09-08 | Formosa Laboratories, Inc. | Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof |
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| US10766900B2 (en) | 2017-12-29 | 2020-09-08 | Formosa Laboratories, Inc. | Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof |
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