WO2021042535A1 - 一种Tezacaftor中间体II的制备方法 - Google Patents
一种Tezacaftor中间体II的制备方法 Download PDFInfo
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- WO2021042535A1 WO2021042535A1 PCT/CN2019/117502 CN2019117502W WO2021042535A1 WO 2021042535 A1 WO2021042535 A1 WO 2021042535A1 CN 2019117502 W CN2019117502 W CN 2019117502W WO 2021042535 A1 WO2021042535 A1 WO 2021042535A1
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- Prior art keywords
- tezacaftor
- preparing
- reaction
- compound
- formula
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- MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 title claims abstract description 46
- 229950005823 tezacaftor Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001879 copper Chemical class 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 30
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000012046 mixed solvent Chemical class 0.000 claims description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 3
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 235000009518 sodium iodide Nutrition 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 229940126601 medicinal product Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000005909 Kieselgur Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- VKHWQJGOWVVAHW-UHFFFAOYSA-N CC(C)(COCc1ccccc1)C#C Chemical compound CC(C)(COCc1ccccc1)C#C VKHWQJGOWVVAHW-UHFFFAOYSA-N 0.000 description 3
- PPKZJBLQGJMIPF-RUZDIDTESA-N CC(C)(COCc1ccccc1)C#Cc(cc(c(F)c1)N)c1NC[C@H](COCc1ccccc1)O Chemical compound CC(C)(COCc1ccccc1)C#Cc(cc(c(F)c1)N)c1NC[C@H](COCc1ccccc1)O PPKZJBLQGJMIPF-RUZDIDTESA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XFEDZKLXQZLTRU-GFCCVEGCSA-N Nc(c(F)c1)cc(Br)c1NC[C@H](COCc1ccccc1)O Chemical compound Nc(c(F)c1)cc(Br)c1NC[C@H](COCc1ccccc1)O XFEDZKLXQZLTRU-GFCCVEGCSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- FWXAUDSWDBGCMN-UHFFFAOYSA-N 3-diphenylphosphanylbutan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention relates to the field of organic synthesis, in particular to a preparation method of Tezacaftor intermediate II.
- Tezacaftor The structure of Tezacaftor is: The cas number of its key intermediate II is 1294504-67-8, and the structural formula is as follows: The prior art has reported the preparation method of the key intermediate II of Tezacaftor. For example, the patent CN103038214B discloses the following synthetic route:
- the present invention provides a method for preparing the key intermediate II of Tezacaftor at a lower cost and a higher yield.
- the present invention provides the following technical solutions:
- a method for preparing Tezacaftor Intermediate II comprises using a compound of formula I as a reaction material, under the action of a catalyst and a base, reacting in an organic solvent to obtain Tezacaftor Intermediate II, the reaction equation is as follows:
- the catalyst is copper salt and N-methylpyrrolidone.
- the copper salt is one or more of cuprous chloride, cuprous bromide or cuprous iodide.
- the copper salt is cuprous iodide.
- the alkali is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate;
- the organic solvent is chlorobenzene, toluene, acetonitrile, acetone, methanol
- ethanol or halogenated alkanes preferably chlorobenzene or toluene.
- the reaction temperature of the reaction is 60-200°C, preferably 100-150°C.
- the reaction time of the reaction is 5 to 60 hours, preferably 10 to 60 hours.
- the molar ratio of the compound of formula I and the copper salt is 1:0.1-3
- the molar ratio of the compound of formula I and N-methylpyrrolidone is 1:0.05-5
- the molar ratio of the compound of formula I and the base is 1:1 ⁇ 50.
- the method further includes the step of preparing the compound of formula I, and the steps include: compounds A and B are reacted in an organic solvent under the action of palladium acetate, cuprous iodide, alkali and dppb to obtain the compound of formula I ,
- the reaction equation is as follows:
- the base is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate
- the organic solvent is chlorobenzene One or more of, toluene, acetonitrile, acetone, methanol, ethanol or halogenated alkanes or a mixed solvent with water.
- the present invention also provides a method for preparing Tezacaftor, which is characterized in that the method includes the following steps:
- the present invention finds a brand-new CuI/NMP (N-methylpyrrolidone) catalyst system by optimizing the catalyst system in the key step of preparing the intermediate II of Tezacaftor.
- CuI/NMP N-methylpyrrolidone
- the reaction yield of the key step in the synthesis of Tezacaftor's Intermediate II has been significantly improved, which greatly improves the production efficiency of Tezacaftor's Intermediate II and further reduces its production cost.
- the present invention provides a method for preparing Tezacaftor Intermediate II.
- the method includes using a compound of formula I as a reaction material, reacting with a catalyst and a base in an organic solvent to obtain Tezacaftor Intermediate II.
- the reaction equation is as follows:
- the catalyst for the reaction is copper salt and N-methylpyrrolidone.
- the compound of formula I can be directly purchased or obtained through preparation, and the compound of formula I can be pure or crude.
- the copper salt includes monovalent copper salt and divalent copper salt commonly used in the art, including but not limited to halogenated copper salt, copper sulfate or copper carbonate salt, etc.
- the copper salt and N-methylpyrrolidone may be a mixture , Can also be added to the reaction system separately.
- the organic solvents include all common organic solvents in the art, including solvents such as esters, alcohols, ethers, ketones, nitriles, halogenated hydrocarbons, benzene or substituted benzene.
- the copper salt is one or more of cuprous chloride, cuprous bromide or cuprous iodide, preferably cuprous iodide.
- the catalyst does not include Pd.
- the organic solvent is one or more of chlorobenzene, toluene, acetonitrile, acetone, methanol, ethanol, dichloromethane or chloroform, etc., preferably chlorobenzene or toluene.
- the reaction temperature of the reaction is 60-200°C, preferably 100-150°C, more preferably 110-130°C.
- the reaction time of the reaction is 5 to 60 hours, preferably 10 to 60 hours.
- the molar ratio of the compound of formula I and the copper salt is 1:0.1 ⁇ 3, preferably 1:0.2 ⁇ 2, and the molar ratio of the compound of formula I and N-methylpyrrolidone is 1:0.05 ⁇ 5.
- it is 1:0.1-2, and the molar ratio of the compound of formula I to the base is 1:1-50, preferably 1:2-30.
- the method further includes the step of preparing the compound of formula I, compounds A and B, under the action of palladium acetate, cuprous iodide, alkali and dppb (bisdiphenylphosphinobutane) , Reacting in an organic solvent to obtain the compound of formula I, the reaction equation is as follows:
- the alkali is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
- the present invention also provides a method for preparing Tezacaftor, the method comprising:
- Compound A was purchased from Suzhou Wangshan Wangshui Biological Medicine Co., Ltd.
- Compound B was purchased from Suzhou Wangshan Wangshui Biological Medicine Co., Ltd.
- Tezacaftor Intermediate II mainly includes two steps.
- the reaction equation of the first step is as follows:
- reaction equation of the second step is as follows:
- the present invention also includes other embodiments, and all technical solutions formed by equivalent transformations or equivalent substitutions should fall within the protection scope of the claims of the present invention.
Abstract
本发明提供了一种Tezacaftor中间体II的制备方法，所述方法包括以式Ⅰ化合物为反应原料，在催化剂和碱的作用下，在有机溶剂中反应得到Tezacaftor中间体II，反应方程式如下： (I), (II), 所述反应的催化剂为铜盐和N-甲基吡咯烷酮的混合物。本发明通过使用一种全新的CuI/NMP催化体系，不仅革除了现有技术中使用Pd试剂的问题，极大的降低了生产成本，同时也可以避免金属钯的残留对于药品Tezacaftor的影响，更为重要的是，通过使用全新的上述催化体系，合成Tezacaftor的中间体II的关键步骤的反应收率得到了显著的提升，极大了提高了Tezacaftor的中间体II的生产效率并进一步降低了其生产成本。
Description
本发明涉及一种有机合成领域，尤其是涉及一种Tezacaftor中间体II的制备方法。
Tezacaftor的结构为：
其关键中间体II的cas号为1294504-67-8，结构式如下：
现有技术已经报道了Tezacaftor的关键中间体II的制备方法，如专利CN103038214B公开了如下合成路线：
该专利文献报道的技术方案中，以化合物Ⅰ为反应原料，在钯催化剂的作用下反应得到Tezacaftor的关键中间体II，由于Pd试剂的使用增加了产品成本，且该步反应的收率较低，不利于工业化放大生产，同时增加API中元素杂质残留的风险。因此，寻找一种能 够以较低成本、较高收率制备得到Tezacaftor的关键中间体II的方法，成为生产Tezacaftor并保证其药品质量急需要解决的课题。
发明内容
发明要解决的问题
为了解决上述技术问题，本发明提供了一种能够以较低成本、较高收率制备Tezacaftor的关键中间体II的方法。
用于解决问题的方案
为了解决上述技术问题，本发明提供了以下技术方案：
一种Tezacaftor中间体II的制备方法，所述方法包括以式Ⅰ化合物为反应原料，在催化剂和碱的作用下，在有机溶剂中反应得到Tezacaftor中间体II，反应方程式如下：
优选的，所述铜盐为氯化亚铜、溴化亚铜或碘化亚铜中的一种或多种。
优选的，所述铜盐为碘化亚铜。
优选的，所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种；所述有机溶剂为氯苯、甲苯、乙腈、丙酮、甲醇、乙醇或卤代烷烃中的一种或多种，优选为氯苯或甲苯。
优选的，所述反应的反应温度为60～200℃，优选为100～150℃。
优选的，所述反应的反应时间为5～60小时，优选为10～60小时。
优选的，式Ⅰ化合物和铜盐的摩尔比为1:0.1～3，式Ⅰ化合物和N-甲基吡咯烷酮的摩尔比为1:0.05～5，式Ⅰ化合物和碱的摩尔比为1:1～50。
优选的，所述方法还包括制备式Ⅰ化合物的步骤，所述步骤包括：化合物A和B，在醋酸钯、碘化亚铜、碱和dppb的作用下，在有机溶剂中反应得到式Ⅰ化合物，反应方程式如下：
优选的，制备式Ⅰ化合物的步骤中，所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种，所述有机溶剂为氯苯、甲苯、乙腈、丙酮、甲醇、乙醇或卤代烷烃中的一种或多种或与水的混合溶剂。
本发明还提供了一种Tezacaftor的制备方法，其特征在于，所述方法包括如下步骤：
(1)权利要求1-9任一项所述的制备Tezacaftor中间体II的步骤；
(2)Tezacaftor中间体II制备Tezacaftor的步骤。
发明的效果
本发明通过对制备Tezacaftor的中间体II的关键步骤中催化剂体系的优化，寻找到一种全新的CuI/NMP(N-甲基吡咯烷酮)催化体系。通过使用该催化体系，不仅革除了现有技术中使用Pd试剂的问 题，极大地降低了生产成本，同时也可以避免金属钯的残留对于药品Tezacaftor的影响，更为重要的是，通过使用全新的上述催化体系，合成Tezacaftor的中间体II的关键步骤的反应收率得到了显著的提升，极大了提高了Tezacaftor的中间体II的生产效率并进一步降低了其生产成本。
本发明提供了一种Tezacaftor中间体II的制备方法，所述方法包括以式Ⅰ化合物为反应原料，在催化剂和碱的作用下，在有机溶剂中反应得到Tezacaftor中间体II，反应方程式如下：
所述反应的催化剂为铜盐和N-甲基吡咯烷酮。所述的式Ⅰ化合物可以是直接购买得到，也可以是通过制备得到，所述的式Ⅰ化合物可以是纯品也可以是粗品。
所述铜盐包括本领域常见的一价铜盐和二价铜盐，包括但不限于卤代铜盐，硫酸铜盐或碳酸铜盐等，所述铜盐和N-甲基吡咯烷酮可以是混合物，也可以是分别加入到反应体系中。
所述的有机溶剂包含所有本领域常见的有机溶剂，包括酯类、醇类、醚类、酮类、腈类、卤代烃类、苯或取代的苯等溶剂。
在一项优选的实施方案中，所述的所述铜盐为氯化亚铜、溴化亚铜或 碘化亚铜中的一种或多种，优选为碘化亚铜。
在一项优选的实施方案中，所述催化剂不包括Pd。
在一项优选的实施方案中，所述有机溶剂为氯苯、甲苯、乙腈、丙酮、甲醇、乙醇、二氯甲烷或三氯甲烷等中的一种或多种，优选为氯苯或甲苯。
在一项优选的实施方案中，所述反应的反应温度为60～200℃，优选为100～150℃，更优选为110～130℃。
在一项优选的实施方案中，所述反应的反应时间为5～60小时，优选为10～60小时。
在一项优选的实施方案中，式Ⅰ化合物和铜盐的摩尔比为1:0.1～3，优选为1：0.2～2，式Ⅰ化合物和N-甲基吡咯烷酮的摩尔比为1:0.05～5，优选为1：0.1～2，式Ⅰ化合物和碱的摩尔比为1:1～50，优选为1:2～30。
在一项优选的实施方案中，所述方法还包括制备式Ⅰ化合物的步骤，化合物A和B，在醋酸钯、碘化亚铜、碱和dppb(双二苯基膦丁烷)的作用下，在有机溶剂中反应得到式Ⅰ化合物，反应方程式如下：
在一项优选的实施方案中，所述的碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种。
另外，本发明还提供了一种Tezacaftor的制备方法，所述方法包括：
(1)上述任一所述的制备Tezacaftor中间体II的步骤；
(2)Tezacaftor中间体II制备Tezacaftor的步骤，所述步骤包含任意现有技术中从中间体II制备得到Tezacaftor的方法，例如：：化合物Ⅱ通过如下反应制备得到Tezacaftor：
为了可以更充分地理解本文所述的发明，描述以下实施例。应当理解这些实施例仅起到说明目的并且不得解释为以任何方式限制本发明。
方法和材料
化合物A从苏州旺山旺水生物医药有限公司购买。化合物B从苏州旺山旺水生物医药有限公司购买。
制备Tezacaftor中间体II主要包含两步，第一步的反应方程式如下：
第二步的反应方程式如下：
实施例1
式Ⅰ化合物的合成
将化合物A(300g)，化合物B(136g)，NaOH(55.45g)，dppb(7.1g)，CuI(6.3g)，醋酸钯(2.5g)分别加入到反应瓶中，加入2.4L乙腈溶解，氮气置换3次后，升温至回流反应，反应过夜。次日进行后处理：硅藻土助滤反应液，少量乙腈洗涤滤饼，滤液浓缩。向浓缩液中加入乙酸乙酯溶解，用水洗3次，有机相浓缩直接用于下一步反应。
实施例2
式Ⅰ化合物的合成
将化合物A(30g)，化合物B(14g)，Cs
2CO
3(60g)，dppb(0.7g)，CuI(0.6g)，醋酸钯(0.3g)分别加入到反应瓶中，加入300mL乙腈溶解，氮气置换3次后，升温至回流反应，反应过夜。次日进行后处理：硅藻土助滤反应液，少量乙腈洗涤滤饼，滤液浓缩，向浓缩液中加入700ml氯苯稀释溶解浓缩液，直接用于下一步反应。
实施例3
化合物I的合成
将化合物A(30g)，化合物B(14g)，NaOH(5.6g)，dppb(0.7g)，CuI(0.6g)，醋酸钯(0.3g)分别加入到反应瓶中，加入300mL乙 腈溶解，氮气置换3次后，升温至回流反应，反应过夜。次日进行后处理：硅藻土助滤反应液，少量乙腈洗涤滤饼，滤液浓缩，直接用于下一步反应。
实施例4
化合物II的合成
将实施例1制备得到的化合物I粗品(260g),CuI(62g)，NMP(108g)，NaOH(1.0g)和氯苯(2L)分别加入到反应瓶中，升温至130℃，反应约30h。HPLC显示原料消耗完全，进行后处理，体系降温至室温，硅藻土助滤，滤饼用氯苯洗涤，滤液依次用氯化铵溶液、盐水、水洗涤。有机相浓缩得化合物II粗品，用乙酸乙酯/正庚烷结晶得到化合物II(185g，两步总收率70.1％，纯度99.4％)。
实施例5
化合物II的合成
将实施例2制备得到的化合物I粗品(26g),CuI(6g)，NMP(22g)，NaOH(0.1g)和氯苯(250mL)分别加入到反应瓶中，升温至130℃，反应约30h。HPLC显示原料消耗完全，进行后处理，体系降温至室温，硅藻土助滤，滤饼用氯苯洗涤，滤液依次用氯化铵溶液、盐水、水洗涤。有机相浓缩得化合物II粗品，用乙酸乙酯/正庚烷结晶得到化合物II(18.9g，两步总收率71.6％，纯度98.9％)。
实施例6
化合物II的合成
将实施例3制备得到的化合物I粗品(26g),CuI(6g)，NMP(11g)，NaOH(0.1g)和甲苯(250mL)分别加入到反应瓶中，升温至110℃，反应约60h。HPLC显示原料<1.0％，进行后处理，体系降温至室温，硅藻土助滤，滤饼用甲苯洗涤，滤液依次用氯化铵溶液、盐水、水洗涤。有机相浓缩得化合物II粗品，用乙酸乙酯/正庚烷结晶得到化合物II(13.7g，两步总收率51.9％，纯度98.1％)。
实施例7
式Ⅰ化合物的合成
将化合物A(300g)，化合物B(136g)，NaOH(55.45g)，dppb(7.1g)，CuI(6.3g)，醋酸钯(2.5g)分别加入到反应瓶中，加入1.5L氯苯和150mL水溶解，氮气置换3次后，升温至回流反应，反应过夜。次日进行后处理：硅藻土助滤反应液，少量氯苯洗涤滤饼，有机相直接用于下一步反应。
将上述有机相、CuI(62g)、NMP(108g)和NaOH(1.0g)依次加入到反应瓶中，升温至130℃，反应约30h。HPLC显示原料消耗完全，进行后处理，体系降温至室温，硅藻土助滤，滤饼用氯苯洗涤，滤液依次用氯化铵溶液、盐水、水洗涤。有机相浓缩得化合物II粗品，用乙酸乙酯/正庚烷结晶得到化合物II(188g，两步总收率71.2％，纯度99.2％)。
除上述实施例外，本发明还包括有其他实施方式，凡采用等同变换或者等效替换方式形成的技术方案，均应落入本发明权利要求的保护范围之内。
Claims (10)
- 一种Tezacaftor中间体II的制备方法，所述方法包括以式Ⅰ化合物为反应原料，在催化剂和碱的作用下，在有机溶剂中反应得到Tezacaftor中间体II，反应方程式如下：其特征在于，所述催化剂为铜盐和N-甲基吡咯烷酮。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述铜盐为氯化亚铜、溴化亚铜或碘化亚铜中的一种或多种。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述铜盐为碘化亚铜。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种；所述有机溶剂为氯苯、甲苯、乙腈、丙酮、甲醇、乙醇或卤代烷烃中的一种或多种，优选为氯苯或甲苯。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述反应的反应温度为60～200℃，优选为100～150℃。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述反应的反应时间为5～60小时，优选为10～60小时。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，式Ⅰ化合物和铜盐的摩尔比为1:0.1～3，式Ⅰ化合物和N-甲基吡咯 烷酮的摩尔比为1:0.05～5，式Ⅰ化合物和碱的摩尔比为1:1～50。
- 根据权利要求1所述的一种Tezacaftor中间体II的制备方法，其特征在于，所述方法还包括制备式Ⅰ化合物的步骤，所述步骤包括：化合物A和B，在醋酸钯、碘化亚铜、碱和dppb的作用下，在有机溶剂中反应得到式Ⅰ化合物，反应方程式如下：
- 根据权利要求8所述的一种Tezacaftor中间体II的制备方法，其特征在于，制备式Ⅰ化合物的步骤中，所述碱为氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯中的一种或多种，所述有机溶剂为氯苯、甲苯、乙腈、丙酮、甲醇、乙醇或卤代烷烃中的一种或多种或与水的混合溶剂。
- 一种Tezacaftor的制备方法，其特征在于，所述方法包括如下步骤：(1)权利要求1-9任一项所述的制备Tezacaftor中间体II的步骤；(2)Tezacaftor中间体II制备Tezacaftor的步骤。
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| WO2011021000A2 (en) * | 2009-08-20 | 2011-02-24 | Cipla Limited | A process for the synthesis of naratriptan |
| CN103038214A (zh) * | 2010-04-22 | 2013-04-10 | 弗特克斯药品有限公司 | 制备环烷基甲酰胺基-吲哚化合物的方法 |
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