CN103819385A - (3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 - Google Patents
(3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 Download PDFInfo
- Publication number
- CN103819385A CN103819385A CN201410075116.1A CN201410075116A CN103819385A CN 103819385 A CN103819385 A CN 103819385A CN 201410075116 A CN201410075116 A CN 201410075116A CN 103819385 A CN103819385 A CN 103819385A
- Authority
- CN
- China
- Prior art keywords
- cyclohexyl
- benzyloxy
- dimethoxyphenyl
- preparation
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 18
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims abstract description 14
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims abstract description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 5
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 229910000077 silane Inorganic materials 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- -1 toluyl tartrate Chemical compound 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000007348 radical reaction Methods 0.000 claims description 2
- 238000002444 silanisation Methods 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N bromo-2-chloroethane Natural products ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- JMHYCBFEEFHTMK-IIUXMCBISA-N (3r)-1-[(1r,2r)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCO[C@H]1[C@H](N2C[C@H](O)CC2)CCCC1 JMHYCBFEEFHTMK-IIUXMCBISA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229950010489 vernakalant hydrochloride Drugs 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- VBHQKCBVWWUUKN-KZNAEPCWSA-N vernakalant Chemical compound C1=C(OC)C(OC)=CC=C1CCO[C@H]1[C@H](N2C[C@H](O)CC2)CCCC1 VBHQKCBVWWUUKN-KZNAEPCWSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 150000001934 cyclohexanes Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229960000527 vernakalant Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- CWBMYKUPMLRKQK-LLVKDONJSA-N C(c1ccccc1)O[C@H]1CNCC1 Chemical compound C(c1ccccc1)O[C@H]1CNCC1 CWBMYKUPMLRKQK-LLVKDONJSA-N 0.000 description 1
- 0 CC(C)(C)C=*N(CC1)C[C@]1OCc1ccccc1 Chemical compound CC(C)(C)C=*N(CC1)C[C@]1OCc1ccccc1 0.000 description 1
- BESOLXULURWXGX-UHFFFAOYSA-N CC1[I]=CN1C Chemical compound CC1[I]=CN1C BESOLXULURWXGX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 229940127316 Potassium Channel Antagonists Drugs 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XEBCWEDRGPSHQH-HTQZYQBOSA-N dipropan-2-yl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-HTQZYQBOSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明公开了一种新型抗心律失常药:(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法:以(3R)-羟基吡咯烷为原料与硅烷保护剂反应得(R)-N-硅烷保护基-3-羟基吡咯烷,再与氯苄反应得(R)-N-硅烷保护基-3-苄氧基吡咯烷,脱去硅烷保护基得(3R)-苄氧基吡咯烷,与顺-1,2环氧环己烷经开环反应,经拆分得(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇,再与4-(2-氯乙基)-1,2-二甲氧基苯基反应得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷,再经脱苄基得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇。
Description
技术领域
本发明属于医药化工领域,具体涉及一种新型抗心律失常药:(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇及其盐以及中间体的制备方法。
背景技术
盐酸维那卡兰(vernakalant hydrochloride)化学名:(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇盐酸盐,目前该药物公开的制备专利非常非常少,而该发明的收率高,该发明得到的盐酸维那卡兰化学纯度和光学纯度非常高,适合工业化生产,该药物是加拿大Cardiome药物公司和美国Astellas公司合作开发的一种新型抗心律失常药,2010年9月在欧洲批准上市,商品名Kynapid。本品是一种选择性作用于心房离子通道的混合性钠/钾通道阻滞剂,在新近发作心房颤动的急性转复方面的疗效优于胺碘酮,临床用于治疗心房纤维性颤动,而本发明恰好填补了此药物市场供应的空缺。
发明内容
本发明针对现有技术不足,提供了一种(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇及其盐的制备方法,本法优点在于收率高,所用到的试剂毒性小,光学纯度,化学纯度较高,工艺稳定适合工业化批量生产。
本发明具体技术方案如下:
一种(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法,包括以下步骤:
(1)(3R)-羟基吡咯烷与硅烷保护剂在碱的作用下进行硅烷化保护,得(R)-N-硅烷保护基-3-羟基吡咯烷;,反应式如下所示;
上述反应所述硅烷保护剂优选为三异丙基氯硅烷、三甲基氯硅烷、三乙基氯硅烷中的一种,对应产生的硅烷保护基分别为三异丙基硅烷基、三甲基硅烷基、三乙基硅烷基;碱选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾中的一种;反应溶剂选自N,N-二甲基甲酰胺、四氢呋喃、丙酮或乙腈中的一种;反应温度优选为15-50℃,反应时间优选4-12小时。
(2)将步骤(1)所得(R)-N-保护基-3-羟基吡咯烷在碱的作用下与氯苄或溴苄反应得(R)-N-硅烷保护基-3-苄氧基吡咯烷,反应式如下所示;
所述碱选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾中的一种;反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮中的一种或几种;反应温度优选为20-80℃,反应时间优选2-6小时。
(3)将步骤(2)所得(R)-N-R-3-苄氧基吡咯烷在酸的作用下脱去硅烷保护基得(3R)-苄氧基吡咯烷,反应式如下所示;
上述反应所述酸为:盐酸、三氟乙酸、四丁基氟化铵、氯化铵中的一种或多种;反应溶剂选自二氯甲烷、二氯乙烷、丙酮、四氢呋喃中的一种或几种;反应温度优选为20-50℃,反应时间优选0.5-2小时。
(4)将步骤(3)所得(3R)-苄氧基吡咯烷与顺-1,2环氧环己烷经开环反应后,再经拆分得(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇,反应式如下所示:
上述反应溶剂选自异丙醇、乙醇、水中的一种或多种;开环反应优选加热回流反应2-4小时,所用拆分剂优选D-二对甲基苯甲酰酒石酸或D-酒石酸二乙酯。
(5)将步骤(4)所得(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇再与4-(2-卤代乙基)-1,2-二甲氧基苯基反应得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷反应式如下所示;
X=Cl,Br或I
上述反应所述反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮中的一种;反应温度优选为15-80℃,反应时间优选4-12小时,所述4-(2-卤代乙基)-1,2-二甲氧基苯基是4-(2-氯乙基)-1,2-二甲氧基苯基、4-(2-溴乙基)-1,2-二甲氧基苯基或4-(2-碘乙基)-1,2-二甲氧基苯基中的一种。
(6)将步骤(5)所得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷脱去苄基得到(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇,反应式如下所示;
上述反应所述脱去苄基的方法可采用本领域通常使用的脱苄基方法,优选两种,一种使用三氯化硼,优选溶剂为二氯甲烷、四氢呋喃溶液或乙醚,优选反应温度为0-10℃,反应时间为1-3小时,另一种方法为在催化剂为Pd/C、Pd/BaSO4或Pd(OH)2/C的作用下通氢气脱苄基,优选反应温度为20-30℃,反应时间为1-4小时。
本发明还提供了一种(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇盐的制备方法,其特征在于将上述方法制备得到的(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇与酸反应形成盐,所述酸为氯化氢气体、酒石酸、草酸、醋酸、苹果酸、富马酸、甲磺酸中的一种,所用溶剂为异丙醇、乙醇、甲醇、二氯甲烷、甲基叔丁基醚中的一种或几种。
本发明还提供了制备上述(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的中间体,具有如下结构:
本发明方法收率高,所用到的试剂毒性小,光学纯度,化学纯度较高,工艺稳定适合工业化批量生产。
附图说明
图1为本发明方法制备得到的维那卡兰盐酸盐HPLC色谱图。
具体实施方式
以下通过实施例说明本发明的具体步骤,但不受实施例限制。
在本发明中所使用的术语,除非另有说明,一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明。应理解,这些实施例只是为了举例说明本发明,而非以任何方式限制本发明的范围。
在以下实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1:(R)-N-三异丙基-3-羟基吡咯烷(Ⅱ)的制备
(3R)-羟基吡咯烷(Ⅰ)(200g2.29moL)溶解在丙酮中,加入碳酸钾(348g2.52moL)混合液中加入三异丙基氯硅烷(485g2.52moL)加完室温反应4小时,过滤,滤液旋干,得黄色油状物,直接用于下步反应。
实施例2:(R)-N-三异丙基-3-苄氧基吡咯烷(Ⅲ)的制备
(R)-N-三异丙基-3-羟基吡咯烷(Ⅱ)(120g0.49moL)溶于120mLDMF中,加入氢氧化钠(23.69g0.59moL),滴加溴苄(100g0.59moL),加完40℃下反应2小时,过滤,反应液倒入到600mL水中,甲基异丁基酮萃取,减压蒸干,直接用于下步反应。
实施例3:(3R)-苄氧基吡咯烷(Ⅳ)的制备
(R)-N-三异丙基-3-苄氧基吡咯烷(Ⅲ)(220g0.66moL)溶于200mL二氯甲烷中,加入盐酸,室温下反应1小时,减压蒸干,加入甲基叔丁基醚,搅拌,过滤得到类白色固体87g,收 率:75%。
MS(m/z):178[M+H]+;1H NMR(CDCl3):7.24~7.38(m,5H,Ar-H),4.54(s,2H,OCH2Ph),4.16~4.23(m,1H,CHOCH2Ph),3.49~3.67[m,4H,CH2CH(OCH2Ph)CH2],1.95~2.17(m,2H,NCH2CH2)。
实施例4:反-[(3R)-3-苄氧基-1-吡咯烷基]环己醇
(3R)-苄氧基吡咯烷(Ⅳ)(300g1.69moL),溶于乙醇中,加入顺-1,2环氧环己烷(249g2.54moL),碳酸钾(513g3.71moL)升温至回流反应2小时,旋干溶剂,加入水,用盐酸调节pH4,用乙酸乙酯萃取,水层氢氧化钠溶液调pH12,用乙酸乙酯萃取,经无水硫酸钠干燥,旋干得油状物直接用于下步反应。
实施例5:(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇(Ⅴ)
反-[(3R)-3-苄氧基-1-吡咯烷基]环己醇(260g0.95moL),溶于异丙醇(260mL),20~25℃滴加(+)-DIPT(190g0.47moL)的异丙醇(190ml)溶液。滴毕于0℃搅拌10h,抽滤,所得灰白色固体用异丙醇重结晶,得(1R,2R)-[(3R)-3-氧基-1-吡咯烷基]环己醇·1/2D-二对甲基苯甲酰酒石酸盐。该固体悬浮在水(300mL)和甲基叔丁醚(200mL)的混合液中,加10%盐酸(200mL)调至pH1。分出有机相,水相用甲基叔丁醚(200mL×2)洗涤,再加32%氢氧化钠溶液调至pH10,用甲基叔丁醚(300mL、150mL)萃取。合并有机层,经无水硫酸钠干燥后过滤,滤液减压浓缩,得黄色油状物Ⅵ(104g,40%)。ee值99.4%HPLC法:色谱柱ChiralpakAD-H柱;流动相乙腈(含0.25%二乙胺);检测波长210nm;柱温30℃;流速0.5mL/min]MS(m/z):276[M+H]+;1H NMR(CDCl3):7.26~7.35(m,5H,Ar-H);4.48(s,2H,CHOCH2Ph);4.07~4.14(m,1H,CHOH),3.89(br s,1H,OH)3.32~3.38(m,1H,CHOCH2Ph),2.59~2.95(m,4H,CH2NCH2),2.50(m,1H,CHN),2.00~2.13(m,2H,NCH2CH2),1.71~1.91(m,4H,CH2CH2CH2CH2),1.16~1.24(m,4H,CH2CH2CH2CH2)。
实施例6:(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷(Ⅶ)制备
(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇(Ⅴ)(100g0.36moL),加入DMF40mL,加入4-(2-氯乙基)-1,2-二甲氧基苯基(Ⅵ)(87g0.43moL),碳酸钾(74g0.54moL),室温下搅拌8小时,反应液倒入水中,乙酸乙酯萃取,旋干直接用于下步反应。
实施例7:维那卡兰(Ⅷ)的制备
(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷(Ⅶ)(150g0.34moL),溶解在二氯甲烷中,缓慢滴加0.68mL的三氯化硼的二氯甲烷溶液。滴加完毕, 10℃下反应3小时,滴加纯水,旋干溶剂,氢氧化钠溶液调pH12,甲基叔丁基醚萃取,经无水硫酸钠干燥,得油状物95g,收率:80%。
实施例8:维那卡兰盐酸盐(Ⅸ)的制备
将维那卡兰(Ⅷ)(80g0.22mmoL)溶于异丙醇(800mL)中,0℃通入氯化氢气体至pH2,0℃搅拌6h,抽滤,滤饼用异丙醇(100mLl×2)洗涤,再用异丙醇重结晶,得类白色晶体Ⅹ,83g,收率:95%),mp143~145℃,纯度99.15%[HPLC归一化法:色谱柱Diamonsil C18柱(4.6mm×250mm,5μm);流动相0.15%磷酸二氢钾溶液(加磷酸调至pH2.5)-乙腈(1∶4);检测波长210nm;柱温25℃;流速1.0mL/min。
IR(KCl)(cm-1):3441,2933,2860,1591,1517,1261,1078,1030,807。
MS(m/z):350[M-HCl+H]+
1H NMR(CDCl3):6.73~6.81(m,3H,Ar-H),4.03~4.05(m,1H,CHOH),3.87(s,6H,2×OCH3),3.56~3.65(m,2H,OCH2CH2),3.33~3.44(m,1H,CHOCH2)3.07~3.09(m,1H,NCH),2.70~2.94(m,4H,CH2NCH2),2.48~2.55(m,2H,OCH2CH2Ar),1.97~2.13(m,2H,NCH2CH2),1.71~1.88(m,4H,CH2CH2CH2CH2),1.22~1.33(m,4H,CH2CH2CH2CH2)。
Claims (8)
1.一种(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法,其特征在于,所述方法包括以下步骤:
(1)(3R)-羟基吡咯烷与硅烷保护剂在碱的作用下进行硅烷化保护,得(R)-N-硅烷保护基-3-羟基吡咯烷;
(2)将步骤(1)所得(R)-N-保护基-3-羟基吡咯烷在碱的作用下与氯苄或溴苄反应得(R)-N-硅烷保护基-3-苄氧基吡咯烷;
(3)将步骤(2)所得(R)-N-硅烷保护基-3-苄氧基吡咯烷在酸的作用下脱去硅烷保护基得(3R)-苄氧基吡咯烷;
(4)将步骤(3)所得(3R)-苄氧基吡咯烷与顺-1,2环氧环己烷经开环反应后,再经拆分得(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇;
(5)将步骤(4)所得(1R,2R)-[(3R)-3-苄氧基-1-吡咯烷基]环己醇与4-(2-卤代乙基)-1,2-二甲氧基苯基反应得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷;
(6)将步骤(5)所得(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-苄氧基吡咯烷脱去苄基得到(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇。
2.如权利要求1所述的制备方法,其特征在于步骤(1)所述硅烷保护剂为三异丙基氯硅烷、三甲基氯硅烷、三乙基氯硅烷中的一种。
3.如权利要求1所述的制备方法,其特征在于步骤(1)所用溶剂为N,N-二甲基甲酰胺或四氢呋喃。
4.如权利要求1所述的制备方法,其特征在于步骤(4)所用拆分试剂为D-二对甲基苯甲酰酒石酸或D-酒石酸二乙酯。
5.如权利要求1所述的制备方法,其特征在于步骤(6)所述脱苄基试剂为H2和催化剂,所述催化剂为Pd/C、Pd/BaSO4或Pd(OH)2/C。
6.如权利要求1所述的制备方法,其特征在于步骤(6)所述脱苄基试剂为三氯化硼。
7.一种(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇盐的制备方法,其特征在于将如权利要求1-6任一项所述方法制备得到的(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇与酸反应形成盐,所述酸为氯化氢、硫酸、磷酸、酒石酸、草酸、醋酸、苹果酸、富马酸或甲磺酸。
8.如权利要求1-6任一项所述方法制备(3R)-1-[(1R,2R)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的中间体,其特征在于具有如下结构:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410075116.1A CN103819385B (zh) | 2014-03-03 | 2014-03-03 | (3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410075116.1A CN103819385B (zh) | 2014-03-03 | 2014-03-03 | (3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103819385A true CN103819385A (zh) | 2014-05-28 |
CN103819385B CN103819385B (zh) | 2016-06-08 |
Family
ID=50754722
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410075116.1A Active CN103819385B (zh) | 2014-03-03 | 2014-03-03 | (3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103819385B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104610121A (zh) * | 2015-01-07 | 2015-05-13 | 北京哈三联科技有限责任公司 | 一种维纳卡兰盐酸盐的制备方法 |
CN105294530A (zh) * | 2015-11-30 | 2016-02-03 | 北京哈三联科技有限责任公司 | 一种维纳卡兰盐酸盐的精制方法 |
CN106220544A (zh) * | 2016-08-03 | 2016-12-14 | 北京诺泓医药科技有限公司 | 一种盐酸维纳卡兰的纯化方法 |
CN114200034A (zh) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | 一种维纳卡兰有关物质的分析方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006088525A1 (en) * | 2004-11-18 | 2006-08-24 | Cardiome Pharma Corp. | Synthetic process for aminocyclohexyl ether compounds |
WO2012040846A1 (en) * | 2010-09-27 | 2012-04-05 | Alphora Research Inc. | Process for preparation of aminocyclohexyl ethers and intermediate products used in the process |
CN102603591A (zh) * | 2011-09-08 | 2012-07-25 | 浙江工业大学 | 一种维纳卡兰关键中间体的合成方法 |
-
2014
- 2014-03-03 CN CN201410075116.1A patent/CN103819385B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006088525A1 (en) * | 2004-11-18 | 2006-08-24 | Cardiome Pharma Corp. | Synthetic process for aminocyclohexyl ether compounds |
WO2012040846A1 (en) * | 2010-09-27 | 2012-04-05 | Alphora Research Inc. | Process for preparation of aminocyclohexyl ethers and intermediate products used in the process |
CN102603591A (zh) * | 2011-09-08 | 2012-07-25 | 浙江工业大学 | 一种维纳卡兰关键中间体的合成方法 |
Non-Patent Citations (1)
Title |
---|
黄俊,等: "盐酸维那卡兰的合成", 《中国医药工业杂志》, vol. 44, no. 6, 10 June 2013 (2013-06-10), pages 544 - 547 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104610121A (zh) * | 2015-01-07 | 2015-05-13 | 北京哈三联科技有限责任公司 | 一种维纳卡兰盐酸盐的制备方法 |
CN105294530A (zh) * | 2015-11-30 | 2016-02-03 | 北京哈三联科技有限责任公司 | 一种维纳卡兰盐酸盐的精制方法 |
CN105294530B (zh) * | 2015-11-30 | 2018-01-23 | 北京哈三联科技有限责任公司 | 一种维纳卡兰盐酸盐的精制方法 |
CN106220544A (zh) * | 2016-08-03 | 2016-12-14 | 北京诺泓医药科技有限公司 | 一种盐酸维纳卡兰的纯化方法 |
CN114200034A (zh) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | 一种维纳卡兰有关物质的分析方法 |
Also Published As
Publication number | Publication date |
---|---|
CN103819385B (zh) | 2016-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104507910B (zh) | 部分饱和的含氮杂环化合物 | |
CN104837826B (zh) | 制备用于治疗癌症的化合物的新型方法 | |
CN103819385A (zh) | (3r)-1-[(1r,2r)-2-[2-(3,4-二甲氧基苯基)乙氧基]环己基]-3-吡咯烷醇的制备方法 | |
US9975856B2 (en) | Process for the preparation of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid | |
UA122148C2 (uk) | Сполуки як модулятори ror-гамма | |
Inoue et al. | Enantioselective reaction of an imine with methyllithium catalyzed by a chiral ligand | |
KR101560116B1 (ko) | 클로로아세톤을 이용한 메데토미딘의 제조 방법 | |
JP6857219B2 (ja) | ピリミジニルシクロペンタン化合物の調製方法 | |
Roszkowski et al. | Synthesis of new mono-N-tosylated diamine ligands based on (R)-(+)-limonene and their application in asymmetric transfer hydrogenation of ketones and imines | |
CN104520275A (zh) | 用于制备整合酶抑制剂的方法和中间产物 | |
Rachwalski | Limonene oxide derived aziridinyl alcohols as highly efficient catalysts for asymmetric additions of organozinc species to aldehydes | |
CN104418861B (zh) | 一种西格列汀的中间体化合物的制备方法 | |
US20080269496A1 (en) | Method for Producing Optically Active Hydroxymethylated Compounds | |
JP6180533B2 (ja) | ボリコナゾールおよびその類似体の調製のための方法 | |
Christoffers et al. | Synthesis, resolution, and absolute configuration of trans-1-amino-2-dimethylaminocyclohexane | |
JPWO2014051077A1 (ja) | 高純度の含窒素複素環化合物の製造方法 | |
US11124532B2 (en) | Chiral metal complex compounds | |
CN104507948A (zh) | 含氮杂环n-氧化物化合物的制造方法 | |
Roszkowski et al. | Novel (R)-(+)-limonene-derived ligands: synthesis and application in asymmetric transfer hydrogenations | |
JP2021109847A (ja) | アミノアルコール−ボロン−バイノール複合体及びこれを用いた光学活性アミノアルコール誘導体の製造方法 | |
JP2005041791A (ja) | 光学活性四級アンモニウム塩、その製造法、並びにそれを用いた光学活性α−アミノ酸誘導体の製造法 | |
EP0492401A1 (de) | Asymmetrische Hydrierung | |
TW201406457A (zh) | 在包含銥及胺基酸之複合催化劑存在下以均相催化醇胺作用製備胺之方法 | |
JP6815853B2 (ja) | (1S)−4−[4−(ジメチルアミノ)−1−(4’−フルオロフェニル)−1−ヒドロキシブチル]−3−(ヒドロキシメチル)−ベンゾニトリルヘミ(+)−ジ−(p−トルオイル)酒石酸塩の製造方法、及び該酒石酸塩を用いた(1S)−1−[3−(ジメチルアミノ)プロピル]−1−(4−フルオロフェニル)−1,3−ジヒドロイソベンゾフラン−5−カルボニトリル及びその塩の製造方法 | |
Li et al. | Asymmetric Michael Addition and Related Reactions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee after: Shanghai Yunshengyan neoplasm Technology Co.,Ltd. Address before: No. 781 Cailun Road, Zhangjiang, Pudong New Area, Shanghai, March 2012, 1006 Patentee before: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. |
|
CP03 | Change of name, title or address |