CN85107590A - Production of dextrorotatory optical isomer of YM-09730 diastereomer A - Google Patents
Production of dextrorotatory optical isomer of YM-09730 diastereomer A Download PDFInfo
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- CN85107590A CN85107590A CN85107590.8A CN85107590A CN85107590A CN 85107590 A CN85107590 A CN 85107590A CN 85107590 A CN85107590 A CN 85107590A CN 85107590 A CN85107590 A CN 85107590A
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- CN
- China
- Prior art keywords
- diastereomer
- isomer
- dextrorotation
- optically active
- milliliters
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 230000003287 optical effect Effects 0.000 title abstract description 3
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 title description 21
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 12
- 239000011541 reaction mixture Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000001640 fractional crystallisation Methods 0.000 claims abstract description 3
- 238000004587 chromatography analysis Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 26
- 229940124549 vasodilator Drugs 0.000 abstract description 2
- 239000003071 vasodilator agent Substances 0.000 abstract description 2
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940049920 malate Drugs 0.000 description 6
- YQMXOIAIYXXXEE-NSHDSACASA-N (3s)-1-benzylpyrrolidin-3-ol Chemical class C1[C@@H](O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-NSHDSACASA-N 0.000 description 5
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 235000001968 nicotinic acid Nutrition 0.000 description 5
- 239000011664 nicotinic acid Substances 0.000 description 5
- -1 organic acid salt Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- 229920002554 vinyl polymer Polymers 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- XKORCTIIRYKLLG-UHFFFAOYSA-N methyl 3-aminobut-2-enoate Chemical compound COC(=O)C=C(C)N XKORCTIIRYKLLG-UHFFFAOYSA-N 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical class CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003579 shift reagent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-M (R)-mandelate Chemical compound [O-]C(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-M 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- YQMXOIAIYXXXEE-UHFFFAOYSA-N 1-benzylpyrrolidin-3-ol Chemical compound C1C(O)CCN1CC1=CC=CC=C1 YQMXOIAIYXXXEE-UHFFFAOYSA-N 0.000 description 1
- DHGMDHQNUNRMIN-UHFFFAOYSA-N 1-benzylpyrrolidin-3-one Chemical compound C1C(=O)CCN1CC1=CC=CC=C1 DHGMDHQNUNRMIN-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- TZDPJNSHSWMCPN-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 TZDPJNSHSWMCPN-UHFFFAOYSA-N 0.000 description 1
- FWNRRWJFOZIGQZ-UHFFFAOYSA-N 3-oxooctanoic acid Chemical compound CCCCCC(=O)CC(O)=O FWNRRWJFOZIGQZ-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ACLCHVQDIKKBOF-UHFFFAOYSA-N CC(C)(C)OC(=O)C1=CN=CC(=C1)C(=O)OC Chemical compound CC(C)(C)OC(=O)C1=CN=CC(=C1)C(=O)OC ACLCHVQDIKKBOF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The process comprises the following steps: reacting a compound of the following formula (II) with a compound of the formula (III), whereby said dextrorotatory optical isomer (I) can be isolated from the resulting mixture when both compounds (II) and (III) are levorotatory and said isomer (I) can be isolated from the reaction mixture by chromatography or fractional crystallisation when only one of (II) and (III) is racemic, which isomer can be used as a vasodilator or a pharmaceutically acceptable acid addition salt having the melting point of the hydrochloride: 223-230 ℃ (decomposition).
Description
The present invention relates to a kind of novel process of the dextrorotation optically active isomer production of YM-09730 diastereomer A, the dextrorotation optically active isomer of YM-09730 diastereomer A is to be used as on a kind of vasodilator or the medicine to accept acid addition salt.
The chemical name of YM-09730 is 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-1-benzyl-pyrrole alkane-3-yl) ester 5-methyl ester, it is the dihydropyridine of representing with following chemical structural formula fork-like farm tool used in ancient China-3, the derivative of 5-dicarboxylic ester:
According to reports, YM-09730 has persistent expansion vasoactive and the activity (United States Patent (USP) the 4th, 220, No. 649) that brings high blood pressure down.
YM-09730 has two asymmetric carbon atoms, thereby sees that from the stereochemistry viewpoint existence that can be sure of isomer is based on the basis of these unsymmetrical carbons., because the narration of no relevant isomer in the patent of above-mentioned announcement, so the existence of isomer is not confirmed.
In the past, among the present inventor some people to isolate YM-09730 first from diastereomer B be diastereomer isomer A, and find isomer A and isomer B or two kinds of isomer mixtures relatively, show the excellent drug effect (European patent of excess of export, application number 8530266,4)
They further find the available following a kind of method fork-like farm tool used in ancient China preparation of the dextrorotation optically active isomer [fusing point of its hydrochloride is 223～230 ℃ (decomposition)] of diastereomer A, its method comprises, the m-nitrobenzaldehyde, 1-benzyl-3-ethyleneacetic acid base tetramethyleneimine and methyl 3-amino-butenate react, recycle silicon glue is added to the YM-09730 of above-mentioned gained as the wash-out extract as carrier and vinegar ester ethyl ester-acetate that fork-like farm tool used in ancient China separates diastereomer A on the stratography post, using L-(one then) oxysuccinic acid carries out isomer that optical resolution obtained thus and left-handed optically active isomer or both mixture of isomers relatively to diastereomer A, has super excellent drug effect (European patent, application number 8530266,4).
Found to improve to needing a kind of novel process of isomer output as the production technique of the dextrorotation optically active isomer of the useful YM-09730 diastereomer A of this novelty being carried out result of study, thereby obtained the present invention.
Here, revolve blended about diastereomer A() [fusing point of its hydrochloride is 200～206 ℃ (decomposition)] obviously field fusing point of being different from its hydrochloride be the diastereomer B of 180～185 ℃ (decomposition).
The fusing point of the hydrochloride of the dextrorotation optically active isomer of diastereomer A is 223～230 ℃ (decomposition) equally, as mentioned above.The present invention provides new production technique for the dextrorotation optically active isomer of the YM-09730 diastereomer A that can accept acid addition salt on its hydrochloride or a kind of medicine and limit.The additive salt that can accept acid on the medicine refers to a kind of organic acid salt such as L-(one here)-malate etc. and a kind of inorganic acid salt and hydrochloride etc.
The dextrorotation optically active isomer (I) of diastereomer A of the present invention-can be by making the 5-methoxycarbonyl-2 shown in the molecule formula II, 6-dimethyl-4-(m-nitrophenyl)-1, a kind of left-handed optically active isomer of 4-dihydropyridine-3-carboxylic acid or racemoid or its response derivative.
React the fork-like farm tool used in ancient China preparation with the left-handed optically active isomer or the racemoid of the 1-benzyl-3-hydroxyl pyrrolidine shown in the molecule formula III.
This 1 reaction package contains a kind of formation of carboxylicesters and general applicable method also can suitably be used.In this reaction, stereochemistry does not take place transform.The example of the response derivative of compound (II) comprises, acyl group fontanel such as chloride of acid, acid bromide etc.; Acid anhydrides, a kind of blended acid anhydrides, a kind of active ester or the like.Under the situation that compound (II) is employed with the form of free carboxylic acid, this reaction is carried out in the presence of a kind of condensing agent such as dicyclohexyl carbimide etc.
Under cooling or room temperature, this reaction can be carried out in a kind of organic solvent such as methylene dichloride, dimethyl formamide etc. easily, when two kinds of material compounds (II) and compound (III) when being left-handed optically active isomer, the product of reaction only contains the dextrorotation optically active isomer of diastereomer A basically, and this isomer when needed can be with traditional method, as extraction, the fork-like farm tool used in ancient China of from reaction mixture, emanating out such as concentrate, perhaps emanate by stratography post fork-like farm tool used in ancient China.When only few a kind of when being racemoid in compound (II) and (III), the reaction mixture that generates just comprises dextrorotation optically active isomer and the left-handed optically active isomer thereof of needed diastereomer A, the levoisomer of diastereomer B or dextrorotatory isomer etc., and needed isomer can be by stratography post or the fractional crystallization fork-like farm tool used in ancient China of emanating out from reaction mixture.
For example, the mixture of the dextrorotation optically active isomer of the left-handed optically active isomer B of resulting YM-09730 and diastereomer A is added on the stratography post as eluant with vinyl acetic monomer-vinegar ester as carrier with silica gel and separates, thereby the dextrorotation optically active isomer of the diastereomer A of YM-09730 is just isolated fork-like farm tool used in ancient China from mixture, on the other hand, can be this mixture and L-(one)-oxysuccinic acid reacts, then to the L-(of the dextrorotation optically active isomer of the diastereomer A that this obtained once)-L-(one of the left-handed optically active isomer of malate and diastereomer B)-malate carries out the L-(one that the substep recrystallization can obtain the dextrorotation optically active isomer of diastereomer A)-malate.
In the separation of adopting the stratography post, the dextrorotation optically active isomer of diastereomer A can obtain from first elutant, and the left-handed optically active isomer of diastereomer B can obtain from the elutant of back.As long as in the stratography post separates, just use prevailingly, be used as carrier for silica gel and have no particular limits.To also being not have special restriction as the vinyl acetic monomer of eluant and the mixture ratio of acetic acid, still, fork-like farm tool used in ancient China prefers to use vinyl acetic monomer as major ingredient in general, and only mixes a spot of acetic acid therein.Mixture ratio is that acetic acid is approximately 1～10(V/V) preferably, and the Dichlorodiphenyl Acetate ethyl ester is approximately 30 to 50(V/V).When wanting blended acetic acid ratio to descend, the time cycle that elution goes out needed compound will prolong.
Elution speed and treatment temp can suitably be used.
On the other hand, because the L-(one of the dextrorotation optically active isomer of diastereomer A)-malate is a crystal, so use L-(one)-method of oxysuccinic acid also is applicable to the dextrorotation optically active isomer that separates diastereomer A by substep recrystallization fork-like farm tool used in ancient China.The solvent that can be used for the substep recrystallization has: methyl alcohol, ethanol, acetone, acetonitrile etc.
Like this L-(one of the dextrorotation optically active isomer of the diastereomer A that obtains)-malate can be used as medicine, and the acetate of this isomer and analogue can at random be handled a kind of free form of formation with a kind of alkali, handle generating other suitable salt then with suitable sour fork-like farm tool used in ancient China.
Can accept the acid addition salt class on the dextrorotation optically active isomer of the diastereomer A of the YM-09730 that the present invention developed and its medicine is the compounds that any document does not have record, and when directly being applied to coronary artery, increase aspect the coronary flow flow velocity, demonstrate area and relatively increase about 40 times than with left-handed optically active isomer (L-type), and area relatively increases by 2.5 times than the equal amount of mixture (dL-type) with two kinds of isomer, in addition coronary artery is had higher affinity.
According to production technique of the present invention, the dextrorotation optically active isomer of the diastereomer A of YM-09730 is mass production selectively, and on the industry and commerce viewpoint, has high practical value.
Below, to be described in detail the present invention in conjunction with example, can think compound known at material compound used in the present invention (II) and (III), yet in application of the present invention, produce these starting compounds with the technology fork-like farm tool used in ancient China that novelty is useful, shown in reference example.
Reference example 1:
(1) 0.6 milliliter of acetic acid in 6.04 gram m-nitrobenzaldehydes, 6.32 cut butyl acetoacetic acid acid esters, 0.17 gram piperidines and the 20 milliliters of benzene is mixed with a kind of solution and was placed in the azeotropic dehydration device reflux 6 hours.After this system cools, add 10 ml waters, the layering of benzene layer goes out fork-like farm tool used in ancient China.After in turn washing the benzene layer with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the benzene layer carries out drying on anhydrous magnesium sulfate.Under the decompression situation, except that after desolvating, resulting residue is separated at the enterprising circumstances in which people get things ready for a trip layer of silicagel column by distillation.With using the n-normal hexane: vinyl acetic monomer (5: 1 volume ratios) thus crystal that part obtained of wash-out obtains 5.82 cut butyl 2-(m-oil of mirbane methylene radical with n-normal hexane washing) mixture of the geometrical isomer of acetoacetate, it is a kind of clear crystal.
Fusing point: 35～36 ℃
The 3.56 cut butyl 2-(m-oil of mirbane methylene radical that (2) will in (1), obtain) acetoacetate and be dissolved in 7 milliliters of trimethyl carbinols a kind of mixture reflux 20 hours of 1.41 gram methyl 3-amino-butenates, under reduced pressure remove and desolvate by distillation, so the oily residue that is obtained is handled with the n-normal hexane and is just obtained needed 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3,5-dicarboxylic acid-3-tertbutyl ester-5-methyl ester.
Fusing point: 120～122 ℃
2.5 grams 2 that (3) will in (2), be obtained, 6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3, the solution that 5-dicarboxylic acid-3-tertbutyl ester-5-methyl ester is dissolved in 5 milliliters of toluene adds dropwise in the acetum of 5 milliliter of 25% frozen water refrigerative hydrogen bromide, stirred the mixture 5 minutes down ice-cooled then, again this mixture is injected 50 milliliters of frozen water, mixture makes alkalization with 10% aqueous sodium hydroxide solution again, and then extracts with toluene.Water layer makes its acidifying with concentrated hydrochloric acid, again by filtering the crystal of collecting precipitation.These crystal ether washing more just obtain the needed 5-methoxyl group carboxyl-2 of 1.24 grams, 6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3-carboxylic acid (racemoid).
Fusing point: 203～204 ℃ (decomposition temperature)
Reference example 2
With 7.53 gram m-nitrobenzaldehydes, 5.75 gram methyl 3-amino-butenate and 7.90 cut butyl acetyl acid esters are dissolved in a kind of solution reflux 22 hours in 25 milliliters the trimethyl carbinol, under reduced pressure with distillating method remove desolvate after, the residue that is generated is dissolved in 150 milliliters of toluene.Hydrochloric acid with 10% after saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution wash successively, carries out drying to this solution again on anhydrous magnesium sulfate.Decompression under, remove solvent with distillating method and just obtain a kind of 19.62 gram oily maters.This oily mater is dissolved in 20 milliliters of toluene, and splashes in the acetum of ice-cooled following 20 milliliter of 25% hydrogen bromide this solution is one after another drop of.Under same temperature, after stirring the mixture 5 minutes, again this mixture is injected 200 milliliters of frozen water.Adding with 250 milliliter 10% sodium hydroxide solution after mixed solution makes its alkalify, use 100 milliliters of methyl cleaning mixtures again.Water layer concentrated hydrochloric acid acidifying.Obtain sedimentary crystal by filtering fork-like farm tool used in ancient China again, promptly obtain the needed 5-methoxy carboxyl-2 of 4.51 grams, 6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3-carboxylic acid (racemoid).
According to the processing method that [Chem.Pharm.Bull., 282809(1980)] such as T.Shibanuma delivered, can obtain every kind of optically active isomer of above-mentioned racemoid.
Reference example 3
With 17.7 gram racemize-1-benzyl-3-hydroxyl pyrrolidines and 15.2 gram D-(one)-the amygdalic acid heating for dissolving is in 66 milliliters of acetone.This solution can be placed down at 4 ℃ and spend the night, and the 8.5 sedimentary crystal of gram recrystallize from 26 milliliters of acetone just obtains (D)-(the one)-mandelate of 5.1 gram (S)-(one)-1-benzyl-3-hydroxyl pyrrolidines.Specific rotatory power [d]
+ 45.5 ° (C=1 methyl alcohol).To its further recrystallize, any variation is not arranged but observe the D specific rotatory power.
Fusing point: 101～102 ℃
(single line 2H) locates to observe N-CH at the 4.03ppm place
2The nuclear magnetic resonance spectrum of-ph, but do not observe the quartet (J-12.5H of the AB type of (R)-(one) shape at the 4.01ppm place
2)
(2) (D)-(the one)-mandelates of 22 gram (S-(one)-1-benzyl-3-hydroxyl pyrrolidines are dissolved in 50 milliliters the chloroform.Chloroform layer be dissolved with in 90 ml waters 14.4 the gram anhydrous sodium carbonates solution washing, be placed on and carry out drying on the anhydrous magnesium sulfate, after chloroform was removed in distillation, residue under reduced pressure distills just can obtain 11.5 gram S-(-)-1-benzyl-3-hydroxyl pyrrolidine boiling point is 109 ℃/0.65mm Hg.[a]
-3.77 ° (C=5, methyl alcohol).
Reference example 4
75 restrain (S)-(-) oxysuccinic acid and just obtained 52.7 gram (S)-(-)-1-benzyl-3-N-Hydroxysuccinimide, fusing point: be 99～101 ℃ 170 ℃ of following 75 milliliters of benzylamine phase reactions in 3 hours; Specific rotatory power [a]
-51.1 ° (C=1, methyl alcohol).9.73 the gram lithium aluminum hydride is suspended in 340 milliliters of anhydrous pure tetrahydrofurans, will be dissolved with in 200 milliliters of anhydrous tetrahydro furans in the one after another drop of suspension that is added under ice-cooled of 20.5 gram imide solutions.After 3 hours, allow this mixture cooling then the 100 sour sodium sulfate+hydrates of gram (Sodium sulfate decahydrate) be added wherein at reflux.This mixture is stirred in spends the night under ice-cooled.Insoluble substance is by removing by filter, and under reduced pressure, removes with distillation and desolvates.Residue under reduced pressure distills and just obtains 13.8 gram (S)-(-)-1-benzyl-3-hydroxyl pyrrolidines, and its boiling point is 109～115 ℃/0.8mmHg, and specific rotatory power is [a]
-3.0 ° of bases will adopt shift reagent (Eu-TFMC(III)] nuclear magnetic resonance spectrum of 3-position hydrogen learns that so (S)-(-) type that obtains contains 10% R-(+) type.As in reference example 3, (s)-(-) type is transformed into D-(-) mandelate, it is 3 times of volume of ethanol, then in 6 times of volume of ethanol-methyl (1: 5) by recrystallize.Handle the mandelate that obtains like this ([a] by above-mentioned method
-45.2 °) just can obtain 8.6 the gram (S)-(-)-1-benzyl-3-hydroxyl pyrrolidines [boiling point 115-120 ℃/1.2-1.5mmHg[a]
-3.77 ° (C=5, methyl alcohol) }
Reference example 5
3.4 gram 2-(+)-firpene is added to 50 milliliters of 9-boron two ring, 3.3,1 nonanes (9=borabicyclo 3.3lnonane) (0.5M tetrahydrofuran solution), and stirred the mixture under 60 ℃ 5 hours.Allow the mixture cool to room temperature, and 1.75 gram 1-benzyl-3-pyrrolidone are added wherein.After at room temperature stirring the mixture 4 days, under 0 ℃, 1.3 milliliters of acetyl aldehyde are added in the mixture.Under reduced pressure, desolvate by distilling to remove, and 20 milliliters ether is added in the residue.Allow this mixture be cooled to 0 ℃, and 1.5 milliliters of monoethanolamines are joined wherein, stir said mixture, remove formed throw out by distillation.With the above-mentioned ethereal solution of 1N hcl as extraction agent.The hydrochloric acid layer makes its alkalization with yellow soda ash, and extracts with the methylene dichloride fork-like farm tool used in ancient China.Extract is placed on the anhydrous magnesium sulfate dry and concentrated, thereby obtains the thick products of 1.1 grams, and this thick product under reduced pressure distills and promptly obtains 0.6 gram straight product.Boiling point is 106 ℃/0.9mmHg.According to the nuclear magnetic resonance spectrum that adds a kind of shift reagent [EU-TFMC(III)] back hydrogen on the 3-position as can be known so (S)-(-)-1-benzyl-3-hydroxyl pyrrolidine of gained be 30% enantiomorphous excess (e.e) (enantio excess).
Example 1
332 milligrams of 5-methoxy carboxyls-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3-carboxylic acid is dissolved in 3 milliliters the methylene dichloride, and 250 milligrams phosphorus pentachloride is added in the above-mentioned solution, stir down ice-cooled simultaneously, under identical temperature, this mixture restir 1 hour.This reaction mixture is cooled to-30 ℃, and (S)-1-benzyl-3-hydroxyl pyrrolidine of 177 milligrams joined wherein, stirring is after 2 hours down at-30 ℃, and reaction mixture washes with water subsequently again with saturated sodium bicarbonate aqueous solution washing.Solvent is removed by distillation just can obtain a kind of buttery material.This buttery material is added on the silica gel chromatography separator column, (5: 1v/v) wash-out just can obtain the dextrorotation optically active isomer (I) of the diastereomer A of YM-09730 with vinyl acetic monomer-acetic acid, in a kind of high speed liquid phase stratography system, show that the residence time is 28 minutes [stratography posts: Nucleosil R5c
184.6mm φ * 300mm: column temperature: 30 ℃; Moving phase: 0.05M potassium primary phosphate (PH3)-acetyl nitrile (80: 20v/v) contain four-n-bromination amyl group ammonium, flow velocity: 0.9 ml/min, ultraviolet ray (UV) detector (λ 254nm)].In chloroform, the isomer that obtains like this is handled the hydrochloride of the dextrorotation optically active isomer of the diastereomer A that just can obtain 161 milligrams of YM-09730 then with saturated sodium bicarbonate aqueous solution with rare hydrochloric acid.
Fusing point: 228～230 ℃ (decomposition)
Specific rotatory power: [a]
+ 116.3 ° (C=5, methyl alcohol)
Example 2
332 milligrams (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3-carboxylic acid is dissolved in 3 milliliters the methylene dichloride, and 250 milligrams of phosphorus pentachlorides are added in the solution, stirs down ice-cooled simultaneously.Under identical temperature, will mix further and stir 1 hour.Allow reaction mixture be cooled to-30 ℃, and 177 milligrams of (S)-1-benzyl-3-hydroxyl pyrrolidines are joined wherein.-30 ℃ stir 2 hours after, with 5 milliliters of methylene dichloride diluted reaction mixtures, and water and saturated sodium bicarbonate aqueous solution in turn wash this reaction mixture, each 5 milliliters, twice totally.Under reduced pressure, solvent is removed by the distillation fork-like farm tool used in ancient China and is just obtained a kind of oily mater.This oily mater is added on silica gel (15 gram) the stratography post, with toluene one acetic acid (4: 1 v/v) fork-like farm tool used in ancient China wash-out.Under reduced pressure, level part of containing needed isomer is concentrated, and formed residue is dissolved in 5 milliliters of chloroforms.After 1 milliliter of 0.8N ethanol solution hydrochloride added above-mentioned chloroformic solution, under reduced pressure, concentrate above-mentioned solution once more.Residue is dissolved in 2 ml methanol, and allows this solution placement spend the night under ice-cooled.The hydrochloride of the dextrorotation optically active isomer of crystal by filtering collecting precipitation and the dry diastereomer A that just obtains 350 milligrams of YM-09730.
Fusing point: 226～228 ℃ (decomposition temperature)
Specific rotatory power: [a]
+ 116.4 ° (=1, methyl alcohol)
Nuclear magnetic resonance spectrum is (at CD
3Among the OD, TMS internal standard δ ppm):
1.80-2.70(2H, wide m, C
4,-H
2)
2.32，2.34（6H，S，C
2，6-CH
3）
3.0-4.0（4H，m，C，，-H）
3.64（3H，S，-COOCH
3）
4.42（2H，S，-CH
2φ）
5.08（1H，S，C
4-H）
5.30（1H，m，C
4，-H）
7.30-8.20(9H, m, phenyl ring-H)
Example 3
With 840 milligrams (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dioxy pyridine-3-carboxylic acid is suspended in 6 milliliters of methylene dichloride and N, 4: 1 V/V of the mixed solution of dinethylformamide) in, and 0.2 milliliter of thionyl chloride joined in ice-cooled low suspension liquid.Under identical temperature, mixture was stirred 1 hour.Under ice-cooled, 450 milligrams of (S)-1-benzyls-3-hydroxyl pyrrole alkane is dissolved in 3 milliliters of solution in the methylene dichloride adds reaction mixture dropwise, resulting mixture further stirred 15 hours down ice-cooled, mixed the well thing with 10 milliliters of methylene dichloride diluting reactions then.After the aqueous solution with 10 ml waters and 10 milliliters of saturated sodium bicarbonates in turn washed resulting solution, this solution was placed on the anhydrous sal epsom dry.Under reduced pressure, must arrive a kind of oily mater by distillation except that desolvating.This oily mater is added on silica gel (40 gram) the stratography post, and (4: 1 V/V) uses 1 subsequently with toluene one acetic acid: 1v/v) wash-out.Under reduced pressure, the fraction that contains needed isomer concentrated just obtain 990 milligrams of dense oily maters, this oily mater is dissolved in 10 milliliters of chloroforms.Behind the ethanolic soln that adds 2.6 milliliters of 0.8N hydrochloric acid, under reduced pressure, this solution of reconcentration in 5 ml methanol, allows the residue solution that is obtained this solution spend the night ice-cooled the placement down.The hydrochloride of the dextrorotation optically active isomer by filter taking out sedimentary crystal and the dry diastereomer A that just obtains 850 milligrams of YM-09730.
Fusing point: 226～228 ℃ (decomposition temperature)
Specific rotatory power: [a]
+ 116.4(C=1, methyl alcohol)
Nuclear magnetic resonance spectrum is consistent with the nuclear magnetic resonance spectrum of example 2 prepared products.Example 4(1) the dense oily mater (990 milligrams) that is obtained according to example 3 methods is dissolved in 10 milliliters of ethanol, under reduced pressure to this solution reconcentration.The resulting residue of result is dissolved in 5 milliliters of ethanol, and this solution spends the night ice-cooled the placement down.By crystal and the dry free alkali of the dextrorotation optically active isomer of the diastereomer A of totally 730 milligrams of YM-09730 that just obtains that filters collecting precipitation.
Fusing point: 137～139 ℃ (decomposition temperature)
Specific rotatory power: [a]
+ 64.8(C=1, methyl alcohol)
Nuclear magnetic resonance spectrum is (at CDCL
3, TMS internal standard δ ppm):
1.4-3.0（6H，m，C
2′
4′
6′-H
2）
2.34，2.36（6H，S，C，-CH）
3.65(5H, S ,-COOCH and-CHO)
5.10（1H，S，C-H）
5.12（1H，m C，-H）
5.78(1H, wide S, NH)
7.16-8.24(9H, m, phenyl ring-H)
(2) the above-mentioned free alkali that obtains (700 milligrams) is dissolved in the ethanolic soln of 10 milliliters of chloroforms and 1.8 milliliters of 0.8N hydrochloric acid, under reduced pressure, this solution is concentrated.The residue that obtains is dissolved in 3.5 milliliters the methyl alcohol, allows this solution spend the night ice-cooled the placement down.The hydrochloride of the dextrorotation optically active isomer of crystal by filtering collecting precipitation and the dry diastereomer A that just obtains 630 milligrams of YM-09730.
Fusing point: 226～228 ℃ (decomposition temperature)
Specific rotatory power: [a]
+ 116.7 ° (C=1, methyl alcohol)
The prepared product nuclear magnetic resonance spectrum of nuclear magnetic resonance spectrum and example 2 is consistent.
Claims (1)
- Produce (±)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, the dextrorotation rotational isomerism part (I) of the diastereomer A of 5-dicarboxyl 3-(1-benzyl-pyrrole alkane-3-yl) ester 5-methyl ester, or can accept a kind of production technique of additive salt of acid on its medicine, hydrochloride-the fusing point of above-mentioned dextrorotation rotational isomerism part (I) is: 223～230 ℃ (decomposition), its technology comprises: the compound of following molecule formula II representative
With the compound phase reaction of molecule formula III representative,When above-claimed cpd (II) and (III) when the both is levo-rotatory substance, just can from the reaction mixture that generates, be separated to above-mentioned dextrorotation rotational isomerism part (I), perhaps when only lacking one in above-claimed cpd (II) and (III) when being a kind of racemoid, so just can from the mixture of the reaction of generation, separate above-mentioned dextrorotation optically active isomer (I) with post chromatography or fractional crystallization.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12051/85 | 1985-01-24 | ||
| JP1205185 | 1985-01-24 | ||
| JP12051/1985 | 1985-01-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85107590A true CN85107590A (en) | 1986-07-23 |
| CN1023483C CN1023483C (en) | 1994-01-12 |
Family
ID=11794796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85107590A Expired - Lifetime CN1023483C (en) | 1985-01-24 | 1985-10-11 | Novel process for production of the dextrorotatory optical isomer of diastereomer a of ym-09730 |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS61267577A (en) |
| KR (1) | KR900002342B1 (en) |
| CN (1) | CN1023483C (en) |
| AT (1) | AT390613B (en) |
| CA (1) | CA1273931A (en) |
| DK (1) | DK468385A (en) |
| ES (1) | ES8607284A1 (en) |
| FI (1) | FI83517C (en) |
| GR (1) | GR852497B (en) |
| IT (1) | IT1221762B (en) |
| MX (1) | MX260A (en) |
| NO (1) | NO166643C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101643469B (en) * | 2008-12-27 | 2012-11-21 | 武汉百科药物开发有限公司 | Synthesis process of barnidipine hydrochloride |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7033808B2 (en) | 2000-08-01 | 2006-04-25 | Kaneka Corporation | Carbonyl reductase, gene thereof and method of using the same |
| KR100939347B1 (en) | 2005-07-20 | 2010-01-29 | (주)카이로드 | Synthetic Method of optically pure S-3-hydroxypyrrolidine |
-
1985
- 1985-09-26 FI FI853697A patent/FI83517C/en not_active IP Right Cessation
- 1985-10-08 ES ES547696A patent/ES8607284A1/en not_active Expired
- 1985-10-11 CN CN85107590A patent/CN1023483C/en not_active Expired - Lifetime
- 1985-10-14 NO NO854062A patent/NO166643C/en not_active IP Right Cessation
- 1985-10-14 KR KR1019850007554A patent/KR900002342B1/en not_active IP Right Cessation
- 1985-10-14 AT AT0297085A patent/AT390613B/en not_active IP Right Cessation
- 1985-10-14 DK DK468385A patent/DK468385A/en not_active Application Discontinuation
- 1985-10-14 MX MX260A patent/MX260A/en unknown
- 1985-10-15 IT IT22489/85A patent/IT1221762B/en active
- 1985-10-15 GR GR852497A patent/GR852497B/el unknown
- 1985-10-15 CA CA000492966A patent/CA1273931A/en not_active Expired
-
1986
- 1986-01-22 JP JP61012358A patent/JPS61267577A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101643469B (en) * | 2008-12-27 | 2012-11-21 | 武汉百科药物开发有限公司 | Synthesis process of barnidipine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| FI853697L (en) | 1986-07-25 |
| NO854062L (en) | 1986-07-25 |
| KR860005637A (en) | 1986-08-11 |
| ES547696A0 (en) | 1986-05-16 |
| FI83517B (en) | 1991-04-15 |
| IT8522489A0 (en) | 1985-10-15 |
| CA1273931A (en) | 1990-09-11 |
| NO166643C (en) | 1991-08-21 |
| ATA297085A (en) | 1989-11-15 |
| NO166643B (en) | 1991-05-13 |
| FI83517C (en) | 1991-07-25 |
| DK468385A (en) | 1986-07-25 |
| GR852497B (en) | 1986-02-18 |
| AT390613B (en) | 1990-06-11 |
| CN1023483C (en) | 1994-01-12 |
| JPS61267577A (en) | 1986-11-27 |
| ES8607284A1 (en) | 1986-05-16 |
| IT1221762B (en) | 1990-07-12 |
| DK468385D0 (en) | 1985-10-14 |
| FI853697A0 (en) | 1985-09-26 |
| KR900002342B1 (en) | 1990-04-12 |
| MX260A (en) | 1995-01-31 |
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