CN1305863C - Method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine - Google Patents
Method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine Download PDFInfo
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- CN1305863C CN1305863C CNB2004100105052A CN200410010505A CN1305863C CN 1305863 C CN1305863 C CN 1305863C CN B2004100105052 A CNB2004100105052 A CN B2004100105052A CN 200410010505 A CN200410010505 A CN 200410010505A CN 1305863 C CN1305863 C CN 1305863C
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- phenyl
- methacrylic
- chloro
- borate
- tartar
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- 238000000034 method Methods 0.000 title claims abstract description 5
- HPBUMMGDIOGYFS-UHFFFAOYSA-N N-[2-(1H-imidazol-5-yl)ethyl]-N-methylaniline Chemical compound C1(=CC=CC=C1)N(CCC1=CNC=N1)C HPBUMMGDIOGYFS-UHFFFAOYSA-N 0.000 title abstract 2
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 allyl borane Chemical compound 0.000 claims abstract description 10
- 229910000085 borane Inorganic materials 0.000 claims abstract description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002140 halogenating effect Effects 0.000 claims abstract description 4
- 239000003446 ligand Substances 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 24
- 208000006558 Dental Calculus Diseases 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 19
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 17
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 238000010189 synthetic method Methods 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000012454 non-polar solvent Substances 0.000 claims description 7
- 150000003053 piperidines Chemical class 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 abstract description 5
- 229960002354 repaglinide Drugs 0.000 abstract description 5
- 238000006717 asymmetric allylation reaction Methods 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Chemical group 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 125000001624 naphthyl group Chemical group 0.000 abstract description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 abstract 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 abstract 1
- 150000001540 azides Chemical class 0.000 abstract 1
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 230000001808 coupling effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 1
- 235000002906 tartaric acid Nutrition 0.000 abstract 1
- 239000011975 tartaric acid Substances 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- GRMNJXQBRPJVQV-UHFFFAOYSA-N 2,3-dihydroxybutanediamide Chemical compound NC(=O)C(O)C(O)C(N)=O GRMNJXQBRPJVQV-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052756 noble gas Inorganic materials 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical class CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LEGRNPNGQAQRSE-WUUYCOTASA-N C(OC(C)(C)C)(OC(C)(C)C)=O.C(=O)(O)[C@@H](O)[C@H](O)C(=O)O Chemical compound C(OC(C)(C)C)(OC(C)(C)C)=O.C(=O)(O)[C@@H](O)[C@H](O)C(=O)O LEGRNPNGQAQRSE-WUUYCOTASA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- FOSCDBCOYQJHPN-UHFFFAOYSA-M Cl[Mg] Chemical compound Cl[Mg] FOSCDBCOYQJHPN-UHFFFAOYSA-M 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- XEBCWEDRGPSHQH-YUMQZZPRSA-N dipropan-2-yl (2s,3s)-2,3-dihydroxybutanedioate Chemical compound CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-YUMQZZPRSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- LUMVCLJFHCTMCV-UHFFFAOYSA-M potassium;hydroxide;hydrate Chemical compound O.[OH-].[K+] LUMVCLJFHCTMCV-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine. O-chlorobenzaldehyde and II have an asymmetric allylation reaction, and III is obtained. After halogenating operation, III and azide have a rwaction, and V is obtained. Through catalytic reduction, VI is obtained. VI and piperidine have a coupling action, and a target product I is obtained, wherein trimethyl allyl borane and optical voidness tartaric acid derivate chiral ligand react, and II is obtained. The present invention uses the o-chlorobenzaldehyde as raw material to synthesize a repaglinide intermediate compound. The source of the material is wide, a synthetic route is simple, the operation is easy, and the reaction yield rate is high. The optical purity of a target product is high, the synthesis cost is low, and the product is suitable for industrial production. R is OR1 or NR2R3, R1, R2 and R3 are H, or fatty groups, or aromatic substituents, such as, isopropyl, tert-butyl, phenyl, benzyl group, o-chlorophenyl, o-tolyl, p-tolyl, m-nitrophenyl and naphthyl, and X is chlorine, or bromine.
Description
Technical field
The present invention relates to the synthetic method of a kind of (S)-sec.-propyl-(2-piperidines) phenyl-methylamine.
Background technology
Repaglinide is a kind of novel non-sulfonylurea Drugs Promoting Insulin Secretion, and the adjuvant drug when being used for dietetic treatment and motion as monotherapy can be used as type ii diabetes first-line treatment medicine.(S)-sec.-propyl-(2-piperidines) phenyl-methylamine is the important intermediate of synthetic repaglinide.
Several representational route is as follows:
1.1998 year, people such as Grell (J.Med.Chem.1998,41,5219) have reported several synthetic methods of repaglinide intermediate, chirality synthetic (1-2), catalytic asymmetric synthesis (3) and kinetic resolution several methods such as (4) that the control of chirality prothetic group wherein, is arranged.
Used chirality prothetic group costs an arm and a leg in the route 1,2, can not reclaim, synthetic cost height; Route 3 raw material sources are difficult for, and asymmetry catalysis reduction reaction conditions harshness; Route 4 kinetic resolution yields are not high, and R configuration product is difficult to carry out configuration conversion and becomes effective intermediate.
2.2000 year, people such as Wang Ensi (Jilin University's natural science journal, 2000,4,83) have reported the synthetic of Racemic Repaglinide.
This route total recovery only 28.3%, and product is racemic mixture, needs split through chirality.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of (S)-sec.-propyl-(2-piperidines) phenyl-methylamine.The step of method is as follows:
1) be that 1: 1～3.5 trimethylammonium allyl group borine and D-(-)-tartaric acid derivatives chiral ligand are dissolved in the non-polar solvent with mol ratio, 0～30 ℃ of reaction 4～18 hours, concentrating under reduced pressure, D-(-)-methacrylic borate tartar acid derivative ester;
2) be that 1: 1.5～10 D-(-)-methacrylic borate tartar acid derivative ester and o-chlorobenzaldehyde are dissolved in the non-polar solvent with mol ratio,-100～40 ℃ were reacted 0.5～22 hour, after acid or alkali lye cancellation reaction, organic phase concentrate (R)-methacrylic-2-chloro-phenyl--methylol;
3) with mol ratio be 1: 1～3 (R)-methacrylic-2-chloro-phenyl--methylol and halogenating agent in 0～90 ℃ of reaction 0.5～5 hour, organic solvent extraction after the reaction cancellation, concentrating under reduced pressure gets (R)-methacrylic-2-chloro-phenyl--methyl halide;
4) be the 30-114 ℃ of reaction 0.5～8 hour in non-polar solvent of 1: 1～3 (R)-methacrylic-2-chloro-phenyl--methyl halide and trinitride with mol ratio, filter after washing, organic phase concentrate (S)-methacrylic-2-chloro-phenyl--triazonmethane;
5) in the non-polar solution of (S)-methacrylic-2-chloro-phenyl--triazonmethane, add 0.1～5%mol catalyzer, feed hydrogen, 40～80 ℃ of normal pressure hydrogenation reductase 12 .5～8 hours, (S)-sec.-propyl-2-chloro-phenyl--methylamine;
6) with (S)-sec.-propyl-2-chloro-phenyl--methylamine of mol ratio 1: 1～3 with after piperidines mixes, add equimolar amount alkali and make acid binding agent, after reaction finishes, washing, organic phase through concentrate target product (S)-sec.-propyl-(2-piperidines) phenyl-methylamine.
Conversion of the present invention starting raw material, be raw material with inexpensive o-chlorobenzaldehyde, the allylic structure compound that obtains containing chiral centre and be easy to derivatize through the asymmetric allylation of chirality prothetic group control.Reaction raw materials is cheap and easy to get; Synthetic route is simple; Higher and the per step reaction yield height of product optical yield; Reaction conditions reaches easily, is fit to suitability for industrialized production.
Embodiment
The present invention utilizes o-chlorobenzaldehyde to be raw material, gets final product (S)-sec.-propyl-(2-piperidines) phenyl-methylamine after asymmetric allylation, replacement, reduction and coupling:
R is OR
1Or NR
2R
3, R
1, R
2, R
3Be H or aliphatics or aromatic substituents, as sec.-propyl, the tertiary butyl, phenyl, benzyl, Chloro-O-Phenyl, o-tolyl, p-methylphenyl, a nitre phenyl, naphthyl; X is chlorine, bromine.
The present invention utilizes trimethylammonium allyl group borine (to be prepared by methacrylic chloro-magnesium lattice reagent and boron trifluoride reaction, concrete operations are seen with reference to the preparation method of triallyl borine: Mikhailov, and B.M.Organomet.Chem.Rev.Sec.A 1972,8,1; Brwon, H.C., Racherla, U.S.J.Org.Chem.1986,51,427) prepare II with chiral ligand, be reflected in the anhydrous solvent and carry out, 0-30 ℃ was reacted 4-18 hour, two material mol ratios are 1: 1-3.5, preferred 1: 1-2, preferred temperature 5-25 ℃, 5-15 hour preferred reaction time.
When the present invention uses o-chlorobenzaldehyde and II to carry out asymmetric allylation, be prepared into R configuration III through six-ring chair form transition state, be reflected at-100-40 ℃ stirred 0.5-22 hour, after alkali lye or diluted acid cancellation reaction, organic solvent extraction, concentrating under reduced pressure gets III, preferable reaction temperature-80-0 ℃.
When the present invention used III and halides to carry out substitution reaction to prepare IV, both effective mol ratios were 1: 3, preferred 1: 2.5, and be reflected at 0-90 ℃ and carried out 0.5-8 hour, preferable reaction temperature 0-60 ℃, preferred time 0.5-6 hour.
When the present invention uses trinitride and IV prepared in reaction V, the noble gas protection, mixture was in 30-114 ℃ of reaction 0.5-8 hour, and the product configuration overturns, preferred temperature 50-110 ℃.
The present invention uses catalyzer to V reduction preparation VI, and hydrogenation carries out on azido-and alkene simultaneously, and the product retention of configuration is constant.The mol ratio of catalyst levels and substrate consumption is 0.001-0.05: 1, and preferred 0.002-0.03: 1, system is a synthesis under normal pressure.
The present invention uses piperidines and V coupling to prepare target product, reacts to be nucleophilic substitution reaction, adds the hydrogen halide that the alkali complexing generates.The consumption of alkali is chemical consumption, is reflected at 70-180 ℃ and carries out 3-10 hour.Preferable reaction temperature 80-160 ℃, preferred time 3-8 hour.
Embodiment 1
20 mmole D-(-)-tartrate diisopropyl ester and 25 moles of trimethylammonium allyl group borines be dissolved in 50 milliliters the anhydrous diethyl ether, 0 ℃ of reaction is after 18 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 17 mmole D-(-)-methacrylic borate tartar isopropyl propionate ester, reaction yield 85%.
Embodiment 2
20 mmole D-(-)-tartrate di tert butyl carbonate and 45 moles of trimethylammonium allyl group borines be dissolved in 50 milliliters the anhydrous diethyl ether, 30 ℃ of reactions are after 4 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.6 mmole D-(-)-methacrylic borate tartar tert-butyl acrylate ester, reaction yield 83%.
Embodiment 3
With 20 mmole D-(-)-N, N '-phenylbenzene tartramide and 40 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 20 ℃ of reactions are after 10 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.2 mmole D-(-)-N, N '-phenylbenzene-methacrylic borate tartar carboxylic acid amide esters, reaction yield 81%.
Embodiment 4
With 20 mmole D-(-)-N, N '-dibenzyl tartramide and 60 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 10 ℃ of reactions are after 15 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.6 mmole D-(-)-N, N '-phenylbenzene-methacrylic borate tartar carboxylic acid amide esters, reaction yield 83%.
Embodiment 5
With 20 mmole D-(-)-N, N '-two Chloro-O-Phenyl tartramide and 50 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 15 ℃ of reactions are after 12 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.4 mmole D-(-)-N, N '-two Chloro-O-Phenyls-methacrylic borate tartar carboxylic acid amide esters, reaction yield 82%.
Embodiment 6
With 20 mmole D-(-)-N, N '-di-o-tolyl tartramide and 65 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 5 ℃ of reactions are after 16 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.8 mmole D-(-)-N, N '-di-o-tolyl-methacrylic borate tartar carboxylic acid amide esters, reaction yield 84%.
Embodiment 7
With 20 mmole D-(-)-N, N '-di-p-tolyl tartramide and 45 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 10 ℃ of reactions are after 15 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.4 mmole D-(-)-N, N '-di-p-tolyl-methacrylic borate tartar carboxylic acid amide esters, reaction yield 82%.
Embodiment 8
With 20 mmole D-(-)-N, N '-two m-nitro base tartramide and 64 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 4 ℃ of reactions are after 14 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 17 mmole D-(-)-N, N '-two m-nitro base-methacrylic borate tartar carboxylic acid amide esters, reaction yield 85%.
Embodiment 9
With 20 mmole D-(-)-N, N '-dinaphthyl tartramide and 44 moles of trimethylammonium allyl group borines are dissolved in 50 milliliters the anhydrous diethyl ether, 25 ℃ of reactions are after 6 hours, concentrating under reduced pressure, and add the heat extraction byproduct of reaction, get 16.5 mmole D-(-)-N, N '-dinaphthyl base-methacrylic borate tartar carboxylic acid amide esters, reaction yield 82.5%.
Embodiment 10
D-(-)-methacrylic borate tartar isopropyl propionate ester of 16 mmoles is dissolved in 50 milliliters of methylene dichloride, drips 0.16 mole o-chlorobenzaldehyde ,-100 ℃ were reacted 22 hours.Naturally rise to the 1N dilute hydrochloric acid that drips 16 mmoles after the room temperature, stirring reaction 1 hour, use the anhydrous diethyl ether aqueous layer extracted after the layering, anhydrous sodium sulfate drying behind the merging organic layer, concentrating under reduced pressure gets 14.1 mmoles (R)-methacrylic-2-chloro-phenyl--methylol, reaction yield 88%, enantiomeric excess 95%e.e..。
Embodiment 11
With D-(-)-N of 16 mmoles, N '-phenylbenzene tartramide adds in 50 milliliters of anhydrous diethyl ethers, and-78 ℃ drip 24 mmole o-chlorobenzaldehydes, stirring reaction 18 hours.Naturally drip 20 milliliters of unsaturated carbonate aqueous solutions of potassium cancellation reactions after rising to room temperature, filter, after the filtrate layering, water layer extracts three times with anhydrous diethyl ether, merge organic layer, the saturated sodium-chloride water solution washed twice, concentrating under reduced pressure gets 13.7 mmoles (R)-methacrylic-2-chloro-phenyl--methylol, reaction yield 85.6%, enantiomeric excess 92%e.e..
Embodiment 12
With D-(-)-N of 16 mmoles, N '-two Chloro-O-Phenyl tartramide adds in 50 milliliters of dry toluenes, 40 ℃ of Dropwise 50 mmole o-chlorobenzaldehydes, stirring reaction 0.5 hour.Drip the 1N dilute hydrochloric acid cancellation reaction of 16 mmoles, behind the standing demix, water layer extracts three times with anhydrous diethyl ether, merge organic layer, the saturated sodium-chloride water solution washed twice, concentrating under reduced pressure gets 13.4 mmoles (R)-methacrylic-2-chloro-phenyl--methylol, reaction yield 84%, enantiomeric excess 72%e.e..
Embodiment 13
With 16 mmole D-(-)-N, N '-di-p-tolyl tartramide adds in 50 milliliters of hexanaphthenes, drips 60 mmole o-chlorobenzaldehydes, 0 ℃ was reacted 3 hours, add 20 milliliters of unsaturated carbonate aqueous solutions of potassium cancellation reactions, filter, after the filtrate layering, water layer extracts three times with anhydrous diethyl ether, merge organic layer, the saturated sodium-chloride water solution washed twice, concentrating under reduced pressure gets 13.2 mmoles (R)-methacrylic-2-chloro-phenyl--methylol, reaction yield 82.5%, enantiomeric excess 78%e.e..
Embodiment 14
With 16 mmole D-(-)-N, N '-dinaphthyl tartramide adds in 40 milliliters of tetrahydrofuran (THF)s,-60 ℃ of agitation conditions drip 70 mmole o-chlorobenzaldehydes down, reacted 15 hours, add 20 milliliters of unsaturated carbonate aqueous solutions of potassium cancellation reactions, filter, after the filtrate layering, water layer extracts three times with anhydrous diethyl ether, merge organic layer, the saturated sodium-chloride water solution washed twice, concentrating under reduced pressure gets 13.6 mmoles (R)-methacrylic-2-chloro-phenyl--methylol, reaction yield 85%, enantiomeric excess 86%e.e..
Embodiment 15
(R)-methacrylic-2-chloro-phenyl--methylol of 13 mmoles is dissolved in 30 milliliters of dioxane, 0 ℃ of phosphorus trichloride that drips 13 mmoles, the control rate of addition keeps system temperature to be no more than 30 degree, rise to stirring at room reaction 0.5 hour, be heated to 90 ℃ of reactions 1 hour, with excessive 5% sodium hydroxide water liquid washed twice, concentrating under reduced pressure gets 12.6 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide, reaction yield 97% after the dried over anhydrous sodium carbonate.
Embodiment 16
(R)-methacrylic-2-chloro-phenyl--methylol of 13 mmoles is dissolved in 40 milliliters of pimelinketone, 0 ℃ of phosphorus tribromide that drips 39 mmoles, reacted 3 hours, with excessive 5% potassium hydroxide water liquid washed twice, concentrating under reduced pressure gets 12.8 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide, reaction yield 98.5% behind the anhydrous sodium sulfate drying.
Embodiment 17
(R)-methacrylic-2-chloro-phenyl--methylol and the 10 mmole carbon tetrabromides of 13 mmoles are dissolved in 40 milliliters of tetrahydrofuran (THF)s, the triphenyl phosphorus that adds 25 mmoles, heating reflux reaction 5 hours, the reaction after washing, anhydrous diethyl ether extraction back merges organic phase, the saturated sodium-chloride water solution washed twice, the decompression desolventize product 12.9 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide, reaction yield 99.2%.
Embodiment 18
The noble gas protection down; 12.5 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide is dissolved in 30 milliliters of normal heptanes; add 12.5 mmole sodiumazide; stirring and refluxing 2 hours; cold filtration; filtrate decompression concentrate 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane, reaction yield 96%.
Embodiment 19
The noble gas protection down; 12.5 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide is dissolved in 30 milliliters of anhydrous diethyl ethers; add 25 mmole potassium azide; stirring and refluxing 8 hours; cold filtration; filtrate decompression concentrate 11.8 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane, reaction yield 94%.
Embodiment 20
The noble gas protection down; 12.5 mmoles (R)-methacrylic-2-chloro-phenyl--methyl halide is dissolved in 30 milliliters of toluene; add 37.5 mmole sodiumazide; stirring and refluxing 0.5 hour; cold filtration; filtrate decompression concentrate 12.2 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane, reaction yield 97.6%.
Embodiment 21
Above-mentioned 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane is dissolved in 30 milliliters of isopropyl ethers, the 5%Pd/C that adds 0.012 mmole makes catalyzer, 50 ℃ of stirrings, feed hydrogen, reacted 3 hours, filter, concentrating under reduced pressure gets (S)-sec.-propyl-2-chloro-phenyl--methylamine of 11.2 mmoles, reaction yield 93%.
Embodiment 22
Above-mentioned 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane is dissolved in 30 milliliters of isopropyl ethers, the 10%Pd/C that adds 0.03 mmole makes catalyzer, 60 ℃ of stirrings, feed hydrogen, reacted 5 hours, filter, concentrating under reduced pressure gets (S)-sec.-propyl-2-chloro-phenyl--methylamine of 11.1 mmoles, reaction yield 92.5%.
Embodiment 23
Above-mentioned 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane is dissolved in 40 milliliters of normal heptanes, the 10%Pt/C that adds 0.6 mmole makes catalyzer, 70 ℃ of stirrings, feed hydrogen, reacted 2.5 hours, filter, concentrating under reduced pressure gets (S)-sec.-propyl-2-chloro-phenyl--methylamine of 11.6 mmoles, reaction yield 96.7%.
Embodiment 24
Above-mentioned 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane is dissolved in 40 milliliters of toluene, the Pd (OH) 2 that adds 0.04 mmole makes catalyzer, 80 ℃ of stirrings, feed hydrogen, reacted 4 hours, filter, concentrating under reduced pressure gets (S)-sec.-propyl-2-chloro-phenyl--methylamine of 11.4 mmoles, reaction yield 95%.
Embodiment 25
Above-mentioned 12 mmoles (S)-methacrylic-2-chloro-phenyl--triazonmethane is dissolved in 40 milliliters of methylene dichloride, the Raney-Ni that adds 0.1 mmole makes catalyzer, reflux and stir, feed hydrogen, reacted 8 hours, filter, concentrating under reduced pressure gets (S)-sec.-propyl-2-chloro-phenyl--methylamine of 11.7 mmoles, reaction yield 97.5%.
Embodiment 26
(S)-sec.-propyl-2-chloro-phenyl--methylamine and the 11 mmole piperidines of 11 mmoles are dissolved in 20 milliliters of dimethyl formamides, the triethylamine that adds 11 mmoles, mixture was in 152 ℃ of reactions 5 hours, reduce to the room temperature after washing, ethyl acetate extraction three times merges organic phase, after the washing of saturated ammonium chloride water liquid, anhydrous sodium sulfate drying, concentrating under reduced pressure get 10.1 mmoles (S)-sec.-propyl-(2-piperidines) phenyl-methylamine, reaction yield 92%.
Embodiment 27
(S)-sec.-propyl-2-chloro-phenyl--methylamine and the 11 mmole piperidines of 11 mmoles are dissolved in 25 milliliters of dimethyl sulfoxide (DMSO), the pyridine that adds 33 mmoles, mixture was in 180 ℃ of reactions 3 hours, reduce to the room temperature after washing, ethyl acetate extraction, after the washing of saturated ammonium chloride water liquid, anhydrous magnesium sulfate drying, concentrating under reduced pressure gets 10.3 mmoles (S)-sec.-propyl-(2-piperidines) phenyl-methylamine, reaction yield 93.6%.
Embodiment 28
(S)-sec.-propyl-2-chloro-phenyl--methylamine and the 11 mmole piperidines of 11 mmoles are dissolved in 30 ml n-hexanes, the salt of wormwood that adds 25 mmoles, mixture was in 69 ℃ of reactions 10 hours, reduce to the room temperature after washing, ethyl acetate extraction, after the washing of saturated sodium-chloride water liquid, dried over anhydrous sodium carbonate, concentrating under reduced pressure gets 10.0 mmoles (S)-sec.-propyl-(2-piperidines) phenyl-methylamine, reaction yield 91%.
Embodiment 29
(S)-sec.-propyl-2-chloro-phenyl--methylamine and the 11 mmole piperidines of 11 mmoles are dissolved in 22 milliliters of toluene, the yellow soda ash that adds 20 mmoles, mixture was in 110 ℃ of reactions 8 hours, reduce to the room temperature after washing, ethyl acetate extraction, after the washing of saturated sodium-chloride water liquid, the Calcium Chloride Powder Anhydrous drying, concentrating under reduced pressure gets 9.8 mmoles (S)-sec.-propyl-(2-piperidines) phenyl-methylamine, reaction yield 89%.
Claims (6)
1. the synthetic method of (S)-sec.-propyl-(2-piperidines) phenyl-methylamine is characterized in that the step of method is as follows:
1) be that 1: 1～3.5 trimethylammonium allyl group borine and D-(-)-tartaric acid derivatives chiral ligand are dissolved in the non-polar solvent with mol ratio, 0～30 ℃ of reaction 4～18 hours, concentrating under reduced pressure, D-(-)-methacrylic borate tartar acid derivative ester;
2) be that 1: 1.5～10 D-(-)-methacrylic borate tartar acid derivative ester and o-chlorobenzaldehyde are dissolved in the non-polar solvent with mol ratio,-100～40 ℃ were reacted 0.5～22 hour, after acid or alkali lye cancellation reaction, organic phase concentrate (R)-methacrylic-2-chloro-phenyl--methylol;
3) with mol ratio be 1: 1～3 (R)-methacrylic-2-chloro-phenyl--methylol and halogenating agent in 0～90 ℃ of reaction 0.5～5 hour, organic solvent extraction after the reaction cancellation, concentrating under reduced pressure gets (R)-methacrylic-2-chloro-phenyl--methyl halide;
4) with mol ratio be 30～114 ℃ of reactions 0.5～8 hour in non-polar solvent of 1: 1～3 (R)-methacrylic-2-chloro-phenyl--methyl halide and trinitride, filter after washing, organic phase concentrate (S)-methacrylic-2-chloro-phenyl--triazonmethane;
5) in the non-polar solution of (S)-methacrylic-2-chloro-phenyl--triazonmethane, add 0.1～5%mol catalyzer, feed hydrogen, 40～80 ℃ of normal pressure hydrogenation reductase 12 .5～8 hours, (S)-sec.-propyl-2-chloro-phenyl--methylamine;
6) with (S)-sec.-propyl-2-chloro-phenyl--methylamine of mol ratio 1: 1～3 with after piperidines mixes, add equimolar amount alkali and make acid binding agent, after reaction finishes, washing, organic phase through concentrate target product (S)-sec.-propyl-(2-piperidines) phenyl-methylamine.
2. the synthetic method of a kind of (S)-sec.-propyl according to claim 1-(2-piperidines) phenyl-methylamine, it is characterized in that described D-(-)-methacrylic borate tartar acid derivative ester is meant D-(-)-methacrylic borate tartar isopropyl propionate ester, D-(-)-methacrylic borate tartar tert-butyl acrylate ester, D-(-)-N, N '-phenylbenzene-methacrylic borate tartar carboxylic acid amide esters, D-(-)-N, N '-dibenzyl-methacrylic borate tartar carboxylic acid amide esters, D-(-)-N, N '-two Chloro-O-Phenyls-methacrylic borate tartar carboxylic acid amide esters, D-(-)-N, N '-di-o-tolyl-methacrylic borate tartar carboxylic acid amide esters, D-(-)-N, N '-di-p-tolyl-methacrylic borate tartar carboxylic acid amide esters, D-(-)-N, N '-two m-nitro base-methacrylic borate tartar carboxylic acid amide esters or D-(-)-N, N '-diformazan naphthyl-methacrylic borate tartar carboxylic acid amide esters.
3. the synthetic method of a kind of (S)-sec.-propyl according to claim 1-(2-piperidines) phenyl-methylamine is characterized in that described halogenating agent is meant phosphorus trichloride, phosphorus tribromide or carbon tetrabromide.
4. the synthetic method of a kind of (S)-sec.-propyl according to claim 1-(2-piperidines) phenyl-methylamine is characterized in that described trinitride is meant sodiumazide, potassium azide.
5. according to the synthetic method of claims 1 described a kind of (S)-sec.-propyl-(2-piperidines) phenyl-methylamine, it is characterized in that described non-polar solvent is meant ether, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, benzene, toluene, normal hexane, hexanaphthene, normal heptane or sherwood oil.
6. the synthetic method of a kind of (S)-sec.-propyl according to claim 1-(2-piperidines) phenyl-methylamine is characterized in that described alkali is meant yellow soda ash, salt of wormwood, triethylamine or pyridine.
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| CN101781272A (en) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | Method for preparing repaglinide amine and intermediate thereof |
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| CN101209976B (en) * | 2006-12-29 | 2012-01-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Substituted tartaric acid derivatives and use thereof for preparing beta-secretase inhibitor |
| CN105906583B (en) * | 2015-12-23 | 2018-03-09 | 嘉实（湖南）医药科技有限公司 | A kind of preparation technology of repaglinide intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0058779A2 (en) * | 1981-01-10 | 1982-09-01 | Dr. Karl Thomae GmbH | Carboxamides, their preparation and their use as medicines |
| EP0147850A2 (en) * | 1983-12-30 | 1985-07-10 | Dr. Karl Thomae GmbH | Phenylacetic-acid derivatives, medicines containing these compounds and process for their preparation |
| CN1048722C (en) * | 1991-06-21 | 2000-01-26 | 卡尔·托马有限公司 | (S)(+)-2-Ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]-benzoic acid, pharmaceutical compositions containing compound and processes for preparation thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0058779A2 (en) * | 1981-01-10 | 1982-09-01 | Dr. Karl Thomae GmbH | Carboxamides, their preparation and their use as medicines |
| EP0147850A2 (en) * | 1983-12-30 | 1985-07-10 | Dr. Karl Thomae GmbH | Phenylacetic-acid derivatives, medicines containing these compounds and process for their preparation |
| CN1048722C (en) * | 1991-06-21 | 2000-01-26 | 卡尔·托马有限公司 | (S)(+)-2-Ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]-benzoic acid, pharmaceutical compositions containing compound and processes for preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781272A (en) * | 2010-02-11 | 2010-07-21 | 上海百灵医药科技有限公司 | Method for preparing repaglinide amine and intermediate thereof |
| CN101781272B (en) * | 2010-02-11 | 2012-12-05 | 上海百灵医药科技有限公司 | Method for preparing repaglinide amine and intermediate thereof |
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