JP2002520313A - ケトロラクの製造に有用な化合物の合成 - Google Patents
ケトロラクの製造に有用な化合物の合成Info
- Publication number
- JP2002520313A JP2002520313A JP2000559086A JP2000559086A JP2002520313A JP 2002520313 A JP2002520313 A JP 2002520313A JP 2000559086 A JP2000559086 A JP 2000559086A JP 2000559086 A JP2000559086 A JP 2000559086A JP 2002520313 A JP2002520313 A JP 2002520313A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ethyl
- moiety
- ketorolac
- reaction
- 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.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 38
- 229960004752 ketorolac Drugs 0.000 title abstract description 17
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 9
- 238000004519 manufacturing process Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000008096 xylene Substances 0.000 claims description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 7
- 150000003738 xylenes Chemical class 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims 4
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 27
- QBAVHEZVBGASER-UHFFFAOYSA-N 1-(2-bromoethyl)pyrrole Chemical compound BrCCN1C=CC=C1 QBAVHEZVBGASER-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000004821 distillation Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 238000006114 decarboxylation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- FDDQRDMHICUGQC-UHFFFAOYSA-N pyrrole-1-carboxylic acid Chemical compound OC(=O)N1C=CC=C1 FDDQRDMHICUGQC-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 2
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- -1 ketorolac carboxamide Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- ZIOLCZCJJJNOEJ-UHFFFAOYSA-N 2-pyrrol-1-ylethanol Chemical compound OCCN1C=CC=C1 ZIOLCZCJJJNOEJ-UHFFFAOYSA-N 0.000 description 1
- OXTNCQMOKLOUAM-UHFFFAOYSA-L 3-oxopentanedioate Chemical compound [O-]C(=O)CC(=O)CC([O-])=O OXTNCQMOKLOUAM-UHFFFAOYSA-L 0.000 description 1
- HZKHUYLRRZJMEH-UHFFFAOYSA-N 5-benzoyl-2,3-dihydro-1h-pyrrolizine-1-carboxamide Chemical compound NC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 HZKHUYLRRZJMEH-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 235000003332 Ilex aquifolium Nutrition 0.000 description 1
- 235000002296 Ilex sandwicensis Nutrition 0.000 description 1
- 235000002294 Ilex volkensiana Nutrition 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
- 239000005909 Kieselgur Substances 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 239000004247 glycine and its sodium salt Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004384 ketorolac tromethamine Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LDNSHTVNGGHGQJ-UHFFFAOYSA-N pyrrole-1-carboxamide Chemical compound NC(=O)N1C=CC=C1 LDNSHTVNGGHGQJ-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940029258 sodium glycinate Drugs 0.000 description 1
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9240898P | 1998-07-10 | 1998-07-10 | |
| US60/092,408 | 1998-07-10 | ||
| PCT/US1999/015496 WO2000002855A2 (en) | 1998-07-10 | 1999-07-08 | Synthesis of compounds useful in the manufacture of ketorolac |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002520313A true JP2002520313A (ja) | 2002-07-09 |
| JP2002520313A5 JP2002520313A5 (enExample) | 2006-08-31 |
Family
ID=22233070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000559086A Withdrawn JP2002520313A (ja) | 1998-07-10 | 1999-07-08 | ケトロラクの製造に有用な化合物の合成 |
Country Status (8)
| Country | Link |
|---|---|
| US (3) | US6376681B1 (enExample) |
| EP (1) | EP1097152B1 (enExample) |
| JP (1) | JP2002520313A (enExample) |
| AT (1) | ATE323703T1 (enExample) |
| AU (1) | AU5209699A (enExample) |
| DE (1) | DE69930940T2 (enExample) |
| ES (1) | ES2259475T3 (enExample) |
| WO (1) | WO2000002855A2 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050070906A1 (en) * | 1999-11-30 | 2005-03-31 | Ron Clark | Endosteal tibial ligament fixation with adjustable tensioning |
| GB0000569D0 (en) | 2000-01-12 | 2000-03-01 | Ici Plc | Organometallic compositions |
| GB0112901D0 (en) | 2001-05-29 | 2001-07-18 | Ici Plc | Organometallic compositions |
| US7341502B2 (en) * | 2002-07-18 | 2008-03-11 | Micron Technology, Inc. | Methods and systems for planarizing workpieces, e.g., microelectronic workpieces |
| LU91605B1 (fr) | 2009-09-07 | 2011-03-08 | Terra Nobilis S A | Procédé de sécurisation du stockage de déchets radioactifs de longue vie. |
| CN113087626A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 一种酮咯酸氨丁三醇中间体化合物ⅵ |
| CN113087619A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 一种酮咯酸氨丁三醇中间体化合物 |
| CN113087710A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 一种酮咯酸氨丁三醇中间体的制备方法 |
| CN112898307A (zh) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 一种酮咯酸杂质c及其制备方法与应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4089969A (en) * | 1976-07-14 | 1978-05-16 | Syntex (U.S.A.) Inc. | 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives and process for the production thereof |
| US4140698A (en) * | 1977-07-25 | 1979-02-20 | Syntex (Usa) Inc. | 1,2-Dihydro-3H-pyrrolo[1,2-a]pyrrole-1-nitriles |
| CH616808B (fr) * | 1978-06-14 | Piquerez Sa Ervin | Procede de fabrication d'une boite de montre et boite de montre obtenue par ce procede. | |
| US4458081A (en) * | 1980-10-20 | 1984-07-03 | Syntex (U.S.A.) Inc. | 5-Aroyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-decarboxylates |
| US5082951A (en) * | 1990-10-12 | 1992-01-21 | Syntex (U.S.A.) Inc. | Process for preparing 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates (I) and intermediates therefor |
| KR0140134B1 (ko) * | 1994-11-16 | 1998-06-01 | 강재헌 | 피롤리진 유도체의 제조방법 |
-
1999
- 1999-07-08 JP JP2000559086A patent/JP2002520313A/ja not_active Withdrawn
- 1999-07-08 US US09/719,033 patent/US6376681B1/en not_active Expired - Fee Related
- 1999-07-08 ES ES99937220T patent/ES2259475T3/es not_active Expired - Lifetime
- 1999-07-08 DE DE69930940T patent/DE69930940T2/de not_active Expired - Fee Related
- 1999-07-08 EP EP99937220A patent/EP1097152B1/en not_active Expired - Lifetime
- 1999-07-08 WO PCT/US1999/015496 patent/WO2000002855A2/en not_active Ceased
- 1999-07-08 AT AT99937220T patent/ATE323703T1/de not_active IP Right Cessation
- 1999-07-08 AU AU52096/99A patent/AU5209699A/en not_active Abandoned
-
2002
- 2002-02-05 US US10/072,649 patent/US6489491B2/en not_active Expired - Fee Related
- 2002-09-03 US US10/233,809 patent/US6559319B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000002855A2 (en) | 2000-01-20 |
| EP1097152B1 (en) | 2006-04-19 |
| US6489491B2 (en) | 2002-12-03 |
| WO2000002855A3 (en) | 2000-02-24 |
| US20020137945A1 (en) | 2002-09-26 |
| US6376681B1 (en) | 2002-04-23 |
| DE69930940D1 (de) | 2006-05-24 |
| AU5209699A (en) | 2000-02-01 |
| ATE323703T1 (de) | 2006-05-15 |
| ES2259475T3 (es) | 2006-10-01 |
| EP1097152A2 (en) | 2001-05-09 |
| US20030036660A1 (en) | 2003-02-20 |
| US6559319B2 (en) | 2003-05-06 |
| DE69930940T2 (de) | 2006-12-14 |
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