DE69930940T2 - Synthese von verbindungen die zur herstellung von ketorolac dienen - Google Patents
Synthese von verbindungen die zur herstellung von ketorolac dienen Download PDFInfo
- Publication number
- DE69930940T2 DE69930940T2 DE69930940T DE69930940T DE69930940T2 DE 69930940 T2 DE69930940 T2 DE 69930940T2 DE 69930940 T DE69930940 T DE 69930940T DE 69930940 T DE69930940 T DE 69930940T DE 69930940 T2 DE69930940 T2 DE 69930940T2
- Authority
- DE
- Germany
- Prior art keywords
- reaction
- compound
- cycloalkyl
- ethyl
- alkyl
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 229960004752 ketorolac Drugs 0.000 title abstract description 15
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 238000002360 preparation method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 239000008096 xylene Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims 5
- 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 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 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
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- -1 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids Chemical class 0.000 description 5
- 238000006114 decarboxylation reaction Methods 0.000 description 5
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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
- 238000002955 isolation Methods 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 150000003738 xylenes Chemical class 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 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
- ASPKTJDOGDABFY-LDIADDGTSA-N C/C=C\C=C/CCC(c1ccc2[n]1CCC2C(N)=O)=O Chemical compound C/C=C\C=C/CCC(c1ccc2[n]1CCC2C(N)=O)=O ASPKTJDOGDABFY-LDIADDGTSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical class FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229910004373 HOAc Inorganic materials 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
- 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
- 125000003118 aryl group Chemical group 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
- 239000003990 capacitor Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical class Cl* 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 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
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 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
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229910052731 fluorine Chemical class 0.000 description 1
- 239000011737 fluorine Chemical class 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
- 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
- 239000000463 material Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 238000012546 transfer Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000005406 washing Methods 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 | |
| US92408P | 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 |
|---|---|
| DE69930940D1 DE69930940D1 (de) | 2006-05-24 |
| DE69930940T2 true DE69930940T2 (de) | 2006-12-14 |
Family
ID=22233070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69930940T Expired - Fee Related DE69930940T2 (de) | 1998-07-10 | 1999-07-08 | Synthese von verbindungen die zur herstellung von ketorolac dienen |
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. |
| 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 |
| 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 |
| 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 AT AT99937220T patent/ATE323703T1/de not_active IP Right Cessation
- 1999-07-08 DE DE69930940T patent/DE69930940T2/de not_active Expired - Fee Related
- 1999-07-08 US US09/719,033 patent/US6376681B1/en not_active Expired - Fee Related
- 1999-07-08 EP EP99937220A patent/EP1097152B1/en not_active Expired - Lifetime
- 1999-07-08 JP JP2000559086A patent/JP2002520313A/ja not_active Withdrawn
- 1999-07-08 ES ES99937220T patent/ES2259475T3/es not_active Expired - Lifetime
- 1999-07-08 WO PCT/US1999/015496 patent/WO2000002855A2/en not_active Ceased
- 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 |
|---|---|
| ES2259475T3 (es) | 2006-10-01 |
| US20030036660A1 (en) | 2003-02-20 |
| JP2002520313A (ja) | 2002-07-09 |
| US6489491B2 (en) | 2002-12-03 |
| ATE323703T1 (de) | 2006-05-15 |
| US6376681B1 (en) | 2002-04-23 |
| WO2000002855A2 (en) | 2000-01-20 |
| US20020137945A1 (en) | 2002-09-26 |
| US6559319B2 (en) | 2003-05-06 |
| EP1097152B1 (en) | 2006-04-19 |
| AU5209699A (en) | 2000-02-01 |
| EP1097152A2 (en) | 2001-05-09 |
| WO2000002855A3 (en) | 2000-02-24 |
| DE69930940D1 (de) | 2006-05-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |