ZA200402006B - Process for the preparation of cilastatin. - Google Patents
Process for the preparation of cilastatin. Download PDFInfo
- Publication number
- ZA200402006B ZA200402006B ZA200402006A ZA200402006A ZA200402006B ZA 200402006 B ZA200402006 B ZA 200402006B ZA 200402006 A ZA200402006 A ZA 200402006A ZA 200402006 A ZA200402006 A ZA 200402006A ZA 200402006 B ZA200402006 B ZA 200402006B
- Authority
- ZA
- South Africa
- Prior art keywords
- cilastatin
- solution
- crude
- preparation
- pure
- Prior art date
Links
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 title claims description 63
- 229960004912 cilastatin Drugs 0.000 title claims description 63
- 238000000034 method Methods 0.000 title claims description 38
- 238000002360 preparation method Methods 0.000 title claims description 11
- 239000011347 resin Substances 0.000 claims description 14
- 229920005989 resin Polymers 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003463 adsorbent Substances 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920001447 polyvinyl benzene Polymers 0.000 claims description 2
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000006317 isomerization reaction Methods 0.000 description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 239000003729 cation exchange resin Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229960001305 cysteine hydrochloride Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- YBZQRYWKYBZZNT-SCSAIBSYSA-N (1s)-2,2-dimethylcyclopropane-1-carboxamide Chemical compound CC1(C)C[C@@H]1C(N)=O YBZQRYWKYBZZNT-SCSAIBSYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- 238000010669 acid-base reaction Methods 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000005518 carboxamido group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- YJJLIIMRHGRCFM-UHFFFAOYSA-N ethyl 7-chloro-2-oxoheptanoate Chemical compound CCOC(=O)C(=O)CCCCCCl YJJLIIMRHGRCFM-UHFFFAOYSA-N 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 238000007040 multi-step synthesis reaction Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- -1 sodium chioride Chemical class 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- YURNCBVQZBJDAJ-UHFFFAOYSA-N 2-heptenoic acid Chemical compound CCCCC=CC(O)=O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000000774 cystein-S-yl group Chemical group 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN879DE2001 IN192179B (de) | 2001-08-24 | 2001-08-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200402006B true ZA200402006B (en) | 2004-09-15 |
Family
ID=11097101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200402006A ZA200402006B (en) | 2001-08-24 | 2004-03-12 | Process for the preparation of cilastatin. |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US20050119346A1 (de) |
| EP (1) | EP1423360B1 (de) |
| JP (1) | JP2005525996A (de) |
| CN (1) | CN1592737A (de) |
| AR (1) | AR052751A1 (de) |
| AT (1) | ATE360610T1 (de) |
| BR (1) | BR0212390A (de) |
| CA (1) | CA2458505A1 (de) |
| DE (1) | DE60219800T2 (de) |
| ES (1) | ES2282448T3 (de) |
| IN (1) | IN192179B (de) |
| RU (1) | RU2004108465A (de) |
| SI (1) | SI1423360T1 (de) |
| WO (1) | WO2003018544A1 (de) |
| ZA (1) | ZA200402006B (de) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100638471B1 (ko) * | 2004-08-25 | 2006-10-25 | 동국제약 주식회사 | 실라스타틴 나트륨염의 신규한 제조 방법 |
| EP2402312B1 (de) | 2005-11-09 | 2013-07-17 | Orchid Chemicals&Pharmaceuticals Limited | Verbesserter Herstellungsprozess für Cilastatinsäure |
| KR100833202B1 (ko) * | 2006-12-11 | 2008-05-28 | (주)위즈켐 | 7-클로로-(2,2-디메틸시클로프로판카르복스아미도)-2-헵텐산 제조방법 |
| CN101307015B (zh) * | 2007-05-16 | 2012-06-13 | 深圳市海滨制药有限公司 | 一种制备西司他丁钠的方法 |
| KR100913694B1 (ko) * | 2008-07-09 | 2009-08-24 | (주)하이텍팜 | 신규한 결정형 실라스타틴 암모늄염 및 그 제조방법 |
| CN101851186B (zh) * | 2010-05-31 | 2012-11-14 | 浙江师范大学 | 西司他丁钠的合成方法 |
| CN102675175B (zh) * | 2011-03-08 | 2014-02-19 | 深圳市海滨制药有限公司 | 一种西司他丁的分离纯化方法 |
| CN102702051B (zh) * | 2011-03-26 | 2016-04-13 | 山东新时代药业有限公司 | 一种西司他丁钠的制备方法 |
| CN102875433A (zh) * | 2012-10-29 | 2013-01-16 | 江西金顿香料有限公司 | 一种西司他丁酸的制备方法 |
| CA2937311A1 (en) | 2014-01-24 | 2015-07-30 | Ea Pharma Co., Ltd. | Megalin antagonist |
| CN104926701B (zh) * | 2015-06-30 | 2017-05-03 | 西安蓝晓科技新材料股份有限公司 | 一种蛋氨酸纯化的工艺 |
| CN107522642A (zh) * | 2017-08-14 | 2017-12-29 | 新乡海滨药业有限公司 | 一种西司他丁的精制方法 |
| CN115260067A (zh) * | 2022-08-26 | 2022-11-01 | 同舟纵横（厦门）流体技术有限公司 | 一种西司他丁母液纯化的方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
-
2001
- 2001-08-24 IN IN879DE2001 patent/IN192179B/en unknown
-
2002
- 2002-08-23 WO PCT/IB2002/003399 patent/WO2003018544A1/en active IP Right Grant
- 2002-08-23 ES ES02758720T patent/ES2282448T3/es not_active Expired - Lifetime
- 2002-08-23 RU RU2004108465/04A patent/RU2004108465A/ru not_active Application Discontinuation
- 2002-08-23 CN CNA028212843A patent/CN1592737A/zh active Pending
- 2002-08-23 AT AT02758720T patent/ATE360610T1/de not_active IP Right Cessation
- 2002-08-23 EP EP02758720A patent/EP1423360B1/de not_active Expired - Lifetime
- 2002-08-23 DE DE60219800T patent/DE60219800T2/de not_active Expired - Fee Related
- 2002-08-23 SI SI200230537T patent/SI1423360T1/sl unknown
- 2002-08-23 BR BR0212390-8A patent/BR0212390A/pt not_active IP Right Cessation
- 2002-08-23 CA CA002458505A patent/CA2458505A1/en not_active Abandoned
- 2002-08-23 US US10/487,629 patent/US20050119346A1/en not_active Abandoned
- 2002-08-23 JP JP2003523208A patent/JP2005525996A/ja not_active Withdrawn
- 2002-08-26 AR ARP020103200A patent/AR052751A1/es not_active Application Discontinuation
-
2004
- 2004-03-12 ZA ZA200402006A patent/ZA200402006B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE360610T1 (de) | 2007-05-15 |
| WO2003018544A1 (en) | 2003-03-06 |
| CA2458505A1 (en) | 2003-03-06 |
| SI1423360T1 (sl) | 2007-08-31 |
| EP1423360A1 (de) | 2004-06-02 |
| CN1592737A (zh) | 2005-03-09 |
| DE60219800D1 (de) | 2007-06-06 |
| AR052751A1 (es) | 2007-04-04 |
| EP1423360B1 (de) | 2007-04-25 |
| JP2005525996A (ja) | 2005-09-02 |
| IN192179B (de) | 2004-03-06 |
| DE60219800T2 (de) | 2008-01-17 |
| US20050119346A1 (en) | 2005-06-02 |
| BR0212390A (pt) | 2004-07-27 |
| ES2282448T3 (es) | 2007-10-16 |
| RU2004108465A (ru) | 2005-09-20 |
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