RU2000116019A - METHOD FOR PRODUCING N- (1 (S) -CARBOXY-3-Phenylpropyl) -L-Lysyl-L-Proline - Google Patents
METHOD FOR PRODUCING N- (1 (S) -CARBOXY-3-Phenylpropyl) -L-Lysyl-L-ProlineInfo
- Publication number
- RU2000116019A RU2000116019A RU2000116019/04A RU2000116019A RU2000116019A RU 2000116019 A RU2000116019 A RU 2000116019A RU 2000116019/04 A RU2000116019/04 A RU 2000116019/04A RU 2000116019 A RU2000116019 A RU 2000116019A RU 2000116019 A RU2000116019 A RU 2000116019A
- Authority
- RU
- Russia
- Prior art keywords
- stage
- inorganic
- water
- organic solvent
- hydrophilic organic
- Prior art date
Links
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000011780 sodium chloride Substances 0.000 claims 10
- 239000003960 organic solvent Substances 0.000 claims 9
- 150000003839 salts Chemical class 0.000 claims 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 9
- 150000007522 mineralic acids Chemical class 0.000 claims 6
- 239000002904 solvent Substances 0.000 claims 6
- 150000007529 inorganic bases Chemical class 0.000 claims 5
- 239000002585 base Substances 0.000 claims 4
- CYIPWTDJHYRQSV-UVJOBNTFSA-N (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;molecular nitrogen Chemical compound N#N.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CYIPWTDJHYRQSV-UVJOBNTFSA-N 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- 239000012046 mixed solvent Substances 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 238000001556 precipitation Methods 0.000 claims 3
- -1 salt organic acid Chemical class 0.000 claims 3
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 150000007514 bases Chemical class 0.000 claims 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 2
- 230000005712 crystallization Effects 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L Potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 230000005591 charge neutralization Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 239000012452 mother liquor Substances 0.000 claims 1
- 230000001264 neutralization Effects 0.000 claims 1
- 238000006386 neutralization reaction Methods 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 150000003112 potassium compounds Chemical class 0.000 claims 1
- 229910052939 potassium sulfate Inorganic materials 0.000 claims 1
- 235000011151 potassium sulphates Nutrition 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 150000003388 sodium compounds Chemical class 0.000 claims 1
Claims (15)
из N2-(1(S)-алкоксикарбонил-3-фенилпропил)-N6-трифторацетил-L-лизил-L-пролина общей формулы (1)
в которой R представляет собой алкильную группу, включающий первую стадию: осуществление щелочного гидролиза N2-(1(S)-алкоксикарбонил-3-фенилпропил)-N6-трифторацетил-L-лизил-L-пролина (1): в системе растворителей, выбираемой из смешанного раствора, состоящего из воды и гидрофильного органического растворителя, и воды с использованием неорганического основания в количестве n молярных эквивалентов (n≥3) на моль вышеуказанного соединения (1), вторую стадию: осуществление нейтрализации продукта гидролиза с использованием неорганической кислоты в количестве от (n-1) до n молярных эквивалентов (n≥3) и отделение и удаление неорганической соли, образованной в реакционной смеси из вышеуказанных неорганического основания и неорганической кислоты путем ее осаждения из системы растворителей, пригодной для снижения растворимости неорганической соли, при этом указанную систему растворителей выбирают из гидрофильного органического растворителя, смешанного растворителя, состоящего из воды и гидрофильного органического растворителя, и воды, и третью стадию: выкристаллизовывание N2-(1(S)-карбокси-3-фенилпропил)-L-лизил-L-пролина (2), присутствующего в смеси после удаления неорганической соли, из системы растворителей в его изоэлектрической точке, при этом указанную систему растворителей выбирают из гидрофильного органического растворителя, смешанного растворителя, состоящего из воды и гидрофильного органического растворителя, и воды, и тем самым, выделение N2-(1(S)-карбокси-3-фенилпропил)-L-лизил-L-пролина (2) в кристаллической форме при сохранении солей, преимущественно содержащих соль органической кислоты, трифторуксусной кислоты в растворенном состоянии в маточном растворе.1. The method of obtaining N 2 - (1 (S) -carboxy-3-phenylpropyl) -L-lysyl-L-proline of the formula (2)
from N 2 - (1 (S) -alkoxycarbonyl-3-phenylpropyl) -N 6- trifluoroacetyl-L-lysyl-L-proline of the general formula (1)
in which R represents an alkyl group comprising the first stage: alkaline hydrolysis of N 2 - (1 (S) -alkoxycarbonyl-3-phenylpropyl) -N 6 -trifluoroacetyl-L-lysyl-L-proline (1): in a solvent system selected from a mixed solution of water and a hydrophilic organic solvent and water using an inorganic base in an amount of n molar equivalents (n≥3) per mole of the above compound (1), the second stage: the neutralization of the hydrolysis product using inorganic acid in an amount of (n-1) to n molar equivalents (n≥3) and separating and removing the inorganic salt formed in the reaction mixture from the above inorganic base and inorganic acid by precipitation from a solvent system suitable for reducing the solubility of the inorganic salt, wherein said solvent system is selected from a hydrophilic organic solvent, a mixed solvent of water and a hydrophilic organic solvent and water, and the third step: crystallization of N 2 - (1 (S) -kar oxy-3-phenylpropyl) -L-lysyl-L-proline (2) present in the mixture after removal of the inorganic salt from the solvent system at its isoelectric point, wherein said solvent system is selected from a hydrophilic organic solvent, a mixed solvent consisting of water and a hydrophilic organic solvent, and water, and thereby, the allocation of N 2 - (1 (S) -carboxy-3-phenylpropyl) -L-lysyl-L-proline (2) in crystalline form while maintaining salts, mainly containing salt organic acid, trifluoroacetic acid s dissolved in the mother liquor.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10/268676 | 1998-09-22 | ||
JP26867698 | 1998-09-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
RU2000116019A true RU2000116019A (en) | 2002-05-10 |
RU2220152C2 RU2220152C2 (en) | 2003-12-27 |
Family
ID=17461854
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
RU2000116019/04A RU2220152C2 (en) | 1998-09-22 | 1999-09-22 | Method for preparing n2-[1(s)-carboxy-3-phenylpropyl]-l-lysyl-l-proline |
Country Status (16)
Country | Link |
---|---|
US (1) | US6271393B1 (en) |
EP (1) | EP1035131B1 (en) |
JP (1) | JP4307733B2 (en) |
KR (1) | KR100625553B1 (en) |
CN (1) | CN1200946C (en) |
AT (1) | ATE346086T1 (en) |
CA (1) | CA2311407A1 (en) |
CZ (1) | CZ292494B6 (en) |
DE (1) | DE69934084T2 (en) |
ES (1) | ES2277446T3 (en) |
HU (1) | HUP0100831A3 (en) |
IL (1) | IL136271A (en) |
PL (1) | PL340685A1 (en) |
RU (1) | RU2220152C2 (en) |
SI (1) | SI20271A (en) |
WO (1) | WO2000017229A1 (en) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0168769A3 (en) * | 1984-07-16 | 1989-02-08 | Merck & Co. Inc. | Process for preparing carboxyalkyl dipeptides |
JPH0653757B2 (en) * | 1985-12-06 | 1994-07-20 | 味の素株式会社 | Aromatic sulfonate of proline derivative |
JPH01254651A (en) * | 1988-04-04 | 1989-10-11 | Kanegafuchi Chem Ind Co Ltd | N2-(1-carboxy-3-phenylpropyl)-l-lysin derivative and production of lysinopuryl using said compound |
EP0645398B1 (en) * | 1993-01-08 | 2003-03-05 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Method of crystallizing n?2 -((s)-1-ethoxycarbonyl-3-phenylpropyl)-n?6 -trifluoroacetyl-l-lysyl-l-proline |
DE4331540A1 (en) * | 1993-09-17 | 1995-03-23 | Degussa | Process for the purification of 1- [N · 2 · - ((S) -ethoxycarbonyl) -3-phenylpropyl) -N · 6 · -trifluoroacetyl] -L-lysyl-L-proline (Lisinopril (Tfa) ethyl ester) |
HU214579B (en) * | 1995-03-14 | 1998-04-28 | Richter Gedeon Vegyészeti Gyár Rt. | New process for producing lysinoprile |
JP3792777B2 (en) * | 1996-05-10 | 2006-07-05 | 株式会社カネカ | Method for producing 1-alkoxycarbonyl-3-phenylpropyl derivative |
-
1999
- 1999-09-22 EP EP99944783A patent/EP1035131B1/en not_active Expired - Lifetime
- 1999-09-22 DE DE69934084T patent/DE69934084T2/en not_active Expired - Lifetime
- 1999-09-22 RU RU2000116019/04A patent/RU2220152C2/en not_active IP Right Cessation
- 1999-09-22 US US09/554,827 patent/US6271393B1/en not_active Expired - Lifetime
- 1999-09-22 HU HU0100831A patent/HUP0100831A3/en unknown
- 1999-09-22 SI SI9920011A patent/SI20271A/en not_active IP Right Cessation
- 1999-09-22 ES ES99944783T patent/ES2277446T3/en not_active Expired - Lifetime
- 1999-09-22 JP JP2000574137A patent/JP4307733B2/en not_active Expired - Fee Related
- 1999-09-22 CZ CZ20001897A patent/CZ292494B6/en not_active IP Right Cessation
- 1999-09-22 KR KR1020007005439A patent/KR100625553B1/en not_active IP Right Cessation
- 1999-09-22 CA CA002311407A patent/CA2311407A1/en not_active Abandoned
- 1999-09-22 CN CNB99801639XA patent/CN1200946C/en not_active Expired - Fee Related
- 1999-09-22 IL IL13627199A patent/IL136271A/en not_active IP Right Cessation
- 1999-09-22 AT AT99944783T patent/ATE346086T1/en not_active IP Right Cessation
- 1999-09-22 WO PCT/JP1999/005189 patent/WO2000017229A1/en active IP Right Grant
- 1999-09-22 PL PL99340685A patent/PL340685A1/en unknown
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