CS271892B1 - Method of (+-)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic racemic acid and its(-)antiiodine mixture division in pure components - Google Patents
Method of (+-)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic racemic acid and its(-)antiiodine mixture division in pure components Download PDFInfo
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- CS271892B1 CS271892B1 CS886264A CS626488A CS271892B1 CS 271892 B1 CS271892 B1 CS 271892B1 CS 886264 A CS886264 A CS 886264A CS 626488 A CS626488 A CS 626488A CS 271892 B1 CS271892 B1 CS 271892B1
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- acid
- aminophenylthio
- hydroxy
- methoxyphenyl
- mixture
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000009835 boiling Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 abstract 3
- 230000002526 effect on cardiovascular system Effects 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000019766 L-Lysine Nutrition 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
- 229960004166 diltiazem Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- YQHGNESHWVPZPT-BFJHMZIZSA-N (2S,3S)-3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanoic acid (2S)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.COc1ccc(cc1)[C@H](Sc1ccccc1N)[C@@H](O)C(O)=O YQHGNESHWVPZPT-BFJHMZIZSA-N 0.000 description 1
- -1 2-aminophenylthio Chemical group 0.000 description 1
- KHQWPNQLSKDWAR-UHFFFAOYSA-N 3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanoic acid Chemical compound C1=CC(OC)=CC=C1C(C(O)C(O)=O)SC1=CC=CC=C1N KHQWPNQLSKDWAR-UHFFFAOYSA-N 0.000 description 1
- 150000008545 L-lysines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Description
(75) Autor vvnálezu KAMINSKÁ ZDENA, PÍCHÁ FRANTIŠEK RNDr., } TREFULKA MOJMÍR ING., BRNO.(75) Author of the Invention KAMINSKÁ ZDENA, PÍCHÁ FRANTIŠEK, RNDr., } TREFULKA MOJMÍR ING., BRNO.
WOJNAR VLADIMÍR ING., ČESKA U BRNA STUDENČÍK ZDENĚK RNDr., BRNOWOJNAR VLADIMÍR ING., CZECH REPUBLIC U BRNO STUDENČÍK ZDENĚK RNDr., BRNO
Způsob rozděleni směsi racemlcké kyseliny (54) (+)-threo-2-hydroxy-3-(2-aminofenylthio)-3(5-methoxyfenyl)propionové a jejiho (-)antipodu na čisté komponenty (57) Raoemická kyselina (-)-threo-2-hydroxy-3-(2-aminofenylthio)-3-(4-methoxyfenyDpropionová vzorce I Je meziproduktem při výrobě kardiovaskulárního léčiva diltiazem. Tato kyselina se získá rozdělením směsi kyseliny a jejího (-)antipodu na čisté komponenty tak, že na směs se působí methanolem nebo ethanolem, nejlépe methanolem při teplotě od 10 °C do bodu varu alkoholu po dobu 0,5 až 10 hodin. Nerozpuštěná raoemická kyselina se izoluje a Její (-)antipod ae získá po odstranění použitého alkoholu.A method for separating a mixture of racemic acid (54) (+) - threo-2-hydroxy-3- (2-aminophenylthio) -3 (5-methoxyphenyl) propionic acid and its (-) antipode into pure components (57) Raoemic acid (-) -threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenylpropionic formula I) It is an intermediate in the preparation of a cardiovascular drug diltiazem, which is obtained by separating the mixture of acid and its (-) antipode into pure components by the mixture is treated with methanol or ethanol, preferably methanol at a temperature of from 10 ° C to the boiling point of the alcohol for 0.5 to 10 hours The undissolved raoemic acid is recovered and its (-) antipode is recovered after removal of the alcohol used.
COOHCOOH
CS 271392 BlCS 271392 Bl
Vynález se týká způsobu rozdělení směsi racemické kyseliny (-)-threo-2-hydroxy-3-/2-aminofenylthio/-3-/4-methoxyíenyl/propionové vzorce IThe present invention relates to a process for separating a racemic (-) - threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid mixture of the formula I
(I)(AND)
CH - COOHCH-COOH
IAND
OH a jejího /-/antipodu na čisté komponenty.OH and its / - / antipode for pure components.
Racemická kyselina /í/-1 hře o-2-hydroxy-3-/2-ami no f eny lthi o/-3-/4-me thoxy fenyl/p rop i onová vzorce I je meziproduktem při výrobě kardiovaskulárního léčiva diltiazem.Racemic acid (1-o-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid of formula I is an intermediate in the manufacture of a cardiovascular drug by diltiazem.
/-/-Antipod racemické sloučeniny 1 může najít uplatnění při optické resoluci racemických organických bází.(-) - The antipod of racemic compound 1 can find use in the optical resolution of racemic organic bases.
Směs racemické sloučeniny vzorce I a jejího /-/-antipodu vzniká jako odpad při štěpení racemické sloučeniny vzorce I na optické antipody.A mixture of the racemic compound of formula I and its (-) - antipode is produced as a waste by the resolution of the racemic compound of formula I into optical antipodes.
Optická resoluce racemické sloučeniny vzorce I se provádí pomooí L-lysinu v methanolu. L-lysinová sůl kyseliny /2S,3S/-2-hydroxy-3-/2-aniinofenylthio/-3-/4-methoxyfenyl/propionové se vyloučí z methanolu jako nerozpustná krystalická látka, zatímco L-lysinová sůl kyseliny /2R,3R/-2-hydroxy-3-/2-aminofenylthio/-3-/4-methoxyfenyl/-propionové zůstává rozpuštěna v methanolu.Optical resolution of the racemic compound of formula I is performed using L-lysine in methanol. The (2S, 3S) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid L-lysine salt precipitates from methanol as an insoluble crystalline substance, while the L-Lysine acid salt (2R, 3R) The (2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid) remains dissolved in methanol.
Po odstranění methanolu účinkem kyseliny chlorovodíkové na vodné roztoky L-lysinových solí se vyloučí jednotlivé antipody sloučeniny vzorce I.After removal of methanol by hydrochloric acid on aqueous solutions of L-lysine salts, the individual antipodes of the compound of formula I precipitate.
Výtěžek kyseliny /23,3S/-2-hydroxy-3-/2-aminofenylthio/-3-/4-methoxyfeny 1/propionové se pohybuje v průměru kolem 80 % theorie. Zbytek tohoto /+/-antipodu zůstává ve formě racemické sloučeniny I ve směsi s /-/-antipodem. Podíl racemické sloučeniny I rovnají se hmotnostně dvojnásobku /+/-antipodu není z hlediska ekonomického zanedbatelný.The yield of (23,3S) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid is on average about 80% of theory. The remainder of this (+) - antipode remains in the form of the racemic compound I in admixture with the (-) - antipode. The proportion of racemic compound I equals twice the weight of the (+) - antipode is not economically negligible.
V patentové literatuře ani v původních sděleních není popsán způsob získání racemické sloučeniny vzorce I a její směsi s /-/-antipodem.Neither the patent literature nor the original disclosures disclose a method for obtaining a racemic compound of formula I and a mixture thereof with a - / - antipode.
Byla stanovena rozpustnost racemické sloučeniny vzorce I a rozpustnost /+/ respektive /-/-antipodu této sloučeniny, v methanolu a ethanoluThe solubility of the racemic compound of formula I and the solubility of the (+) and / - / - antipode thereof in methanol and ethanol were determined.
Na základě zjištěných rozpustností byl nalezen způsob rozdělení směsi racemické kyseliny /-/-threo-2-hydroxy-3/2-aminofenylthio/-3-/4-methoxyfenyl/propionové vzorce I a jejího /-/ -antipodu na čisté komponenty, spočívající v tom, že na směs se působí methanolem nebo ethanolem, při teplotě od 10 °C až do teploty varu alkoholu, po dobu 0,5 až 10 hodin, nejlépe 2 až 3 hodiny, nerozpuštěná racemické kyselina vzorce I se izoluje a její /-/-antipod se získá po odstranění použitého alkoholu.On the basis of the solubilities found, a method of separating the racemic acid mixture of - (-) - threo-2-hydroxy-3 (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid I and its (-) - anipod into pure components was found. in that the mixture is treated with methanol or ethanol, at a temperature of from 10 ° C to the boiling point of the alcohol, for 0.5 to 10 hours, preferably 2 to 3 hours, the undissolved racemic acid of formula I is isolated and its / - The ant -antipod is obtained after removal of the alcohol used.
S 271892 BlS 271892 Bl
PřikladlHe did
Do kotle se předloží 640 1 methanolu a 150 kg směsi racemické kyseliny vzorce I a je jího /-/-antipodu. Za míchání se refluxuje 2 hodiny. Potom se reakčni směs ochladí na 25 až 20 °C a nerozpuštěná racemická kyselina vzorce I se separuje a promyje asi 400 1 metha nolu do ztráty záporné rotace filtrátu.The boiler is charged with 640 L of methanol and 150 kg of the racemic acid mixture of formula I and is the (-) - antipode. It is refluxed for 2 hours with stirring. Thereafter, the reaction mixture is cooled to 25 to 20 ° C and the undissolved racemic acid of formula I is separated and washed with about 400 L of methanol until the negative rotation of the filtrate is lost.
Filtrační koláč racemické kyseliny vzorce I se suší do konstantní hmotnosti při teplotě do 70 °C.The filter cake of the racemic acid of formula I is dried to constant weight at a temperature of up to 70 ° C.
Výtěžek je 15 až 20 kg.The yield is 15-20 kg.
Spojené methanolové filtráty se podrobí destilaci. Odestilovaný methanol se recykluje.The combined methanol filtrates are distilled. The distilled methanol is recycled.
Z destilačního zbytku se vodou vyloučí /-/-antipod racemické kyseliny vzorce I.The (-) - antipod of the racemic acid of formula I is separated from the distillation residue with water.
Příklad 2Example 2
Na 150 kg směsi racemické kyseliny vzorce X a jejího /-/-antipodu se použije 1 500 1 ethanolu a na promytí filtračního koláče 1 000 1 ethanolu. Pracovní postup je stejný jako v příkladu 1.1500 l of ethanol are used per 150 kg of the mixture of racemic acid of formula X and its - / - antipode and 1000 l of ethanol are used to wash the filter cake. The procedure is the same as in Example 1.
Výtěžek je 16 až 20 kg.The yield is 16-20 kg.
Příklad?Example?
Do kotle se předloží 640 1 methanolu a 150 kg směsi racemické kyseliny vzorce I a je jího /-/-antipodu. Reakčni směs se míchá při 20 °C 8 hodin. Dále se postupuje podle příkladu 1.The boiler is charged with 640 L of methanol and 150 kg of the racemic acid mixture of formula I and is the (-) - antipode. The reaction mixture was stirred at 20 ° C for 8 hours. The procedure of Example 1 is followed.
Výtěžek je 15 až 18 kg.The yield is 15-18 kg.
Příklad 4Example 4
Oo kotle se předloží 640 1 methanolu a 150 kg směsi racemické kyseliny vzorce I a je jího /-/-antipodu. Reakčni směs se míchá při 40 °C 5 hodin. Dále se postupuje podle příkl du 1.The boiler is charged with 640 L of methanol and 150 kg of the racemic acid mixture of formula (I) and is the (-) - antipode. The reaction mixture was stirred at 40 ° C for 5 hours. The procedure of Example 1 is then followed.
Výtěžek je 15 až 18 kg.The yield is 15-18 kg.
PŘEDMĚT VYNÁLEZUSUBJECT OF THE INVENTION
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886264A CS271892B1 (en) | 1988-09-21 | 1988-09-21 | Method of (+-)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic racemic acid and its(-)antiiodine mixture division in pure components |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886264A CS271892B1 (en) | 1988-09-21 | 1988-09-21 | Method of (+-)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic racemic acid and its(-)antiiodine mixture division in pure components |
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| Publication Number | Publication Date |
|---|---|
| CS626488A1 CS626488A1 (en) | 1990-03-14 |
| CS271892B1 true CS271892B1 (en) | 1990-12-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS886264A CS271892B1 (en) | 1988-09-21 | 1988-09-21 | Method of (+-)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic racemic acid and its(-)antiiodine mixture division in pure components |
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| Country | Link |
|---|---|
| CS (1) | CS271892B1 (en) |
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- 1988-09-21 CS CS886264A patent/CS271892B1/en not_active IP Right Cessation
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| Publication number | Publication date |
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| CS626488A1 (en) | 1990-03-14 |
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| Date | Code | Title | Description |
|---|---|---|---|
| IF00 | In force as of 2000-06-30 in czech republic | ||
| MM4A | Patent lapsed due to non-payment of fee |
Effective date: 20030921 |