WO2012056285A1 - An improved process for the preparation of pemetrexed - Google Patents
An improved process for the preparation of pemetrexed Download PDFInfo
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- WO2012056285A1 WO2012056285A1 PCT/IB2011/002513 IB2011002513W WO2012056285A1 WO 2012056285 A1 WO2012056285 A1 WO 2012056285A1 IB 2011002513 W IB2011002513 W IB 2011002513W WO 2012056285 A1 WO2012056285 A1 WO 2012056285A1
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- 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
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Abstract
improved process for the preparation of Pemetrexed of Formula (I) or its salt, the process comprises Reacting 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)- ethyl) benzoic acid with L-glutamic acid or its ester, or its acid salt, in the presence of acid activating reagent having carbodiimide group, to obtain Pemetrexed Diester; hydrolysis of the same to obtain Pemetrexed; and optionally converting Pemetrexed to Pemetrexed disodium.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF PEMETREXED
Field of the Invention
An improved process for the preparation of Pemetrexed is provided, which comprises reacting 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid with acid salt of L-glutamic acid or its ester in the presence of acid activating reagent having carbodiimide group followed by deprotection and optional salt formation such as Pemetrexed disodium.
Background of the Invention
Pemetrexed is chemically N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH pyrrolo[2,3-t ]pyrimidin- 5-yl)ethyl]benzoyl]-L-Glutamic acid and is known from US 4,997,838 and US 5,344,932. It is represented by Formula I and has antifolate activity as chemotherapeutic agent for the treatment of cancer. Pemetrexed disodium is represented by Formula II.
Formula I Formula II Processes for the preparation of Pemetrexed have been reported in literature such as those described in US 4,997,838, US 5,344,932, US 5,416,211 , US 6,262,262, which are herein incorporated for reference only.
US Patent No 4,997,838 describes the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid with diethyl L-glutamate hydrochloride in the presence of diphenyl phosphorylazide and triethyl amine at room temperature. The process is troublesome and time consuming as it involves 63 hours to complete the reaction.
US Patent No 5,416,21 1 describes the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid with dimethyl L-glutamate hydrochloride in the presence of 4-chloro-2,6-dimethoxytriazine and N-methyl Morpholine at room temperature. The process reported in preparation 5 of US 5,416,211 is not industrial viable because it results in very less yield of only 43%. It has been observed that the product, obtained by repeating the process given in US 5,416,211 by present inventors, is green in color and has purity of about 50% only due to the presence of several undesired byproducts as impurities. It has been practically experienced that the green color of the product is very difficult to remove and it carries to final Pemetrexed Disodium.
In view of above prior art processes, there remains a need for an improved process for the preparation of Pemetrexed and its intermediates, which minimizes or eliminates the above problems and is convenient to operate on a commercial scale. The process of present invention provides white to off white colored product having good Chromatographic Purity of more that 99% and in good yield of about 85%. Isolation of product in the present invention is also very simple as all the byproducts of present process are water soluble.
Summary of the Invention
Accordingly, there is provided an improved process for the preparation of Pemetrexed of Formula I or its salt comprising the steps of: a) Reacting 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)-ethyl) benzoic acid of Formula III
Formula III
with L-glutamic acid or its ester of Formula IV, or its acid salt
Formula IV
wherein R is hydrogen or alkyl, in the presence of acid activating reagent having carbodiimide group, to obtain Pemetrexed Diester of Formula V;
Formula V
Hydrolysis of compound of Formula V to obtain Pemetrexed of Formula I; and
Formula I
c) Optionally converting Pemetrexed of Formula I Pemetrexed disodium of Formula II
Formula II Detailed Description of the Invention
4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of
Formula III may be prepared from methods known to one of ordinary skill in the art, including methods disclosed in US 4,997,838; US 5,344,932; US 5,416,21 1 and US 6,262,262, which are herein incorporated for reference only. Esters of L-glutamic acid of Formula IV, wherein R is alkyl may include methyl or ethyl ester of L-glutamic acid. Acid salt may include hydrochloride, hydrobromide or hydroiodide salt of L-glutamic acid or its esters.
The reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl)benzoic acid of Formula III with acid salt of L-glutamic acid or its ester of Formula IV may be carried out in the presence of a suitable solvent.
Suitable solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile ; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride ; dipolar aprotic solvents, such as dimethylsulfoxide and dimethylformamide ; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran ; and mixtures thereof.
The reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl)benzoic acid of Formula III with acid salt of L-glutamic acid or its ester of Formula IV may be carried out in the presence of a base, which may be selected from the group comprising of organic or inorganic base. The organic base may be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri CI - C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; and pyrrolidine.
The inorganic base may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide. Reagent having carbodiimide group may be selected from the group comprising of Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC) and l-Ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) or its acid salt such as hydrochloride salt. EDC may also be used in the presence of 1-Hydroxybenzotriazole (HOBT).
Carbodiimide reagent may be added to the reaction mixture at the temperature range of about -5°C to about 10°C, preferably at about 0°C to about 5°C.
The reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl)benzoic acid of Formula III with acid salt of L-glutamic acid or its ester of Formula IV may be carried out at about ambient temperature i.e. at about room temperature, which may range from about 20° to about 35°C.
The reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl)benzoic acid of Formula III with acid salt of L-glutamic acid or its ester of Formula IV may be carried out for about 1 hour to about 5 hours.
Isolation of compound of Formula V, obtained by the reaction of 4-(2-(2-amino-4,7-dihydro- 4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of Formula III with acid salt of L- glutamic acid or its ester of Formula IV, may be accomplished by one or more of concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. Pemetrexed Diester of Formula V may also be purified by crystallization with suitable solvent. Hydrolysis of Pemetrexed Diester of Formula V may be carried out in the presence of metal hydroxide such as sodium hydroxide or potassium hydroxide, to obtain Pemetrexed of Formula I.
Pemetrexed of Formula I may be converted to Pemetrexed Disodium of Formula II by the methods known to one having ordinary skill in the art, including methods disclosed in WO2001 14379; US 7,138,521 and US 6,262,262, which are herein incorporated for reference only.
Examples
Example -1: Preparation of Pemetrexed Dimethyl ester of Formula V (R=methyl)
4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid (lOg, 0.034 moles) and N,N-dimethylformamide (50 mL) were stirred for 10-15 minutes under nitrogen atmosphere at room temperature and the reaction mass was cooled to 0 - 5°C. 1 -Hydroxybenzotriazole (4.53g) and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.43) was added at 0 -5°C and the reaction mass was maintained for 1-2 hours at 0 - 5°C. Then L- glutamic acid dimethyl ester Hydrochloride (8.50g, 0.040 moles) and Diisopropyl ethylamine (4.34g) was then added to reaction mass at 0-5°C and the temperature was raised to room temperature. The reaction mass was stirred at room temperature for 2-3 hours and DM Water
(500ml) was added. The reaction mass was stirred at room temperature for 10-15 hours. The product was thus filtered under vacuum was crystallized with methanol: acetone mixture and Methanol and Dichloromethane mixture. The product was dried under vacuum oven at 50- 55°C for 10-15 hours. Yield (w/w) : 12.5g
Yield (%) : 80.4%
Purity : 98.0%
Example -2: Preparation of Pemetrexed of Formula I
Sodium hydroxide (2.19 g) was added to the mixture of DM water (80 mL) and Pemetrexed Dimethyl ester (10 g) under Nitrogen atmosphere at room temperature. The reaction mass was stirred for 5-6 hours and then cooled to 0-5°C. The pH of reaction mass was adjusted to 4-5 with Hydrochloric acid (~5 mL) solution at 0-5°C. The reaction mass was maintained at 0-5 for 30 minutes to 1 hour. Isopropyl alcohol (300 mL) was then added drop wise within an hour. The reaction mass was maintained at room temperature for 2-3 hours. The product was filtered under vacuum. The product was crystallized with DMSO/Ethanol and solvents likewise. The product was dried under vacuum oven at 50-55°C for 10-15 hours.
Yield (w/w) : 8.0g
Yield (%) : 85.0%
Purity : 99.5% Example -3: Preparation of Pemetrexed Disodium of Formula II
Preparation -I:
Sodium hydroxide (1.78g in 5 mL DM water) was added to the mixture of Isopropyl alcohol (30 mL) and Pemetrexed (10 g) under Nitrogen atmosphere at room temperature. The reaction mass was stirred for 1-2 hours. Cyclohexane or DCM (100 mL) was then added at
room temperature. Water was removed azeotropically. The reaction mass was cooled to room temperature. The reaction mass was maintained at room temperature for 1-2 hours. The product was filtered under vacuum. The product was dried under vacuum oven at 50-55°C for 10-15 hours. Yield (w/w) : 10.8g
Yield (%) : 98.0%
Purity : 99.5%
M/c (w/w) : 12.0%
Preparation -II:
Pemetrexed of Formula-I (lOg) was dissolved in Methanol (lOOmL) and Sodium Hydroxide (1.87g) and DM Water (lmL) was added into reaction mass under Nitrogen atmosphere at room temperature. Reaction mass was stirred for 1-2 hours. Ethyl acetate (200 mL) was then added into reaction mass at room temperature and stirred for 5-6 hours. The product was filtered under vacuum. The product was dried under vacuum oven at 50-55°C for 10-15 hours.
Yield (w/w) : 10.0 g
Yield (%) : 90.0% Purity : 99.5%
M/c (w/w) : about 10.0%
Claims
1. An improved process for the preparation of Pemetrexed of Formula I or its salt comprising the steps of: a) reacting 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)-ethyl) benzoic acid of Formula III
Formula III
with L-glutamic acid or its ester of Formula IV, or its acid salt
Formula IV
wherein R is hydrogen or alkyl, in the presence of acid activating reagent having carbodiimide group, to obtain Pemetrexed Diester of Formula V;
Formula V b) hydrolysis of compound of Formula V to obtain Pemetrexed of Formula I;
Formula I and c) Optionally converting Pemetrexed of Formula I to Pemetrexed disodium of Formula II
Formula II
2. The process of claim 1 , wherein R is methyl or ethyl.
3. The process of claim 1, wherein Acid salt is hydrochloride, hydrobromide or hydroiodide salt of L-glutamic acid or its esters.
4. The process of claim 1 , wherein the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of Formula III with acid salt of L- glutamic acid or its ester of Formula IV is carried out in the presence of a suitable solvent.
5. The process of claim 4, wherein suitable solvent is selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; and mixtures thereof.
6. The process of claim 1 , wherein the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of Formula III with acid salt of L- glutamic acid or its ester of Formula IV is carried out in the presence of a base.
7. The process of claim 6, wherein base is- organic or inorganic base.
8. The process of claim 7, wherein the organic base is selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri CI- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; and pyrrolidine.
9. The process of claim 7, wherein the inorganic base may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
10. The process of claim 1, wherein reagent having carbodiimide group may be selected from the group comprising of Dicyclohexylcarbodiimide (DCC), Ν,Ν'- Diisopropylcarbodiimide (DIC) and l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide
(EDC) or its acid salt.
1 1. The process of claim 10, wherein EDC is used in the presence of 1 - Hydroxybenzotriazole (HGBT).
12. The process of claim 1, wherein. Carbodiimide reagent is added to the reaction mixture at the temperature range of about -5°C to about 10°C.
13. The process of claim 1 , wherein the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of Formula III with acid salt of L- glutamic acid or its ester of Formula IV is carried out at about ambient temperature.
14. The process of claim 1, wherein the reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid of Formula III with acid salt of L- glutamic acid or its ester of Formula IV is carried out for about 1 hour to about 5 hours.
15. The process of claim 1, wherein hydrolysis of Pemetrexed Diester of Formula V is carried out in the presence of metal hydroxide such as sodium hydroxide or potassium hydroxide, to obtain Pemetrexed of Formula I.
16. The process of claim 1, wherein Pemetrexed of Formula I is converted to Pemetrexed Disodium of Formula II.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102796106A (en) * | 2012-08-28 | 2012-11-28 | 信泰制药(苏州)有限公司 | Pemetrexed quality control method, and preparation of pemetrexed impurity and salt thereof |
ITRM20120398A1 (en) * | 2012-08-08 | 2014-02-09 | Berlin Chemie Ag | PEMETREXED SYNTHESIS PROCESS AND ITS LYSINE SALT. |
WO2015023064A1 (en) * | 2013-08-12 | 2015-02-19 | 제일약품주식회사 | Method for preparing highly-pure pemetrexed disodium salt |
WO2015034293A1 (en) * | 2013-09-05 | 2015-03-12 | 주식회사 삼양바이오팜 | Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate |
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Cited By (13)
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CN104736540B (en) * | 2012-08-08 | 2017-08-25 | 柏林化学股份有限公司 | The preparation method of pemetrexed and its lysine salt |
ITRM20120398A1 (en) * | 2012-08-08 | 2014-02-09 | Berlin Chemie Ag | PEMETREXED SYNTHESIS PROCESS AND ITS LYSINE SALT. |
WO2014024164A1 (en) * | 2012-08-08 | 2014-02-13 | Berlin-Chemie Ag | Process for the preparation of pemetrexed and lysin salt thereof |
KR20150045458A (en) * | 2012-08-08 | 2015-04-28 | 베를린-케미 악티엔 게젤샤프트 | Process for the preparation of pemetrexed and lysin salt thereof |
CN104736540A (en) * | 2012-08-08 | 2015-06-24 | 柏林化学股份有限公司 | Process for the preparation of pemetrexed and lysin salt thereof |
RU2609006C2 (en) * | 2012-08-08 | 2017-01-30 | Берлин-Хеми Аг | Process for preparation of pemetrexed and lysin salt thereof |
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KR102288417B1 (en) | 2012-08-08 | 2021-08-11 | 베를린-케미 악티엔 게젤샤프트 | Process for the preparation of pemetrexed and lysin salt thereof |
CN102796106A (en) * | 2012-08-28 | 2012-11-28 | 信泰制药(苏州)有限公司 | Pemetrexed quality control method, and preparation of pemetrexed impurity and salt thereof |
WO2015023064A1 (en) * | 2013-08-12 | 2015-02-19 | 제일약품주식회사 | Method for preparing highly-pure pemetrexed disodium salt |
WO2015034293A1 (en) * | 2013-09-05 | 2015-03-12 | 주식회사 삼양바이오팜 | Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate |
CN105531276A (en) * | 2013-09-05 | 2016-04-27 | 株式会社三养生物制药 | Method for preparing improved intermediate for producing high-purity pemetrexed and method for producing high-purity pemetrexed using intermediate |
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