WO2012017443A1

WO2012017443A1 - Process for preparation of highly pure dialkyl pemetrexed

Info

Publication number: WO2012017443A1
Application number: PCT/IN2010/000700
Authority: WO
Inventors: Mahesh Bhagoji Dalvi; Rajesh Shashikant Kenny; Pradeep Kisan Tarade
Original assignee: Neon Laboratories Ltd.
Priority date: 2010-08-02
Filing date: 2010-10-27
Publication date: 2012-02-09
Also published as: RU2013109299A; UA105580C2; RU2552519C2

Abstract

The invention discloses a process for preparation of highly pure dialkyl pemetrexed by reacting a 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid with a glutamatic acid diester or its salt in presence of a safe, mild, inexpensive, non-oxidative and easy to handle reagent such as substituted triphenyl phosphate. The invention further discloses purification of dialkyl pemetrexed by crystallization or trituration and conversion of purified dialkyl pemetrexed to pemetrexed or its disodium salt.

Description

"PROCESS FOR PREPARATION OF HIGHLY PURE DIALKYL

PEMETREXED"

Technical Field:

The present invention relates to a novel process for preparation of highly pure dialkyl pemetrexed of formula (I) using substituted triphenyl phosphate reagent of formula (IV), which is a mild, safe, inexpensive, non-oxidative and easy to handle reagent.

(I) where Rl and R2 are independently carboxyl protecting groups.

(IV) where X is electron withdrawing group; Y and Z are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or Y and Z when placed ortho to each other form benzene ring; R3 and R4 are independently hydrogen, alky] containing 1 to 7 carbon atoms, or R3 and R4 together with nitrogen form 3 to 7 members heterocyclic ring.

The invention also relates to a process for purification of dialkyl pemetrexed of formula (I) by crystallization or trituration, and its conversion to highly pure pemetrexed or its disodium salt.

Background and Prior art:

Dialkyl pemetrexed of formula (I) is an intermediate of pemetrexed which is chemically N{4-[2(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethyl]benzoyl}-L-glutamic acid. Pemetrexed is known to have antifolate activity. Pemetrexed disodium is a multitargeted antifolate agent approved as a single agent for the treatment of non-small cell lung cancer, and in combination with cisplastin for the treatment of patients with malignant pleural mesothelioma, under the trade name Alimta ®.

The European patent EP0334636 discloses preparation of pyrrolopyrimidineglutamate by condensation of pyrrolopyrimidinylalkylbenzoic acid with glutamic acid or its diester using carbodiimide, diphenylphosphoryl azide or phosphorocyanidate as condensing agents which are toxic and hazardous. The quantity of the reagent required is 1 to 20 equivalents. The preferred reagent used in this patent is dicyclohexylcarbodiimide (DCC), which is a potent allergen and a sensitizer, often causes skin rashes.

EP0334636 also discloses preparation of pyrrolopyrimidineglutamate by condensation of reactive derivatives of pyrrolopyrimidinylalkylbenzoic acid with glutamic acid or its diester. The reactive derivatives include acid halides, acid anhydrides, mixed acid anhydride with monoalkyl carbonic esters, active esters, acid azide, mixed acid anhydride with phosphoric acid diesters, mixed acid anhydride with phosphorous acid diesters of the pyrrolopyrimidinylalkylbenzoic acid.

EP0334636 does not specifically disclose the process for preparation of diethyl pemetrexed and its conversion to pemetrexed or its pharmaceutically acceptable salts. Pemetrexed and its preparation have been described for the first time in the US patent US5344932. The synthesis of dialkyl pemetrexed disclosed in this patent is not suitable for industrial production due to the number of process steps and the poor overall yield. The US patents US6013828 and US6066732 disclose preparation of pemetrexed disodium by condensation of 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3- yl)ethylbenzoic acid with diethyl L-glutamate using 4-chloro-2,6-dimethoxytriazine (CDMT) as a condensing agent. This process is not suitable for industrial application as CDMT is hazardous as well as expensive reagent which is not easily available. Use of CDMT causes irritation to eyes, respiratory system and skin. It is found that the products obtained by using triazene reagents are not colourless but has bluish to grey colour and need column chromatography to get colourless products.

Preparation of diethyl pemetrexed by condensation of 2-(4-hydroxy-6-aminopyrrolo(2,3- d)pyrimidin-3-yl)ethylbenzoic acid with diethyl L-glutamate using CDMT and N- methylmorpholine is disclosed in Organic Process Research and Development, 2005, 9, 738 - 742. The article also discloses formation of N-methyl pemetrexed as an impurity, which is formed by the side reaction of CDMT with N-methylmorpholine.

Hence there is a need in the art for economic and industrially applicable method for synthesis of dialkyl pemetrexed.

Like any synthetic compound pyrrolopyrimidineglutamates can contain extraneous compounds or impurities that can come from any source. The impurities can be in the form of unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. The pyrrolopyrimidineglutamates containing impurities can lead to impure pemetrexed or its salts. Impurities in pemetrexed or its salts are undesired and might even be harmful to a patient being treated with a dosage form containing the same.

The known methods for purification of dialkyl pemetrexed are column chromatography and purification by salt formation (e.g. tosylate salt). Purification by column chromatography is not industrially applicable. WOOl I4379 discloses purification of diethyl pemetrexed via tosylate salt formation which may affect the yield of pemetrexed. Purification of diethyl pemetrexed via tosylate salt formation does not result into more than 99% purity.

US6066732 discloses purification of diethyl pemetrexed via column chromatography and hence not suitable for industrial application.

Thus, the search for a manufacturing process for the preparation and purification of dialkyl pemetrexed resulting in a satisfactory yield and satisfactory purity of a final product remains undoubtedly of interest.

We have surprisingly found that, hardly any literature discloses the use of substituted triaryl phosphates in the synthesis of carboxamides from carboxylic acids and amines.

Object of the invention:

It is therefore an object of the invention is to overcome or ameliorate atleast one disadvantage of the prior art or to provide a useful alternative.

Another object of the invention is to provide a process for preparation of highly pure dialkyl pemetrexed by using safe, mild, inexpensive, non-oxidative and easy to handle reagent.

Another object of the invention is to provide an economic and industrially applicable process for preparation of highly pure dialkyl pemetrexed.

Yet another object of the invention is to provide a concise and industrially applicable process for purification of dialkyl pemetrexed to provide the product with more than 99% purity when measured by HPLC.

Yet another object of the invention is to convert dialkyl pemetrexed which are obtained by the present method, into highly pure pemetrexed and its disodium salt. Summary of the invention:

In accordance with the above objectives, the present invention provides concise, economic and industrially feasible process for the preparation of highly pure dialkyl pemetrexed using safe, mild, inexpensive, non-oxidative and easy to handle reagent.

According to one aspect, the present invention provides a process for preparation of dialkyl pemetrexed comprising reacting 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3- yl)ethylbenzoic acid with glutamic acid diester or its salt in presence of a substituted triphenyl phosphate .

In another aspect, the present invention provides a method for purification of pyrrolopyrimidineglutamic acid derivatives via crystallization or trituration in a suitable solvent.

Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Detailed description of the invention:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and material or equivalent to those described herein can be used in the practice - or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specified as follows:

Unless stated to the contrary, any of the words 'having', 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitations' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose illustration rather than limitation of the invention as set forth the appended claims. Accordingly, the present invention provides a process to prepare highly pure dialkyl pemetrexed comprising the following steps:

a) reacting 2-(4-hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid of formula (II) with a triaryl phosphate of formula (IV) to provide a mixed anhydride of formula (V).

where X is electron withdrawing group; Y and Z are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or Y and Z when placed ortho to each other form benzene ring; R3 and R4 are independently hydrogen, alkyl containing 1 to 7 carbon atoms, or R3 and R4 together with nitrogen form 3 to 7 members heterocyclic ring. b) reacting the mixed anhydride of formula (V) obtained in the step a, in situ with glutamic acid diester or its salt of formula (III) to obtain dialkyl pemetrexed formula (I).

(I) wherein Rl and R2 are carboxyl protecting groups. Preferably R l and R2 are independently alkyl group containing 1 to 7 carbon atoms. More preferably Rl and R2 are independently methyl or ethyl group.

The process of the present invention is advantageously carried by reacting the carboxyl ic acid of formula (II) with diethyl L-glutamate using tris(para-nitrophenyl)phosphate, tris(ortho-nitrophenyl)phosphate or tris(para-cyanophenyl)phosphate as a reagent. The. reagents are mild, safe, inexpensive, non-oxidative and easy to handle. The preferred reagent is tris(para-nitrophenyl)phosphate or tris(ortho-nitrophenyl)phosphate.

The triphenylphosphate of formula (IV) used for the synthesis is 1 to 4 equivalent of 2-(4- hydroxy-6-aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid, more preferably 1.2 to 3.5 equivalents. The most preferred quantity of the reagent is 1 .5 to 1 .7 equivalents.

Preferably the process of the present invention is carried out in the presence of a base and a suitable solvent. The base which may be used in the present invention is organic or inorganic. Examples of organic base include tertiary amines such as trialkyl amine. Examples of inorganic base include alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate and mixture thereof. Examples of alkali metal carbonate include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate. Examples of alkaline earth metal carbonate include calcium carbonate and magnesium carbonate. Examples of alkaline earth metal bicarbonate include calcium bicarbonate and magnesium bicarbonate. The preferred base is triethyl amine or sodium carbonate.

The base is conveniently used in an amount, relative to 2-(4-hydroxy-6-aminopyrrolo(2,3- d)pyrimidin-3-yl)ethylbenzoic acid, preferably in a range between 1 to 6 equivalents, more preferably 2 to 5 equivalents. The most preferred quantity of the base is 4 equivalents.

The solvent may be selected from any polar solvent. The preferred solvent is acetonitrile or dimethyl formamide.

The process of the present invention may be carried out at suitable temperature. To minimize the decomposition of products and impurity formation the reaction is carried out at 25 to 60°C, more preferably at 35 to 55°C. The most preferred reaction temperature is 45 to 50°C.

The reaction normally completes in a span of 2 to 24 hours, more preferably 10 to 18 hours, most preferably 12 to 13 hours.

On completion of the reaction pemetrexed diester can be recovered from the reaction mass in a convenient manner. The workup of the reaction involves quenching of the reaction mixture in water followed by extracting the mixture using a water insoluble organic solvent. The water insoluble organic solvent is selected from a group of halogenated or a non-halogenated solvent. The most preferred solvent is ethyl acetate, chloroform, dichloromethane, dichloroethane or mixture thereof. The organic solvent containing diethyl pemetrexed is made free of substituted diphenyl hydrophosphates and substituted phenols by washing with aqueous alkali carbonate solution. The alkali metal carbonates are selected from the group of lithium, sodium or potassium carbonate, most preferably sodium carbonate. The process further involves evaporation of the organic solvent containing pemetrexed diester till dryness. The solvent evaporation is carried out by distillation of the solvent at its boiling point. The solvent evaporation is carried out under reduced pressure and the crude pemetrexed diester is isolated with the HPLC purity of at least 98%.

The isolated pemetrexed diester is purified by crystallization or trituration in a suitable solvent. The solvent used for crystallization or trituration is selected from a class of halogenated or non-halogenated solvent or a mixture thereof. Preferably the solvent used for purification of dialkyl pemetrexed is selected from ethyl acetate, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dimethyl acetamide or mixture thereof. The most preferred solvent used for purification of pemetrexed diester is a mixture of dimethyl formamide and acetone in the ratio of 1 :3 to 1 :8 vol/vol, more preferably 1 :4 to 1 :7 vol/vol or most preferably 1 :5 to 1 :6 vol/vol. The purified diakyl pemetrexed has the purity of greater than 99%.

The purified pemetrexed diester is subjected to hydrolysis to obtain pemetrexed disodium either by methods known in the art or the process disclosed herein. In a typical procedure, the pemetrexed diester is hydrolyzed using sodium hydroxide to provide pemetrexed disodium salt. The hydrolysis may be carried out at a room temperature.

The substituted triphenyl phosphate of formula (IV) can be easily prepared by methods known in the prior art or the process disclosed herein. In a typical procedure a substituted phenol is reacted with phosphorous oxychloride in presence of a base and a solvent to yield substituted triphenyl phosphate of formula (IV).

The solvent used for the preparation of the substituted triphenyl phosphate of formula (IV) is an aprotic solvent selected from not limited to dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, toluene acetonitrile and dimethyl sulfoxide. The preferred solvent used for preparing the triaryl phosphate is toluene. The base used for the preparation of the triaryl phosphate is preferably pyridine.

The pure pemetrexed disodium obtained by the process of the invention may be formulated into a dosage form by combining with one or more pharmaceutically acceptable excipients using known techniques. Further the dosage form may be immediate release or extended release. Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

Examples:

Example 1

Preparation tris(para-nitrophenyl)phosphate

A 2000 ml four neck round bottom flask with water condenser and calcium chloride tube was charged with para-nitrophenol (100.16 gm, 0.72 moles), toluene ( 1000 ml) and pyridine (135 gm, 1.708 moles) at room temperature. Phosphorous oxychloride (36.8 gm, 0.024 moles) was added drop wise within 15 minutes. The reaction mass was gently refluxed at 1 10°C for 4 hours. The reaction mixture was copied to 60°C. Toluene was removed by distillation under reduced pressure to obtain a crude solid. The solid was dissolved in dichloromethane (1000 ml). Dichloromethane layer was washed with 5% sodium hydroxide solution (3 x 500 ml) followed by water washing (1 x 500 ml). The organic layer was dried over sodium sulphate and concentrated to dryness to afford 89 gm of tris(para-nitrophenyl)phosphate as colourless crystals (yield 89 gm, melting point 154 tol 56°C, lit melting point 156°C (mentioned in Green Chemistry, 2005, 7, 217) ). The product was used for further reaction without purification.

Example 2

Preparation tris(ortho-nitrophenyl)phosphate

Preparation of tris(ortho-nitrophenyl)phosphate was carried out according to the example 1 using o-nitrophenol instead of p-nitrophenol. Yield 70%.

Example 3

Preparation of diethyl pemetrexed

A clean and dry 250 ml. round bottom flask (A) was charged with 2-(4-hydroxy-6- aminopyrrolo(2,3.-d)pyrimidin-3-yl)ethylbenzoic acid (20 gm, 0.067 moles), dimethylformide (100 ml) and triethyl amine (23.04 gm, 0.228 moles). The reaction mixture was stirred for 5 minutes at 30 - 35 °C. Tris(para-nitrophenyl)phosphate (34 gm, 0.0736 moles) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 30 - 35°C. Tris(para-nitrophenyl)phosphate (15.4 gm, 0.0334 moles) was added to the reaction mixture. The reaction mixture was maintained for one hour at 30 to 35 °C. In another flask (B), diethyl-L-glutamate hydrochloride (17.4 gm, 0.0726 moles) was dissolved in dimethylformamide (30 ml) and triethyl amine (7.92 gm, 0.078 moles). The reaction mixture was stirred for 5 minutes and filtered.

The filtrate was added in the reaction mixture in the flask (A), and stirred for 1 1 hours at 40 to 45°C. The reaction mixture was cooled to 20 °C, quenched into distilled water (600 ml) at 20 to 25°C, extracted with dichloromethane (3 X 150 ml). Dichloromethane layers were collected and washed with 5% sodium carbonate solution (3 X 300 ml). Dichloromethane layer was separated, washed with distilled water (300 ml), dried over sodium sulfate, and concentrated. Acetone (400 ml) was charged into the concentrated reaction mixture and stirred at 30 to 35°C for i hour. The solid was filtered, washed with acetone (2 X 50 ml) to yield crude diethyl pemetrexed (yield 20 gm, 98.12% HPLC purity).

Example 4

Preparation of diethyl pemetrexed

A clean and dry 100 ml. round bottom flask was charged with 2-(4-hydroxy-6- aminopyrrolo(2,3-d)pyrimidin-3-yl)ethylbenzoic acid (5 gm), diethyl-L-glutamate hydrochloride (4.5 gm), dimethylformide (40 ml) and triethyl amine (9.4 ml). The reaction mixture was heated to 40°C and stirred for 15 to 25 minutes. Tris(para- nitrophenyl)phosphate (1 1.5 gm) was added to the reaction mixture at 40°C and maintained for 3 hours. Work-up was carried out as per the example 3 to obtain diethyl pemetrexed (yield 5.8 gm, 98% HPLC purity).

Example 5

Preparation of diethyl pemetrexed

Preparation of diethyl pemetrexed was carried out according to the example 3 using tris(ortho-nitrophenyl)phosphate instead of tris(para-nitrophenyl)phosphate. (Yield 6.0 gm, 99.2% HPLC purity). Example 6

Purification of diethyl pemetrexed

The wet and crude diethyl pemetrexed obtained in the example 3 was charged with dimethylformamide (60 ml) and stirred at 30 to 35°C till the reaction mixture was clear. Acetone (400 ml) was charged in the reaction mixture, stirred at 30 to 35°C for 1 hour, filtered and washed with acetone (2 X 50 ml) to get purified diethyl pemetrexed (yield 17.5 gm, 99.05% HPLC purity ).

Example 7

Purification of diethyl pemetrexed

Diethyl pemetrexed obtained in the example 4 was purified as per the example 6 to obtained purified product with 99.01 % HPLC purity.

Example 8

Purification of diethyl pemetrexed

Diethyl pemetrexed obtained in the example 5 was purified as per the example 6 to obtained purified product with 99.5% HPLC purity.

Example 9

Preparation of pemetrexed disodium heptahydrate

Diethyl pemetrexed (17 g) obtained in the example 6 was charged with 1 N sodium hydroxide solution (1 19 ml). The reaction mass was stirred for 1 hour at room temperature. The pH of the reaction mass was adjusted between 7 to 9 using acetic acid. The reaction mixture was heated to 40°C. Acetone (425 ml) was added to the reaction mixture and stirred at 40 to 45°C for 10 minutes. The reaction mass was further cooled to room temperature and maintained for 1 hour. The solid obtained was filtered and washed with acetone, and dried to afford pemetrexed disodium heptahydrate ( 18.5 gm, 99.09% HPLC purity). The HPLC of pemetrexed disodium heptahydrate was compared with the standard sample.

Example 10

Preparation of pemetrexed disodium heptahydrate Pure diethyl pemetrexed (1 gm) obtained in the example 7 was hydrolyzed as per the example 9 to obtain pemetrexed disodium heptahydrate (yield 1 gm, 99.13% HPLC purity). The HPLC of pemetrexed disodium heptahydrate was compared with the standard sample.

Example 11

Preparation of pemetrexed disodium heptahydrate

Pure diethyl pemetrexed (1 gm) obtained in the example 8 was hydrolyzed as per the example 9 to obtain pemetrexed disodium heptahydrate (yield 4.9 gm, 99.2% HPLC purity). The HPLC of pemetrexed disodium heptahydrate was compared with the standard sample.

Example 12

Preparation of pemetrexed

Pemetrexed disodium heptahydrate (3 gm) obtained in the example 9 was dissolved in water (60 ml). Acetic acid (4 ml) was added to the reaction mixture and heated at 70°C for 3 hours. The reaction mixture was cooled tb room temperature, stirred for one hour, filtered and washed with distilled water to obtain pemetrexed (2.5 gm, 99.42% HPLC purity). The HPLC of pemetrexed was compared with the standard sample.

Claims

We claim,

1. A process for preparing dialkyl pemetrexed of formula (I),

(I) comprising, reacting a carboxylic acid of formula

(II) with a glutamic acid diester of formula (III) or its salt

(III) wherein Rl and R2 are independently carboxyl protecting groups, in presence of a substituted triphenyl phosphate of formula (IV)

where X is electron withdrawing group; Y and Z are independently hydrogen, electron withdrawing group, alkyl containing 1 to 7 carbon atoms, alkoxy containing 1 to 7 carbon atoms, halogen, NR3R4, mercapto, thioalkyl containing 1 to 7 carbon atoms, or Y and Z when placed ortho to each other form benzene ring; R3 and R4 are independently hydrogen, alkyl containing 1 to 7 carbons atoms, substituted or unsubstituted phenyl, or 3 and R4 together with nitrogen form 3 to 7 membered heterocyclic ring.

The process for preparing dialkyi pemetrexed as claimed in claim 1 , wherein X is nitro or cyano; Y and Z are hydrogen.

The process for preparing dialkyi pemetrexed as claimed in claims 1 and 2, wherein the substituted triphenyl phosphate is tris(para-nitrophenyl)phosphate or tris(ortho-nitrophenyl)phosphate.

The process for preparing dialkyi pemetrexed as claimed in claim 1 , wherein Rl and R2 are independently alkyl groups containing 1 to 7 carbon atoms.

The process for preparing dialkyi pemetrexed as claimed in claim 4, wherein Rl and R2 are independently methyl or ethyl.

6. The process for preparing dialkyl pemetrexed as claimed in claim 1, wherein the process is carried out in presence of a base and a solvent.

7. The process for preparing dialkyl pemetrexed as claimed in claim 6, wherein the base is selected from tertiary amines, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate.

8. The process for preparing dialkyl pemetrexed as claimed in claim 7, wherein the base is triethylamine or sodium carbonate.

9. The process for preparing dialkyl pemetrexed as claimed in claim 6, wherein the solvent is selected from polar solvents.

10. The process for preparing dialkyl pemetrexed as claimed in claim 9, wherein the solvent is acetonitrile or dimethyl formamide.

1 1. A process for purification of dialkyl pemetrexed of formula (I)

wherein Rl and R2 are independently carboxyl protecting groups, comprising crystallization or trituration of the compound of formula (1) in a solvent.

12. The process for purification of compound of formula (1) as claimed in claim 1 1 , wherein Rl and R2 are independently methyl or ethyl.

13. The process for purification of the compound of formula (I) as claimed in claim 1 1 wherein the solvent is selected from ethyl acetate, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dimethyl acetamide or mixture thereof.

14. The process for purification of the compound of formula (1) as claimed in claim 13, wherein the solvent is a mixture of dimethylformamide and acetone.

15. The process for purification of the compound of formula (I) as claimed in claims 13' and 14 wherein the process provides diethyl pemetrexed of more than 99% purity.

16. The process for purification of the compound of formula (I) as claimed in claim 1 1, further comprising a step of converting diethyl pemetrexed into pemetrexed or its disodium salt in presence of sodium hydroxide.