CN112442038B

CN112442038B - Industrial preparation method of pemetrexed disodium

Info

Publication number: CN112442038B
Application number: CN202011287095.1A
Authority: CN
Inventors: 潘秀芝; 邵黎明; 李成文; 潘永祥; 王延杰; 王文波
Original assignee: DEZHOU DEYAO PHARMACEUTICAL CO LTD
Current assignee: DEZHOU DEYAO PHARMACEUTICAL CO LTD
Priority date: 2020-11-17
Filing date: 2020-11-17
Publication date: 2022-09-02
Anticipated expiration: 2040-11-17
Also published as: CN112442038A

Abstract

The invention relates to a preparation method of pemetrexed disodium, which is characterized in that an alkali modified mesoporous molecular sieve catalyst is adopted as a catalyst to replace NaOH as a reaction catalyst, so that good yield and product purity can be obtained under the condition of reaction scale expansion.

Description

Industrial preparation method of pemetrexed disodium

Technical Field

The invention relates to a preparation method of a raw material medicine, in particular to a preparation method of a pemetrexed disodium raw material medicine.

Background

Pemetrexed disodium (Pemetrexed disodium), chemically known as N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid disodium salt bishemihydrate. It is a novel pyrimidine analog, a thymidylate synthase inhibitor. It has antitumor effect by interfering with folate-dependent metabolic process in cell replication process, is a multi-target folate blocker, and can block multiple enzymes required in cancer cell division and proliferation process, including thymidylate synthase, dihydrofolate reductase, glycine ribonucleoside formyltransferase, etc.

Pemetrexed disodium was developed by elillilly in the united states and first marketed in 2004 in the united states for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. It can also be used for treating head and neck cancer, colon cancer, breast cancer, etc. The pemetrexed disodium is also combined with other anti-cancer drugs, particularly cisplatin, so that a better effect on treating mesothelioma can be achieved.

Methods for the preparation of pemetrexed disodium are disclosed in, for example, US5248775, US6066732, CN1038415, CN1778798 and the like.

The preparation method of pemetrexed disodium mainly adopts the following route:

4- (2-formyl ethyl) ethyl benzoate (21) and paraformaldehyde react under the action of N-ethylbenzothiazole bromide and triethylamine to obtain 4-hydroxy-3-oxo butyl derivatives (22), the condensation reaction of the 4-hydroxy-3-oxo butyl derivatives (22) and ethyl cyanoacetate generates an intermediate (23), the intermediate and guanidine generate cyclization to generate 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] ethyl benzoate (24), the saponification reaction generates free acid (25) under the action of sodium hydroxide, the intermediate is condensed with L-diethyl glutamate to obtain an intermediate (26), and the intermediate is hydrolyzed to obtain N- (4- [2- (2-amino-4), 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid, and finally reacting with sodium hydroxide to obtain pemetrexed disodium hydrate (1).

The specific route is shown in the following chart:

however, in this method, there are some drawbacks. For example, in CN1406238, for example, it is disclosed that in the process of preparing pemetrexed disodium from pemetrexed, an acetone solvent is employed, and in the subsequent purification process, an acetone solvent is also used. However, this results in acetone solvent residue. For example, WO0114379 proposes crystallization by heating to 60 to 70 ℃ using a 3A ethanol/water mixed solvent, CN10778802, CN1778797 and the like disclose crystallization by heating to 45 to 50 ℃ using an ethanol/water mixed solvent, and WO0114379 also discloses crystallization by heating to 60 to 65 ℃ using an isopropanol/water mixed solvent.

However, these purification methods all involve a process of thermal crystallization from a mixed solvent. Because pemetrexed disodium are easily oxidized, oxidation of pemetrexed disodium is easily accelerated under heating, and product quality is reduced.

CN101417998 also discloses a method for the salting out purification of pemetrexed disodium by adding a water soluble salt solid to an aqueous solution of pemetrexed disodium without heating. However, this method still has a problem that only a part of water-soluble impurities having a relatively high polarity can be removed because of crystallization in an aqueous system, and it is difficult to remove organic impurities having a polarity less than that of pemetrexed disodium. Therefore, the pemetrexed disodium raw material purified by the method still has partial impurity content exceeding the impurity limit of the drug registration requirement. Due to the possible introduction of salt impurities, not only the actual yield of the product is reduced, but also the stability of the product may be affected.

CN102206218 discloses a purification method of pemetrexed disodium, which removes impurities by combining a crystallization operation of salting out a mixed solvent of organic solvent/water at normal temperature. However, this method has many steps, resulting in an increase in product cost.

In CN102911176A filed by the applicant itself, although the yield reaches 80% or more, in this method, the use of an aqueous sodium hydroxide solution as a catalyst is disadvantageous for industrial mass production because of the problem of environmental pollution caused by waste water discharge, and the yield is rapidly reduced after the reaction scale is enlarged to an industrial level, which cannot meet the demand of industrial production. In addition, the use of ethanol and dimethyl sulfoxide in the purification process is not recommended in industrial production because of its toxicity.

Therefore, it is desirable to provide a method for preparing pemetrexed disodium, which can be produced on an industrial scale.

Disclosure of Invention

In view of the above-mentioned problems, the present application aims to provide an industrial preparation method of pemetrexed disodium, which can obtain a final product in high yield without using sodium hydroxide and can improve purity, thereby avoiding the use of organic solvents in subsequent refining procedures.

In the technical scheme of the application, on the basis of the technical scheme disclosed in CN102911176A, by selecting a specific catalyst to replace sodium hydroxide, the environmental pollution caused by strong alkaline waste water can be effectively avoided, the reaction yield is improved, and the generation of impurities is reduced.

Molecular sieve catalysts are currently widely used in the industrial field due to their excellent catalyst properties. However, since there are many acid sites, the alkali modification is difficult, the activity is low, and the stability is insufficient, there are few studies on the alkali modification in the early stage.

However, the alkali-modified molecular sieve catalyst has a proper amount of mesoporous channels, can be used for catalyzing macromolecular reactions, improving the service life of the catalyst and improving the stability of the catalyst, and therefore, the attention to the alkali-modified molecular sieve catalyst is increasing in the last decade.

At present, there are many methods for preparing alkali-modified mesoporous molecular sieves, such as a framework removal method and a single template method. Among them, the soft template method is superior to the simple preparation process, and thus receives much attention. For example, the synthesis, characterization and catalytic performance research of novel acid-base bifunctional mesoporous materials of chenying et al, and the base modification and catalytic performance of the surface of the mesoporous organosilicon molecular sieve of Yuanxindong et al are all mentioned.

The applicant has surprisingly found, after a large number of experiments, that by using an alkali-modified mesoporous molecular sieve, the mass production of pemetrexed disodium can be effectively realized, and even under the condition of scale-up production, the yield can still be kept good, and meanwhile, the by-products are less, so that the effective control of the product quality can be realized.

The technical scheme of the application is as follows: the method comprises the following steps:

hydrolyzing methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoate (S1) in the presence of an alkali modified mesoporous molecular sieve to generate acid (S2), condensing with L-diethyl glutamate to obtain an intermediate (S3), finally degrading in the presence of the alkali modified mesoporous molecular sieve, performing saponification to obtain a crude pemetrexed disodium disesquihydrate (S4), and purifying at normal temperature to obtain a final product.

In the technical scheme of the application, the mesoporous molecular sieve mentioned in Yuanxingdong et al 'alkali modification of mesoporous organosilicone molecular sieve surface and catalytic performance thereof' is adopted, the applicant researches the relationship between the components, preparation conditions and the like of the catalyst and the yield and absence of pemetrexed disodium, improves the composition and the like of the catalyst, and thus determines the optimal catalyst suitable for preparing pemetrexed disodium.

Specifically, the synthesis method of the alkali-modified mesoporous molecular sieve catalyst used in the application uses 1, 2-bis-trialkoxysilyl ethane as a silicon source, amine substances as a modified organic base raw material, and quaternary ammonium substances as a template agent.

The specific preparation method comprises the following steps: putting a template agent into water, heating to 40-60 ℃, adding alkali after the template agent is dissolved, adding a silicon source and a modified organic alkali raw material, cooling to room temperature, stirring to obtain an aged gel liquid, crystallizing and drying at 80-120 ℃, and performing post-treatment to obtain the alkali modified mesoporous molecular sieve catalyst.

The amine substance is trialkoxysilylamine or dialkoxyl disilazane, and preferably trialkoxysilylethylamine, trialkoxysilylpropylamine, dialkoxyl disilazane or dialkoxyl disilazane. The alkoxy is preferably ethoxy or propoxy.

The quaternary ammonium substances are high-carbon alkyl trialkyl ammonium chlorides, preferably octadecyl trimethyl ammonium chloride, octadecyl triethyl ammonium chloride, hexadecyl trimethyl ammonium chloride and hexadecyl triethyl ammonium chloride.

The alkali is sodium hydroxide or potassium hydroxide.

The molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.5-1: 0.1-1: 2-4, wherein the mass ratio of the template agent to water is 1: 200-300.

The applicant found that when the specific molecular sieve is used as a catalyst for pemetrexed disodium reaction, the catalytic performance is excellent, side reactions are few, and the reaction yield is not significantly reduced even if the reaction is scaled up to an industrial scale.

Specifically, the method of the invention comprises the following steps:

(1) synthesis of 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (S-2)

Firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidine-5-yl) ethyl ] methyl benzoate (S1), stirring for reaction, and detecting the basic disappearance of the raw material points by TLC to be the reaction end point. Ethanol was added, the pH of the reaction solution was adjusted to 4 with hydrochloric acid, and a yellow solid was precipitated, washed with ethanol, and dried in vacuo to obtain the target product (S-2).

(2) Synthesis of N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid diethyl ester p-toluenesulfonate (S-3)

Stirring S-2 and DMF under the protection of nitrogen, adding N-methylmorpholine, keeping the temperature at 10 ℃, adding 6-chloro-2, 4-dimethoxy-1, 3, 5-triazine, stirring uniformly, adding L-glutamic acid diethyl ester hydrochloride, heating the mixture to room temperature, continuing stirring for reaction, detecting the end point of a raw material point by TLC (thin layer chromatography), adding deionized water and dichloromethane, stirring, taking out an organic layer, extracting a water layer for 1 time by using dichloromethane, combining the organic layers, washing by using the deionized water, concentrating the organic layer to evaporate the dichloromethane, adding ethanol, slowly adding a solution consisting of p-toluenesulfonic acid and ethanol under heating, reacting at 40-60 ℃, cooling a reaction solution, filtering, and heating and drying the obtained solid to obtain a target product (S-3).

(3) Synthesis of N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid (S-4):

firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding an S-3 solution, heating to 65 ℃, and reacting under stirring. After the reaction is finished, cooling to room temperature, filtering, and washing the solid with deionized water to obtain the target product (S-4).

(4) Synthetic pemetrexed disodium

Firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding an S-4 solution, heating to 50 ℃, reacting under stirring, cooling to room temperature after the reaction is finished, adding an ethanol/water mixed solvent for recrystallization, filtering, washing with cold ethanol, and drying in vacuum to obtain the crystal of the disodium pemetrexed hemihydrate.

Wherein the ratio of ethanol to water is 1-5: 1-5.

Wherein the vacuum drying is carried out under heating at a temperature of 30-50 deg.C, preferably 40 deg.C, for a period of 3-10 hours.

The invention has the beneficial effects that:

by the technical scheme, NaOH solution is not used, the discharge of alkaline wastewater can be avoided in industrial production, the problem of yield reduction after production amplification can be solved, fewer byproducts are produced, and the purity of the final product is high, so that the method meets the national requirements on the purity of related chemical medicaments.

Detailed Description

The present invention will be further described with reference to the following examples. In the following examples, various procedures and methods not described in detail are conventional methods well known in the art. It should be understood that: the examples of the present invention are given for the purpose of illustration and not for the purpose of limitation, and therefore, the present invention is susceptible to modification in the form of a method of the present invention.

In the following description, unless otherwise specified, "%" and "part" are both expressed by weight.

Catalyst preparation example 1: preparation of catalyst A (see Yuanxingdong et al alkali modification and catalytic Properties of mesoporous organosilicate molecular sieves)

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: placing a template agent of octadecyl trimethyl ammonium chloride into water, heating to 40 ℃, stirring for 30 minutes until the solution is dissolved, adding NaOH, stirring until the solution is transparent, cooling to room temperature, adding a silicon source of 1, 2-bis (trialkoxysilyl) ethane and a modified organic base raw material of triethoxysilylpropylamine, stirring for 10 hours at room temperature to obtain an aged gel liquid, transferring the gel liquid into a stainless steel thermal synthesis reaction kettle, sealing, crystallizing for 48 hours at 100 ℃, centrifuging, washing and drying a solid with water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.7: 0.25: 3, the mass ratio of the template agent to the water is 1: 200.

catalyst preparation example 2: preparation of catalyst B

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: placing a template agent of octadecyl trimethyl ammonium chloride into water, heating to 40 ℃, stirring for 30 minutes until the solution is dissolved, adding NaOH, stirring until the solution is transparent, cooling to room temperature, adding silicon source 1, 2-bis (trialkoxysilyl) ethane and modified organic base raw material of triethoxy silyl ethylamine, stirring for 12 hours at room temperature to obtain aged gel liquid, transferring the gel liquid into a stainless steel thermal synthesis reaction kettle for sealing, crystallizing for 72 hours at 100 ℃, centrifuging, washing and drying a solid by water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.6: 0.3: 3, the mass ratio of the template agent to the water is 1: 200.

catalyst preparation example 3: preparation of catalyst C

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: placing a template agent of octadecyl trimethyl ammonium chloride into water, heating to 40 ℃, stirring for 30 minutes until the solution is dissolved, adding NaOH, stirring until the solution is transparent, cooling to room temperature, adding a silicon source of 1, 2-bis (trialkoxysilyl) ethane and a modified organic base raw material of diethoxydiallypropylamine, stirring for 16 hours at room temperature to obtain an aged gel liquid, transferring the gel liquid into a stainless steel thermal synthesis reaction kettle, sealing, crystallizing for 48 hours at 100 ℃, centrifuging, washing and drying a solid by water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.8: 0.4: 3, the mass ratio of the template agent to the water is 1: 250.

catalyst preparation example 4: preparation of catalyst D

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: placing a template agent, namely hexadecyltrimethylammonium chloride into water, stirring for 30 minutes at room temperature until the hexadecyltrimethylammonium chloride is dissolved, adding NaOH, stirring until the solution is transparent, cooling to the room temperature, then adding a silicon source, namely 1, 2-bis (trialkoxysilyl ethane), and a modified organic base raw material, namely triethoxysilylpropylamine, stirring for 12 hours at the room temperature to obtain an aged gel liquid, transferring the gel liquid into a stainless steel hydrothermal synthesis reaction kettle for sealing, crystallizing for 60 hours at 90 ℃, centrifuging, washing and drying a solid with water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material to the alkali is 1: 0.8: 0.5: 3, the mass ratio of the template agent to the water is 1: 300.

catalyst preparation example 5: preparation of catalyst E

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: placing a template agent of hexadecyl trimethyl ammonium chloride into water, stirring for 30 minutes at room temperature until the solution is dissolved, adding NaOH, stirring until the solution is transparent, cooling to the room temperature, then adding silicon source 1, 2-bis (trialkoxy silicon-based ethane and modified organic base raw material of diethoxy disilyl ethylamine, stirring for 12 hours at the room temperature to obtain aged gel liquid, transferring the gel liquid into a stainless steel hydrothermal synthesis reaction kettle for sealing, crystallizing for 60 hours at 90 ℃, centrifuging, washing and drying a solid by water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.5: 0.7: 3, the mass ratio of the template agent to the water is 1: 300.

catalyst preparation example 5: preparation of catalyst F

A synthetic method of an alkali modified molecular sieve catalyst comprises the following steps: putting a template agent of hexadecyltrimethylammonium chloride into water, stirring for 30 minutes at room temperature until the hexadecyltrimethylammonium chloride is dissolved, adding NaOH, stirring until the solution is transparent, cooling to the room temperature, then adding silicon source 1, 2-bis (trialkoxy) silyl ethane and modified organic base raw material of triethoxy silyl ethylamine, stirring for 12 hours at the room temperature to obtain aged gel liquid, transferring the aged gel liquid into a stainless steel hydrothermal synthesis reaction kettle, sealing, crystallizing for 60 hours at 90 ℃, centrifuging, washing and drying a solid by using water, and calcining for 6 hours at 550 ℃ to obtain an alkali modified molecular sieve catalyst;

the molar ratio of the silicon source, the template agent, the modified organic alkali raw material and the alkali is 1: 0.6: 0.8: 3, the mass ratio of the template agent to the water is 1: 200.

comparative example 1 (see CN102911176A example 1):

(I) synthesis of 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (S-2)

The reaction formula is as follows:

feeding:

methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoate (S-1) 58.4g

2mol/L sodium hydroxide 200ml

Ethanol 200ml

58.4g S-1 and 200ml2mol/l sodium hydroxide were added to a three-necked flask, and when the reaction was stirred at 45 ℃ for 3 hours, the starting point substantially disappeared as the end point of the reaction by TLC (developing solvent: ethyl acetate: cyclohexane: 4: 1). 200ml of ethanol was added thereto, the reaction solution was adjusted to pH 4 with 5mol/L hydrochloric acid under cooling with water, and a yellow solid was precipitated, filtered, washed with 50% ethanol, and vacuum-dried at 50 ℃ for 5 hours to obtain 40.6g of 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (S-2) as a pale yellow solid, with a yield of 76.0%.

(II) Synthesis of N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid diethyl ester p-toluenesulfonate (S-3)

The reaction formula is as follows:

feeding:

adding 40g S-2 and 200ml DMF into a four-mouth bottle, stirring for 30 minutes under the protection of nitrogen, adding 31.2g of N-methylmorpholine, cooling to less than 5 ℃ in an ice bath, adding 24g of 6-chloro-2, 4-dimethoxy-1, 3, 5-triazine, stirring for 1 hour, adding 33.6g of L-diethyl glutamate hydrochloride, heating the mixture to room temperature, continuing stirring for 3 hours, detecting that the raw material point basically disappears as the reaction end point by TLC (developing agent: ethyl acetate: cyclohexane 4: 1), adding 300ml of deionized water and 300ml of dichloromethane, stirring for 15 minutes, separating an organic layer, extracting 1 time by using 200ml of dichloromethane for a water layer, combining the organic layer, washing twice by using 400ml of deionized water, concentrating and distilling the dichloromethane by adding 500ml of ethanol, diluting until no solvent is distilled out, adding 500ml of ethanol, heating to 75 ℃, dropwise adding a solution consisting of 56g of p-toluenesulfonic acid and 200ml of ethanol, refluxing for 2 hours after dropwise adding, cooling the reaction solution to about 5 ℃, filtering, and drying the solid at 50 ℃ in vacuum to obtain 63g of white-like solid, namely N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid diethyl ester p-toluenesulfonic acid salt (S-3), wherein the yield is 71.0%.

(III) Synthesis of N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid (S-4)

The reaction formula is as follows:

feeding proportion:

S-3 52.4g

2mol/L sodium hydroxide 200ml

52.4g S-3 and 200ml of 2mol/L sodium hydroxide solution are added into a three-neck flask, the mixture is stirred for 1 hour, the pH value is adjusted to 3 by 0.5mol/L hydrochloric acid solution, and the obtained suspension is heated to 65 ℃ and the temperature is controlled for reaction for 2.5 hours. Cooling to room temperature, filtering, washing the solid with deionized water to obtain N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidine-5-yl) ethyl ] benzoyl) -L-glutamic acid (S-4).

(IV) Synthesis of Pemetrexed disodium

The reaction formula is as follows:

feeding:

s-4 all of the previous step

0.5mol/L sodium hydroxide 200ml

Acetone 300ml

Adding the S-4 obtained in the previous step and 200ml of 0.5mol/L sodium hydroxide into a three-neck flask, stirring for 1 hour, filtering to remove insoluble substances to obtain a transparent solution, adjusting the pH to 8 by using 0.5mol/L hydrochloric acid, heating the obtained solution to 50 ℃, stirring for 30 minutes, cooling to room temperature, adding 300ml of a mixed solvent of ethanol and dimethyl sulfoxide (the volume ratio is 10: 1.8), stirring for 10 minutes, stirring for 2 hours at 0 ℃, filtering, washing a solid by using 60ml of a mixed solvent of ethanol and dimethyl sulfoxide (the volume ratio is 10: 1.8), and drying in vacuum at 50 ℃ for 5 hours to obtain 27.2g of crude pemetrexed disodium, wherein the yield of the third step and the fourth step is 65.9% (based on S-3).

(V) refining pemetrexed disodium:

27.2g of crude pemetrexed disodium is taken and added into 200ml of water for dissolving, filtration is carried out, 280ml of mixed solvent of ethanol and dimethyl sulfoxide (volume ratio is 10: 2.0) is added into filtrate, stirring is carried out for 15 minutes, the mixture is placed at minus 6 ℃ for 2 hours, filtration is carried out, cold ethanol washing is carried out, vacuum drying is carried out at 50 ℃ for 5 hours, 21.6g of crystal of the disesquihydrate of pemetrexed disodium is obtained, the yield is 79.4%, and the HPLC purity of the product is 99.3%.

Comparative example 2 (amplified experiment of comparative example 1)

Feeding:

6.2kg of methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoate (S-1)

2mol/L sodium hydroxide 30L

30l of ethanol

6.2kgS-1 and 30l of 2mol/l sodium hydroxide were added to a reaction vessel, and the mixture was stirred at 40 ℃ for reaction for 3 hours, 30l of ethanol was added after the reaction was completed, the reaction solution was taken out, the pH of the reaction solution was adjusted to 4 with dilute hydrochloric acid, a yellow solid was precipitated, and the yellow solid was filtered, washed with 50% ethanol, and vacuum-dried at 50 ℃ for 5 hours to obtain 3.81kg of 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoic acid (S-2) as a pale yellow solid with a yield of 64.0%.

Synthesis of N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid diethyl ester p-toluenesulfonate (S-3)

Adding the S-2 and 6000ml of DMF into a reaction kettle, adding 200g of N-methylmorpholine, stirring uniformly under the protection of nitrogen, adding 150g of 6-chloro-2, 4-dimethoxy-1, 3, 5-triazine, stirring uniformly, slowly adding 3kg of L-diethyl glutamate hydrochloride, heating the mixture to room temperature, continuing stirring for 3 hours, adding a solution consisting of 1.4kg of p-toluenesulfonic acid and 2L of ethanol after the reaction is finished, heating to 70 ℃ for reaction, reducing the temperature to room temperature after the reaction is finished, taking out the reaction solution, filtering, and drying the solid in vacuum at 50 ℃ to obtain 5.5kg of white-like solid, namely N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2 ], 3-d ] pyrimidin-5-yl) ethyl ] benzoyl) -L-glutamic acid diethyl ester p-toluenesulfonate (S-3) in 68.5% yield.

The above S-3 and 20L of a 2mol/L sodium hydroxide solution were added to the reaction vessel, stirred for 1 hour, adjusted to pH 3 with 0.5mol/L hydrochloric acid solution, and reacted at 65 ℃ for 3 hours. Cooling to room temperature, taking out the reaction liquid, filtering, and washing the solid with deionized water to obtain N- (4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidine-5-yl) ethyl ] benzoyl) -L-glutamic acid (S-4).

(IV) Synthesis of Pemetrexed disodium

Adding the S-4 and 20L of 0.5mol/L sodium hydroxide into a reaction kettle, stirring for 1 hour, taking out reaction liquid, filtering to remove insoluble substances to obtain transparent solution, adjusting the pH to 8 by using 0.5mol/L hydrochloric acid, heating the obtained solution to 50 ℃, stirring for 30 minutes, adding 10L of mixed solvent of ethanol and dimethyl sulfoxide (the volume ratio is 10: 1.8), stirring for 2 hours, filtering, washing a solid by using the mixed solvent of the ethanol and the dimethyl sulfoxide (the volume ratio is 10: 1.8), and drying in vacuum for 5 hours at 50 ℃ to obtain 2.4kg of crude pemetrexed disodium, wherein the yield of the third step and the fourth step is 58.1 percent (based on S-3).

(V) refining pemetrexed disodium:

and (2) adding the crude pemetrexed disodium product into 10l of water for dissolving, filtering, adding 5l of mixed solvent (the volume ratio is 10: 2.0) of ethanol and dimethyl sulfoxide into the filtrate, stirring for 15 minutes, standing for 2 hours, filtering, washing with cold ethanol, and vacuum-drying at 50 ℃ for 5 hours to obtain crystals of the dimeric hemihydrate of the pemetrexed disodium, wherein the HPLC purity of the product is 99.3%.

As can be seen by comparing comparative example 1 and comparative example 2 above, the yield is significantly reduced upon direct scale-up of the protocol of CN 102911176A.

Example 1

The same procedure as in comparative example 2 was followed, except that 150g of catalyst A was fixed in the reaction vessel and the reaction was carried out by adding the reaction materials without using NaOH solution in step 1 and step 3, and recrystallization purification was carried out using a solvent of ethanol and water (volume ratio 1: 1) in steps 4 and 5.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 82.1 percent

Step 2: the yield is 67.6%

And 3, step 4: the yield is 68 percent

And 5: and (3) product purity: 99.1 percent

Example 2

The same procedure as in example 1 was repeated, except that 150g of catalyst B was used in step 1 and step 3, as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 80.6 percent

Step 2: the yield is 69.1 percent

And 3, step 4: the yield is 69.1 percent

And 5: and (3) product purity: 99.3 percent of

Example 3

The same procedure as in example 1 was repeated, except that 150g of catalyst C was used in steps 1 and 3, as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 83.2 percent

Step 2: the yield is 67.9%

And 3, step 4: the yield is 70.2 percent

And 5: and (3) product purity: 99.4 percent

Example 4

The procedure of example 1 was repeated, except that 150g of catalyst D was used in step 1 and step 3, as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 80.9%

Step 2: the yield is 67.6%

And 3, step 4: the yield is 69.3 percent

And 5: and (3) product purity: 99.1 percent

Example 5

The procedure of example 1 was repeated, except that 150g of catalyst E was used in step 1 and step 3, as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 81.1%

Step 2: the yield is 67.6%

And 3, step 4: the yield is 68 percent

And 5: the product purity is as follows: 99.1 percent

From the above examples it can be seen that when using the base modified mesoporous molecular sieve specified in the present application, the yield of steps 1,3 is not reduced after the reaction is scaled up to industrial scale, maintaining a yield comparable to that at laboratory scale. When the mixed solvent of ethanol and water is used for recrystallization, the purity is basically equivalent to that of the mixed solvent of ethanol and dimethyl sulfoxide.

Example 6

The procedure was carried out in the same manner as in example 1 except that 100g of catalyst A was used in step 1 and step 3 as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 79.9 percent

Step 2: the yield is 69.1 percent

And 3, step 4: the yield is 68.7 percent

And 5: the product purity is as follows: 99.4 percent

Example 7

The procedure was carried out in the same manner as in example 1 except that 200g of catalyst A was used in step 1 and step 3 as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 81.1%

Step 2: the yield is 68.1 percent

And 3, step 4: the yield is 69 percent

And 5: and (3) product purity: 99.5 percent

Example 8

The procedure was carried out in the same manner as in example 1 except that 250g of catalyst A was used in step 1 and step 3 as compared with example 1.

The yields and final product purities for the various steps were as follows:

step 1: the yield is 81.8 percent

Step 2: the yield is 67.1 percent

And 3, step 4: the yield is 70.5 percent

And 5: the product purity is as follows: 99.4 percent

It can be seen from the above examples that the amount of molecular sieve used does not have much influence on the reaction yield, and that the yield is slightly increased only when the amount is increased in step 3. And has no obvious influence on the purity of the final product.

According to the data, the technical scheme of the application can effectively ensure the relevant indexes such as product yield, product purity and the like even if the reaction scale is enlarged to industrial production. Is obviously superior to the prior art in all aspects. And the molecular sieve is used for replacing NaOH, so that the environmental problem caused by wastewater discharge in industrial production can be avoided, and the current environmental protection requirement is better met.

Claims

1. A preparation method of pemetrexed disodium is characterized in that,

the method comprises the following steps:

In the presence of an alkali modified mesoporous molecular sieve catalyst, degrading methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoate (S-1) to obtain a target product (S-2);

Mixing S-2, N-methylmorpholine and 6-chloro-2, 4-dimethoxy-1, 3, 5-triazine in a solvent under the protection of nitrogen, adding L-glutamic acid diethyl ester hydrochloride after uniformly stirring, reacting under stirring, adding a solution consisting of p-toluenesulfonic acid and ethanol, and continuously reacting to obtain a target product (S-3);

in the presence of an alkali modified mesoporous molecular sieve catalyst, degrading the (S-3) to obtain a target product (S-4);

(4) synthetic pemetrexed disodium

Reacting (S-4) with NaOH to obtain pemetrexed disodium;

the preparation method of the alkali modified mesoporous molecular sieve catalyst comprises the following steps: putting a template agent into water, heating to 40-60 ℃, adding alkali after the template agent is dissolved, adding a silicon source and a modified organic alkali raw material, cooling to room temperature, stirring to obtain an aged gel liquid, crystallizing and drying at 80-120 ℃, and performing post-treatment to obtain an alkali modified mesoporous molecular sieve catalyst;

the 1, 2-bis-trialkoxysilyl ethane is a silicon source, and the modified organic base raw material is trialkoxysilyl ethylamine, trialkoxysilyl propylamine, dialkoxyl disilanyl ethylamine or dialkoxyl disilanyl propylamine, wherein the alkoxy is ethoxy and propoxy;

quaternary ammonium substances are used as template agents, and the quaternary ammonium substances are octadecyl trimethyl ammonium chloride and hexadecyl trimethyl ammonium chloride.

2. The production method according to claim 1,

the method comprises the following steps:

Firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d ] pyrimidine-5-yl) ethyl ] methyl benzoate (S-1), stirring for reaction, and detecting the basic disappearance of a raw material point by TLC to be a reaction end point; adding ethanol, adjusting the pH value of the reaction solution to be 4 by hydrochloric acid, separating out yellow solid, washing by the ethanol, and drying in vacuum to obtain a target product (S-2);

Stirring S-2 and DMF under the protection of nitrogen, adding N-methylmorpholine, keeping the temperature at 10 ℃, adding 6-chloro-2, 4-dimethoxy-1, 3, 5-triazine, stirring uniformly, adding L-glutamic acid diethyl ester hydrochloride, heating the mixture to room temperature, continuing stirring for reaction, detecting the end point of a raw material by TLC (thin layer chromatography), adding deionized water and dichloromethane, stirring, taking out an organic layer, extracting a water layer for 1 time by using dichloromethane, combining the organic layers, washing by using the deionized water, concentrating and evaporating the dichloromethane of the organic layer, adding ethanol, slowly adding a solution consisting of p-toluenesulfonic acid and ethanol under heating, reacting at 40-60 ℃, cooling a reaction solution, filtering, and heating and drying the obtained solid to obtain a target product (S-3);

firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding an S-3 solution, heating to 65 ℃, and reacting under stirring. After the reaction is finished, cooling to room temperature, filtering, and washing the solid with deionized water to obtain a target product (S-4);

(4) synthetic pemetrexed disodium

Firstly fixing the prepared alkali modified mesoporous molecular sieve catalyst in a reaction kettle, then adding an S-4 solution and NaOH, heating to 50 ℃, reacting under stirring, cooling to room temperature after the reaction is finished, adding an ethanol/water mixed solvent for recrystallization, filtering, washing with cold ethanol, and drying in vacuum to obtain crystals of the disodium pemetrexed dihydrate;

3. the method of claim 2, wherein the molar ratio of the silicon source, the templating agent, the modified organic base starting material, and the base is 1: 0.5-1: 0.1-1: 2-4, wherein the mass ratio of the template agent to water is 1: 200-300.

4. The method according to claim 2, wherein the ratio of ethanol to water in the reaction is 1 to 5: 1-5.

5. The method according to claim 2, wherein the vacuum drying is carried out under heating at a temperature of 30 to 50 ℃ for 3 to 10 hours.

6. The method of claim 5, wherein the temperature is 40 ℃.