Method for efficiently synthesizing methotrexate

Abstract

The application discloses a method for efficiently synthesizing methotrexate, and relates to the technical field of methotrexate preparation. The method comprises the following steps: preparing three intermediates, and then preparing methotrexate by using the three intermediates. In the process of preparing the intermediates, a step of improving the purity of tribromoacetone is added, so that the content of the tribromoacetone is increased from 89-90% to more than 98%, thereby reducing the separation difficulty of the product, reducing the generation of impurities, and improving the yield; in the step of preparing the methotrexate, a new catalyst is used, sodium acetate trihydrate and potassium dihydrogen phosphate are used as a composite catalyst, and the yield of the methotrexate is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of methotrexate synthesis, and particularly relates to a method for efficiently synthesizing methotrexate. BACKGROUND

[0002] Methotrexate is an antitumor drug with quite wide application in the field of cancer chemotherapy, especially in the past 20 years, the clinical use of high-dose methotrexate therapy, and the approval of the United States FDA for treating rheumatoid arthritis in 1988, which increases the demand for the drug. In recent years, there are many patent reports on the improvement of the synthesis process at home and abroad, but the purpose is mostly to shorten the reaction steps, simplify the process conditions, reduce the by-products, improve the purity and total yield, so as to reduce the cost and improve the curative effect. And the existing synthesis process has low conversion rate, which needs to separate impurities, resulting in low yield. SUMMARY

[0003] In order to solve the above problems, that is, to solve the problems raised in the above background, the present application provides a method for efficiently synthesizing methotrexate, and the specific technical scheme is as follows:

[0004] A method for efficiently synthesizing methotrexate, the method comprising the following steps:

[0005] (1) Preparation of intermediate ①: L-glutamic acid and ethanol are added to a reaction kettle, stirred uniformly, and p-chlorobenzoyl chloride solution is added dropwise at room temperature. After the reaction time is greater than 6h, the reaction liquid is concentrated, and the discharge is centrifuged to obtain p-chlorobenzoyl-L-glutamic acid. The product is put into a high-pressure kettle, ethanol and monomethylamine are added, and the high pressure is 100-120℃ for 8-12h. The pressure is released and discharged, the reaction liquid is pressed into a normal-pressure reaction kettle, zinc chloride is added, and the stirring reaction time is greater than 4h at room temperature. After the discharge is centrifuged, the crude product of p-methylaminobenzoyl-L-glutamic acid zinc is obtained. The crude product is added to n-hexane, heated and pulped at 40-50℃ for more than 1h, and the discharge is obtained. The intermediate ①, that is, p-methylaminobenzoyl-L-glutamic acid zinc, is prepared for use;

[0006] (2) Preparation of intermediate ②: acetone, dichloromethane, reduced iron powder and water are added to a reaction kettle, bromine is slowly added dropwise at room temperature until the color of the reaction liquid changes to brown red. After the dropwise addition is completed, the reaction time is greater than 6h at room temperature, the sample target product is greater than 60%, 10% sodium sulfite aqueous solution is added for quenching, the organic phase is separated, and the crude product is obtained by desolventizing. The crude product is added with 2 times of 20% hydrobromic acid aqueous solution, stirred for more than 0.5h, and then frozen and crystallized for more than 4h. The centrifugation obtains the intermediate ②, that is, tribromoacetone, which is prepared for use;

[0007] (3) Preparation of intermediate ③: a reaction kettle is charged with guanidine nitrate, methanol, sodium methoxide, and refluxed for more than 0.5 h, and then propiolaldehyde methanol solution is added dropwise, and refluxed for more than 5 h, and then cooled, and crystallized, and discharged and centrifuged to obtain material 3-1, which is transferred to another reaction kettle; after the transfer of material 3-1 is completed, water is added, and heated to 40℃, and acetic acid is added dropwise, and reacted for more than 1 h, and then sodium nitrite aqueous solution is added dropwise, and the reaction system turns to purple red, and reacted for more than 3 h, and then discharged and centrifuged, and the product is slurried with hot water, and centrifuged again, and dried at 80℃ to obtain material 3-2; the reaction is carried out by adding material 3-2 and methanol into the reaction kettle, controlling the temperature to be 5-10℃, slowly adding sodium borohydride through a solid feeder, and adding for more than 2 h, and then heated to 60℃ and reacted for more than 2 h, and the reaction is monitored by LC, and then cooled to 5-10℃, and slowly added with concentrated hydrochloric acid, and then heated to 60℃ and reacted for more than 4 h, and then added with activated carbon for decolorization for more than 0.5 h, and then centrifuged, and the mother liquor is acidified with concentrated hydrochloric acid, and cooled and crystallized for more than 4 h, and then discharged and centrifuged, and the product is slurried with 2 times of toluene, and centrifuged again to obtain pure tetraminopyrimidine, and dried at 60℃ to obtain intermediate ③, i.e., tetraminopyrimidine, which is ready for use;

[0008] (4) Preparation of methotrexate: a reaction kettle is charged with intermediate ①, intermediate ③ and water, and then added with concentrated hydrochloric acid to make the pH less than 3, and then added with tetrahydrofuran solution of intermediate ② at 30℃, and then refluxed at 70℃ for more than 3 h, and then added with sodium acetate trihydrate and potassium dihydrogen phosphate as catalyst after the reaction is completed as monitored by LC, and then cooled to room temperature, and then discharged and centrifuged to obtain methotrexate crude product, which is added with water, and then adjusted to alkaline with 30% sodium hydroxide aqueous solution, and then centrifuged to collect the mother liquor, and then added with 3-5 times of acetone to precipitate the solid for more than 12 h, and then centrifuged to obtain pure methotrexate disodium salt, which is dissolved in water, and then acidified with hydrochloric acid and centrifuged to obtain pure methotrexate.

[0009] Further, the intermediate ②, tribromoacetone, is 98% content of tribromoacetone.

[0010] The present application has the following beneficial technical effects: in the process of preparing the intermediate, a step of improving the purity of tribromoacetone is added, so that the content of tribromoacetone is increased from 89-90% to more than 98%, thereby reducing the difficulty of product separation, reducing the generation of impurities, and improving the yield; in the step of preparing methotrexate, a new catalyst is used, i.e., sodium acetate trihydrate and potassium dihydrogen phosphate are used as a composite catalyst, thereby improving the yield of methotrexate. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 The flow chart for preparing methotrexate. DETAILED DESCRIPTION

[0012] The preferred embodiments of the present application will be described below with reference to the accompanying drawings. Those skilled in the art will appreciate that the embodiments are only used to explain the technical principles of the present application, and are not intended to limit the scope of protection of the present application.

[0013] A method for efficiently synthesizing methotrexate, the method comprising the following steps:

[0014] (1) Preparation of intermediate ①: L-glutamic acid and ethanol are added to a reaction kettle and stirred uniformly. A p-chlorobenzoyl chloride solution is added dropwise at room temperature. After the reaction time is greater than 6 h, the reaction solution is concentrated, and the discharge is centrifuged to obtain p-chlorobenzoyl-L-glutamic acid. The product is put into an autoclave, ethanol and monomethylamine are added, and the high pressure is 100-120℃ for 8-12 h. The pressure is released and discharged, the reaction solution is pressed into an atmospheric pressure reaction kettle, zinc chloride is added, and the stirring reaction time is greater than 4 h at room temperature. After the discharge is centrifuged, the crude p-methylaminobenzoyl-L-glutamic acid zinc is obtained. The crude product is added to n-hexane, heated and pulped at 40-50℃ for more than 1 h, and the discharge is obtained. Intermediate ①, i.e., p-methylaminobenzoyl-L-glutamic acid zinc, is obtained and used as needed.

[0015] (2) Preparation of intermediate ②: A reaction kettle is added with acetone, dichloromethane, reduced iron powder and water. Bromine is slowly added dropwise at room temperature until the color of the reaction solution changes to brown red. After the dropwise addition is completed, the reaction time is greater than 6 h at room temperature. The target product is greater than 60%. A 10% sodium sulfite aqueous solution is added to quench, the organic phase is separated, and the crude product is obtained by desolventizing. The crude product is added with 2 times 20% hydrobromic acid aqueous solution, stirred for more than 0.5 h, and then frozen and crystallized for more than 4 h. The centrifugation obtains intermediate ②, i.e., 98% content of tribromoacetone, which is used as needed.

[0016] (3) Preparation of intermediate ③: a reaction kettle is charged with guanidine nitrate, methanol, sodium methoxide, and refluxed for more than 0.5 h, and then propiolaldehyde methanol solution is added dropwise, and refluxed for more than 5 h, and then cooled, crystallized, discharged, centrifuged, and then intermediate 3-1 is obtained, and then the intermediate 3-1 is transferred to another reaction kettle; after the transfer of the intermediate 3-1 is completed, water is added, and then heated to 40℃, and then acetic acid is added dropwise, and then reacted for more than 1 h, and then sodium nitrite aqueous solution is added dropwise, and then the reaction system turns to purple red, and then reacted for more than 3 h, and then discharged, centrifuged, and then the product is slurried with hot water, and then centrifuged again, and then the product is dried at 80℃ to obtain intermediate 3-2; then the intermediate 3-2 and methanol are added to the reaction, and then the temperature is controlled at 5-10℃, and then sodium borohydride is slowly added through a solid feeder, and then the feeding time is more than 2 h, and then the temperature is increased to 60℃, and then reacted for more than 2 h, and then the reaction is monitored by LC, and then the temperature is decreased to 5-10℃ after the reaction is completed, and then concentrated hydrochloric acid is slowly added dropwise, and then the temperature is increased to 60℃ after the dropwise addition is completed, and then reacted for more than 4 h, and then activated carbon is added for decolorization for more than 0.5 h, and then centrifuged, and then concentrated hydrochloric acid is added to the mother liquor for acidification, and then cooled and crystallized for more than 4 h, and then discharged, centrifuged, and then the product is slurried with 2 times of toluene, and then centrifuged again to obtain pure tetraminopyrimidine, and then dried at 60℃ to obtain intermediate ③, i.e., tetraminopyrimidine, which is ready for use;

[0017] (4) Preparation of methotrexate: a reaction kettle is charged with intermediate ①, intermediate ③, and water, and then concentrated hydrochloric acid is added dropwise to make the pH less than 3, and then intermediate ② tetrahydrofuran solution is added dropwise at 30℃, and then refluxed at 70℃ for more than 3 h, and then sodium acetate trihydrate and potassium dihydrogen phosphate are added as catalysts after the reaction is completed by LC monitoring, and then reacted for more than 24 h, and then cooled to room temperature, and then discharged, centrifuged to obtain methotrexate crude product, and then the crude product is added with water, and then the pH is adjusted to alkaline with 30% sodium hydroxide aqueous solution, and then the mother liquor is collected by centrifugation, and then 3-5 times of acetone is added to precipitate the solid for more than 12 h, and then centrifuged to obtain pure methotrexate disodium salt, and then the pure product is dissolved in water, and then acidified with hydrochloric acid, and then centrifuged to obtain pure methotrexate.

[0018] In the traditional method, raw material tribromoacetone is directly used, and only 90% of the content of tribromoacetone is used, and 4% of the content of tetrabromoacetone will participate in the reaction to generate impurities, consume other raw materials, and cause product loss when the impurities are separated, resulting in reduced product yield. In this paper, the raw material tribromoacetone is purified to 98% of the content of tribromoacetone before reaction, and the content of tetrabromoacetone is less than 0.2%, which reduces the generation of impurities. At the same time, sodium acetate trihydrate and potassium dihydrogen phosphate are selected as a composite catalyst, which improves the product yield. After testing, the yield of methotrexate prepared according to the method described in this patent is increased by 25% compared with the existing ordinary method.

[0019] Although the present application has been described with reference to preferred embodiments, various modifications can be made to the application without departing from the scope of the application, and equivalent elements can be substituted for those components recited in the preferred embodiments, and various combinations of elements from the various embodiments can be made, without departing from the scope of the application, especially, the technical features mentioned in each embodiment can be combined in any manner, provided that there is no structural conflict. The present application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

[0020] In the description of the present application, the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", and the like indicating the direction or positional relationship are based on the direction or positional relationship shown in the drawings, which is merely for the convenience of description, and does not indicate or imply that the device or element must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second", "third" are only for the purpose of description, and cannot be understood as indicating or implying relative importance.

[0021] In addition, it should be noted that, in the description of the present application, unless otherwise explicitly specified and limited, the terms "mounting", "connecting", "connecting" should be understood broadly, for example, it can be fixedly connected, or it can be detachably connected, or integrally connected; it can be mechanically connected, or it can be electrically connected; it can be directly connected, or it can be indirectly connected through an intermediate medium, or it can be the communication inside two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0022] The term "comprising" or any other similar word is intended to cover non-exclusive inclusion, so that the process, article or equipment / device including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or also includes the elements inherent in the process, article or equipment / device.

[0023] So far, the technical solutions of the present application have been described in combination with the preferred embodiments shown in the drawings, but those skilled in the art can easily understand that the protection scope of the present application is obviously not limited to these specific embodiments. Those skilled in the art can make equivalent changes or replacements to the related technical features without departing from the principles of the present application, and the technical solutions after the changes or replacements will fall within the protection scope of the present application.

Claims

1. A method for efficient synthesis of methotrexate, characterized by: The method comprises the following steps: (1) Preparation of intermediate ①: L-glutamic acid and ethanol are added into a reaction kettle, stirred uniformly, and p-chlorobenzoyl chloride solution is added dropwise at room temperature. After the reaction time is greater than 6 hours, the reaction solution is concentrated, and the discharge is centrifuged to obtain p-chlorobenzoyl-L-glutamic acid. The product is put into an autoclave, ethanol and monomethylamine are added, the high pressure is 100-120 DEG C, the reaction time is 8-12 hours, the pressure is released, the discharge is put into a normal-pressure reaction kettle, zinc chloride is added, the stirring reaction time is greater than 4 hours at room temperature, the discharge is centrifuged, and the crude p-methylaminobenzoyl-L-glutamic acid zinc is obtained. The crude product is added into n-hexane, heated and pulped at 40-50 DEG C for more than 1 hour, and the discharge is obtained. Intermediate ①, namely p-methylaminobenzoyl-L-glutamic acid zinc, is prepared and reserved; (2) Preparation of intermediate ②: acetone, dichloromethane, reduced iron powder and water are added into a reaction kettle, bromine is slowly added dropwise at room temperature until the color of the reaction solution changes to brown red, the reaction time is greater than 6 hours at room temperature after the dropwise addition is completed, the target product is greater than 60%, 10% sodium sulfite aqueous solution is added for quenching, the organic phase is separated, and the crude product is obtained by desolventizing. The crude product is added into 2 times of 20% hydrobromic acid aqueous solution, stirred for more than 0.5 hours, frozen and crystallized for more than 4 hours, centrifuged, and intermediate ②, namely tribromoacetone, is prepared and reserved; (3) Preparation of intermediate ③: guanidine nitrate, methanol and sodium methoxide are added into a reaction kettle, the reflux reaction time is greater than 0.5 hours, propionitrile methanol solution is added dropwise, the reflux reaction is continued for 4-7 hours, the temperature is lowered, crystallization is performed, the discharge is centrifuged, and material 3-1 is obtained. Material 3-1 is transferred to another reaction kettle; after the transfer of material 3-1 is completed, water is added, the temperature is increased to 40 DEG C, acetic acid is added dropwise, the reaction time is greater than 1 hour, sodium nitrite aqueous solution is added dropwise, the reaction system turns to purple red, the heat preservation reaction time is greater than 3 hours, the discharge is centrifuged, the product is pulped with hot water, centrifuged again, the product is dried at 80 DEG C, material 3-2 is obtained. The reaction is controlled by LC. After the reaction is completed, the temperature is lowered to 5-10 DEG C, concentrated hydrochloric acid is slowly added dropwise, the temperature is increased to 60 DEG C after the dropwise addition is completed, the reaction time is greater than 4 hours, activated carbon is added for decolorization for more than 0.5 hours, centrifuged, concentrated hydrochloric acid is added into the mother liquor for acidification, the temperature is lowered for crystallization for more than 4 hours, the discharge is centrifuged, the product is added into 2 times of toluene for pulping, centrifuged again to obtain pure tetraminopyrimidine, and intermediate ③, namely tetraminopyrimidine, is prepared and reserved. (4) Preparation of methotrexate: the reactor is charged with intermediate ①, intermediate ③ and water, and concentrated hydrochloric acid is added dropwise to make the pH less than 3; tetrahydrofuran solution of intermediate ② is added dropwise at 30°C, and the reaction is carried out at 70°C for more than 3h; after the reaction is completed as monitored by LC, sodium acetate trihydrate and potassium dihydrogen phosphate are added as catalysts, and the reaction is continued for more than 24h, and then the temperature is lowered to room temperature; the product is discharged and centrifuged to obtain methotrexate crude product; the crude product is added with water, and 30% sodium hydroxide aqueous solution is used to adjust the pH to alkaline; the mother liquor is collected by centrifugation, and 3-5 times of acetone is added to precipitate the solid for more than 12h; methotrexate disodium salt is obtained by centrifugation; the pure product is dissolved in water, acidified with hydrochloric acid, and centrifuged to obtain methotrexate pure product.

2. The process for the synthesis of methotrexate according to claim 1, characterized in that: The intermediate ② is 98% content of tribromoacetone.

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