CN117946110A - Synthetic method of methotrexate - Google Patents
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- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 title claims abstract description 155
- 229960000485 methotrexate Drugs 0.000 title claims abstract description 155
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- ADAHADRJWVCICR-UHFFFAOYSA-N isoquinoline-6-carboxylic acid Chemical compound C1=NC=CC2=CC(C(=O)O)=CC=C21 ADAHADRJWVCICR-UHFFFAOYSA-N 0.000 claims description 34
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- FNYCCOFOQIUTIM-UHFFFAOYSA-N 1,1,3-tribromopropan-2-one Chemical compound BrCC(=O)C(Br)Br FNYCCOFOQIUTIM-UHFFFAOYSA-N 0.000 description 1
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
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- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- MQEFDQWUCTUJCP-UHFFFAOYSA-N pyrimidine-2,4,5,6-tetramine;sulfuric acid Chemical compound OS(O)(=O)=O.NC1=NC(N)=C(N)C(N)=N1 MQEFDQWUCTUJCP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of methotrexate. Firstly, mixing L-para-methylamino benzoyl zinc glutamate, 2,4,5, 6-tetraaminopyrimidine, 1, 3-trichloroacetone, phosphoric acid and distilled water to react to generate a crude product of the methotrexate, then preparing the crude product of the methotrexate into a wet pure product of disodium salt of the methotrexate, dissolving the wet pure product of disodium salt of the methotrexate in water, regulating the pH value of the wet pure product of the disodium salt of the methotrexate by using concentrated hydrochloric acid, stirring, reacting, filtering, decompressing and steaming a filter cake to obtain a fresh yellow solid, namely the pure product of the methotrexate. The method has the advantages of simple operation, high synthesis yield, few by-products, high product purity, and the purity of the detected compound is more than 99.5 percent. Less pollution and short production period, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical compounds, in particular to a synthesis method of methotrexate.
Background
In recent years, the incidence rate of cancers is increasing, the treatment means of the cancers are mainly traditional medicine treatment, and a plurality of medicines for treating the cancers exist at present, but the problems of side effects, safety and the like of most medicines are not thoroughly solved, so that the research of new treatment means of the cancers is very important. Based on the higher and higher mortality rate of tumors, the safe and effective medicine for treating tumor diseases is researched, and the method has very important practical significance.
Methotrexate (methotrexa), chemical name N- [4- [ [ (2, 4-diamino-6-pteridinyl) methyl ] methylamino ] benzoyl ] -L-glutamic acid. Methotrexate belongs to an anti-leaf acid type antitumor drug, can selectively act on the S phase in the cell growth cycle, so that the S phase growth of cells is inhibited, and the main principle is that dihydrofolate reductase is inhibited to block the synthesis of tumor cell DNA, thereby preventing the growth and propagation of tumor cells. In clinical medicine application, the methotrexate has very good curative effect on acute leukemia, chorionic epithelial cancer, malignant grape embryo and other diseases, and can also play a certain role in treating head and neck tumors, breast cancer, lung cancer and the like. In recent years, methotrexate has been used in large-dose therapy clinically, and the demand for such drugs has greatly increased. As the range of methotrexate use increases, several side effects associated with impurities generated by the reaction are successively discovered after understanding the therapeutic effects of methotrexate, resulting in no guarantee of safety.
At present, the common methotrexate synthesis method is a one-pot method, namely, methotrexate is synthesized by dissolving 2,4,5, 6-tetraminopyrimidine sulfate and L-p-methylaminobenzoyl glutamic acid zinc salt in water, adjusting the pH value to be 2.0 by using 12mol/L hydrochloric acid, dripping 1, 3-tribromoacetone which is dissolved in ethanol in advance into the mixed solution, keeping the pH value to be 2by using 2% sodium hydroxide solution, reacting for 3-3.5 hours, and then carrying out 5-6 simple refining treatments. However, the method has low synthesis yield, more impurities and complicated refining treatment, and the product obtained by synthesis has high purity of more than 99.0 percent.
Based on this, the present invention has developed a method for synthesizing high purity methotrexate. The method is greatly improved on the traditional method for synthesizing the methotrexate, so that the reaction synthesis conditions are simplified, the production of byproducts is reduced, and the purity and the yield of the target product methotrexate are improved.
Disclosure of Invention
The invention aims to provide a synthetic method of methotrexate.
The synthesis method of the methotrexate comprises the following steps:
(1) Synthesis of methotrexate crude product
Taking 100-200ml of distilled water, 15-25g of L-p-methylaminobenzoyl glutamic acid zinc salt, 8-11g of 2,4,5, 6-tetraaminopyrimidine, putting into a flask, adding 8-14g of 1, 3-trichloroacetone, stirring and reacting at 20-30 ℃, adding 1-4g of phosphoric acid after the reaction is carried out for 1-4h, and continuing to react for 20-28h to obtain a methotrexate crude product;
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round bottom flask, adding 50-150ml of distilled water to dissolve part, adjusting the pH to 10-11 with 35-45% NaOH solution, continuing stirring for 40-60min until the solution is reddish brown clear, filtering to obtain reddish brown filtrate, slowly adding 1-4 times of absolute ethyl alcohol into the filtrate under stirring, continuing to stand and stir for 3-5h after adding, so that solid can be completely separated out, and filtering to obtain a wet pure methotrexate disodium salt product;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 4-10 times of water, regulating the pH value to 5-6 by using concentrated hydrochloric acid, stirring for 3-5 hours at room temperature, filtering, and rotationally steaming a filter cake at the temperature of 50-60 ℃ for 4-6 hours under reduced pressure to obtain a fresh yellow solid, namely the pure product of the methotrexate.
Preferably, the specific method for synthesizing the methotrexate crude product in the step (1) comprises the following steps: 120-180ml of distilled water, 16-24g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9-11g of 2,4,5, 6-tetraaminopyrimidine are put into a flask, 9-13g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 22-28 ℃, after the reaction is carried out for 1-3h, 1-3g of phosphoric acid is added, and the reaction is continued for 22-26h, thus obtaining the crude product of methotrexate.
Further preferably, the specific method for synthesizing the methotrexate crude product in the step (1) comprises the following steps: 140-160ml of distilled water, 18-22g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9-10g of 2,4,5, 6-tetraaminopyrimidine are taken and put into a flask, 10-12g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 24-26 ℃, after the reaction is carried out for 2-3h, 2-3g of phosphoric acid is added, and the reaction is continued for 23-25h, thus obtaining the crude product of methotrexate.
Still more preferably, the specific method for synthesizing the crude methotrexate product in step (1) of the present invention comprises: 150ml of distilled water and 10g of L-para-methylaminobenzoyl glutamic acid zinc salt, 2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 10g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 25 ℃, after the reaction is carried out for 2.5h, 2.5g of phosphoric acid is added, and the reaction is continued for 24h, thus obtaining the crude product of methotrexate.
Preferably, the specific method of step S1 in the present invention is as follows: placing the methotrexate crude product obtained in the step (1) into a round bottom flask, adding 60-120ml of distilled water to dissolve part, regulating the pH to 10-11 with 35-40% NaOH solution, continuing stirring for 40-50min until the solution is reddish brown clear, carrying out suction filtration to obtain reddish brown filtrate, slowly adding 1-3 times of absolute ethyl alcohol into the filtrate under stirring, continuing to stand and stir for 3-4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain the methotrexate disodium salt wet product pure product.
Further preferably, the specific method of step S1 of the present invention is as follows: placing the methotrexate crude product obtained in the step (1) into a round bottom flask, adding 80ml of distilled water to dissolve part, regulating the pH to 10.5 with 40% NaOH solution, continuously stirring for 50min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt.
Preferably, the specific method of step S2 in the present invention is as follows: dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 6-8 times of water, regulating the pH value to 5-6 by using concentrated hydrochloric acid, stirring for 3-4 hours at room temperature, filtering, and rotationally steaming a filter cake at the temperature of 50-55 ℃ for 4-5 hours under reduced pressure to obtain a fresh yellow solid, namely the pure product of the methotrexate.
Further preferably, the specific method of step S2 of the present invention is as follows: dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 5.5 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure methotrexate.
The methotrexate pure product prepared by the synthesis method is applied to the preparation of antitumor drug preparations.
The methotrexate pure product prepared by the synthesis method is added with pharmaceutically acceptable auxiliary materials to prepare pharmaceutically acceptable preparations, including solid preparations or liquid preparations, wherein the solid preparations are granules, capsules, tablets, pills, powder and freeze-dried powder injection; the liquid preparation is injection and oral liquid.
Compared with the prior art, the invention has the following beneficial effects:
1. high purity, high yield and less by-products. The methotrexate synthesized by the method has purity as high as 99.50 percent and yield of 75-85 percent through HPLC detection.
2. The invention not only reduces the generation of reaction byproducts, but also improves the purity and yield of the target product, thereby improving the therapeutic effect of the methotrexate, ensuring safer use and few impurities of the purified product.
3. The synthesis method is simple, the production period is short, the cost is low, the pollution is less, and the method is suitable for industrial production of methotrexate.
Drawings
Fig. 1: HPLC chromatogram of methotrexate
Detailed Description
The present invention will be further understood by those skilled in the art by reference to the following examples, which are included herein by way of illustration and not limitation, and various changes and modifications may be made by those skilled in the art without departing from the spirit of the invention.
EXAMPLE 1 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
150Ml of distilled water and 10g of L-para-methylaminobenzoyl glutamic acid zinc salt, 2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 10g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 25 ℃, after the reaction is carried out for 2.5h, 2.5g of phosphoric acid is added, and the reaction is continued for 24h, thus obtaining a crude product of methotrexate;
(2) Refining the synthesized methotrexate crude product into pure methotrexate
Placing the methotrexate crude product obtained in the step (1) into a round bottom flask, adding 80ml of distilled water to dissolve part, regulating the pH to 10.5 with 40% NaOH solution, continuously stirring for 50min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 5.5 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure product of the methotrexate. Calculated, the synthetic yield was 85%.
The purity of the obtained methotrexate pure product is up to 99.5% by HPLC detection.
EXAMPLE 2 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
Taking 100ml of distilled water, 15g of L-p-methylaminobenzoyl glutamic acid zinc salt, 8g of 2,4,5, 6-tetraaminopyrimidine, putting into a flask, adding 8g of 1, 3-trichloroacetone, stirring at 20 ℃ for reaction, adding 1g of phosphoric acid into the mixture after the reaction is carried out for 1h, and continuing the reaction for 20h to obtain a methotrexate crude product.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 50ml of distilled water to dissolve part, regulating the pH to 10 by using 35% NaOH solution, continuously stirring for 40min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 1 time of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 3h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 4 times of water, regulating the pH value to 5 by using concentrated hydrochloric acid, stirring for 3 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 50 ℃ for 4 hours to obtain a fresh yellow solid, namely the pure methotrexate. Calculated, the synthetic yield was 75.6%.
EXAMPLE 3 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
200Ml of distilled water and 25g of L-p-methylaminobenzoyl glutamic acid zinc salt, 11g of 2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 14g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 30 ℃, after the reaction is carried out for 4 hours, 4g of phosphoric acid is added, and the reaction is continued for 28 hours, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step1 into a round-bottom flask, adding 150ml of distilled water to dissolve part, adjusting the pH to 11 with 45% NaOH solution, continuously stirring for 60min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 4 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 5h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 10 times of water, regulating the pH value to 6 by using concentrated hydrochloric acid, stirring for 5 hours at room temperature, filtering, and rotationally steaming a filter cake at a reduced pressure of 60 ℃ for 4-6 hours to obtain a fresh yellow solid, namely the pure product of the methotrexate. Calculated, the synthetic yield was 80.5%.
EXAMPLE 4 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
Taking 120ml of distilled water, 16g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9g of 2,4,5, 6-tetraaminopyrimidine, putting into a flask, adding 9g of 1, 3-trichloroacetone, stirring and reacting at 22-28 ℃, adding 1g of phosphoric acid into the mixture after the reaction is carried out for 1h, and continuing to react for 22h to obtain a methotrexate crude product.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 60ml of distilled water to dissolve part, regulating the pH to 10 by using 35% NaOH solution, continuously stirring for 40min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 1 time of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 3h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 4 times of water, regulating the pH value to 5 by using concentrated hydrochloric acid, stirring for 3 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 50 ℃ for 4 hours to obtain a fresh yellow solid, namely the pure methotrexate. Calculated, the synthetic yield was 78.6%.
EXAMPLE 5 methotrexate Synthesis method
(1) Synthesis of methotrexate crude product
180Ml of distilled water, 24g of L-p-methylaminobenzoyl glutamic acid zinc salt, 11g of 2,4,5, 6-tetraminopyrimidine are taken, put into a flask, 13g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 28 ℃, 3g of phosphoric acid is added after the reaction is carried out for 3 hours, and the reaction is continued for 26 hours, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step1 into a round-bottom flask, adding 120ml of distilled water to dissolve part, adjusting the pH to 11 with 40% NaOH solution, continuously stirring for 50min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 3 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt;
s2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 10 times of water, regulating the pH value to 6 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure methotrexate. Calculated, the synthetic yield was 81.4%.
EXAMPLE 6 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
Taking 140ml of distilled water, 18g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9g of 2,4,5, 6-tetraminopyrimidine, placing into a flask, adding 10g of 1, 3-trichloroacetone, stirring and reacting at 24 ℃, adding 2g of phosphoric acid after the reaction is carried out for 2 hours, and continuing to react for 23 hours to obtain a crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 80ml of distilled water to dissolve part, regulating the pH to 10 by using 35% NaOH solution, continuously stirring for 40min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 3h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 6 times of water, regulating the pH value to 5 by using concentrated hydrochloric acid, stirring for 3 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 50 ℃ for 4 hours to obtain a fresh yellow solid, namely the pure methotrexate. The synthesis yield was calculated to be 76.6%.
EXAMPLE 7 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
160Ml of distilled water and 22g of L-p-methylaminobenzoyl glutamic acid zinc salt, 10g of 2,4,5, 6-tetraminopyrimidine are taken, put into a flask, 12g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 26 ℃, 3g of phosphoric acid is added after the reaction is carried out for 3 hours, and the reaction is continued for 25 hours, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step1 into a round-bottom flask, adding 120ml of distilled water to dissolve part, adjusting the pH to 11 with 40% NaOH solution, continuously stirring for 50min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 3 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt;
S2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 6 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure methotrexate. Calculated, the synthetic yield was 83.5%.
EXAMPLE 8 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
150Ml of distilled water and 10.5g of L-para-methylaminobenzoyl glutamic acid zinc salt, namely 20g,2,4,5, 6-tetraaminopyrimidine are taken and put into a flask, 11.6g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 26 ℃, after the reaction is carried out for 3 hours, 2.5g of phosphoric acid is added, and the reaction is continued for 24 hours, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 100ml of distilled water to dissolve part, regulating the pH to 10.5 by using 40% NaOH solution, continuously stirring for 50min, carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 5.5 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure product of the methotrexate.
EXAMPLE 9 Synthesis of methotrexate
(1) Synthesis of methotrexate crude product
160Ml of distilled water and 18.5g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9g of 2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 10.5g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 24 ℃, after the reaction is carried out for 2.5h, 2g of phosphoric acid is added, and the reaction is continued for 24h, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 90ml of distilled water to dissolve part, adjusting the pH to 10 by using 35% NaOH solution, continuously stirring for 45min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously placing and stirring for 3.5h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 6 times of water, regulating the pH value to 5 by using concentrated hydrochloric acid, stirring for 3.5 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 50 ℃ for 4 hours to obtain a fresh yellow solid, namely the pure product of the methotrexate.
EXAMPLE 10 methotrexate Synthesis method
(1) Synthesis of methotrexate crude product
150Ml of distilled water and 10.4g of L-p-methylaminobenzoyl glutamic acid zinc salt 21g,2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 12.5g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 26 ℃, after the reaction is carried out for 3 hours, 2.6g of phosphoric acid is added, and the reaction is continued for 25 hours, thus obtaining the crude product of methotrexate.
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round-bottom flask, adding 110ml of distilled water to dissolve part, regulating the pH to 10.5 by using 40% NaOH solution, continuously stirring for 50min, carrying out suction filtration to obtain reddish brown filtrate, slowly adding 3 times of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 3h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of the methotrexate disodium salt;
S2, dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 6 by using concentrated hydrochloric acid, stirring for 3 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 50 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure methotrexate.
The pure methotrexate product obtained in examples 1 to 10 was used in the preparation of the pharmaceutical preparations of the following examples
Example 11
Taking methotrexate as a raw material, adding 8 times of soluble starch, granulating, and drying to obtain granules.
Example 12
Taking methotrexate as a raw material, adding 7 times of poly-starch and dextrin, uniformly mixing, and tabletting to obtain tablets.
Example 13
Taking methotrexate as a raw material, adding 7 times of soluble starch, uniformly mixing, and encapsulating to obtain the capsule.
Example 14
Taking methotrexate as a raw material, adding 9 times of polyethylene glycol, uniformly mixing and dripping to prepare pills.
Example 15
Taking methotrexate as a raw material, adding 20 times of water for injection, uniformly mixing, filtering and sterilizing to obtain the injection.
To further verify the feasibility and effectiveness of the invention, the inventors performed a series of experiments, specifically as follows:
Experimental example 1
The reaction product was produced by thin layer chromatography. Dissolving the reaction solution with dimethyl sulfoxide, spotting with methotrexate reference substance, running with petroleum ether, and then ethyl acetate: methanol=1: 1.5, adding two drops of concentrated ammonia water to prepare a developing agent running plate, and observing in an ultraviolet analyzer to see whether methotrexate products are generated or not, whether the reaction can be completed or not, and how much byproducts are generated.
The synthesis method of the methotrexate crude product comprises the following steps: 150ml of distilled water and 10g of 20g of 2,4,5, 6-tetraaminopyrimidine zinc salt of L-p-methylaminobenzoyl glutamic acid are taken, the mixture is put into a flask, 10g of 1, 3-trichloroacetone is added, the mixture is stirred at 25 ℃ for reaction, after the reaction is carried out for 2.5 hours, 2.5g of phosphoric acid is added, the reaction is continued for 24 hours, and a thin layer plate is used for monitoring the reaction condition at any time.
Results: the synthesis rate of the methotrexate crude product obtained by calculation is 88.5% and the amount of the produced by-products is small.
Experimental example 2
The crude methotrexate is purified and the reaction product is produced by thin layer chromatography. Dissolving synthesized methotrexate and methotrexate reference substance with dimethyl sulfoxide, running on petroleum ether, and then using ethyl acetate: methanol=1: 1.5, developing under the condition of adding two drops of strong ammonia water, observing whether the obtained product is methotrexate in an ultraviolet analyzer, and completely removing impurities after refining.
The purification method of the methotrexate crude product comprises the following steps: adding the synthesized methotrexate crude yellow solid into a 250ml round bottom flask, adding 80ml distilled water dissolution part, regulating the pH value to 10.5 by using 40% NaOH solution, continuously stirring for 50min, carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 4h after adding, enabling the solid to be completely separated out, carrying out suction filtration to obtain a methotrexate disodium salt wet product pure product, dissolving the methotrexate disodium salt wet product pure product into 8 times of water, regulating the pH value to 5.5 by using concentrated hydrochloric acid, stirring for 4h at room temperature, filtering, and carrying out rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5h.
Results: the fresh yellow solid is obtained, and the product is methotrexate after being confirmed by 1H NMR、13 C NMR and HRMS, and the purity of the product is up to 99.50 percent after HPLC detection.
Experimental example 3
Purity detection of synthetic methotrexate. HPLC detection was used.
Detection conditions of high performance liquid chromatography: chromatographic column: c 18 column (5 μm,6 mm. Times.150 mm); mobile phase: 0.001% disodium hydrogen phosphate dihydrate with acetonitrile (85:15); flow rate: 0.6mL/min; column temperature: 35 ℃; sample injection amount: 10 mu L. The chromatogram is shown in FIG. 1.
Results: the purity of the methotrexate pure product synthesized by the method is 99.5 percent through HPLC detection. The method has high yield, high purity and less impurity.
In conclusion, the synthesis method disclosed by the invention is simple to operate, few in reaction byproducts, high in yield, high in purity and few in impurities. Is suitable for industrial production of methotrexate.
The embodiments of the present invention are merely described in terms of preferred embodiments of the present invention, and are not intended to limit the spirit and scope of the present invention, but various modifications and improvements of the technical solutions of the present invention should be made by those skilled in the art without departing from the design concept of the present invention.
Claims (10)
1. A method for synthesizing methotrexate, comprising the steps of:
(1) Synthesis of methotrexate crude product
Taking 100-200ml of distilled water, 15-25g of L-p-methylaminobenzoyl glutamic acid zinc salt, 8-11g of 2,4,5, 6-tetraaminopyrimidine, putting into a flask, adding 8-14g of 1, 3-trichloroacetone, stirring and reacting at 20-30 ℃, adding 1-4g of phosphoric acid after the reaction is carried out for 1-4h, and continuing to react for 20-28h to obtain a methotrexate crude product;
(2) Refining the synthesized methotrexate crude product into pure methotrexate
S1, placing the methotrexate crude product obtained in the step 1 into a round bottom flask, adding 50-150ml of distilled water to dissolve part, adjusting the pH to 10-11 with 35-45% NaOH solution, continuing stirring for 40-60min until the solution is reddish brown clear, filtering to obtain reddish brown filtrate, slowly adding 1-4 times of absolute ethyl alcohol into the filtrate under stirring, continuing to stand and stir for 3-5h after adding, so that solid can be completely separated out, and filtering to obtain a wet pure methotrexate disodium salt product;
S2, dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 4-10 times of water, regulating the pH value to 5-6 by using concentrated hydrochloric acid, stirring for 3-5 hours at room temperature, filtering, and rotationally steaming a filter cake at the temperature of 50-60 ℃ for 4-6 hours under reduced pressure to obtain a fresh yellow solid, namely the pure product of the methotrexate.
2. The synthesis method according to claim 1, wherein the specific method for synthesizing the methotrexate crude product in step (1) comprises the following steps: 120-180ml of distilled water, 16-24g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9-11g of 2,4,5, 6-tetraaminopyrimidine are put into a flask, 9-13g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 22-28 ℃, after the reaction is carried out for 1-3h, 1-3g of phosphoric acid is added, and the reaction is continued for 22-26h, thus obtaining the crude product of methotrexate.
3. The synthesis method according to claim 2, wherein the specific method for synthesizing the methotrexate crude product in step (1) comprises the following steps: 140-160ml of distilled water, 18-22g of L-p-methylaminobenzoyl glutamic acid zinc salt, 9-10g of 2,4,5, 6-tetraaminopyrimidine are taken and put into a flask, 10-12g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 24-26 ℃, after the reaction is carried out for 2-3h, 2-3g of phosphoric acid is added, and the reaction is continued for 23-25h, thus obtaining the crude product of methotrexate.
4. The synthesis method according to claim 3, wherein the specific method for synthesizing the methotrexate crude product in the step (1) is as follows: 150ml of distilled water and 10g of L-para-methylaminobenzoyl glutamic acid zinc salt, 2,4,5, 6-tetraaminopyrimidine are taken, put into a flask, 10g of 1, 3-trichloroacetone is added, stirring reaction is carried out at 25 ℃, after the reaction is carried out for 2.5h, 2.5g of phosphoric acid is added, and the reaction is continued for 24h, thus obtaining the crude product of methotrexate.
5. The synthesis method according to claim 1, wherein the specific method of step S1 is as follows: placing the methotrexate crude product obtained in the step (1) into a round bottom flask, adding 60-120ml of distilled water to dissolve part, regulating the pH to 10-11 with 35-40% NaOH solution, continuing stirring for 40-50min until the solution is reddish brown clear, carrying out suction filtration to obtain reddish brown filtrate, slowly adding 1-3 times of absolute ethyl alcohol into the filtrate under stirring, continuing to stand and stir for 3-4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain the methotrexate disodium salt wet product pure product.
6. The synthesis method according to claim 5, wherein the specific method of step S1 is as follows: placing the methotrexate crude product obtained in the step (1) into a round bottom flask, adding 80ml of distilled water to dissolve part, regulating the pH to 10.5 with 40% NaOH solution, continuously stirring for 50min, and carrying out suction filtration to obtain reddish brown filtrate, slowly adding 2 times of absolute ethyl alcohol into the filtrate under stirring, continuously standing and stirring for 4h after adding, so that solid can be completely separated out, and carrying out suction filtration to obtain a wet product of methotrexate disodium salt.
7. The synthesis method according to claim 1, wherein the specific method of step S2 is as follows: dissolving the wet pure product of the methotrexate disodium salt obtained in the step S1 in 6-8 times of water, regulating the pH value to 5-6 by using concentrated hydrochloric acid, stirring for 3-4 hours at room temperature, filtering, and rotationally steaming a filter cake at the temperature of 50-55 ℃ for 4-5 hours under reduced pressure to obtain a fresh yellow solid, namely the pure product of the methotrexate.
8. The synthesis method according to claim 7, wherein the specific method of step S2 is as follows: dissolving the wet pure methotrexate disodium salt obtained in the step S1 in 8 times of water, regulating the pH value to 5.5 by using concentrated hydrochloric acid, stirring for 4 hours at room temperature, filtering, and performing rotary evaporation on a filter cake at a reduced pressure of 55 ℃ for 5 hours to obtain a fresh yellow solid, namely the pure methotrexate.
9. Use of a pure product of methotrexate prepared by the synthetic method according to any one of claims 1-8 for the preparation of an anti-tumor pharmaceutical formulation.
10. The use according to claim 9, wherein the pharmaceutical preparation is prepared by adding pharmaceutically acceptable auxiliary materials into pure methotrexate prepared by the synthesis method according to any one of claims 1 to 8, and preparing pharmaceutically acceptable preparations, including solid preparations or liquid preparations, wherein the solid preparations are granules, capsules, tablets, pills, powder and freeze-dried powder injection; the liquid preparation is injection and oral liquid.
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