The synthesis process of methotrexate

Abstract An overview of the progress of the main synthetic methods of methotrexate and the preparation of key intermediates is given.

Keywords Methotrexate, synthesis

Methotrexate(1),chemically known as N-(4-(((2,4-diamino-6-phthalimide)methyl)methylamino)benzoyl)-L-glutamate is a widely used antitumor drug in the field of cancer chemotherapy.111, Especially after the clinical adoption of high-dose methotrexate therapy in the past 20 years and the approval of the US FDA for the treatment of rheumatoid arthritis in 1988,3 the demand for this drug, has increased. The demand for this drug has increased. In recent years, many foreign patents have been published on the improvement of the synthesis process, aiming at shortening the reaction steps, simplifying the process conditions, reducing the by-products, increasing the purity and total yield, thus reducing the cost and improving the therapeutic efficacy. Since 1975, the main progress of the synthesis process and the preparation of key intermediates are briefly described.

The chemical structure of methotrexate can be divided into two parts: the parent nucleus of methotrexate and the side chain of p-methylaminobenzoyl glutamate.


The synthesis process of methotrexate

I. Preparation of methotrexate

Method A was patented by Balwant et al. 141 in 1983, using the one-pot synthesis method, in which 4, H2SO, and 3b were first dissolved in water and the pH was adjusted to 2.0 with 12 mol of hydrochloric acid.

The pH was adjusted to 2.0 with 12 mol of hydrochloric acid, and then 1, 3, 3-triacetone, pre-dissolved in ethanol, was added dropwise to the above mixture, and the pH was maintained at 2.0 with 2’fu sodium hydroxide solution, reacting 3,…, _,3_5 h. After a simple refining process, 1 with a purity greater than 98% was obtained. The yield was estimated to be 17.8% (calculated with a small stop so,). Compared with the early one-pot synthesis method “‘, the advantages in the thousand synthesis process are more simple, easy to refine, high purity of the product, high yield, worthy of attention.

Method B was patented by Piper et al. 171 in 1980. In the first step, 4- 2 HCl aqueous solution was prepared by treating 4- 2 HCl with two molecules of crystalline barium chloride. Then it was added to 1,3-delight acetone containing sodium acetate and cysteine hydrochloride, and the air was slowly introduced for 26 h. The nucleus was cyclized to produce 2a-HBr, which was treated with 48% hydrochloric acid to produce 2a-HBr. In step 2, 2a-HBr was differentiated to 2c-HBr in the presence of triphenyl transient. In step 3, 2c-HBr was reacted with 3a in dimethylacetamide solvent for 4 h and then refined by hydrolysis to yield 1 with three molecules of water. The total yield of this method was estimated to be 8.4% (based on 4-H2S0,-H20). In addition, 2C can also be obtained by combining 4 with 1, 2-diranoparaffin to obtain 4 [Methotrexate operating procedures of a domestic pharmaceutical company, 1973].

Method C9, 10 is similar to method B, which is also synthesized in three steps. Compared with method B, the first step of the cyclization reaction uses selenium dioxide and sodium bicarbonate as catalysts to improve the yield of 2a. In step 2, 2a is chlorinated with thionyl chloride to give almost quantitative 2b. In step 3, the reaction with 3C is followed by chromatographic refinement to give 1 with >95% purity, and the total yield is estimated to be 7.6,… The advantage of this method is that the high purity of 1,3-dibenzylacetone is not needed in the first step of the cyclization reaction as in the B method, and the by-products of 2,4-diamino-7-methyl benzoate are avoided. The disadvantage is that the yield of the 3rd step is low (only 10.7,… _,16%), and the purity of the resulting 1 is 60% without chromatographic refinement. However, the reaction of 2b-HC1 with 3a in the presence of potassium dimethylamine solvent and hydrolysis in step 3 was carried out by Alster’s method to produce 1 with a purity of 95% and a total yield of 64.3% (based on 2a). This method of linking the parent nucleus to the side chain is noteworthy. In addition, 2a can also be obtained by combining a and quat ring 2: 0D method is a European patent 13 I 1 by Jensen et al. 1982, which uses the reaction of 5b with 3d, which is sounded by ethyl acetate to obtain 6, and hydrolyzed to 7, followed by the combination with quat carbonate ring to obtain 1, with a total yield of 43.2% (calculated as an assist). The D-method is characterized by the level and conditions of the reaction, the simplicity of the post-treatment, and the high yield of each step.

The synthesis process of methotrexate

II. Preparation of key intermediate 4

The 8 and 9 are cyclized to obtain 10, followed by nitrosation to obtain 11. There are three methods to make 11 into 4: @method 111 using Raney baht ionization to reduce 11 into 4 (yield not reported). The @ method [15] uses 5% sulfide to reduce 11 to 4. The @ method [16] first makes II over, then by hydrolysis to 4. The 1st to 3rd methods use the more difficult supply of propylene glycol, and the @ method to prepare 4 uses 13 and 14 rings to 15, then by nitrosation, reduction to 16, followed by chlorination and ammoniation to 4, the route is longer, but the raw material is easy to obtain, so it is still used in China.

The synthesis process of methotrexate

|||. the preparation of intermediates 3 teams 3b and 3d

(i) method [17] will be 17 and sodium glutamate reaction to get 18, followed by reduction to 19, after diazotization, Australia to get 20, and then by methylamination to get 3d. (ii) method [17] will be the knife chlorination, after coupling with glutamate to get 22, and then by methylamination can also get 3d, the total yield of 57% (calculated by 21) o (iii) method, 1sJ will be 23 and acetic anhydride reaction in benzene to get 24, and then The reaction of 23 with acetic anhydride in benzene gives 25, followed by N-formylation, chlorination, and hydrolysis with glutamic acid. The reaction of 3d with zinc chloride gives 3 cut and lb acetylation gives 3aC19J.


The synthesis process of methotrexate

With the combination of the above routes, the A method uses a one-pot synthesis method, simple operation, fewer side reactions, easy refining, product purity business, yield is also higher. B method or C method for the preparation of 2a, are used 1,3-ditibial acetone as raw material, because the raw material is in short supply in China, mainly rely on imports, not easy to obtain. Therefore, it is easier to prepare 2a by Taylor’s method I121, and then chlorinate 2a into 2b, and then use Alster’s method Ill in conjunction with 3a, can also be produced in high yield 1. D method is 5b as the starting material, after four steps of reaction to obtain J ‘each step yield of more than 70%, the reaction conditions are also more moderate, and simple post-treatment. In conclusion, according to their respective production conditions and operational experience, the above-mentioned different synthetic processes can be developed and improved, with emphasis on the high-quality belly to meet the urgent needs of clinical treatment.