Preparation method of fosphenytoin sodium intermediate

A technology of fosphenytoin sodium and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of low process yield, unsatisfactory mass production, increased production cost and the like, and achieve the effects of simplified operation steps, high production efficiency and economical reaction

Pending Publication Date: 2022-07-01
SICHUAN CREDIT PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the process yield is generally not high, the highest is only 69.2%, wherein with di-tert-butyl phosphate potassium salt as the reaction substrate, its yi

Method used

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  • Preparation method of fosphenytoin sodium intermediate

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[0036] The invention provides a preparation method of a fosphenytoin sodium intermediate, comprising the following steps:

[0037] A) under the action of a catalyst, react the compound represented by formula II with the compound represented by formula III in solvent a;

[0038] B) mixing the reacted product of step A) with solvent b, cooling down, and crystallizing to obtain the compound represented by formula I;

[0039]

[0040] Wherein, R is selected from C1~C6 alkyl or aralkyl;

[0041] M is an alkali metal ion.

[0042] In certain embodiments of the present invention, the R is selected from methyl, ethyl, tert-butyl or benzyl.

[0043] In certain embodiments of the present invention, the M is Na ion or K ion.

[0044] The present invention has no special limitation on the source of the compound represented by the formula II (3-chloromethylphenytoin). prepared by the method in .

[0045] In some embodiments of the present invention, the compound represented by the ...

Embodiment 1

[0073] Preparation of compound 3-hydroxymethyl-phenytoin di-tert-butyl phosphate shown in formula I:

[0074] 50.00 g (166.26 mmol) of the compound represented by formula II, 53.67 g (216.14 mmol) of di-tert-butyl phosphate potassium salt and 0.28 g (1.66 mmol) of potassium iodide were added to 300 mL of acetone, and the temperature was raised to 50 °C with stirring for 8 h. Heating was stopped, 350 mL of water was added, the temperature was lowered to -5°C with stirring, and crystallization was maintained for 2 h. After filtration, the filter cake was dried under reduced pressure to obtain 70.00 g of 3-hydroxymethyl-phenytoin di-tert-butyl phosphate with a yield of 88.7%. The HPLC purity was 99.10% and the content was 99.6% (indicating that the inorganic salts can be effectively removed).

Embodiment 2

[0076] Preparation of compound 3-hydroxymethyl-phenytoin di-tert-butyl phosphate shown in formula I:

[0077] 50.00 g (166.26 mmol) of the compound represented by formula II, 49.54 g (199.51 mmol) of di-tert-butyl phosphate potassium salt and 0.18 g (0.50 mmol) of tetrabutylammonium iodide were added to 200 mL of N,N-dimethylformamide , the temperature was raised to 60 °C with stirring, and the reaction was maintained for 3 h. Heating was stopped, 500 mL of water was added, the temperature was lowered to 15°C with stirring, and crystallization was maintained for 2 h. After filtration, the filter cake was dried under reduced pressure to obtain 70.60 g of 3-hydroxymethyl-phenytoin di-tert-butyl phosphate with a yield of 89.5%. The HPLC purity was 99.14%, and the content was 99.5%.

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a fosphenytoin sodium intermediate, which comprises the following steps: A) under the action of a catalyst, reacting a compound as shown in a formula II with a compound as shown in a formula III in a solvent a; and B) mixing a product obtained after the reaction in the step A) with a solvent b, cooling, and crystallizing to obtain the compound shown in the formula I. In the preparation process of the compound as shown in the formula I, expensive dibenzyl phosphate silver salt does not need to be used, the reaction is more economical, and residues of heavy metals such as silver are avoided; meanwhile, inorganic salts such as potassium chloride and sodium chloride can be effectively removed without a desalting step, so that the operation steps are simplified, and the production efficiency is improved. Moreover, the preparation method provided by the invention can obtain higher yield and purity, is simple and convenient to operate, high in production efficiency, safe and suitable for industrial mass production, and has a good market application prospect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of a fosphenytoin sodium intermediate. Background technique [0002] Fosphenytoin sodium (2,4-imidazolinedione-5,5-diphenyl-3-[(phosphonooxy)methyl]disodium salt) is a phosphate ester prodrug of phenytoin, developed by Warner-Lamber The drug developed by the special company for the prevention and treatment of epilepsy was launched in the United States in 1996. Its water solubility is 4,000 times that of phenytoin sodium, and it is converted into phenytoin by phosphatase in the body. Because it overcomes the adverse reactions caused by the clinical use of phenytoin sodium, it has become a phenytoin sodium substitute drug with good efficacy, high safety and less irritation. [0003] The specific structure of fosphenytoin sodium is as follows: [0004] [0005] In the preparation method of the fosphenytoin sodium of the existing reports, mo...

Claims

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Application Information

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IPC IPC(8): C07F9/6506
CPCC07F9/6506C07B2200/13
Inventor 阳海余麟庆宿磊傅霖陈刚
Owner SICHUAN CREDIT PHARMA
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