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Synthetic method for methotrexate drug intermediate malononitrile

A technology of malononitrile and methotrexate, which is applied in the field of synthesis of methotrexate drug intermediate malononitrile, can solve the problem of weak cell action in G1 phase, reduce reaction temperature and reaction time, and reduce intermediate link, the effect of improving the reaction yield

Inactive Publication Date: 2016-04-20
CHENGDU QIANYE LONGHUA PETROLEUM ENG TECH CONSULTING
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

In addition, this product also has an inhibitory effect on thymonucleotide synthetase, but its inhibitory effect on RNA and protein synthesis is relatively weak. This product mainly acts on the S phase of the cell cycle, and is a cell cycle-specific drug. The cells in the phase also have a delaying effect, and the effect on the cells in the G1 phase is weak

Method used

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  • Synthetic method for methotrexate drug intermediate malononitrile

Examples

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example 1

[0012] In the reaction vessel that reactor, thermometer, dropping funnel are installed, add cyanoacetyl bromide (2) 3.9mol, cuprous chloride 0.56mol, mass fraction is 70% 4-nitro-benzonitrile solution ( 3) 4.6-4.9mol, mass fraction is 50% cyclohexane 500ml, control the stirring speed at 150rpm, increase the solution temperature to 50°C, react for 5h, keep the pressure at 8kPa, raise the solution temperature to 80°C, react for 90min, liter Raise the solution temperature to 130°C, react for 4-6h, lower the solution temperature to 10°C, precipitate solids, filter, wash with 40% acetonitrile by mass fraction, wash with 40% ethylenediamine by mass fraction, and dehydrate activated alumina. Recrystallized from 90% nitromethane to obtain 185.33 g of crystalline malononitrile with a yield of 72%.

example 2

[0014] In the reaction vessel that reactor, thermometer, dropping funnel are installed, add cyanoacetyl bromide (2) 3.9mol, cuprous chloride 0.56mol, massfraction is 72% 4-nitro-benzonitrile solution ( 3) 4.7mol, 500ml of cyclohexane with a mass fraction of 52%, control the stirring speed at 170rpm, raise the solution temperature to 52°C, react for 7h, keep the pressure at 9kPa, raise the solution temperature to 82°C, react for 110min, raise the solution Temperature to 132°C, react for 5 hours, lower the solution temperature to 12°C, precipitate solid, filter, wash with acetonitrile with a mass fraction of 425%, wash with ethylenediamine with a mass fraction of 42%, and dehydrate the solid sodium hydroxide at a mass fraction of 92% Recrystallized in nitromethane to obtain 203.35 g of crystalline malononitrile with a yield of 79%.

example 3

[0016] In the reaction vessel that reactor, thermometer, dropping funnel are installed, add cyanoacetyl bromide (2) 3.9mol, cuprous chloride 0.56mol, mass fraction is 75% 4-nitro-benzonitrile solution ( 3) 4.9mol, 500ml of cyclohexane with a mass fraction of 55%, control the stirring speed at 190rpm, raise the solution temperature to 55°C, react for 8h, keep the pressure at 10kPa, raise the solution temperature to 85°C, react for 130min, raise the solution Temperature to 135°C, react for 6h, lower the solution temperature to 15°C, precipitate solid, filter, wash with 45% acetonitrile by mass fraction, wash with 45% ethylenediamine by mass fraction, dehydrate activated alumina, and dehydrate at 95% nitric acid Recrystallized from methyl methane to obtain 211.07 g of crystalline malononitrile with a yield of 82%.

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Abstract

The invention relates to a synthetic method for methotrexate drug intermediate malononitrile. The synthetic method includes the following steps that 3.9 mol of cyanoacetyl bromine, 0.56 mol of cuprous chloride, 4.6-4.9 mol of a 1,4-nitro-cyanobenzene solution and 500 ml of cyclohexane are added into a reaction container provided with a reactor, a thermometer and a dropping funnel, the stirring speed is controlled to be 150-190 rpm, the solution temperature is raised to 50 DEG C-55 DEG C to carry out a reaction for 5-8 h, pressure is kept at 8-10 kPa, the solution temperature is raised to 80 DEG C-85 DEG C to carry out a reaction for 90-130 min, the solution temperature is raised to 130 DEG C-135 DEG C to carry out a reaction for 4-6 h, the solution temperature is lowered to 10 DEG C-15 DEG C, and a solid is separated, filtered, washed with acetonitrile and ethanediamine, dehydrated with a dehydrating agent, and recrystallized in nitromethane to obtain crystal malononitrile.

Description

technical field [0001] The invention relates to a method for synthesizing malononitrile, a drug intermediate of methotrexate. Background technique [0002] Methotrexate is indicated for various types of acute leukemia, especially acute lymphoblastic leukemia, malignant lymphoma, and non-Hodgkin's lymphoma; tetrahydrofolate is synthesized in the body of purine nucleotides and pyrimidine deoxynucleotides Important coenzyme, as a folate reductase inhibitor, this product mainly inhibits dihydrofolate reductase so that dihydrofolate cannot be reduced into physiologically active tetrahydrofolate, so that the biological activity of purine nucleotides and pyrimidine nucleotides During the synthesis process, the transfer of the one-carbon group is hindered, resulting in the inhibition of DNA biosynthesis. In addition, this product also has an inhibitory effect on thymonucleotide synthetase, but its inhibitory effect on RNA and protein synthesis is relatively weak. This product mainl...

Claims

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Application Information

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IPC IPC(8): C07C255/04C07C253/00
CPCC07C253/00
Inventor 关艮安
Owner CHENGDU QIANYE LONGHUA PETROLEUM ENG TECH CONSULTING
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