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Industrial production method of Alogliptin benzoate

Inactive Publication Date: 2019-01-18
NANHAI PHARMA CHONGQING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the patent claims to be an industrialized production method, it is actually produced in small doses of grams or milliliters, and the steps are many and complicated. Although the yield of each step is 90.0%, 80.1%, and 70.5%. , 82.2%; when the final output is only 168 grams, the yield of the final product is only 82.2%, and the total yield is only 41.78%, which is still not high

Method used

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  • Industrial production method of Alogliptin benzoate
  • Industrial production method of Alogliptin benzoate
  • Industrial production method of Alogliptin benzoate

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Experimental program
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Embodiment 1

[0050] The industrial production method of alogliptin benzoate of the present invention comprises three major steps, the first step prepares alogliptin intermediate AGⅠ, the second step prepares alogliptin intermediate AGII, and the third step prepares alogliptin benzoate Ting; the specific method is as follows.

[0051] The first step is to prepare the alogliptin intermediate AGI.

[0052](1) Add 24.5kg of N-methylpyrrolidone, 8.0kg of 6-chloro-3-methyluracil and 7.18kg of N,N-diisopropylethylamine into a 300L glass-lined reactor, and stir until dissolved.

[0053] (2) Add 8.16 kg of 2-cyanobenzyl bromide into the reaction kettle, and stir to dissolve.

[0054] (3) Heat the reaction kettle to 60-65°C, stir and keep warm for 3 hours; start TLC monitoring after 3 hours until the reaction ends, that is, the raw material point of 6-chloro-3-methyluracil basically disappears; take samples for monitoring every 0.5 hours.

[0055] The reaction endpoint monitoring method is as foll...

Embodiment 2

[0108] The first step is to prepare the alogliptin intermediate AGI.

[0109] (1) Add 36.75kg of N-methylpyrrolidone, 12.0kg of 6-chloro-3-methyluracil and 10.77kg of N,N-diisopropylethylamine into a 300L glass-lined reactor, and stir until dissolved.

[0110] (2) Add 12.24 kg of 2-cyanobenzyl bromide into the reaction kettle, stir to dissolve.

[0111] (3) Heat the reaction kettle to 60-65°C, stir and keep warm for 3 hours; start TLC monitoring after 3 hours until the reaction ends, that is, the raw material point of 6-chloro-3-methyluracil basically disappears; take samples for monitoring every 0.5 hours.

[0112] The reaction endpoint monitoring method is as follows.

[0113] ①Preparation of the test solution: take about 0.2ml of the reaction solution, add 2ml of N-methylpyrrolidone to dilute, and obtain the product.

[0114] ②Preparation of the control solution: Take about 2mg of 6-chloro-3-methyluracil, add 2ml of N-methylpyrrolidone to dissolve it.

[0115] ③ Chromato...

Embodiment 3

[0157] The first step is to prepare the alogliptin intermediate AGI.

[0158] (1) Add 29.0kg of N-methylpyrrolidone, 16.0kg of 6-chloro-3-methyluracil and 17.36kg of N,N-diisopropylethylamine into a 300L glass-lined reactor, and stir until dissolved.

[0159] (2) Add 16.32 kg of 2-cyanobenzyl bromide into the reaction kettle, and stir to dissolve.

[0160] (3) Heat the reaction kettle to 60-65°C, stir and keep warm for 3 hours; start TLC monitoring after 3 hours until the reaction ends, that is, the raw material point of 6-chloro-3-methyluracil basically disappears; take samples for monitoring every 0.5 hours.

[0161] The reaction endpoint monitoring method is as follows.

[0162] ①Preparation of the test solution: take about 0.2ml of the reaction solution, add 2ml of N-methylpyrrolidone to dilute, and obtain the product.

[0163] ②Preparation of the control solution: Take about 2mg of 6-chloro-3-methyluracil, add 2ml of N-methylpyrrolidone to dissolve it.

[0164] ③ Chrom...

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Abstract

The invention relates to an industrial production method of Alogliptin benzoate, and belongs to the technical field of industrial pharmacy. The method comprises three steps of 1, preparing an Alogliptin intermediate AG I; 2, preparing an Alogliptin intermediate AG II; 3, preparing the Alogliptin benzoate. The industrial production method has the beneficial effects that the reaction conditions areproper; the operation is simple and convenient; the realization is easy; only the Alogliptin intermediate AG II is prepared; then, the AG II and benzoic acid are subjected to tetrahydrofuran synthesis; the Alogliptin benzoate can be obtained; the process is saved; the cost is reduced; used solvents have small environment pollution; the operation is safe; under the large-scale industrial productioncondition, the existing average yield is only about 30 percent; under the condition that the final yield reaches 19.32kg, the finial product yield reaches 94.77 percent; the total yield reaches 60.11percent; high quality and purity can be maintained; the production efficiency is greatly improved.

Description

technical field [0001] The invention belongs to the technical field of industrial pharmacy, in particular to an industrial production method of alogliptin benzoate. Background technique [0002] Alogliptin benzoate, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2 ,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate, its form is white or off-white crystalline powder. Soluble in dimethyl sulfoxide, soluble in methanol, slightly soluble in water, slightly soluble in ethanol. Its molecular formula is: C 18 h 21 N 5 o 2 .C 7 h 6 o 2 , Molecular weight: 461.51. The chemical structure is as follows. [0003] . [0004] Alogliptin benzoate is a highly selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-IV), maintaining glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide in vivo (GIP) levels, promote the secretion of insulin, thereby exerting a hypoglycemic effect. [0005] For the industriali...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C63/06C07C51/41
CPCC07D401/04
Inventor 罗庆林宋绍华龚胡荣
Owner NANHAI PHARMA CHONGQING
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