Industrial production method of Alogliptin benzoate raw material medicine

A technology for benzoic acid and raw materials, applied in the field of industrial production of alogliptin benzoate raw materials, can solve problems such as increased procedures, high production costs, unfavorable production, etc., to reduce the types of solvents used, reduce production costs, and process simple effect

Inactive Publication Date: 2015-07-29
SUZHOU YABAO PHARMA R&D CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Chinese patent 201310106584.6 discloses a crystal compound of alogliptin benzoate, which is refined with methanol and ethyl acetate in the synthesis process, and the yield is only 65%; Chinese patent 201410236391.7 discloses a crystal form of alogliptin benzoate A refining method, in which the crude product of alogliptin benzoate is crystallized in methanol in the presence of benzoic acid to obtain the fine product of alogliptin benzoate; Chinese patent 201410388488.X discloses a polymorphic form of alogliptin benzoate The preparation method of crystals uses methanol and methyl tert-butyl ether as recrystallization solvents; the methanol used in the above patents is a second-class solvent with high toxicity and is not suitable for the final step of refined production of raw materials. The price of methyl tert-butyl ether Expensive, high production costs
[0006] Chinese patent 201310195299.6 discloses a

Method used

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  • Industrial production method of Alogliptin benzoate raw material medicine

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Embodiment 1

[0020] Embodiment 1: the preparation of alogliptin benzoate crude product

[0021]

[0022] 1. Preparation of intermediate AG1

[0023] Add 41.2kg of N-methylpyrrolidone, 10.0kg of 6-chloro-3-methyluracil and 12.07kg of diisopropylethylamine into a 100L enamel reaction kettle, and then add 13.43kg of 2-cyanobenzyl bromide into the reaction solution, the temperature was raised to 60~70°C, and the reaction was stirred for 4h. TLC monitoring showed that the raw material point of 6-chloro-3-methyluracil basically disappeared (developer PE:EA=2:1, GF254). Cool the reaction solution to 20-30°C, then slowly add 50.0kg of purified water into the reaction solution, keeping the temperature below 35°C during the process, and continue stirring for 30 minutes after the addition. Cool down to 5~10°C, keep stirring for 1.5h. Centrifuge, wash with 50.0kg of purified water in batches, then add the obtained solid into the reaction kettle, add 39.3kg of isopropanol, stir for 1.5h, centri...

Embodiment 2

[0029] During the implementation of the invention, a comparative study was carried out with the disclosed related technology, and the key process parameters of the present invention were screened and investigated, and the results are shown in Table 1:

[0030]

[0031] It can be seen from the above results that, compared with the disclosed technology, the technology of the present invention is more environmentally friendly, has high yield, higher product purity, and low solvent residue, which is also conducive to the removal of impurity X.

Embodiment 3

[0033] Add 5.0 kg of alogliptin benzoate crude product, 57 liters of absolute ethanol and 3 liters of water (ethanol / water=95 / 5) into the reaction kettle, heat and reflux until the solution is clear, press filter to a clean area, and cool down to 50°C Add 10.0g of seed crystals, keep warm and crystallize at 40-50°C for 2h, pass cooling circulating water to cool down at 20-30°C and continue to keep warm for 1h, then lower the temperature to 5-10°C and continue to keep warm for 1h, centrifuge, and blow dry at 60°C for 5h. Obtain white alogliptin benzoate finished product 4.52kg, yield 90.4%. The purity is 99.96%, the single impurity is 0.036%, the residual ethanol is 0.07%, and the impurity X is not detected.

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Abstract

The invention discloses an industrial production method of Alogliptin benzoate raw material medicine. According to the method, ethanol/water mixed solvents are used as crystallization solvents; the ethanol/water mixed solvents and Alogliptin benzoate crude products are heated and flow back to a state that the solution is clear; the temperature is lowered, and crystal seeds are added; the gradient temperature reduction crystal separation is carried out; centrifugation and drying are carried out, and the Alogliptin benzoate raw material medicine is obtained. The adopted mixed solvents have low toxicity, and a better environment-friendly effect can be achieved. Compared with the method in the prior art, the industrial production method provided by the invention has the advantages that the solvent use type is reduced, the process is simple, the yield is high, and the production cost is reduced; through the method, the purity of the obtained Alogliptin benzoate finished product is at least 99.8 percent, the single impurity content is lower than or equal to 0.05 percent, the ethanol residue is low (lower than or equal to 0.1 percent) and is much lower than the limit of 0.5 percent of medical raw material medicine; impurities X generated by the reaction between phthalic acid and Alogliptin can be removed.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an industrial production method of alogliptin benzoate bulk drug. Background technique [0002] Alogliptin Benzoate, the chemical name is 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2, 4-dioxo-1(2H)-pyrimidinyl] methyl] benzonitrile benzoate, the structure is shown in formula (I), [0003] [0004] It is a DPP-IV inhibitor developed by Takeda Pharmaceutical. It can promote the insulin secretion related to glucose concentration by increasing the plasma concentration of GLP-1 in the body, maintain the level of glucagon-like-1 peptide and glucose-dependent insulinotropic peptide in the body, increase the secretion of insulin, and thus play a role in reducing blood pressure. Sugar curative effect. [0005] Chinese patent 201310106584.6 discloses a crystal compound of alogliptin benzoate, which is refined with methanol and ethyl acetate in the synthesis process, an...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 姚勇敢刘格平
Owner SUZHOU YABAO PHARMA R&D CO LTD
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