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Method for preparing drug Alogliptin for treating diabetes type II

A technology for a diabetes drug and methyluracil, applied in the field of drug synthesis, can solve the problems of cumbersome steps, long reaction time, low product yield and the like, and achieve the effects of simple operation steps, shortened reaction time, and avoidance of by-products

Inactive Publication Date: 2016-09-28
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to overcome the defects of cumbersome steps, long reaction time and low product yield in the existing method for preparing alogliptin, and provide a method for preparing alogliptin suitable for industrial scale production with high yield and faster reaction. Gliptin's method

Method used

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  • Method for preparing drug Alogliptin for treating diabetes type II
  • Method for preparing drug Alogliptin for treating diabetes type II

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A kind of method for preparing treatment type II diabetes medicine alogliptin, the method comprises the following steps:

[0030] 1) Under nitrogen protection, copper acetate 9.1g (50mmol), triethylamine 25.3g (250mmol), potassium iodide 6.6g (40mmol), 6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano 22.5g (115mmol) of benzyl bromide was carried out contact reaction in 200ml of acetonitrile at 45°C for 1.5 hours. After the reaction, the reaction solution was poured into water, filtered, washed with water, and dried to obtain 6-chloro-1-(2-isocyanobenzyl 26.5 g of )-3-methylpyrimidine-2,4-(1H,3H)-dione, the yield was 96.2%, and the purity was 98.79%.

[0031] 2) 13.8 g (50 mmol) of 6-chloro-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4-(1H,3H)-dione, (R)-3-tert-butyl 12.0g (60mmol) of oxycarbonylaminopiperidine and 15.2g (110mmol) of potassium carbonate were mixed in DMF at 65°C for 3 hours. After the reaction, water was added, extracted with dichloromethane, concentra...

Embodiment 2

[0034] A kind of method for preparing treatment type II diabetes medicine alogliptin, the method comprises the following steps:

[0035] 1) Under nitrogen protection, 9.1g (50mmol) of copper acetate, 25.3g (250mmol) of triethylamine, 5.0g (30mmol) of potassium iodide, 16.1g (100mmol) of 6-chloro-3-methyluracil and 2-cyano 23.5g (120mmol) of benzyl bromide was carried out contact reaction in 200ml of acetonitrile at 40°C for 2 hours. After the reaction, the reaction solution was poured into water, filtered, washed with water, and dried to obtain 6-chloro-1-(2-isocyanobenzyl 26.2 g of )-3-methylpyrimidine-2,4-(1H,3H)-dione, the yield was 95.1%, and the purity was 98.64%.

[0036] 2) 13.8 g (50 mmol) of 6-chloro-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4-(1H,3H)-dione, (R)-3-tert-butyl 11.0g (55mmol) of oxycarbonylaminopiperidine and 20.7g (150mmol) of potassium carbonate were mixed in DMF at 70°C for 3 hours. After the reaction, water was added, extracted with dichloromethane,...

Embodiment 3

[0039] A kind of method for preparing treatment type II diabetes medicine alogliptin, the method comprises the following steps:

[0040] 1) Under nitrogen protection, 10.9g (60mmol) of copper acetate, 20.2g (200mmol) of triethylamine, 8.3g (50mmol) of potassium iodide, 16.1g (100mmol) of 6-chloro-3-methyluracil and 2-cyano 21.6g (110mmol) of benzyl bromide was subjected to a contact reaction at 50°C in 200ml of acetonitrile for 2 hours. After the reaction, the reaction solution was poured into water, filtered, washed with water, and dried to obtain 6-chloro-1-(2-isocyanobenzyl 26.2 g of )-3-methylpyrimidine-2,4-(1H,3H)-dione, the yield was 95.1%, and the purity was 97.73%.

[0041] 2) 13.8 g (50 mmol) of 6-chloro-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4-(1H,3H)-dione, (R)-3-tert-butyl 11.0 g (55 mmol) of oxycarbonylaminopiperidine and 17.3 g (125 mmol) of potassium carbonate were mixed in DMF at 65°C for 2.5 hours. After the reaction, water was added, extracted with dichlo...

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Abstract

The invention discloses a method for preparing alogliptin, a medicine for treating type II diabetes. The method comprises: 1) in the presence of copper acetate and triethylamine, 6-chloro-3-methyluracil and 2-cyano Benzyl bromide is carried out contact reaction in acetonitrile, and after reaction finishes, reaction solution is poured into water, filters, washes with water, dries to obtain 6-chloro-1-(2-isocyanobenzyl)-3-methylpyrimidine-2, 4-(1H,3H)-dione; 2) 6-chloro-1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4-(1H,3H)-dione, (R )‑3‑tert-butyloxycarbonylaminopiperidine and potassium carbonate are mixed in DMF. After the reaction, add water, then extract with dichloromethane and concentrate to obtain (R)‑tert-butyl‑1‑(3‑ (2‑isocyanobenzyl)‑1‑methyl‑2,6‑dioxo‑1,2,3,6‑tetrahydropyrimidin‑4‑yl)piperidin‑3‑ylcarbamate; 3 ) dissolving the formate ester obtained in step 2) in ethanol and reacting with benzoic acid at 65-70°C, then cooling to -5-5°C for crystallization, filtering and drying to obtain alogliptin. The invention has simple steps, high yield and faster reaction.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing alogliptin, a drug for treating type II diabetes. Background technique [0002] Diabetes is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body. The current treatment is mainly through diet control combined with hypoglycemic drugs (for type II diabetes) or insulin supplementation. Studies have found that dipeptidyl peptidase IV (DPP-IV) is one of the key enzymes that mainly promote the degradation and inactivation of glucagon-like peptide-1 (GLP-1) in vivo and in vitro, so DPP-IV inhibitors are A new type of diabetes treatment drug, clinical results have shown that this type of drug has a good hypoglycemic effect, and no adverse reactions such as weight gain and hypoglycemia, which are common in other diabetes drugs, have been found. [0003] Alogliptin Benzoate, the chemical name is (R)-2-((6-(-3-am...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D239/553
CPCC07D401/04C07D239/553
Inventor 陈令浩
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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