Method for preparing DPP-IV inhibitor

A -3-boc-, intermediate technology, applied in the direction of organic chemistry, etc., can solve the problems of complicated post-processing and low reaction yield, and achieve the effect of simple post-processing and easy operation.

Inactive Publication Date: 2015-01-28
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these methods have changed solvents or bases, they still react step by step, and the post-treatment is quite complicated, resulting in low reaction yields.

Method used

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  • Method for preparing DPP-IV inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 (R)-tert-butyl (1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro -4-yl)piperidine-3-

[0040] base) preparation of tert-butyl carbamate

[0041]6-chloro-3-methyluracil (1kg), potassium carbonate powder (2.0kg), 2-cyanobenzyl bromide (2.34kg), N,N-dimethylacetamide (10kg), about 50 After reacting at 100 degrees Celsius for 4 hours, add potassium carbonate powder (1.0kg) to the reaction kettle, (R)-3-Boc-aminopiperidine (2.0kg) was stirred at 100 degrees Celsius for 4 hours, and after the reaction was completed, pour it into the reaction kettle Add a corresponding amount of water, cool to 50 degrees Celsius, stir for 1 hour, and centrifuge after cooling down to room temperature. After the filter cake is dried, it is washed with water and dried to obtain (R)-tert-butyl (1-(3-(2-cyano) Benzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro-4-yl)piperidin-3-yl)carbamate tert-butyl ester, pink solid . Yield 94.5%, purity 99%.

Embodiment 2

[0042] Example 2 (R)-tert-butyl (1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro -4-yl)piperidine-3-

[0043] base) preparation of tert-butyl carbamate

[0044] In 6-chloro-3-methyluracil (1kg), potassium carbonate powder (2.5kg), 2-cyanobenzyl bromide (2.0kg), N,N-dimethylacetamide (15kg), about 85 After reacting for 2 hours at ℃, add potassium carbonate powder (1.5kg) and (R)-3-Boc-aminopiperidine (3.1kg) to the reaction kettle and raise the temperature of the system to 95 ℃, then stir at 95 ℃ 4 hours, add water (20kg) in reaction kettle after completion of reaction, cool down to 60 degrees centigrade, stir for 1 hour, centrifuge after being down to room temperature, wash with water after filter cake is dried, dry, obtain (R)-tert-butyl ( 1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro-4-yl)piperidin-3-yl ) tert-butyl carbamate, pink solid. Yield 93.2%, purity 98%.

Embodiment 3

[0045] Example 3 (R)-tert-butyl (1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro -4-yl)piperidine-3-

[0046] base) preparation of tert-butyl carbamate

[0047] In 6-chloro-3-methyluracil (1kg), potassium carbonate powder (1.8kg), 2-cyanobenzyl bromide (4.2kg), N,N-dimethylacetamide (13kg), about 65 After reacting at 85 degrees Celsius for 3 hours, add potassium carbonate powder (1.8kg) to the reaction kettle, (R)-3-Boc-aminopiperidine (4.0kg) was stirred at 85 degrees Celsius for 7 hours, and after the reaction was completed, pour it into the reaction kettle Add the corresponding amount of water, cool down to 60 degrees Celsius, stir for 1 hour, and centrifuge after cooling down to room temperature. After the filter cake is dried, it is washed with water and dried to obtain (R)-tert-butyl (1-(3-(2-cyano) Benzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro-4-yl)piperidin-3-yl)carbamate tert-butyl ester, pink solid . Yield 94.1%, purity 99%.

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Abstract

The invention relates to a method for preparing a DPP-IV inhibitor, and concretely relates to a method for preparing a modified alogliptin benzoate intermediate (R)-t-butyl{1-[3-(2-cyanbenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro-4-yl]piperidyl-3-yl}-t-butyl carbamate. The method comprises the following steps: 1, carrying out a nucleophilic substitution reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in N,N-dimethyl formamide or N,N-dimethyl acetamide or an N,N-dimethyl formamide and N,N-dimethyl acetamide mixed solvent in the presence of an alkali metal carbonate; and 2, directly adding (R)-3-Boc-aminopiperidine and the alkali metal carbonate into the reaction solution obtained in step 1 for continuous reaction. The preparation method allows the reactions to be carried out in a same reactor and the intermediate to undergo a next step reaction without separation, so the method is simple to operate.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to an improved alogliptin benzoate intermediate (R)-tert-butyl{1-[3-(2-cyanobenzyl)-1-methyl-2, A preparation method of tert-butyl 6-dioxo-1-1,2,3,6-tetrahydro-4-yl]piperidin-3-yl}carbamate. Background technique [0002] Alogliptin Benzoate, also known as 2-{[(6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4- Dihydropyrimidin-1(2H)-yl]methyl}benzonitrile monobenzoate, the compound shown in formula (I), is a series of small molecules with a heterocyclic structure developed by Takeda Company with DPP-IV inhibitory activity Compounds (SYR series of compounds), among which alogliptin (SYR-322) has shown exciting anti-diabetic activity in early studies. Alogliptin can effectively reduce glucose levels in healthy subjects and patients with type 2 diabetes , increase the insulin level in the body, and is well tolerated. It is a highly selective dipeptidyl peptidase IV (dip...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 唐冬军李天亮寇景平
Owner SUNSHINE LAKE PHARM CO LTD
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