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Preparation method for dihydropyrimidine derivative

A technology of dihydropyrimidine and methyluracil, applied in the direction of organic chemistry, can solve the problems of low yield, many impurities, affecting the purity and yield of the final product, etc., and achieve the effect of low cost and favorable industrial production

Inactive Publication Date: 2015-03-11
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this method, the yield of 2-bromomethyl-4-fluorobenzonitrile is low, and there are many impurities, which affect the purity and yield of the final product

Method used

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  • Preparation method for dihydropyrimidine derivative
  • Preparation method for dihydropyrimidine derivative

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specific Embodiment approach

[0031] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0032] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0033] In the present invention, g means gram, and mL means milliliter.

Embodiment 1

[0035] Put 1.00kg of 4-fluoro-2-methylbenzonitrile, 1.98kg of N-bromosuccinimide, 0.025kg of azobisisobutyronitrile, and 7.40kg of chloroform into the reaction kettle, and control the temperature at 60°C- Stir and react at 70°C for 3 hours, cool down to 25°C, add 15% sodium sulfate solution (mass concentration) for washing, collect the organic phase and concentrate to dryness to obtain the first product.

[0036] Add 1.18kg of 6-chloro-3-methyluracil, 1.12kg of triethylamine, and 7.40kg of dimethylacetamide to the first product, and stir at a temperature of 65°C-70°C for 1 hour; then add Diethyl phosphite 0.31kg, stirred for 2.5 hours. Then the temperature was lowered to 25° C., 5.00 kg of water was added to the reaction system, and the resulting mixture was stirred for 0.5 hours. Then the mixture was cooled to 0°C-5°C and stirred for 0.5 hours. The mixture was centrifuged, and the resulting solid was dried at 40°C for 12 hours to obtain 1.97 kg of a light yellow solid, namely...

Embodiment 2

[0038] Put 1.00kg of 4-fluoro-2-methylbenzonitrile, 2.35kg of N-bromosuccinimide, 0.050kg of azobisisobutyronitrile, and 9.00kg of chloroform into the reaction kettle, and control the temperature at 65°C- Stir and react at 70°C for 3 hours, cool down to 25°C, add 20% sodium sulfate solution (mass concentration) for washing, collect the organic phase and concentrate to dryness to obtain the first product.

[0039] Add 1.19kg of 6-chloro-3-methyluracil, 1.34kg of triethylamine, and 8.00kg of dimethylacetamide to the first product, and stir at a temperature of 65°C-75°C for 1 hour; then add Dimethyl phosphite 0.45kg, stirred for 2 hours. Then the temperature was lowered to 25° C., 10.00 kg of water was added to the reaction system, and the resulting mixture was stirred for 0.5 hours. Then the mixture was cooled to 0°C-5°C and stirred for 0.5 hours. The mixture was centrifuged, and the resulting solid was dried at 40°C for 12 hours to obtain 1.96 kg of a light yellow solid, name...

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Abstract

The invention provides a method for preparing 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile, and belongs to the technical field of pharmacy. The method comprises: performing bromination reaction on 4-fluoro-2-methylbenzonitrile and a bromination reagent to obtain a first product, then reacting the first product with 6-chloro-3-methyluracil in an alkali and a solvent for a period, then adding a catalyst, and performing reaction and post-processing, so as to obtain the target product. The catalyst is selected from one or more of diethyl phosphite, dimethyl phosphite and diphenyl phosphite. The provided method does not need to separate and purify 2-bromomethyl-4-fluorobenzonitrile, and is capable of obtaining the high-purity product at a high yield by adding the catalyst, and is low in cost and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a dihydropyrimidine derivative, in particular to a preparation method of an intermediate used for preparing trexagliptin, and belongs to the technical field of pharmacy. Background technique [0002] Trelagliptin (Trelagliptin) is a dipeptidyl peptidase IV (DPP-4) inhibitor once a week, which can selectively and continuously inhibit DPP-4 and control blood sugar levels; its structure is as follows (1 ) as shown: [0003] [0004] The preparation of Trexagliptin is generally carried out by bromination reaction of 4-fluoro-2-methylbenzonitrile (compound (01)), separation and purification to obtain 2-bromomethyl-4-fluorobenzonitrile (compound (02)) , and then reacted with 6-chloro-3-methyluracil (compound (03)), separated and purified to obtain 2-((6-chloro-3-methyl-2,4-dioxo-3,4-di Hydropyrimidin-1 (2 hydrogen)-base) methyl)-4-fluorobenzonitrile (compound (04)), compound (04) is through reaction, sepa...

Claims

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Application Information

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IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 唐冬军李天亮韩小东
Owner SUNSHINE LAKE PHARM CO LTD
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