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Compound for preparing pyrimidinedione DPP-IV (dipeptidyl peptidase IV) inhibitors

A DPP-IV, pyrimidinedione technology, applied in the preparation of pyrimidinedione DPP-IV inhibitors, new intermediates and the field of preparation thereof, can solve the problems of low purity and low yield of compound 4

Active Publication Date: 2013-04-10
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of the prepared compound 4 is about 20%, the yield is low, and the prepared compound 4 is not high in purity, and further purification treatment is required, such as recrystallization, column chromatography and other means to obtain high-purity suitable Medicinal 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H) -yl}methyl)benzonitrile compound

Method used

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  • Compound for preparing pyrimidinedione DPP-IV (dipeptidyl peptidase IV) inhibitors
  • Compound for preparing pyrimidinedione DPP-IV (dipeptidyl peptidase IV) inhibitors
  • Compound for preparing pyrimidinedione DPP-IV (dipeptidyl peptidase IV) inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The synthesis of embodiment 1 compound I'

[0067]

[0068] Synthesis of compound 1-1:

[0069]

[0070] In a 100mL three-necked flask, add R-3-aminopiperidine dihydrochloride (5.0g, 0.029mol), phthalic anhydride (4.3g, 0.029mol), acetic acid (15mL), under stirring, control the temperature to 130°C, traced by TLC, after the basic reaction of the raw materials is complete, cool down to 80°C, add ethanol solution of hydrogen chloride (25%, 15mL), stir for about 30min, there is solid precipitation, continue to stir for 1h, move to room temperature and stir overnight, 0°C Let it stand for 3h, filter, and wash the filter cake with absolute ethanol, and add the resulting white solid to CH 2 Cl 2 (50mL) and water (20mL) mixed solution, with Na 2 CO 3 Adjust the pH to 9-10 with a saturated aqueous solution, extract and collect the organic phase, and wash the aqueous phase with CH 2 Cl 2 (50mL×2 times) extraction, combined organic phase, anhydrous Na 2 SO 4 Dry, fi...

Embodiment 2

[0086] Example 2 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H) The synthesis of -yl} methyl) benzonitrile:

[0087]

[0088] Compound I' (4g, 8.5mmol) was dissolved in a mixed solvent of ethanol (16mL) and hydrazine hydrate (4mL), reacted under reflux conditions, a large amount of solids were precipitated, filtered, and dissolved in CH 2 Cl 2 (60mL) washes the filter cake, adds 40mL water to the filtrate, extracts the organic phase, and the aqueous phase is distilled with CH 2 Cl 2 Extraction (60mL × 2 times), the organic phase was combined, washed with saturated NaCl aqueous solution (150mL × 2 times), the organic phase was washed with anhydrous NaCl 2 SO 4 Dry, filter, decolorize with activated carbon, and evaporate the solvent under reduced pressure to obtain 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-diox Substituted-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile 2.75g (yield 95%).

[0089] 1 HNMR (500MHZ, CDCl 3 ): δ7.6...

Embodiment 3

[0098] The synthesis of embodiment 3 compound 2' and 2

[0099]

[0100] Compound 2' was prepared using the method for preparing compound I' described in Example 1, but using 2-bromomethyl-4-fluorobenzylcyanide instead of o-cyanobenzyl bromide, refer to 2-({6-[(3R) The preparation method of -3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile is prepared Compound 2.

[0101] Compound 2'MS m / z (ESI): 488 (M+1).

[0102] Compound 2 MS m / z (ESI): 358 (M+1).

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a new intermediate shown as a formula I and used for preparing pyrimidinedione DPP-IV (dipeptidyl peptidase IV) inhibitors, such as 2-({6-[(3R)-3-aminopiperidine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl}methyl) cyanophenyl or salts thereof or analogs thereof, and a preparation method of the new intermediate. The formula I is described in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for preparing pyrimidinedione DPP-IV inhibitors, in particular to a new intermediate and a preparation method thereof. Background technique [0002] Diabetes Mellitus (DM) is a metabolic disease with multiple etiologies, which is caused by an absolute or relative deficiency of insulin, resulting in an increase in blood sugar and causing metabolic disorders in the body. It can be divided into insulin-dependent diabetes mellitus (insulin-dependent diabetes mellitus, IDDM, type I diabetes) and noninsulin-dependent diabetes mellitus (NIDDM, type II diabetes), of which type II diabetes is the most common, accounting for diabetes patients More than 90. [0003] Dipeptidyl peptidase IV (DPP-IV) is a serine protease expressed in many tissues in the body, such as intestine, liver, lung, kidney, etc., as well as in circulating T lymphocytes. It is responsible for the metabolic ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/04
Inventor 张喜全张凯刘飞
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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