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Synthesis method of anagliptin

A synthetic method and intermediate technology, which is applied in the field of synthesis of anagliptin (Anagliptin) raw materials, can solve the problems of high price, and achieve the effect of cheap raw materials, mild reaction conditions, and convenient post-treatment

Inactive Publication Date: 2016-04-20
南通佰康生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But it is more expensive than traditional diabetes drugs

Method used

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  • Synthesis method of anagliptin
  • Synthesis method of anagliptin
  • Synthesis method of anagliptin

Examples

Experimental program
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Embodiment

[0023] 1. Preparation of 1,1,1-trichloro-4-ethoxy-3-vinyl-2-one (2)

[0024]

[0025] Vinyl ether (20kg, 277mol, 2.0eq.) was placed in a 100L reactor, cooled to 0°C, and trichloroacetyl chloride (25kg, 139mol, 1.0eq.) was slowly added. After the dropwise addition was completed, the temperature was raised slowly and kept at room temperature for 9 hours until the reaction was completed. First remove the solvent under reduced pressure, then heat up to 100°C and distill under reduced pressure until there is no obvious fraction, and finally heat up to 120°C and then distill under high vacuum to obtain the product 2 It is light yellow liquid (25kg, yield 82%). 1 H-NMR (400MHz, CDCl 3 ) δ 7.81(d,1H, J =12.0Hz), 6.96(d, 1H, J=12.0Hz), 4.05(q, 2H, J=7.2Hz), 1.34(t, 3H, J=7.2Hz)ppm.

[0026] 2. Preparation of ethyl 3,3-diethoxypropionate (3)

[0027]

[0028] Add absolute ethanol (30kg) and K2CO3 (1.6kg, 11.6mol) into a 100L reactor, then slowly add compound 2 (25kg, 115mol)...

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Abstract

The invention relates to a synthesis method of bulk drug of anagliptin for treating II type diabetes, and aims to solve the problem that at present there is no industrial synthesis method of anagliptin. The synthesis method comprises the following steps: (1) taking vinyl ethyl ether and trichloroacetic chloride as the raw materials, carrying out three-step reactions to obtain an intermediate (4) with a protected aldehyde group; carrying out dehydration condensation between the intermediate (4) and 3-amino-5-methylpyrazole to obtain pyrazolopyrimidine parent nucleus; and hydrolyzing carboxyl ethyl ester to obtain 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid6; (2) taking L-proline as the raw material, subjecting L-proline to methyl esterification, ammoniation, acetylation, and cyaniding reactions to obtain a chiral cyanopyrrole intermediate (11); making the chiral cyanopyrrole intermediate (11) and a diamine segment (12) carry out nucleophilic substitution reactions under an alkaline condition to obtain an intermediate (13), and finally removing the Boc protective group from the intermediate (13) in the presence of hydrochloric acid to obtain a cyanopyrrole amine intermediate (14); (3) coupling 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid 6 with the cyanopyrrole amine intermediate (14) under condensation conditions so as to obtain the bulk drug anagliptin.

Description

technical field [0001] The invention provides a method for synthesizing raw materials of an anti-II diabetes drug alaagliptin (Anagliptin). Background technique [0002] Diabetes mellitus is a metabolic disease characterized by hyperglycemia, in which type II diabetes patients account for more than 90% of the total number of cases. Long-term high blood sugar caused by diabetes can lead to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Dipeptidyl peptidase-4 (DipeptidylPeptidase4, DPP-4) is one of the new targets for anti-type II diabetes, and the research and development of its inhibitors has become a hot spot in the research of anti-diabetic drugs. DPP-4 inhibitors can increase endogenous glucagon-like peptide-1 (Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulin-releasing polypeptide ( Glucose-dependent Insulinotropic Peptide, GIP) level to achieve hypoglycemic effect. In addition, DPP-4 inhi...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 魏万国朱信磊刘雪松黄仁才
Owner 南通佰康生物医药有限公司
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