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Method for preparing tirofiban hydrochloride intermediate

A technology for intermediates and inorganic salts, applied in the field of compound preparation, can solve the problems of difficulty in industrialized production of tirofiban hydrochloride, long production cycle, and difficulty in scale-up production, so as to avoid equipment corrosion, environmental pollution, and reaction steps. Short, method-efficient results

Active Publication Date: 2010-12-01
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires a total of 5 steps of reaction, and its production cycle is long, the cost is high, and the yield is low
The decarboxylation step is difficult to scale up production, because there is no solvent and stirring is required during decarboxylation at elevated temperature, and the reaction mixture is solid, resulting in incomplete reaction; the dangerous LiAlH4 is also used in the final reduction of carboxyl groups, which is likely to cause safety accidents
Above-mentioned condition makes tirofiban hydrochloride be difficult to realize suitability for industrialized production
[0013] For the deesterification group of substituted malonic acid diester, there are bibliographical reports (O.P.Vig et al, Indian J.Chem.(B), 1980,19, pp950) that substituted malonic acid diester can directly take off an ester group and To obtain the corresponding monoester, if there is a pyrazine ring in the substituent, the reaction can also be carried out (E.C.Taylor et al, J.Org.Chem., 1977, 42, pp1523), because pyridyl is a basic group, Deesterification of compounds with simple pyridyl groups has not been reported

Method used

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  • Method for preparing tirofiban hydrochloride intermediate
  • Method for preparing tirofiban hydrochloride intermediate
  • Method for preparing tirofiban hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of embodiment 14-(4-pyridyl)-1-butyric acid ethyl ester compound 2

[0037] Dissolve 500 grams of intermediate compound 1 in a mixed solvent of 1500 milliliters of dimethyl sulfoxide and 50 milliliters of water, add 120 grams of NaCl, raise the temperature to 140 ° C for 15 hours, and add 6 liters of water after detecting no raw material spots by thin-plate chromatography. After extraction with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2 as a brownish-red oil, with a yield of 324.4 g and a yield of 89%.

[0038] 1 H NMR (400MHz, CD 3 SOCD 3 ): 1.22 (3H, t, J = 7.2Hz), 1.86 ~ 1.94 (2H, m), 2.31 (2H, t, J = 7.2Hz), 2.63 (2H, t, J = 7.6Hz), 4.05 ~ 4.10 (2H, m), 7.17 (2H, d, J = 4.8 Hz), 8.47 (2H, d, J = 4.0 Hz).

Embodiment 2

[0039] The preparation of embodiment 24-(4-pyridyl)-1-butanoic acid ethyl ester compound 2

[0040] Dissolve 500 grams of intermediate compound 1 in a mixed solvent of 2000 milliliters of dimethyl sulfoxide and 70 milliliters of water, add 120 grams of NaCl, heat up to 160 ° C for 10 hours, follow up and post-process as in Example 2 to obtain compound 2 , The amount was 336.2 grams, and the yield was 92%.

Embodiment 3

[0041] Example 3 Preparation of 4-(4-pyridyl)-1-butanoic acid ethyl ester compound 2

[0042] Dissolve 500 grams of intermediate compound 1 in a mixed solvent of 1500 milliliters of N,N-dimethylformamide and 50 milliliters of water, add 153 grams of KCl, heat up to 120° C. and react for 18 hours, follow up and follow up as in Example 2 Compound 2 was obtained after treatment, with a yield of 318.3 g and a yield of 87%.

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Abstract

The invention relates to a method for preparing a compound, in particular to a method for preparing 4-(4-pyridyl)-1-butanol which is a tirofiban hydrochloride intermediate. The preparation method has high yield, causes little waste solid, liquid and gas, ensures high product purity and successfully realizes industrial production.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of tirofiban hydrochloride intermediate 4-(4-pyridyl)-1-butanol. Background technique [0002] Tirofiban hydrochloride (Tirofiban hydrochloride, 4) is the first non-peptide platelet IIb / IIIa receptor antagonist, its structural formula is as follows: [0003] [0004] Tirofiban is highly selective and specific to platelet IIb / IIIa receptors, reversibly inhibits platelet aggregation with a short half-life, has no antigenicity, and has few adverse reactions. Since its launch, it has been widely used in many clinical fields, especially in patients with unstable angina or non-Q wave myocardial infarction and in the prevention of cardiac ischemic events in percutaneous coronary intervention (PCI). . [0005] 4-(4-pyridyl)-1-butanol compound 3 is an intermediate for preparing tirofiban hydrochloride, and its structural formula is as follows: [0006] ...

Claims

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Application Information

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IPC IPC(8): C07D213/30
Inventor 孙华君黄璐杨尚金刘传志
Owner WUHAN WUYAO SCI & TECH
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