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Method for preparing tirofiban hydrochloride

A technology for tirofiban and hydrochloric acid, which is applied in the field of preparation of tirofiban hydrochloride, can solve the problems of large solvent consumption, harsh reaction conditions, high risk, etc., and achieve easy treatment of three wastes, mild reaction conditions, and easy operation Effect

Inactive Publication Date: 2011-11-16
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route still uses n-butyllithium, which also has the problems of high risk, harsh reaction conditions and difficult industrialization, and the one-step post-treatment of acylation needs to be extracted and washed with a variety of different mixed solvents for many times, the solvent consumption is large, and the operation trouble

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Synthesis of compound Ⅱ-1-1:

[0059] Take 1-benzyl-4-piperidone (50.0 g, 0.26 mol) and operate according to General Method 1 to obtain a mixture of isomers with and without double bonds II-1-1 with a yield of 64.8%. Through column separation, the pure products of the double bond product in the ring and the double bond product outside the ring can be obtained respectively (the eluent is CH 2 Cl 2 :CH 3 OH=50:1).

[0060] Intracyclic double bond product

[0061] 1 HNMR (400MHz, CDCl 3 )δ: 0.90(t, 3H), 1.31(m, 2H), 1.33(m, 2H), 1.75(m, 2H), 1.85(m, 2H), 1.96(m, 2H), 2.04-2.06(m , 4H), 2.39-2.55(m, 4H), 2.97(m, 2H), 2.98-3.16(m, 2H), 3.41(m, 2H), 3.62(s, 2H), 3.80(m, 1H), 4.01(m, 2H), 5.24(m, 1H), 6.74(d, 2H), 7.03(d, 2H)7.28-7.40(m, 5H)

[0062] MS (m / z): 529.2767 (M+H) + .

[0063] exocyclic double bond product

[0064] 1 HNMR (400MHz, CDCl 3 )δ: 0.88(t, 3H), 1.31(m, 2H), 1.58(m, 2H), 1.65(m, 2H), 1.75(m, 2H), 2.04-2.06(m, 4H), 2.39-2.55 (m, 4H), 2.97(m, 2H...

Embodiment 2

[0067] Synthesis of compound Ⅱ-1-2:

[0068] Benzyl 4-oxopiperidine-1-carboxylate (60.6 g, 0.26 mol) was operated according to General Method 1 to obtain a mixture of isomers with and without double bonds II-1-2 with a yield of 63.1%. Through column separation, the pure products of the product in the ring and the product outside the ring can be obtained respectively (the eluent is CH 2 Cl 2 :CH 3 OH=100:1).

[0069] Intracyclic double bond product

[0070] 1 HNMR (400MHz, CDCl 3 )δ: 0.90(t, 3H), 1.31(m, 2H), 1.33(m, 2H), 1.75(m, 2H), 1.85(m, 2H), 1.96(m, 2H), 2.21-2.29(m , 4H), 2.97(m, 2H), 2.98-3.16(m, 2H), 3.02-3.10(m, 4H), 3.41(m, 2H), 3.80(m, 1H), 4.01(m, 2H), 5.24(m, 1H), 5.34(s, 2H), 6.74(d, 2H), 7.03(d, 2H) 7.20(m, 5H)

[0071] MS (m / z): 573.2556 (M+H) + .

[0072] exocyclic double bond product

[0073] 1 HNMR (400MHz, CDCl 3 )δ: 0.88(t, 3H), 1.31(m, 2H), 1.58(m, 2H), 1.65(m, 2H), 1.75(m, 2H), 2.05(m, 2H), 2.97-3.12(m , 4H), 3.40(m, 2H), 3.44(s, 1H), 3.56(...

Embodiment 3

[0076] Synthesis of compound Ⅱ-1-3:

[0077] Take 1-allyl-4-piperidone (36.1 g, 0.26 mol) and operate according to General Method 1 to obtain a mixture of isomers with and without double bonds II-1-3 with a yield of 65.3%. Through column separation, the pure products of the product in the ring and the product outside the ring can be obtained respectively (the eluent is CH 2 Cl 2 :CH 3 OH=50:1).

[0078] Intracyclic double bond product

[0079] 1 HNMR (400MHz, CDCl 3 )δ: 0.90(t, 3H), 1.31(m, 2H), 1.33(m, 2H), 1.75(m, 2H), 1.85(m, 2H), 1.96(m, 2H), 2.11(m, 2H ), 2.44(m, 2H), 2.89(m, 2H), 3.06(m, 2H), 3.02-3.10(m, 2H), 3.41(m, 2H), 3.80(m, 1H), 4.01(m, 2H), 5.14-5.16(m, 2H), 5.85(m, 1H), 6.74(d, 2H), 7.03(d, 2H).

[0080] MS (m / z): 479.2498 (M+H) + .

[0081] exocyclic double bond product

[0082] 1 HNMR (400MHz, CDCl 3 )δ: 0.90(t, 3H), 1.31(m, 2H), 1.75(m, 2H), 1.85(m, 2H), 1.96(m, 2H), 2.06(m, 4H), 2.40(m, 4H ), 3.02(m, 2H), 3.02-3.10(m, 2H), 3.41(m, 2H), 3.80(m, 1H...

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Abstract

The invention discloses a method for preparing tirofiban hydrochloride. The method comprises the following steps: reducing a compound represented by a formula II-1 or a compound represented by a formula II-2 to obtain tirofiban represented by a formula III; carrying out salt formation for the tirofiban to transform into the target compound tirofiban hydrochloride (I). The method provided by the present invention has advantages of safe preparation process, mild reaction conditions, few steps, easy operation, high yield, cheap and available raw materials, easy treatment of three waste and convenience of industrial implementation. The reaction formulas for preparing the tirofiban hydrochloride are as follows.

Description

technical field [0001] The invention relates to a method for preparing tirofiban hydrochloride. Background technique [0002] Tirofiban hydrochloride is a salt compound of platelet GPIIb / IIIa antagonist. It is clinically used as an antithrombotic agent for the treatment of coronary artery syndrome (ACS), including non-Q wave myocardial infarction (MI) and unstable angina. Its chemical name is: (2S)-2-(butylsulfonylamino)-3-[4-[4-(4-piperidinyl)butoxy]phenyl]propionic acid, and its English name is: [0003] (2S)-2-(Butylsulfonylamino)-3-[4-[4-(4-piperidyl)butoxy]phenyl]propanoic acid; [0004] Its structural formula is as follows: [0005] [0006] In the prior art, EP478328, EP478363, and US522756 first disclose this type of compound and a synthetic method thereof, using 4-piperidine-2-ethanol as a starting material, and preparing 4-(4-N-tert. Butoxycarbonylpiperidinyl) butyl bromide, and then carry out acylation reaction with N-CBZ-L-tyrosine in NaH / DMF, and then ket...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
Inventor 李建其殷涛王冠张飞龙
Owner SHANGHAI INST OF PHARMA IND CO LTD
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