The preparation method of n-n-butylsulfonyl-o-(4-(4-pyridyl)-butyl)-l-tyrosinic acid alkyl ester

A technology of n-butylsulfonyl and tyrosine alkyl ester, which is applied in N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine alkyl In the field of ester preparation, it can solve the problems of difficult scale-up production, long steps, and low total yield, and achieve the effects of avoiding environmental pollution, mild reaction conditions, and fewer reaction steps

Inactive Publication Date: 2011-12-21
SHANGHAI JINGFENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The purpose of this invention is to provide a kind of method for preparing N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosinic acid alkyl ester, this method mainly solves the...

Method used

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  • The preparation method of n-n-butylsulfonyl-o-(4-(4-pyridyl)-butyl)-l-tyrosinic acid alkyl ester
  • The preparation method of n-n-butylsulfonyl-o-(4-(4-pyridyl)-butyl)-l-tyrosinic acid alkyl ester
  • The preparation method of n-n-butylsulfonyl-o-(4-(4-pyridyl)-butyl)-l-tyrosinic acid alkyl ester

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Embodiment 1

[0033] 1.1 Preparation of methylsulfonyl pyridine butanol (2)

[0034] A solution of 4-pyridinebutanol (1.5g, 10.0mmol) in dichloromethane (30mL) was cooled to 0°C, and triethylamine (2.1mL, 15mmol) and MsCl (3.5g, 30.6mmol) were added sequentially. Stir at 0°C for 10 minutes after the addition is complete. The reaction system was washed with anhydrous Na 2 SO 4 After drying and removing the solvent under reduced pressure, methanesulfonylpyridinebutanol (2) (2.46g, quant.) was obtained.

[0035] 1.2 Preparation of methylsulfonyl pyridine butanol (2)

[0036] A solution of 4-pyridinebutanol (8.0 g, 53.3 mmol) in dichloromethane (60 mL) was cooled to -5°C, and triethylamine (11.2 mL, 80.8 mmol) and MsCl (4.3 mL, 55.6 mmol) were added in sequence. Stir at 0°C for 10 minutes after the addition is complete. The reaction system was washed with anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain methanesulfonylpyridinebutanol (2) (12.50 g...

Embodiment 2

[0048] 2.1 N-Butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine ethyl ester (4)

[0049] In N-n-butylsulfonyl-L-tyrosine ethyl ester (3.30g, 10.00mmol) solution in anhydrous DMF (30mL), the reaction system was sequentially added K 2 CO 3 (1.86g, 13.5mmol) and mesylpyridinebutanol (2) (2.46g, 10.73mmol). After the addition, the system was heated to 80°C and reacted for 12 hours. After routine post-treatment of the system, the target product N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine ethyl ester 4 (1.5g, 32.5% ). 1 H NMR (300MHz, CDCl 3 ), δppm: 8.48(br, 2H), 7.13(d, J=4.8Hz, 2H), 7.10(d, J=9.0Hz, 2H), 6.80(d, J=8.7Hz, 2H), 5.10(d , J=9.0Hz, 1H), 4.33-4.18(m, 3H), 3.93(t, J=5.4Hz, 2H), 3.11-2.93(m, 2H), 2.79-2.66(m, 4H), 1.83- 1.81 (m, 4H), 1.66-1.56 (m, 2H), 1.34-1.23 (m, 5H), 0.86 (t, J=7.2Hz, 3H).

[0050] 2.2 N-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine ethyl ester (4)

[0051] In N-n-butylsulfonyl-L-tyrosine ethyl ester (16.33g, 49.57mmol) solution anh...

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Abstract

The preparation method of a kind of N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosinic acid alkyl ester that the present invention relates to comprises the following steps: the first step reaction : take pyridine butanol as the starting material, react with methanesulfonyl chloride under the action of alkali to obtain methanesulfonyl pyridine butanol; second step reaction: methanesulfonyl pyridine butanol under alkaline conditions, in the presence of phase transfer catalyst , and N-n-butylsulfonyl L-tyrosine alkyl ester condensation to N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine alkyl ester. The reaction formula is as follows: the synthesis method of the present invention has few reaction steps, high total yield, mild reaction conditions, is suitable for industrial scale-up production, and avoids the use of dangerous and environmentally polluting reagents. Intermediate 2 was directly used in the next reaction without purification after simple treatment.

Description

technical field [0001] The invention relates to a preparation method of the key intermediate of tirofiban hydrochloride---N-n-butylsulfonyl-O-(4-(4-pyridyl)-butyl)-L-tyrosine alkyl ester. Background technique [0002] Tirofiban hydrochloride (N-n-butylsulfonyl-O-4-(4-piperidinyl)butyl)-L-tyrosine hydrochloride monohydrate, TRFB·HCl·H 2 O) As a reversible non-peptide platelet GPIIb / IIa receptor antagonist, it was developed by the international pharmaceutical giant Merck in the 1990s and successfully approved by the US FDA in May 1998. Currently, the platelet antagonist The agent has been widely marketed and used in Switzerland, China, Germany and the Netherlands. The drug is suitable for patients with unstable angina or non-Q wave myocardial infarction to prevent cardiac ischemic events. Cardiac ischemic complications associated with sudden occlusion of treated coronary arteries. The structural formula of tirofiban hydrochloride is as follows: [0003] [0004] So far,...

Claims

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Application Information

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IPC IPC(8): C07D213/30
Inventor 葛亮刘时奎邱小龙
Owner SHANGHAI JINGFENG PHARMA
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