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Zolmitriptan and preparation method thereof

A technology of oxazolidinone and reaction, which is applied in the field of pharmaceutical preparations and can solve problems such as lengthiness

Active Publication Date: 2013-09-04
CHENGDU TIANTAISHAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0035] The main disadvantages of the method described in WO2005 / 105792 are as follows: it is a multi-step and lengthy process involving 5-7 steps to obtain Zolmitriptan (I) was obtained from the diazonium salt (XV) of -2-ketone (IX); the process involved highly basic conditions that could cleave the oxazolidinone ring; reported overall yields were only 9-22 %

Method used

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  • Zolmitriptan and preparation method thereof
  • Zolmitriptan and preparation method thereof
  • Zolmitriptan and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1: the preparation of L-4-nitro-phenylalanine

[0105] Reaction formula:

[0106] Feeding ratio: L-phenylalanine 1kg, concentrated sulfuric acid 1700ml, concentrated nitric acid 450ml

[0107] Operation: In a reaction vessel equipped with a thermometer, add concentrated sulfuric acid according to the ratio, cool in an ice-salt bath to below 0°C and start to slowly add concentrated nitric acid dropwise. During the dropping process, control the temperature below 2°C; after dropping, control the temperature below 20°C Add L-phenylalanine in batches; after the addition, remove the ice-salt bath and let it rise to room temperature naturally, and stir for 30 minutes. Pour the reaction solution into 7L of ice water, control the temperature below 5°C while stirring, adjust the pH to 9.5-10.5 with 25% ammonia water, cool and crystallize, filter, and collect the solid; add 14L of hot water to heat and stir to dissolve the solid, and use the amount of feed Stir an...

Embodiment 2

[0108] Embodiment 2: the preparation of L-4-nitrophenylalanine methyl ester

[0109] Reaction formula:

[0110] Feed ratio: L-4-nitro-phenylalanine 720g, thionyl chloride 858ml, anhydrous methanol 3430ml

[0111] Operation: In a reaction vessel equipped with a thermometer, add anhydrous methanol according to the ratio, cool in an ice-salt bath to below 0°C and add thionyl chloride dropwise; after dropping, control the temperature below 2°C and stir for 30 minutes, then add L- 4-Nitro-phenylalanine was stirred in an ice-salt bath for 8 hours, removed from the ice bath, allowed to rise to room temperature naturally, and stirred for reaction. TLC monitors the reaction process (developing agent: chloroform: methanol = 1: 2), after the completion of the reaction (R f =0.8~0.85), use a rotary evaporator (control temperature 85±5°C) to concentrate under reduced pressure until no liquid drops out, add 750ml ice water and 1500mL ethyl acetate, and use saturated Na 2 CO 3 Soluti...

Embodiment 3

[0112] Embodiment 3: Preparation of (S)-3-(4-nitrophenyl)-2-amino-1-propanol

[0113] Reaction formula:

[0114] Feeding ratio: L-4-nitrophenylalanine methyl ester 200g, sodium borohydride 130g, methanol 2000ml, purified water 1000ml

[0115] Operation: In a reaction vessel equipped with a thermometer, add methanol and purified water according to the ratio, cool in an ice-salt bath to below 0°C, and add sodium borohydride in batches (control the reaction temperature not to exceed 2°C). After the addition is completed, add L-4-nitrophenylalanine methyl ester in batches (control the reaction temperature not to exceed 5°C). After the addition, stir and react at 0-5°C for 0.5 hours; then slowly rise to room temperature (about 20°C) , stirred for 3-5 hours; heated in a water bath to 50°C for 2-3 hours, TLC showed that the reaction was complete (developing solvent: dichloromethane: methanol = 2:1). Add 5% activated carbon to the reaction solution, decolorize at 50°C for 20 min...

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Abstract

The invention relates to zolmitriptan and a preparation method thereof, in particular to the preparation method of zolmitriptan. The preparation method comprises the following steps: (1) reacting (S)-3-(4-nitrophenyl)-2-amino-1-propanol with triphosgene in an organic solvent in the presence of an alkaline reagent, and cyclizing to obtain (S)-4-(4-nitrobenzyl)-2-oxazolidinone; (2) carrying out hydrogenation reduction on (S)-4-(4-nitrobenzyl)-2-oxazolidinone in a solvent in the presence of a catalyst to obtain (S)-4-(4-aminobenzyl)-2-oxazolidinone; (3) carrying out diazo-reaction on (S)-4-(4-aminobenzyl)-2-oxazolidinone in an acidic solution in the presence of a diazotization reagent to obtain (S)-4-(4-hydrazinobenzyl)-2-oxazolidinone; and (4) reacting (S)-4-(4-hydrazinobenzyl)-2-oxazolidinone with 4-(N,N-dimethyl)-amino-dibutyl acetal to generate the zolmitriptan. The zolmitriptan prepared with the method is high in purity.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and relates to a medicine for treating or preventing migraine and a preparation method thereof, in particular to zolmitriptan and a preparation method thereof for treating migraine. The method of the invention prepares Zolmitriptan has good characteristics. Background technique [0002] Migraine is one of clinical common disease, frequently-occurring disease, and its incidence rate is about 10%. The International Headache Society defines migraine as intermittent attacks of headache accompanied by autonomic disturbances. Clinically manifested as paroxysmal headache: often accompanied by dizziness, hearing loss and so on. The incidence of migraine in my country ranges from 4.2% to 14.6%, with a male to female ratio of 1:4. With the acceleration of the pace of life and the increase of work pressure, the incidence of migraine in China is on the rise, and it has become a common ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06A61K31/4178A61P25/06
Inventor 赵东明方专王敬江威张莲莲董国明
Owner CHENGDU TIANTAISHAN PHARMA
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