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Preparation method of almotriptan key intermediate 1-(4-amino-phenylmethylsulfonyl)pyrrolidine

A technology of phenylmethylsulfonyl and almotriptan is applied in the field of preparation of key intermediate 1-pyrrolidine, and can solve the problems of difficult post-processing, unsuitable large-scale industrialization and the like

Inactive Publication Date: 2018-08-24
JIAXING CITY NO 2 HOSPITAL
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  • Summary
  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0006] WO2006129190 discloses a Heck connection to synthesize almotriptan, still starting from 1-(4-amino-phenylmethylsulfonyl)pyrrolidine through halogenation and coupling to obtain the product, but this method requires n-butyl Expensive reagents such as lithium-based, difficult post-processing, etc., are not suitable for large-scale industrialization, etc.

Method used

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  • Preparation method of almotriptan key intermediate 1-(4-amino-phenylmethylsulfonyl)pyrrolidine
  • Preparation method of almotriptan key intermediate 1-(4-amino-phenylmethylsulfonyl)pyrrolidine
  • Preparation method of almotriptan key intermediate 1-(4-amino-phenylmethylsulfonyl)pyrrolidine

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preparation example Construction

[0025] A kind of preparation method of key intermediate 1-(4-amino-phenylmethylsulfonyl) pyrrolidine of almotriptan, its main steps are as follows:

[0026] Step 1: Prepare the Vilsmeier reagent with triphosgene (BTC) and N-dimethylformamide (DMF) for subsequent use, p-nitrobenzene methanesulfonic acid is a raw material, and react with Vilsmeier reagent sulfonylation under alkali-catalyzed conditions, and use TLC Monitor the reaction process, generate p-nitrobenzene methanesulfonyl chloride (formula 1), directly carry out the next step reaction without processing;

[0027]

[0028] Step 2: Using the p-nitrobenzenesulfonyl chloride obtained in Step 1 as a raw material, carry out a nucleophilic addition-elimination reaction with pyrrole under alkali catalysis, monitor the reaction with TLC, and extract it with saturated sodium bicarbonate and saturated saline after the reaction , the organic phase was dried with anhydrous sodium sulfate and distilled under reduced pressure to...

Embodiment 1

[0043] Step 1: Preparation of p-nitrobenzenesulfonyl chloride:

[0044] Take 7.3g of DMF (0.1mol) in an ice bath and cool down to below 0°C, stir with a magnetic force, dissolve 9.86g of Sanguangchrome BTC (0.033mol) in 10ml of anhydrous dichloromethane, slowly drop into DMF, and control the reaction at 0°C Below, stir and react for 30 minutes after the dropwise addition is completed, and the Vilsmeier reagent is seen as a white solid; Reaction, TLC detection (development phase: ethyl acetate:petroleum ether=2:1) ​​After reacting for 2h, the system was cooled and concentrated to 10ml for later use;

[0045] Step 2: Preparation of 1-(4-nitro-phenylmethylsulfonyl)pyrrolidine:

[0046] Take 10ml of the p-nitrobenzenemethanesulfonyl chloride system in step 1, add 10.1g (0.1mol) of triethylamine, dissolve 6.7g (0.1mol) of pyrrole in 10ml of dichloromethane, drop into the p-nitrobenzenemethanesulfonyl chloride system, After 30 minutes of dropwise addition, keep the reaction at 60°C ...

Embodiment 2

[0050] Step 1: the preparation of p-nitrobenzene methanesulfonyl chloride:

[0051] Take 7.3g of DMF (0.1mol) and cool it down to below 0°C in an ice bath, stir it magnetically, dissolve 9.86g of BTC (0.033mol) in 10ml of anhydrous tetrahydrofuran, slowly drop it into DMF, control the reaction below 0°C, and complete the dropwise addition After stirring the reaction for 30min. 21.6g of p-nitrobenzenemethanesulfonic acid (0.1mol) was dissolved in 10ml of anhydrous tetrahydrofuran, slowly dropped into the Vilsmeier reagent system, reacted at 40°C, and detected by TLC (developing phase: ethyl acetate:petroleum ether=2:1) After 3.5 hours, the system was cooled and concentrated to 10ml for later use;

[0052] Step 2: Preparation of 1-(4-nitro-phenylmethylsulfonyl)pyrrolidine

[0053] Take 10ml of the p-nitrobenzenemethanesulfonyl chloride system in step 1, add 7.91g (0.1mol) of pyridine, dissolve 6.7g (0.1mol) of pyrrole in 10ml of dichloromethane, drop into the p-nitrobenzenemet...

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Abstract

The invention discloses a preparation method of an almotriptan key intermediate 1-(4-amino-phenylmethylsulfonyl)pyrrolidine. The main steps comprise: 1) preparing a Vilsmeier reagent by using BTC andDMF, and carrying out a sulfonylation reaction on p-nitrobenzene methanesulfonic acid as a raw material and the Vilsmeier reagent under the catalysis of an alkali to generate p-nitrobenzene methanesulfonyl chloride; 2) carrying out a nucleophilic addition-elimination reaction on the p-nitrobenzene methanesulfonyl chloride as a raw material and pyrrole under the catalysis of an alkali, and treatingafter the reaction to obtain 1-(4-nitro-phenylmethylsulfonyl)pyrrolidine; and 3) carrying out a catalytic hydrogenation reaction on the 1-(4-nitro-phenylmethylsulfonyl)pyrrolidine by introducing hydrogen under the action of a metal catalyst, combing the organic phase, drying with anhydrous sodium sulfate, and carrying out pressure reducing distillation to obtain the 1-(4-amino-phenylmethylsulfonyl)pyrrolidine. According to the present invention, the preparation method of the key intermediate for the synthesis of almotriptan is provided, and has characteristics of economical synthesis, environmental friendliness and simple process.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of 1-(4-amino-phenylmethylsulfonyl)pyrrolidine, a key intermediate of almotriptan. Background technique [0002] Almotriptan (Almotriptan), the chemical name is 3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole. A 5-HT developed by the company 1B / 1D Receptor agonist, clinically mainly used for the treatment of migraine, its structural formula is as follows: [0003] [0004] In the existing synthetic technology, both WO2008151584 and WO2009016414 use the indole synthesis method to synthesize almotriptan, and both start from 1-(4-amino-phenylmethylsulfonyl)pyrrolidine, and pass through diazo Reaction, reduction, protection in hydrazone form, cyclization, and methylation give the product. The synthetic route is as follows: [0005] [0006] WO2006129190 discloses a Heck connection to synthesize almotriptan, still starting from 1-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/26
CPCC07D295/26
Inventor 王琰萍杨毅韩晨阳李文燕张晓玲官俏兵周清河徐从英
Owner JIAXING CITY NO 2 HOSPITAL
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