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Method for preparing almotriptan malate

A technology of almotriptan and malic acid, applied in the field of medicinal chemical synthesis, can solve the problems of insecurity, increased production cost, inconvenience and the like

Inactive Publication Date: 2012-12-19
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, the preparation of 1-triethylsilyloxy-4-triethylsilyl-3-butyne involves the use of n-butyllithium, which is inconvenient and unsafe for industrial mass production
Moreover, the use of n-butyllithium requires strict reaction conditions, and the moisture content in the reaction process needs to be strictly controlled, and the required special storage conditions lead to increased production costs.

Method used

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  • Method for preparing almotriptan malate
  • Method for preparing almotriptan malate
  • Method for preparing almotriptan malate

Examples

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Embodiment 1

[0023] Example 1 Synthesis of Almotriptan Malate

[0024] 1.1 Preparation of 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole

[0025] Reaction equation:

[0026]

[0027] Steps:

[0028] 19.3L of water, 380ml of concentrated hydrochloric acid and 1556.0g of 4-chlorobutyraldehyde diethyl acetal were added to the 50L reaction kettle, stirred at room temperature for 1 hour, and used for later use.

[0029] Under nitrogen protection, put 21.4L of methanol, 2000g of 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine, 4.6L of water and 700ml of concentrated HCl into the stirred 100L reactor, dropwise at 20±5°C Add the 4-chlorobutyraldehyde diethanol acetal solution prepared above. During the dropwise addition, a yellow solid was precipitated. After the dropwise addition was completed, the mixture was stirred at 0-5° C. for 2 hours. TLC monitoring of raw materials basically completed the reaction. Centrifuge and filter to dryness to obtain a yellow solid. ...

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Abstract

The invention provides a method for preparing almotriptan malate, which comprises that (1) 4-(1-pyrrolidinylsulforylmenthyl)phenylhydrazine and 4-chlorobutyraldehyde are reacted with each other to obtain the corresponding phenylhydrazone, and 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulforylmenthyl)-1H-benzazole (ATP-2) is formed through cyclization under the acid condition; (2) ATP-2 is methylated under the action of formaldehyde and sodium borohydride to obtain crude almotriptan alkali (ATP-3); (3) the crude almotriptan alkali (ATP-3) is respectively salified and crystallized in fumaric acid and salicylic acid ethanol solution; and (4) the refined ATP-3 and DL-malic acid are reacted with each other in carbine to obtain the almotriptan malate. The almotriptan malate with high purity can be prepared through adopting the method; and the method has a simple synthetic technology, easily obtained raw materials, high product yield and low impurity content, and can satisfy the requirement of industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemical synthesis, in particular to a preparation method of almotriptan malate. Background technique [0002] Almotriptan malate, chemical name is 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole malate , is a migraine treatment drug for adolescents and adults. It was first listed in Spain in September 2000, and was approved by the US FDA in May 2001 for the treatment of adult migraine. [0003] Almotriptan malate is a brand-new chemically synthesized compound. There are not many synthetic methods reported in the literature. Almost all synthetic routes start from p-aminobenzenesulfonylpyrrole (compound II), and then obtain through different methods. Target compound: [0004] [0005] For example, the method described in ES2084560 is a synthetic method originally reported by the original manufacturer. The compound II is diazotized to obtain the corresponding hydrazine, and then a...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07C51/41C07C59/245
Inventor 谢义鹏彭熙林周维兰李元波蓝海
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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