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Preparation method of milnacipran hydrochloride

A technology for milnacipran hydrochloride and compounds, which is applied to the preparation of carboxylic acid amides, preparation of organic compounds, chemical instruments and methods, etc., can solve problems such as not being very economical and affecting yield, and achieve mild conditions, simple operation, The effect of high yield

Inactive Publication Date: 2014-02-26
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the first step of the synthesis method, sodium methylate is used. In the reaction, the cyclic compound ring-opens to generate a certain proportion of methyl ester, which affects the yield; the second step introduces the amino group through the potassium salt of phthalic acid imide, which is not very economical.

Method used

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  • Preparation method of milnacipran hydrochloride
  • Preparation method of milnacipran hydrochloride
  • Preparation method of milnacipran hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0037] Embodiment 1-3: the synthesis of formula II compound

[0038] (A) Dissolve 100 g of the compound of formula I in 500 ml of methanol, and then slowly add 137 g of thionyl chloride dropwise. After the addition is complete, react at room temperature for 10 hours. After TLC monitors that the reaction is complete, filter and filter the cake at 40 ° C. Press dry. 122 g of the product was obtained with a yield of 94.5%.

[0039] 1 HNMR (400MHz, CDCl 3 ):δ7.374-7.277(m,5H),3.685(s,3H),3.645-3.589(m,2H),1.891-1.875(m,1H),1.780-1.760(m,1H),1.493-1.467 (m,1H)

[0040] (B) Dissolve 100g of the compound of formula I in 500ml of methanol, then slowly add 137g of thionyl chloride dropwise, after the dropwise addition, react at -5-5°C for 15 hours, monitor the reaction by TLC, filter, and filter the cake in Dry under reduced pressure at 40°C. 120 g of the product was obtained with a yield of 93%.

[0041] (C) Dissolve 100 g of the compound of formula I in 500 ml of methanol, the...

Embodiment 4-5

[0042] Embodiment 4-5: the synthesis of formula III compound

[0043] (A) 100 g of compound II and 30 g of sodium azide were added to 500 ml of toluene, and reacted at 80° C. for 12 hours. After the completion of the reaction was monitored by TLC, it was cooled to room temperature, 200 ml of water was added, the liquid was extracted and separated, and the organic layer was evaporated to dryness to obtain a white solid. Filter and dry the filter cake under reduced pressure at 40°C. 91 g of the product was obtained with a yield of 88%.

[0044] (B) 100 g of compound II and 30 g of sodium azide were added to 200 ml of dimethylformamide, and reacted at 80° C. for 7 hours. After the completion of the reaction as monitored by TLC, it was cooled to room temperature, poured into 200 ml of ice water, and a solid was precipitated. Filter and dry the filter cake under reduced pressure at 40°C. 100 g of the product was obtained with a yield of 98%.

[0045] 1 HNMR (400MHz, CDCl 3 )...

Embodiment 6

[0046] Embodiment 6: the synthesis of formula IV compound

[0047] Add 100 g of the compound of formula III into the mixed solution (400 ml of toluene, 50 ml of methanol, 105 ml of 20% NaOH), and react at 80° C. for 6 hours. After the completion of the reaction was monitored by TLC, it was cooled to room temperature, and the liquid was separated. The aqueous layer was adjusted to weak acidity with 6N hydrochloric acid, and a solid was precipitated. Filter and dry the filter cake under reduced pressure at 40°C. 90 g of the product was obtained with a yield of 95.6%. (melting point: 95.1-95.7°C) 1 HNMR (400MHz, CDCl 3 ):δ7.395-7.262(m,5H),3.737-3.605(m,2H),1.997-1.918(m,1H),1.756-1.727(m,1H),1.566-1.532(m,1H)

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Abstract

The invention discloses a preparation method of milnacipran hydrochloride, which comprises the following steps: reducing a compound V disclosed as the formula in the specification in an inert solvent by using a reducer, and salifying. The existing compound I is subjected to five-step reaction to generate the compound V, and the compound V is reduced and salified to obtain the milnacipran hydrochloride. Every reaction step is simple to operate and mild in conditions; the obtained intermediate and end product have high yield and high purity; and thus, the invention provides an economical efficient preparation method of milnacipran hydrochloride, which is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of a synthesis method of milnacipran hydrochloride. Background technique [0002] Milnacipran hydrochloride is an oral selective serotonin and norepinephrine reuptake inhibitor (SNRI) developed and promoted by the French company Pierre Fabre. Its efficacy in treating major depressive disorder is significantly higher than that of Desipramine and imipramine, which have no anticholinergic effect, are safer and more reliable, and were first launched in France in 1997. In 2009, it was developed by Forest Laboratories Inc of the United States for Fibromyalgia or approved by the FDA for marketing. [0003] The chemical name of milnacipran hydrochloride is: 2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride, which has the following structure: [0004] [0005] Patent EP0200638 first disclosed a synthetic route for the synthesis of milnacipran hydrochloride. The first step of the synthetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/24C07C231/12
Inventor 许冠兵沈文婧秦欣荣沈钢井羽茜史裕明陈文
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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