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Milnacipran hydrochloride intermediate and its preparation method and application

A compound and inert solvent technology, applied in the field of synthesis of milnacipran hydrochloride, can solve problems such as being not very economical, affecting yield, etc., and achieve the effects of mild conditions, simple operation and high purity

Active Publication Date: 2016-01-20
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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  • Milnacipran hydrochloride intermediate and its preparation method and application
  • Milnacipran hydrochloride intermediate and its preparation method and application
  • Milnacipran hydrochloride intermediate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0048] Embodiment 1-3: the synthesis of formula II compound

[0049] (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%.

[0050] 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)

[0051] (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%.

[0052] (C) Dissolve 100 g of the compound of formula I in 500 ml of methanol, the...

Embodiment 4-5

[0053] Embodiment 4-5: the synthesis of formula III compound

[0054] (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%.

[0055] (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%.

[0056] 1 HNMR (400MHz, CDCl 3 )...

Embodiment 6

[0057] Embodiment 6: the synthesis of formula IV compound

[0058] 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, CDCl3 ):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 relates to the technical field of synthesis methods of milnacipran hydrochloride. The present invention utilizes existing compounds to undergo five-step reactions to generate new compound V, and then reduces compound V to form a salt to obtain milnacipran hydrochloride. The operation of each step is simple, the conditions are mild, and the yield of the obtained intermediate and final product is high. , high purity, provides an economical and efficient preparation method for milnacipran hydrochloride, and 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 PierreFabre, which is significantly more effective than desipa in the treatment of major depressive disorder Ming and imipramine, and no anticholinergic effect, more safe and reliable, in 1997, the first market in France. In 2009, it was developed by Forest Laboratories Inc of the United States for fibromyalgia or approved by the FDA for marketing in the United States. [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 synthe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C247/12C07C67/307C07C69/65C07C237/24C07C231/12
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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