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Synthesis method of tianeptine sodium

A technology for tianeptine sodium and a synthesis method is applied in the field of synthesizing tianeptine sodium by spray-drying salt-forming, and can solve the problems of high cost, low product purity, low yield and the like of salt-forming sodium isonovate, Achieving the effect of high product yield and purity, good purity, and improving product yield and purity

Inactive Publication Date: 2013-12-04
陕西方舟制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is that due to the simultaneous progress of salt formation and hydrolysis, the product after the reaction is an oily viscous substance, which requires multiple recrystallizations to obtain a solid product, and the product has low purity and low yield
Its disadvantage is that the cost of salt-forming sodium isocyanate is relatively high
[0005] Method 3 (freeze-drying method): the hydrolyzed tianeptine acid and sodium hydroxide aqueous solution are dissolved and directly freeze-dried to form a salt. This method can also obtain a product with higher purity and yield, but its cost is higher

Method used

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  • Synthesis method of tianeptine sodium
  • Synthesis method of tianeptine sodium
  • Synthesis method of tianeptine sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0025] The first step: 7-[(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo[c,f][1,2]thiazol-11yl)amino] Preparation of ethyl heptanoate:

[0026]

[0027] Into a 5L reaction flask, add 540g, 1.64mol (3,11-dichloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2]thiazepine in sequence Zhuo-5,5-dioxide); 430g, 2.05mol 7-aminoheptanoic acid ethyl ester hydrochloride, 2.6L acetonitrile, stir well, then add 368g, 3.64mol triethylamine, heat to 50°C-60°C After reacting for 2 hours, concentrate to dryness under reduced pressure; add 2.2 L of dichloromethane, 1.0 L of water and stir for 0.5 hours, let stand to separate layers, take the organic layer, wash with 1 L of water, combine the organic phases, and concentrate under reduced pressure to obtain a viscous substance 7 -[(3-Chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo[c,f][1,2]thiazol-11yl)amino]heptanoic acid ethyl ester 610g , 81% yield, 98.5% purity, reddish-brown, sticky substance.

[0028] The second step: 7-[(3-chloro-6,11-dihyd...

Embodiment 2

[0035] The synthetic method of tianeptine sodium of the present invention is basically the same as that of Example 1, except that other inorganic alkali potassium hydroxide is used in the hydrolysis reaction of the second step ester, which is different from the alkali used in the first step hydrolysis reaction. The specific instructions are as follows:

[0036] The first step: 7-[(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo[c,f][1,2]thiazol-11yl)amino] Preparation of ethyl heptanoate:

[0037]In a 5L reaction flask, add 540g (3,11-dichloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2]thiazepine-5 , 5-dioxide), 433g of ethyl 7-aminoheptanoate hydrochloride, 2500ml of acetonitrile, 370g of triethylamine, heated to 50°C-60°C for 2 hours, then concentrated to dryness under reduced pressure; cooled to room temperature by freezing, adding two Chloromethane 2L, water 1L, stir for 0.5 hours, let stand to separate layers, take the organic layer, wash with 1L of water, combine the organ...

Embodiment 3

[0043] The synthesis method of tianeptine sodium of the present invention is the same as that of Example 1, except that the molar ratio of the two starting reactants is adjusted.

[0044] The first step: 7-[(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo[c,f][1,2]thiazol-11yl)amino] Preparation of ethyl heptanoate:

[0045] In a 5L reaction flask, add 540g (3,11-dichloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2]thiazepine-5 , 5-dioxide), 379g of ethyl 7-aminoheptanoate hydrochloride, 2500ml of acetonitrile, 375g of triethylamine, heated to 50°C-60°C for 2 hours and concentrated under reduced pressure to dryness. Freeze and cool down to room temperature, add 2 L of dichloromethane, 1 L of water and stir for 0.5 hours, let stand to separate layers, take the organic layer, wash with 1 L of water, combine the organic phases, and concentrate under reduced pressure to obtain a viscous 7-[(3-chloro- 6,11-dihydro-5,5-dioxo-6-methyldibenzo[c,f][1,2]thiazol-11yl)amino]heptanoic acid et...

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Abstract

The invention relates to a synthesis method of the medicine of tianeptine sodium. The conventional salifying method comprises the following steps: hydrolyzed tianeptine acid and sodium hydroxide aqueous solution are dissolved and then subjected to freeze drying to form salt. According to the conventional salifying method, a product with higher purity and yield can be obtained, but the cost of the product is higher. The invention aims to develop a novel synthesis method of tianeptine sodium. The novel synthesis method comprises the following steps: step 1, 3,11-dichloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2]thiazepine-5,5-dioxide is taken as starting material, subjected to an condensation reaction, hydration and spray drying to form salt so as to synthesize the tianeptine sodium, which is the preparation process of 7-[(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo(c, f) (1,2) thiazole-11 group) amino] ethyl enanthate; step 2, tianeptine acid is prepared; step 3, the tianeptine sodium is prepared. The synthesis method has the advantages that the technological process is simplified, the salifying process is efficient and environment-friendly, and the product yield and purity are improved.

Description

1. Technical field [0001] The present invention relates to a synthesis process of tianeptine sodium, specifically referring to 3,11-dichloro-6,11-dihydro-6-methyl-dibenzo[c,f][1,2] Thiazepine-5,5-dioxide is a synthetic method for synthesizing tianeptine sodium through condensation reaction, hydrolysis, and spray drying to form a salt as a starting material. 2. Background technology [0002] Tianeptine sodium, chemical name 7-[(3-chloro-6,11-dihydro-5,5-dioxo-6-methyldibenzo-[c,f][1, 2] Sodium thiazopin-11-yl)amino]heptanoate, which is mainly used for the treatment of patients with mild, moderate or severe depressive disorder, including neurogenic and reactive depression, anxiety and depression of the body, especially gastrointestinal discomfort , Anxiety and depression in alcohol-dependent patients during the withdrawal process. Tianeptine sodium is a 5-HT reuptake agonist that can regulate the remodeling of dendrites in hippocampus and amygdala cells. It has a low inciden...

Claims

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Application Information

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IPC IPC(8): C07D281/02
Inventor 王宇杜小英
Owner 陕西方舟制药有限公司
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