KR102199871B1 - A process for preparing 3,11-Dichloro-6-methyl -6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide - Google Patents

Abstract

The present invention relates to a method for preparing 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide, in more detail To explain, starting material 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2] by using hydrogen chloride gas generated in situ in an alcohol environment of the same equivalent as acetyl chloride. By substituting the hydroxy group of thiazepin-11-ol 5,5-dioxide with chlorine, it is a quantitative reaction that does not introduce excessive hydrogen chloride gas from the outside. High purity 3,11-dichloro-6-methyl-6, It relates to a method of preparing 11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide in high yield.

Description

Method for preparing 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide{A process for preparing 3,11-Dichloro- 6-methyl -6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide}

The present invention relates to a method for preparing 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide, in more detail To explain, starting material 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2] by using hydrogen chloride gas generated in situ in an alcohol environment of the same equivalent as acetyl chloride. By substituting the hydroxy group of thiazepin-11-ol 5,5-dioxide with chlorine, it is a quantitative reaction that does not introduce excessive hydrogen chloride gas from the outside. High purity 3,11-dichloro-6-methyl-6, It relates to a method of preparing 11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide in high yield.

The target substance of the present invention, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide, is shown in the following [Scheme 1] As described above, it is a compound that is very useful as an intermediate for the production of tianeptine sodium, an antidepressant treatment.

[Scheme 1]

The tianeptine sodium is a material developed by Science Union & CIE, and the first patent registration (FR 2104728) in France was completed in 1972. Tianeptine sodium is the first antidepressant treatment with anti-anxiety and redynamizing effects, and has the effect of alleviating somatic complaints, including gastrointestinal signs that are prominent in anxiety and mood disorders. do. It also relieves anxiety that appears when alcoholism and drug withdrawal, improves depression, and relieves mental pain and physical symptoms.

Looking at the synthesis method of 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide known in the prior art, FR reported so far 2104728, EP 0671173, US 6441165, WO 2010/070667, etc., 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine as shown in the following [Scheme 2]. A substitution reaction in which -11 -ol 5,5-dioxide is suspended in a solvent substituted with chlorine, and hydrogen chloride gas is added thereto to foam (bubbling) has been reported.

[Scheme 2]

The conventional method introduced in the above patents is a classical method using hydrogen chloride gas, and has advantages in that the reaction process is simple and the hydrogen chloride gas is easily removed after completion of the reaction. However, 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide suspension was added to the human body for 2-4 hours at low temperature. There is a problem in that more than necessary hydrogen chloride gas is consumed because hydrogen chloride gas, which is a very harmful toxic substance, must be continuously injected and foamed until the reaction is completed.

Particularly in mass production, there is a concern that serious problems may arise for the health and safety of workers due to the use of excessive hydrogen chloride gas, and production costs increase due to air pollution and costs for neutralizing waste. have.

FR 2104728 EP 0671173 US 6441165 WO 2010/070667

Therefore, the problem to be solved by the present invention is 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-, an intermediate for producing tianeptine sodium. In the preparation of dioxide, a new manufacturing method that can produce high-purity target substances with high efficiency at low cost in a safe process and eco-friendly atmosphere by using the same equivalent amount of alcohol as acetyl chloride in a quantitative amount in an aprotic organic solvent. To provide.

The method for preparing 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide according to the present invention includes (a) 3- Suspending chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide in an aprotic organic solvent; (b) 1-3 equivalents of alcohol based on the 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide Cooling to 0 ~ 10 ℃ by adding; (c) adding 1 to 3 equivalents of acetyl chloride dropwise at a temperature of 0 to 10°C and stirring at 25 to 35°C; (d) filtering and washing with acetone after completion of the reaction; It characterized in that it is manufactured, including.

In the present invention, the starting material 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide is used in an aprotic solvent. By using a quantitative amount of acetyl chloride and the same equivalent of alcohol, the overall process is improved very safely and the yield of the target substance is improved by about 10% or more, compared to the conventional method in which a large amount of hydrogen chloride gas harmful to the human body is used. Can be obtained.

That is, in the present invention, the reaction efficiency is high because hydrogen chloride gas is generated in the reaction system instead of foaming by introducing hydrogen chloride gas from the outside. In addition, by quantitatively generating hydrogen chloride gas to participate in the reaction, there is an effect that the target material can be manufactured eco-friendly, safe and economically by refraining from the use of unnecessary hydrogen chloride gas.

1 is a high performance of 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide prepared according to an embodiment of the present invention It is liquid chromatography.
Figure 2 is a high performance of 3,11-dichloro-6-methyl-6,11-dihydrdibenzo[c,f][1,2]thiazepine 5,5-dioxide prepared according to the comparative example of the present invention It is liquid chromatography.
3 is a nuclear magnetic resonance spectrum of tianeptine sodium prepared according to Preparation Example of the present invention.

The method for preparing 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide according to the present invention is shown in [Scheme 3] Is displayed.

[Scheme 3]

In the present invention, the starting material, 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide, is first used as an aprotic solvent. Suspend in As the aprotic solvent, any one or more selected from dichloromethane, 1,2-dichloroethane, chloroform, methyl acetate, ethyl acetate, acetone, ether, tetrahydrofuran, acetonitrile, and toluene may be used. It is most preferred to use methane.

Next, 1-3 equivalents of alcohol based on the 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide Add. As the alcohol, any one or more selected from methanol, ethanol, n-propanol, and isopropanol may be used, but methanol is most preferably used.

Next, after cooling the suspended starting material to 0 ~ 10 ℃, the 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11- Slowly add 1 to 3 equivalents of acetyl chloride based on 5,5-dioxide. In this case, the amount of acetyl chloride is preferably used in the same amount as the previously added alcohol.

In the present invention, if the amount of the alcohol or the acetyl chloride used is less than 1 equivalent, the reaction is not completed and the yield decreases. On the contrary, if the amount of alcohol or acetyl chloride used exceeds 3 equivalents each, environmental pollution and worker safety due to the release of a large amount of hydrogen chloride gas cannot be guaranteed, and the cost-effectiveness decreases compared to the existing manufacturing method. .

Next, the reaction solution is stirred at 25 ~ 35 ℃ to confirm the completion of the reaction. Here, if the temperature is less than 25° C., the reactivity of the substitution reaction decreases, and the yield decreases due to incomplete reaction. Conversely, if it exceeds 35°C, the solubility of hydrogen chloride gas in the reaction solvent decreases, and the yield decreases due to incomplete reaction.

Finally, the reaction solution after the completion of the reaction was aged at 0~5℃, filtered, washed with acetone, and the target substance of the present invention, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f ][1,2]thiazepine 5,5-dioxide is obtained.

Hereinafter, examples of the present invention will be described.

[Example]

In a 50 ml reaction vessel, 5 g of 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide was added, and the following table 25 ml of the aprotic solvent of 1] was added. Then, after adding 1 to 3 equivalents of alcohol as shown in the following [Table 1], it was cooled to 0 to 10°C. Acetyl chloride in the same amount as the alcohol was slowly added at a temperature of 0 to 10°C, and stirred at a temperature of 25 to 35°C.

After the reaction solution was cooled to 0 ~ 5 ℃ the reaction was completed, and aged with stirring. The aged solid was filtered, washed with acetone, and a white solid target material, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5, 5-dioxide was obtained. The yield of the target substance identified for each example is shown in Table 1 below. For reference, in the following [Table 1], “AcCl” means acetyl chloride.

Example Alcohol Aprotic
menstruum AcCl
Equivalent yield Kinds Equivalent to use One Methanol 2.0 Dichloromethane 2.0 96% 2 Methanol 1.2 Dichloromethane 1.2 93% 3 Methanol 3.0 Dichloromethane 3.0 96% 4 Methanol 1.0 Dichloromethane 1.0 90% 5 ethanol 2.0 Dichloromethane 2.0 94% 6 n-propanol 2.0 Dichloromethane 2.0 94% 7 iso-propanol 2.0 Dichloromethane 2.0 93% 8 Methanol 2.0 Acetone 2.0 93% 9 Methanol 2.0 1,2-dichloroethane 2.0 94% 10 Methanol 2.0 ether 2.0 92% 11 Methanol 2.0 Tetrahydrofuran 2.0 93% 12 Methanol 2.0 Acetonitrile 2.0 92% 13 Methanol 2.0 toluene 2.0 93% 14 Methanol 2.0 Methyl acetate 2.0 92% 15 Methanol 2.0 Ethyl acetate 2.0 93%

In Table 1, the equivalent amount of alcohol and acetyl chloride used is 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5, which is a starting material, It represents the relative value for the number of moles of 5-dioxide.

[Production Example 1]

In a 250 ml reaction vessel, 50 g of dichloromethane, 4.4 g of triethylamine, and 3.6 g of ethyl 7-aminoheptanoate hydrochloride were added and dissolved. In addition, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5- prepared according to [Example 1] of [Table 1] above. 4.7 g of dioxide was added, refluxed for 8 hours, and then washed with 50 g of purified water.

The dichloromethane solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 20 g of methanol was added to the concentrated residue and diluted. To this solution, 8 ml of a 9% aqueous sodium hydroxide solution was added, followed by reflux reaction for 3 hours. The reaction solution was concentrated under reduced pressure, and then diluted with 30 g of purified water. To this, 8 ml of 9% diluted hydrochloric acid was added and extracted with dichloromethane.

The dichloromethane solution was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized by adding 30 g of methanol. The precipitated crystals were filtered, washed with methanol, and 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11- Yl]amino]-heptanoic acid S,S-dioxide (yield: 80%, purity: 99.88%) was obtained.

[Production Example 2]

In a 100 ml reaction vessel, 25 g of methanol and 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1] prepared in [Preparation Example 1] above. 5 g of,2]thiazepin-11-yl]amino]-heptanoic acid S,S-dioxide was added and dispersed. 0.5 g of sodium hydroxide was dissolved in 5 g of methanol, which was then 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thia Zepin-11-yl]amino]-heptanoic acid S,S-dioxide was added to the suspension and stirred for 1 hour.

The resulting reaction solution was concentrated under reduced pressure, dissolved in 25 g of dichloromethane, and crystallized by adding diethyl ether. The precipitated crystals were filtered and washed with diethyl ether to obtain tianeptine sodium (yield: 95%, purity: 99.88%).

[Comparative Example 1]

In a 250 ml reaction vessel, 10 g of 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide was added, and dichloromethane 100 ml was added. Subsequently, after cooling to 0-10° C., hydrogen chloride gas was added for 2-4 hours.

The reaction solution after the reaction was completed was filtered, washed with dichloromethane, and the target material, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5, 5-dioxide (yield: 83%) was obtained. For reference, the comparative example was carried out by the method described in International Patent Publication No. WO2010/070667 previously introduced in the prior art.

[High-performance liquid chromatograph and nuclear magnetic resonance spectrum analysis]

end. High performance liquid chromatography analysis

3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5 obtained as the target substance in the above [Example 1] and [Comparative Example] -Analyze the high performance liquid chromatography (HPLC) data of the oxide, and the results are included in the attached [Fig. 1] and [Fig. 2].

As shown in Figs. 1 and 2, the target material prepared according to the embodiment of the present invention showed almost the same peak characteristics as the target material prepared according to the comparative example, which is a conventional method. At this time, the measurement conditions of high performance liquid chromatography (HPLC) were carried out in the same manner as in the European Pharmacopoeia.

I. Nuclear magnetic resonance spectrum analysis

As a result of analyzing nuclear magnetic resonance (NMR) data for tianeptine sodium synthesized according to the above preparation example, d 7.77 (s, 1H), 7.70 (d, 2H), 7.49 ( m, 2H), 7.39(td, 1H), 7.34(td, 1H), 5.16(s, 1H), 3.50(s, 1H), 3.37(s, 3H), 2.67(s, 1H), 2.37(m , 2H), 1.84 (t, 2H), 1.40 (m, 4H), 1.17 (m, 4H) showed peaks, respectively.

At this time, the measurement conditions for nuclear magnetic resonance (NMR) are as follows.

1) Device: Bruker Model DRX NMR 400

2) Measurement range: -1.0 ~ 15 ppm

3) Number of scans: 16

As can be seen from the results of Examples and Comparative Examples, 3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5 according to the present invention -The method of preparing the dioxide shows the effect of improving the overall manufacturing process environmentally and safely compared to the conventional manufacturing method by refraining from the use of unnecessary hydrogen chloride gas, and further improving the yield of the target substance by about 10% or more.

Claims (5)

(a) suspending 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide in dichloromethane;
(b) 1 to 3 equivalents of alcohol based on the 3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ol 5,5-dioxide Cooling to 0 ~ 10 ℃ by adding;
(c) adding acetyl chloride in the same amount as the alcohol at a temperature of 0 to 10°C dropwise and stirring at 25 to 35°C;
(d) filtering and washing with acetone after completion of the reaction;
3,11-dichloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide, characterized in that prepared, including.
delete The method of claim 1, wherein the alcohol in step (b) is 3,11-dichloro-6-methyl-6, characterized in that at least one selected from methanol, ethanol, n-propanol, and iso-propanol is used. ,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide production method.
delete delete

Images