WO2005016937A1

WO2005016937A1 - A SYNTHETIC METHOD FOR 6-CHLORO-4-HYDROXY-2-METHYL-2H-THIENO (2,3-e)-1,2-THIAZINE1, 1-DIOXIDE-3-CARBOXYLATE

Info

Publication number: WO2005016937A1
Application number: PCT/CN2004/000792
Authority: WO
Inventors: Weiming Fan; Hanghui Weng; Jianming Ding; Bingjun Ren
Original assignee: Zhejiang Zhenyuan Phamaceutical Co., Ltd.
Priority date: 2003-08-01
Filing date: 2004-07-13
Publication date: 2005-02-24
Also published as: CN1266155C; CN1580059A

Abstract

This invention provided a synthetic method for 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e)-1,2-thiazine-1, 1-dioxide-3-carboxylate of formula 3. The method included following steps: (a) cyclizing the compound of formula 4 by alkoxy magnesium which used as an alkaline cyclization agent, in the organic solvent and at 40°C-157°C reaction temperature, and (b) the compound of formula 3 was separated from the reaction mixture. The method in this invention could enhanced the yield of production remarkably.

Description

Azine-1,1-dioxide-3-carboxylic acid ester

Synthetic method

Technical field

The present invention relates to a method for synthesizing a key intermediate of the non-steroidal anti-inflammatory analgesic "lornoxicam", and more particularly to 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, Synthetic method of 3-e) -1, 2-thiazine-1, 1-dioxide-3-carboxylic acid ester. technical background

At present, tablets and lyophilized preparations with "Lornoxicam" as the active ingredient have been marketed at home and abroad for the treatment of rheumatoid arthritis, osteoarthritis and various pains after surgery. Its outstanding analgesic effect is comparable to morphine and tramadol commonly used in clinical practice.

The clinical research on this product at home and abroad has also increased with the gradual optimism of its market prospect. However, due to the difficulty in chemical synthesis of key intermediates of "Lornoxicam", relevant synthetic literature published at home and abroad is also rare.

U.S. Patent No. 4,180,662 discloses a method for preparing 5-chloro-3- (N-methoxycarbonylmethylene-N-methyl) -aminosulfonylthiophene 2-carboxylic acid The ester (Formula 2) was used as a raw material, and the cyclization reaction was performed by heating in a methanol solution containing sodium methoxide. After the reaction was completed, 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3 -e) -l, 2-thiazine-1,1-dioxide-3-carboxylic acid methyl ester (formula 1). However, in the above synthesis process, a large amount of side reactions occurred, and the color of the reaction solution was very dark, resulting in a low final yield, and the molar yield was only about 24%.

Therefore, there is an urgent need in the art to develop new preparations of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e) -1, 2-thiazine-1, 1- Dioxide-3-carboxylic acid ester method. Summary of the invention

The object of the present invention is to provide a 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e) -1, 2-thiazine-1, 1-diol with high yield. Method of oxide-3-carboxylic acid ester.

After intensive and extensive research, the inventors believe that the low yield of the existing production method is directly related to the too strong alkalinity of the sodium cyclizing reagent sodium methoxide. According to the order relationship of the metal activity, the basic cyclization reagent made by the simple metal with a slightly lower metal activity than the metal sodium will give better results. By reducing the basicity of the cyclization reagent used in the cyclization reaction, for example, an organic magnesium reagent is used instead of an organic sodium reagent, and the cyclization reaction is performed in an alcohol solvent, thereby greatly improving the reaction yield.

Based on the above reasons, the present invention provides a method for preparing 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e) -1,2-thiazine-1 having the general formula 3 , 1-dioxide-3-carboxylic acid ester method,

3

In the formula, ^ is ^-^ 垸 group;

The method includes:

(a) Using methoxy magnesium of formula 5 as a basic cyclizing agent, in an organic solvent and a reaction temperature of 40 ° C -157 ° C

(R ₂ 0) ₂ Mg In the formula,! ^ Is ^-^ alkyl;

Cyclizing a compound of formula 4,

In the formula, 1 ₃ and} ₄ respectively represent a c _r c ₄ fluorenyl group; (b) isolating the compound of formula 3 from the reaction mixture.

In the method of the present invention, the use of magnesium alkoxide as the basic cyclization can reduce the occurrence of side reactions, thereby greatly improving the yield of the compound of formula 3, and further reducing the production cost of the compound of formula 3. detailed description

The present invention provides a method for synthesizing a compound of formula 3, which comprises the steps of: (a) using a magnesium alkoxide as a basic cyclizing agent, and cyclizing a corresponding compound of formula 4 in an organic solvent to form a compound of formula 3, ( b) The compound of formula 3 is then isolated.

In the above method, the general formula of the compound of formula 3 is:

3 Among them, selected from C fluorenyl. Preferably, it is selected from the group consisting of methyl, ethyl, propyl and butyl; more preferably, ^ is methyl and ethyl. The compound of formula 4 has the general formula:

among them! ^ And are selected from C CJ amidino, respectively. Preferably, R ₃ and! ^ Are respectively selected from methyl, ethyl, propyl and butyl; more preferably, and are methyl and ethyl, respectively.

Magnesium ethoxide can be expressed by Formula 5:

(R ₂ 0) ₂ Mg

5 wherein R _{2 is} selected from a fluorenyl group of C ₆ . Preferably, R _{2 is} selected from methyl, ethyl, propyl, butyl, pentyl and Hexyl; more preferably, R _{2 is} selected from methyl, ethyl, propyl and butyl; most preferably, R ₂ is methyl, ethyl isopropyl and n-propyl.

The preparation of the magnesium alkoxide can be carried out by reacting and synthesizing elemental magnesium with excess C _r C ₆ alcohol at a temperature higher than room temperature. In a preferred embodiment of the present invention, the temperature is preferably the reflux temperature of the alcohol. The alcohol may be a monohydric alcohol or -Ce comprising (^ - (: Solvent ₆ monohydric alcohol; preferably, the solvent is preferably alone ( "C ₆ monohydric alcohol; and more preferably, the solvent is More preferred are methanol, ethanol, isopropanol, and n-propanol alone.

The solvent of the present invention may also be a mixed solution mainly containing (1% alcohol: ₆ alcohol (mainly refers to a content greater than 70%, preferably greater than 80%), such as a tetrahydrofuran mixed solution mainly containing 1% alcohol ( ₆ alcohol).

The cyclization reaction step (a) of the present invention is performed in a solvent. The solvent used is preferably an alcohol (especially a monohydric alcohol) or a mixed solvent thereof. C _r (: ₆ monohydric alcohol or C _r ( ₆ A mixed solvent of a monohydric alcohol, especially a monohydric alcohol of d-C ₆ is used as a solvent, and methanol, ethanol, isopropanol, and n-propanol are more preferably used as a solvent.

The temperature range of the cyclization reaction is not particularly limited, and is usually between 40 ° F and the reflux temperature of the selected solvent, especially the reflux temperature of the C ₆ alcohol can reach 157 ° C. Preferably, the reaction temperature ranges from 40 to 125 ° C, more preferably from 55 to 120 ° C, and most preferably from 60 to 10 ° C. The boiling points of common solvents are as follows (normal pressure):

In step (b), the compound of formula 3 can be isolated by methods conventional in the art (such as those described in US 4, 180, 662). A preferred separation method is extraction with dichloromethane / 2N HC1 mixed solution, and drying and concentration to obtain a crude product of the compound of formula 3. The product can be obtained after washing with organic solution (such as methanol), filtering, and drying. For separated products, the yield can be calculated as follows: Yield = (product quality X raw material molecular weight) / (raw material input amount X product molecular weight) X 100%

The following describes the present invention in detail with reference to the examples. These examples are for illustrative purposes only and do not limit the scope of the present invention. Example 1

Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e) -1,2-thiazine-1, 1-dioxide-3-carboxylic acid methyl ester

1500 ml of methanol and 19.2 g of powdered metallic magnesium were put into a two-liter three-necked flask, and the mixture was stirred and dispersed and heated under reflux for 3 hours to prepare a gray magnesium methoxide methanol solution.

Then, 160 g of 5-chloro-3- (N-methoxycarbonylmethylene-N-methyl) -sulfamoylthiophene-2-carboxylic acid methyl ester (synthesized according to US 4, 180, 662) was added at once, The temperature was raised to 65 ° C and the reaction was detected by HPLC (Alltiraa C18 5u Length 150mm) as the end point of the reaction (about 12 hours).

After the reaction is completed, after cooling, it is poured into a mixed solution consisting of 1500 ml of 2N HC1 and 800 ml of CH ₂ C1 ₂ , the layers are separated, and the organic phase is taken. The aqueous phase was extracted with 2 × 100 ml of CH ₂ C1 _{2. The} organic phases were combined and dried over anhydrous Na ₂ S 0 ₄ . After filtration, the solid obtained after concentration was immersed in methanol, and dried after filtration to obtain 112 g of pale yellow crystalline solid with a yield of 77.2% and a melting point of 200 ° C-202 ° C, which was consistent with the melting point of the title compound. Example 2

Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e) -1,2-thiazine-1,1-dioxide-3-carboxylic acid methyl ester

In a two-liter three-necked flask, 1600 ml of ethanol and 19.2 g of powdered metal magnesium were added, and 0.5 ml of iodoformamidine was stirred and dispersed for 3 hours under reflux to prepare a gray ethanol solution containing magnesium ethoxide.

Then, 160 g of 5-chloro-3- (N-methoxycarbonylmethylene-N-methyl) -aminosulfonylthiophene-2-carboxylic acid methyl ester was put in one portion, and the temperature was raised to 80 ° C, and the reaction was detected by HPLC. Product content no longer rises to the end of the reaction.

After the reaction, after cooling, it was poured into a mixed solution consisting of 2000ral 2N HC1 and 800ral CH ₂ C1 ₂ and the organic phase was taken. The aqueous phase was extracted with 2 × 100 ml CH ₂ Cl ₂ and the organic phases were combined. The organic phase was dried over anhydrous Na ₂ S 0 ₄ . The solid obtained after concentrating the thousand organic phases was immersed in methanol, and dried to obtain 84 g of a pale yellow crystalline solid with a yield of 58% and a melting point of 200 ° C-202 ° C. Example 3

Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e) -1,2-thiazine-1, 1-dioxide-3 Methyl carboxylate

In a 2-liter three-necked flask, 1600 ml of isopropanol and 19.2 g of powdered metal magnesium, and 1.5 ml of iodoformamidine were stirred and dispersed for 3 hours under reflux to prepare a gray isopropanol solution containing magnesium isopropoxide.

Then, add 160 g of 5-chloro-3- (N-methoxycarbonylmethylene-N-methyl) -sulfamoylthiophene-2-carboxylic acid methyl ester at one time, and raise the temperature to about 95 ° C to react, and detect by HPLC Until the product content no longer rises as the end of the reaction.

After the reaction, after cooling, it was poured into a mixed solution consisting of 2000 ml of 2N HC1 and 800 ml of CH ₂ C1 ₂ , and the organic phase was taken. The aqueous phase was extracted with 2 × 100 ml CH ₂ Cl ₂ and the organic phases were combined. The organic phase was dried over anhydrous Na ₂ S 0 ₄ . After the organic phase was concentrated to dryness, the obtained solid was crystallized from methanol, and dried to obtain a light yellow crystalline solid 60.9 g, a yield of 42%, and a melting point of 200 ° C-202 ° C. As mentioned above, the molar yield of Compound 1 in the prior art is only 24%, while the molar yield of Compound 1 in the present invention can reach up to 77.2%, which is more than 3 times higher than the prior art, thereby greatly reducing The production cost has a very large application prospect.

All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above-mentioned teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

Rights request

1. Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e) -1,2-thiazine-1, 1-dioxide of formula 3 -3-carboxylic acid ester method,

In the formula, ^ is a fluorenyl group of ^-^;

It is characterized in that the method includes steps:

(a) Using methoxy magnesium of formula 5 as a basic cyclizing agent, at an organic solvent and a reaction temperature of 40 ° C-157 ° C,

(R ₂ 0) ₂ Mg In the formula,! ^ Is an alkyl group of ^-^;

Cyclizing a compound of formula 4,

In the formula, and ₁₄ respectively represent (^-( ₄ alkyl groups;

(b) isolating the compound of formula 3 from the reaction mixture.

2. The method according to claim 1, wherein said R ,, R _3, 1 ₄ are independently selected from methyl, ethyl, propyl and butyl.

3. The method according to claim 2, wherein the R ,, R ₃ , and R ₄ are selected from methyl and ethyl, respectively.

4. The method according to claim 1, wherein said R ₂ is selected from methyl, ethyl, propyl, butyl, pentyl and hexyl.

5. The method according to claim 4, wherein the R _{2 is} selected from the group consisting of methyl, ethyl, propyl and butyl.

6. The method according to claim 4, wherein the R _{2 is} selected from the group consisting of methyl, ethyl, isopropyl and n-propyl.

7. The method according to claim 1, wherein the reaction temperature is 40-125 ° C.

8. The method according to claim 1, wherein the reaction temperature is 60-100 ° C.

9. The method according to claim 1, wherein the organic solvent is (^-(: ₆ -alcohol or a mixed solvent thereof). 10.

10. The method according to claim 1, wherein the organic solvent has a water content of less than 5%.