Title of Invention

"METHOD FOR PREPARATION OF 6-CHLORO-4-HYDROXY-2-METHYL-2H-THIENO(2,3-E)-1, 2-THIAZINE-1,1-DIOXIDE-3-CARBOXYLATE"

Abstract The invention provides a synthetic method for 6-chloro-4-hydroxy-2-methyl-2h-thieno (2,3-e)-l, 2-thiazine-l, l-dioxide-3-carboxylate (formula 3). The method comprises the following steps: (a) cyclizing the compound of Formula 4 in an organic solvent and at a reaction temperature ranged from 40°C to 157°C by using alkoxy magnesium as an alkaline cyclization agent, and (b) separating the compound of Formula 3 from the reaction mixture. The method of this invention can remarkably increase the yield of product.
Full Text A SYNTHETIC METHOD FOR 6-CHLORO-4-HYDROXY-2-METHYL-2H-THIENO (2,3-e)-l, 2-THIAZINE-l,
l-DIOXIDE-3-CARBOXYLATE
FIELD OF THE INVENTION
The invention relates to a method for the synthesis of the key intermediate of lornoxicam, which is a non-steroidal anti-inflammatory and antalgic drug. More specifically, the invention relates to a method for the synthesis of 6-chloro-4-hydroxy-2-methyl-2H-thieno (2, 3-e)-l,2-thiazine -l,l-dioxide-3-carboxylate.
BACKGROUND OF THE INVENTION
Tablets or lyophilization dosage forms containing "Lornoxicam" as the active ingredient are currently commercially available in domestic and overseas markets, which are used to treat various pains caused by rheumatoid arthritis, osteoarthritis, or postoperative pains. Its outstanding antalgic effect can be compared with morphine and Tramadol which are commonly used in clinical.
Along with the rising of the marketing prospect, the clinical research of Lornoxicam has increased. However, few domestic or foreign literature related to the synthesis of lornoxicam were published due to the difficulty of chemical synthesis of its key intermediate.
U.S. Patent No. 4,180,662 disclosed a method for preparing the compound of Formula I, in which the starting material methyl 5 -chloro-3 -(N-methoxy-carbonyl-methylene-N-methyl)
-aminosulfonylthiophene-2-carboxylate of Formula 2 was cyclized in methanol solution containing sodium methoxide while heating, and methyl 6-chloro-4-hydroxy-2-mefhyl-2H-fhieno (2,3-e)-l,2-thiazine-1,1 -dioxide -3- carboxylate of Formula 1 was obtained by separation after the reaction was over. However, a lot of side reactions occurred during the process of synthesis and the reaction solution was dark-colored, which resulted in a very low recovery yield of only about 24% by molar.
(Formula Removed)
Therefore, there is an urgent need for developing a new method for the synthesis of

6-chloro-4-hydroxy-2-methyl-2H-thieno(2,3-e)-l,2-thazine-l,l-dioxide-3-carboxylate with a high yield.
STATEMENT OF THE INVENTION
Accordingly, the present invention relates to a method for preparing 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e)-l,2-thiazine-l,l-dioxide-3-carboxylate of Formula 3,
(Formula Removed)
wherein R1 is C1-C4 alkyl;
wherein the method comprises the following steps:
(a) cyclizing the compound of Formula 4 in an organic solvent such as herein
described and at a reaction temperature ranging from 40°C to 157°C by using
alkoxy magnesium of Formula 5 as an alkaline cyclization agent,
(Formula Removed)
wherein R3 and R4 independently represents C1-C4 alkyl;
(Formula Removed)
wherein R2 is C1-C6 alkyl;
(b) separating the compound of Formula 3 from the reaction mixture.


CONTENTS OF THE INVENTION
The object of the invention is to provide a new method for the synthesis of 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2,3-e)-1,2-thiazine-1,1 -dioxide-3-carboxylate with a high yield.
After intensive and extensive study, the inventor deemed that the low yield of prior synthetic methods directly related to the strong basicity of the alkaline cyclizing agent, i.e. sodium methoxide. According to the sequence of the metal reactivity, the alkaline Cyclizing agent prepared from a metal whose reactivity is slightly poorer than sodiurrfinstead of sodium will give a better result. When the cyclization reaction was performed in alcohol solvent, the yield of the reaction was greatly increased by lowering the basicity of the cyclization agent used in the cyclization reaction, for example, using an organo-magnium agent instead of an organo-sodium agent.
Based on the above reasons, the present invention provides a method for preparing 6-chloro-4-hydroxy-2-methyl-2H-thieno(2,3-e)-l,2-thiazine-l,l -dioxide-3-carboxylate of Formula 3,

(Formula Removed)
wherein R1 is C1-C4 alkyl;
The method of the invention comprises the following steps: (a) cyclizing the compound of Formula 4 in an organic solvent and at a reaction temperature ranged from 40°C to 157°C by using alkoxy magnesium of Formula 5 as an alkaline cyclization agent,
(Formula Removed)
wherein R2 is C1-C6 alkyl;

(Formula Removed)
wherein R3, and R4 independently represent C1-C4 alkyl;
(b) separating the compound of Formula 3 from the reaction mixture.
The use of alkoxy magnesium as an alkaline cyclization agent in the method according to this invention reduces the occurrence of side reaction, thus remarkably enhancing the yield of the compound of Formula 3 and thereby reducing the production cost for producing the same.
MODE OF CARRYING OUT THE INVENTION
The invention provides a method for preparing the compound of Formula 3. The method comprises the following steps: (a) cyclizing the compound of Formula 4 in an organic solvent by using alkoxy magnesium as an alkaline cyclization agent, and (b) separating the compound of Formula 3.
In this method, the compound of Formula 3 has the following general Formula:
(Formula Removed)
wherein R1 is selected from C1-C4 alkyl. Preferably, R1 is selected from the group consisting of methyl, ethyl, propyl and butyl. More preferably, R1 is methyl or ethyl.
The compound of Formula 4 has the following general Formula:
(Formula Removed)
wherein R3, and R4 are independently C1-C4 alkyl. Preferably, R3, and R4 are independently selected from the group consisting of methyl, ethyl, propyl and butyl; more preferably, R3, and R4 are independently methyl or ethyl. Alkoxy magnesium can be expressed by Formula 5:

(Formula Removed)
wherein R2 is C1-C6 alkyl. Preferably, R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl; more preferably, R2 is selected from the group consisting of methyl, ethyl, propyl, and butyl; most preferably, R2 is methyl, ethyl, /-propyl or /7-propyl.
Alkoxy magnesium may be prepared as follows: it may be prepared by reacting metal magnesium with excess C1-C6 alcohol at the temperature above ambient temperature. In a preferred embodiment of this invention, said temperature is preferably the refluxing temperature of the alcohol. The alcohol may be C1-C6monohydric alcohol or a mixed solvent containing C1-C6 monohrdric alcohol; preferably, the solvent is C1-C6 monohrdric alcohol; more preferably, the solvent is methanol, ethanol, isopropanol or 1-propanol.
The solvent of this invention may be a mixed solution containing mainly ("mainly" means that the amount of the C1-C6 alcohol is more than 70%, preferably more than 80%) of C1-C6 alcohol, such as the tetrahydrofuran mixed solution mainly containing C1-C6 alcohol.
The cyclization reaction step (a) of the present invention was performed in a solvent. Preferably, the solvent is C1-C6 alcohol (especially monohydric alcohol) or the mixtures thereof. The alcohol may be C1-C6 monohydric alcohol or a mixed solvent containing C1-C6 monohrdric alcohol; preferably, the solvent is C1-C6 monohrdric alcohol; more preferably, the solvent is methanol, ethanol, isopropanol or 1-propanol.
The temperature for cyclization reaction is not specifically limited, typically at the temperature ranged from 40°C to the refluxing temperature of the solvent (in particular, the refluxing temperature of the solvent C6 alcohol can reach 157°C). Preferably, the reaction temperature is from 40 to 125°C, more preferably from 55 to 120°C, most preferably from 60 to 100°C. The boiling point of solvent often used is as follows (normal pressure):

(Table Removed)

In step (b), conventional methods (such as that disclosed in US 4,180,662) may be used to separate the compound of Formula 3. Extraction with the mixture of CH2Cl2/2N HC1 is preferred. After drying and condensation, the crude product of the compound according to Formula 3 is obtained. The product is afforded after rinsing with organic solvent (such as methanol), filtration and oven-drying.


With respect to the isolated product, the yield may be calculated as follows:
Yield = (the mass of the product x the molecular weight of the starting material)/(the mass of the charged starting material x the molecular weight of the product) x 100%
The present invention is further illustrated in more detail by way of the following Examples. However, these examples are only intended to illustrate the invention, not to limit the scope of the invention.
Example 1
Preparation of methyl 6-chloro-4-hydroxy-2-methyl-2H-thieno(2,3-e)-
l,2-thiazine-l,l- dioxide-3-carboxylate
To a 2 Liter of three-necked flask were charged 1500 ml of methanol and 19.2 g of powdered metal magnesium. The mixture was refluxed for 3 h with stirring. Grey solution of magnesium methoxide in methanol was obtained.
Then, 160 g of methyl 5-chloro-3-(N-methoxycarbonylmethylene-N-methyl)-amino sulfonyl thiophene-2-carboxylate was added in one portion (as described in US 4,180,662), and the temperature was elevated to 65°C. The ending point of the reaction was reached when the amount of the product did not increase (about 12h) as determined by HPLC (Alltima C18 5u Length 150mm) detection.
After the completion of the reaction, the mixture was cooled down and poured into the mixture of 1500 ml of 2N HC1 and 800 ml of CH2CI2. The mixture was partitioned and the organic phase was collected. The aqueous phase was extracted with 2 x 100 ml of CH2CI2, and the organic phase was combined and dried over Na2SO4. After filtration and condensation, the resultant solid was soaked with methanol, filtered and oven-dried to give 112g light yellow crystal solid, with yield 77.2%, m.p. 200°C-202°C, corresponding with the melting point of the subject compound.
Example 2
Preparation of methyl 6-chloro-4-hydroxy-2-methyl-2H-thieno(2,3-e)-
1,2-thiazine -l,l-dioxide-3-carboxylate
To a 2 Liter of three-necked flask was charged 1600 ml of ethanol, 19.2 g of powdered metal magnesium and 0.5 ml of methyl idiodide. The mixture was refluxed for 3h with stirring. Grey solution of magnesium ethoxide in ethanol was obtained.
Then, 160 g of methyl 5-chloro-3-(N-methoxycarbonylmethylene-N-methyl)-amino sulfonyl thiophene-2-carboxylate was added in one portion, and the

temperature was elevated to 80°C. The ending point of the reaction was reached when the amount of the product did not increase as determined by HPLC detection.
After the completion of the reaction, the mixture was cooled down and poured into the mixture of 2000 ml of 2N HC1 and 800 ml of CH2C12. The organic phase was collected and the aqueous phase was extracted with 2 x 100 ml of CH2CI2, and the organic phase was combined and dried over Na2SO4. After filtration and condensation, the resultant solid was soaked with methanol, filtered and oven-dried to give 84 g light yellow crystal solid, with yield 58%, m.p. 200°C-202°C.
Example 3
Preparation of methyl 6-chloro-4-hydroxy-2-methyI-2H-thieno(2,3-e)-l,2
-thiazine -l,l-dioxide-3-carboxylate
To a 2 Liter of three-necked flask was charged 1600 ml of isopropanol, 19.2 g powdered metal magnesium and 1.5 ml of methyl iodide. The mixture was refluxed for 3h with stirring. Grey solution of isopropoxy magnesium in isopropanol was obtained.
Then, 160 g of methyl 5-chloro-3-(N-methoxycarbonylmethylene-N -methyl)-amino sulfonyl thiophene-2-carboxylatewas was added in one portion, and the temperature was elevated to about 95°C. The ending point of the reaction was reached when the amount of the product did not increase as determined by HPLC detection.
After the completion of the reaction, the mixture was cooled down and poured into the mixture of 2000 ml of 2N HC1 and 800 ml of CH2CI2. The organic phase was collected and the aqueous phase was extracted with 2 x 100 ml of CH2CI2, and the organic phase was combined and dried over Na2S04. After filtration and condensation, the resultant solid was crystallized with methanol and oven-dried to give 60.9 g light yellow crystal, with yield 42%, m.p. 200°C-202°C.
As described above, the yield of compound 1 is only 24% by molar in prior art, while the yield of compound 1 in the present invention is up to 77.2% by molar. The yield of compound 1 in this invention was increased over 3 fold in comparison with that of the prior art, thus the production cost is reduced greatly and the method of this invention has a great prospect of application.
All the documents cited herein are incorporated into the invention as reference, as if each of them is individually incorporated. Further, it would be appreciated that, in light of the above described teaching of the invention, the skilled in the art could make various changes or modifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended claims of the application.










We Claim:
1. A method for preparing 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e)-l,2-thiazine-
l,l-dioxide-3-carboxylate of Formula 3,
(Formula Removed)
wherein R| is C1-C4 alkyl;
wherein the method comprises the following steps:
(a) cyclizing the compound of Formula 4 in an organic solvent such as herein
described and at a reaction temperature ranging from 40°C to 157°C by using
alkoxy magnesium of Formula 5 as an alkaline cyclization agent,
(Formula Removed)
COOR4 4 wherein R3 and R4 independently represents C1-C4 alkyl;
(Formula Removed)
wherein R2 is C1-C6 alkyl;
(b) separating the compound of Formula 3 from the reaction mixture.
2. The method as claimed in claim 1, wherein R1, R3 and R4 are independently selected from the group consisting of methyl, ethyl, propyl, and butyl.
3. The method as claimed in claim 2, wherein R1, R3 and R4 are independently selected from group consisting of methyl and ethyl.
4. The method as claimed in claim I, wherein R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.
5. The method as claimed in claim 4, wherein R2 is selected from the group consisting of methyl, ethyl, propyl and butyl.
6. The method as claimed in claim 4, wherein R2 is selected from the group consisting of methyl, ethyl, i-propyl, and n-propyl.
7. The method as claimed in claim 1, wherein the reaction temperature is in the range of from 40 °C to 125 °C.
8. The method as claimed in Claim 1, wherein the reaction temperature is in the range of from 60 °C to 100 °C.
9. The method as claimed in Claim 1, wherein the organic solvent is C1-C6 monohydric alcohol or mixtures thereof.
10. The method as claimed in claim 1, wherein the organic solvent contains water in an amount of less than 5%.
11. A method of preparing 6-chloro-4-hydroxy-2-methyl-2H-thieno (2,3-e)-l,2-thiazine-l,l-dioxide-3-carboxylate substantially as herein described with reference to the foregoing examples.



Documents:

806-DELNP-2006-Abstract-(07-12-2009).pdf

806-delnp-2006-abstract.pdf

806-DELNP-2006-Claims-(07-12-2009).pdf

806-delnp-2006-claims.pdf

806-DELNP-2006-Correspondence-Others-(07-12-2009).pdf

806-DELNP-2006-Correspondence-Others-(16-02-2006).pdf

806-delnp-2006-correspondence-others.pdf

806-DELNP-2006-Description (Complete)-(07-12-2009).pdf

806-delnp-2006-description (complete).pdf

806-delnp-2006-form-1.pdf

806-delnp-2006-form-18.pdf

806-delnp-2006-form-2.pdf

806-DELNP-2006-Form-26-(07-12-2009).pdf

806-delnp-2006-form-3.pdf

806-delnp-2006-form-5.pdf

806-delnp-2006-pct-210.pdf

806-delnp-2006-pct-304.pdf

806-delnp-2006-pct-308.pdf

abstract.jpg


Patent Number 239731
Indian Patent Application Number 806/DELNP/2006
PG Journal Number 15/2010
Publication Date 09-Apr-2010
Grant Date 31-Mar-2010
Date of Filing 16-Feb-2006
Name of Patentee ZHEJIANG ZHENYUAN PHARMACEUTICAL CO. LTD.
Applicant Address NO. 1015 SHENGLI WEST ROAD,SHAOXING. ZHEJIANG, CHINA.
Inventors:
# Inventor's Name Inventor's Address
1 FAN, WEIMING NO.1015 SHENGLI WEST ROAD, SHAOXING,ZHEJIANG, CHINA.
2 WENG, HANGHUI NO.1015 SHENGLI WEST ROAD, SHAOXING,ZHEJIANG, CHINA.
3 DING,JIANMING NO.1015 SHENGLI WEST ROAD, SHAOXING,ZHEJIANG, CHINA.
4 REN,BINGJUN NO.1015 SHENGLI WEST ROAD, SHAOXING,ZHEJIANG, CHINA.
PCT International Classification Number C07D 513/04
PCT International Application Number PCT/CN2004/000792
PCT International Filing date 2004-07-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03142015.X 2003-08-01 China