CN102020667A - Method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate - Google Patents
Method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate Download PDFInfo
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- CN102020667A CN102020667A CN 201010273251 CN201010273251A CN102020667A CN 102020667 A CN102020667 A CN 102020667A CN 201010273251 CN201010273251 CN 201010273251 CN 201010273251 A CN201010273251 A CN 201010273251A CN 102020667 A CN102020667 A CN 102020667A
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Abstract
The invention provided a method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate, which is used for solving the problems of low total yield, poor quality, high long-run cost for lines, severe pollution and the like existing in the prior art. Therefore, the technical scheme adopted by the invention is as follows: the 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate is prepared by using 5-chloro-3-[(2-methoxy-2-oxoethy) amino] sulphonyl-2-methyl formate as raw materials through two steps. By utilizing the technical scheme provided by the invention, 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate is synthesized by using a two-step one-pot method, therefore, the yield is over 60 percent, the cost is low, and the emission of the three wastes (waste gas, waste water and waste residue) is greatly reduced; and meanwhile, the production risk is reduced, and the product quality is also very good.
Description
Technical field
The present invention relates to the synthetic method of 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate.
Background technology
6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate is the key intermediate of non-steroidal anti-inflammatory analgesic lornoxicam (lornoxicam).
At present, having gone up the city both at home and abroad is that the tablet of activeconstituents and freeze-dried preparation are used for smelting and treat class wind-warm syndrome sacroiliitis with " lornoxicam ", osteoarthritis and postoperative various convulsion pain, its outstanding analgesic effect can with morpholine commonly used clinically, U-26225A compares favourably, and externally the clinical study of product is also had an optimistic view of gradually along with its market outlook and increased to some extent both at home and abroad.Yet the chemosynthesis of key intermediate 6-chloro-4-hydroxy-2-methyl-2H-thieno-(the 2.3.e)-1.2 thiazines-1.1-dioxide-3-carboxylate methyl ester of lornoxicam is sad bigger, and wind hair rare thing is offered by disclosed both at home and abroad relevant synthetic side.At present, important intermediate 6-chloro-4-carboxyl-2-methyl-2H-thieno-(the 2.3.e)-1.2 thiazines-3-methyl-formiate-1.1-dioxide synthetic route of lornoxicam has following three:
A) Norway Nycomed public affairs are in the synthetic route of 1997 Denmark listings:
This synthetic route total recovery 0.45
B) synthetic route of Zhejiang Zhenyuan Pharmaceutical Co., Ltd:
This route total recovery brings up to 12.3%.
B) the 3rd synthetic route is that Jiangsu Polytechnic University is the synthetic route that proposes in the Chinese invention patent application specification publication document of CN1699372A at publication number:
This route synthesis step find that through experimental verification its cyclization yield is still lower and unstable, and by product is many, is not easy to purify, and does not accomplish to methylate the more difficult purification of product if do not purify.
Summary of the invention
Technical problem to be solved by this invention provides the synthetic method of a kind of 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate, overcomes that the total recovery that existing synthetic technology exists is low, poor quality, route standing cost height, problem such as seriously polluted.For this reason, the present invention is by the following technical solutions: it is a raw material with 5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters, by following reaction process, 2 steps generated 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate:
Wherein, M represents Na, Mg, and n is 1 or 2, and R is the C1-C6 alkyl.
Owing to adopt technical scheme of the present invention, the present invention synthesizes 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate and adopts two step one kettle ways, the yield height is more than 60%, cost is low, three waste discharge significantly reduces, and reduce and produce danger, and product quality is also fine.
When adopting technique scheme, the present invention also can adopt following further technical scheme simultaneously:
In the first step reaction, with 5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters is raw material, in organic solvent, add methyl-sulfate, drip alkoxy base, and finish in 10～80 ℃ of insulation degree 10～50h reaction, product 5-chloro-3-(3-methoxy carboxyl methylene radical one N monomethyl)-thionamic acid thiophene.
In the reaction of second step, with the reacted product of the first step without separation, directly in former reactor, cool to 0～10 ℃, continue to drip alkoxy base, be warmed up to 40～160 ℃ then, 5 chloro-3-(3-methoxy carboxyl methylene radical one N monomethyl)-thionamic acid thiophene ring-closure reaction is finished, cool 0～10 ℃, pour in 0～15 ℃ of acid, extracting and demixing is isolated 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate.
Described organic solvent is selected from: dimethylbenzene, toluene, benzene etc. and similar organic solvent.
Described alkoxy base is selected from: sodium methylate, alcohol sodium solution, sodium isopropyl, magnesium ethylate, magnesium isopropoxide.
After the cooling, pour 0～15 ℃ of hydrochloric acid into after, extracting and demixing again, dry filter concentrates, adds recrystallizing methanol, 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate.
Embodiment
Embodiment 1
100g5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters, 1000ml toluene are added in the 2000ml four-hole boiling flask, add methyl-sulfate 90g again, drip 30% sodium methoxide solution (volume percent) 250g and dropwise at 40 ℃ of insulation 30h, HPLL follows the tracks of reaction and finishes.
Fluid temperature in the reactor is cooled to 5 ℃, drip the 120g30% sodium methylate again, be warmed up to 65 ℃ of reaction 15h then, the HPLL detection reaction is complete, reaction finishes and is cooled to 0-10 ℃, pours layering among the 800ml2NHCL into, with toluene 100ml*2 aqueous phase extracted, merge organic phase, use anhydrous sodium sulfate drying, filter condensation gained solid, add 800ml methyl alcohol, drip washing 1.0h cooling is below 5 ℃, suction filtration, dry product 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate 74.0g, yield 74%, HPLL 〉=99.5%.
Embodiment 2
In four-hole boiling flask, drop into dimethylbenzene 1000ml and 100g5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters, add methyl-sulfate 90.0g again, drip 20% magnesium methylate solution (volume percent) 340g, dropwise at 50 ℃ of insulation 25h, HPLL follows the tracks of reaction and finishes.
Fluid temperature in the reactor is cooled to 6 ℃, drip 170g20% magnesium methylate solution again, be warmed up to 65 ℃ of reaction 15h then, the HPLL detection reaction is complete, aftertreatment gets product 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate 76.0g, yield 80.6.% with embodiment 1.HPLC≥99.5％
Embodiment 3
100g5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters, 1000ml toluene are added in the 2000ml four-hole boiling flask, add methyl-sulfate 90g again, drip 30% alcohol sodium solution (volume percent) 280g and dropwise at 40 ℃ of insulation 30h, HPLL follows the tracks of reaction and finishes.
Fluid temperature in the reactor is cooled to 5 ℃, drip the 150g30% sodium ethylate again, be warmed up to 65 ℃ of reaction 15h then, the HPLL detection reaction is complete, reaction finishes and is cooled to 0-10 ℃, pours layering among the 800ml2NHCL into, with toluene 100ml*2 aqueous phase extracted, merge organic phase, use anhydrous sodium sulfate drying, filter condensation gained solid, add 800ml methyl alcohol, drip washing 1.0h cooling is below 5 ℃, suction filtration, dry product 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate 73.0g, yield 77%, HPLC 〉=99.5%.
Embodiment 4
Drop into dimethylbenzene 1000ml and 100g5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters in the four-hole boiling flask, add methyl-sulfate 90.0g again, drip 20% magnesium ethylate solution (volume percent) 360g, dropwise at 50 ℃ of insulation 25h, HPLL follows the tracks of reaction and finishes.
Fluid temperature in the reactor is cooled to 6 ℃, drip 190g20% magnesium ethylate solution again, be warmed up to 65 ℃ of reaction 15h then, the HPLC detection reaction is complete, aftertreatment gets product 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate 75.0g, yield 79.5.% with embodiment 1.HPLC≥99.5％。
Claims (6)
1.6-the synthetic method of chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate, it is characterized in that it is a raw material with 5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters, by following reaction process, 2 steps generated 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate:
Wherein, M represents Na, Mg, and n is 1 or 2, and R is the C1-C6 alkyl.
2. the synthetic method of as claimed in claim 1,6-chloro-4 hydroxy-2-methyls-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate, it is characterized in that in the first step reaction, with 5-chloro-3-sulfoamido methyl acetate thiophene-2-carboxylic acid methyl esters is raw material, in organic solvent, add methyl-sulfate, drip alkoxy base, and finish in 10～80 ℃ of insulation degree 10～50h reaction, product 5-chloro-3-(3-methoxy carboxyl methylene radical one N monomethyl)-thionamic acid thiophene.
3. the synthetic method of 6-chloro-4-hydroxy-2-methyl as claimed in claim 1-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-carboxylate methyl ester, it is characterized in that in the reaction of second step, with the reacted product of the first step without separation, directly in former reactor, cool to 0～10 ℃, continue to drip alkoxy base, be warmed up to 40～160 ℃ then, 5-chloro-3-(3-methoxy carboxyl methylene radical one N monomethyl)-thionamic acid thiophene ring-closure reaction is finished, cool 0～10 ℃, pour in 0～15 ℃ of acid, extracting and demixing is isolated 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate.
4. the synthetic method of 6-chloro-4-carboxyl as claimed in claim 2-2-methyl-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate is characterized in that described organic solvent is selected from: dimethylbenzene, toluene, benzene.
5. the synthetic method of 6-chloro-4-hydroxy-2-methyl as claimed in claim 2-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate, it is characterized in that described alkoxy base is selected from: sodium methylate, alcohol sodium solution, sodium isopropyl,, magnesium ethylate, magnesium isopropoxide.
6. the synthetic method of 6-chloro-4-hydroxy-2-methyl as claimed in claim 3-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate, after it is characterized in that cooling, pour into 0～15 ℃ hydrochloric in after, extracting and demixing again, dry filter, concentrate, add recrystallizing methanol, get 6-chloro-4 hydroxy-2-methyls-2H-thieno-(2.3.e)-1.2 thiazines-1.1-dioxide-3-methyl-formiate.
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| CN 201010273251 CN102020667B (en) | 2010-09-06 | 2010-09-06 | Method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate |
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| CN 201010273251 CN102020667B (en) | 2010-09-06 | 2010-09-06 | Method for synthesizing 6-chloro-4-hydroxyl-2-methyl-2H-thieno(2.3.e)-1.2thiazide-1.1-dioxide-3-methyl formate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916169A (en) * | 2017-05-17 | 2017-07-04 | 江苏工程职业技术学院 | A kind of synthetic method of tenoxicam |
| CN108218895A (en) * | 2018-04-13 | 2018-06-29 | 北京朗依制药有限公司沧州分公司 | The method of one pot process Lornoxicam intermediate |
| CN115894525A (en) * | 2023-01-04 | 2023-04-04 | 河北国龙制药有限公司 | Synthesis method of lornoxicam intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224445A (en) * | 1974-08-26 | 1980-09-23 | Hoffmann-La Roche Inc. | Thienothiazine derivatives |
| CN1580059A (en) * | 2003-08-01 | 2005-02-16 | 浙江震元制药有限公司 | 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2,3-e)-1,2-thiazine-1,1-dioxide-3 |
| CN1699372A (en) * | 2005-04-30 | 2005-11-23 | 江苏工业学院 | Process for synthesizing lornoxicam intermediate against inflammation and pain |
-
2010
- 2010-09-06 CN CN 201010273251 patent/CN102020667B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224445A (en) * | 1974-08-26 | 1980-09-23 | Hoffmann-La Roche Inc. | Thienothiazine derivatives |
| CN1580059A (en) * | 2003-08-01 | 2005-02-16 | 浙江震元制药有限公司 | 6-chloro-4-hydroxy-2-methyl-2H-thieno-(2,3-e)-1,2-thiazine-1,1-dioxide-3 |
| CN1699372A (en) * | 2005-04-30 | 2005-11-23 | 江苏工业学院 | Process for synthesizing lornoxicam intermediate against inflammation and pain |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916169A (en) * | 2017-05-17 | 2017-07-04 | 江苏工程职业技术学院 | A kind of synthetic method of tenoxicam |
| CN108218895A (en) * | 2018-04-13 | 2018-06-29 | 北京朗依制药有限公司沧州分公司 | The method of one pot process Lornoxicam intermediate |
| CN115894525A (en) * | 2023-01-04 | 2023-04-04 | 河北国龙制药有限公司 | Synthesis method of lornoxicam intermediate |
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| CN102020667B (en) | 2013-02-27 |
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