CN103420891A - Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus - Google Patents
Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus Download PDFInfo
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- CN103420891A CN103420891A CN2013102288292A CN201310228829A CN103420891A CN 103420891 A CN103420891 A CN 103420891A CN 2013102288292 A CN2013102288292 A CN 2013102288292A CN 201310228829 A CN201310228829 A CN 201310228829A CN 103420891 A CN103420891 A CN 103420891A
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Abstract
The invention discloses a triphosgene method for synthesizing benzene sulphanilamide, the intermediate of glimepiride, a drug for Type ii Diabetes Mellitus. Triphosgene is slowly dropped into a solution which contains phenethylamine and 3-ethyl-4-methyl pyrroline ketone, at a controlled temperature, so that N-[2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formylamino)ethyl]-benzene (3) is obtained; the product reacts with chlorosulfonic acid to generate sulfonated product; the sulfonated product reacts with ammonia water to generate crude product benzenesulfonamide; the crude product is refined through solvent treatment to generate fine product; the reaction formula is show in the specification. The triphosgene method is simple in technology, simple in operation and high in yield; compared with the conventional method of phosgene, the solid phosgene (triphosgene) method is safer and is convenient to operate.
Description
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Technical field
The present invention relates to a kind of synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene, belong to the compound preparation field.
Background technology
Glimepiride third generation sulfonylurea oral hypoglycemic, the dominant mechanism of its hypoglycemic activity is to stimulate the beta Cell of islet excreting insulin, part improves the susceptibility of surrounding tissue to Regular Insulin.This product is combined with insulin receptor and is fast than Glyburide from the speed of separating, and lessly causes heavier hypoglycemia.After oral administration, glimepiride 100% is in gastrointestinal absorption, and within 2～3 hours, Plasma Concentration reaches peak value (Cmax), and protein binding rate is greater than 99.5%.Glimepiride is by the complete metabolism of oxidation biotransformation, main metabolites is cyclohexyl hydroxymethyl derivative (M1) and carboxylation derivant (M2), M1 through one or several cytosol enzyme effect and further metabolism is M2, and M1 compares with its parent the pharmacologically active that has about 1/3 on animal model.And M2 does not have this activity.And its intermediate N-4-［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzsulfamide (being called for short benzsulfamide in literary composition) is as its parent nucleus mesosome in the heart, it is synthetic crucial especially.
Glimepiride intermediate N 4-［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzsulfamide is as a core intermediate of type II diabetes medicine, its synthetic method report is a lot, Indian Pat. Appl., 2006MU00502, with China Medicine University journal 38 (1), 1-5; 2007; Fine-chemical intermediate 36 (3), 16-18; 2006 grades have reported that the synthetic of this intermediate is all that phenylethylamine is first made to the styroyl isocyanic ester, and then with 3-ethyl-4-methylpyrroline reactive ketone, then the property advanced sulfonation and amination, this method processing step complexity, be not easy to operation.
Summary of the invention
The object of the invention is to solve defect of the prior art, provide a kind of technique simple and safe reliable benzsulfamide simple synthesis.The method step is simplified, the contrast phosgene method, and triphosgene is safer than phosgene, convenient operation.
For solving the problems of the technologies described above, the present invention adopts following technical scheme to realize:
Phenylethylamine and 3-ethyl-4-methylpyrroline ketone are joined in methylene dichloride or ethylene dichloride, control temperature-20～20 ℃ (preferably-20～5 ℃), control-20～5 ℃ and drip triphosgene solution, react after 5～20 hours, the point plate disappears to raw material 3-ethyl-4-methylpyrroline ketone, add water to stir, combination cooling filters, filter cake washing with alcohol post-drying.Obtain intermediate 3.In 0～30 ℃ of chlorsulfonic acid that intermediate 3 is joined in batches to metering, add rear stirring, the rear ice solution that reacts completely, wash neutrality with water, and PH is 6～7, then adds the ammoniacal liquor of metering to be reacted to fully, filters the refining qualified product that obtain of filter cake.
Reaction formula:
Beneficial effect of the present invention: synthetic method craft of the present invention is simple, and safety is easy to operate, and product yield is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is elaborated.
Embodiment 1
Add 1200 milliliters of methylene dichloride in the there-necked flask of 3000 milliliters, 170 gram phenylethylamines, the 3-ethyl of 175 grams-4-methylpyrroline ketone, control temperature-5 to 5 ℃ of mixing solutionss that drip the methylene dichloride of triphosgene 132 grams and 600 milliliters, within about 3 hours, drip and finish, drip and finish the rear reaction 3 hours that continues, then be warmed up to room temperature, stir and finish to reaction in 2 hours, add 800
Ml water stirs, concentrated desolventizing methylene dichloride, add again 1000 ml waters, stirring is cooled to 0 ℃, and stir 3 hours at this temperature, filter, 100 milliliters of washing with alcohol, dry and obtain 190 gram intermediate N ［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzene.
Suction chlorsulfonic acid 640 grams in the reactor of 2000 milliliters, after chuck advances icy salt solution and is cooled to 10 ℃ of left and right, in keeping, 10～15 ℃ of gradation of temperature are stirred 15 minutes after adding 190 gram previous step intermediate N ［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzene to add material, slowly be warmed up to room temperature, insulation reaction 3 hours.Be incubated complete, more slowly be warming up to 42 ℃ the reaction 3 hours.After reaction finishes, the slow suction of feed liquid has been prepared to maintain interior temperature lower than 5 ℃ of dilutions in the reactor of 0～5 ℃ of water of 3000 grams while hot, after dilution finishes, continued to stir 0.5h.Filter, be washed with water to washing lotion pH=6～7, be filtered dry, above-mentioned SULPHURYL CHLORIDE wet product is put in 3000 milliliters of reactors to suction ammoniacal liquor 2000 grams, stirring at normal temperature 3h.Slowly be warming up to 35～45 ℃, keep 2h, more slowly be warming up to 65～70 ℃ of insulation reaction 5h.Insulation reaction is cooled to 10 ℃ of left and right after finishing.Filter, the filter cake washing, drying obtains off-white color benzsulfamide crude product 210 grams, above-mentioned crude product 210 grams is added to carbon 10 gram decolorization filterings with 2100 milliliters of dissolve with ethanol cooling, and filtering drying obtains product 123 grams, (HPLC 98.3%).
Embodiment 2:
Add 1200 milliliters of methylene dichloride in the there-necked flask of 2000 milliliters, phenylethylamine 170 grams, the 3-ethyl of 175 grams-4-methylpyrroline ketone, control temperature-5 to 5 ℃ of mixing solutionss that drip the methylene dichloride of triphosgene 152 grams and 800 milliliters, within about 3 hours, drip and finish, drip and finish the rear reaction 3 hours that continues, then be warmed up to room temperature, stir and finish to reaction in 2 hours, add 800 ml waters to stir, concentrated desolventizing methylene dichloride, add again 1000 ml waters, stirring is cooled to 0 ℃, and stir 3 hours at this temperature, filter, 100 milliliters of washing with alcohol, oven dry obtains 193 gram intermediates 3.
Suction chlorsulfonic acid 640 grams in the reactor of 2000 milliliters, after chuck advances icy salt solution and is cooled to 10 ℃ of left and right, in keeping, 10～15 ℃ of gradation of temperature are stirred 15 minutes after adding 193 gram previous step intermediate N ［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzene to add material, slowly be warmed up to room temperature, insulation reaction 3 hours.Be incubated complete, more slowly be warming up to 42 ℃ the reaction 3 hours.After reaction finishes, the slow suction of feed liquid has been prepared to maintain interior temperature lower than 5 ℃ of dilutions in the reactor of 0～5 ℃ of water of 3000 grams while hot, after dilution finishes, continued to stir 0.5h.Filter, be washed with water to washing lotion pH=6～7, be filtered dry, above-mentioned SULPHURYL CHLORIDE wet product is put in 3000 milliliters of reactors to suction ammoniacal liquor 2000 grams, stirring at normal temperature 3h.Slowly be warming up to 35～45 ℃, keep 2h, more slowly be warming up to 65～70 ℃ of insulation reaction 5h.Insulation reaction is cooled to 10 ℃ of left and right after finishing.Filter, the filter cake washing, drying obtains off-white color benzsulfamide crude product 213 grams, above-mentioned crude product 213 grams is added to carbon 10 gram decolorization filterings with 2200 milliliters of dissolve with ethanol cooling, and filtering drying obtains product 119 grams, (HPLC 97.4%).
Above-described embodiment is only in order to technical scheme of the present invention to be described but not design of the present invention and protection domain are limited; those of ordinary skill of the present invention is modified or is equal to replacement technical scheme of the present invention; and not breaking away from aim and the scope of technical scheme, it all should be encompassed in claim scope of the present invention.
Claims (6)
- A kind of synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene, it is characterized in that: at low temperatures by phenylethylamine (4) with the 3-ethyl-4-methylpyrroline ketone (5) is uniformly mixed cooling, by triphosgene with being added drop-wise to after dissolution with solvents in above-mentioned reaction system, start reaction, TLC analyzes raw material and disappears, obtain N-［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzene (3) through aftertreatment, (3) and chlorsulfonic acid are carried out to sulfonation reaction and obtain N-4-［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-benzene sulfonyl chloride (2), react again ammonification with ammoniacal liquor and obtain the target crude product, obtain product after solvent treatment.
- Reaction formula:
The synthetic method of a kind of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene according to claim 1, it is characterized in that: ［ 2-(3-ethyl-4-methyl-2-oxidation-3-pyrroline-1-formamido-) ethyl ］-synthetic method of benzene sulfonyl chloride (3) is to be uniformly mixed in solvent by benzene feedstock ethamine (4) and 3-ethyl-4-methylpyrroline ketone (5) to midbody compound N-4-, drip the triphosgene solution reaction and obtain (3), then through conventional chlorosulphonation and aminating reaction, obtain target product (1). - Synthetic method according to the described a kind of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene of right 1 or 2 is characterized in that: the solvent used in compound (4) and compound (5) reaction is methylene dichloride or ethylene dichloride.
- Synthetic method according to the described a kind of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene of right 1 or 2 is characterized in that: the temperature that drips triphosgene is-20～40 ℃.
- Synthetic method according to the described a kind of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene of right 4 is characterized in that: the temperature that drips triphosgene is preferably-20～5 ℃.
- The synthetic method of a kind of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene according to claim 1 and 2, is characterized in that: the mol ratio=1:0.8 of compound (5), compound (4) and triphosgene～1.5:0.2～0.8.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106699631A (en) * | 2017-02-08 | 2017-05-24 | 深圳市新阳唯康科技有限公司 | Glimepiride gamma crystal form and preparation method thereof |
| CN106866486A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride alpha-crystal form and preparation method thereof |
| CN106866485A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride δ crystal formations and preparation method thereof |
| CN106866487A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride ε crystal formations and preparation method thereof |
| CN106883161A (en) * | 2017-02-08 | 2017-06-23 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride beta crystal and preparation method thereof |
| CN107382813A (en) * | 2017-08-21 | 2017-11-24 | 扬子江药业集团江苏海慈生物药业有限公司 | The synthetic method of glimepiride key intermediate |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699631A (en) * | 2017-02-08 | 2017-05-24 | 深圳市新阳唯康科技有限公司 | Glimepiride gamma crystal form and preparation method thereof |
| CN106866486A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride alpha-crystal form and preparation method thereof |
| CN106866485A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride δ crystal formations and preparation method thereof |
| CN106866487A (en) * | 2017-02-08 | 2017-06-20 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride ε crystal formations and preparation method thereof |
| CN106883161A (en) * | 2017-02-08 | 2017-06-23 | 深圳市新阳唯康科技有限公司 | A kind of Glimepiride beta crystal and preparation method thereof |
| CN107382813A (en) * | 2017-08-21 | 2017-11-24 | 扬子江药业集团江苏海慈生物药业有限公司 | The synthetic method of glimepiride key intermediate |
| CN107382813B (en) * | 2017-08-21 | 2019-12-17 | 扬子江药业集团江苏海慈生物药业有限公司 | synthesis method of key intermediate of glimepiride |
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