CN103420891B - The synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene - Google Patents
The synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene Download PDFInfo
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- CN103420891B CN103420891B CN201310228829.2A CN201310228829A CN103420891B CN 103420891 B CN103420891 B CN 103420891B CN 201310228829 A CN201310228829 A CN 201310228829A CN 103420891 B CN103420891 B CN 103420891B
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Abstract
The invention discloses a kind of synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene, by phenylethylamine and 3-ethyl-4-methylpyrroline ketone in a solvent, control certain temperature, slowly drip triphosgene post-reaction treatment and obtain N-［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzene (3), sulfonated product is obtained by reacting again with chlorsulfonic acid, crude product benzsulfamide is obtained by reacting in ammoniacal liquor, solvent treatment obtains finished product, and reaction formula is:
Description
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 field of compound preparation.
Background technology
Glimepiride third generation sulfonylurea oral hypoglycemic, the dominant mechanism of its hypoglycemic activity stimulates islet β cell Regular Insulin, and part improves surrounding tissue to the susceptibility of Regular Insulin.This product be combined with insulin receptor and the speed of dissociation comparatively Glyburide is fast, lessly cause 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 oxidative biotransformation effect, main metabolites is cyclohexyl hydroxymethyl derivative (M1) and carboxylation derivant (M2), through one or several cytosol enzyme effect, further metabolism is M2 to M1, and M1 has the pharmacologically active of about 1/3 on animal model compared with its parent.And M2 does not have this active.And its intermediate N-4-［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzsulfamide (being called for short benzsulfamide in literary composition) is as its parent nucleus mesosome in the heart, its synthesis is crucial especially.
Glimepiride intermediate N-4-［ 2-(3-ethyl-4-methyl-2-is oxidized-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; The synthesis reporting this intermediate such as 2006 are all phenylethylamine is first made styroyl isocyanic ester, and then with 3-ethyl-4-methylpyrroline reactive ketone, then the property entered sulfonation and amination, this method processing step is complicated, is 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 simplifies, and contrast phosgene method, 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 DEG C (preferably-20 ~ 5 DEG C), control-20 ~ 5 DEG C and drip triphosgene solution, react after 5 ~ 20 hours, 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.Joined in the chlorsulfonic acid of metering by intermediate 3 at 0 ~ 30 DEG C in batches, add rear stirring, after reacting completely, ice solution, washes neutrality with water, and PH is 6 ~ 7, and the ammoniacal liquor then adding metering is reacted to completely, filters, and filter cake is refining obtains qualified product.
Reaction formula:
Beneficial effect of the present invention: synthetic method craft of the present invention is simple, safety is easy to operate, and product yield is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is elaborated.
embodiment 1
1200 milliliters of methylene dichloride are added in the there-necked flask of 3000 milliliters, 170 grams of phenylethylamines, 3-ethyl-4-methylpyrroline the ketone of 175 grams, control temperature-5 drips the mixing solutions of the methylene dichloride of triphosgene 132 grams and 600 milliliters to 5 DEG C, within about 3 hours, drip and terminate, drip and terminate rear continuation reaction 3 hours, be then warmed up to room temperature, stir and terminate to reaction for 2 hours, add 800
Ml water stirs, concentrated desolventizing methylene dichloride, add 1000 ml waters again, stirring is cooled to 0 DEG C, and stir 3 hours at such a temperature, filter, 100 milliliters of washing with alcohol, dry and obtain 190 grams of intermediate N ［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzene.
Suction chlorsulfonic acid 640 grams in the reactor of 2000 milliliters, chuck enters after icy salt solution is cooled to about 10 DEG C, 10 ~ 15 DEG C of gradation of the interior temperature of maintenance add 190 grams of previous step intermediate N ［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzene and add the rear stirring of material 15 minutes, slowly be warmed up to room temperature, insulation reaction 3 hours.Be incubated complete, be more slowly warming up to 42 DEG C of reactions 3 hours.After reaction terminates, slow for feed liquid suction is prepared to maintain interior temperature in the reactor of 3000 grams of 0 ~ 5 DEG C of water lower than 5 DEG C of dilutions while hot, after dilution terminates, 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, suction ammoniacal liquor 2000 grams, stirring at normal temperature 3h.Slowly be warming up to 35 ~ 45 DEG C, keep 2h, be more slowly warming up to 65 ~ 70 DEG C of insulation reaction 5h.After insulation reaction terminates, be cooled to about 10 DEG C.Filter, filter cake is washed, and drying obtains off-white color benzsulfamide crude product 210 grams, and above-mentioned crude product 210 grams 2100 milliliters of dissolve with ethanol are added carbon 10 grams of decolorization filtering coolings, and filtering drying obtains product 123 grams, (HPLC 98.3%).
embodiment 2:
1200 milliliters of methylene dichloride are added in the there-necked flask of 2000 milliliters, phenylethylamine 170 grams, 3-ethyl-4-methylpyrroline the ketone of 175 grams, control temperature-5 drips the mixing solutions of the methylene dichloride of triphosgene 152 grams and 800 milliliters to 5 DEG C, within about 3 hours, drip and terminate, dropping terminates rear continuation reaction 3 hours, then room temperature is warmed up to, stir and terminate to reaction for 2 hours, add 800 ml waters to stir, concentrated desolventizing methylene dichloride, add 1000 ml waters again, stirring is cooled to 0 DEG C, and stir 3 hours at such a temperature, filter, 100 milliliters of washing with alcohol, oven dry obtains 193 grams of intermediates 3.
Suction chlorsulfonic acid 640 grams in the reactor of 2000 milliliters, chuck enters after icy salt solution is cooled to about 10 DEG C, 10 ~ 15 DEG C of gradation of the interior temperature of maintenance add 193 grams of previous step intermediate N ［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzene and add the rear stirring of material 15 minutes, slowly be warmed up to room temperature, insulation reaction 3 hours.Be incubated complete, be more slowly warming up to 42 DEG C of reactions 3 hours.After reaction terminates, slow for feed liquid suction is prepared to maintain interior temperature in the reactor of 3000 grams of 0 ~ 5 DEG C of water lower than 5 DEG C of dilutions while hot, after dilution terminates, 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, suction ammoniacal liquor 2000 grams, stirring at normal temperature 3h.Slowly be warming up to 35 ~ 45 DEG C, keep 2h, be more slowly warming up to 65 ~ 70 DEG C of insulation reaction 5h.After insulation reaction terminates, be cooled to about 10 DEG C.Filter, filter cake is washed, and drying obtains off-white color benzsulfamide crude product 213 grams, and above-mentioned crude product 213 grams 2200 milliliters of dissolve with ethanol are added carbon 10 grams of decolorization filtering coolings, and filtering drying obtains product 119 grams, (HPLC 97.4%).
Above-described embodiment is only in order to illustrate technical scheme of the present invention but not to limit design of the present invention and protection domain; those of ordinary skill of the present invention is modified to technical scheme of the present invention or equivalent replacement; and not departing from aim and the scope of technical scheme, it all should be encompassed in right of the present invention.
Claims (4)
1. the synthetic method of a type II diabetes medicine glimepiride intermediate benzsulfamide triphosgene, it is characterized in that: phenylethylamine (4) and 3-ethyl-4-methylpyrroline ketone (5) are joined in solvent, control temperature-20 ~ 20 DEG C drips triphosgene solution, react after 5 ~ 20 hours, point plate disappears to raw material 3-ethyl-4-methylpyrroline ketone, add water to stir, boil off solvent, the combination cooling that adds water again filters, filter cake washing with alcohol post-drying, obtain intermediate N ［ 2-(3-ethyl-4-methyl-2-is oxidized-3-pyrroline-1-formamido-) ethyl ］-benzene (3), under 0 ~ 30 DEG C of condition, joined in the chlorsulfonic acid of metering by intermediate 3 in batches, add rear stirring, ice solution after reacting completely, washing neutral pH with water is 6-7, and the ammoniacal liquor then adding metering is reacted to completely, filters, and filter cake is refining obtains qualified product,
Reaction formula:
。
2. according to the synthetic method of a kind of type II diabetes medicine glimepiride intermediate benzsulfamide described in claim 1, it is characterized in that: the solvent used during compound (4) and compound (5) react is methylene dichloride or ethylene dichloride.
3. according to the synthetic method of a kind of type II diabetes medicine glimepiride intermediate benzsulfamide described in claim 1, it is characterized in that: the temperature dripping phosgene is-20 ~ 5 DEG C.
4., according to the synthetic method of a kind of type II diabetes medicine glimepiride intermediate benzsulfamide described in claim 1, it is characterized in that: mol ratio=1 of compound (5), compound (4) photoreactive gas: 0.8 ~ 1.5: 0.2 ~ 0.8.
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| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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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