CN101503413B - Preparation of 5,6-dihydro-6-methieno [2,3-b] thiopyran-2-sulfonic acid amide-4-keto - Google Patents
Preparation of 5,6-dihydro-6-methieno [2,3-b] thiopyran-2-sulfonic acid amide-4-keto Download PDFInfo
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- CN101503413B CN101503413B CN2009101150113A CN200910115011A CN101503413B CN 101503413 B CN101503413 B CN 101503413B CN 2009101150113 A CN2009101150113 A CN 2009101150113A CN 200910115011 A CN200910115011 A CN 200910115011A CN 101503413 B CN101503413 B CN 101503413B
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Abstract
The invention relates to a preparation method of 5,6-dihydro-6-methylthieno(2,3-b) thiopyran-2-sulfamide-4-ketone, which is characterized by comprising the following processing steps of: adding 0.125 mol of thiophene and 150 milliliter of tetrahydrofuran in a four-hole flask, and cooling down to -20 DEG C; dropwise adding 63 milliliter of 2 mol/liter butyl lithium pentane solution, and adding 0.125 mol of sulfur and 0.125 mol of (R)-beta-butyrolactone; when heating to room temperature, adding 0.125 mol of trifluoro acetic anhydride, and carrying out mechanical intense stirring; after the completion of reaction, slowly adding the mixture in a flask containing 0.166 mol of chlorosulfonic acid at the temperature of 0 DEG C; and heating the obtained dark solution to 50 DEG C, keeping for 12 hours, then cooling to 20 DEG C, adding thionyl chloride and strong ammonia, stirring and diluting at the temperature of 0 DEG C, and drying to obtain target products. The preparation method has the advantages of stable reaction, stronger antimicrobial bactericidal effects of the target products than those of common antimicrobial drugs, easy enlarging production and no pollution in the production process.
Description
Technical field
The present invention relates to a kind ofly 5,6-dihydro-6-thiotolene is the preparation method of [2,3-b] thiapyran-2-sulphonamide-4-ketone also.
Background technology
5,6-dihydro-6-thiotolene also [2,3-b] thiapyran-2-sulphonamide-4-ketone is a kind of important medicine intermediate, belongs to sulfa drugs and itself has stronger antibiotic pharmacological action, so have potential research and using value.Abroad to this compound research be not a lot, and do not have complete synthetic this organic preparation method; Not domestic the appearance as yet to its synthetic report.At this fact, the present invention is a raw material with the thiophene, has made target product by series reaction.
Summary of the invention
The object of the present invention is to provide a kind ofly 5,6-dihydro-6-thiotolene is the preparation method of [2,3-b] thiapyran-2-sulphonamide-4-ketone also, and this preparation method's stable reaction is easy to amplify and produces.
The present invention is achieved like this, and it is characterized in that the processing method step is:
1, in the four-hole boiling flask of clean dried, add 10.5 gram (0.125 mole) thiophene, 150 milliliters of tetrahydrofuran (THF)s are cooled to-20 ℃, drip the pentane solution of 63 milliliters 2 moles every liter butyllithium, after dropwising, obtain a yellow solution, continue to stir 1 hour at-20 ℃ then, add 4.01 gram (0.125 mole) sulphur, get an orange-yellow solution, continue again to continue stirring reaction down, follow the tracks of reaction up to HPLC and finish at-20 ℃;
2, add in the four-hole boiling flask of step 1 10.8 grams (0.125 mole) (R)-beta-butyrolactone, solution becomes orange, temperature is slowly risen to room temperature, boil off tetrahydrofuran (THF), remaining orange jelly is suspended in 70 milliliters of toluene, and stirring hydrochloric acid to the pH value that drips 1 mole every liter down fast is 1-2, tell toluene layer, water with toluene extraction 3-5 time, merges organic phase again, concentrated orange;
3, in oily matter, add 625 milliliters of toluene then, be cooled to 0 ℃, slowly add 26.2 gram (0.125 mole) trifluoroacetic anhydrides, the deepening gradually of reaction solution color, finish, reaction at room temperature is after HPLC tracking cyclisation reacts completely, the cold water that adds 200 milliliters 0 ℃, stir, branch vibration layer, organic phase is with the saturated common salt water washing once, be evaporated to dried, standby;
4, in flask, add 11 milliliters of (0.166 mole) chlorsulfonic acids, be cooled to 0 ℃, slowly add 3.8 gram (0.02 mole) above-mentioned standby materials that make, obtain dark-coloured solution and be heated to 50 ℃ of maintenances 12 hours, be cooled to 20 ℃, slowly add 11 milliliters of (0.151 mole) thionyl chlorides, finish, be warmed up to 50 ℃ and follow the tracks of until HPLC and to react completely, be cooled to 15 ℃, add 0 ℃ 330 ml waters under the vigorous stirring, stirred 1 hour down at 0-5 ℃, filter, washing gets crude product;
5, in above-mentioned crude product, add 11 milliliters of tetrahydrofuran (THF)s, 0 ℃ adds 6.5 milliliters (15 moles every liter down, 0.0975 strong aqua mole), reaction solution stirred 1 hour down at 0-5 ℃, thin up, decompression boils off remaining ammonia and tetrahydrofuran (THF) down, and the product of separating out filters, washing is drying to obtain target product.
Reaction formula of the present invention is:
Advantage of the present invention is: stable reaction, the action effect of target product antibiotic and sterilizing is better than general antimicrobial drug, is easy to amplify produce, and is pollution-free in the production process.
Embodiment
1. the preparation of thiophene-2-mercaptan lithium
In 500 milliliters of four-hole boiling flasks of clean dried, add 10.5 gram (0.125 mole) thiophene, 150 milliliters of tetrahydrofuran (THF)s are cooled to-20 ℃, drip the pentane solution of 63 milliliters 2 moles every liter butyllithium, dropwise about 10 minutes.Obtain a yellow solution, continue to stir 1 hour at-20 ℃ then.Add 4.01 gram (0.125 mole) sulphur, get an orange-yellow solution, continue again to continue stirring reaction down, follow the tracks of reaction up to HPLC and finish at-20 ℃;
2. intermediate product 5, and 6-dihydro-6-thiotolene is the preparation of [2,3-b] thiapyran-4-ketone also
With syringe add in the top four-hole boiling flask 10.8 grams (0.125 mole) (R)-beta-butyrolactone, solution becomes orange, and temperature is slowly risen to room temperature.Boil off tetrahydrofuran (THF), remaining orange jelly is suspended in 70 milliliters of toluene, and stirring hydrochloric acid to the pH value that drips 1 mole every liter down fast is 1-2, tells toluene layer, and water with toluene extraction 3 times, merges organic phase again, concentrate orange;
In oily matter, add 625 milliliters of toluene, be cooled to 0 ℃, slowly add 26.2 gram (0.125 mole) trifluoroacetic anhydrides, the deepening gradually of reaction solution color, finish, reaction at room temperature is after HPLC tracking cyclisation reacts completely, the cold water that adds 200 milliliters 0 ℃, stirred 30 minutes, branch vibration layer, organic phase is with the saturated common salt water washing once, be evaporated to and do promptly yield 72%;
3. target product 5, and 6-dihydro-6-thiotolene is the preparation of [2,3-b] thiapyran-2-sulphonamide-4-ketone also
In flask, add 11 milliliters of (0.166 mole) chlorsulfonic acids, be cooled to 0 ℃, slowly add 3.8 gram (0.02 moles) 5,6-dihydro-6-thiotolene is [2,3-b] thiapyran-4-ketone also, obtains dark-coloured solution and be heated to 50 ℃ of maintenances 12 hours, be cooled to 20 ℃, slowly add 11 milliliters of (0.151 mole) thionyl chlorides, finish, be warmed up to 50 ℃ and follow the tracks of until HPLC and to react completely.Be cooled to 15 ℃, add 0 ℃ 330 ml waters under the vigorous stirring, stirred 1 hour down, filter at 0-5 ℃, washing, crude product;
In above-mentioned crude product, add 11 milliliters of tetrahydrofuran (THF)s, 0 ℃ adds 6.5 milliliters (15 moles every liter down, 0.0975 strong aqua mole), reaction solution stirred 1 hour down at 0-5 ℃, thin up, and decompression boils off remaining ammonia and tetrahydrofuran (THF) down, the product of separating out filters, washing is drying to obtain yield 76%.
Claims (1)
1. one kind 5,6-dihydro-6-thiotolene is the preparation method of [2,3-b] thiapyran-2-sulphonamide-4-ketone also, it is characterized in that the processing method step is:
(1) preparation of thiophene-2-mercaptan lithium: in 500 milliliters of four-hole boiling flasks of clean dried, add 10.5 gram thiophene, 150 milliliters of tetrahydrofuran (THF)s are cooled to-20 ℃, drip the pentane solution of 63 milliliters 2 moles every liter butyllithium, dropwise about 10 minutes, obtain a yellow solution, continue to stir 1 hour at-20 ℃ then, add 4.01 gram sulphur, get an orange-yellow solution, continue again to continue stirring reaction down, follow the tracks of reaction up to HPLC and finish at-20 ℃;
(2) intermediate product 5,6-dihydro-6-thiotolene also [2,3-b] preparation of thiapyran-4-ketone: add 10.8 with syringe in the top four-hole boiling flask and restrain (R)-beta-butyrolactones, solution becomes orange, temperature is slowly risen to room temperature, boil off tetrahydrofuran (THF), remaining orange jelly is suspended in 70 milliliters of toluene, stirring hydrochloric acid to the pH value that drips 1 mole every liter down fast is 1-2, tell toluene layer, water with toluene extraction 3 times, merges organic phase again, concentrate orange, in oily matter, add 625 milliliters of toluene, be cooled to 0 ℃, slowly add 26.2 gram trifluoroacetic anhydrides, the deepening gradually of reaction solution color, finish, reaction at room temperature is after HPLC tracking cyclisation reacts completely, the cold water that adds 200 milliliters 0 ℃, stirred 30 minutes, branch vibration layer, organic phase is with the saturated common salt water washing once, be evaporated to and do promptly yield 72%;
(3) target product 5, and 6-dihydro-6-thiotolene is the preparation of [2,3-b] thiapyran-2-sulphonamide-4-ketone also: add 11 milliliters of chlorsulfonic acids in flask, be cooled to 0 ℃, slowly add 3.8 grams 5,6-dihydro-6-thiotolene also [2,3-b] thiapyran-4-ketone, obtain dark-coloured solution and be heated to 50 ℃ of maintenances 12 hours, be cooled to 20 ℃, slowly add 11 milliliters of thionyl chlorides, finish, be warmed up to 50 ℃ and follow the tracks of until HPLC and to react completely, be cooled to 15 ℃, 330 ml waters that add 0 ℃ under the vigorous stirring, stirred 1 hour down at 0-5 ℃, filter, washing, get crude product, in crude product, add 11 milliliters of tetrahydrofuran (THF)s, 0 ℃ of strong aqua that adds 6.5 milliliters 15 moles every liter down, reaction solution stirred 1 hour down at 0-5 ℃, thin up, decompression boils off remaining ammonia and tetrahydrofuran (THF) down, and the product of separating out filters, washing, be drying to obtain yield 76%.
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| CN2009101150113A CN101503413B (en) | 2009-03-06 | 2009-03-06 | Preparation of 5,6-dihydro-6-methieno [2,3-b] thiopyran-2-sulfonic acid amide-4-keto |
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| CN108586485B (en) * | 2018-05-30 | 2020-05-15 | 沈阳药科大学 | 1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compound and application thereof |
| CN108822125B (en) * | 2018-05-30 | 2020-01-31 | 沈阳药科大学 | 1- (thieno [2,3-b ] thiopyranoformyl) -4-aliphatic alkyl piperazine compound and medical application thereof |
| CN108484635B (en) * | 2018-05-30 | 2020-01-31 | 沈阳药科大学 | 4H-thieno [2,3-b ] thiopyran-4-one compound and application thereof |
| CN108586484B (en) * | 2018-05-30 | 2020-05-15 | 沈阳药科大学 | Thienopyran carboxamides and their use |
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