CN105541749A - Synthetic method for timonacic pharmaceutical intermediate--L-N-acetyl thioproline - Google Patents
Synthetic method for timonacic pharmaceutical intermediate--L-N-acetyl thioproline Download PDFInfo
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- CN105541749A CN105541749A CN201510971403.5A CN201510971403A CN105541749A CN 105541749 A CN105541749 A CN 105541749A CN 201510971403 A CN201510971403 A CN 201510971403A CN 105541749 A CN105541749 A CN 105541749A
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- thioproline
- synthetic method
- ethanoyl
- pharmaceutical intermediate
- solid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthetic method for a timonacic pharmaceutical intermediate--L-N-acetyl thioproline. The synthetic method comprises the following steps: (I) adding 0.11 mol of L-thioproline and 80 to 100 ml of a potassium chloride solution into a reaction vessel, controlling a stirring speed in a range of 100 to 150 rpm, heating the mixed solution to 80 to 85 DEG C, slowly dropwise adding 50 ml of 2-thiopheneacetylnitrile and controlling addition time in a range of 30 to 40 min, keeping the stirring speed in a range of 90 to 120 min, carrying out reduced pressure distillation until a solid is precipitated, adding 80 ml of p-xylene, carrying out heating and redissolving the solid, carrying out decolorizing by using a molecular sieve, keeping a solution temperature in a range of 10 to 15 DEG C, carrying out standing for 30 to 35min, filtering a solid, and carrying out dehydrating by using a dehydrating agent so as to obtain white L-N-acetyl thioproline (1), wherein the mass fraction of the potassium chloride solution in the step (I) is 10 to 15%, and the mass fraction of 2-thiopheneacetylnitrile in the step (I) is 70 to 85%.
Description
Technical field
The present invention relates to a kind of synthetic method of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline.
Background technology
Thiazolidinecarboxylic acid is euglycemic agent, by increase peripheral tissues to the susceptibility of Regular Insulin, improve insulin resistant and reduce blood sugar, and can improve and lowly with Regular Insulin resist relevant multiple cardiovascular risk factors.Add surrounding tissue (the especially target tissue of insulin action: skeletal muscle, liver, fatty tissue) to the responsing reaction (susceptibility) of Regular Insulin, thus add the utilization of muscle to glucose, decrease the generation of liver endogenous glucose, promote the synthesis of fat, it is suppressed to decompose and make internal metabolism disorder be tending towards normal, indirectly reach the curative effect of hypoglycemic, obviously can improve insulin resistant (but Liver and kidney function needs normal).L-N-ethanoyl thioproline is as thiazolidinecarboxylic acid pharmaceutical intermediate, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline, comprise the steps:
I () adds L-thioproline 0.11mol in reaction vessel, Klorvess Liquid 80-100ml, control stirring velocity 100-150rpm, make solution warms to 80--85 DEG C, slow dropping 2-thienyl acetyl nitrile 50ml, time for adding controls at 30-40min, stirring velocity is kept to maintain 90-120min, underpressure distillation, separate out to solid, add p-Xylol 80ml, heating makes solid again dissolve, decolour with molecular sieve, keep solution temperature 10--15 DEG C, leave standstill 30-35min, leach solid, dewatering agent dewaters, obtain white L-N-ethanoyl thioproline (1), wherein, the massfraction of the Klorvess Liquid described in step (i) is 10-15%, 2-thienyl acetyl nitrile massfraction described in step (i) is 70--85%, underpressure distillation described in step (i), residing pressure is 2.1-2.3kPa, the massfraction of the p-Xylol described in step (i) is 85--90%, and the dewatering agent described in step (i) is any one in Vanadium Pentoxide in FLAKES, Anhydrous potassium carbonate.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
A kind of synthetic method of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline
Example 1:
L-thioproline 0.11mol is added in reaction vessel, massfraction is 10% Klorvess Liquid 80ml, control stirring velocity 100rpm, make solution warms to 80 DEG C, slow dropping massfraction is the 2-thienyl acetyl nitrile 50ml of 70%, time for adding controls at 30min, stirring velocity is kept to maintain 90min, 2.1kPa underpressure distillation, separate out to solid, adding massfraction is 85% p-Xylol 80ml, heating makes solid again dissolve, decolour with molecular sieve, keep solution temperature 10 DEG C, leave standstill 30min, leach solid, Vanadium Pentoxide in FLAKES dewaters, obtain white L-N-ethanoyl thioproline (1) 15.79g, yield 82%.
Example 2:
L-thioproline 0.11mol is added in reaction vessel, Klorvess Liquid 90ml, control stirring velocity 120rpm, make solution warms to 83 DEG C, slow dropping massfraction is the 2-thienyl acetyl nitrile 50ml of 80%, time for adding controls at 35min, stirring velocity is kept to maintain 110min, 2.2kPa underpressure distillation, separate out to solid, adding massfraction is 86% p-Xylol 80ml, heating makes solid again dissolve, decolour with molecular sieve, keep solution temperature 13 DEG C, leave standstill 32min, leach solid, Anhydrous potassium carbonate dewaters, obtain white L-N-ethanoyl thioproline (1) 16.36g, yield 85%.
Example 3:
L-thioproline 0.11mol is added in reaction vessel, Klorvess Liquid 100ml, control stirring velocity 150rpm, make solution warms to 85 DEG C, slow dropping massfraction is the 2-thienyl acetyl nitrile 50ml of 85%, time for adding controls at 40min, stirring velocity is kept to maintain 120min, 2.3kPa underpressure distillation, separate out to solid, adding massfraction is 90% p-Xylol 80ml, heating makes solid again dissolve, decolour with molecular sieve, keep solution temperature 15 DEG C, leave standstill 35min, leach solid, Vanadium Pentoxide in FLAKES dewaters, obtain white L-N-ethanoyl thioproline (1) 17.13g, yield 89%.
Claims (4)
1. a synthetic method for thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline, is characterized in that, comprise the steps:
I () adds L-thioproline 0.11mol in reaction vessel, Klorvess Liquid 80-100ml, control stirring velocity 100-150rpm, make solution warms to 80--85 DEG C, slow dropping 2-thienyl acetyl nitrile 50ml, time for adding controls at 30-40min, stirring velocity is kept to maintain 90-120min, underpressure distillation, separate out to solid, add p-Xylol 80ml, heating makes solid again dissolve, decolour with molecular sieve, keep solution temperature 10--15 DEG C, leave standstill 30-35min, leach solid, dewatering agent dewaters, obtain white L-N-ethanoyl thioproline (1), the massfraction of the Klorvess Liquid described in step (i) is 10-15%, and the 2-thienyl acetyl nitrile massfraction described in step (i) is 70--85%.
2. the synthetic method of a kind of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline according to claim 1, it is characterized in that, the underpressure distillation described in step (i), residing pressure is 2.1-2.3kPa.
3. the synthetic method of a kind of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline according to claim 1, it is characterized in that, the massfraction of the p-Xylol described in step (i) is 85--90%.
4. the synthetic method of a kind of thiazolidinecarboxylic acid pharmaceutical intermediate L-N-ethanoyl thioproline according to claim 1, is characterized in that, the dewatering agent described in step (i) is any one in Vanadium Pentoxide in FLAKES, Anhydrous potassium carbonate.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510971403.5A CN105541749A (en) | 2015-12-22 | 2015-12-22 | Synthetic method for timonacic pharmaceutical intermediate--L-N-acetyl thioproline |
| CN201610826613.XA CN106432128A (en) | 2015-12-22 | 2016-09-18 | Method for synthesizing timonacic drug intermediate L-N-acetyl thia-proline |
| AU2016102143A AU2016102143A4 (en) | 2015-12-22 | 2016-12-20 | Timonacic drug intermediates L-N-acetyl sulfur impurity proline synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510971403.5A CN105541749A (en) | 2015-12-22 | 2015-12-22 | Synthetic method for timonacic pharmaceutical intermediate--L-N-acetyl thioproline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105541749A true CN105541749A (en) | 2016-05-04 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510971403.5A Pending CN105541749A (en) | 2015-12-22 | 2015-12-22 | Synthetic method for timonacic pharmaceutical intermediate--L-N-acetyl thioproline |
| CN201610826613.XA Pending CN106432128A (en) | 2015-12-22 | 2016-09-18 | Method for synthesizing timonacic drug intermediate L-N-acetyl thia-proline |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610826613.XA Pending CN106432128A (en) | 2015-12-22 | 2016-09-18 | Method for synthesizing timonacic drug intermediate L-N-acetyl thia-proline |
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| Country | Link |
|---|---|
| CN (2) | CN105541749A (en) |
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2015
- 2015-12-22 CN CN201510971403.5A patent/CN105541749A/en active Pending
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2016
- 2016-09-18 CN CN201610826613.XA patent/CN106432128A/en active Pending
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| Publication number | Publication date |
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| CN106432128A (en) | 2017-02-22 |
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Application publication date: 20160504 |