CN100551906C - A kind of preparation method of thio-iso-butanamide - Google Patents
A kind of preparation method of thio-iso-butanamide Download PDFInfo
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- CN100551906C CN100551906C CNB2007101322341A CN200710132234A CN100551906C CN 100551906 C CN100551906 C CN 100551906C CN B2007101322341 A CNB2007101322341 A CN B2007101322341A CN 200710132234 A CN200710132234 A CN 200710132234A CN 100551906 C CN100551906 C CN 100551906C
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- butanamide
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- thiophosphoric anhydride
- alkali
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Abstract
The present invention relates to field of medicine and chemical technology, be specifically related to a kind of preparation method of thio-iso-butanamide.The present invention has synthesized thio-iso-butanamide, yield 〉=90%, content 〉=99% with high yield with isobutyramide following and thiophosphoric anhydride reaction under normal temperature and pressure in alkaline condition.
Description
Technical field
The present invention relates to field of medicine and chemical technology, be specifically related to a kind of preparation method of thio-iso-butanamide.
Background technology
2-sec.-propyl-4-(((N-methyl) amido) methyl) thiazole hydrochloride is the important intermediate of anti-AIDS drug ritonavir.The synthetic route of disclosed this compound of WO2006/090270A1 may further comprise the steps:
1, adopts isobutyramide and thiophosphoric anhydride in organic solvent, to react and generate thio-iso-butanamide.
2, thio-iso-butanamide and Dichloro acetone ring-closure reaction generate 2-sec.-propyl-4-5-chloromethyl thiazole.
3,2-sec.-propyl-4-5-chloromethyl thiazole and methylamine react down in room temperature condition and generate 2-sec.-propyl-4-(((N-methyl) amido) methyl) thiazole.
4,2-sec.-propyl-4-(((N-methyl) amido) methyl) thiazole and hydrochloric acid salify, crystallization in organic solvent gets target product.
As seen thio-iso-butanamide is the important intermediate of Synthetic 2-sec.-propyl-4-(((N-methyl) amido) methyl) thiazole hydrochloride.Adopt isobutyramide and thiophosphoric anhydride in organic solvent, to react in the above-mentioned the first step and generate in the thio-iso-butanamide step, the by product Vanadium Pentoxide in FLAKES of generation, water absorbability is very strong, and is insoluble to organic solvent, and the reactant thickness makes reaction be difficult to carry out.Product is difficult to separate with raw material, and yield is low, and about 80%.
Summary of the invention
The invention discloses a kind of novel method for preparing thio-iso-butanamide, the present invention has synthesized thio-iso-butanamide with high yield with isobutyramide following and thiophosphoric anhydride reaction under normal temperature and pressure in alkaline condition.Yield 〉=90%, content 〉=99%.Prepared thio-iso-butanamide obtains high-load 2-sec.-propyl-4-(((N-methyl) amido) methyl) thiazole hydrochloride through cyclization, amination, salt-forming reaction.
Preparation method of the present invention comprises: thiophosphoric anhydride and alkali are reacted formation solubility double salt thiophosphoric anhydride alkali in solvent, thiophosphoric anhydride alkali reacts with isobutyramide again, filter, and distillation, promptly.
The wherein preferred tetrahydrofuran (THF) of solvent, dioxane, dioxolane, ethyl acetate, propyl acetate, butylacetate, ether or methyl tertiary butyl ether.Preferred solvent is ethyl acetate, propyl acetate or butylacetate.
Wherein preferred salt of wormwood of alkali or yellow soda ash.
Preferred 112～120 ℃/5mmHg fraction of collecting.
Temperature of reaction of the present invention is a room temperature.
Reaction formula is as follows:
The invention has the advantages that:
1, isobutyramide and thiophosphoric anhydride thio reaction under alkaline condition obtain thio-iso-butanamide with high yield, content 〉=99%, yield 90～95%.
2, according to existing technology, thiophosphoric anhydride and isobutyramide reaction, because of the by product Vanadium Pentoxide in FLAKES moisture absorption that generates, the thickness that induces reaction can't carry out thio reaction in esters solvents such as ethyl acetate, could react in special solvent.And employing present method, the double salt energy uniform dissolution that thiophosphoric anhydride and alkali form is in each kind solvent such as ester class, the alkali formation double salt that discharges in the by product Vanadium Pentoxide in FLAKES that generates with isobutyramide reaction and the reaction process is dispersed in the esters solvent reacting balance.Filter, reclaim solvent, distillation can obtain target product.Solved the problem that thiophosphoric anhydride and isobutyramide thio reaction can't carry out at esters solvents such as ethyl acetate.
Embodiment
Embodiment 1
In the ethyl acetate of 600ml, add the 12g thiophosphoric anhydride, add the 5.8g anhydrous sodium carbonate in batches, in 20～25 ℃, stir 30mins.Deng solid molten to the greatest extent after, add isobutyramide 20g in batches, reactant stirs 5hrs in 25 ℃.Reaction mixture filters, solution concentration, and underpressure distillation, 115～118 ℃/5mmHg of yield fraction gets the pale yellow oily liquid body, gets thio-iso-butanamide 22.5g, yield 95.00%, GC content: 99.2%.
Embodiment 2
In the 400ml tetrahydrofuran (THF), add the 8g thiophosphoric anhydride, add the 9.35g anhydrous sodium carbonate in batches, T=23-25 ℃, stir 25mim.Add isobutyramide 15.2g in batches.Reactant stirs 5hrs in 20～25 ℃.The reclaim under reduced pressure tetrahydrofuran (THF) adds 50ml water, transfers PH=7.5 with 5% aqueous sodium carbonate, uses 50mlx3 ethyl acetate extraction three times, merges organic layer, with the washing of 100ml saturated brine.Anhydrous sodium sulfate drying filters, the reclaim under reduced pressure ethyl acetate, and 112-118 ℃/4mmHg fraction is collected in the residue underpressure distillation, gets yellow oily liquid, weight 16.2g, yield 91.2%.
Embodiment 3
In the 400ml methyl tertiary butyl ether, add the 12.5g thiophosphoric anhydride, add the 7.6g Anhydrous potassium carbonate in batches, stir 30mins in 20～25 ℃.Add isobutyramide 20.2g in batches.React on 25～30 ℃ and stir 5.5hrs.Reactant filters, solution concentration, and 116～120 ℃/5mmHg fraction is collected in the residue underpressure distillation, gets the pale yellow oily liquid body.Weight 21.8g, yield 92%, GC content 99.1%.
Claims (3)
1, a kind of method for preparing thio-iso-butanamide is characterized in that: thiophosphoric anhydride and alkali are reacted formation solubility double salt thiophosphoric anhydride alkali in solvent, thiophosphoric anhydride alkali reacts with isobutyramide again, filter, distillation, that is, wherein solvent is ethyl acetate, propyl acetate or butylacetate.
2, the process of claim 1 wherein that alkali is salt of wormwood or yellow soda ash.
3, the process of claim 1 wherein that temperature of reaction is a room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101322341A CN100551906C (en) | 2007-09-26 | 2007-09-26 | A kind of preparation method of thio-iso-butanamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007101322341A CN100551906C (en) | 2007-09-26 | 2007-09-26 | A kind of preparation method of thio-iso-butanamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101121681A CN101121681A (en) | 2008-02-13 |
| CN100551906C true CN100551906C (en) | 2009-10-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2007101322341A Active CN100551906C (en) | 2007-09-26 | 2007-09-26 | A kind of preparation method of thio-iso-butanamide |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102993075A (en) * | 2012-11-29 | 2013-03-27 | 江苏长青农化股份有限公司 | Synthesis process for diafenthiuron as thiourea insecticide and acaricide |
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2007
- 2007-09-26 CN CNB2007101322341A patent/CN100551906C/en active Active
Non-Patent Citations (2)
| Title |
|---|
| 噻唑环衍生物的合成. 张荣华等.化学研究与应用，第18卷第2期. 2006 |
| 噻唑环衍生物的合成. 张荣华等.化学研究与应用，第18卷第2期. 2006 * |
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| CN101121681A (en) | 2008-02-13 |
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Address after: 225453 Hongqiao Industrial Park, Taixing Economic Development Zone, Jiangsu Patentee after: JIANGSU SENXUAN PHARMACEUTICAL AND CHEMICAL CO., LTD. Address before: 225453 Hongqiao Industrial Park, Taixing Economic Development Zone, Jiangsu Patentee before: Jiangsu Senxuan Pharmaceutical Co., Ltd. |
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Effective date of registration: 20190227 Address after: 226400 No. 20-1 Haibin Third Road, Rudong Coastal Economic Development Zone, Nantong City, Jiangsu Province Patentee after: Nantong Senxuan Pharmaceutical Co., Ltd. Address before: 225453 Hongqiao Industrial Park, Taixing Economic Development Zone, Jiangsu Province Patentee before: JIANGSU SENXUAN PHARMACEUTICAL AND CHEMICAL CO., LTD. |
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