CN102731431A - Preparation method of 5-bromothiazole-4-formic acid - Google Patents
Preparation method of 5-bromothiazole-4-formic acid Download PDFInfo
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- CN102731431A CN102731431A CN2012102033994A CN201210203399A CN102731431A CN 102731431 A CN102731431 A CN 102731431A CN 2012102033994 A CN2012102033994 A CN 2012102033994A CN 201210203399 A CN201210203399 A CN 201210203399A CN 102731431 A CN102731431 A CN 102731431A
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- methyl
- formiate
- bromo thiazole
- bromine
- formic acid
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- 0 CCNC(*C)=C(*)C(OC)=O Chemical compound CCNC(*C)=C(*)C(OC)=O 0.000 description 3
Abstract
The invention discloses a preparation method of 5-bromothiazole-4-formic acid. According to the invention, 2-aminothiazole-4-methyl formate is adopted as an initial raw material. Bromine is applied on 2-site, and the material is subjected to diazotization deamination. The material is then subjected to hydrolysis, such that the target compound is obtained.
Description
Technical field
The synthesis technology that the present invention relates to a kind of 5-bromo thiazole-4-formic acid improves, and belongs to the medicine bioengineering chemical technology field.Also relate to some midbody that obtains through this method.
Background technology
5-bromo thiazole-4-formic acid is pale solid, is a kind of important biology,drug and chemical industry midbody.
The preparation of 5-bromo thiazole-4-formic acid is to be starting raw material with thiazolamine-4-methyl-formiate, bromine on the 2-position, and the diazotization deaminizating, hydrolysis obtains target compound again.
Summary of the invention
The present invention mainly improves former operational path, makes per step operation controlled easy to operate, is beneficial to amplify to produce, and improves yield.
The present invention provides formula (4) compound
.
The present invention also provides by formula (3) compound
Ammonification prepares the method for formula (4) compound
This method is to obtain 5-bromo thiazole-4-formic acid by 5-bromo thiazole-4-methyl-formiate with basic hydrolysis, and the used alkali of hydrolysis includes but not limited to yellow soda ash, salt of wormwood, Lithium Hydroxide MonoHydrate, sodium hydroxide and Pottasium Hydroxide, preferred sodium hydroxide; Reaction solvent includes but not limited to methyl alcohol, second alcohol and water, preferably water; Temperature of reaction 0 ~ 100 degree is about preferred 100 degree; 1 ~ 24 hour reaction times, preferred 2 ~ 3 hours.
The present invention provides by formula (2) compound
The method for preparing formula (3) compound
2-amino-5-bromo thiazole-4-methyl-formiate is dissolved in N; Dinethylformamide drips the nitrite tert-butyl deaminizating and gets 5-bromo thiazole-4-methyl-formiate, and reaction solvent includes but not limited to acetonitrile, methylene dichloride, chloroform, acetone, THF, N; Dinethylformamide and N; The N-N,N-DIMETHYLACETAMIDE, preferred N, dinethylformamide; Diazo reagent includes but not limited to nitrite tert-butyl and Isopentyl nitrite etc., preferred nitrite tert-butyl and Isopentyl nitrite; Temperature of reaction 0 ~ 100 degree, preferred 60 ~ 70 degree; 0.5 ~ 12 hour reaction times, preferred 0.5 ~ 1 hour.
The present invention provides by formula (1) compound
The method for preparing formula (2) compound
Thiazolamine-4-methyl-formiate adds Glacial acetic acid min. 99.5, drips bromine, and bromine obtains 2-amino-5-bromo thiazole-4-methyl-formiate on the 2-position, and reaction solvent includes but not limited to methylene dichloride, chloroform, acetonitrile, acetic acid, benzene, toluene and water, preferred acetic acid; The reagent that bromine is provided is N-bromo-succinimide and bromine, preferred bromine; Temperature of reaction 0 ~ 120 degree, preferred 50 ~ 60 degree; 0.5 ~ 16 hour reaction times, preferred 1 ~ 2 hour.
Embodiment
Embodiment 1
120 gram thiazolamine-4-methyl-formiates are dissolved in 500 milliliters of Glacial acetic acid min. 99.5 and are heated to 50 ~ 60 degree, and 146 gram bromines mix with 50 milliliters of Glacial acetic acid min. 99.5, are added drop-wise in the glacial acetic acid solution of starting raw material.Dropwise, stirred 1 ~ 2 hour at 50 ~ 60 degree.Concentrating under reduced pressure boils off most of Glacial acetic acid min. 99.5, adds frozen water, and saturated sodium carbonate is transferred pH ~ 7, filters, and obtains 140 gram 2-amino-5-bromo thiazole-4-methyl-formiates.
Embodiment 2
Under the nitrogen protection, 100 gram 2-amino-5-bromo thiazole-4-methyl-formiates are dissolved in 500 milliliters of N, dinethylformamide; Be heated to 60 ~ 70 degree, 86 gram nitrite tert-butyls are dissolved in 250 milliliters of N, dinethylformamide; Drop in the above-mentioned solution insulated and stirred 1 ~ 2 hour.Be cooled to room temperature, the ETHYLE ACETATE dilution, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying concentrates, and column chromatography purification gets 67 gram 5-bromo thiazole-4-methyl-formiates.
Embodiment 3
16 gram sodium hydroxide add 200 ml waters, add 45 gram 5-bromo thiazole-4-methyl-formiates, reflux 2 hours.Be cooled to room temperature, under the ice-water bath, transfer pH ~ 7, separate out solid with hydrochloric acid.Filter, obtain 32 gram target compound 5-bromo thiazole-4-formic acid.
Claims (4)
1. the preparation method of 5-bromo thiazole-4-formic acid; Thiazolamine-4-methyl-formiate adds Glacial acetic acid min. 99.5, drips bromine, and bromine obtains 2-amino-5-bromo thiazole-4-methyl-formiate on the 2-position; 2-amino-5-bromo thiazole-4-methyl-formiate is dissolved in N; Dinethylformamide drips the nitrite tert-butyl deaminizating and gets 5-bromo thiazole-4-methyl-formiate, and 5-bromo thiazole-4-methyl-formiate obtains target compound with basic hydrolysis.
2. the preparation method of 5-bromo thiazole-4-formic acid according to claim 1; It is characterized in that: thiazolamine-4-methyl-formiate adds Glacial acetic acid min. 99.5, drips bromine, and bromine obtains 2-amino-5-bromo thiazole-4-methyl-formiate on the 2-position; Reaction solvent includes but not limited to methylene dichloride, chloroform, acetonitrile, acetic acid, benzene, toluene and water; The reagent that bromine is provided is N-bromo-succinimide and bromine, temperature of reaction 0 ~ 120 degree, 0.5 ~ 16 hour reaction times.
3. the preparation method of 5-bromo thiazole-4-formic acid according to claim 1; It is characterized in that: 2-amino-5-bromo thiazole-4-methyl-formiate is dissolved in N, and dinethylformamide drips the nitrite tert-butyl deaminizating and gets 5-bromo thiazole-4-methyl-formiate; Reaction solvent includes but not limited to acetonitrile, methylene dichloride, chloroform, acetone, THF, N; Dinethylformamide and DMAC N,N, diazo reagent include but not limited to nitrite tert-butyl and Isopentyl nitrite etc.; Temperature of reaction 0 ~ 100 degree, 0.5 ~ 12 hour reaction times.
4. the preparation method of 5-bromo thiazole-4-formic acid according to claim 1; It is characterized in that: 5-bromo thiazole-4-methyl-formiate obtains target compound 5-bromo thiazole-4-formic acid with basic hydrolysis; The used alkali of hydrolysis includes but not limited to yellow soda ash, salt of wormwood, Lithium Hydroxide MonoHydrate, sodium hydroxide and Pottasium Hydroxide; Reaction solvent includes but not limited to methyl alcohol, second alcohol and water, temperature of reaction 0 ~ 100 degree, 1 ~ 24 hour reaction times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102033994A CN102731431A (en) | 2012-06-20 | 2012-06-20 | Preparation method of 5-bromothiazole-4-formic acid |
Applications Claiming Priority (1)
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| CN2012102033994A CN102731431A (en) | 2012-06-20 | 2012-06-20 | Preparation method of 5-bromothiazole-4-formic acid |
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| CN102731431A true CN102731431A (en) | 2012-10-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN2012102033994A Pending CN102731431A (en) | 2012-06-20 | 2012-06-20 | Preparation method of 5-bromothiazole-4-formic acid |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102036561A (en) * | 2008-02-29 | 2011-04-27 | 赛林药物股份有限公司 | Protein kinase modulators |
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- 2012-06-20 CN CN2012102033994A patent/CN102731431A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102036561A (en) * | 2008-02-29 | 2011-04-27 | 赛林药物股份有限公司 | Protein kinase modulators |
Non-Patent Citations (1)
| Title |
|---|
| 张秀芹 等: "2-氨基噻唑-4-甲酸合成方法的改进", 《广东化工》 * |
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Application publication date: 20121017 |