CN106045937A - Synthesizing method of {2-[2-(2-amino-4-thiazolyl)-amino acetyl]-4-thiazolyl}-acetic acid - Google Patents
Synthesizing method of {2-[2-(2-amino-4-thiazolyl)-amino acetyl]-4-thiazolyl}-acetic acid Download PDFInfo
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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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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Abstract
The invention discloses a synthesizing method of {2-[2-(2-amino-4-thiazolyl)-amino acetyl]-4-thiazolyl}-acetic acid, belongs to the technical field of medicine synthesis, and provides a new synthesizing method of {2-[2-(2-amino-4-thiazolyl)-amino acetyl]-4-thiazolyl}-acetic acid. The synthesizing method comprises the following synthesizing steps of (1) esterification reaction: reacting (2-Aminothiazole-4-yl)acetic acid and ethanol into ester, so as to obtain an intermediate product A; (2) amino protection: reacting (2-Aminothiazole-4-yl)acetic acid and t-butyloxycarboryl, so as to generate an intermediate product B; (3) amide condensation reaction: condensing the intermediate product A and the intermediate product B by a condensing agent, so as to generate an intermediate product C; (4) deprotection reaction: removing ester and t-butyloxycarboryl from the intermediate product C by trifluoroacetic acid, so as to obtain a target product. The synthesizing method has the advantages that the cost is low, the yield rate of the product is high, and the synthesizing method is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to one { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid
Synthetic method, belong to chemicals synthesis technical field.
Background technology
{ 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid is that Mirabegron is correlated with
Product, is mainly used in the medicine of the overactive bladder (OAB) for the treatment of companion's urge incontinence, urgent micturition, frequency symptoms.
The English name of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid: { 2-[2-
(2-Amino-thiazol-4-yl)-acetylamino]-thiazol-4-yl}-acetic acid, chemical structural formula is:
So far, do not has the synthetic method report of this product.
Summary of the invention
The synthesis of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid of the present invention
The reaction equation of method is as follows:
The synthetic method of a kind of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid, it is special
Levying and be, the method comprises the following steps:
A, esterification: with aminothiazole acid as raw material, react with ethanol in the presence of a catalyst by it, obtains middle product
Thing A；
B, amido protecting: with aminothiazole acid as raw material, react with amino protecting group in a solvent by it, obtains intermediate product
B；
C, amide condensed reaction: above-mentioned prepared intermediate product A and intermediate product B is entered under the effect of condensing agent and acid binding agent
Row condensation reaction, obtains intermediate product C；
D, deprotection reaction: above-mentioned prepared intermediate product C sloughs protection group in a solvent with acid reaction, generate target and produce
Thing.
Further, in step a, specifically include following steps: with aminothiazole acid as raw material, itself and ethanol are existed
React in the presence of catalyst so that it is reactant liquor completely, is concentrated to give intermediate product A by reaction after question response.
Further, in step a, described catalyst is thionyl chloride.
Further, in stepb, following steps are specifically included: be dissolved in solvent by aminothiazole acid, and molten at this
Adding amino protecting agent in agent and form reactant liquor, stirring makes aminothiazole acid and amino protecting agent reaction completely, reacts complete
After by reactant liquor concentrate, be recrystallized to give intermediate product B.
Further, in stepb, described amino protecting agent selected from alkoxy carbonyl group class protective agent, acyl group class protective agent,
One or more in alkyls protective agent, wherein, described alkoxy carbonyl group class protective agent is selected from benzyloxycarbonyl group (Cbz), tablet held before the breast by officials methoxy
One or many in carbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first or carbethoxyl group
Kind；Described acyl group class protective agent is selected from phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), neighbour
(to) nitrobenzenesulfonyl (Ns), pivaloyl group, one or more in benzoyl；Described alkyls amino protecting agent choosing
From trityl (Trt), 2,4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (Pmb), benzyl (Bn), tertbutyloxycarbonyl
(Boc) one or more in.
Further, in stepb, described solvent selected from oxolane, Isosorbide-5-Nitrae-dioxane, methanol, the tert-butyl alcohol, third
Ketone, ethanol, normal propyl alcohol, isopropanol, DMF, acetonitrile, 1,2-dimethoxy-ethane, normal hexane, dichloromethane,
One or more in water.
Further, in step c, specifically include following steps:
S1, by the intermediate product B of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid and
Solvent stirs to mix homogeneously formation mixed solution at 20～25 DEG C；
S2, condensing agent and acid binding agent are added reactant liquor, stir 1h；
S3, general's { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid intermediate product A
Add reactant liquor, be stirred at room temperature to reaction completely；
S4, in reactant liquor add frozen water, separate out a large amount of solid, filter, wash filter cake, filtration cakes torrefaction obtains intermediate product C.
Further, in step c, the solvent described in step S1 is selected from DMF, acetonitrile, dichloromethane
Alkane, N,N-dimethylacetamide, chloroform, tetrachloromethane, 1,2-dichloroethanes, dimethyl sulfoxide, oxolane, ethanol, water,
One or many in hexamethylene, ether, methyl tertiary butyl ether(MTBE), N-Methyl pyrrolidone, toluene, dimethylbenzene, chlorobenzene, dichloro-benzenes
Kind；Condensing agent described in step S2 is selected from N, N-dicarbapentaborane imidazoles, EDC hydrochloric acid
Salt, I-hydroxybenzotriazole, N, N-DIC, dicyclohexylcarbodiimide, N-hydroxyl-7-azepine benzo three nitrogen
Azoles, 3,4-dihydro-3-hydroxy-4-oxo-1, one or more in 2,3-phentriazines；Acid binding agent described in step S2 is selected from
N-methylmorpholine, pyridine, Feldalat NM, Sodium ethylate, sodium tert-butoxide, potassium tert-butoxide, methylamine, ethamine, dimethylamine, diethylamine, front three
One or more in amine, triethylamine, tripropyl amine (TPA), tri-n-butylamine, triamylamine, DIPEA.
Further, in step d, specifically include following steps: be dissolved in solvent by intermediate product C, 0～5 DEG C of stirring
Uniformly, being slowly added dropwise acid, stirring makes reaction complete, concentrates, and adds sodium bicarbonate solution stirring, and organic facies is extracted, and washing is dried,
Concentrate, obtain target product { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid.
Further, in step d, described solvent selected from oxolane, methanol, ethanol, hexamethylene, dichloromethane,
Chloroform, tetrachloromethane, 1, one or more in 2-dichloroethanes, isopropanol, water；Described acid is selected from concentrated hydrochloric acid, ice
One or more in acetic acid, trifluoroacetic acid.
The invention have the advantages that
1, raw material is cheap and easy to get, does not uses expensive actual, reduces production cost, have the strongest market competitiveness.
2, the synthetic method aminothiazole acid of the present invention is raw material, through esterification, amido protecting, condensation, Deprotection four
Step reaction can be prepared by product, and production process is convenient, it is simple to large-scale industrial production.
3, the synthetic method post processing of the present invention is simple, and side reaction is few, and product yield and purity are higher., and product
Quality is preferable.
Detailed description of the invention
The following is the present invention is embodied as example, is to be further described technical scheme, but this
Bright it is not limited in these embodiments.
Embodiment 1
A, in 100ml single port bottle, add aminothiazole acid 5g and ethanol 50ml, be slowly added dropwise dichloro under 0 DEG C of stirring condition sub-
Sulfone 4.6ml, solution clear, it is warming up to room temperature about 25 DEG C reaction 16h, TLC and detects after completion of the reaction, concentrating under reduced pressure reacts
Liquid, concentrate dry after again with twice of ethanol band, obtain 4.8g brown oil i.e. intermediate product A, yield 96%.
B, under the conditions of 0 DEG C, the isopropanol that 3.18g aminothiazole acid is dissolved in 100ml forms reactant liquor, and stirring is lower will
6.57g (Boc) 2O is added drop-wise in reactant liquor.Reactant liquor is warming up to be stirred at room temperature 12h, TLC and monitors reaction process, react complete
After by reactant liquor concentrate, obtain crude product, crude product ethanol water recrystallization obtains 4.8g intermediate product B, yield 92%.
C, in 100mL single port bottle add 9g amido thiazole acetic acetate, 12.4g (2-tertbutyloxycarbonylamino-4-thiophene
Azoles)-acetic acid, 5.9g DIPEA and 100mL dichloromethane, add 7.9gHOBt after being stirred at room temperature uniformly, and
12.0gEDCI.Room temperature continues to be stirred overnight.Put plate next day to confirm after completion of the reaction, successively with water, 5% citric acid, water, saturated carbon
Acid hydrogen sodium solution, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and then adds trifluoroacetic acid stirring 2h under the conditions of 0 DEG C, then
Being stirred at room temperature, TLC detection complete addition 20% sodium hydrate aqueous solution of reaction, to about pH=10, stirs half an hour, organic layer water
Washing twice, saturated common salt is washed once, is dried, and filtering and concentrating is done, and obtains 19.1g intermediate product C, yield 93%.
D, being dissolved in 25ml chloroform by 5g intermediate product C, ice bath is cooled to 0～5 DEG C, is slowly added dropwise trifluoroacetic acid
10ml, drips complete, is warming up to 25 DEG C, and TLC monitors after completion of the reaction, concentrates, and adds sodium bicarbonate solution stirring, adds ethyl acetate
Extracting, organic layer is washed, and saturated common salt is washed, and is dried, is concentrated to give 3.2g product, yield 93%.
Embodiment 2
A, in 100ml single port bottle add aminothiazole acid 4.3g and ethanol 50ml, be slowly added dropwise dichloro under 0 DEG C of stirring condition
Sulfoxide 4.6ml, solution clear, it is warming up to room temperature about 25 DEG C reaction 16h, TLC and detects after completion of the reaction, concentrating under reduced pressure is anti-
Answer liquid, concentrate dry after again with twice of ethanol band, obtain 5.7g brown oil i.e. intermediate product A, yield 98%.
B, under the conditions of 0 DEG C, the oxolane that 1.59g aminothiazole acid is dissolved in 50ml forms reactant liquor, and stirring is lower will
3.27g (Boc) 2O is added drop-wise in reactant liquor.Reactant liquor is warming up to be stirred at room temperature 12h, TLC and monitors reaction process, react complete
After by reactant liquor concentrate, obtain crude product, crude product ethanol water recrystallization obtains 2.3g intermediate product B, yield 90%.
C, in 100mL single port bottle add 5g amido thiazole acetic acetate, 6.9g (2-tertbutyloxycarbonylamino-4-thiophene
Azoles)-acetic acid, 3.3g triethylamine and 50mL dichloromethane, add 4.4gHOBt, and 6.7gEDCI after being stirred at room temperature uniformly.Room temperature
Continue to be stirred overnight.Put plate next day to confirm after completion of the reaction, successively with water, 5% citric acid, water, saturated sodium bicarbonate solution, full
And brine It, anhydrous sodium sulfate is dried, and then adds trifluoroacetic acid stirring 2h under the conditions of 0 DEG C, then is stirred at room temperature, TLC
Detection complete addition 20% sodium hydrate aqueous solution of reaction, to about pH=10, stirs half an hour, and organic layer is washed twice, saturated food
Salt is washed once, is dried, and filtering and concentrating is done, and obtains 10.5g intermediate product C, yield 92%.
D, being dissolved in 25ml dichloromethane by 5g intermediate product C, ice bath is cooled to 0～5 DEG C, is slowly added dropwise trifluoroacetic acid
10ml, drips complete, is warming up to 25 DEG C, and TLC monitors after completion of the reaction, concentrates, and adds sodium bicarbonate solution stirring, adds ethyl acetate
Extracting, organic layer is washed, and saturated common salt is washed, and is dried, is concentrated to give 3.2g product, yield 93%.
Embodiment 3
A, in 100ml single port bottle add aminothiazole acid 7.3g and ethanol 85ml, be slowly added dropwise dichloro under 0 DEG C of stirring condition
Sulfoxide 7.8ml, solution clear, it is warming up to room temperature about 25 DEG C reaction 16h, TLC and detects after completion of the reaction, concentrating under reduced pressure is anti-
Answer liquid, concentrate dry after again with twice of ethanol band, obtain 9.3g brown oil i.e. intermediate product A, yield 95%.
B, under the conditions of 0 DEG C, the acetonitrile that 1.59g aminothiazole acid is dissolved in 50ml forms reactant liquor, by 3.27g under stirring
(Boc) during 2O is added drop-wise to reactant liquor.Reactant liquor is warming up to be stirred at room temperature 12h, TLC and monitors reaction process, after completion of the reaction will
Reactant liquor concentrates, and obtains crude product, and crude product ethanol water recrystallization obtains 2.3g intermediate product B, yield 90%.
C, in 100mL single port bottle add 5g amido thiazole acetic acetate, 6.9g (2-tertbutyloxycarbonylamino-4-thiophene
Azoles)-acetic acid, 3.3g triethylamine and 50mL dichloromethane, add 4.4gHOBt, and 6.7gEDCI after being stirred at room temperature uniformly.Room temperature
Continue to be stirred overnight.Put plate next day to confirm after completion of the reaction, successively with water, 5% citric acid, water, saturated sodium bicarbonate solution, full
And brine It, anhydrous sodium sulfate is dried, and then adds trifluoroacetic acid stirring 2h under the conditions of 0 DEG C, then is stirred at room temperature, TLC
Detection complete addition 20% sodium hydrate aqueous solution of reaction, to about pH=10, stirs half an hour, and organic layer is washed twice, saturated food
Salt is washed once, is dried, and filtering and concentrating is done, and obtains 10.5g intermediate product C, yield 92%.
D, being dissolved in 25ml dichloromethane by 5g intermediate product C, ice bath is cooled to 0～5 DEG C, is slowly added dropwise hydrochloric acid 10ml,
Dripping complete, be warming up to 25 DEG C, TLC monitors after completion of the reaction, concentrates, and adds sodium bicarbonate solution stirring, adds ethyl acetate and extracts,
Organic layer is washed, and saturated common salt is washed, and is dried, is concentrated to give 3.2g product, yield 93%.
Claims (10)
1. the synthetic method of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid, its
Being characterised by, the method comprises the following steps:
A, esterification: with aminothiazole acid as raw material, react with ethanol in the presence of a catalyst by it, obtains centre
Product A；
B, amido protecting: with aminothiazole acid as raw material, react with amino protecting group in a solvent by it, obtains middle product
Thing B；
C, amide condensed reaction: by above-mentioned prepared intermediate product A and intermediate product B under the effect of condensing agent and acid binding agent
Carry out condensation reaction, obtain intermediate product C；
D, deprotection reaction: above-mentioned prepared intermediate product C sloughs protection group in a solvent with acid reaction, generate target
Product.
The most according to claim 1 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
The synthetic method of acid, it is characterised in that in step a, specifically include following steps: with aminothiazole acid as raw material, by it
React in the presence of a catalyst with ethanol so that it is reactant liquor completely, is concentrated to give intermediate product after question response by reaction
A。
The most according to claim 1 and 2 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-
The synthetic method of acetic acid, it is characterised in that in step a, described catalyst is thionyl chloride.
The most according to claim 1 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
The synthetic method of acid, it is characterised in that in stepb, specifically include following steps: be dissolved in solvent by aminothiazole acid,
And in this solvent, add amino protecting agent formation reactant liquor, stirring makes aminothiazole acid and amino protecting agent reaction completely,
After completion of the reaction reactant liquor is concentrated, be recrystallized to give intermediate product B.
5. according to { 2-[2-(2-amino-4-thiazolyl)-the acetyl-amino]-4-thiazolyl } described in claim 1 or 4-
The synthetic method of acetic acid, it is characterised in that in stepb, described amino protecting agent is selected from alkoxy carbonyl group class protective agent, acyl group
One or more in class protective agent, alkyls protective agent；Wherein, described alkoxy carbonyl group class protective agent is selected from benzyloxycarbonyl group
(Cbz), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first or carbethoxyl group
In one or more；Described acyl group class protective agent is selected from phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoro
Acetyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, one or more in benzoyl；Described alkyl
Class amino protecting agent selected from trityl (Trt), 2,4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (Pmb), benzyl
(Bn), one or more in tertbutyloxycarbonyl (Boc).
The most according to claim 1 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
The synthetic method of acid, it is characterised in that in stepb, described solvent is selected from oxolane, Isosorbide-5-Nitrae-dioxane, methanol, uncle
Butanol, acetone, ethanol, normal propyl alcohol, isopropanol, DMF, acetonitrile, 1,2-dimethoxy-ethane, normal hexane, two
One or more in chloromethanes, water.
The most according to claim 1 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
Acid synthetic method, it is characterised in that in step c, specifically include following steps:
S1, by the intermediate product B of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid and
Solvent stirs to mix homogeneously formation mixed solution at 20～25 DEG C；
S2, condensing agent and acid binding agent are added reactant liquor, stir 1h；
S3, the intermediate product A of { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid is added
Enter reactant liquor, be stirred at room temperature to reaction completely；
S4, in reactant liquor add frozen water, separate out a large amount of solid, filter, wash filter cake, filtration cakes torrefaction obtains intermediate product C.
The most according to claim 7 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
The synthetic method of acid, it is characterised in that in step c, the solvent described in step S1 is selected from DMF, second
Nitrile, dichloromethane, N,N-dimethylacetamide, chloroform, tetrachloromethane, 1,2-dichloroethanes, dimethyl sulfoxide, tetrahydrochysene furan
Mutter, in ethanol, water, hexamethylene, ether, methyl tertiary butyl ether(MTBE), N-Methyl pyrrolidone, toluene, dimethylbenzene, chlorobenzene, dichloro-benzenes
One or more；Condensing agent described in step S2 is selected from N, N-dicarbapentaborane imidazoles, 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimmonium salt hydrochlorate, I-hydroxybenzotriazole, N, N-DIC, dicyclohexylcarbodiimide, N-hydroxyl-7-nitrogen
Miscellaneous BTA, 3,4-dihydro-3-hydroxy-4-oxo-1, one or more in 2,3-phentriazines；Described in step S2
Acid binding agent selected from N-methylmorpholine, pyridine, Feldalat NM, Sodium ethylate, sodium tert-butoxide, potassium tert-butoxide, methylamine, ethamine, dimethylamine, two
One or more in ethamine, trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine, triamylamine, DIPEA.
The most according to claim 1 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-second
The synthetic method of acid, it is characterised in that in step d, specifically include following steps: be dissolved in solvent by intermediate product C, 0～5
DEG C stirring, be slowly added dropwise acid, stirring makes reaction complete, concentrates, and adds sodium bicarbonate solution stirring, and organic facies is extracted, washing,
It is dried, concentrates, obtain target product { 2-[2-(2-amino-4-thiazolyl)-acetyl-amino]-4-thiazolyl }-acetic acid.
10. according to { 2-[2-(2-amino-4-thiazolyl)-the acetyl-amino]-4-thiazolyl } described in claim 1 or 9
The synthetic method of-acetic acid, it is characterised in that in step d, described solvent be oxolane, methanol, ethanol, hexamethylene,
Dichloromethane, chloroform, tetrachloromethane, 1, one or more in 2-dichloroethanes, isopropanol, water；Described acid is dense
One or more in hydrochloric acid, glacial acetic acid, trifluoroacetic acid.
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| CN107857796A (en) * | 2017-11-29 | 2018-03-30 | 陕西慧康生物科技有限责任公司 | A kind of synthetic method of trifluoroacetyl tripeptides 2 |
| CN110372631A (en) * | 2019-07-24 | 2019-10-25 | 东南大学成贤学院 | A kind of preparation method of cefotaxime amide acetaldehyde |
| CN111072592A (en) * | 2019-12-20 | 2020-04-28 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107857796A (en) * | 2017-11-29 | 2018-03-30 | 陕西慧康生物科技有限责任公司 | A kind of synthetic method of trifluoroacetyl tripeptides 2 |
| CN110372631A (en) * | 2019-07-24 | 2019-10-25 | 东南大学成贤学院 | A kind of preparation method of cefotaxime amide acetaldehyde |
| CN110372631B (en) * | 2019-07-24 | 2021-03-02 | 东南大学成贤学院 | Preparation method of aminothiazoly loximate acetaldehyde |
| CN111072592A (en) * | 2019-12-20 | 2020-04-28 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
| CN111072592B (en) * | 2019-12-20 | 2021-07-20 | 河北合佳医药科技集团股份有限公司 | High-purity selective preparation and purification method of aminothiazoly loximate dimer |
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