CN107286116A - A kind of synthetic method of the Ethyl formate of 2 acetylthiazole 4 - Google Patents
A kind of synthetic method of the Ethyl formate of 2 acetylthiazole 4 Download PDFInfo
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- CN107286116A CN107286116A CN201610565956.5A CN201610565956A CN107286116A CN 107286116 A CN107286116 A CN 107286116A CN 201610565956 A CN201610565956 A CN 201610565956A CN 107286116 A CN107286116 A CN 107286116A
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- synthetic method
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- cys
- organic phase
- carbethoxy hydrochloride
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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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthetic method of the Ethyl formate of 2 acetylthiazole 4, comprise the following steps：(1) under nitrogen protection, L ethylcysteine hydrochlorides, the pyroracemic aldehyde aqueous solution, inorganic base and phase transfer catalyst are added in dicyandiamide solution and carry out annulation；(2) under nitrogen protection, the reaction product of step (1) is separated into organic phase, the organic phase is mixed into progress oxidation reaction with manganese dioxide；(3) by the reaction product of step (2) after purification, the Ethyl formate of 2 acetylthiazole 4 is produced.The present invention's simple to operate, high income and with low cost.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of synthesis of 2- acetylthiazoles -4- Ethyl formates
Method.
Background technology
Cancer is being accelerated as that the world is No.1 " killer's disease ", and the raising of cancer morbidity is promoting world's anticarcinogen
The fast development in thing market.At present, tumor Drugs have increased to hundreds of on world pharmaceutical market, and the larger anticancer of sales volume
Medicine is extracted from plant mostly.Medicine of one class specially using cellular tubulin as target spot has been played the part of increasingly in treatment of cancer
Important role.Wherein, natural products Tubulysins is with its special anticancer mechanism, outstanding active anticancer and novelty
Molecular structure, has attracted concern of numerous scientists to it, to its study on the synthesis also with expansion.
Chemical synthesis to natural products Tubulysins, according to anti-synthesis analysis, Tubulysins is by four amino acid
Composition, wherein amino acid fragment Tuv is an emphasis and key for synthesis.The synthesis of Tuv fragments is related to the introducing of thiazole ring, by
Various synthetic schemes are have also been developed in the formation of thiazole ring and introducing method difference.One of which scheme is related to 2- acetyl group thiophenes
The synthesis of azoles -4- Ethyl formates.The one of which synthetic method of thiazole derivatives is to be condensed using aldehyde with cysteine, then with
Manganese dioxide acts on forming thiazolium compounds.Document report is condensed in alcohol-water system mostly, and low temperature is evaporated off extracting after alcohol
Concentration, then aoxidized in acetonitrile system, two step yields are in 50% or so (Org.Bomol.Chem., 2013,11,2273-2287)
(J.AM.CHEM.SOC.2005,127,156454-15651)(Synlett 2009,No.8,1341-1345).Its weak point
It is cumbersome time-consuming, yield is low, cost is high.
The content of the invention
It is an object of the invention to overcome prior art defect, there is provided a kind of conjunction of 2- acetylthiazoles -4- Ethyl formates
Into method.
The reaction scheme of the present invention is as follows：
The concrete technical scheme of the present invention is as follows：
A kind of synthetic method of 2- acetylthiazoles -4- Ethyl formates, comprises the following steps：
(1) under nitrogen protection, Cys carbethoxy hydrochloride, the pyroracemic aldehyde aqueous solution, inorganic base and phase transfer are urged
Agent, which is added in dicyandiamide solution, carries out annulation, and reaction temperature is 25~35 DEG C, and the reaction time is 12~36h, the Guangs of L- half
The mol ratio of propylhomoserin carbethoxy hydrochloride and pyroracemic aldehyde is 1~1.5:1, the mol ratio of inorganic base and Cys carbethoxy hydrochloride
For 1~2:1, phase transfer catalyst is the 1~5% of the mole of Cys carbethoxy hydrochloride, and above-mentioned dicyandiamide solution is by four
Hydrogen furans and water composition, and the volume ratio of tetrahydrofuran and water is 1~5:1, the concentration of the reaction system of the step is with the Guangs of L- half
The quality of propylhomoserin carbethoxy hydrochloride is calculated as 0.1~0.01g/mL；
(2) under nitrogen protection, the reaction product of step (1) is separated into organic phase, the organic phase and manganese dioxide is mixed
Close and carry out oxidation reaction, reaction temperature is 25~65 DEG C, the reaction time is 4~18h, manganese dioxide and Cys ethyl ester salt
The mol ratio of hydrochlorate is 10~20:1；
(3) by the reaction product of step (2) after purification, the 2- acetylthiazoles -4- Ethyl formates are produced.
In a preferred embodiment of the invention, the concentration of the pyroracemic aldehyde aqueous solution is 40%.
In a preferred embodiment of the invention, the inorganic base is sodium acid carbonate or saleratus.
In a preferred embodiment of the invention, the phase transfer catalyst is benzyltriethylammoinium chloride, four fourths
Base ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC or
Tetradecyl trimethyl ammonium chloride.
In a preferred embodiment of the invention, the step (2) is：Under nitrogen protection, in the anti-of step (1)
Answer and sodium chloride is added in product to separate organic phase, the organic phase is mixed into progress oxidation reaction with manganese dioxide.
It is further preferred that the consumption of the sodium chloride is the 35~40% of the quality of the dicyandiamide solution reclaimed water.
In a preferred embodiment of the invention, the step (3) is：The reaction product of step (2) is filtered
Filtrate, crosses post purifying, produces the 2- acetylthiazoles -4- Ethyl formates after filtrate is spin-dried for.
The beneficial effects of the invention are as follows：
1st, synthetic method of the invention is under inorganic base and phase transfer catalyst effect, with Cys carbethoxy hydrochloride
It is reactant with pyroracemic aldehyde, carries out annulation in tetrahydrofuran/aqueous systems, annulation, which terminates to separate organic phase, is directly led to
Manganese dioxide generation 2- acetylthiazole -4- Ethyl formates are crossed, it is simple to operate, low temperature concentration alcohol is eliminated after cyclization molten
The operation of agent, extraction and concentration, need to only divide liquid to operate.
2nd, synthetic method high income of the invention, reduces the loss in cyclic intermediate last handling process, two step yields
Bring up to 60%~70%.
3rd, synthetic method of the invention is with low cost, i.e. the raising of yield and the recyclable of solvent is applied mechanically and substantially reduce work
Skill cost.
Embodiment
Technical scheme is further detailed and described below by way of embodiment.
Embodiment 1
(1) under nitrogen protection, water 10mL, Cys carbethoxy hydrochloride are sequentially added into 500mL there-necked flasks
10mmol, tetrahydrofuran 10mL, stirring is lower to add sodium bicarbonate solid 10mmol, 40% pyroracemic aldehyde solution of disposable addition
10mmol, is eventually adding 4-butyl ammonium hydrogen sulfate 0.5mmol and carries out annulation, reaction temperature is 25 DEG C, and the reaction time is
18h；
(2) under nitrogen protection, 36% chlorine of the water that step (1) is added is added in the reaction product of step (1)
Change sodium, stir 10min, standing separates organic phase, the organic phase is directly transferred to 250mL tri- that is another clean and being protected with nitrogen
In mouth bottle, add 200mmol manganese dioxide and carry out oxidation reaction while stirring, reaction temperature is 65 DEG C, and the reaction time is 18h；
(3) reaction product of step (2) is filtered to get filtrate, post purifying is crossed after filtrate is spin-dried for, 1.3g white solids are obtained,
I.e. described 2- acetylthiazoles -4- Ethyl formates, yield 63%.
Embodiment 2
Tetrahydrofuran consumption is 50mL, and other experimental method and condition be the same as Examples 1 are real that yield is 65%.
Embodiment 3
The consumption of water is 50mL, and other experimental method and condition be the same as Examples 2 are real that yield is 64%.
Embodiment 4
Inorganic base used is saleratus, and other experimental method and condition be the same as Examples 2 are real that yield is 67%.
Embodiment 5
Inorganic base amount is 15mmol, and other experimental method and condition be the same as Examples 4 are real that yield is 68%.
Embodiment 6
Pyroracemic aldehyde consumption is 15mmol, and other experimental method and condition be the same as Examples 5 are real that yield is 70%.
Embodiment 7
Phase transfer catalyst is tetrabutyl ammonium fluoride, other experimental method and condition be the same as Examples 6, real that yield is
71%.
Embodiment 8
Phase transfer catalyst is DTAC, other experimental method and condition be the same as Examples 6, must be received in fact
Rate is 67%.
Embodiment 9
Manganese dioxide consumption is 100mmol, and other experimental method and condition be the same as Examples 7 are real that yield is 63%.
Embodiment 10
Manganese dioxide consumption is 150mmol, and other experimental method and condition be the same as Examples 7 are real that yield is 66%.
Embodiment 11
The reaction temperature of step (1) is 35 DEG C, other experimental method and condition be the same as Examples 7, real that yield is 67%.
Embodiment 12
The reaction time of step (1) is 36h, and other experimental method and condition be the same as Examples 7 are real that yield is 72%.
Embodiment 13
The reaction temperature of step (2) is 25 DEG C, other experimental method and condition be the same as Examples 12, real that yield is 65%.
Embodiment 14
The reaction temperature of step (2) is 45 DEG C, other experimental method and condition be the same as Examples 12, real that yield is 69%.
Embodiment 15
The reaction time of step (2) is 6h, and other experimental method and condition be the same as Examples 12 are real that yield is 67%.
Embodiment 16
The reaction time of step (2) is 12h, and other experimental method and condition be the same as Examples 12 are real that yield is 69%.
Those of ordinary skill in the art understand, when technical scheme changes in following ranges, remain able to
To technique effect same as the previously described embodiments or close, protection scope of the present invention is still fallen within：
A kind of synthetic method of 2- acetylthiazoles -4- Ethyl formates, it is characterised in that：Comprise the following steps：
(1) under nitrogen protection, Cys carbethoxy hydrochloride, the pyroracemic aldehyde aqueous solution, inorganic base and phase transfer are urged
Agent, which is added in dicyandiamide solution, carries out annulation, and reaction temperature is 25~35 DEG C, and the reaction time is 12~36h, the Guangs of L- half
The mol ratio of propylhomoserin carbethoxy hydrochloride and pyroracemic aldehyde is 1~1.5:1, the mol ratio of inorganic base and Cys carbethoxy hydrochloride
For 1~2:1, phase transfer catalyst is the 1~5% of the mole of Cys carbethoxy hydrochloride, and above-mentioned dicyandiamide solution is by four
Hydrogen furans and water composition, and the volume ratio of tetrahydrofuran and water is 1~5:1, the concentration of the reaction system of the step is with the Guangs of L- half
The quality of propylhomoserin carbethoxy hydrochloride is calculated as 0.1~0.01g/mL；
(2) under nitrogen protection, the reaction product of step (1) is separated into organic phase, the organic phase and manganese dioxide is mixed
Close and carry out oxidation reaction, reaction temperature is 25~65 DEG C, the reaction time is 4~18h, manganese dioxide and Cys ethyl ester salt
The mol ratio of hydrochlorate is 10~20:1；
(3) by the reaction product of step (2) after purification, the 2- acetylthiazoles -4- Ethyl formates are produced.
The inorganic base is sodium acid carbonate or saleratus.The phase transfer catalyst is benzyltriethylammoinium chloride, four
Butylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC
Or tetradecyl trimethyl ammonium chloride.
The foregoing is only a preferred embodiment of the present invention, therefore can not limit the scope that the present invention is implemented according to this, i.e.,
The equivalent changes and modifications made according to the scope of the claims of the present invention and description, all should still belong in the range of the present invention covers.
Claims (7)
1. a kind of synthetic method of 2- acetylthiazoles -4- Ethyl formates, it is characterised in that：Comprise the following steps：
(1) under nitrogen protection, by Cys carbethoxy hydrochloride, the pyroracemic aldehyde aqueous solution, inorganic base and phase transfer catalyst
It is added in dicyandiamide solution and carries out annulation, reaction temperature is 25~35 DEG C, the reaction time is 12~36h, Cys
The mol ratio of carbethoxy hydrochloride and pyroracemic aldehyde is 1~1.5:1, the mol ratio of inorganic base and Cys carbethoxy hydrochloride is 1
~2:1, phase transfer catalyst is the 1~5% of the mole of Cys carbethoxy hydrochloride, and above-mentioned dicyandiamide solution is by tetrahydrochysene furan
Mutter and water composition, and the volume ratio of tetrahydrofuran and water is 1~5:1, the concentration of the reaction system of the step is with Cys
The quality of carbethoxy hydrochloride is calculated as 0.1~0.01g/mL；
(2) under nitrogen protection, the reaction product of step (1) is separated into organic phase, the organic phase and manganese dioxide is mixed into
Row oxidation reaction, reaction temperature is 25~65 DEG C, and the reaction time is 4~18h, manganese dioxide and Cys carbethoxy hydrochloride
Mol ratio be 10~20:1；
(3) by the reaction product of step (2) after purification, the 2- acetylthiazoles -4- Ethyl formates are produced.
2. synthetic method as claimed in claim 1, it is characterised in that：The concentration of the pyroracemic aldehyde aqueous solution is 40%.
3. synthetic method as claimed in claim 1, it is characterised in that：The inorganic base is sodium acid carbonate or saleratus.
4. synthetic method as claimed in claim 1, it is characterised in that：The phase transfer catalyst is benzyl triethyl ammonium chlorination
Ammonium, TBAB, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, trimethyl chlorine
Change ammonium or tetradecyl trimethyl ammonium chloride.
5. synthetic method as claimed in claim 1, it is characterised in that：The step (2) is：Under nitrogen protection, in step
(1) sodium chloride is added in reaction product to separate organic phase, the organic phase is mixed into progress oxidation reaction with manganese dioxide.
6. synthetic method as claimed in claim 5, it is characterised in that：The consumption of the sodium chloride is the dicyandiamide solution reclaimed water
Quality 35~40%.
7. synthetic method as claimed in claim 1, it is characterised in that：The step (3) is：By the reaction product of step (2)
Filter to get filtrate, post purifying is crossed after filtrate is spin-dried for, the 2- acetylthiazoles -4- Ethyl formates are produced.
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| CN201610565956.5A CN107286116A (en) | 2016-07-19 | 2016-07-19 | A kind of synthetic method of the Ethyl formate of 2 acetylthiazole 4 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305074A (en) * | 2019-04-02 | 2019-10-08 | 上海克琴科技有限公司 | A kind of green synthesis method of quaternary ammonium salt -73 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8980833B2 (en) * | 2007-05-10 | 2015-03-17 | R&D-Biopharmaceuticals Gmbh | Tubulysine derivatives |
-
2016
- 2016-07-19 CN CN201610565956.5A patent/CN107286116A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8980833B2 (en) * | 2007-05-10 | 2015-03-17 | R&D-Biopharmaceuticals Gmbh | Tubulysine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| RACHAEL A.HUGHES,等人: "Total Synthesis of Thiopeptide Antibiotic Amythiamicin D", 《J.AM.CHEM.SOC.》 * |
| SREEJITH P.SHANKAR等人: "Syntnesis and structure-activity relationship studies of novel tubulysin U analogues-effect on cytotoxicity of structural variations in the tubuvaline fragment", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305074A (en) * | 2019-04-02 | 2019-10-08 | 上海克琴科技有限公司 | A kind of green synthesis method of quaternary ammonium salt -73 |
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