CN106977471A - A kind of method for preparing the Ethyl formate of 4 methylthiazol 5 - Google Patents
A kind of method for preparing the Ethyl formate of 4 methylthiazol 5 Download PDFInfo
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- CN106977471A CN106977471A CN201710264519.4A CN201710264519A CN106977471A CN 106977471 A CN106977471 A CN 106977471A CN 201710264519 A CN201710264519 A CN 201710264519A CN 106977471 A CN106977471 A CN 106977471A
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- thioformamide
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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 preparation method of the Ethyl formate of 4 methylthiazol 5, using tetrahydrofuran as solvent formamide, phosphoric sulfide is raw material, first phosphoric sulfide is dissolved in tetrahydrofuran, formamide is added dropwise, reacts 12 hours, is concentrated to dryness, dissolved with low-concentration sodium hydroxide solution, ethyl acetate is extracted, and organic layer is dried, filtering, concentration, obtains thioformamide.Using absolute ethyl alcohol as solvent, thioformamide, 2 chloroacetyl acetacetic esters are raw material, and back flow reaction is concentrated to dryness, is dissolved in water, and ethyl acetate is extracted, and organic layer is dried, and are filtered, concentration.Rectification under vacuum obtains the Ethyl formate of 4 methylthiazol 5.The preparation method cost of the present invention is low, easy to operate.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of side for preparing 4- methylthiazole-5-carboxylates
Method.
Background technology
4- methylthiazole-5-carboxylates are to treat gout medicine Febuxostat, the key intermediate of cefditoren,
Preparing 4- methylthiazole-5-carboxylates at this stage mainly has following several method：Carbon disulfide and ammonia are reacted raw first
Into amino mesylate, then reacted with 2- chloroacetyl acetacetic esters, generate sulfur-bearing intermediate, finally use hydrogen peroxide oxidation sulfur-bearing
Intermediate obtains 4- methylthiazole-5-carboxylates, and the route uses inflammable and explosive carbon disulfide and ammonia, while dioxygen
Water oxygen is also easy to produce accessory substance；Using 2- chloroacetyl acetacetic esters as initiation material, reacted in ethanol with thiocarbamide, generate 2-
Amino-4-methylthiazole-5-carboxylate, then carries out diazo-reaction and obtains 4- methylthiazole-5-carboxylates, the route
Using phosphorus-containing compound, the extensive environmentally friendly difficulty of processing is big.
The content of the invention
Present invention aims at the system for providing a kind of low synthesis 4- methylthiazole-5-carboxylates of easy to operate, cost
Preparation Method.
To achieve these goals, the present invention uses following technical scheme：A kind of system of 4- methylthiazole-5-carboxylates
Preparation Method, comprises the following steps：
(1) thioformamide is synthesized：Tetrahydrofuran and phosphorus pentasulfide are stirred at room temperature, and treat that phosphorus pentasulfide disperses molten
Solution, is cooled to after room temperature and puts into formamide, be stirred at room temperature 1~2 hour, reaction solution is concentrated to dryness, and adds dilute sodium hydroxide and adjusts pH
=8~9 dissolved solids, processing lysate obtains yellow oily liquid thioformamide；
(2) cyclization：Thioformamide, absolute ethyl alcohol and 2- chloroacetyl acetacetic esters are put into reaction bulb, is warming up to back
Stream 2~3 hours, reaction solution is concentrated to dryness, and be dissolved in water solid, and processing lysate obtains white solid 4- methylthiazol-5-formic acids
Ethyl ester.
Further, the mol ratio that phosphorus pentasulfide and formamide are added in step 1 is 1：2~5.
Further, the processing lysate of step 1 uses following steps：Extracted 5 times with ethyl acetate, merge organic layer,
With saturated aqueous common salt rinsing once, anhydrous sodium sulfate drying is filtered, and concentration obtains yellow oily liquid thioformamide.
Further, the mol ratio that thioformamide and 2- chloroacetyl acetacetic esters are added in step 2 is 1：1~2.
Further, the processing lysate of step 2 uses following steps：Extracted 2~3 times, merged organic with ethyl acetate
Layer, anhydrous sodium sulfate drying is filtered, and concentration obtains red oil；Rectification under vacuum, removes foreshot, and positive fraction adds a small amount of oil
Ether, freezes crystallization, and filtering obtains white solid 4- methylthiazole-5-carboxylates.
The invention provides a kind of cost is low, the method for easy to operate synthesis 4- methylthiazole-5-carboxylates.The road
Line avoids using inflammable and explosive carbon disulfide and ammonia, while avoiding hydrogen peroxide oxidation produces accessory substance.
Brief description of the drawings
Fig. 1 is the mass spectrogram of 4- methylthiazole-5-carboxylates prepared by embodiment 1.
Embodiment
With reference to specific embodiment, the present invention is described further.
Embodiment 1
3L reaction bulbs match somebody with somebody mechanical agitation, thermometer and constant pressure funnel, added under ice-water bath 2.5L tetrahydrofurans,
50g formamides are added dropwise below 10 DEG C in 135.6g phosphoric sulfides, control temperature, are warming up to room temperature, react 2 hours.It is concentrated under reduced pressure into
It is dry.With 5%NaOH solution dissolved solids, extracted 5 times with ethyl acetate, each 300mL.Merge organic layer, use saturated aqueous common salt
Once, anhydrous sodium sulfate drying is filtered for rinsing, and concentration obtains yellow oily liquid 53g.
2L reaction bulbs match somebody with somebody mechanical agitation, condenser pipe and thermometer, add 53g thioformamides, 178g2- chloroethene ethyl acetoacetic acids
Ethyl ester and 1000mL absolute ethyl alcohols, are warming up to backflow, are incubated 3 hours.It is concentrated under reduced pressure into dry, be dissolved in water solid, uses acetic acid second
Ester is extracted 3 times, each 200mL.Merge organic layer, anhydrous sodium sulfate drying is filtered, and concentration obtains red oil.Decompression essence
Evaporate, remove foreshot, positive fraction adds a small amount of petroleum ether, freeze crystallization, filtering.Obtain white solid 4- methylthiazole-5-carboxylates
138g, molar yield：57.1%.
The mass spectrogram of obtained product is shown in Fig. 1, and mass spectrogram is shown, object ion [ES+] karyoplasmic ratio is within 10.28 minutes
172.3, it is consistent with molecular weight 171.22.
Embodiment 2
3L reaction bulbs match somebody with somebody mechanical agitation, thermometer and constant pressure funnel, added under ice-water bath 2.5L tetrahydrofurans,
50g formamides are added dropwise below 10 DEG C in 135.6g phosphoric sulfides, control temperature, are warming up to room temperature, react 2 hours.It is concentrated under reduced pressure into
It is dry.With 5%NaOH solution dissolved solids, extracted 5 times with ethyl acetate, each 300mL.Merge organic layer, use saturated aqueous common salt
Once, anhydrous sodium sulfate drying is filtered for rinsing, and concentration obtains yellow oily liquid 55g.
2L reaction bulbs match somebody with somebody mechanical agitation, condenser pipe and thermometer, add 55g thioformamides, 185g2- chloroethene ethyl acetoacetic acids
Ethyl ester and 1000mL absolute ethyl alcohols, are warming up to backflow, are incubated 3 hours.It is concentrated under reduced pressure into dry, be dissolved in water solid, uses acetic acid second
Ester is extracted 3 times, each 200mL.Merge organic layer, anhydrous sodium sulfate drying is filtered, and concentration obtains red oil.Decompression essence
Evaporate, remove foreshot, positive fraction adds a small amount of petroleum ether, freeze crystallization, filtering.Obtain white solid 142g, molar yield：58.7%.
The above described is only a preferred embodiment of the present invention, not doing any type of limitation to the present invention.It is every
Any simple modification, equivalent variations and modification that technology and method according to the present invention are substantially made to above example, still
In the range of the technology and method scheme that belong to the present invention.
Claims (5)
1. a kind of preparation method of 4- methylthiazole-5-carboxylates, it is characterised in that comprise the following steps：
(1) thioformamide is synthesized：Tetrahydrofuran and phosphorus pentasulfide are stirred at room temperature, and treat phosphorus pentasulfide dispersing and dissolving,
It is cooled to after room temperature and puts into formamide, be stirred at room temperature 1~2 hour, reaction solution is concentrated to dryness, adds dilute sodium hydroxide and adjust pH=8
~9 dissolved solids, processing lysate obtains yellow oily liquid thioformamide；
(2) cyclization：Thioformamide, absolute ethyl alcohol and 2- chloroacetyl acetacetic esters are put into reaction bulb, be warming up to backflow 2~
3 hours, reaction solution was concentrated to dryness, and be dissolved in water solid, and processing lysate obtains white solid 4- methylthiazole-5-carboxylates.
2. preparation method according to claim 1, it is characterised in that：Phosphorus pentasulfide and formyl are added in the step 1
The mol ratio of amine is 1：2~5.
3. preparation method according to claim 1, it is characterised in that：The processing lysate of the step 1 uses following step
Suddenly：Extracted 5 times with ethyl acetate, merge organic layer, with saturated aqueous common salt rinsing once, anhydrous sodium sulfate drying, filtering is dense
Contracting, obtains yellow oily liquid thioformamide.
4. preparation method according to claim 1, it is characterised in that：Thioformamide and 2- chlorine are added in the step 2
The mol ratio of ethyl acetoacetate is 1：1~2.
5. preparation method according to claim 1, it is characterised in that：The processing lysate of the step 2 uses following step
Suddenly：Extracted 2~3 times with ethyl acetate, merge organic layer, anhydrous sodium sulfate drying is filtered, and concentration obtains red oil；Subtract
Rectifying is pressed, foreshot is removed, positive fraction adds a small amount of petroleum ether, crystallization is freezed, filtering obtains white solid 4- methylthiazol-5-formic acids
Ethyl ester.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710264519.4A CN106977471A (en) | 2017-04-21 | 2017-04-21 | A kind of method for preparing the Ethyl formate of 4 methylthiazol 5 |
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| CN201710264519.4A CN106977471A (en) | 2017-04-21 | 2017-04-21 | A kind of method for preparing the Ethyl formate of 4 methylthiazol 5 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115925649A (en) * | 2022-10-09 | 2023-04-07 | 深圳市茵诺圣生物科技有限公司 | Method for preparing 4-methylthiazole-5-formaldehyde by continuous flow |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130924A (en) * | 2015-07-22 | 2015-12-09 | 蚌埠中实化学技术有限公司 | Preparation method of 4-methylthiazole-5-ethyl formate |
-
2017
- 2017-04-21 CN CN201710264519.4A patent/CN106977471A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130924A (en) * | 2015-07-22 | 2015-12-09 | 蚌埠中实化学技术有限公司 | Preparation method of 4-methylthiazole-5-ethyl formate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115925649A (en) * | 2022-10-09 | 2023-04-07 | 深圳市茵诺圣生物科技有限公司 | Method for preparing 4-methylthiazole-5-formaldehyde by continuous flow |
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