CN108586386A - A kind of synthetic method of thiazole carboxylic acid's class chemical intermediate - Google Patents
A kind of synthetic method of thiazole carboxylic acid's class chemical intermediate Download PDFInfo
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- CN108586386A CN108586386A CN201810478053.2A CN201810478053A CN108586386A CN 108586386 A CN108586386 A CN 108586386A CN 201810478053 A CN201810478053 A CN 201810478053A CN 108586386 A CN108586386 A CN 108586386A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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Abstract
The present invention relates to a kind of synthetic methods of thiazole carboxylic acid's class chemical intermediate, it includes：（a）Cyanoformic ester, isopropyl ether and isopropanol are mixed, are cooled to 20 DEG C ~ 5 DEG C under inert gas protection；（b）Water, sodium bicarbonate, ice and methyl tertiary butyl ether(MTBE) are stirred mixing, are added the intermediate, it less than 0 DEG C and pH is alkalescent with the intermediate that dissociates to keep water temperature；（c）The compound 2 is added in ethyl alcohol, is cooled down under inert gas protection with ice bath, ammonium chloride is added and is reacted；（d）The compound 3 is dissolved in dichloromethane, perchlormethyl is added under conditions of 10 DEG C ~ 5 DEG C；（e）The compound 4 is dissolved in ethyl alcohol, alcohol sodium alcohol solution is added dropwise under conditions of ice-water bath, inert gas shielding and is reacted；（f）The compound 5 is dissolved in tetrahydrofuran, the aqueous solution that lithium hydroxide is added dropwise under conditions of ice-water bath is reacted.The chemical synthesis that variation route is carried out to 5 ethyoxyl, 1,2,4 thiadiazoles, 3 carboxylic acid can be realized in this way.
Description
Technical field
The invention belongs to fine chemical product fields, are related to a kind of synthetic method of thiazole carboxylic acid's class chemical intermediate, tool
Body is related to a kind of synthetic method of 5- ethyoxyls -1,2,4- thiadiazoles -3- carboxylic acids.
Background technology
No. CAS of 5- ethyoxyls -1,2,4- thiadiazoles -3- carboxylic acids is 67472-43-9, it belongs to fine chemical product；It is close
Degree is 1.471g/cm3, boiling point is 335.9 DEG C of at 760mmHg, and flash-point is 156.9 DEG C, refractive index 1.573.Existing 5- ethoxies
The synthetic method route of base -1,2,4- thiadiazoles -3- carboxylic acids is more conventional and outmoded, causes the yield of product and purity poor,
It is difficult to meet the synthesis demand of biological medicine.
Invention content
A kind of conjunction of thiazole carboxylic acid's class chemical intermediate is provided the invention aims to overcome the deficiencies in the prior art
At method.
In order to achieve the above objectives, the technical solution adopted by the present invention is：A kind of synthesis of thiazole carboxylic acid's class chemical intermediate
Method, it includes：
(a) cyanoformic ester, isopropyl ether and isopropanol are mixed, is cooled to -20 DEG C under inert gas protection
~-5 DEG C, it is passed through HCl gases under stirring conditions and is reacted, stands to room temperature, filter, obtain white solid intermediate；
(b) water, sodium bicarbonate, ice and methyl tertiary butyl ether(MTBE) are stirred mixing, the intermediate is added, keep water temperature
Less than 0 DEG C and pH be alkalescent with dissociate the intermediate；Organic phase is isolated, is filtered after dry, filtrate decompression is concentrated to give
Bright oily compound 2；
(c) compound 2 is added in ethyl alcohol, is cooled down under inert gas protection with ice bath, ammonium chloride is added and carries out
Reaction；It is concentrated under reduced pressure and removes ethyl alcohol, be then added in isopropyl ether and stir, filter, obtain white compound 3；
(d) compound 3 is dissolved in dichloromethane, perchlormethyl is added under conditions of -10 DEG C~-5 DEG C；Add
N is added dropwise after complete, N- diisopropylethylamine is reacted；Add water to be extracted, organic phase with saturation NaCl wash, anhydrous sodium sulfate
It is dry, it is concentrated under reduced pressure, column chromatography purifies to obtain yellow compound 4；
(e) compound 4 is dissolved in ethyl alcohol, sodium ethoxide second is added dropwise under conditions of ice-water bath, inert gas shielding
Alcoholic solution is reacted；Reaction solution is poured into the ice water solution of ammonium chloride, is extracted with ethyl acetate, saturated nacl aqueous solution is washed
It washs, anhydrous sodium sulfate is dry, brown yellow oil compound 5 is concentrated under reduced pressure to obtain；
(f) compound 5 is dissolved in tetrahydrofuran, under conditions of ice-water bath be added dropwise lithium hydroxide aqueous solution into
Row reaction；Salt acid for adjusting pH is added to be stripped to 8~10, then with ethyl acetate, organic phase is abandoned；Water phase is extracted with ethyl acetate
It takes repeatedly, saturated nacl aqueous solution washing, anhydrous sodium sulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain.
Optimally, in step (b), the organic phase is extracted repeatedly with methyl tertiary butyl ether(MTBE), and saturated sodium-chloride is used after merging
Wash re-dry.
Optimally, in step (f), salt acid for adjusting pH is continuously added to 1, then is extracted with ethyl acetate repeatedly.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：Thiazole carboxylic acid of the present invention
The synthetic method of class chemical intermediate successively obtains intermediate, compound 2,3 and of compound by redesigning synthetic route
Compound 4 etc. can realize that, to 5- ethyoxyls -1,2,4- thiadiazoles -3- carboxylic acids carry out the chemical synthesis of variation route, have in this way
Higher yield and purity, are conducive to industrialized mass production.
Description of the drawings
Attached drawing 1 is the route map of the synthetic method of thiazole carboxylic acid's class chemical intermediate of the present invention；
Attached drawing 2 is the nuclear magnetic spectrogram of the compounds of this invention 3；
Attached drawing 3 is the nuclear magnetic spectrogram of the compounds of this invention 5- ethyoxyl -1,2,4- thiadiazoles -3- carboxylic acids.
Specific implementation mode
The synthetic method of thiazole carboxylic acid's class chemical intermediate of the present invention, as shown in Figure 1, it includes：(a) by cyan carbonic acid second
Ester, isopropyl ether and isopropanol are mixed, and are cooled to -20 DEG C~-5 DEG C under inert gas protection, are led under stirring conditions
Enter HCl gases to be reacted, stands to room temperature, filter, obtain white solid intermediate；(b) by water, sodium bicarbonate, ice and methyl
Tertbutyl ether is stirred mixing, is added the intermediate, and it less than 0 DEG C and pH is alkalescent with the centre of dissociating to keep water temperature
Body；Organic phase is isolated, is filtered after dry, filtrate decompression is concentrated to give clear oil compound 2；(c) compound 2 is added
In ethyl alcohol, cooled down under inert gas protection with ice bath, ammonium chloride is added and is reacted；It is concentrated under reduced pressure and removes ethyl alcohol, then add
Enter in isopropyl ether and stir, filters, obtain white compound 3；(d) compound 3 is dissolved in dichloromethane, -10 DEG C~-5
Perchlormethyl is added under conditions of DEG C；N is added dropwise after adding, N- diisopropylethylamine is reacted；Water is added to be extracted, it is organic
It is mutually washed, anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain yellow compound 4 with saturation NaCl；(e) by describedization
It closes object 4 to be dissolved in ethyl alcohol, alcohol sodium alcohol solution is added dropwise under conditions of ice-water bath, inert gas shielding and is reacted；It will be anti-
Answer liquid to pour into the ice water solution of ammonium chloride, be extracted with ethyl acetate, saturated nacl aqueous solution washing, anhydrous sodium sulfate are dry,
Brown yellow oil compound 5 is concentrated under reduced pressure to obtain；(f) compound 5 is dissolved in tetrahydrofuran, is dripped under conditions of ice-water bath
The aqueous solution of lithium hydroxide is added to be reacted；Salt acid for adjusting pH is added to be stripped to 8~10, then with ethyl acetate, has abandoned
Machine phase；Water phase is extracted with ethyl acetate repeatedly, saturated nacl aqueous solution washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure yellowish
Color solid.Intermediate, compound 2, compound 3 and compound 4 etc. successively are obtained by redesigning synthetic route, this
Sample can realize that 5- ethyoxyls -1,2,4- thiadiazoles -3- carboxylic acids carry out the chemical synthesis of variation route, have higher yield and
Purity is conducive to industrialized mass production.
In step (b), the organic phase is extracted repeatedly with methyl tertiary butyl ether(MTBE), is washed with saturated sodium-chloride after merging and is done again
It is dry；To improve the yield and purity of corresponding product.In step (f), continuously adds salt acid for adjusting pH and extract to 1, then with ethyl acetate
It takes repeatedly, to improve the yield and purity of corresponding product.
It is described in detail below in conjunction with to the preferred embodiment of the invention：
Embodiment 1
The present embodiment provides a kind of synthetic methods of thiazole carboxylic acid's class chemical intermediate, it includes：
(a) cyanoformic ester (100g, 1.0mol, 1.0eq), isopropyl ether (800ml) and different are added into 2L there-necked flasks
Propyl alcohol (67g, 1.1mmol, 1.1eq), in N2It is cooled to -10 DEG C under protection, HCl gas reaction 15h are passed through under stirring, stands extremely
Room temperature filters, obtains white solid intermediate；
(b) 1L water, 250g sodium bicarbonates, 200g ice, 350mL methyl tertiary butyl ether(MTBE)s are added into 2L reaction bulbs, stirring is mixed
After conjunction, it less than 0 DEG C, pH be alkalescent (pH value be 8~9) that above-mentioned intermediate, which is added, while keeping water temperature, dissociate and complete (i.e. by
Intermediate is dispersed in above-mentioned mixture), organic phase is separated, 100L is extracted with methyl tertiary butyl ether(MTBE), merges organic phase, saturation
Sodium chloride is washed twice, and dry organic phase filters, and filtrate decompression concentration obtains 110g transparent oily liquids compound 2 (step a and step
The yield of two steps of rapid b is 72%, purity 99%)；
(c) compound 2 (110g, 7.26mol, 1.0eq) and 350mLEtOH are added into 1L there-necked flasks, in N2Under protection
Cooled down with ice bath, 34g ammonium chlorides are added, react at room temperature 20h, is concentrated under reduced pressure and remove most of ethyl alcohol, it is different that 200mL is added in reaction solution
Propyl ether is vigorously stirred 30min, filters, obtains 68g compound as white solid 3 (yield 80%, purity 99.2%)；Its nuclear-magnetism is composed
Figure as shown in Fig. 2,1H NMR(400MHz,DMSO-d6)δ(ppm):9.70 (br, 2H), 7.31 (br, 2H), 4.36 (q, J=
8.0Hz, 2H), 1.32 (t, J=8.0Hz, 3H)；ESI-MS m/z calcd:C4H8N2O2([M+H]+)；117.06,found:
117.2.；
(d) compound 3 and 140ml dichloroethanes are added into 500mL single port bottles, perchlormethyl is added (i.e. at -10 DEG C
CCl3SCl, 22g, 146mmol, 1.1equiv), it finishes, slow (1h is dripped off) dropwise addition n,N-diisopropylethylamine (DIPEA,
69g, 665mmol, 5.0eq), it drips and finishes room temperature reaction 20h；Add 100mL water stratifications extract, organic phase be saturated NaCl wash, nothing
Aqueous sodium persulfate is dry, is concentrated under reduced pressure, column chromatography purifying, obtains 11g yellow solid compounds 4 (yield 42%, purity 99.0%)；
(e) compound 4 (10g, 53mmol, 1.0equiv) and 50ml ethyl alcohol are added into 200mL there-necked flasks, is dropped with ice water
Temperature is to 10 DEG C or so, in N2Ethyl alcohol (50ml) solution (1h drops of sodium ethoxide (4.4g, 64mmol, 1.2eq) are slowly added dropwise under protection
It is complete), the reaction was continued 10 minutes for room temperature, and reaction solution is poured slowly into the ice water (300mL) of 5.3g ammonium chlorides, is extracted with ethyl acetate
It takes (3 × 100mL), saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, be concentrated under reduced pressure, obtain 9g brown yellow oil fluidizations
Close object 5 (yield 85%, purity 99.5%)；
(f) compound 5 (9g, 44.5mmol, 1.0eq) and 50mlTHF are added into 200mL single port bottles, delays at 10 DEG C
Slow water (50mL) solution (1h is added dropwise to complete) that lithium hydroxide (2.3g, 55.6mmol, 1.25eq) is added dropwise, insulation reaction 10 are divided
Clock is added 2N hydrochloric acid (5mL) and adjusts pH to 9 or so；It is stripped with ethyl acetate, abandons organic phase；Water phase continues to adjust pH to 1, second
Acetoacetic ester extraction is repeatedly, saturated nacl aqueous solution washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and obtains 5.6g faint yellow solids
Object 1 (i.e. final product) is closed, yield 74%, purity 99.5%, nuclear magnetic spectrogram is as shown in figure 3, be specially：1H NMR
(400MHz,DMSO-d6)δ(ppm):13.78 (s, 1H), 4.55 (q, J=7.0Hz, 2H), 1.41 (t, J=7.0Hz, 3H)
.ESI-MS m/z calcd:C5H5ClN2O2S([M+H]+)；192.98,found:192.2.
Embodiment 2
The present embodiment provides a kind of synthetic method of thiazole carboxylic acid's class chemical intermediate, it and basic one in embodiment 1
It causes, unlike：In step (b), the unused methyl tertiary butyl ether(MTBE) extraction of organic phase is separated, 104g transparent oily liquid compounds are obtained
2 (yield of two step of step a and step b is 68%, purity 98.0%).
Embodiment 3
The present embodiment provides a kind of synthetic method of thiazole carboxylic acid's class chemical intermediate, it and basic one in embodiment 1
It causes, unlike：In step (f), salt acid for adjusting pH is not added to 1, final 4.91g compounds 1, yield 68%, purity
97.5%,.
Comparative example 1
The present embodiment provides a kind of synthetic method of thiazole carboxylic acid's class chemical intermediate, it and basic one in embodiment 1
It causes, unlike：Step (a) is not carried out, cannot obtain 5- ethyoxyls -1,2,4- thiadiazoles -3- carboxylic acids in this way.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (3)
1. a kind of synthetic method of thiazole carboxylic acid's class chemical intermediate, which is characterized in that it includes：
（a）Cyanoformic ester, isopropyl ether and isopropanol are mixed, are cooled to -20 DEG C ~ -5 under inert gas protection
DEG C, it is passed through HCl gases under stirring conditions and is reacted, stands to room temperature, filters, obtain white solid intermediate；
（b）Water, sodium bicarbonate, ice and methyl tertiary butyl ether(MTBE) are stirred mixing, the intermediate is added, water temperature is kept to be less than
0 DEG C and pH for alkalescent with dissociate the intermediate；Organic phase is isolated, is filtered after dry, filtrate decompression is concentrated to give clean oil
Shape compound 2；
（c）The compound 2 is added in ethyl alcohol, is cooled down under inert gas protection with ice bath, ammonium chloride is added and is reacted；
It is concentrated under reduced pressure and removes ethyl alcohol, be then added in isopropyl ether and stir, filter, obtain white compound 3；
（d）The compound 3 is dissolved in dichloromethane, perchlormethyl is added under conditions of -10 DEG C ~ -5 DEG C；After adding
N is added dropwise, N- diisopropylethylamine is reacted；Water is added to be extracted, organic phase is washed with saturation NaCl, anhydrous sodium sulfate is dry
It is dry, it is concentrated under reduced pressure, column chromatography purifies to obtain yellow compound 4；
（e）The compound 4 is dissolved in ethyl alcohol, it is molten that sodium ethoxide ethyl alcohol is added dropwise under conditions of ice-water bath, inert gas shielding
Liquid is reacted；Reaction solution is poured into the ice water solution of ammonium chloride, be extracted with ethyl acetate, saturated nacl aqueous solution washing,
Anhydrous sodium sulfate is dry, brown yellow oil compound 5 is concentrated under reduced pressure to obtain；
（f）The compound 5 is dissolved in tetrahydrofuran, the aqueous solution that lithium hydroxide is added dropwise under conditions of ice-water bath carries out instead
It answers；Salt acid for adjusting pH is added to be stripped to 8 ~ 10, then with ethyl acetate, organic phase is abandoned；Water phase is extracted with ethyl acetate more
Anhydrous sodium sulfate drying, faint yellow solid is concentrated under reduced pressure to obtain in secondary, saturated nacl aqueous solution washing.
2. the synthetic method of thiazole carboxylic acid's class chemical intermediate according to claim 1, it is characterised in that：Step（b）In, institute
It is multiple to state the extraction of organic phase methyl tertiary butyl ether(MTBE), re-dry is washed with saturated sodium-chloride after merging.
3. the synthetic method of thiazole carboxylic acid's class chemical intermediate according to claim 1, it is characterised in that：Step（f）In, after
The continuous salt acid for adjusting pH that is added is to 1, then is extracted with ethyl acetate repeatedly.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321583A (en) * | 2020-12-02 | 2021-02-05 | 安徽理工大学 | Synthesis method of 1,2, 4-thiadiazole compound |
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| WO2001090095A1 (en) * | 2000-05-23 | 2001-11-29 | Apotex Inc. | Thiadiazole compounds useful as inhibitors of cysteine activity dependent enzymes |
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| US3260725A (en) * | 1961-03-15 | 1966-07-12 | Olin Mathieson | 3-trichloromethyl-5-substituted-1, 2, 4-thiadiazole |
| US3890339A (en) * | 1974-05-28 | 1975-06-17 | Olin Corp | Process for preparing 3-trichloromethyl-5-ethoxy-1,2,4-thiadiazole from trichloroacetonitrile in ethanol |
| WO2001090095A1 (en) * | 2000-05-23 | 2001-11-29 | Apotex Inc. | Thiadiazole compounds useful as inhibitors of cysteine activity dependent enzymes |
| WO2010136474A2 (en) * | 2009-05-28 | 2010-12-02 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321583A (en) * | 2020-12-02 | 2021-02-05 | 安徽理工大学 | Synthesis method of 1,2, 4-thiadiazole compound |
| CN112321583B (en) * | 2020-12-02 | 2023-05-09 | 安徽理工大学 | Synthesis method of 1,2, 4-thiadiazole compound |
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