CN101050204A - Method for preparing compound of thiazole formaldehyde class - Google Patents
Method for preparing compound of thiazole formaldehyde class Download PDFInfo
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- CN101050204A CN101050204A CN 200710068866 CN200710068866A CN101050204A CN 101050204 A CN101050204 A CN 101050204A CN 200710068866 CN200710068866 CN 200710068866 CN 200710068866 A CN200710068866 A CN 200710068866A CN 101050204 A CN101050204 A CN 101050204A
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- thiazole
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- carboxaldehyde compounds
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 title claims description 14
- NPXCYFITEFMSEM-UHFFFAOYSA-N formaldehyde;1,3-thiazole Chemical class O=C.C1=CSC=N1 NPXCYFITEFMSEM-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 22
- -1 2-bromothiazole compound Chemical class 0.000 claims abstract description 17
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical class O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical group BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 claims description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- 241001597008 Nomeidae Species 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000002994 raw material Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 150000004795 grignard reagents Chemical class 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- YQWKKYUKBQHMJG-UHFFFAOYSA-N 2-bromo-4-ethyl-1,3-thiazole Chemical compound CCC1=CSC(Br)=N1 YQWKKYUKBQHMJG-UHFFFAOYSA-N 0.000 description 3
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical class CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 description 3
- JDGBKOBUBCHSGF-UHFFFAOYSA-N 4-ethyl-1,3-thiazole-2-carbaldehyde Chemical compound CCC1=CSC(C=O)=N1 JDGBKOBUBCHSGF-UHFFFAOYSA-N 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 229910008293 Li—C Inorganic materials 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VDTIGYKLTROQAH-UHFFFAOYSA-N 4-bromo-1,3-thiazole Chemical compound BrC1=CSC=N1 VDTIGYKLTROQAH-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Abstract
This invention discloses a method for preparing 2-thiazole formaldehyde compound (chemical formula I). The method comprises: performing halogen-Grignard exchange reaction to 2-bromothiazole compound to obtain a 2-thiazole aromatic Grignard reagent, reacting with formamide compound, and hydrolyzing to obtain high-purity 2-thiazole formaldehyde compound with a high yield. The method has such advantages as mild reaction conditions, high speed, high yield, and easy operation, and is suitable for industrialization.
Description
Technical field
The invention belongs to chemical technology field, relate to the preparation of medicine series products and intermediate thereof, be specially the preparation method of 2-thiazole carboxaldehyde compounds.
Background technology
2-thiazole carboxaldehyde compounds can be used as the synthetic compound that contains thiazole heterocycle functional group, comprises pesticide, dye class, pharmaceutical product and intermediate thereof.
For example, be used as synthetic (WO-A2-02/096359 Merck, the WO-A1-2004/037818 ﹠amp of antiviral; WO2006045613 Glaxo), be used as synthetic (the WO9011278 ﹠amp of Claritin as the preparation (WO2006019957 Schering Corp.) of treatment of obesity heterogeneous ring compound; JP-A2-04264076 Green Cross Corp, WO9714686 AstraPharma), be used as microbiotic synthetic (J of Antibiotics 1988 41-1 134-8 Pfizer Inc.) etc.
Known 2-thiazole carboxaldehyde compounds can be prepared by following method:
(1) by the hydrolysis of 2-dichloromethyl thiazole compound;
(2) by the direct oxidation of 2-methylthiazol compounds;
(3), react with the oxime analogue again by thiazolamine compound diazotization;
(4) be raw material with 2-halo thiazole compound, preparation 2-thiazole compound lithium salts reacts with DMF again.
But above these methods are all not ideal enough, need by the preparation of 2-methylthiazol such as the raw material in first method, and the 2-methylthiazol is difficult for obtaining; Need to use harsh reaction conditions such as high temperature, high pressure, strong acid in second method, and three-waste pollution is serious; Though the 3rd method raw material is cheap and easy to get, yield is very low, about 10%; The 4th method is because the strong polarity of Li-C key, and the activity height need react under very low temperature (75 ℃) condition, therefore is difficult for industrialization.
Summary of the invention
For solving the problems referred to above that prior art exists, the purpose of this invention is to provide a kind of reaction conditions gentleness, speed of response is fast, yield is high, method simple to operate, as to be easy to the industrialized 2-of preparation thiazole carboxaldehyde compounds.
The preparation method who the invention provides 2-thiazole carboxaldehyde compounds (formula I) is following steps:
(1) carries out the Ge Shi permutoid reaction with 2-bromo thiazole functional group derivant (formula II) and halohydrocarbon Grignard reagent RMgBr (formula III), obtain heteroaryl Grignard reagent (formula IV);
(2) with heteroaryl Grignard reagent (formula IV) and amides (formula V) reaction, obtain intermediate complex compound (formula VI);
(3) above-mentioned complex compound (formula VI) obtains 2-thiazole carboxaldehyde compounds (formula I) through organic solvent extraction or distillation extraction again through hydrolysis;
In the above-mentioned steps,
R among formula I, formula II, formula IV and the formula VI
1Be hydrogen, R
2Be hydrogen or ethyl;
R among formula V and the formula VI
3And R
4Respectively do for oneself methyl or piperazinyl;
R in the formula III is selected from C2-8 alkyl or C5-12 heteroaryl.
The reaction solvent of step (1) Ge Shi permutoid reaction is a tetrahydrofuran (THF).
The reaction solvent of preparation intermediate complex compound (VI) is a tetrahydrofuran (THF), or tetrahydrofuran (THF) and toluene are 1～5 by volume: the mixture of the arbitrary proportion between 5～1.
The selected hydrolytic reagent of step (3) hydrolysis complex compound (formula VI) is a saturated aqueous ammonium chloride; The organic solvent that extracts usefulness is a toluene.
Above invention scheme is further described below:
With 2-bromo thiazole compounds (formula II) is starting raw material, by reacting with alkyl or aromatic hydrocarbon Grignard reagent (formula III),
Thereby obtain being difficult to the assorted fragrant Grignard reagent (formula IV) of 2-bromo thiazole class of directly preparation
Wherein the reaction medium solvent can be ether solvent, also can adopt the mixed solvent of toluene and ether solvent, preferred ether, tetrahydrofuran (THF); The preferred monobromethane of alkyl or aromatic hydrocarbon Ge Shi agent (formula III), N-PROPYLE BROMIDE; Wherein temperature of reaction can be-40～80 ℃, preferred-10～10 ℃.
Test-results shows assorted fragrant Grignard reagent (formula IV) the purity height of the 2-bromo thiazole class that obtains like this, and it is fast that speed is carried out in reaction, and reaction conditions is also gentle relatively, is easy to preparation.The assorted fragrant Grignard reagent (formula IV) of the 2-bromo thiazole class that wherein obtains can not done aftertreatment, directly descends the step to feed intake with the solution form of its reaction solvent.
With the assorted fragrant Grignard reagent (formula IV) of the 2-bromo thiazole class that obtains of aforesaid method is raw material and Carbox amide (formula V)
React, obtain a complex compound (formula VI)
Formula VI
The solution of reaction solvent.Wherein the reaction medium solvent can be ether solvent, also can adopt the mixed solvent of toluene and ether solvent; The preferred ether of single solvent, tetrahydrofuran (THF); Preferred tetrahydrofuran (THF) of mixed solvent and toluene are with the mixed solvent of 1: 5 to 5: 1 ratio.The preferred N of reaction raw materials Carbox amide (formula V), N dimethyl formamide and N-formyl piperazine.Wherein temperature of reaction can be-40～80 ℃, preferred-10～10 ℃.
The solution of the reaction solvent of the intermediate complex compound (formula VI) that obtains like this can obtain target product 2-thiazole carboxaldehyde compounds (formula I) through hydrolysis reaction.Wherein selected hydrolysising solvent can be water, the aqueous solution of organic acid or salt, the aqueous solution of mineral acid or salt, preferably water, saturated aqueous ammonium chloride, 1～35% hydrochloric acid, 1～50% aqueous sulfuric acid.Hydrolysis temperature can be-40～80 ℃, preferred-10～10 ℃.
After reaction was finished, the difference according to reaction institute working medium solvent generally can adopt solvent extraction process, obtains above-mentioned 2-thiazole carboxaldehyde compounds (formula I) product, or takes distillating method to obtain product.Through the check and analysis to the finished product of high pressure liquid chromatography (HPLC) (HPLC) method and gas chromatography, the result shows that the content of the compound (formula I) in the aforesaid method products obtained therefrom of the present invention is all more than 98%.
Wherein, the R among formula I, formula II, formula IV and the formula VI
1Be hydrogen, R
2Be hydrogen or ethyl;
R among formula V and the formula VI
3And R
4Respectively do for oneself methyl or piperazinyl;
R in the formula III is selected from C2-8 alkyl or C5-12 heteroaryl
We are raw material with 2-bromo thiazole compounds, by preparing its Grignard reagent, obtain 2-thiazole carboxaldehyde compounds.At first, therefore more stable because the Mg-C bond polarity is littler than Li-C key, so novel method needn't be carried out under condition of ultralow temperature.Secondly, 2-bromo thiazole compounds for short of electricity, directly its Grignard reagent of preparation is very difficult thing, we use for reference people such as Paul Knokel and were published in heterocyclic compound halogen-magnesium switching method on the J.Org.Chem in 2000, at first prepare its Grignard reagent with active halogenated alkane, then under certain condition with this Grignard reagent and the reaction of 2-bromo thiazole compounds, successfully made the assorted fragrant Grignard reagent of 2-bromo thiazole class, not only speed of response is fast for this method, yield is high, and simple to operate, be easy to industrialization.
To sum up, the present invention adopts earlier by 2-bromo thiazole compounds (formula II) and obtains the assorted fragrant Grignard reagent (formula IV) of 2-bromo thiazole class through carrying out the Ge Shi permutoid reaction with the aliphatic hydrocarbon of cheapness or aromatic hydrocarbon Ge Shi agent, itself and Carbox amide are reacted, thereby obtain target compound 2-thiazole carboxaldehyde compounds through hydrolysis.Compare with the preparation method of traditional 2-thiazole carboxaldehyde compounds, the present invention has following advantage: at first, the reaction conditions gentleness can be finished reaction under gentle conditions such as room temperature, normal pressure, thereby has reduced requirement and expense to aspects such as conversion units significantly; Secondly, reaction yield height of the present invention, thus reduced production cost significantly; In addition, the present invention can obtain high purity product by simple distillating method, needn't be beneficial to the industrialization operation through chromatographic purification.In sum, the present invention has cost and technical advantage, thereby helps making above-claimed cpd 2-thiazole carboxaldehyde compounds (formula I) to realize large-scale industrial production, has had great commercial application value.
Embodiment
Method of the present invention can be designed for laboratory and technical scale, describes the present invention below with reference to embodiment.
Embodiment 1
The preparation of 2-bromo thiazole Grignard reagent
Dropping into concentration in a 500ml four-hole bottle is monobromethane Grignard reagent/tetrahydrofuran solution 200ml (0.40mol) of 2mol/L, stir, ice-water bath is cooled to 0～5 ℃, slowly is added dropwise to 2-bromo thiazole 59g (0.36mol), dripped in about 0.5 hour and finish, continue at 0 ℃ of reaction 2 hours.TLC detects, and raw material 2-bromo thiazole reacts completely.Extract reaction solution 0.5ml and place test tube, add ethyl acetate and each 2ml of 0.1N dilute hydrochloric acid, concussion, layering is got organic layer and is done the GC analysis, and raw material 2-bromo thiazole content is less than 1%.
Embodiment 2
The preparation of 2-thiazole carboxaldehyde
(1) in a 1000ml four-hole bottle, drops into toluene 200mL, N, N dimethyl formamide 73g (1.0mol), stir, water-bath is cooled to 5～10 ℃, with gained 2-bromo thiazole grignard reagent solution in the above-mentioned example 1, slowly add, finish, in 10 ℃ of stirring reactions about 12 hours.In another 1000ml four-hole bottle, must drop into 2N hydrochloric acid 200ml, about 15 ℃ of water-bath temperature controls slowly add above-mentioned reaction solution wherein, stir 0.5 hour, and standing demix, water layer continue to use twice of 200ml methylbenzene extraction; Merge organic layer, use the 100ml water washing, dry 0.5 hour of anhydrous MgSO4 filters, and mother liquor is evaporated to dried in 70 ℃,
Obtain pink liquid 40.5g, analyze through GC, the content of 2-thiazole carboxaldehyde is 86%, crude product yield 99%.
(2) get above-mentioned gained 2-thiazole carboxaldehyde crude product 40.0g vacuum distilling, vacuum tightness 2Hgmm collects 41 ℃ of cuts, gets little yellow liquid 28.2g, yield 70.5%.154 ℃ of boiling points, GC detect 2-bromo thiazole content 98.8%.
1H?NMR(CDCl
3)：δ(ppm)＝7.82(d，3Hz，1H)，8.16(d，3Hz，1H)，10.04(s，1H).
13CNMR(CDCl
3)：δ(ppm)＝126.4，149.6，165.9，184.9.
Embodiment 3
The preparation of 4-ethyl-2-bromo thiazole Grignard reagent
In reaction flask A, drop into 4-ethyl-2-bromo thiazole 38.4g (0.20mol), ether 100ml stirs, and is cooled to-5～0 ℃, and slowly adding concentration is the solution 120ml (0.24mol) of N-PROPYLE BROMIDE Ge Shi agent/ether of 2mol/L, finishes in 15 minutes.In about 0 ℃, continued stirring reaction 3 hours, TLC detects raw material 4-, and ethyl-2-bromo thiazole primitive reaction is complete.Extract reaction solution 0.5ml and place test tube, add ethyl acetate and each 2ml of 0.1N dilute hydrochloric acid, concussion, layering is got organic layer and is done the GC analysis, and raw material 4-ethyl-2-bromo thiazole is less than 2%.
Embodiment 4
The preparation of 4-ethyl-2-formyl thiazole
(1) by embodiment 3 gained, the reaction solution in the reaction flask A is warming up to 10～15 ℃, slowly is added dropwise to N-formyl piperazine 56.5g (0.50mol), and controlled temperature is no more than 20 ℃, drips complete in about 1 hour.In about 15 ℃, continue reaction 8 hours.Stopped reaction.In another reaction flask B, drop into 2N hydrochloric acid 200ml, ethyl acetate 200ml, about 15 ℃ of water-bath temperature controls slowly add above-mentioned reaction solution wherein, stir 0.5 hour, and standing demix, water layer continue to use twice of 150ml ethyl acetate extraction; Merge organic layer, use the 100ml water washing, dry 0.5 hour of anhydrous MgSO4 filters, and mother liquor is evaporated to dried, gets brown liquid 27.2g, and GC analyzes, and the content of 4-L base-2-thiazole carboxaldehyde is 82%, thick yield 96.5%.
(2) get above-mentioned gained 4-ethyl-2-formyl thiazole crude product 27.0g vacuum distilling, vacuum tightness 2mmHg collects 47 ℃ of cuts, gets yellow liquid 19.8g, yield 73.3%.154 ℃ of boiling points, GC detects 4-ethyl-2-formyl thiazole content 98.6%.
1H?NMR(CDCl
3)：
δ(ppm)＝1.24(t，7Hz，3H)，2.59(q，5Hz，2H)，7.41(s，1H)，9.61(s，1H).
13CNMR(CDCl
3)：δ(ppm)＝14.3，25.9，114.9，153，153，190.0
The embodiment of above-mentioned specific examples representative is the detailed description to content of the present invention, but this should be interpreted as that the scope of aforementioned body of the present invention only limits to above embodiment.Allly all belong to scope of the present invention based on the technology that content of the present invention realized.
Claims (5)
1. prepare the method for 2-thiazole carboxaldehyde compounds (formula I), it is characterized in that following step:
Formula I
(1) carries out the Ge Shi permutoid reaction with 2-bromo thiazole functional group derivant (formula II) and halohydrocarbon Grignard reagent RMgBr (formula III), obtain heteroaryl Grignard reagent (formula IV);
(2) with heteroaryl Grignard reagent (formula IV) and amides (formula V) reaction, obtain intermediate complex compound (formula VI);
(3) above-mentioned complex compound (formula VI) obtains 2-thiazole carboxaldehyde compounds (formula I) through organic solvent extraction or distillation extraction again through hydrolysis;
Formula VI
In the above-mentioned steps,
R among formula I, formula II, formula IV and the formula VI
1Be hydrogen, R
2Be hydrogen or ethyl;
R among formula V and the formula VI
3And R
4Respectively do for oneself methyl or piperazinyl;
R in the formula III is selected from C2-8 alkyl or C5-12 heteroaryl.
2. prepare the method for 2-thiazole carboxaldehyde compounds (formula I) according to claim 1, it is characterized in that: the reaction solvent of step (1) Ge Shi permutoid reaction is a tetrahydrofuran (THF).
3. the method for preparing 2-thiazole carboxaldehyde compounds (formula I) according to claim 1, it is characterized in that: the reaction solvent of preparation intermediate complex compound (VI) is a tetrahydrofuran (THF), or tetrahydrofuran (THF) and toluene are 1～5 by volume: the mixture of the arbitrary proportion between 5～1.
4. prepare the method for 2-thiazole carboxaldehyde compounds (formula I) according to claim 1, it is characterized in that: the selected hydrolytic reagent of step (3) hydrolysis complex compound (formula VI) is a saturated aqueous ammonium chloride.
5. prepare the method for 2-thiazole carboxaldehyde compounds (formula I) according to claim 1, it is characterized in that: the organic solvent that step (3) is extracted usefulness is a toluene.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100688666A CN100548995C (en) | 2007-05-17 | 2007-05-17 | The preparation method of 2-thiazole carboxaldehyde compounds |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100688666A CN100548995C (en) | 2007-05-17 | 2007-05-17 | The preparation method of 2-thiazole carboxaldehyde compounds |
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| Publication Number | Publication Date |
|---|---|
| CN101050204A true CN101050204A (en) | 2007-10-10 |
| CN100548995C CN100548995C (en) | 2009-10-14 |
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|---|---|---|---|
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| Country | Link |
|---|---|
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