CN100548995C - The preparation method of 2-thiazole carboxaldehyde compounds - Google Patents

Abstract

The invention discloses the preparation method of a kind of 2-thiazole carboxaldehyde compounds (formula I).With 2-bromo thiazole compounds is raw material, prepares its Grignard reagent by halogen-Ge Shi permutoid reaction, obtains 2-thiazoles fragrance Grignard reagent; Under certain condition with this Grignard reagent and Carbox amide reaction, make highly purified 2-thiazole carboxaldehyde compounds through hydrolysis with high yield more then.This method reaction conditions gentleness, speed is fast, yield is high, and is simple to operate, be easy to industrialization.

Description

The preparation method of 2-thiazole formaldehyde compound

technical field

The invention belongs to the technical field of chemical industry and relates to the preparation of pharmaceutical products and intermediates thereof, in particular to the preparation method of 2-thiazole formaldehyde compounds.

Background technique

2-thiazole formaldehyde compounds can be used to synthesize compounds containing thiazole heterocyclic functional groups, including pesticides, dyes, pharmaceutical products and their intermediates.

For example, for the synthesis of antiviral drugs (WO-A2-02/096359Merck, WO-A1-2004/037818&WO2006045613Glaxo), for the preparation of heterocyclic compounds for treating obesity (WO2006019957 Schering Corp.) for the synthesis of antiallergic drugs (WO9011278&JP-A2-04264076 Green Cross Corp, WO9714686 AstraPharma), used for antibiotic synthesis (J of Antibiotics 1988 41-1 134-8Pfizer Inc.), etc.

Known 2-thiazole formaldehyde compounds can be prepared by the following method:

(1) hydrolyzed by 2-dichloromethylthiazole compounds;

(2) direct oxidation by 2-methylthiazole compounds;

(3) diazotization by 2-aminothiazole compound, and then react with oxime analog;

(4) Using 2-halogenated thiazole compounds as raw materials to prepare lithium salts of 2-thiazole compounds, and then reacting with DMF.

However, these methods are not ideal enough. For example, the raw material in the first method needs to be prepared by 2-methylthiazole, which is not easy to obtain; in the second method, harsh reactions such as high temperature, high pressure, and strong acid are required. conditions, and the pollution of the three wastes is serious; although the third method is cheap and easy to get raw materials, the yield is very low, about 10%; the fourth method needs to be processed at ultra-low temperature ( -75°C) conditions, so it is not easy to industrialize.

Contents of the invention

In order to solve the above-mentioned problems in the prior art, the object of the present invention is to provide a method for preparing 2-thiazole carboxaldehyde compounds with mild reaction conditions, fast reaction speed, high yield, simple operation and easy industrialization.

The present invention provides the preparation method of 2-thiazole formaldehyde compounds (formula I) as follows:

式I

Formula I

(1) Carry out Grignard exchange reaction with 2-bromothiazole functional group derivative (formula II) and halogenated hydrocarbon Grignard reagent RMgBr (formula III) to obtain heteroaryl Grignard reagent (formula IV);

式II    RMgBr 式III

Formula II RMgBr Formula III

(2) reacting a heteroaryl Grignard reagent (formula IV) with an amide compound (formula V) to obtain an intermediate complex (formula VI);

式IV

式V

Formula IV

Formula V

(3) The above complex (formula VI) is hydrolyzed, and then extracted with an organic solvent or distilled to obtain 2-thiazole formaldehyde compounds (formula I);

式VI

Formula VI

In the above steps,

R in formula I, formula II, formula IV and formula VI ₁ is hydrogen, R ₂ is hydrogen or ethyl;

R ₃ and R ₄ in formula V and formula VI are each methyl or piperazinyl;

R in formula III is selected from C2-8 alkyl or C5-12 heteroaryl.

The reaction solvent of the step (1) Grignard exchange reaction is tetrahydrofuran.

The reaction solvent for preparing the intermediate complex (VI) is tetrahydrofuran, or a mixture of tetrahydrofuran and toluene in any ratio of 1-5:5-1 by volume.

Step (3) The selected hydrolyzing agent for hydrolyzing the complex (formula VI) is saturated ammonium chloride aqueous solution; the organic solvent used for extraction is toluene.

Above invention scheme is further described as follows:

With 2-bromothiazole compound (formula II) as starting material, by reacting with alkane group or aromatic hydrocarbon Grignard reagent (formula III),

Formula II RMgBr Formula III

Thereby obtain the 2-bromothiazole heteroaromatic Grignard reagent (formula IV) that is difficult to prepare directly

式IV

Formula IV

Wherein the reaction medium solvent can be ether solvent, also can adopt the mixed solvent of toluene and ether solvent, preferred ether, tetrahydrofuran; Alkane group or aromatic hydrocarbon Grignard agent (formula III) preferably bromoethane, bromopropane; Wherein reaction temperature It may be -40 to 80°C, preferably -10 to 10°C.

The test results show that the obtained 2-bromothiazole heteroaromatic Grignard reagent (formula IV) has high purity, fast reaction speed, relatively mild reaction conditions and easy preparation. The obtained 2-bromothiazole heteroaromatic Grignard reagent (formula IV) can be fed directly in the form of a reaction solvent solution without post-treatment.

The 2-bromothiazole heteroaromatic Grignard reagent (formula IV) obtained by the above method is used as raw material and formamide compound (formula V)

式V

Formula V

Carry out reaction, obtain a complex compound (formula VI)

式VI

Formula VI

solution of the reaction solvent. Wherein the reaction medium solvent can be an ether solvent, or a mixed solvent of toluene and an ether solvent; the preferred single solvent is ether and tetrahydrofuran; the mixed solvent is preferably a mixed solvent of tetrahydrofuran and toluene in a ratio of 1:5 to 5:1. The reaction raw material formamide compounds (formula V) are preferably N,N dimethylformamide and N-formylpiperazine. Wherein the reaction temperature may be -40-80°C, preferably -10-10°C.

The solution of the reaction solvent of the intermediate complex compound (formula VI) obtained in this way can be hydrolyzed to obtain the target product 2-thiazole carboxaldehyde compound (formula I). Wherein the selected hydrolysis solvent can be water, organic acid or salt aqueous solution, inorganic acid or salt aqueous solution, preferably water, saturated ammonium chloride aqueous solution, 1-35% hydrochloric acid, 1-50% sulfuric acid aqueous solution. The hydrolysis temperature may be -40-80°C, preferably -10-10°C.

After the reaction is completed, according to the difference of the medium solvent used in the reaction, a solvent extraction method can generally be used to obtain the above-mentioned 2-thiazole formaldehyde compound (Formula I) product, or a distillation method can be used to obtain the product. Through the detection and analysis of the final product by high pressure liquid chromatography (HPLC) and gas chromatography, the results show that the content of the compound (Formula I) in the product obtained by the above method of the present invention is above 98%.

Wherein, R in formula I, formula II, formula IV and formula VI ₁ is hydrogen, R ₂ is hydrogen or ethyl;

R ₃ and R ₄ in formula V and formula VI are each methyl or piperazinyl;

R in formula III is selected from C2-8 alkyl or C5-12 heteroaryl

We use 2-bromothiazole compounds as raw materials to obtain 2-thiazole formaldehyde compounds by preparing their Grignard reagents. First, because the Mg-C bond is less polar and therefore more stable than the Li-C bond, the new method does not have to be performed at ultra-low temperatures. Secondly, it is very difficult to directly prepare the Grignard reagents of the 2-bromothiazole compounds that are deficient in electricity. We refer to the heterocyclic compound halogen-magnesium that Paul Knokel et al. published on J.Org.Chem in 2000. The exchange method first prepares its Grignard reagent with active halogenated alkanes, and then reacts the Grignard reagent with 2-bromothiazole compounds under certain conditions to successfully prepare 2-bromothiazole heteroaromatic Grignard reagents. The method not only has fast reaction speed and high yield, but also has simple operation and easy industrialization.

In summary, the present invention adopts 2-bromothiazole heteroaromatic Grignard reagents (formula IV) by first carrying out Grignard exchange reaction with cheap aliphatic or aromatic hydrocarbon Grignard agents from 2-bromothiazole compounds (formula II), Then make it react with formamide compounds, and undergo hydrolysis to obtain the target compound 2-thiazole carboxaldehyde compounds. Compared with the traditional preparation method of 2-thiazole formaldehyde compounds, the present invention has the following advantages: first, the reaction conditions are mild, and the reaction can be completed at room temperature, normal pressure and other mild conditions, thereby greatly reducing the need for reaction equipment, etc. Second, the present invention has a high reaction yield, thereby greatly reducing production costs; in addition, the present invention can obtain high-purity products through simple distillation methods without chromatographic separation and purification, which is beneficial to industrial operations. To sum up, the present invention has cost and technical advantages, which is conducive to the large-scale industrial production of the above-mentioned compound 2-thiazole carboxaldehyde (Formula I), and has great commercial application value.

Detailed ways

The method of the present invention can be designed for laboratory and industrial scale, and the present invention will be described below with reference to examples.

Example 1

Preparation of 2-bromothiazolyl Grignard reagent

200ml (0.40mol) of bromoethane Grignard reagent/tetrahydrofuran solution with a concentration of 2mol/L was put into a -500ml four-necked flask, stirred, cooled in an ice-water bath to 0-5°C, and 59g (0.36 mol), after about 0.5 hours, the reaction was continued at 0°C for 2 hours. As detected by TLC, the raw material 2-bromothiazole was completely reacted. Take 0.5ml of the reaction solution and place it in a test tube, add 2ml each of ethyl acetate and 0.1N dilute hydrochloric acid, shake, separate layers, take the organic layer for GC analysis, the content of the raw material 2-bromothiazole is less than 1%.

Example 2

Preparation of 2-thiazolecarbaldehyde

(1) In a 1000ml four-necked flask, put 200mL of toluene, 73g (1.0mol) of N,N dimethylformamide, stir, and cool in a water bath to 5-10°C. Stirring reagent solution, slowly added, after completion, stirred and reacted at 10°C for about 12 hours. In another 1000ml four-necked bottle, put 200ml of 2N hydrochloric acid into it, and control the temperature in a water bath at about 15°C. Slowly add the above reaction solution into it, stir for 0.5 hours, let it stand for stratification, and continue to extract the water layer twice with 200ml of toluene; combine The organic layer was washed with 100ml of water, dried over anhydrous MgSO for 0.5 hours, filtered, and the mother liquor was concentrated to dryness at 70°C under reduced pressure,

40.5 g of a light red liquid was obtained. According to GC analysis, the content of 2-thiazole formaldehyde was 86%, and the crude product yield was 99%.

(2) Take 40.0 g of the above obtained 2-thiazole formaldehyde crude product and vacuum distill it at a vacuum degree of 2 Hgmm, collect fractions at 41° C. to obtain 28.2 g of a yellowish liquid with a yield of 70.5%. The boiling point is 154°C, and the content of 2-bromothiazole detected by GC is 98.8%.

¹ HNMR(CDCl ₃ ): δ(ppm)=7.82(d, 3Hz, 1H), 8.16(d, 3Hz, 1H), 10.04(s, 1H).

¹³ CNMR (CDCl ₃ ): δ (ppm) = 126.4, 149.6, 165.9, 184.9.

Example 3

Preparation of 4-ethyl-2-bromothiazole Grignard reagent

In reaction flask A, put 38.4g (0.20mol) of 4-ethyl-2-bromothiazole and 100ml of diethyl ether, stir, cool to -5～0°C, slowly add bromopropane Grignard agent with a concentration of 2mol/L/ 120ml (0.24mol) of ether solution was added in 15 minutes. At about 0°C, the stirring reaction was continued for 3 hours, and the reaction of the raw material 4-ethyl-2-bromothiazole was basically complete as detected by TLC. Take 0.5ml of the reaction solution and put it in a test tube, add 2ml each of ethyl acetate and 0.1N dilute hydrochloric acid, shake, separate layers, take the organic layer for GC analysis, the raw material 4-ethyl-2-bromothiazole is less than 2%.

Example 4

Preparation of 4-ethyl-2-formylthiazole

(1) As obtained in Example 3, the temperature of the reaction liquid in the reaction bottle A was raised to 10-15°C, and 56.5 g (0.50 mol) of N-formylpiperazine was slowly added dropwise, and the temperature was controlled not to exceed 20°C for about 1 hour. complete. At about 15°C, the reaction was continued for 8 hours. Abort the reaction. In another reaction bottle B, put 200ml of 2N hydrochloric acid, 200ml of ethyl acetate, and control the temperature in a water bath at about 15°C. Slowly add the above reaction solution into it, stir for 0.5 hours, let stand to separate layers, and continue to wash the water layer with 150ml of ethyl acetate. Extract twice; Merge organic layer, wash with 100ml water, anhydrous MgSO Dry 0.5 hour, filter, mother liquor is concentrated to dryness under reduced pressure, obtain brown liquid 27.2g, GC analysis, the content of 4-ethyl-2-thiazole formaldehyde is 82%, crude yield 96.5%.

(2) 27.0 g of the crude 4-ethyl-2-formylthiazole obtained above was vacuum distilled at a vacuum degree of 2 mmHg, and fractions at 47° C. were collected to obtain 19.8 g of a yellow liquid with a yield of 73.3%. The boiling point is 154°C, and the content of 4-ethyl-2-formylthiazole detected by GC is 98.6%. ¹ HNMR (CDCl ₃ ):

δ(ppm)=1.24(t, 7Hz, 3H), 2.59(q, 5Hz, 2H), 7.41(s, 1H), 9.61(s, 1H).

¹³ CNMR (CDCl ₃ ): δ (ppm) = 14.3, 25.9, 114.9, 153, 153, 190.0

The implementations represented by the above specific examples are detailed descriptions of the content of the present invention, but it should not be understood that the scope of the above-mentioned subject of the present invention is limited to the above specific implementations. All technologies implemented based on the content of the present invention belong to the scope of the present invention.

Claims (5)

1. the method for preparing 2-thiazole formaldehyde compound (formula I), is characterized in that following steps:

(1) Carry out Grignard exchange reaction with 2-bromothiazole functional group derivative (formula II) and halogenated hydrocarbon Grignard reagent RMgBr (formula III) to obtain heteroaryl Grignard reagent (formula IV);

RMgBr III (2) reacting a heteroaryl Grignard reagent (formula IV) with an amide compound (formula V) to obtain an intermediate complex (formula VI);

(3) The above complex (formula VI) is hydrolyzed, and then extracted with an organic solvent or distilled to obtain 2-thiazole formaldehyde compounds (formula I);

In the above steps, R in formula I, formula II, formula IV and formula VI ₁ is hydrogen, R ₂ is hydrogen or ethyl; R ₃ and R ₄ in formula V and formula VI are methyl; R in formula III is selected from C2-8 alkyl or C5-12 heteroaryl. 2. according to the method for preparing 2-thiazole formaldehyde compound (formula I) according to claim 1, it is characterized in that: the reaction solvent of step (1) Grignard exchange reaction is tetrahydrofuran. 3. according to the method for preparing 2-thiazole formaldehyde compound (formula I) according to claim 1, it is characterized in that: the reaction solvent of preparation intermediate complex compound (VI) is tetrahydrofuran, or tetrahydrofuran and toluene are 1～5 by volume : A mixture of any ratio between 5 and 1. 4. The method for preparing 2-thiazole formaldehyde compound (formula I) according to claim 1, characterized in that: the hydrolyzing agent selected for step (3) hydrolysis complex (formula VI) is a saturated aqueous ammonium chloride solution. 5. according to the method for preparing 2-thiazole formaldehyde compounds (formula I) according to claim 1, it is characterized in that: the organic solvent that step (3) extracts is toluene.