CN101412699A - Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate - Google Patents

Abstract

The invention provides a method for preparing 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate. The method uses p-cyanophenol and thioacetamide as raw materials, The reaction gives 4-hydroxythiobenzamide, and the resulting product reacts with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, which is then reacted with uroto Product reaction to obtain ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

Description

Preparation method of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

technical field

The invention relates to the field of medicinal chemistry, in particular to a preparation method of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

Background technique

Ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate is an important intermediate in the synthesis of the antihyperuricemia drug Febuxostat. Its structure It is shown in the following formula (1).

JP1045733 and JP11060552 report the synthetic method of formula I compound, take p-cyanophenol and thioacetamide as raw material, carry out Hantzch reaction with ethyl 2-chloroacetoacetate in polyphosphoric acid to obtain 2-(4-hydroxyphenyl )-4-methyl-5-thiazolecarboxylic acid ethyl ester, reacted at 85°C, as shown in the following formula II. Then the compound of formula II and hexatropine are subjected to Duff-Bills reaction in polyphosphoric acid at 80° C. to obtain the compound of formula I after treatment.

In the preparation method provided by this synthetic route, the yield of the compound of formula II is low, only 46%, and the yield of the compound of formula I prepared by the compound of formula II is 70%, which undoubtedly increases the cost of preparation; and in the preparation of formula II All used polyphosphoric acid in the two-step reaction of I compound, can produce a large amount of three waste substances in aftertreatment.

The literature The chemistry of Hereocyclic compounds: Thiazole and its derivative, 1979, 34 (1): 165 records the preparation process for the synthesis of thiazole ring derivatives with thioamide compounds, which mentions that ethanol, 1,4-diox When the hexacyclic ring is used as a solvent and phosphorus pentasulfide is catalyzed, thiazole ring derivatives similar to formula II can be obtained, and the yield can reach up to 85%.

In addition, according to the summary of the above literature, it can be known that the mechanism of the Hantzsch reaction is as follows:

In addition, the Duff-Bills reaction is a method for phenolic compounds to introduce aldehyde groups at the ortho or meta positions. In the document JP1045733, PPA is used as a solvent, and the yield is acceptable (70%), but the aftertreatment is cumbersome, the three wastes are produced in a large amount, and PPA has poor fluidity, making mass production more difficult.

Related literature Tetrehedron 1968, 24:5001 and J.Org.Chem, 1972,37 (24): 3972 report that Duff-Bills uses acetic acid, boric acid/glycerin, trifluoroacetic acid as reaction solvent more, wherein with acetic acid, boric acid/glycerin as solvent The yield is usually about 50%, and the yield is higher (95%) when trifluoroacetic acid is used as a solvent, but it is mainly the product of the para-position of the phenolic hydroxyl group.

The reaction mechanism of Duff-Bills is as follows:

Invention content:

The object of the present invention is to provide a kind of synthetic method of ethyl 2-(3-formaldehyde-4-hydroxyl phenyl)-4-methyl-5-thiazolecarboxylate.

In the preparation method shown in comparative document JP1045733, thioacetamide reacts with p-cyanophenol to generate 4-hydroxyl-thiobenzamide shown in formula III, which is then cyclized with ethyl 2-chloroacetoacetate The thiazole ring is obtained.

The key to the synthesis of thiazole rings lies in the stability of thioamides during the reaction, which are usually unstable under acidic conditions. Based on theoretical research and actual analysis results, the inventor believes that the main reason for the low yield of Hantzsch reaction shown in document JP1045733 is to use the acidic solvent of PPA, which causes the decomposition of 4-hydroxy-thiobenzamide shown in formula III, thereby lead to a decrease in yield.

In the preparation process described in documents JP1045733 and JP11060552, after p-cyanophenol and thioacetamide react in acidic solvent PPA to obtain 4-hydroxythiobenzamide, ethyl 2-chloroacetoacetate is directly added without separation to continue After the reaction, ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate was finally obtained, and the yield was only 46%. Although p-cyanophenol and thioacetamide generate 4-hydroxythiobenzamide in the acidic solvent PPA, the reaction can be completed under mild conditions, for example, at a temperature of about 40°C. However, the subsequent reaction of 4-hydroxythiobenzamide with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate requires a higher reaction rate. temperature, for example 70°C. As the temperature rises, the above-mentioned product 4-hydroxythiobenzamide becomes unstable in an acidic environment, and it decomposes easily. This may be the reason for the lower yield.

In view of this, the present invention mainly adopts following two kinds of measures to improve described Hantzsch reaction:

Reaction is carried out in two steps: that is, at first react separately with thioacetamide and p-cyanophenol to obtain 4-hydroxyl-thiobenzamide shown in formula III; then use formula III compound and ethyl 2-chloroacetoacetate The ester is cyclized in a non-acidic environment such as ethanol or 1,4-dioxane to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate represented by formula II. In this way, the self-decomposition of the compound of formula III in the reaction process can be avoided, the yield of the compound of formula II can be increased, and at the same time, since polyphosphoric acid is no longer used, the discharge of three wastes is also reduced.

In addition, regarding the Duff-Bills reaction described in the background technology, after combining theoretical analysis and actual research results, the inventor believes that the reason for the low yield of acetic acid and boric acid system may be that the acidity is not strong enough. After using trifluoroacetic acid , the yield can be greatly improved, although its para-position selectivity is stronger, but the raw material 2-(4-hydroxyphenyl)-4-methyl-5thiazole ethyl ester used in the synthetic route involved in the present invention has thiazole ring substituents, so can be expected to uniquely give ortho-substituted aldehyde compounds.

Specifically, the synthesis method provided by the present invention is to use p-cyanophenol and thioacetamide as raw materials to react to obtain the compound of formula III, and the obtained product is directly reacted with ethyl 2-chloroacetoacetate to obtain the compound of formula II without purification, and then Then react with urotropine in trifluoroacetic acid to obtain the compound of formula I.

In the process of obtaining the compound of formula III, p-cyanophenol is reacted with thioacetamide in an organic solvent passing through hydrochloric acid gas, and the organic solvent includes one or more of the following solvents: DMF, ethanol, methanol and the like. Since the yield of the product obtained in DMF is the highest and the solvent can also be recovered, it is preferred to use DMF as the reaction solvent. The reaction temperature is 20-80° C., and the reaction time is 24-48 hours.

In the process of obtaining the compound of formula II, it is characterized in that the compound of formula III reacts with ethyl 2-chloroacetoacetate in an organic solvent, and the organic solvent includes one or more of the following solvents: ethanol, methanol, ethyl acetate, dioxygen Hexacyclic, because ethanol as a solvent has a high yield and is beneficial to reduce production costs, so ethanol is preferred, and the reaction temperature is 60-80°C.

In the process of obtaining the compound of formula I, it is characterized in that the compound of formula II reacts with urotropine in trifluoroacetic acid. The reaction temperature is 80-120°C. Since the reaction is relatively complete at 100°C and no impurities are produced, 100°C is preferred, and the reaction time is 12-24 hours.

The present invention has the following advantages through the improvement of the process: 1. The yield is greatly improved, the yield of the compound shown in the preparation formula I is increased from 78% to about 97%, and the yield of the compound shown in the preparation formula II is increased from 46% increased to around 70%. 2. Avoiding the use of polyphosphoric acid as a reaction solvent, reducing the discharge of three wastes. 3. The DMF and trifluoroacetic acid used in the reaction can be recycled and reused, which reduces the production cost.

Detailed ways

The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention.

In the following examples, for convenience, (1) is used to represent ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, and (2) represents 2-(4 -Hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, (3) represents 4-hydroxythiobenzamide.

Embodiment 1: the preparation of 4-hydroxyl thiobenzamide (3)

In a 5L reaction flask, 400g of p-cyanophenol and 584g of thioacetamide were added to 4000ml of saturated HCl/DMF solution. Reacted at 40°C for 48 hours, TLC showed that the reaction was almost complete, concentrated to dryness, added 1350ml of saturated Na ₂ CO ₃ solution, stirred for 2 hours, filtered, and dried to obtain 465.8g of brown solid (3). Yield 87.6%.

Embodiment 2: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (2)

Add 465.8g of 4-hydroxythiobenzamide (3) and 2.8L of absolute ethanol into a 5L reaction flask, heat to 60°C, add 560g of ethyl 2-chloroacetoacetate dropwise, and then reflux for 2 hours. Then it was cooled to 10°C under stirring, filtered, washed with ethanol, and dried to obtain 721.1 g of yellow solid (2), with a yield of 80.6%.

Example 3: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (1)

Add 120g of (2), 63.8g of urotropine and 660ml of trifluoroacetic acid into a 3L reaction flask, heat to 100°C for 24 hours, then concentrate the reaction solution to dryness, add 2L of water and stir for 5 hours, filter and dry to obtain 126.5 g of yellow solid (1), yield 95.3%.

Embodiment 4: the preparation of 4-hydroxyl thiobenzamide (3)

In a 1L reaction flask, 40 g of p-cyanophenol and 58.4 g of thioacetamide were added to 400 ml of saturated HCl/methanol solution. Reacted at 20°C for 48 hours, TLC showed that the reaction was almost complete, concentrated to dryness, added saturated Na ₂ CO ₃ solution until the pH was 7-8, stirred for 2 hours, filtered, and dried to obtain 38 g of brown solid (3). Yield 71.5%.

Example 5: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (2)

Add 38g of 4-hydroxythiobenzamide (3) and 200ml of absolute ethanol into a 500ml reaction flask, heat to 80°C, add 45.7g of ethyl 2-chloroacetoacetate dropwise, and then reflux for 2 hours. Then it was cooled to 10° C. with stirring, filtered, washed with ethanol, and dried to obtain 46.7 g of yellow solid (2) with a yield of 70.5%.

Example 6: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (1)

Add 46.7g of (2), 24.8g of urotropine and 250ml of trifluoroacetic acid into a 500ml reaction bottle, heat to 80°C and react for 24 hours, then concentrate the reaction solution to dryness, add 800ml of water and stir for 5 hours, filter and dry 43.9 g of orange-yellow solid (1) was obtained, yield 85%.

Embodiment 7: the preparation of 4-hydroxyl thiobenzamide (3)

In a 1L reaction flask, 40g of p-cyanophenol and 58.4g of thioacetamide were added to 400ml of saturated HCl/ethanol solution. Reacted at 80°C for 48 hours, TLC showed that the reaction was almost complete, concentrated to dryness, added saturated Na ₂ CO ₃ solution to adjust the pH to 7-8, stirred for 2 hours, filtered, and dried to obtain 41 g of brown solid (3). Yield 77.1%.

Example 8: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (2)

Add 41 g of 4-hydroxythiobenzamide (3) and 300 ml of 1,4-dioxane into a 500 ml reaction flask, heat to 80°C, add 49 g of ethyl 2-chloroacetoacetate dropwise, and then reflux for 2 hours. Then it was cooled to 10° C. with stirring, filtered, washed with ethanol, and dried to obtain 49.3 g of yellow solid (2) with a yield of 69%.

Example 9: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (1)

Add 49.3g of (2), 26.2g of urotropine and 270ml of trifluoroacetic acid into a 500ml reaction bottle, heat to 120°C and react for 24 hours, then concentrate the reaction solution to dryness, add 800ml of water and stir for 5 hours, filter and dry 35.8 g of yellow solid (1) was obtained, yield 65.5%.

Embodiment 10: Preparation of 4-hydroxythiobenzamide (3)

In a 1L reaction flask, 40 g of p-cyanophenol and 58.4 g of thioacetamide were added to 200 ml of saturated HCl/methanol solution and 200 ml of saturated HCl/DMF solution. React at 40°C for 48 hours, concentrate the reaction solution to dryness, add saturated Na ₂ CO ₃ solution until the pH is 7-8, stir for 2 hours, filter, and dry to obtain 36 g of brown solid (3). Yield 37.7%.

Example 11: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (2)

Add 36g of 4-hydroxythiobenzamide (3), 100ml of absolute ethanol and 100ml of 1.4-dioxane into a 500ml reaction flask, heat to 80°C, add 45.7g of ethyl 2-chloroacetoacetate dropwise, and then Reflux for 2 hours. Then it was cooled to 10° C. with stirring, filtered, washed with ethanol, and dried to obtain 41 g of yellow solid (2) with a yield of 65.6%.

Example 12: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (1)

Add (2) 41g, 21.8g of urotropine, 20ml of trifluoroacetic acid and 200ml of glacial acetic acid into a 500ml reaction bottle, heat to 100°C for 24 hours, then concentrate the reaction solution to dryness, add 700ml of water and stir for 5 hours, After filtration and drying, 32 g of orange-yellow solid (1) was obtained, with a yield of 70.6%.

Claims (11)

1, a kind of preparation method of 2-(3-formaldehyde group-4-hydroxyl phenyl)-4-methyl-5-thiazole formic acid ethyl ester, the reaction process of this method is as follows:

Taking p-cyanophenol and thioacetamide as raw materials, the reaction obtains 4-hydroxyl thiobenzamide shown in formula III, and the compound of gained formula III reacts with ethyl 2-chloroacetoacetate to obtain 2- (4-hydroxyphenyl)-4-methyl-5-thiazole formic acid ethyl ester, then formula II compound reacts with urotropine to obtain 2-(3-formaldehyde group-4-hydroxyl phenyl shown in formula I )-4-methyl-5-thiazolecarboxylic acid ethyl ester, is characterized in that: In the preparation process, 4-hydroxythiobenzamide and ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate are synthesized separately in steps, that is, 4-hydroxythiobenzamide is synthesized separately first Substituted benzamide, and then use it as a raw material to further synthesize ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate in a non-acidic environment to avoid the latter's self-decomposition in the reaction process. 2. preparation method according to claim 1 is characterized in that, p-cyanophenol and thioacetamide react in the organic solvent that logically has hydrochloric acid gas, generate 4-hydroxyl thiobenzamide, and described organic The solvent is selected from one or more of the following solvents: DMF, ethanol, methanol. 3. The preparation method according to claim 2, characterized in that, the solvent is DMF. 4. The preparation method according to claim 2 or 3, characterized in that, the conditions for the reaction of the p-cyanophenol and thioacetamide are that the reaction temperature is 20-80° C., and the reaction time is 24-48 hours . 5. preparation method according to claim 1, is characterized in that, described 4-hydroxyl thiobenzamide and ethyl 2-chloroacetoacetate react in organic solvent to obtain 2-(4-hydroxyl phenyl)- Ethyl 4-methyl-5-thiazolecarboxylate, the organic solvent is selected from one or more of the following solvents: ethanol, methanol, ethyl acetate, dioxane. 6. The preparation method according to claim 5, characterized in that, the organic solvent is ethanol. 7. according to the described preparation method of claim 5 or 6, it is characterized in that, the condition that described 4-hydroxyl thiobenzamide reacts with ethyl 2-chloroacetoacetate is, reaction temperature is 60～80 ℃, The reaction time is 24 to 48 hours. 8. preparation method according to claim 1 is characterized in that, 2-(4-hydroxyl phenyl)-4-methyl-5-thiazole formic acid ethyl ester and urotropine react synthetically in acidic organic solvent 2 -(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl carboxylate, the acidic organic solvent is selected from trifluoroacetic acid, acetic acid or a combination thereof. 9. The preparation method according to claim 8, characterized in that, the acidic organic solvent is trifluoroacetic acid. 10. according to the described preparation method of claim 8 or 9, it is characterized in that, the condition that described 2-(4-hydroxyphenyl)-4-methyl-5-thiazole formic acid ethyl ester reacts with urotropine Yes, the reaction temperature is 80-120°C, and the reaction time is 12-24 hours. 11. The preparation method according to claim 10, characterized in that the reaction temperature is 100°C.