CN102372680A - A kind of method for preparing thiazole-4-carboxylic acid - Google Patents

Abstract

The invention discloses a method for preparing thiazole-4-carboxylic acid, which belongs to the technical field of intermediate synthesis in fine chemical industry. The preparation steps are as follows: use L-cysteine hydrochloride and formaldehyde as starting materials, undergo condensation and esterification to obtain methyl thiazolidine-4-carboxylate, and then oxidize and synthesize methyl thiazole-4-carboxylate under the action of _MnO2 Esters, hydrolyzed to give thiazole-4-carboxylic acid. The invention has the advantages of adopting cheap and easy-to-obtain L-cysteine hydrochloride as a raw material, condensing, esterifying, oxidizing, and hydrolyzing the worth product, simplifying the operation procedure and reducing the production cost. The invention has the advantages of mild reaction conditions, simple operation, high conversion rate, good selectivity and simple and clean process.

Description

A kind of method for preparing thiazole-4-carboxylic acid

technical field

The invention relates to a method for preparing thiazole-4-carboxylic acid, which belongs to the technical field of synthesis of fine chemical intermediates.

Background technique

Thiazole-4-carboxylic acid is the key intermediate for the synthesis of thiabendazole. Thiabendazole is one of the earliest developed benzimidazole drugs. It was successfully developed by Merck in 1968. Thiabendazole is widely used, mainly as an anti-parasitic Insecticides, fungicides and preservatives are widely used.

The synthesis process reported by Li Shulian et al. uses pyruvic acid as a raw material, prepares bromopyruvic acid by bromination, and then cyclizes with thioformamide to prepare thiazole-4-carboxylic acid, and can also prepare thiazole by reacting dichloroacetone and thioformamide. -4-Formic acid, and then cyclized with o-phenylenediamine to prepare thiabendazole. The process of this method is more complicated, the pollution is more serious, and the reaction yield is lower.

The synthesis process reported by Houssin, Raymond, etc., prepares ethyl aminothiazole-4-carboxylate by cyclic condensation of bromopyruvate and thiourea; bromination of ethyl aminothiazole-4-carboxylate prepares bromothiazole-4-carboxylate Ethyl ester, and then undergo catalytic hydrodebromination to generate thiazole-4-carboxylic acid ethyl ester, which is hydrolyzed to produce thiazole-4-carboxylic acid. The process of this method is more complicated, the pollution is more serious, and the reaction yield is lower.

Contents of the invention

On the basis of modern organic synthesis, the present invention simplifies the experimental steps, reduces the cost, the raw materials are cheap and easy to obtain, the solvent is easy to recycle, and on the premise of ensuring product quality and yield, the generation of pollutants and energy consumption are reduced waste.

A kind of method for preparing thiazole-4-carboxylic acid of the present invention, carries out according to the following steps:

(1) Condensation reaction: use L-cysteine hydrochloride as raw material, adopt a one-pot cooking process, add water to it, stir evenly, add formaldehyde solution with a mass concentration of 37~40%, stir at room temperature for 8 hours, and then Pyridine was added thereto to adjust the pH to neutral, filtered and dried to obtain the crude product; recrystallized from water-ethanol solution to obtain thiazolidine-4-carboxylic acid.

(2) Esterification reaction: use thiazolidine-4-carboxylic acid as raw material, add methanol to it, stir evenly, start to pass dry hydrogen chloride gas until saturated, stir at room temperature for 12 hours, add ether to it, there are white flakes crystals were precipitated, filtered and dried to obtain methyl thiazolidine-4-carboxylate hydrochloride, and methyl thiazolidine-4-carboxylate was obtained after dehydrochlorination;

(3) Oxidation reaction: use methyl thiazolidine-4-carboxylate as raw material, add acetonitrile to it, stir evenly, then slowly add MnO ₂ , stir and react at 60~100°C for 24-72h, filter after cooling, and distill the filtrate under reduced pressure Removal of solvent affords methyl thiazole-4-carboxylate;

(4) Hydrolysis reaction: using methyl thiazole-4-carboxylate as raw material, add 10% sodium hydroxide aqueous solution to it, heat to reflux for 1 hour, cool, add HCl solution in ice bath, acidify to pH=3 , to be precipitated solid, suction filtration, washed with a small amount of water, and dried to obtain thiazole-4-carboxylic acid.

In the condensation reaction described in step (1), n (L-cysteine hydrochloride): n (formaldehyde) = 1:1.05~1:1.4 (molar ratio), water is used as a solvent during the reaction, n ( L-cysteine hydrochloride): n (water) = 1:5~1:8 (molar ratio), the volume ratio of water-ethanol solution is 1:1~1:1.5.

In the esterification reaction described in step (2), n (thiazolidine-4-carboxylic acid): n (methanol) = 1:35~1:45 (molar ratio); n (thiazolidine-4-carboxylic acid): n (Ethyl ether)=1:47.5~1:97.5 (molar ratio); hydrogen chloride gas is passed to saturation.

In the oxidation reaction described in step (3), n(thiazolidine-4-methyl carboxylate):n(MnO ₂ )=1:20~1:26 (molar ratio), n(thiazolidine-4-formyl carboxylate ester): n (acetonitrile)=1:200~1:230 (molar ratio), the reaction time is 24~72h, and the reaction temperature is 60~80℃.

Wherein in the hydrolysis reaction described in step (4), n (methyl thiazole-4-carboxylate):n (sodium hydroxide)=1:2.0~1:2.9 (molar ratio).

the

The advantages of the present invention are mainly reflected in the following aspects:

1. This process uses cheap and easy-to-obtain L-cysteine hydrochloride as raw material, and the product is produced through condensation, esterification, oxidation and hydrolysis, which simplifies the operation procedure and reduces the operation cost.

2. The process uses _MnO2 as the oxidant, acetonitrile as the solvent, and the reaction conditions are mild. Compared with the existing synthetic routes, the present invention has the advantages of mild reaction conditions, simple operation, high conversion rate, good selectivity and simple and clean process.

Description of drawings:

Fig. 1 The 1H NMR collection of books of product thiazole-4-carboxylic acid of the present invention,

Fig. 2 is the mass spectrogram of product thiazole-4-carboxylic acid of the present invention.

Detailed ways:

The following examples will further illustrate the present invention, but do not thereby limit the present invention.

Example 1

step one:

Add 25.0 g ( 0.14 mol ) L-cysteine hydrochloride and 20 mL water into a 150 mL single-necked flask, stir at room temperature for 5 min, the solution becomes white and transparent, then add 16.1 mL ( 0.192 mol ) 37-40 % formaldehyde solution, continue to react for 8 h to stop the reaction. Add 13 mL ( 0.16 mol ) 99 % pyridine solution to the solution, stir, and a white solid precipitates out. After cooling and filtering, the filter cake was recrystallized from a solution with a volume ratio of water/ethanol = 1:1, and dried to obtain 16.1 g of thiazolidine-4-carboxylic acid in the form of white needles, with a yield of 85%. m.p.191~192℃ (literature value 191℃~192℃).

Step two:

In a dry round bottom flask, add 10.00 g (0.075 mol) thiazolidine-4-carboxylic acid and 120 mL (2.96 mol) methanol, and continuously feed dry HCl gas until saturation. React at room temperature for 12 hours to stop the reaction, add 200 mL (1.92mol) of ether, white flaky crystals precipitate, filter and dry to obtain thiazolidine-4-carboxylic acid methyl ester hydrochloride, after dehydrochlorination to obtain thiazolidine-4-carboxylic acid methyl ester Esters 9.84g, yield 89%.

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 80°C for 48h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 2.36 g of methyl thiazole-4-carboxylate with a yield of 80.8%.

Step four:

Add 2.0g (0.014mol) methyl thiazole-4-carboxylate and 12mL (0.03mol) 10% aqueous sodium hydroxide solution into a 100mL three-necked flask, heat to reflux for 1 h, cool, and add 6 mol/L of HCl solution, acidified to pH = 3, until the solid precipitated, suction filtered, washed with a small amount of water. After drying, 1.72 g of the product thiazole-4-carboxylic acid was obtained, with a yield of 95.6%. m.p.196~197℃ (literature value: 195~199℃).

Example 2

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02mol) methyl thiazolidine-4-carboxylate, 175mL acetonitrile, 35g (0.40mol) into a 250 mL four-neck flask. The reaction was stirred at 80°C for 48h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 2.07 g of methyl thiazole-4-carboxylate, with a yield of 70.8%.

Step 4 is the same as embodiment 1

Example 3

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 30 g (0.35 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 80°C for 48h. After cooling, it was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 1.88 g of methyl thiazole-4-carboxylate, with a yield of 64.3%.

Step 4 is the same as embodiment 1

Example 4

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 80°C for 24h. After cooling, it was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 1.14 g of methyl thiazole-4-carboxylate, with a yield of 39%.

Step 4 is the same as embodiment 1

Example 5

Step one, step two, with embodiment 1

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 80°C for 72h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 2.38 g of methyl thiazole-4-carboxylate, with a yield of 81.4%.

Step 4 is the same as embodiment 1

Example 6

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 70°C for 48h. After cooling, it was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 1.98 g of methyl thiazole-4-carboxylate, with a yield of 67.8%.

Step 4 is the same as embodiment 1

Example 7

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 175 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ into a 250 mL four-neck flask. The reaction was stirred at 60°C for 48h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 1.73 g of methyl thiazole-4-carboxylate with a yield of 59.2%.

Step 4 is the same as embodiment 1

Example 8

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 165 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ activated at 300°C for 500 min into a 250 mL four-neck flask. The reaction was stirred at 80°C for 60 h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 2.15 g of methyl thiazole-4-carboxylate with a yield of 73.6%.

Step 4 is the same as embodiment 1

Example 9

Step one, step two, with embodiment 1

Step three:

Add 3.0 g (0.02 mol) of methyl thiazolidine-4-carboxylate, 185 mL of acetonitrile, and 40 g (0.46 mol) of MnO ₂ activated at 300°C for 500 min into a 250 mL four-neck flask. The reaction was stirred at 80°C for 72h. After cooling and filtering, the filtrate was distilled off under reduced pressure to remove the solvent to obtain 2.35 g of methyl thiazole-4-carboxylate with a yield of 80.4%.

Step 4 is the same as embodiment 1

Example 10

step one:

Add 25.0 g ( 0.14 mol ) L-cysteine hydrochloride and 15 mL water into a 150 mL single-necked flask, stir at room temperature for 5 min, the solution turns white and transparent, then add 16.1 mL ( 0.192 mol ) 37-40 % formaldehyde solution, continue to react for 8 h to stop the reaction. Add 13 mL ( 0.16 mol ) 99 % pyridine solution to the solution, stir, and a white solid precipitates out. After cooling and filtering, the filter cake was recrystallized with a solution of water/ethanol = 1:1 by volume, and dried to obtain 14.7 g of white needle-like crystals of thiazolidine-4-carboxylic acid, with a yield of 78%. m.p.191~192℃ (literature value 191℃~192℃).

Step 2, step 3, step 4 are the same as embodiment 1

Example 11

step one:

Add 25.0 g ( 0.14 mol ) L-cysteine hydrochloride and 20 mL water into a 150 mL single-necked flask, stir at room temperature for 5 min, the solution becomes white and transparent, then add 14 mL ( 0.168 mol ) 37-40 % formaldehyde solution, continue to react for 8 h to stop the reaction. Add 13 mL ( 0.16 mol ) 99 % pyridine solution to the solution, stir, and a white solid precipitates out. After cooling and filtering, the filter cake was recrystallized with a solution of water/ethanol = 1:1 by volume, and dried to obtain 12.2 g of white needle-like crystals of thiazolidine-4-carboxylic acid, with a yield of 64.7%. m.p.191~192℃ (literature value 191℃~192℃).

Step 2, step 3, step 4 are the same as embodiment 1

Example 12

step one:

Add 25.0 g ( 0.14 mol ) L-cysteine hydrochloride and 20 mL water into a 150 mL single-necked flask, stir at room temperature for 5 min, the solution becomes white and transparent, then add 16.1 mL ( 0.192 mol ) 37-40 % formaldehyde solution, continue to react for 8 h to stop the reaction. Add 13 mL ( 0.16 mol ) 99 % pyridine solution to the solution, stir, and a white solid precipitates out. After cooling and filtering, the filter cake was recrystallized from a solution with a volume ratio of water/ethanol = 1:1.2, and dried to obtain 11.5 g of white needle-like crystals of thiazolidine-4-carboxylic acid, with a yield of 60.7%. m.p.191~192℃ (literature value 191℃~192℃).

Step 2, step 3, step 4 are the same as embodiment 1

Example 13

Steps are the same as Example 1

Step two:

In a dry round-bottomed flask, add 10.00 g (0.075 mol) thiazolidine-4-carboxylic acid and 120 mL methanol, and continuously feed dry HCl gas until saturation. React at room temperature for 12 hours to stop the reaction, add 100 mL (0.96mol) of ether, white flaky crystals precipitate, filter and dry to obtain thiazolidine-4-carboxylic acid methyl ester hydrochloride, after dehydrochlorination to obtain thiazolidine-4-carboxylic acid methyl ester Esters 4.92g, yield 44.5%.

Step 3 and step 4 are the same as in Example 1

Example 14

Steps are the same as Example 1

Step two:

In a dry round bottom flask, add 10.00 g (0.075 mol) thiazolidine-4-carboxylic acid, 136.5 mL (3.37 mol) methanol, and continuously feed dry HCl gas. React at room temperature for 12 hours to stop the reaction, add 200 mL (1.92mol) of ether, white flaky crystals precipitate, filter and dry to obtain thiazolidine-4-carboxylic acid methyl ester hydrochloride, after dehydrochlorination to obtain thiazolidine-4-carboxylic acid methyl ester Esters 9.85g, yield 89%.

Step three, step four are the same as embodiment 1

Example 15

Step one, step two, step three are the same as embodiment 1

Step four:

Add 2.0g (0.014mol) methyl thiazole-4-carboxylate and 16mL (0.04mol) 10% sodium hydroxide aqueous solution into a 100mL three-necked flask, heat and reflux for 1 h, cool, and add 6 mol/L of HCl solution, acidified to pH = 3, until the solid precipitated, suction filtered, washed with a small amount of water. After drying, 1.61 g of the product thiazole-4-carboxylic acid was obtained, with a yield of 89.4%. m.p.196~197℃ (literature value: 195~199℃).

the

Structural characterization of thiazole-4-carboxylic acid: (see Figures 1 and 2 of the specification)

MS m/z:129[M] ⁺ ,112[M-OH] ⁺ ,85[M-COOH] ⁺

¹ H NMR (C ₃ H ₆ O): δ: 8.468 (s, 1H, N=CH), 9.086 (s, 1H, C=CH).

Claims (5)

1. method for preparing thiazole-4-formic acid is characterized in that carrying out according to following step:

(1) condensation reaction: with the L-cysteine hydrochloride is raw material, adopts the technology of treating different things alike, after wherein adding water, stirring; The adding mass concentration is 37 ~ 40% formaldehyde solution, and stirring at room is reacted 8 h, regulates pH to neutral to wherein adding pyridine again; Filter, drying obtains bullion; Water-ethanolic soln recrystallization obtains thiazolidine-4-formic acid again;

(2) esterification: with thiazolidine-4-formic acid is raw material, after wherein adding methyl alcohol, stirring, begins to feed the exsiccant hydrogen chloride gas; To saturated; Stirring at room is reacted 12 h, and to wherein adding ether, the adularescent tabular crystal is separated out; Dry thiazolidine-4-methyl-formiate the hydrochloride that gets of suction filtration obtains thiazolidine-4-methyl-formiate behind the desalination hydrochlorate;

(3) oxidizing reaction: with thiazolidine-4-methyl-formiate is raw material, after wherein adding acetonitrile, stirring, slowly adds MnO ₂, 60 ~ 100 ℃ of stirring reaction 24-72h, cooled and filtered, the filtrate decompression distillation removes desolvates, and obtains thiazole-4-methyl-formiate;

(4) hydrolysis reaction: with thiazole-4-methyl-formiate is raw material, to the aqueous sodium hydroxide solution that wherein adds mass concentration 10%, is heated to backflow 1h; Adding HCl solution in the ice bath is put in cooling, is acidified to pH=3; Solid to be separated out, suction filtration washs with less water, obtains thiazole-4-formic acid after the oven dry.

2. a kind of method for preparing thiazole-4-formic acid according to claim 1; It is characterized in that wherein described in the step (1) molar ratio computing L-cysteine hydrochloride in the condensation reaction: formaldehyde=1:1.05 ~ 1:1.4; Use water as solvent in the reaction process; N molar ratio computing L-cysteine hydrochloride: water=1:5 ~ 1:8, the volume ratio of water-ethanol solution is 1:1 ~ 1:1.5.

3. a kind of method for preparing thiazole-4-formic acid according to claim 1 is characterized in that wherein described in the step (2) molar ratio computing thiazolidine-4-formic acid in the esterification: n methyl alcohol=1:35 ~ 1:45; Molar ratio computing thiazolidine-4-formic acid: ether=1:47.5 ~ 1:97.5; Hydrogen chloride gas feeds to state of saturation.

4. a kind of method for preparing thiazole-4-formic acid according to claim 1 is characterized in that wherein described in the step (3) molar ratio computing thiazolidine-4-methyl-formiate: MnO in the oxidizing reaction ₂=1:20 ~ 1:26, molar ratio computing thiazolidine-4-methyl-formiate: acetonitrile=1:200 ~ 1:230, the reaction times is 24 ~ 72h, temperature of reaction is 60 ~ 80 ℃.

5. a kind of method for preparing thiazole-4-formic acid according to claim 1 is characterized in that wherein described in the step (4) molar ratio computing thiazole-4-methyl-formiate: sodium hydroxide=1:2.0 ~ 1:2.9 in the hydrolysis reaction.

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