Preparation method of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester

Abstract

The invention discloses a preparation method of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, and belongs to the field of synthesis of medical intermediates. 5-methyl-4-oxotetrahydrothiophene-3-methyl formate is used as a raw material, an aminating agent and a dehydrogenating agent are used for directly obtaining a 4-amino-5-methylthiophene-3-carboxylic acid methyl ester hydrochloride aqueous solution through a one-pot method under specific reaction conditions, alkali is added to dissociate the product, and solvent extraction and concentration are performed to obtain the 4-amino-5-methylthiophene-3-carboxylic acid methyl ester. The preparation method of the high-purity 4-amino-5-methylthiophene-3-carboxylic acid methyl ester is simple to operate and easy for industrial production, and a high-quality raw material can be provided for synthesis of downstream thiencarbazone-methyl.

Description

Technical Field

[0001] The invention relates to a preparation method of a thiathionsulfuron intermediate 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, and belongs to the technical field of pharmaceutical intermediate synthesis. Technical Background

[0002] 4-Amino-5-methylthiophene-3-carboxylic acid methyl ester, CAS: 81528-48-5, molecular weight: 171.21, appearance is yellow-green powder, melting point is 77-78°C, easily soluble in methanol and dichloromethane, slightly soluble in water, used as an important intermediate for the preparation of thiophenecarboxylic acid sulfone and other thienylaminocarbonyl triazolinone pesticide active ingredients, the chemical structure is as follows:

[0003]

[0004] The intermediate can be subjected to the steps of diazotization, chlorosulfonylation, amination, isocyanate formation, addition and the like to obtain thiazolinonesulfuron.

[0005] At present, it is known that the preparation method of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester is reported, using methyl mercaptopropionate and methyl chloropropionate as raw materials, performing thioetherification and Dieckmann condensation to obtain the ring-closing intermediate 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester (CN 101180289A), and then performing aromatization to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, and finally performing acid-base neutralization to release free amine to obtain the product. Among them, the aromatization step has the following method:

[0006] A. Semmler-Wolff reaction using hydroxylamine hydrochloride (US20050130843A1):

[0007]

[0008] This method uses 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester and hydroxylamine hydrochloride to reflux in acetonitrile for direct oximation and aromatization to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester hydrochloride. After acid-base replacement in this step, the patent records a yield of only 53%, and experiments have found that decarboxylation impurities are difficult to remove.

[0009] B. Chlorination agent chlorine oxidation (CN 101180289A):

[0010]

[0011] This method uses 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester and ammonium formate to reflux in methanol for amination, and then uses a chlorinating agent such as sulfonyl chloride to carry out chlorination oxidation dehydrogenation aromatization at -10°C-0°C to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester hydrochloride. The highest content recorded in the patent is only 62.5%, and the tar produced in the reaction is difficult to remove, which affects the subsequent synthesis of thiophenesulfonyl.

[0012] C. Hydrogen peroxide oxidation aromatization (US 5166346A):

[0013]

[0014] This method uses 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester and ammonium formate to reflux in methanol for amination, and then uses hydrogen peroxide to oxidize the aromatic structure under acidic conditions to directly obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, but the reaction yield is low and the degree of oxidation is difficult to control. Summary of the invention

[0015] In order to overcome the above technical defects, the technical problem to be solved by the present invention is to provide an improved preparation method of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, an intermediate of thiazolinonesulfuron, which is simple to operate, high in purity and high in yield. 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester is used as a raw material, and the preparation method of the raw material is prepared by referring to CN 101180289A and other related patents; it is found through experiments that the raw material can be aromaticized and aminated at the same time under specific reaction conditions using a suitable aminating agent and a dehydrogenating agent, and a one-pot method can directly obtain a 4-amino-5-methylthiophene-3-carboxylic acid methyl ester hydrochloride aqueous solution, and then acid-base replacement, solvent extraction and concentration can obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, and the chemical reaction equation is expressed as follows:

[0016]

[0017] Among them, after the addition of a suitable dehydrogenating agent, the following intermediate structure was captured in the reaction solution (mass spectrum see Figure 3 ) and the dehydrogenating agent to form the product (mass spectrum see Figure 4-Figure 6 ):

[0018]

[0019] The intermediate that completes the dehydrogenation aromatization is simultaneously converted to 4-amino-5-methylthiophene-3-carboxylic acid methyl ester hydrochloride in a suitable aminating agent, and the reaction is finally completed.

[0020] To achieve the above technical solution, the preparation method of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester comprises the following operations:

[0021] Mix 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester and a reaction solvent, add an aminating agent and a dehydrogenating agent to react, and complete aromatization and amination; quench the reaction solution, separate the liquids, wash the oil phase with acid, combine the water phases, add alkali to the water phase for freeing, and extract and concentrate with a solvent to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester.

[0022] Furthermore, in the above technical solution, the reaction solvent is selected from at least one of toluene, ethylbenzene, xylene and chlorobenzene, preferably toluene, xylene and chlorobenzene.

[0023] Furthermore, in the above technical solution, the aminating agent is selected from ammonium carbonate, ammonium bicarbonate or ammonia water.

[0024] Furthermore, in the above technical solution, the molar ratio of 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to the aminating agent (based on effective NH3) is 1:0.8-2, preferably 1:1.2-1.6.

[0025] Furthermore, in the above technical solution, the dehydrogenating agent is selected from p-toluenesulfonyl chloride or methanesulfonyl chloride.

[0026] Furthermore, in the above technical solution, the molar ratio of 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to the dehydrogenating agent is 1:0.9-1.2; preferably 1:1.02-1.15.

[0027] Furthermore, in the above technical solution, the reaction temperature is -10°C to 45°C, preferably 0-35°C; the reaction time is 2-18h, preferably 4-12h.

[0028] Furthermore, in the above technical solution, after separation, the oil phase is washed with 10% dilute hydrochloric acid and then combined with the water phase.

[0029] Furthermore, in the above technical solution, the aqueous phase is neutralized with sodium carbonate, the pH is adjusted to 8-9, and the mixture is extracted and concentrated with dichloromethane to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester.

[0030] Beneficial effects of the present invention

[0031] 1. A new preparation method is provided, the raw materials are easily available, the operation is simple, and the previous methods using hydroxylamine hydrochloride, hydrogen peroxide, chlorine and other dangerous materials or harsh reaction conditions are improved. The reaction temperature is relatively mild and easy to industrialize.

[0032] 2. The final product content is stably higher than 99%, and no impurities that are difficult to separate are found, which can provide high-quality raw materials for the downstream synthesis of thiocarbamide.

[0033] 3. There are no side reactions such as decarboxylation, peroxidation, coupling, etc. in the previous process, and the product yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the HPLC spectrum of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester in Example 1;

[0035] Figure 2 is the MS spectrum of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester in Example 1;

[0036] Figure 3 is the MS spectrum of the reaction intermediate;

[0037] Figure 4 This is the MS spectrum of the product generated after the dehydrogenating agent reacts in Example 1;

[0038] Figure 5 This is the MS spectrum of the product generated after the dehydrogenating agent reacts in Example 2;

[0039] Figure 6 This is the MS spectrum of the product generated after the dehydrogenating agent reacts in Example 3; DETAILED DESCRIPTION

[0040] Example 1

[0041] Add 89.8 g (97% content, 0.5 mol) of 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to a four-necked flask, add 200 mL of toluene, place in an ice-water bath, stir and cool to 0-5°C, add 28.5 g of ammonium carbonate (40% NH3 content, 0.67 mol) in 5 batches, and at the same time, add 350 g (30% content, 0.55 mol) of p-toluenesulfonyl chloride-toluene mixed solution dropwise, control the dropping speed according to the degree of heat release, so that the reaction temperature is always maintained at 0-5°C, and the dropping is completed. Keep warm for 4 hours, and the reaction is completed (the MS spectrum of the product after the dehydrogenation agent reaction is attached Figure 4 ), return to room temperature, add 200 mL of water, stir thoroughly, and separate the liquids.

[0042] The oil phase was washed with 100 mL of 10% dilute hydrochloric acid, the aqueous phases were combined, 100 mL of dichloromethane was added, the mixture was placed in an ice-water bath and stirred, sodium carbonate was added in batches to neutralize the aqueous phase to pH 8-9, the liquids were separated, the oil phase was washed with 50 mL of saturated brine, the liquids were separated, and the mixture was concentrated to obtain 82.6 g of methyl 4-amino-5-methylthiophene-3-carboxylate, with a yield of 96% and an HPLC content of 99.5% (HPLC and MS spectra are attached). Figure 1 and 2 ).

[0043] Example 2

[0044] Add 89.8 g (97% content, 0.5 mol) of 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to a four-necked flask, add 400 mL of mixed xylene, place in a cold water bath and stir to cool to 10-15°C, add 63.9 g (99% content, 0.8 mol) of ammonium bicarbonate in 3 batches, and at the same time, dropwise add 62 g (98% content, 0.53 mol) of methanesulfonyl chloride, control the dropping speed according to the degree of heat release, keep the reaction temperature at 10-15°C, finish the dropping, keep warm for 6 hours, and end the reaction (see the attached MS spectrum of the product after the dehydrogenation agent reaction). Figure 5 ), return to room temperature, add 150 mL of water, stir thoroughly, and separate the liquids.

[0045] The oil phase was washed with 80 mL of 10% dilute hydrochloric acid, the aqueous phases were combined, 100 mL of dichloromethane was added, the mixture was placed in an ice-water bath and stirred, sodium carbonate was added in batches to neutralize the aqueous phase to pH 8-9, the liquids were separated, the oil phase was washed with 50 mL of saturated brine, the liquids were separated, and the mixture was concentrated to obtain 80.7 g of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, with a yield of 94% and an HPLC content of 99.7%.

[0046] Example 3

[0047] Add 179.6 g (97% content, 1 mol) of 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to a four-necked flask, add 350 mL of chlorobenzene, place in a water bath and stir at 30-35°C, and at the same time, dropwise add 91.1 g (28% content, 1.5 mol) of ammonia water and 777.8 g (25% content, 1.02 mol) of a mixed solution of p-toluenesulfonyl chloride and chlorobenzene. Control the dropping speed according to the degree of heat release to keep the reaction temperature at 30-35°C. After the dropping is completed, keep warm for 12 hours and the reaction is completed (see the attached MS spectrum of the product after the dehydrogenation agent reaction). Figure 6 ), add 400 mL of water, stir thoroughly, and separate the liquids.

[0048] The oil phase was washed with 150 mL of 10% dilute hydrochloric acid, the aqueous phases were combined, 250 mL of dichloromethane was added, the mixture was placed in an ice-water bath and stirred, sodium carbonate was added in batches to neutralize the aqueous phase to pH 8-9, the liquids were separated, the oil phase was washed with 100 mL of saturated brine, the liquids were separated, and the mixture was concentrated to obtain 153.6 g of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, with a yield of 89% and an HPLC content of 99.2%.

[0049] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, characterized in that: The method comprises the following steps: mixing 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester and a reaction solvent, adding an aminating agent and a dehydrogenating agent to react, and completing aromatization and amination; quenching the reaction solution, separating the liquids, washing the oil phase with acid, combining the water phases, adding alkali to the water phases to free them, and extracting and concentrating with solvents to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester.

2. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The reaction solvent is selected from at least one of toluene, ethylbenzene, xylene and chlorobenzene.

3. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The aminating agent is selected from ammonium carbonate, ammonium bicarbonate or ammonia water.

4. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The molar ratio of the 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to the aminating agent is 1:0.8-2.

5. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The dehydrogenating agent is selected from p-toluenesulfonyl chloride or methanesulfonyl chloride.

6. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The molar ratio of the 5-methyl-4-oxotetrahydrothiophene-3-carboxylic acid methyl ester to the dehydrogenating agent is 1:0.9-1.

2.

7. The method for preparing methyl 4-amino-5-methylthiophene-3-carboxylate according to any one of claims 1 to 6, characterized in that: The reaction temperature is -10°C to 45°C; the reaction time is 2-18h.

8. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: After separation, the oil phase was washed with 10% dilute hydrochloric acid and combined with the aqueous phase.

9. The method for preparing 4-amino-5-methylthiophene-3-carboxylic acid methyl ester according to claim 1, characterized in that: The aqueous phase was neutralized with sodium carbonate to adjust the pH to 8-9, and extracted and concentrated with dichloromethane to obtain 4-amino-5-methylthiophene-3-carboxylic acid methyl ester.

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