A preparation method of 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide

Abstract

The invention discloses a method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, comprising the following steps: 1. preparing a sodium disulfide solution for standby; 2. reacting 4-amino-5-methylthiophene-3-methyl formate with sodium nitrite to obtain a diazo solution for standby; 3. reacting sodium disulfide with the diazo solution prepared in step 2 to obtain 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene]; 4. reacting 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] with sulfonyl chloride; 5. adding water to separate layers, and treating the organic layer with ammonia to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide. The invention provides a new preparation route for 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, wherein sulfur dioxide or chlorine is not used in the preparation process, thereby improving operational safety, reducing environmental pressure, reducing production costs, and being suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a thiocarbazonesulfuron intermediate 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide. Background Art

[0002] Thiazonsulfuron-methyl belongs to the sulfonamide carbonyl triazolinone herbicide, and is an ALS (acetolactate synthase) inhibitor developed by Bayer. It has soil activity and stem and leaf herbicidal activity. After application, the active ingredients are absorbed into the plant body through the roots and stems and leaves of sensitive plants, preventing the biosynthesis of branched-chain amino acids, and eventually causing the sensitive plants to die. Thiazonsulfuron-methyl can effectively control grass weeds and broad-leaved weeds in corn fields, and can be used both before and after budding.

[0003] 4-Methoxycarbonyl-2-methylthiophene-3-sulfonamide is an important intermediate of thiocarbazonesulfuron, with the structural formula as follows:

[0004] .

[0005] 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide can be prepared by the following route to obtain thiophenesulfonamide:

[0006]

[0007] 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide is usually obtained by ammoniation of 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride. Regarding the preparation method of 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride, U.S. Patent Document US6964939A1 uses 2-methyl-3-amino-4-methoxycarbonylthiophene as a raw material, diazotizes it with sodium nitrite at a low temperature of (0 to 5) ° C, adds it dropwise to a dichloromethane solution dissolved with sulfur dioxide at (0 to 5) ° C, reacts at 20 ° C for 12 hours to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride with a yield of 81%. Sulfur dioxide gas is used in the reaction.

[0008] "Aromatization of Dihydrothiophenes. Thiophenesaccharin: A Sweet Surprise" (J. Org. Chem., 1980, 45 (4), 617-620) discloses a method for synthesizing analogs, and the reaction process is as follows:

[0009] .

[0010] The method uses 4-methoxycarbonyl-3-oxotetrahydrothiophene as a raw material, and synthesizes 4-methoxycarbonyl-3-sulfonylchlorothiophene through four-step reactions, with a total yield of 58.52%. In the method, chlorine gas is used to oxidize disulfide.

[0011] Chinese patent document CN 111732568 A (application number 202010579821.0) discloses a method for synthesizing 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride, which comprises the following steps:

[0012] S1, reacting methyl 5-methyl-4-oxotetrahydrothiophene-3-carboxylate of formula (I) and methanesulfonyl chloride in the presence of a catalyst to obtain an intermediate of formula (II);

[0013] S2, mixing the intermediate of formula (II), anhydrous sodium sulfide and a polar aprotic solvent for reaction, introducing oxygen for aromatization reaction, and obtaining a reaction solution of the intermediate of formula (III);

[0014] S3, subjecting the intermediate reaction liquid of formula (III) to chlorine oxidation and conventional post-treatment in sequence to obtain the target compound of formula (IV) 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride;

[0015] .

[0016] The above method also uses chlorine gas for oxidation. Summary of the invention

[0017] The technical problem to be solved by the present invention is to provide a method for preparing the thiocarbazonesulfuron intermediate 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide which avoids the use of sulfur dioxide or chlorine and has high reaction safety.

[0018] The technical solution to achieve the purpose of the present invention is a method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, comprising the following steps:

[0019] ① Prepare sodium disulfide solution for use.

[0020] ②4-Amino-5-methylthiophene-3-carboxylic acid methyl ester reacts with sodium nitrite to obtain diazo solution for use.

[0021] ③ The sodium disulfide solution prepared in step ① is reacted with the diazo solution prepared in step ② to obtain 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

[0022] ④ The 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③ is reacted with sulfonyl chloride.

[0023] ⑤ Add water to the reaction material obtained in step ④ to separate the layers, and treat the organic layer with ammonia to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide.

[0024] In the above step ②, add 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, hydrochloric acid and water to the reaction bottle, stir, cool to -5°C, add sodium nitrite aqueous solution dropwise, keep the temperature in the reaction bottle at -5°C to 0°C during the addition process, after the addition is completed, react at -5°C to 0°C for 20min to 60min to obtain diazo solution for standby use.

[0025] Preferably, in the above step ②, the molar ratio of methyl 4-amino-5-methylthiophene-3-carboxylate to sodium nitrite is 1:1.0-3.0.

[0026] In the above step ③, the sodium disulfide solution prepared in step ① is transferred to a reaction bottle, cooled to below 5°C, and the diazo solution prepared in step ② is added dropwise. During the addition process, the temperature in the reaction bottle is kept not exceeding 5°C. After the addition is completed, the reaction solution is slowly warmed to room temperature and reacted at room temperature for 1.5h to 4h. After the reaction is completed, the solution is filtered and the filter cake is washed with water to obtain 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

[0027] Preferably, in the above step ③, the molar ratio of the diazo compound prepared in step ② to sodium disulfide is 1:0.5-2.0.

[0028] In the above step ④, 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③, potassium nitrate and a catalyst are added to an organic solvent, and after cooling to 10° C., sulfonyl chloride is added dropwise, and after the addition is completed, the mixture is reacted at 15-20° C. for 4-6 hours.

[0029] Preferably, in the above step ④, the molar ratio of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] to potassium nitrate is 1:1.5-3.

[0030] Preferably, in the above step ④, the catalyst is a phase transfer catalyst, and the amount of the catalyst used is 0.3% to 1% of the mass of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

[0031] In the above step ④, the phase transfer catalyst is tetrabutylammonium bromide, benzyltriethylammonium chloride or 18-crown-6.

[0032] In the above step ④, the organic solvent is dichloromethane, dichloroethane, chloroform or acetonitrile.

[0033] In the above step ④, the molar ratio of sulfonyl chloride to 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] is 1.0-3.0:1.

[0034] In the above step ⑤, water or saturated brine is added to the reaction material obtained in step ④ to separate the layers, the organic layer is washed with water or saturated brine and then transferred to a reaction flask, ammonia is introduced into the reaction flask, the temperature in the reaction flask is controlled at 15 to 20° C., and aeration is stopped when the pH value of the reaction solution is stabilized at 8 to 9. After reacting at 15 to 20° C. for 0.5 h to 1 h, suction filtration is performed, and the filter cake is washed and dried to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide.

[0035] The present invention has positive effects: the present invention provides a new preparation route of 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, and the preparation process does not use sulfur dioxide or chlorine, thereby improving operation safety, reducing environmental pressure, reducing production costs, and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The synthetic route of the present invention is shown in FIG.

[0037] Figure 2 This is the mass spectrum of the compound prepared in Example 1.

[0038] Figure 3 HPLC spectrum of the compound prepared in Example 1. DETAILED DESCRIPTION

[0039] (Example 1)

[0040] The preparation method of 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide of the present embodiment comprises the following steps:

[0041] ① Prepare sodium disulfide solution for use. In this embodiment, the sodium sulfide method is used for preparation.

[0042] Specifically, 65 g (0.27 mol) of aqueous sodium sulfide, 9 g (0.28 mol) of sulfur and 80 mL of water were added to a 500 mL four-necked reaction bottle, and 36 g (0.27 mol) of 30% sodium hydroxide solution was added after stirring for 10 minutes. The temperature was raised to 85° C., and the mixture was reacted at this temperature for 2 hours, cooled to room temperature, filtered, and the filtrate was a sodium disulfide solution for standby use.

[0043] ② Add 34 g (0.2 mol) of 4-amino-5-methylthiophene-3-carboxylic acid methyl ester, 73 g of 30% hydrochloric acid, and 75 mL of water to a 500 mL four-necked reaction bottle, stir for 0.5 h, then cool to -5 ° C, and start to drop 80 g (0.26 mol) of 22% sodium nitrite aqueous solution. Keep the temperature in the reaction bottle at -5 ° C ~ 0 ° C during the dropwise addition process. After the dropwise addition is completed, react at -5 ° C ~ 0 ° C for 20 min ~ 60 min (30 min in this embodiment) to obtain a diazo solution for standby use.

[0044] ③ The sodium disulfide solution prepared in step ① was transferred to a 1000 mL reaction bottle, cooled to below 5°C, and the diazo solution prepared in step ② was added dropwise. The temperature in the reaction bottle was kept at no more than 5°C during the addition process. After the addition was completed, the reaction solution was slowly raised to room temperature (10°C to 35°C), and reacted at room temperature for 1.5h to 4h (2h in this embodiment). After the reaction was completed, the mixture was filtered and the filter cake was washed with water to obtain 32.4g of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

[0045] ④ Add 32.4g (0.086mol) of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③, 300g of dichloroethane, 22.2g (0.22mol) of potassium nitrate and 0.2g of tetrabutylammonium bromide into the reaction flask, stir, cool to 10°C and start to drop 29.7g (0.22mol) of sulfonyl chloride. Keep the temperature in the reaction flask at 15-20°C during the dropwise addition process. After the dropwise addition is completed, react at 15-20°C for 5h.

[0046] In addition to the above-mentioned dichloroethane, the organic solvent may also be dichloromethane, chloroform or acetonitrile.

[0047] The phase transfer catalyst may be, in addition to the tetrabutylammonium bromide used above, benzyltriethylammonium chloride or 18-crown-6.

[0048] ⑤ Add 300g of water to the reaction mass obtained in step ④, separate the layers, wash the organic layer with 100g of water and move it into a reaction flask, introduce ammonia into the reaction flask, control the temperature in the reaction flask at 15-20°C, stop aeration when the pH value of the reaction solution is stable at 8-9, react at 15-20°C for 0.5h and then filter, wash the filter cake with dichloroethane and water until neutral, and dry to obtain 39.2g of 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, with a content of 97.2% and a yield of 81% (based on 4-amino-5-methylthiophene-3-carboxylic acid methyl ester).

[0049] The mass spectrum of the compound prepared in this example is shown in Figure 2 , the measured molecular weight is consistent with the theoretical molecular weight.

[0050] (Example 2 to Example 6)

[0051] The amounts of the reaction materials, reaction parameters, yields and purities used in Examples 2 to 6 are shown in the following table (the reaction materials and conditions not mentioned are the same as those in Example 1):

[0052] .

[0053] In addition, in Example 4, in step ⑤, 300 g of saturated brine was added to separate the layers, and the organic layer was washed with 100 g of saturated brine.

Claims

1. A method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide, characterized in that The following steps are involved: ① Prepare sodium disulfide solution for use; ②4-amino-5-methylthiophene-3-carboxylic acid methyl ester reacts with sodium nitrite to obtain a diazo solution for use; ③ reacting the sodium disulfide solution prepared in step ① with the diazo solution prepared in step ② to obtain 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene]; ④ reacting the 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③ with sulfonyl chloride; adding the 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③, potassium nitrate and a catalyst to an organic solvent, adding sulfonyl chloride dropwise and reacting at 15 to 20° C. for 4 to 6 hours; the organic solvent is dichloromethane, dichloroethane, chloroform or acetonitrile; the catalyst is tetrabutylammonium bromide; ⑤ Add water to the reaction material obtained in step ④ to separate the layers, and treat the organic layer with ammonia to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide.

2. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 1, characterized in that: In step ②, methyl 4-amino-5-methylthiophene-3-carboxylate, hydrochloric acid and water are added to the reaction bottle, stirred, cooled to -5°C, and sodium nitrite aqueous solution is added dropwise. The temperature in the reaction bottle is kept at -5°C to 0°C during the addition process. After the addition is completed, the reaction is carried out at -5°C to 0°C for 20min to 60min to obtain a diazo solution for standby use.

3. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 2, characterized in that: In step ②, the molar ratio of methyl 4-amino-5-methylthiophene-3-carboxylate to sodium nitrite is 1:1.0-3.

0.

4. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 1, characterized in that: In step ③, the sodium disulfide solution prepared in step ① is transferred to a reaction bottle, cooled to below 5°C, and the diazo solution prepared in step ② is added dropwise. During the addition process, the temperature in the reaction bottle is kept not exceeding 5°C. After the addition is completed, the reaction solution is slowly warmed to room temperature and reacted at room temperature for 1.5h to 4h. After the reaction is completed, the solution is filtered and the filter cake is washed with water to obtain 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

5. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 4, characterized in that: In step ③, the molar ratio of the diazo compound prepared in step ② to sodium disulfide is 1:0.5-2.

0.

6. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 1, characterized in that: In step ④, 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] prepared in step ③, potassium nitrate and a catalyst are added to an organic solvent, and the temperature is lowered to 10° C., and then sulfonyl chloride is added dropwise.

7. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 6, characterized in that: In step ④, the molar ratio of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] to potassium nitrate is 1:1.5-3.

8. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 6, characterized in that: In step ④, the catalyst is a phase transfer catalyst, and the amount of the catalyst used is 0.3% to 1% of the mass of 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene].

9. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 1, characterized in that: In step ④, the molar ratio of sulfonyl chloride to 3,3'-disulfide-bis[4-methoxycarbonyl-2-methylthiophene] is 1.0 to 3.0:

1.

10. The method for preparing 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide according to claim 1, characterized in that: In step ⑤, water or saturated brine is added to the reaction material obtained in step ④ to separate the layers, the organic layer is washed with water or saturated brine and then transferred to a reaction flask, ammonia is introduced into the reaction flask, the temperature in the reaction flask is controlled at 15 to 20° C., and aeration is stopped when the pH value of the reaction solution is stabilized at 8 to 9. After reacting at 15 to 20° C. for 0.5 h to 1 h, suction filtration is performed, and the filter cake is washed and dried to obtain 4-methoxycarbonyl-2-methylthiophene-3-sulfonamide.

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