Novel derivative of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid, its preparation method and application

[0084] Example 1 Preparation of F1-1

[0085] 1.1 Preparation of p-[(dipropylamino)sulfonyl]benzoyl chloride

[0086]

[0087] 2.85g of p-[(dipropylamino)sulfonyl]benzoic acid was added to 25ml of toluene, then 1ml of thionyl chloride was added, and then refluxed at 50°C for 2 hours and concentrated to dryness under reduced pressure to obtain 3.12g The pale yellow solid was directly used in the next reaction.

[0088] 1.2 Preparation of ethylene glycol monoester of p-[(dipropylamino)sulfonyl]benzoate

[0089]

[0090] Add 3.12g of p-[(dipropylamino)sulfonyl]benzoyl chloride and 10g of ethylene glycol to 50ml of tetrahydrofuran, stir at room temperature for 10 minutes, add 2ml of triethylamine under stirring, and then react at 50°C. After hours, the reaction was stopped and concentrated under reduced pressure to dryness. After the product was dissolved in 50ml ethyl acetate, it was washed with saturated saline and water successively for 3×10ml, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to constant weight to obtain a white color. The powdered solid was 2.84 g, and the yield was 87.4%.

[0091] 1 H-NMR (400MHz, d 6 DMSO): δ 8.28-8.30 (d, 2H), 8.03-8.05 (d, 2H), 4.41-4.44 (t, 2H), 4.01-4.04 (t, 2H), 3.19-3.20 (t, 4H), 1.43-1.44 (m, 4H), 0.94-0.96 (t, 6H).

[0092] 1.3 Preparation of 2-[3-chloro-4-isobutoxyphenyl]-4-methylthiazole-5-carbonyl chloride

[0093]

[0094] Add 3.16g of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid to 25ml of dichloromethane, then add 1ml of thionyl chloride, and then After refluxing at 50°C for 2 hours, it was concentrated to dryness under reduced pressure to obtain 3.39 g of light yellow solid, which was directly used in the next reaction.

[0095] 1.4 Preparation of F1-1

[0096]

[0097] Add the p-[(dipropylamino)sulfonyl]benzylglycol monoester from step 1.2 above and the acid chloride from step 1.3 into 50ml of tetrahydrofuran, stir at room temperature for 10 minutes, then add 2ml of triethylamine under stirring, then After reacting at 50°C for 2 hours, the reaction was stopped and concentrated under reduced pressure to dryness. After dissolving the product with 50ml ethyl acetate, it was washed with saturated brine and water for 3×10ml each, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to Constant weight, 2.84 g of white powdery solid and 4.16 g of column chromatography were obtained, and the yield was 71.3%.

[0098] 1 H-NMR (400MHz, d 6 DMSO): 8.17-δ8.19 (m, 3H), 8.06-8.09 (dd, 1H), 7.88-7.90 (d, 2H), 7.01-7.03 (d, 1H), 4.65-4.69 (m, 4H), 3.89-3.91(d, 2H), 3.08-3.12(t, 4H), 2.77(s, 3H), 2.19-2.22(m, 1H), 1.52-1.64(m, 4H), 1.08-1.10(d, 6H) ), 0.85-0.88 (m, 6H).

[0099] ESI-MS: m/z 628, 629, 630 (M+1).

[0100] Example 2 Preparation of compound F2-1

[0101] 2.1 Preparation of intermediate p-[(dipropylamino)sulfonyl]benzoic acid N-methyl-N-hydroxyethyl ethyl ester

[0102]

[0103] Add 3.13g of p-[(dipropylamino)sulfonyl]benzoyl chloride and 35g of diethanolamine prepared according to the method described in step 1.1 in Example 1 into 50ml of tetrahydrofuran, stir at room temperature for 10 minutes and then under stirring Add 2ml of triethylamine, then react at 50℃ for 2 hours, then stop the reaction, concentrate to dryness under reduced pressure, the product is dissolved in 50ml ethyl acetate, washed with saturated brine 7×10ml, then dried with anhydrous sodium sulfate and reduced After pressing and concentrating to constant weight, 2.65 g of white powdery solid was obtained, and the yield was 76.3%.

[0104] 1 H-NMR (400MHz, d 6 DMSO): δ 8.24-8.26 (d, 2H), 8.08-8.10 (d, 2H), 4.37-4.40 (t, 2H), 3.61-3.64 (t, 2H), 3.15-3.19 (t, 2H), 2.82-2.85 (t, 2H), 2.52-2.55 (t, 4H), 2.11 (s, 3H), 1.48-1.52 (m, 4H), 0.96-1.0 (t, 6H).

[0105] 2.2 Preparation of compound F2-1

[0106]

[0107] Prepare 3.34 g of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid chloride prepared according to the method described in step 1.3 in Example 1, and prepare in step 2.1 above The ester was added to 100ml of tetrahydrofuran, then 2ml of triethylamine was added, and the reaction was stirred at 50°C for 2 hours. After TLC monitoring, the reaction was stopped and the reaction was stopped. The product was concentrated under reduced pressure to dryness. Wash 3×10 ml each, then dry with anhydrous sodium sulfate and concentrate under reduced pressure to a constant weight to obtain 2.84 g of a white powdery solid, 4.29 g by column chromatography, with a yield of 66.3%.

[0108] 1 H-NMR (400MHz, d 6 DMSO): 8.05-δ8.22 (m, 4H), 7.86-7.88 (d, 2H), 7.01-7.03 (d, 1H), 4.91-4.94 (wide front, 4H), 3.91-3.92 (d, 2H) , 3.58-3.73 (m, 4H), 3.07-3.11 (m, 7H), 2.75 (s, 3H), 2.19-2.23 (m, 1H), 1.51-1.53 ​​(m, 4H), 1.09-1.10 (d, 6H), 0.86-0.88 (t, 6H).

[0109] ESI-MS: m/z685, 686, 687 (M+1).

[0110] Example 3 Preparation of compound F3-1

[0111] 3.1 Preparation of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride

[0112]

[0113] It was prepared according to the method described in step 1.1 in Example 1, and was directly used in the next reaction.

[0114] 3.2 Preparation of intermediate 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid N-methyl-N-hydroxyethyl ethyl ester

[0115]

[0116] Refer to the method described in step 2.1 in Example 1 to prepare a white solid with a yield of 81%.

[0117] 1 H-NMR (400MHz, d 6 DMSO): δ7.53-7.66 (m, 4H), 7.25-7.27 (d, 2H), 7.08-7.10 (d, 2H), 4.21-4.24 (t, 2H), 3.67-3.69 (t, 2H), 2.61-2.64 (t, 2H), 2.59 (t, 2H), 2.34 (s, 3H), 1.68 (s, 6H).

[0118] 3.3 Preparation of compound F3-1

[0119]

[0120] With reference to the method described in 2.2 in Example 1, the product of step 3.1 and the product of step 3.2 were used to prepare the target product, which was a white solid with a yield of 64%.

[0121] 1 H-NMR (400MHz, d 6 DMSO): 8.16 (d, 1H), 8.07-8.10 (d, 1H), δ 7.68-7.76 (d, 4H), 7.42-7.44 (d, 2H), 7.01-7.03 (d, 1H), 6.86 6.88(d, 2H), 4.70-4.77(d, 4H), 3.90-3.92(d, 2H), 3.19-3.47(d, 4H), 2.73(s, 3H), 2.76(s, 3H), 2.19- 2.23(m, 1H), 1.71(s, 6H), 1.09-1.10(d, 6H)

[0122] ESI-MS: m/z: 718, 720, 721, 722 (M+1).