Pyrroloquinoline quinone derivative or medicinal salt thereof, preparation method and application

[0037] Example 1

[0038] Synthesis of PQQ trimethyl ester: Take a single-neck flask, dissolve PQQ (3.3 g, 10 mmol) in DMF (200 mL), then add potassium carbonate (6.9 g, 50 mmol) in small portions and stir for 1 hour. Dimethyl sulfate (25 g) was dropped into the reaction suspension at room temperature, and the reaction was continued at room temperature for 5 days after the drop was completed. After DMF was evaporated with an oil pump, water (200 mL) was added to the residue and the residue was made acidic with 4N hydrochloric acid. The reaction solution was stirred at room temperature for 6 hours, and suction filtered to obtain an orange solid PQQ trimethyl ester (3.17 g, yield 85%).

[0039] Reduction of PQQ trimethyl ester: Take a single-neck flask, suspend PQQ trimethyl ester (1.86 g, 5 mmol) in acetonitrile (100 mL), add 1M sodium hydrosulfite solution (100 mL), and stir at room temperature overnight. The reaction solution was directly suction filtered, and the filter cake was dried to obtain reduced PQQ trimethyl ester (1.9 g), which was directly used in the next reaction without purification.

[0040] Synthesis of compound 1: The intermediate of the previous step (187 mg, 0.5 mmol) was placed in a two-necked flask, and dichloromethane (2 mL) was added to the reaction flask after nitrogen protection; A solution of acid chloride (157 mg, 2 mmol) in dichloromethane (2 mL) and triethylamine (220 mg) was allowed to warm and react overnight. Water (2 mL) was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and evaporated to dryness, and the residue was subjected to column chromatography (PE:EA=10:1-2:1) to obtain compound 1 ( 155 mg, 68%). 1 H NMR (300MHz, Chloroform-d) δ 12.67(s, 1H), 8.93(s, 1H), 7.33(s, 1H), 4.19(s, 3H), 4.07(s, 3H), 4.02(s, 3H), 2.57(s, 3H), 2.51(s, 3H).

[0041] Example 2

[0042] Referring to the method of Example 1, the acetyl chloride in Example 1 was replaced with palmitoyl chloride to obtain compound 2 (319 mg, 75%). 1 H NMR (300MHz, Chloroform-d) δ 12.67(s, 1H), 8.94(s, 1H), 7.32(s, 1H), 4.20(s, 3H), 4.06(s, 3H), 4.03(s, 3H), 2.83 (t, J=7.6Hz, 2H), 2.75 (t, J=7.5Hz, 2H), 1.91 (dt, J=14.3, 7.2Hz, 4H), 1.30 (d, J=8.3Hz, 54H), 0.90(t, J=6.3Hz, 6H).

[0043] Example 3

[0044]Referring to the method of Example 1, acetyl chloride in Example 1 was replaced with benzoyl chloride to obtain compound 3 (230 mg, 79%). 1 H NMR (300MHz, Chloroform-d) δ 12.74 (s, 1H), 8.96 (s, 1H), 8.47-8.11 (m, 4H), 7.95-6.91 (m, 7H), 4.21 (s, 3H), 4.01(s, 3H), 3.82(s, 3H).