A kind of synthetic method of tenofovir disoproxil fumarate impurity
A technology of tenofovir disoproxil fumarate and synthetic method, which is applied in the field of synthesis of tenofovir disoproxil fumarate impurities, can solve the problems of low impurity yield, achieve simple operation, stability promotion, and reaction equipment less demanding effect
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Embodiment 1
[0034] (1) Step 1: Esterification reaction
[0035] Add 40.0g of T-A, 24.0g of DIPEA, and 50.0g of EDC.HCl into 240g of isopropanol, under nitrogen protection, keep the reaction at 0-5°C for 12 hours, and pull dry at 45-50°C to obtain an oily concentrate.
[0036] Add 1000ml of dichloromethane and 600ml of pure water to the oily concentrate, and stir at about 40°C for 10 minutes; at the same time, adjust the pH to about 10 with 1N sodium hydroxide solution, let it stand for layers, and use dichloromethane for the water layer (500ml each time) After extraction twice, adjust the pH of the water layer to about 6 with 1N hydrochloric acid; adjust the pH of the water layer to about 6 with 1N hydrochloric acid until solid precipitates, stir and crystallize at 0-5°C for 2 hours, filter and dry The solid compound 33.2g T-B was obtained, the purity was greater than 92% (HPLC), and the yield was about 82%; directly proceeded to the next step without purification.
[0037] (2) Step 2: C...
Embodiment 2
[0043] (1) Step 1: Esterification reaction
[0044] Add 60.0g of T-A, 36.0g of DIPEA, and 750.0g of EDC.HCl into 360g of isopropanol, protect it under nitrogen, keep it warm at 0-5°C for 12 hours, and spin dry to obtain an oily concentrate.
[0045] Add 1500ml of dichloromethane and 800ml of pure water to the oily concentrate, and stir at about 40°C for 10 minutes; at the same time, adjust the pH to about 10 with 1N sodium hydroxide solution, let it stand for layers, and use dichloromethane for the water layer (750ml each time) After extraction twice, adjust the pH of the water layer to about 6 with 1N hydrochloric acid; adjust the pH of the water layer to about 6 with 1N hydrochloric acid until solid precipitates, stir and crystallize at 0-5°C for 2 hours, filter and dry 50.1 g of compound T-B was obtained, with a purity greater than 92% (HPLC), and a yield of about 81.5%; directly proceeded to the next step without purification.
[0046] (2) Step 2: Condensation reaction
...
Embodiment 3
[0052] (1) Step 1: Esterification reaction
[0053] Add 80.0g of T-A, 48.0g of DIPEA, and 100.0g of EDC.HCl into 480g of isopropanol, under nitrogen protection, keep the reaction at 0-5°C for 12 hours, and spin the reaction solution to obtain an oily concentrate.
[0054] Add 2000ml of dichloromethane and 1200ml of pure water to the oily concentrate, and stir at about 40°C for 10 minutes; at the same time, adjust the pH to about 10 with 1N sodium hydroxide solution, let it stand for layers, and use dichloromethane for the water layer (1000ml each time) After extraction twice, adjust the pH of the water layer to about 6 with 1N hydrochloric acid; adjust the pH of the water layer to about 6 with 1N hydrochloric acid until solid precipitates, stir and crystallize at 0-5°C for 2 hours, filter and dry The compound 67.1g T-B was obtained, the purity was greater than 92% (HPLC), and the yield was about 81.6%; directly proceeded to the next step without purification.
[0055] (2) Ste...
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