With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.219823-47-9,(R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate,as a common compound, the synthetic route is as follows.
Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl) tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 C. The reaction mixture was maintained for 1 hour at -80 C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 C. The reaction mass was heated to -10 C and stirred for 30 minutes and heated to 30 C and stirred for 12 hours at 30 C. The reaction mass was cooled to 5 C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 C. Temperature was raised to -5 C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 C. The reaction mass was heated to 30 C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 C and stirred for 2 hours at 45 C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 C. The reaction mass was cooled to 30 C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 C and the resulted mixture was heated to 45 C and the mixture was stirred for 6 hours at 45 C. The suspension was cooled to 25 C and stirred for 7 hours at 25 C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 C and stirred for 6 hours. The suspension was cooled to 25 C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%., 219823-47-9
219823-47-9 (R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate 13837325, aTetrahydrofurans compound, is more and more widely used in various fields.
Reference£º
Patent; DR. REDDY’S LABORATORIES LIMITED; CHAKKA, Ramesh; PATHIVADA, Deepika; PEDDI REDDY, Subba Reddy; IPPALAPALLI, Sandeep; CHINTADA, Krishnarao; KOYA, Ravi Teja; ORUGANTI, Srinivas; BADARLA, Venkata Krishna Rao; DONIPARTHI, Kiran Kumar; SUD, Abhishek; MADAVARAM, Sateesh; LEKKALA, Amarnath Reddy; KUNHIMON, Syam Kumar Unniaran; JAWLEKAR, Suhas; KANDAGATLA, Bhaskar; (72 pag.)WO2017/203457; (2017); A1;,
Tetrahydrofuran – Wikipedia
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