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US 10,696,657 B2Granted
Methods and intermediates for preparing therapeutic compounds
AssigneeGilead Sciences, Inc.
InventorsAmanda L. Vandehey, Gediminas Brizgys, Vinh X. Ngo, Brian M. O'Keefe, Trevor J. Rainey, Bing Shi, Winston C. Tse, Anna M. Wagner, Xianghong Wang, Scott A. Wolckenhauer, Chloe Y. Wong
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Abstract
The present disclosure relates to methods and intermediates useful for preparing a compound of formula I: or a co-crystal, solvate, salt or combination thereof.
Claims21
A process for preparing a compound of formula I:
- or a co-crystal, solvate, salt, or combination thereof, comprising:
- (a) combining a compound of formula III:
- or a co-crystal, solvate, salt, or combination thereof with a mesylating reagent selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride;
- a base selected from the group consisting of N-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide;
- and a solvent selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof, to provide a compound of formula II:
- or a co-crystal, solvate, salt, or combination thereof;
- and
- (b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isoropoxide, sodium t-butoxide, methylamine, ethylamine, n-propylamine, dimethylamine, diethylamine, and hydroxylamine;
- in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, 1-propanol, n-butanol, s-butanol, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and combinations thereof;
- to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.
7 more elements
A process for preparing a compound of formula I:
- or a co-crystal, solvate, salt, or combination thereof, comprising:
- (a) combining a compound of formula VIII:
- or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:
- or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:
- or a co-crystal, solvate, salt, or combination thereof;
- (b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:
- or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:
- or a co-crystal, solvate, salt, or combination thereof;
- (c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:
- or a co-crystal, solvate, salt, or combination thereof, wherein R1 is B(OH)2, B(OCH(Me)CH2C(Me)2O), B((1,2-di-O)C6H4), B(OCH2C(Me)2CH2O), BF3K, B(O2CCH2N(Me)CH2CO2), or B(OC(Me)2C(Me)2O), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:
- or a co-crystal, solvate, salt, or combination thereof;
- and
- (d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.
10 more elements
Dependencies are inferred from the claim text.