A method of asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one derivatives

摘要

A method of asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one derivatives of a compound of formula (VI) comprises: a) contacting a compound of formula (I) with a compound of formula (VII) or formula (VIII) in the presence of a suitable acid catalyst to form a compound of formula (II); b) contacting a compound of formula (IX) with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide and c) contacting the mixture of step (b) with a compound formula (II) to form a compound of formula (III); d) contacting a compound of formula (III) with a suitable oxidizing agent to form a compound of formula (IV); e) contacting a compound of formula (IV) with a suitable cleaving agent, in the presence of a suitable trapping agent, to form a compound of formula (V) and f) contacting a compound of formula (V) with a suitable cyclizing agent to form a compound of formula (VI). The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one derivatives can also be prepared by: g) contacting a compound of formula (I) with a compound of formula (VII) in the presence of a suitable acid catalyst to form a compound of formula (II); h) contacting a compound of formula (IX) with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide; i) contacting the mixture of step (h) with a compound formula (II) to form a compound of formula (III); j) contacting a compound of formula (III) with a suitable deprotecting agent to form a compound of formula (V) and k) contacting a compound of formula (V) with a suitable cyclizing agent to form a compound of formula (VI). A compound of formula (IV-i) is disclosed. In the above formulae: X is Cl or F; A is -CF3, -C2 F5 or -C3F7 ; R1 is H, alkyl or alkylcarbonyl; R2 is H; R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12; R4, R5, R4a, R5a, R6, R8 and R9 are independently H, alkyl, alkoxy or alkylthio; R12 is alkyl, alkoxy or alkylthio; Y is -(CH2)n or -O- and n is 0, 1, 2 or 3; P is an amine protecting group; R10 and R11 are independently alkyl or the group -NR10R11 together is pyrrolidinyl, piperidinyl or morpholinyl and P" is a group of formula 2 or 3. In formula (VII): R2 and R3 are independently is -CH3, -CH2CH3 or phenyl substituted with 0-3 R12.