Process of making derivatives of substituted morpholines

A method of manufacturing a morpholine derivative of formula Ilf or a pharmaceutically acceptable salt thereof, the method comprising:

• (a) reacting a compound of formula
• with (S)-(+) epichlorohydrin to form a chlorohydrin compound of formula
• (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of formula
• (c) contacting the epoxide compound with a base and a compound of formula:
• (Ia) to form a diol compound of formula
• (d) contacting the diol compound with a base followed by addition of a sulfonyl halide compound to form an intermediate sulfonate of formula
• (IIa'), wherein Z is a sulfonyl leaving group, that cyclizes in situ to form an N-benzyl protected morpholine compound of formula
• (e) forming the HCl salt of the compound of formula (IIb) and recrystallizing it to afford the highly pure (S)-enantiomer as an HCl salt;
• (f) converting the HCl salt of compound (IIb) to the free base;
• (g) contacting the N-benzyl protected morpholine compound with a chloroformate of formula:
• (Ic);
• to form an intermediate N-benzyl chlorocarbamate salt of formula
• that loses benzyl chloride upon heating to give a compound of formula
• (h) addition of the chlorocarbamate compound to a metal salt of an amino acid derivative of formula
• wherein the amino acid derivative has been pretreated with a metal compound, to form a protected amine of formula
• and,
• (i) contacting the protected amine with an acid to provide the morpholine derivative (IIf) as an acid salt:
• wherein R1 is C1-C6 alkyl, aryl, or heteroaryl;
• each R2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl;
• R3 is a C1-C6 alkyl, R4 is a the C1-C6 alkyl, R5 is an amino protecting group;
• and n is 0, 1, 2, 3, or 4.