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US 2023/0295100 A1Published application
Process of making derivatives of substituted morpholines
AssigneeSupernus Pharmaceuticals, Inc.
InventorsYanjun Sun, Bhaskara Rao Nallaganchu, Gary L. Olson
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Abstract
Provided here are methods of making derivatives and prodrugs of substituted morpholines or pharmaceutically acceptable salts thereof. Further provided are methods of making derivatives and prodrugs of substituted morpholines having the following chemical structure:
Claims29
A method of manufacturing a morpholine derivative of formula (IIb):
- 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 phase transfer catalyst to form an epoxide compound of formula
- (c) contacting the epoxide compound with a base and a compound of formula:
- 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
- wherein Z is a sulfonyl leaving group, that cyclizes in situ to give an N-benzyl protected morpholine compound of formula
- and
- (e) forming the HCl salt of the compound of formula IIb and recrystallizing it to afford the highly pure (S)-enantiomer HCl salt;
- and
- (f) converting the HCl salt of compound (I %) to the free base;
- 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;
- and n is 0, 1, 2, 3, or 4.
12 more elements
A method of manufacturing a morpholine derivative of formula (IIe):
- 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 phase transfer catalyst to form an epoxide compound of formula
- (c) contacting the epoxide compound with a base and a compound of formula:
- 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
- wherein Z is a sulfonyl leaving group, that cyclizes in situ to give an N-benzyl protected morpholine compound of formula
- (e) contacting the N-benzyl protected morpholine compound (IIb) with a chloroformate of formula:
- to form an intermediate N-benzyl chlorocarbamate salt of formula
- that loses benzyl chloride upon heating to give a compound of formula
- wherein R1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl;
- each R2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl;
- is a C1-C6 alkyl;
- and n is 0, 1, 2, 3, or 4.
12 more elements
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Dependencies are inferred from the claim text.