- Document Number:
20230357173
- Appl. No:
18/206953
- Application Filed:
June 07, 2023
- 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: [chemical expression included]
- Assignees:
Supernus Pharmaceuticals, Inc. (Rockville, MD, US)
- Claim:
1. A method of manufacturing a morpholine derivative or a pharmaceutically acceptable salt thereof, the method comprising: (a) reacting a compound of formula [chemical expression included] with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of formula [chemical expression included] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of formula [chemical expression included] (c) contacting the epoxide compound with a base and a compound of formula: [chemical expression included] to form a diol compound of formula [chemical expression included] (d) contacting the diol compound with a base followed by addition of a sulfonyl halide compound to form an intermediate sulfonate of formula [chemical expression included] wherein Z is a sulfonyl leaving group, that cyclizes in situ to form an N-benzyl protected morpholine compound of formula [chemical expression included] (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: [chemical expression included] to form an intermediate N-benzyl chlorocarbamate salt of formula [chemical expression included] that loses benzyl chloride upon heating to give a compound of formula [chemical expression included] (h) addition of the chlorocarbamate compound to a metal salt of an amino acid derivative of formula [chemical expression included] wherein the amino acid derivative has been pretreated with a metal compound, to form a protected amine of formula [chemical expression included] and, (i) contacting the protected amine with an acid to provide the morpholine derivative (IIf) as an acid salt: [chemical expression included] 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.
- Claim:
2. The method according to claim 1, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.
- Claim:
3. The method according to claim 1, wherein a phase transfer catalyst is utilized in step (d).
- Claim:
4. The method according to claim 3, wherein the phase transfer catalyst is benzyltriethylammonium chloride.
- Claim:
5. The method according to claim 4, wherein the product contains greater than 60% of the (S) enantiomer and the (S)—HCl salt may be crystallized to give the HCl salt with greater than 90% of one enantiomer.
- Claim:
6. The method according to claim 1, wherein the sulfonyl halide selected from the group consisting of p-toluenesulfonyl chloride (tosyl chloride), brosyl chloride, nosyl chloride, and mesyl chloride.
- Claim:
7. The method according to claim 6, wherein the sulfonyl halide compound is p-toluenesulfonyl chloride.
- Claim:
8. The method according to claim 1, wherein cyclization is performed using NaOH.
- Claim:
9. The method according to claim 1, wherein the crude product chlorocarbamate compound formed step (g) is washed with an alkane solvent, evaporated, or treated with triethylamine to remove benzyl chloride byproduct before performing the next step.
- Claim:
10. The method according to claim 1, wherein the metal salt of step (h) is a cesium salt.
- Claim:
11. The method according to claim 1, wherein the metal compound of step (h) is cesium carbonate.
- Claim:
12. The method according to claim 1, wherein step (a) further comprises an organic solvent.
- Claim:
13. The method according to claim 12, wherein step (a) further comprises heating to a temperature of at least 30° C.
- Claim:
14. The method according to claim 1, wherein step (b) is performed at room temperature.
- Claim:
15. The method according to claim 1, wherein R1 is —CH3 or —CH2CH3.
- Claim:
16. The method according to claim 1, wherein each R2 is independently selected from —F, —Cl, —Br, —I, or C1-C6 alkyl.
- Claim:
17. The method according to claim 1, wherein R3 is —CH3 or isopropyl.
- Claim:
18. The method according to claim 1, wherein R4 is isopropyl.
- Claim:
19. The method according to claim 1, wherein R5 is tert-butoxycarbonyl (Boc).
- Claim:
20. The method according to claim 1, wherein n is 0.
- Claim:
21. The method according to claim 1, wherein the morpholine derivative from step (i) has the following formula: [chemical expression included] or a pharmaceutically acceptable salt thereof.
- Claim:
22. The method according to claim 1, wherein the morpholine derivative from step (i) has the following formula: [chemical expression included] or a pharmaceutically acceptable salt thereof.
- Claim:
23. The method according to claim 1, wherein the morpholine derivative from step (i) has the following formula: [chemical expression included] or a pharmaceutically acceptable salt thereof.
- Current International Class:
07; 01
- Accession Number:
edspap.20230357173
Processing Request
No Comments.