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1. WO2019006292 - SUBSTITUTED QUINOLINYCYCLOHEXYLPROPANAMIDE COMPOUNDS AND IMPROVED METHODS FOR THEIR PREPARATION

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[ EN ]

What is Claimed:

1. g a compound of formula I, or a stereoisomer thereof:


comprising

contacting a compound of formula II, or a stereoisomer thereof:


wherein Ri is Ci-6alkyl, aryl, or Ci-6haloalkyl;

with a mixture of a Ci-6alkoxide salt and a di-Ci-6alkyl-malonate, in a suitable organic solvent;

for a time and at a temperature sufficient to displace the sulfonate moiety and to produce a compound of formula III, or a stereoisomer thereof:


and

contacting the compound of formula III, or a stereoisomer thereof, with a suitable organic acid, in a suitable aqueous organic solvent, for a time and at a temperature sufficient for hydrolysis and decarboxylation and to produce the compound of formula I, or a stereoisomer thereof.

The method of claim 1, wherein the Ci-6alkoxide salt is sodium t-amylate and the di-Ci-6alkyl-malonate is di-tert-butyl malonate.

The method of claim 1 or 2, wherein the organic acid is methanesulfonic acid.

The method of any one of the preceding claims, wherein Ri is methyl.

The method of any one of the preceding claims, wherein the compound of formula II, or a stereoisomer thereof, is prepared by

contacting a compound of formula IV:


with a Lewis acid and a hydride source, in a suitable alcoholic organic solvent, for a time and at a temperature sufficient to produce reduce the carbonyl and to produce a compound of formula V, or a stereoisomer thereof:


and

contacting the compound of formula V, or a stereoisomer thereof, with X-SO2-R1, wherein X is halo, or with R1-SO2-O-SO2-R1 in the presence of an alkyl-amine base, in a suitable anhydrous organic solvent, for a time and at a temperature sufficient for X displacement to produce the compound of formula II, or a stereoisomer thereof.

6. The method of claim 5, wherein the cerium halide is CeCh, or a hydrate thereof, and the hydride source is NaBH4.

7. The method of claim 5 or claim 6, wherein X is CI and Ri is methyl.

8. The method of any one of claims 5 to 7, wherein the alkyl-amine base is Et3N.

9. The method of any one of claims 5 to 8, wherein the compound of formula IV is prepared by contacting a compound of formula VI- A or VI-B:


VI-B

wherein n is 1 or 2;

with a compound of formula VII


wherein Y is halo;

in the presence of a suitable Ci-6alkylsilylamine base, in a suitable organic solvent, for a time and at a temperature sufficient for Y displacement to produce a compound of


VIII-B

and

contacting the compound of formula VIII-A or formula VIII-B with a suitable hydroxide base, in a suitable aqueous solvent, for a time and at a temperature sufficient for hydrolysis to produce a compound of formula IX-A or formula IX-B;


and

contacting the compound of formula IX-A or formula IX-B, with a suitable mineral acid, in a suitable aqueous solvent, for a time and at a temperature sufficient for hydrolysis and decarboxylation to produce the compound of formula IV.

10. The method of claim 9, wherein n is i .

1 1. The method of claim 9 or claim 10, wherein Y is CI.

12. The method of any one of claims 9 to 11 , wherein the Ci-6alkylsilylamine is NaHMDS.

13. The method of any one of claims 9 to 12, wherein the hydroxide base is KOH or NaOH.

14. The method of any one of claims 9 to 13, wherein the mineral acid is HC1.

15. The method of any one of the preceding claims, wherein the compound of formula I is:


16. The method of any one of the preceding claims, wherein the compound of formula II is:

17. A method for preparin a stereoisomer thereof,


Compound 1

comprising:

converting a compound of formula I, or a stereoisomer thereof, prepared according to any one of the preceding claims, to a Compound 2, or a stereoisomer thereof:


Compound 2

wherein R is phenyl or benzyl; and

converting the Compound 2, or a stereoisomer thereof, to a Compound 3, or a stereoisomer thereof


Compound 3

and

converting the Compound 3, or a stereoisomer thereof, to a Compound 4, or a stereoisomer thereof


and converting the Compound 4, or a stereoisomer thereof, to the Compound 1 , or a stereoisomer thereof; and

optionally preparing a pharmaceutically acceptable salt or co-crystal, for example, a methanesulfonic acid salt, of the Compound 1.

18. , wherein the Compound 1 is


19. Compound 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for example, methanesulfonic acid salt, or a co-crystal thereof, prepared according to claim 17 or claim 18.

20. A compound that is


methanesulfonic acid.

21. A compound that is


or a pharmaceutically acceptable salt thereof

or a co-crystal thereof.

22. A compound that is

or a pharmaceutically acceptable salt thereof.