Methods and intermediates for preparing therapeutic compounds

Patent metadata

Field	Value
Publication number	US-11760746-B2
Application number	US-202117349288-A
Country	US
Kind code	B2
Filing date	Jun 16, 2021
Priority date	Feb 16, 2018
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

The present disclosure relates to methods and intermediates useful for preparing a compound of formula I.

or a co-crystal, solvate, salt or combination thereof.

First claim

What was claimed is:

1. A process for preparing a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof, comprising resolving a compound of formula X:

or a co-crystal, solvate, salt, or combination thereof, with a chiral or achiral acid in a solvent in the temperature range of from about −20° C. to about 50° C., optionally in the presence of an aldehyde catalyst and/or optionally a metal catalyst to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof,
wherein the compound of formula VIII is a compound of formula VIII-02:

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral acid selected from the group consisting of lactic acid, L-lactic acid L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(−)-malic acid, D-glucuronic acid, (1R, 3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthyloxyacetic acid, (−)-pyroglutamic acid, (−)-n-acetyl-L-leucine, (−)-N-acetyl-D-leucine, N-Boc-D-leucine, N-(+)-BOC-phenylalanine, (−)-quinic acid, (+)-n-acetyl-L-phenylalanine, (+)-N—BOC-isoleucine, L-(−)-acetyl glutamic acid, (−)-acetyl mandelic acid, (R)-(−)-citramalic acid, (−)-camphanic acid, and (R)-mandelic acid.

2. The process of claim 1 , wherein HX is N-Boc-D-leucine or (−)-N-acetyl-D-leucine.

3. The process of claim 1 , wherein the solvent is selected from the group consisting of n-heptane, ethyl acetate, butyl acetate, isobutylacetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylenes, toluene, dichloromethane, dichloroethane, chloroform, methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, methylisobutylketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, propionitrile, butyronitrile, water, and combinations thereof.

4. The process of claim 1 , wherein the solvent is toluene.

5. The process of claim 1 , wherein the compound of formula X is treated with a base selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, potassium phosphate dibasic, potassium phosphate tribasic, sodium phosphate dibasic, and sodium phosphate tribasic in a first solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, aromatic solvents, dichloromethane, and a combination thereof prior to the resolving.

6. The process of claim 1 , wherein the compound of formula X is treated with a base, which is sodium hydroxide, prior to the resolving.

7. The process of claim 5 , wherein the first solvent is 2-methyltetrahydrofuran.

8. The process of claim 1 , further comprising:
(a) condensing a compound of formula 1a:

or a co-crystal, solvate, salt, or combination thereof, with aminodiphenylmethane in a solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, benzene, xylenes, toluene, and dichloromethane, to provide a compound of formula 1b-02:

or a co-crystal, solvate, salt, or combination thereof;
(b) alkylating the compound of formula 1b-02, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula 1c:

wherein Y is Br, Cl, I, OMs, OTs, or OSO 2 CF 3 , in the presence of a base selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium chloride complex, n-butyllithium, lithium N,N-dimethylaminoethanol complex, mesityllithium, lithium di-isopropylamide, and phenyllithium in a solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, benzene, xylenes, toluene, dichloromethane, water, and combinations thereof, to provide a compound of formula 1d-02:

or a co-crystal, solvate, salt, or combination thereof; and
(c) deprotecting the compound of formula 1d-02 with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid, in a solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylenes, toluene, dichloromethane, and combinations thereof, to provide a compound of formula X:

or a co-crystal, solvate, salt, or combination thereof.

9. The process of claim 8 , wherein the solvent for the condensing step is 2-methyltetrahydrofuran.

10. The process of claim 8 , wherein Y is Br.

11. The process of claim 8 , wherein the base for the alkylating step is sodium tert-pentoxide.

12. The process of claim 8 , wherein the solvent for the alkylating step is 2-methyltetrahydrofuran.

13. The process of claim 8 , wherein the acid for the deprotecting step is methanesulfonic acid.

14. The process of claim 8 , wherein the solvent for the deprotecting step is 2-methyltetrahydrofuran.

Assignees

• Gilead Sciences Inc

Inventors

• Dhar Sachin
• Goldberg Alex
• Heumann Lars V
• Huang Zilin
• Ngo Vinh Xuan
• Rainey Trevor James
• Steinhuebel Dietrich P
• Wang Xianghong
• Wolckenhauer Scott Alan

Classifications

• C07D213/61 Primary

  Halogen atoms or nitro radicals · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07C45/673

  by change of size of the carbon skeleton · CPC title

• C07C59/50

  Mandelic acid · CPC title

• C07C2602/18

  the ring system containing six carbon atoms · CPC title