CN-121974901-A - Process for preparing compounds and compounds S1P1 modulators

Abstract

This embodiment relates in part to methods and compositions that may be used, for example, to prepare a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Inventors

• HEASLEY BRIAN HAID
• J. Willent
• P. J. kestler

Assignees

• 特维娜有限公司

Dates

Publication Date

20260505

Application Date

20201117

Priority Date

20191119

Claims (10)

1. 1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: Under suitable conditions to cause Is contacted with a compound of (2) To produce a compound having the formula Wherein: A. b and E are each independently N or CR 6 ; x and Y are each independently O, S or NR 7 ; r 1 is H, OH, NH 2 、NO 2 , optionally substituted carbocycle, optionally substituted aryl, optionally substituted heteroaryl, branched or unbranched alkyl alcohol, halogen, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite or alkylthio. R 2 、R 3 、R 4 、R 5 、R 6 and R 7 are each independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, R 2 and R 3 together are optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, or R 4 and R 5 together are optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl.
2. 2. The method of claim 1, wherein the method further comprises Compounds and methods for their preparation Coupling of compounds to produce A compound wherein the variables are as defined in claim 1.
3. 3. The method of claim 2, wherein the coupling comprises contacting the compounds of formula (II) and (III) with a coupling agent and optionally an additive to a solution comprising the compounds of formula (II) and (III).
4. 4. The method of claim 3, further comprising quenching the reaction to form a reaction mixture comprising A slurry of a compound or a pharmaceutically acceptable salt thereof.
5. 5. The method of claim 4, further comprising separating A compound or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.
6. 6. The method of claim 1, wherein the method comprises the steps of: (a) Adding a coupling agent and optional additives to A solution of the compound in a first organic solvent to form a mixture, and stirring the mixture for at least about 5 minutes; (b) Combining the mixture of step (a) with Stirring the compounds together; (c) Heating the mixture of step (b) to a temperature of at least about 40 ℃ and stirring the mixture at that temperature; (d) Cooling the mixture of step (c) and adding water to the mixture to form a slurry; (e) Stirring the slurry of step (d); (f) Filtering the slurry of step (e) to obtain a solid; (g) Washing the solid of step (f) with water and/or a second organic solvent, and (H) Drying the solid of step (g) in vacuo at a temperature of at least about 30 ℃ to form A compound wherein the variables are as defined in claim 1.
7. 7. The method of claim 6, wherein the coupling agent is a carbodiimide.
8. 8. The process of claim 6 wherein the coupling agent is EDC hydrochloride.
9. 9. The method of any one of claims 6-8, wherein the additive is HOBt, HOAt, or cyanohydroxy iminoethyl acetate.
10. 10. The method of any one of claims 6-8, wherein the additive is ethyl cyanohydroxyiminoacetate.

Description

Process for preparing compounds and compounds S1P1 modulators Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 62/937,485 filed on 11, 19, 2019, which is incorporated herein by reference in its entirety. Technical Field Embodiments disclosed herein relate to methods of preparing compounds, or pharmaceutically acceptable salts thereof, that may, for example, be useful in modulating S1P1 receptor activity. Background Compounds of formula (I) are reported in International application publication No. WO2018/231745The entire contents of which are incorporated herein by reference. In addition to methods of preparing such compounds or pharmaceutically acceptable salts thereof, other synthetic methods may be desirable. The present disclosure meets these and other needs. Disclosure of Invention In some embodiments, methods of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, are provided. In some embodiments, the method comprises: under proper conditions, make Contact of compoundsThe compound is used as a carrier of a compound, To produce a product withA compound of the structure of (a), Wherein A, B, E, X, Y, R 1、R2、R3、R4 and R 5 are as provided herein, and may be selected, for example, from the group of corresponding chemical moieties described herein. In some embodiments, the method comprises: (a) Adding a coupling agent and optional additives to A solution of the compound in a first organic solvent to form a mixture, and stirring the mixture for at least about 5 minutes; (b) Combining the mixture of step (a) with Stirring the compounds together; (c) Heating the mixture of step (b) to a temperature of at least about 40 ℃ and stirring the mixture at that temperature; (d) Cooling the mixture of step (c) and adding water to the mixture to form a slurry; (e) Stirring the slurry of step (d); (f) Filtering the slurry of step (e) to obtain a solid; (g) Washing the solid of step (f) with water and/or a second organic solvent, and (H) Drying the solid of step (g) in vacuo at a temperature of at least about 30 ℃ to formA compound, wherein the variables are provided herein. In some embodiments, there is also provided a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) To the direction of The compound is added EDC hydrochloride and cyanoethyl hydroxyiminoacetate to a solution of dimethylformamide to form a mixture, and the mixture is stirred for at least about 1 hour; (b) Combining the mixture of step (a) with Stirring the compounds together; (c) Heating the mixture of step (b) to a temperature of about 95 ℃ and stirring the mixture at that temperature for at least about 5 hours; (d) Cooling the mixture of step (C) to about 15-20 ℃ and adding water to form a slurry; (e) Stirring the slurry of step (d) at about 15-20 ℃ for about 1 hour; (f) Filtering the slurry of step (e) to form a solid; (g) Washing the solid of step (f) with water and methyl tert-butyl ether, and (H) Drying the solid of step (g) in vacuo at about 55 ℃ to formA compound wherein the variables are as defined herein. In some embodiments, there is also provided a method of making a semiconductor device havingA process for the preparation of a compound of structure or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) To the direction of Adding EDC hydrochloride and cyanoethyl hydroxyiminoacetate to a solution in dimethylformamide to form a mixture, and stirring the mixture for at least about 1 hour; (b) Combining the mixture of step (a) with Stirring together for about 1 hour; (c) Heating the mixture of step (b) to a temperature of about 95 ℃ and stirring the mixture at that temperature for at least about 5 hours; (d) Cooling the mixture of step (C) to about 15-20 ℃ and adding water to the mixture to form a slurry; (e) Stirring the slurry of step (d) at about 15-20 ℃ for about 1 hour; (f) Filtering the slurry of step (e) to form a solid; (g) Washing the solid of step (f) with water and methyl tert-butyl ether, and (H) Drying the solid of step (g) in vacuo at a temperature of at least about 55 ℃ to form In some embodiments, provided are methods of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, further comprisingA process for the preparation of a compound which comprises reacting under suitable conditionsCompound is contacted with R 2R3 c=o, wherein the variables are as defined herein. In some embodiments, there is also providedA process for the preparation of a compound comprising the steps of: (a) To the direction of Compound pyrrolidine was added to a solution of compound R 2R3 c=o to form a mixture; (b) Refluxing the mixture of step (a) by heating, stirring the mixture at that temperature for about 19.5 hours, cooling the mixture to a temperature of about 15-20 ℃, and adding water to the mixture; (c) Adjusting the pH o