Search

US-12623993-B2 - Synthesis of vinyl cyclobutyl intermediates

US12623993B2US 12623993 B2US12623993 B2US 12623993B2US-12623993-B2

Abstract

Provided herein are processes for synthesizing intermediates useful in preparing Mcl-1 inhibitors. In particular, provided herein are processes for synthesizing compound F, or a salt thereof, wherein R 1 and OPG 2 are described herein. Compound F can be useful in synthesizing compound A1, or a salt of solvate thereof, and compound A2, or a salt of solvate thereof.

Inventors

  • AUSTIN G. SMITH
  • Michael T. CORBETT
  • Neil Fred Langille
  • Kyle D. BAUCOM
  • Peter K. DORNAN
  • Gabrielle ST- PIERRE
  • Philipp C. Roosen
  • Sheng Cui
  • Roberto Profeta

Assignees

  • AMGEN INC.

Dates

Publication Date
20260512
Application Date
20210504

Claims (20)

  1. 1 . A process for synthesizing compound F or a salt thereof: wherein OPG 2 is a secondary alcohol protecting group and R 1 is a protected aldehyde; comprising: (a) protecting a secondary alcohol of compound B, or a salt thereof, by reacting compound B, or salt thereof, with an alcohol protecting group reagent to form compound C, or a salt thereof: (b) removing compound C's acetyl group to form a primary alcohol of compound D, or a salt thereof: (c) oxidizing the primary alcohol of compound D, or salt thereof, to form an aldehyde of compound E, or a salt thereof: and (d) protecting the aldehyde of compound E, or salt thereof, to form a protected aldehyde of compound F, or a salt thereof.
  2. 2 . The process of claim 1 , wherein OPG 2 comprises an acyl protecting group, an ether protecting group, acetal or ketal protecting group, a sulfonyl protecting group, or a silyl ether protecting group.
  3. 3 . The process of claim 2 , wherein the acyl protecting group is selected from the group consisting of acetyl, pivaloyl, benzoyl, 4-bromobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-iodobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, 2-napthoyl, 4-methoxybenzoyl, and isobutyryl.
  4. 4 . The process of claim 3 , wherein the acyl protecting group is 4-bromobenzoyl.
  5. 5 . The process of claim 2 , wherein the alcohol protecting group reagent of step (a) is an acyl chloride or an acyl anhydride.
  6. 6 . The process of claim 1 , wherein compound B and the alcohol protecting group reagent are present in a molar ratio of 1:1 to 1:2.
  7. 7 . The process of claim 6 , wherein the molar ratio of compound B to alcohol protecting group reagent is 1:1.3.
  8. 8 . The process of claim 2 , wherein OPG 2 is selected from the group consisting of and OSO 2 CF 3 (triflyl).
  9. 9 . The process of claim 2 , wherein the silyl ether protecting group is selected from the group consisting of OSiEt 3 (triethylsilyl ether, TES), OSi( i Pr) 3 (triisopropylsilyl ether, TIPS), OSiMe 3 (trimethylsilyl ether, TMS), OSiMeztBu (tert-butyldimethylsilyl ether, TBS), and OSiPh 2 Bu (tert-butyldiphenylsilyl ether TBDPS).
  10. 10 . The process of claim 2 , wherein step (a) comprises admixing compound B, or salt thereof, the alcohol protecting group reagent, and a nucleophilic catalyst.
  11. 11 . The process of claim 10 , wherein the nucleophilic catalyst comprises pyridine, 4-dimethylaminopyridine, or a combination thereof.
  12. 12 . The process of claim 10 , wherein compound B and the nucleophilic catalyst are present in a molar ratio of 1:1 to 1:5.
  13. 13 . The process of claim 12 , wherein the molar ratio of compound B to the nucleophilic catalyst is 1:2.
  14. 14 . The process of claim 1 , wherein step (a) occurs in an organic solvent selected from the group consisting of a nonpolar aromatic solvent, an ether solvent, a chlorinated solvent, acetonitrile, dimethylformamide (DMF), methyl isobutyl ketone (MIBK), 2-butanone, acetone, isopropyl acetate (IPAc), ethyl acetate, and a combination thereof.
  15. 15 . The process of claim 14 , wherein the organic solvent is selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran (THF), tetrahydropyran, diethyl ether, dibutyl ether, diisopropyl ether, dimethoxymethane, 1,2-dimethoxyethane, 1,4-dioxane, dichloromethane (DCM), carbon tetrachloride, chloroform, 1,2-dichloroethane, 2-methyltetrahydrofuran (2-MeTHF), methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), and a combination thereof.
  16. 16 . The process of claim 15 , wherein the organic solvent is toluene, THF, DCM, or a combination thereof.
  17. 17 . The process of claim 1 , wherein step (a) occurs at a temperature of 20° C. to 100° C.
  18. 18 . The process of claim 17 , wherein step (a) occurs at a temperature of 60° C.
  19. 19 . The process of claim 1 , wherein removing the acetyl protecting group in step (b) comprises admixing compound C, or salt thereof, with a deprotecting agent.
  20. 20 . The process of claim 19 , wherein the deprotecting agent comprises acetyl chloride, an enzyme, an acid, a base, a metal hydride, or a combination thereof.

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/020,877, filed on May 6, 2020, which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein. BACKGROUND Technical Field The present disclosure relates to intermediates and processes for synthesizing intermediates used in synthesizing (1S,3′R,6′R,7'S,8′E,11'S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (compound A1; AMG 176), a salt, or solvate thereof, and (1S,3′R,6′R,7′R,8′E,11'S,12′R)-6-chloro-7′-methoxy-11′,12′-dinethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (compound A2; AMG 397), a salt, or solvate thereof. These compounds are inhibitors of myeloid cell leukemia 1 protein (Mcl-1). Description of Related Technology The compound, (1S,3′R,6′R,7'S,8′E,11'S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (compound A1), is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): The compound, (1S,3′R,6′R,7′R,8′E,11'S,12′R)-6-chloro-7′-methoxy-11′,12′-dinethyl-7′-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (compound A2), is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): One common characteristic of human cancer is overexpression of Mcl-1. Mcl-1 overexpression prevents cancer cells from undergoing programmed cell death (apoptosis), allowing the cells to survive despite widespread genetic damage. Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) which, upon activation, form a homo-oligomer in the outer mitochondrial membrane that leads to pore formation and the escape of mitochondrial contents, a step in triggering apoptosis. Antiapoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit additional regulatory functions. Research has shown that Mcl-1 inhibitors can be useful for the treatment of cancers. Mcl-1 is overexpressed in numerous cancers. U.S. Pat. No. 9,562,061, which is incorporated herein by reference in its entirety, discloses compound A1 as an Mcl-1 inhibitor and provides a method for preparing it. However, improved synthetic methods that result in greater yield and purity of compound A1 are desired, particularly for the commercial production of compound A1. U.S. Pat. No. 10,300,075, which is incorporated herein by reference in its entirety, discloses compound A2 as an Mcl-1 inhibitor and provides a method for preparing it. However, improved synthetic methods that result in greater yield and purity of compound A2 are desired, particularly for the commercial production of compound A2. SUMMARY Provided herein are processes for synthesizing compound F or a salt thereof: wherein OPG2 is a secondary alcohol protecting group and R1 is a protected aldehyde; comprising (a) protecting a secondary alcohol of compound B, or a salt thereof, by reacting compound B, or salt thereof, with an alcohol protecting group reagent to form compound C, or a salt thereof: (b) removing compound C's acetyl group to form a primary alcohol of compound D, or a salt thereof: (c) oxidizing the primary alcohol of compound D, or salt thereof, to form an aldehyde of compound E, or a salt thereof: and (d) protecting the aldehyde of compound E, or salt thereof, to form a protected aldehyde of compound F, or a salt thereof. In various embodiments, OPG2 comprises an acyl protecting group, an ether protecting group, acetal or ketal protecting group, a sulfonyl protecting group, and a silyl ether protecting group. In some cases, the acyl protecting group is selected from the group consisting of acetyl, pivaloyl, benzoyl, 4-bromobenzoyl, 4-chlorobenzoyl, 4-iodobenzoyl, 4-fluorobenzoyl, 4-nitrobenzoyl, 4-phenylbenzoyl, 1-naphthoyl, 2-napthoyl, 4-methoxybenzoyl, and isobutyryl. In some cases, the acyl protecting group is 4-bromobenzoyl. In various embodiments, the alcohol protecting group reagent of step (a) is an acyl chloride or an acyl anhydride. In various embodiments, compound B and the alcohol protecting group reagent are present in a molar ratio of 1:1 to 1:2. In some cases, the molar ratio of compound B to alcohol protecting group reagent is 1:1.3. In various embodiments, OPG2 is selected from the group consisting of and OSO2CF3 (triflyl). In various embodiments, t