Diol desymmetrization by nucleophilic aromatic substitution

Patent metadata

Field	Value
Publication number	US-12552808-B2
Application number	US-202118024716-A
Country	US
Kind code	B2
Filing date	Sep 1, 2021
Priority date	Sep 3, 2020
Publication date	Feb 17, 2026
Grant date	Feb 17, 2026

Abstract

Provided herein are processes for synthesizing Mcl-1 inhibitors and intermediates such as compound Y that can be used to prepare them where the variable R 1 is as defined herein. In particular, provided herein are processes for synthesizing compound A1, and salts or solvates thereof, compound A2, and salts and solvates thereof, and compound A3 and salts and solvates thereof.

First claim

What is claimed is:

1 . A process for synthesizing compound Y, or a salt thereof:

comprising:
admixing compound (I), compound (II), a catalyst, and a base in a bi-phasic solvent system to form compound Y:

wherein
R 1 is CO 2 C 1-6 alkyl, CO 2 H, CON(C 1-6 alkyl) 2 , CO 2 Ar 1 , CO 2 Bn, or CN;
Lg is a leaving group; and
Ar 1 is C 6-22 aryl or a 5-12 membered heteroaryl comprising 1 to 3 ring heteroatoms selected from O, N, and S.

2 . The process of claim 1 , wherein compound Y has the stereochemistry as shown in compound Y1

or as shown in compound Y2

3 . The process of claim 1 , wherein R 1 is —CO 2 Me, —CO 2 Et, —CO 2 iPr, —CO 2 nPr, —CO 2 tBu, —CO 2 nBu, —CO 2 secBu, CO 2 Bn, CO 2 Ph, CN, or —CO 2 H.

4 . The process of claim 1 , wherein Lg is F, Cl, Br, I, mesyl, tosyl, nosyl, or triflyl.

5 . The process of claim 1 , wherein the catalyst is an asymmetric catalyst, and the asymmetric catalyst has a structure of

wherein
each R 2 is independently C 1-22 alkyl, C 5-8 cycloalkyl, or Ar 1 , or
each R 2 , together with the atoms to which they are attached, form a five-to eight-member cycloalkyl;
each R 3 is independently C 1-22 alkyl, C 5-8 cycloalkyl, Bn, or Ar 1 , or
two R 3 , together with the nitrogen to which they are attached, form a five-to twenty five-member heterocycle comprising 0-1 additional ring heteroatoms selected from N, O, and S;
X is OH, NR N C(O)R N , C(O)N(R N ) 2 , N(R N ) 2 , C 1-6 haloalkyl, SH, SC 1-6 alkyl, NHSO 2 Ar 1 , NHSO 2 C 1-6 alkyl, NHSOC 1-6 alkyl, or NHSOAr 1 ;
each R N is independently H, C 1-12 alkyl, or Ar 1 ; and
Z is a counterion.

6 . The process of claim 5 , wherein the asymmetric catalyst has a structure of

7 . The process of claim 5 , wherein:
each R 2 is independently selected from Me, Et, iPr, sBu, fBu, phenyl, tolyl,

 or each R 2 , together with the atoms to which they are attached, form a cyclohexyl or a cyclopentyl;
X is

 and
the asymmetric catalyst comprises a —N(R 3 ) 3 + that is selected from the group consisting of

8 . The process of claim 5 , wherein the asymmetric catalyst has a structure of

wherein each Ar 2 independently is selected from C 6-22 aryl or a 5-12 membered heteroaryl comprising from 1 to 3 ring heteroatoms selected from O, N, and S and Z is a counterion.

9 . The process of claim 8 , wherein at least one Ar 2 is phenyl or substituted phenyl.

10 . The process of claim 9 , wherein each Ar 2 is independently selected from

11 . The process of claim 5 , wherein the asymmetric catalyst has a structure of

wherein Ar 3 is selected from C 6-22 aryl or a 5-12 membered heteroaryl comprising from 1 to 3 ring heteroatoms selected from O, N, and S and Z is a counterion.

12 . The process of claim 11 , wherein Ar 3 is phenyl or substituted phenyl.

13 . The process of claim 12 , wherein Ar 3 is selected from

14 . The process of claim 5 , wherein the asymmetric catalyst is selected from the group consisting of

15 . The process of claim 5 , wherein Z is a halide, triflate, mesylate, tosylate, or nosylate.

16 . The process of claim 1 , wherein the base comprises an inorganic base, and the inorganic base comprises Cs 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , Na 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 , CaCO 3 , MgCO 3 , K 3 PO 4 , Na 3 PO 4 , Li 3 PO 4 ·K 2 HPO 4 , Na 2 HPO 4 , Li 2 HPO 4 , NaHCO 3 , LiHCO 3 , or KHCO 3 .

17 . The process of claim 16 , wherein the inorganic base is present at 0.95 to 6 molar equivalents, based upon 1.0 molar equivalents of compound (I).

18 . The process of claim 1 , wherein the bi-phasic solvent system comprises an aprotic organic solvent and water, and the aprotic organic solvent comprises dichloromethane, tetrahydrofuran, toluene, benzene, cyclopentyl methyl ether, tert-butyl methyl ether, 2-methyltetrahydrofuran, anisole, xylene, benzotrifluoride, 1,2-dichloroethane, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, or a combination thereof.

19 . The process of claim 18 , wherein the aprotic organic solvent comprises toluene, and the toluene is present at a concentration of 3 L/kg to 30 L/kg based upon weight of compound (I).

20 . The process of claim 18 , comprising admixing compound (I), compound (II), and the catalyst in the aprotic organic solvent prior to adding the base.

21 . The process of claim 1 , wherein the admixing occurs at a temperature of: (i) −40° C. to 30° C.; or (ii) −15° C. to −25° C.

22 . The process of claim 1 , wherein the admixing occurs for: (i) 1 hour to 72 hours; or (ii) 14 hours to 18 hours.

23 . The process of claim 1 , wherein compound (II) is present at: (i) 0.9 to 2 molar equivalents, based upon 1.0 molar equivalents of compound (I); or (ii) 1.0 molar equivalents, based upon 1.0 molar equivalents of compound (I).

24 . The process of claim 1 , wherein the asymmetric catalyst is present at: (i) 0.005 to 1.50 molar equivalents, based upon 1.0 molar equivalents of compound (I); or (ii) 0.25 molar equivalents, based upon 1.0 molar equivalents of compound (I).

25 . The process of claim 1 , wherein compound Y is produced with an enantiomeric excess of: (i) 30% or more; or (ii) 40% or more; or (iii) 50% or more.

Assignees

• Amgen Inc

Inventors

• Beaver Matthew G
• Dennis Joseph Michael
• Dornan Peter
• Mennen Steven
• Tedrow Jason S
• Langille Neil F
• Cohen Carolyn Michelle
• Rotheli Andreas Rene

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07D513/10 Primary

  Spiro-condensed systems · CPC title

• C07D267/12

  condensed with carbocyclic rings or ring systems · CPC title