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US 2026/0217643 A1Published application
Synthesis of 2-phenyl-2-amino-cyclohexan-1-one derivatives
OwnerChris Hugh SENANAYAKE, Gopal SIRASANI +6inventors
InventorsChris Hugh SENANAYAKE, Gopal SIRASANI, Bo QU, Lalith Palitha SAMANKUMARA, Santosh Reddy NAINI, Praveen Kumar GAJULA, Satya Aravind GANGU, William LEONG
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Abstract
The present disclosure relates to a process for making a compound of the formula I and to the enantioselective synthesis to prepare the S or R isomers. It also relates to intermediates in the process.
Claims49
A compound of the formula:
- wherein
- each Z1 is independently H or C1-C6 alkyl;
- each Z2 is independently H or C1-C6 alkyl;
- n is 2 or 3;
- Z3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen;
- Z4 is C1-C6 alkyl;
- Z5 is C1-C6 alkyl;
- Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl Ar(C1-C3) alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkyl or C1-C6 alkoxy;
- each Z8 is independently H or D;
- each Z is independently halogen (selected from F, Cl, Br, I), —OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, CF3, or OCF3;
- wherein each Z1 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl which is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen;
- Ar is aryl;
- each Z8 is independently H or D;
- and
- x is 0, 1, 2, 3, 4 or 5;
- with the proviso that when Ar is thiophene, x is 0, 1, 2, or 3,
- and with the further provisos that the following compounds are excluded:
14 more elements
A compound of the formula:
16-55. (canceled)
A process for preparing a compound of Formula I
- or the R isomer thereof of the formula
- or the S isomer thereof of the formula
- comprising
- (i) with respect to the compound of formula I:
- (1) (a)reacting a compound having a ketal protecting group of the formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula V
- (b) reacting the imine of Formula V with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VII
- (c) reacting the sulfinamide of Formula VII with acid to form the corresponding amine of Formula VIII
- (d) reacting the amine of Formula VIII with an acylating agent of formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOXo or a deuterated acylating agent thereof under amide forming conditions to form an amide of Formula IX having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IX with an acyl reducing agent under acyl reducing conditions or when Z8 is D, with a deuterated acyl reducing agent under acyl reducing conditions to form a compound of Formula X
- and
- (f) deprotecting the ketal of the compound of Formula X to form a compound of formula I;
- or
- (2)(a) reacting a compound having a ketal protecting group of the formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VA
- (b) reacting the imine of Formula VA with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIA
- (c) reacting the sulfinamide of Formula VIIA with acid to form the corresponding amine of Formula VIIIA
- (d) reacting the amine of Formula VIIIA with an acylating agent of formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOXo or a deuterated acylating agent thereof to form an amide of Formula IXA having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IXA with an acyl reducing agent or when Z8 is D, with a deuterated acyl reducing agent under acyl reducing conditions to form a compound of Formula XA
- and
- (f) deprotecting the ketal of Formula XA to form a compound of Formula I;
- (ii), with respect a compound of formula IR:
- (a) reacting a compound having a ketal protecting group of formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VR
- (b) reacting the imine of Formula VR with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIR
- (c) reacting the sulfinamide of Formula VIIR with acid to form the corresponding amine of Formula VIIIR
- (d) reacting the amine of Formula VIIIR with an acylating agent of formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOX0 or deuterated acylating agent thereof under amide forming conditions to form an amide of Formula IXR having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IXR with an acyl reducing agent under acyl reducing conditions or when Z8 is D, with a deuterated acyl reducing agent under acyl reducing conditions to form a compound of Formula XR
- and
- (f) deprotecting the ketal of Formula XR to form a compound of Formula IR;
- or
- (2)(a) reacting a compound having a ketal protecting group of the formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VAR
- (b) reacting the imine of Formula VAR with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAR
- (c) reacting the sulfinamide of Formula VIIAR with acid to form the corresponding amine of Formula VIIIAR
- (d) reacting the amine of Formula VIIIAR with an acylating agent of Formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOXo or deuterated acylating agent thereof to form an amide of Formula IXAR having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IXAR with an acyl reducing agent or when Z8 is D, with a deuterated acyl reducing agent under acyl reducing conditions to form a compound of Formula XAR
- and
- (f) deprotecting the ketal of Formula XAR to form a compound of Formula IAR;
- (iii) with respect to a compound of formula IS:
- (1) (a) reacting a compound having a ketal protecting group of the formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VS
- (b) reacting the imine of Formula VS with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIS
- (c) reacting the sulfinamide of Formula VIIS with acid to form the corresponding amine of Formula VIIIS
- (d) reacting the amine of Formula VIIIS with an acylating agent of Formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOXo or deuterated acylating agent thereof under amide forming conditions to form an amide of Formula IXS having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IXS with an acyl reducing agent under acyl reducing conditions to form a compound of Formula XS
- and
- (f) deprotecting the ketal of Formula XS to form a compound of Formula IS;
- or
- (2) (a) reacting a compound having a ketal protecting group of the formula
- with a sulfinamide of the formula
- in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VAS
- (b) reacting the imine of Formula VAS with an aryl nucleophilic agent Nu, capable of delivering an aryl nucleophilic moiety of the formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAS
- (c) reacting the sulfinamide of Formula VIIAS with acid to form the corresponding amine of Formula VIIIAS
- (d) reacting the amine of Formula VIIIAS with an acylating agent of Formula Z3COOH or acid derivative thereof or when Z3 is D, with Z3COOXo or deuterated acylating agent thereof to form an amide of Formula IXAS having an acyl group C(═O)Z3
- (e) reducing the acyl group in Formula IXAS with an acyl reducing agent or when Z8 is D, with a deuterated acyl reducing agent under acyl reducing conditions to form a compound of Formula XAS
- and
- (f) deprotecting the ketal of Formula XAS to form a compound of Formula IS;
- wherein
- each Z1 is independently H or C1-C6 alkyl;
- each Z2 is independently H or C1-C6 alkyl;
- Z4 is C1-C6 alkyl;
- Z5 is C1-C6 alkyl;
- n is 2 or 3;
- Z3 is H or D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen;
- Each Z is independently halogen (selected from F, Cl, Br, I), —OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, CF3, or OCF3;
- wherein each Z1 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl which is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen;
- Z7 is C1-C4 alkyl;
- Each Z8 is H or D;
- Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl Ar(C1-C3) alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy or C1-C6 alkyl;
- X0 is H or D;
- X1 is halo;
- a is 0, 1, 2, 3, or 4;
- b is 0, 1, 2, 3, or 4;
- a+b=4;
- x is 0, 1, 2, 3, 4, or 5;
- and
- Ar is aryl;
- provided that when Ar is thiophene, x is 0, 1, 2, or 3.
81 more elements
Dependencies are inferred from the claim text.