Granted Patent B2

US 12,747,248 · App. 18/122,892 · Granted Sep 29, 2026

Inventors: Kaicheng Zhu (Belmont, MA); Tao Wang (Berkeley Heights, NJ); Xin Zhang (Waltham, MA); Xiaowen Peng (Sudbury, MA); Ruichao Shen (Belmont, MA); Jiajun Zhang (Cambridge, MA); Wei Li (Lexington, MA); Hui Cao (Belmont, MA); Xuri Gao (Newtonville, MA); Guoqiang Wang (Belmont, MA); George G. Wu (Waltham, MA); Yat Sun Or (Waltham, MA)

Assignee: Enanta Pharmaceuticals, Inc.

C07D487/10

Abstract

Claims (108)

1 . A process for producing a compound of Formula (A),

wherein R 1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R 2 is selected from the group consisting of hydrogen, optionally substituted-C 1 -C 6 alkyl, and optionally substituted-C 1 -C 6 alkylaryl,

said process comprising the steps of

a) reacting a compound of Formula (W) with formaldehyde, to produce a compound of Formula (B):

wherein G 1 is methyl, ethyl or phenyl;

b) converting the compound of Formula (B) to a compound of Formula (C):

c) subjecting the compound of Formula (C) to rearrangement to produce a compound of Formula (D-1):

d) converting the compound of Formula (D-1) to a compound (e-1):

e) converting the compound (e-1) to a compound of Formula (F-1):

wherein X is an anion selected from the group consisting of Cl − , Br − , and CF 3 CO 2 − ;

f) reacting the compound of Formula (F-1) with a compound of Formula (K)

wherein PG 1 is selected from the group consisting of -Boc, -Cbz, —C(O) OMe, —C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz, and -Teoc, to produce a compound of Formula (L):

g) converting the compound of Formula (L), optionally in the presence of a suitable acid, to a compound of Formula (M) or a salt thereof:

(J-1) reducing a compound of Formula (G-a) to produce a compound of Formula (G-b):

(J-2) oxidizing the compound of Formula (G-b) to produce a compound of Formula (G):

(J-3) reacting the compound of Formula (G) with a compound of Formula (G-1), in the presence of a base to produce a compound of Formula (H):

wherein R 3 is methyl, ethyl, or benzyl;

(J-4) converting the compound of Formula (H) to a compound of Formula (I) via Hemetsberger indole cyclization:

(J-5) reacting the compound (I) with a base to yield a compound of Formula (J):

h) reacting the compound of Formula (M) or salt thereof with compound of Formula (J)

wherein R 1 is as previously defined; to provide a compound of Formula (N):

i) converting the compound of Formula (N) to the compound of Formula (A):

2 . The process of claim 1 , wherein R 1 is F and R 2 is isobutyl.

3 . The process of claim 2 , wherein G 1 is methyl, X is Cl − and PG 1 is Cbz.

4 . The process of claim 1 , wherein

in step (b), the reaction is conducted in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc protection reagent and triethylamine as a base;

in step (c), the reaction is conducted in the presence of N-bromosuccinimide (NBS), acetic acid, at a temperature about −30° C.;

in step (d), the reaction is conducted in the presence of ammonia in methanol;

in step (e), the reaction is conducted in the presence of hydrogen chloride in ethyl acetate, and Compound (F-1) wherein X is chloride is separated by crystallization in N,N-dimethylformamide (DMF);

in step (f), the reaction is conducted in the presence of n-propanephosphonic acid anhydride (T3P) and N-methylmorpholine;

in step (g), PG 1 is Cbz, and the reaction is conducted in the presence of H 2 as hydrogen source, palladium on carbon as catalyst, and optionally conducted in the presence of p-toluenesulfonic acid; alternatively, in step (g), the reaction is conducted in the presence of hydrogen bromide in acetic acid;

in step (J-1), the reducing agent is sodium borohydride and borane-tetrahydrofuran complex;

in step (J-2), the oxidizing agent is sodium hypochlorite with TEMPO;

in step (J-3), R 3 is ethyl, and the reaction is conducted in the presence of sodium methoxide or sodium ethoxide as a base, and CF 3 CO 2 Et as a sacrificial electrophile;

in step (J-4), the reaction is conducted in a flow chemistry reactor in solvent mixture of xylene and methanol, the volume ratio of xylene to methanol is 5:1 at about 200° C. as reaction temperature and under about 25 minutes as reaction time;

in step (J-5), the reaction is conducted in the presence of sodium hydroxide and followed by treatment with hydrogen chloride;

in step (h), the reaction is conducted in the presence of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), and N-methylmorpholine; and

in step (i), the reaction is conducted in the presence of trifluoroacetic anhydride (TFAA), and triethylamine.

5 . A process for producing a compound of Formula (A),

wherein R 1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R 2 is selected from the group consisting of hydrogen, optionally substituted-C 1 -C 6 alkyl, and optionally substituted-C 1 -C 6 alkylaryl,

said process comprising the steps of,

a) reacting a compound of Formula (W), with formaldehyde, to produce a compound of Formula (B):

wherein G 1 is methyl, ethyl or phenyl;

b) converting the compound of Formula (B) to a compound of Formula (C):

c) subjecting the compound of Formula (C) to rearrangement to produce a compound of Formula (D-1):

d) converting the compound of Formula (D-1) to a compound (e-1):

e) converting the compound (e-1) to a compound of Formula (F-1):

wherein X is an anion, selected from the group consisting of Cl − , Br − , and CF 3 CO 2 − ;

f) reacting the compound of Formula (F-1) with a compound of Formula (K):

wherein PG 1 is selected from the group consisting of -Boc, -Cbz, —C(O) OMe, —C(O) OEt, -Fmoc, -Troc, -Moz, -Pnz, and -Teoc, to produce Compound of Formula (L):

g) converting the compound of Formula (L), optionally in the presence of a suitable acid, to a compound of Formula (M) or a salt thereof:

h) reacting the compound of Formula (M) or salt thereof with compound of Formula (J)

wherein R 1 is as previously defined; to provide a compound of Formula (N):

i) converting the compound of Formula (N) to the compound of Formula (A):

6 . The process of claim 5 , wherein R 1 is F and R 2 is isobutyl.

7 . The process of claim 6 , wherein G 1 is methyl, X is Cl − and PG 1 is Cbz.

8 . The process of claim 5 , wherein

In step (b), the reaction is conducted in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc protection reagent and triethylamine as a base;

In step (c), the reaction is conducted in the presence of N-bromosuccinimide (NBS), acetic acid, at a temperature about −30° C.;

In step (d), the reaction is conducted in the presence of ammonia in methanol;

In step (e), the reaction is conducted in the presence of hydrogen chloride in ethyl acetate, and Compound (F-1), wherein X is chloride, is separated by crystallization in N,N-dimethylformamide (DMF);

In step (f), the reaction is conducted in the presence of n-propanephosphonic acid anhydride (T3P) and N-methylmorpholine;

In step (g), PG 1 is Cbz, and the reaction is conducted in the presence of H 2 as hydrogen source, palladium on carbon as catalyst, and optionally conducted in the presence of p-toluenesulfonic acid; alternatively, in step (g), the reaction is conducted in the presence of hydrogen bromide in acetic acid;

In step (h), the reaction is conducted in the presence of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) and N-methylmorpholine; and

In step (i), the reaction is conducted in the presence of trifluoroacetic anhydride (TFAA) and triethylamine.

9 . A process for preparing a compound of Formula (A),

wherein R 1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R 2 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 1 -C 6 alkylaryl,

said process comprising the steps of

(a) reacting a compound of Formula (W) with formaldehyde, to produce a compound of Formula (B):

wherein G 1 is C 1 -C 6 -alkyl or aryl;

(b) converting the compound of Formula (B) to a compound of Formula (C):

(c) subjecting the compound of Formula (C) to rearrangement to produce a compound of Formula (D-1):

(d) converting the compound of Formula (D-1) to a compound (e-1):

(e) converting Compound (e-1) to a compound of Formula (F-1):

wherein X is an anion selected from Cl − , Br − , and CF 3 CO 2 − ;

(f) reacting the compound of Formula (F-1) with a compound of Formula (K):

wherein PG 1 is selected from -Boc, -Cbz, —C(O) OMe, —C(O) OEt, -Fmoc, -Troc, -Moz, -Pnz, and -Teoc; to produce a compound of Formula (L):

(g) converting the compound of Formula (L), optionally in the presence of a suitable acid, to a compound of Formula (M) or a salt thereof:

(h) Reacting the compound of Formula (M) or salt thereof with a compound of Formula (J):

wherein R 1 is as previously defined to provide a compound of Formula (N):

(i) converting the compound of Formula (N) to the compound of Formula (A).

10 . The process of claim 9 , wherein R 1 is fluorine and R 2 is isobutyl.

11 . The process of claim 2 , wherein G 1 is methyl, X is Cl − and PG 1 is Cbz.

12 . A process for producing a compound of Formula (A),

wherein R 1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R 2 is selected from the group consisting of hydrogen, optionally substituted-C 1 -C 6 alkyl, and optionally substituted-C 1 -C 6 alkylaryl,

said process comprising the steps of

a) reacting a compound of Formula (W), with formaldehyde, to produce a compound of Formula (B):

wherein G 1 is C 1 -C 6 -alkyl or aryl;

b) converting the compound of Formula (B) to a compound of Formula (C):

c) subjecting the compound of Formula (C) to rearrangement to produce a compound of Formula (D-1):

d) converting the compound of Formula (D-1) to compound (e-1):

e) converting compound (e-1) to a compound of Formula (F-1):

wherein X is an anion, selected from the group consisting of Cl − , Br − , and CF 3 CO 2 − ;

f) reacting the compound of Formula (F-1) with a compound of Formula (K):

wherein PG 1 is selected from the group consisting of -Boc, -Cbz, —C(O) OMe, —C(O) OEt, -Fmoc, -Troc, -Moz, -Pnz, and -Teoc, to produce Compound of Formula (L):

g) converting the compound of Formula (L), optionally in the presence of a suitable acid, to a compound of Formula (M) or a salt thereof:

alternatively, with a suitable acid, converting Compound of Formula (L) to a salt form of Compound of Formula (M);

(J-1) reducing a compound of Formula (G-a) to produce a compound of Formula (G-b):

(J-2) oxidizing the compound of Formula (G-b) to produce a compound of Formula (G):

(J-2a) reacting the compound of Formula (G) with sodium bisulfite to produce a compound of Formula (G-c):

(J-2b) reacting the compound of Formula (G-c) with a base to produce a compound of Formula (G):

(J-3) reacting the compound of Formula (G) with a compound of Formula (G-1), in the presence of a base to produce a compound of Formula (H):

wherein R 3 is methyl, ethyl, or benzyl;

(J-4) converting the compound of Formula (H) to a compound of Formula (I) via Hemetsberger indole cyclization:

(J-5) reacting the compound (I) with a base to yield a compound of Formula (J), or a salt thereof:

h) reacting the compound of Formula (M) or salt thereof with compound of Formula (J) or salt thereof

wherein R 1 is as previously defined; to provide a compound of Formula (N):

i) converting the compound of Formula (N) to the compound of Formula (A).

Assignments (1)

Continuity (2)

References Cited (155)