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US 12,747,248 B2Granted
Processes for the preparation of substituted spirooxindole derivatives
AssigneeEnanta Pharmaceuticals, Inc.
InventorsKaicheng Zhu, Tao Wang, Xin Zhang, Xiaowen Peng, Ruichao Shen, Jiajun Zhang, Wei Li, Hui Cao, Xuri Gao, Guoqiang Wang, George G. Wu, Yat Sun Or
Life of this patent
Estimating the term…
Abstract
The present invention relates to processes for preparing a compound of Formula (A): or a pharmaceutically acceptable salt or solvate thereof. Compound of Formula (A) and pharmaceutical compositions are useful as SARS-CoV-2 3CL pro inhibitors.
Claims12
A process for producing a compound of Formula (A),
- wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy;
- and R2 is selected from the group consisting of hydrogen, optionally substituted-C1-C6 alkyl, and optionally substituted-C1-C6 alkylaryl,
- said process comprising the steps of
- a) reacting a compound of Formula (W) with formaldehyde, to produce a compound of Formula (B):
- wherein G1 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 CF3CO2−;
- f) reacting the compound of Formula (F-1) with a compound of Formula (K)
- wherein PG1 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 R3 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 R1 is as previously defined;
- to provide a compound of Formula (N):
- i) converting the compound of Formula (N) to the compound of Formula (A):
20 more elements
A process for producing a compound of Formula (A),
- wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy;
- and R2 is selected from the group consisting of hydrogen, optionally substituted-C1-C6 alkyl, and optionally substituted-C1-C6 alkylaryl,
- said process comprising the steps of,
- a) reacting a compound of Formula (W), with formaldehyde, to produce a compound of Formula (B):
- wherein G1 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 CF3CO2−;
- f) reacting the compound of Formula (F-1) with a compound of Formula (K):
- wherein PG1 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 R1 is as previously defined;
- to provide a compound of Formula (N):
- i) converting the compound of Formula (N) to the compound of Formula (A):
14 more elements
A process for preparing a compound of Formula (A),
- wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy;
- and R2 is selected from the group consisting of hydrogen, optionally substituted —C1-C6 alkyl, and optionally substituted —C1-C6 alkylaryl,
- said process comprising the steps of
- (a) reacting a compound of Formula (W) with formaldehyde, to produce a compound of Formula (B):
- wherein G1 is C1-C6-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 CF3CO2−;
- (f) reacting the compound of Formula (F-1) with a compound of Formula (K):
- wherein PG1 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 R1 is as previously defined to provide a compound of Formula (N):
- (i) converting the compound of Formula (N) to the compound of Formula (A).
14 more elements
A process for producing a compound of Formula (A),
- wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy;
- and R2 is selected from the group consisting of hydrogen, optionally substituted-C1-C6 alkyl, and optionally substituted-C1-C6 alkylaryl,
- said process comprising the steps of
- a) reacting a compound of Formula (W), with formaldehyde, to produce a compound of Formula (B):
- wherein G1 is C1-C6-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 CF3CO2−;
- f) reacting the compound of Formula (F-1) with a compound of Formula (K):
- wherein PG1 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 R3 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 R1 is as previously defined;
- to provide a compound of Formula (N):
- i) converting the compound of Formula (N) to the compound of Formula (A).
23 more elements
Dependencies are inferred from the claim text.