US 2024/0190873 A1Published application

Method for preparing phosphodiesterase inhibitor

AssigneeTransthera Sciences (Nanjing), Inc.

InventorsLin LI, Hao WANG

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Abstract

The present invention belongs to the technical field of medicine, and specifically relates to the preparation process of compounds, as represented by formulas (I) and (I′), and intermediates thereof. The preparation process of the present invention has lower production cost and generates less three wastes.

Claims14

Dependent claims

A preparation method for a compound of formula (I), comprising the following steps:

step (C′):
in an organic solvent, carrying out a halogenation reaction of (I-4) with a halogenation reagent to give (I-5):
step (D′):
in an organic solvent, carrying out a nucleophilic substitution reaction of (I-5) with (I-6) and a base to give (I):
wherein X is a halogen atom;
M is an alkali metal ion;
X1 is CH, X2 is N, X3 is CR3, and X4 is CH;
R3 is selected from hydrogen, amino, cyano, halogen, carboxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, morpholinyl, C2-6 alkenyl, C1-4 alkylcarbonyl, C1-4 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, C1-4 alkylsulfonyl, C1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl and piperazinyl,
a) wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, C2-6 alkenyl, C1-4 alkylcarbonyl, C1-4 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, C1-4 alkylsulfonyl, C1-4 alkylthio and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, amino, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, cyclopropyl, C1-4 alkylcarbonyloxy, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
and
b) wherein the cyclopropyl, azetidinyl, morpholinyl and piperazinyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and C1-4 alkylcarbonyloxy;
preferably, R3 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, morpholinyl, C2-6 alkenyl, C1-4 alkylaminocarbonyl, (C1-4 alkyl)2aminocarbonyl, and aminocarbonyl,
a) wherein the C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl, (C1-4 alkyl)2aminocarbonyl, and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
and
b) wherein the morpholinyl is unsubstituted or optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino and (C1-4 alkyl)2amino;
more preferably, R3 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl and aminocarbonyl,
wherein the C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl, and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
L is a bond;
ring A is 4-7 membered monocyclic heterocyclyl or 7-12 membered spiro-heterocyclyl, wherein a heteroatom of the 4-7 membered monocyclic heterocyclyl is selected from N;
a heteroatom of the 7-12 membered spiro-heterocyclyl is selected from one of or a combination of two of O and N;
the 7-12 membered spiro-heterocyclyl contains at least one N, and ring A is linked to L by the N atom;
preferably, ring A is a 4-7 membered monocyclic heterocyclyl, wherein a heteroatom of the 4-7 membered monocyclic heterocyclyl is selected from N, and ring A is linked to L by the N atom;
more preferably, ring A is selected from
particularly more preferably, ring A is
each R1 is independently selected from hydrogen, hydroxyl, cyano, halogen, C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl, wherein the C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted with hydroxyl;
preferably, each R1 is independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl, wherein the C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted with hydroxyl;
m is 0, 1 or 2;
R2 is selected from hydrogen.

25 more elements

A preparation method for a compound of formula (I′), comprising the following steps:

step (C):
in an organic solvent, carrying out a halogenation reaction of (I′-4) with a halogenation reagent to give (I′-5):
step (D):
in an organic solvent, carrying out a nucleophilic substitution reaction of (I′-5) with (I′-6) and a base to give (I′):
wherein R1 is C1-6 alkyl;
X is a halogen atom;
M is an alkali metal ion.

4 more elements

Dependencies are inferred from the claim text.

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Abstract

A preparation method for a compound of formula (I), comprising the following steps:

step (C′):
in an organic solvent, carrying out a halogenation reaction of (I-4) with a halogenation reagent to give (I-5):
step (D′):
in an organic solvent, carrying out a nucleophilic substitution reaction of (I-5) with (I-6) and a base to give (I):
wherein X is a halogen atom;
M is an alkali metal ion;
X1 is CH, X2 is N, X3 is CR3, and X4 is CH;
R3 is selected from hydrogen, amino, cyano, halogen, carboxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, morpholinyl, C2-6 alkenyl, C1-4 alkylcarbonyl, C1-4 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, C1-4 alkylsulfonyl, C1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl and piperazinyl,
a) wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, C2-6 alkenyl, C1-4 alkylcarbonyl, C1-4 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, C1-4 alkylsulfonyl, C1-4 alkylthio and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, amino, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, (C1-4 alkyl)2amino, cyclopropyl, C1-4 alkylcarbonyloxy, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
and
b) wherein the cyclopropyl, azetidinyl, morpholinyl and piperazinyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and C1-4 alkylcarbonyloxy;
preferably, R3 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, morpholinyl, C2-6 alkenyl, C1-4 alkylaminocarbonyl, (C1-4 alkyl)2aminocarbonyl, and aminocarbonyl,
a) wherein the C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl, (C1-4 alkyl)2aminocarbonyl, and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
and
b) wherein the morpholinyl is unsubstituted or optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino and (C1-4 alkyl)2amino;
more preferably, R3 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl and aminocarbonyl,
wherein the C1-4 alkyl, C1-4 alkoxy, C2-6 alkenyl, C1-4 alkylaminocarbonyl, and aminocarbonyl are unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5, provided that a valence balance is achieved) groups independently selected from hydroxyl, C1-4 alkoxy, cyclopropyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino, and 4-6 membered heterocyclyl which is unsubstituted or substituted with C1-4 alkyl;
L is a bond;
ring A is 4-7 membered monocyclic heterocyclyl or 7-12 membered spiro-heterocyclyl, wherein a heteroatom of the 4-7 membered monocyclic heterocyclyl is selected from N;
a heteroatom of the 7-12 membered spiro-heterocyclyl is selected from one of or a combination of two of O and N;
the 7-12 membered spiro-heterocyclyl contains at least one N, and ring A is linked to L by the N atom;
preferably, ring A is a 4-7 membered monocyclic heterocyclyl, wherein a heteroatom of the 4-7 membered monocyclic heterocyclyl is selected from N, and ring A is linked to L by the N atom;
more preferably, ring A is selected from
particularly more preferably, ring A is
each R1 is independently selected from hydrogen, hydroxyl, cyano, halogen, C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl, wherein the C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted with hydroxyl;
preferably, each R1 is independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl, wherein the C1-4 alkyl, C1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted with hydroxyl;
m is 0, 1 or 2;
R2 is selected from hydrogen.

25 more elements