Optically active PDE10 inhibitor
View Patent ↗The present invention is directed to a pure enantiomer of 1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, in particular, (S)-1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone. The present invention is also directed a crystal structure of (S)-1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, a pharmaceutical composition of (S)-1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, a method of inhibiting PDE10 with (S)-1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, and a process and particular individual intermediates used in the production of (S)-1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone.
1. A compound having the following structure:
in crystalline form having an X-ray powder diffraction pattern comprising 2θ peaks at 11.2, 18, 22.8, 25.6, and 27.5 when measured using CuKα radiation at about 150 K.
2. A compound having the following structure:
in crystalline form having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 .
3. A process to prepare a compound of Formula (II-a):
wherein
Q is S or O,
X is Cl or Br, and
R 1 , R 2 , and R 3 are each independently C (1-6) alkyl, according to the following General Scheme (I):
which process comprises:
converting boronic acid A1 to carbaldehyde B1 through activation of the boronic acid with an activating reactant A2;
converting carbaldehyde B1 to acetal C1 under acid catalysis with a suitable source of orthoformate;
converting acetal C1 to nitrile D1 through catalyzed cyanation with a metal catalyst and a cyanide source;
hydrolyzing D1 with a suitable acid to give carboxylic acid E1;
converting carboxylic acid E1 to amide F1 with a suitable base, a suitable coupling reagent, and a source amine;
converting amide F1 to a compound of Formula (II) with an anionic coupling reagent having structure H1,
wherein
M is a Group I metal, a Group II metal, Cu, or Zn;
R, R 2 , and R 3 are each independently C (1-6) alkyl;
m is 1, 2, 3, or 4;
p is 1, 2, 3, or 4;
separating a compound of Formula (II-a) from a compound of Formula (II-b) by chiral HPLC;
and optionally converting the compound of Formula (II-a) to a salt.
4. The process of claim 3 , wherein the compound of Formula (II-a) is:
5. A process to prepare a compound of Formula (III-a):
wherein Q is S or O and X is Cl or Br,
according to the following General Scheme (III):
which process comprises:
converting boronic acid A1 to carbaldehyde B1 through activation of the boronic acid with an activating reactant A2;
converting carbaldehyde B1 to acetal C1-1 under acid catalysis with a suitable source of orthoformate;
converting acetal C1-1 to nitrile D1-1 through catalyzed cyanation with a metal catalyst and a cyanide source;
hydrolyzing D1-1 with a suitable acid to give carboxylic acid E1-1;
converting carboxylic acid E1-1 to amide F1-1 with a suitable base, a suitable coupling reagent, and a source amine;
converting amide F1-1 to a compound of Formula (III) with an anionic coupling reagent having structure H1-1,
wherein
M is a Group I metal, a Group II metal, Cu, or Zn;
R is C (1-6 )alkyl;
m is 1, 2, 3, or 4;
p is 1, 2, 3, or 4;
separating a compound of Formula (III-a) from a compound of Formula (III-b) by chiral HPLC;
optionally converting the compound of Formula (III-a) to a salt.
6. The process of claim 5 , wherein the compound of Formula (III-a) is: