US2018057484A1PendingUtilityA1
Processes and intermediates for the preparation of a pde10 inhibitor
Est. expiryApr 28, 2034(~7.8 yrs left)· nominal 20-yr term from priority
Inventors:Neil S. CutshallJennifer Lynn GageThomas L. LittleWayne Douglas LukeElisabeth C. A. BrotMarco JonasMichael James McdermottKarl E. Reineke
C07D 417/10C07F 1/02C07D 307/40C07F 3/02C07D 413/10A61K 31/433C07F 19/00A61K 31/4245C07D 285/12
52
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Claims
Abstract
The present invention is directed to an improved process for the preparation of compounds of Formula (II) and Formula (III), which are useful in the inhibition of PDE10. In particular, the present invention is directed to an improved process for the preparation 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, which is useful in the inhibition of PDE10.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process to prepare a compound of Formula (II):
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; and
optionally converting the compound of Formula (II) to a salt.
2 . The process of claim 1 , wherein Q is O.
3 . The process of claim 1 , wherein Q is S.
4 . The process of any one of claims 1 to 3 , wherein X is Cl.
5 . The process of any one of claims 1 to 3 , wherein X is Br.
6 . The process of any one of claims 1 to 5 , wherein M is a Group II metal.
7 . The process of any one of claims 1 to 6 , wherein M is Mg.
8 . The process of any on of claims 1 to 7 , wherein R 1 is methyl, ethyl or propyl.
9 . The process of any one of claims 1 to 8 , wherein R 1 is ethyl.
10 . The process of any one of claims 1 to 9 , wherein R 2 is methyl, ethyl or propyl.
11 . The process of any one of claims 1 to 10 , wherein R 2 is methyl.
12 . The process of any one of claims 1 to 11 , wherein R 3 is methyl, ethyl or propyl.
13 . The process of any one of claims 1 to 12 , wherein R 3 is methyl.
14 . The process of any one of claims 1 to 13 , wherein R is butyl.
15 . The process of any one of claims 1 to 14 , wherein the acid catalyst used to create acetal C1 is para-toluenesulfonic acid monohydrate.
16 . The process of any one of claims 1 to 15 , wherein the suitable source of orthoformate is triethyl orthoformate.
17 . The process of any one of claims 1 to 16 , wherein the metal catalyst of the cyanation step is a cobalt salt.
18 . The process of any one of claims 1 to 17 , wherein the metal catalyst of the cyanation step is CoCl 2 .
19 . The process of any one of claims 1 to 18 , wherein the cyanide source is trimethylsilyl cyanide.
20 . The process of any one of claims 1 to 19 , wherein the suitable acid of the hydrolysis step is HCl.
21 . The process of any one of claims 1 to 20 , wherein the suitable base of the amidation step is triethylamine.
22 . The process of any one of claims 1 to 21 , wherein the suitable coupling reagent of the amidation step is propylphosphonic anhydride.
23 . The process of any one of claims 1 to 22 , wherein the source amine is N,O-dimethylhydroxylamine hydrochloride.
24 . The process of claim 1 , wherein the compound of Formula (II) is:
25 . The process of claim 1 , wherein the compound of Formula (II) is:
26 . The process of claim 1 , wherein the compound of Formula (II) is:
27 . A process to prepare a compound of Formula 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,
X is Cl or Br,
m is 1, 2, 3, or 4, and
p is 1, 2, 3, or 4;
according to the following General Scheme (II):
which process comprises:
preparing in a solvent solution a lithium alkyl metal base from R n —Li and a metal halide comprising M, wherein n is 1, 2, 3 4, or 5; and
preparing a mixed metal lithiate H1 from G1 and the lithium alkyl metal base.
28 . The process of claim 27 , wherein R 2 is methyl, ethyl, or propyl.
29 . The process of claim 27 or 28 , wherein R 2 is methyl.
30 . The process of any one of claims 27 to 29 , wherein R 3 is methyl, ethyl, or propyl.
31 . The process of any one of claims 27 to 30 , wherein R 3 is methyl.
32 . The process of any one of claims 27 to 31 , wherein R is butyl.
33 . The process of any one of claims 27 to 32 , wherein X is Cl.
34 . The process of any one of claims 27 to 33 , wherein X is Br.
35 . The process of any one of claims 27 to 34 , wherein M is a Group II metal.
36 . The process of any one of claims 27 to 35 , wherein M is Mg.
37 . The process of any one of claims 27 to 36 , wherein the lithium alkyl metal base is a lithium alkylmagnesate base.
38 . The process of any one of claims 27 to 37 , wherein the lithium alkyl metal base is Bu 4 MgLi 2 .
39 . The process of any one of claims 27 to 38 , wherein the compound of Formula H1 is:
40 . A process to prepare a compound of Formula (III):
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; and
optionally converting the compound of Formula (III) to a salt.
41 . The process of claim 40 , wherein Q is O.
42 . The process of claim 40 , wherein Q is S.
43 . The process of any one of claims 40 to 42 , wherein X is Cl.
44 . The process of any one of claims 40 to 42 , wherein X is Br.
45 . The process of any one of claims 40 to 44 , wherein M is a Group II metal.
46 . The process of any one of claims 40 to 45 , wherein M is Mg.
47 . The process of any one of claims 40 to 46 , wherein R is butyl.
48 . The process of any one of claims 40 to 47 , wherein the acid catalyst used to create acetal C1-1 is para-toluenesulfonic acid monohydrate.
49 . The process of any one of claims 40 to 48 , wherein the suitable source orthoformate is triethyl orthoformate.
50 . The process of any one of claims 40 to 49 , wherein the metal catalyst of the cyanation step is a cobalt salt.
51 . The process of any one of claims 40 to 50 , wherein the metal catalyst of the cyanation step is CoCl 2 .
52 . The process of any one of claims 40 to 51 , wherein the cyanide source is trimethylsilyl cyanide.
53 . The process of any one of claims 40 to 52 , wherein the suitable acid of the hydrolysis step is HCl.
54 . The process of any one of claims 40 to 53 , wherein the suitable base of the amidation step is triethylamine.
55 . The process of any one of claims 40 to 54 , wherein the suitable coupling reagent of the amidation step is propylphosphonic anhydride.
56 . The process of any one of claims 40 to 55 , wherein the source amine is N,O-dimethylhydroxylamine hydrochloride.
57 . The process of claim 40 , wherein the compound of Formula (III) is:
58 . The process of claim 40 , wherein the compound of Formula (III) is:
59 . The process of claim 40 , wherein the compound of Formula (III) is:
60 . A process to prepare a compound of Formula H1-1:
wherein
M is a Group I metal, a Group II metal, Cu, or Zn,
R is C (1-4) alkyl,
X is Cl or Br,
m is 1, 2, 3, or 4, and
p is 1, 2, 3, or 4;
according to the following General Scheme (IV):
which process comprises:
preparing in a solvent solution a lithium alkyl metal base from R n —Li and a metal halide comprising M, wherein n is 1, 2, 3 4, or 5; and
preparing a mixed metal lithiate H1-1 from G1-1 and the lithium alkyl metal base.
61 . The process of claim 60 , wherein X is Cl.
62 . The process of claim 60 , wherein X is Br.
63 . The process of any one of claims 60 to 62 , wherein M is a Group II metal.
64 . The process of any one of claims 60 to 63 , wherein M is Mg.
65 . The process of any one of claims 60 to 64 , wherein R is butyl.
66 . The process of any one of claims 60 to 65 , wherein the lithium alkyl metal base is a lithium alkylmagnesate base.
67 . The process of any one of claims 60 to 66 , wherein the lithium alkyl metal base is Bu 4 MgLi 2 .
68 . The process of any one of claims 60 to 67 , wherein the compound of Formula H1-1 is:
69 . A compound having the structure of Formula 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,
X is Cl or Br,
m is 1, 2, 3, or 4, and
p is 1, 2, 3, or 4.
70 . A compound having the structure of Formula H1-1:
wherein
M is a Group I metal, a Group II metal, Cu, or Zn,
R is C (1-4) alkyl,
X is Cl or Br,
m is 1, 2, 3, or 4, and
p is 1, 2, 3, or 4.
71 . The compound of claim 69 or 70 , wherein M is magnesium.
72 . A compound having the structure of Formula H1-1a:
wherein X is Cl or Br.
73 . The compound of any one of claims 69 to 72 , wherein X is Cl.
74 . The compound of any one of claims 69 to 72 , wherein X is Br.
75 . The compound of any one of claims 69 to 73 , having the following structure:
76 . A compound having the following structure:
77 . A compound having the following structure:Cited by (0)
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