US2012302745A1PendingUtilityA1
Exo-selective synthesis of himbacine analogs
Individually held — no corporate assignee on recordPriority: Jan 14, 2005Filed: Aug 2, 2012Published: Nov 29, 2012
Est. expiryJan 14, 2025(expired)· nominal 20-yr term from priority
Inventors:Tiruvettipuram K. ThiruvengadamAnantha SudhakarNgiap-Kie LimDaw-Iong KwokGeorge G. WuTao WangMingsheng HuangMichael Green
A61P 9/10A61P 43/00A61P 7/02C07D 493/10C07D 295/185C07D 405/06C07C 235/28C07D 307/92A61P 29/00C07C 271/24C07D 317/72
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Claims
Abstract
This application discloses a novel process for the synthesis of himbacine analogs, as well as the compounds produced thereby. The synthesis proceeds by alternative routes including the cyclic ketal amide route, the chiral carbamate amide route, and the chiral carbamate ester route. The compounds produced thereby are useful as thrombin receptor antagonists. The chemistry disclosed herein is exemplified in the following synthesis sequence:
Claims
exact text as granted — not AI-modified1 - 18 . (canceled)
19 . A process for preparing a compound of the formula
wherein:
R 10 and R 11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R 4 , cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R 4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups; and,
R 15 and R 16 are each independently selected from the group consisting of —H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups or, when together with the nitrogen to which they are attached, may form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms
comprising:
(a) converting Compound 9:
to Compound 10:
and,
(b) converting Compound 10 to Compound 21.
20 . The process of claim 19 , wherein the step of converting Compound 10 to Compound 21 comprises:
(a) reducing Compound 10 to Compound 11:
and,
(b) reacting Compound 11 with Compound 22:
to yield Compound 21.
21 . The process of claim 19 , wherein the step of converting Compound 10 to Compound 21 comprises:
(a) reacting Compound 10 with Compound 22
to yield Compound 23:
and,
(b) reducing Compound 23 to yield Compound 21.
22 . A process for preparing Compound 3C:
comprising:
(a) reducing Compound 20:
wherein R 10 and R 11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R 4 , cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R 4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups;
R 15 and R 16 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when together with the nitrogen to which they are attached, may form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms to yield Compound 25:
(b) hydrolyzing Compound 25 to Compound 4:
(c) converting Compound 4 to Compound 5:
and,
(d) converting Compound 5 to Compound 3C:
23 . The process of claim 22 , wherein the step of converting Compound 5 to Compound 3C comprises reacting Compound 5 with Compound 19:
to yield Compound 3C.
24 . The process of claim 19 , wherein Compound 9 is converted to Compound 10 by a process selected from the group consisting of:
wherein P is a protecting group and X is a leaving group and is selected from the group consisting of Cl, Br, I, and heterocyclic rings,
L is a ligand and is selected from PR′ 3 wherein R′ is selected from the group consisting of alkyl, aryl, alkylaryl, and NR″, wherein R″ is selected from the group consisting of alkyl, aryl, and alkylaryl,
Y is selected from the group consisting of Cl, Br, I, and R′″COO, wherein R′″ is selected from the group consisting of alkyl, aryl, alkylaryl, and arylalkyl, and
n ranges from 0 to 4.
25 . A process for preparing Compound 29:
comprising cyclizing Compound 26:
wherein R 10 and R 11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R 4 , cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R 4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, and
R 17 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and allyl groups.
26 . The process of claim 25 , wherein Compound 26 is prepared by a process comprising:
(a) reacting Compound 27:
with Compound 22:
to yield Compound 28:
and,
(b) reducing Compound 28 to yield Compound 26.
27 . The process of claim 26 wherein compound 27 is prepared by converting Compound 9:
to Compound 27:
28 . A process for preparing Compound 3C:
comprising:
(a) reducing Compound 29:
wherein R 10 and R 11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R 4 , cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R 4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, and R 17 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and allyl groups, to yield Compound 4:
(b) converting Compound 4 to Compound 5:
and,
(c) converting Compound 5 to Compound 3C:
29 . The process of claim 28 , wherein the step of converting Compound 5 to Compound 3C comprises reacting Compound 5 with Compound 19:
to yield Compound 3C.
30 - 36 . (canceled)
37 . A compound of the formulaJoin the waitlist — get patent alerts
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