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US 2006/0217422 A1Published application
Exo-selective synthesis of himbacine analogs
AssigneeSchering Corporation
InventorsTiruvettipuram Thiruvengadam, Anantha Sudhakar, Ngiap Lim, Daw-long Kwok, George Wu, Tao Wang, Mingsheng Huang, Michael Green
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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:
Claims36
A process for preparing Compound 1 via cyclization,
- said cyclization comprising the steps of:
- a) heating Compound 2 in a solvent to an elevated temperature;
- and
- b) treating with a base,
- wherein Compound 2 is given by the formula
- wherein:
- R1 is selected from the group consisting of OR4 and NR5R6,
- R2 and R3 are independently selected from the group consisting of H, NHR7, OR8, NHC(O)R4, and NO2, or R2 and R3, taken together with the carbon to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms, and
- R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when R1 is NR5R6 then R5 and R6 may, together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms.
6 more elements
A process for preparing Compound 3:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups,
- R12 is selected from the group consisting of halogen, —CF3, C1-C6 alkyl, C1-C6 alkoxy, and —COOR13, wherein R13 is selected from the group consisting of H, C1-C6 alkyl, phenyl, and benzyl, and
- n is an integer ranging from 1 to 5, said process comprising the steps of:
- (a) reducing Compound 1,
- to Compound 4:
- (b) converting Compound 4 to Compound 5:
- (c) converting Compound 5 to Compound 3.
4 more elements
A process for preparing Compound 7 via cyclization:
- said cyclization comprising the steps of:
- 1) heating Compound 8 in a solvent to an elevated temperature;
- and,
- 2) treating with a base,
- wherein Compound 8 is given by the formula:
- wherein R1, and R16 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups or, when taken together with the nitrogen to which they are attached, may form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms.
3 more elements
A process for preparing Compound 3A:
- wherein R11 is selected from the group consisting of alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups;
- and R12 is selected from the group consisting of halogen, —CF3, C1-C6 alkyl, C1-C6 alkoxy, and —COOR13, wherein R13 is selected from the group consisting of H, C1-C6 alkyl, phenyl, and benzyl, and n is an integer ranging from 1 to 5,
- comprising:
- (a) reducing Compound 7
- to Compound 7A′:
- wherein R15 and R16 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups or, when taken together with the nitrogen to which they are attached, may form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms;
- (b) hydrolyzing Compound 7A′ to yield Compound 15:
- (c) aminating Compound 15 to yield Compound 4:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups;
- (d) converting Compound 4 to Compound 17:
- (e) converting Compound 17 to Compound 18:
- (f) converting Compound 18 to Compound 3A:
9 more elements
A process for preparing Compound 20:
- comprising cyclizing Compound 21:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups;
- and,
- R15 and R16 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.
1 more element
A process for preparing Compound 3C:
- comprising:
- (a) reducing Compound 20:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups;
- R15 and R16 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:
- (d) converting Compound 5 to Compound 3C:
4 more elements
A process for preparing Compound 29:
- comprising cyclizing Compound 26:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, and
- R17 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and allyl groups.
A process for preparing Compound 3C:
- comprising:
- (a) reducing Compound 29:
- wherein R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, wherein R4 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, and R17 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:
- (c) converting Compound 5 to Compound 3C:
2 more elements
A compound of the following formula:
- wherein R15 and R16 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 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms.
A compound of the following formula:
- wherein R15 and R16 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 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms.
A compound of the following formula:
- wherein R1 is selected from the group consisting of OR4 and NR5R6, R2 and R3 are independently selected from the group consisting of H, NHR7, OR8, NHC(O)R4, and NO2, or R2 and R3, taken together with the carbon to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms, and
- R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when R1 is NR5R6 then R5 and R6 may, together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms.
A compound of the following formula:
- wherein R1 is selected from the group consisting of OR4 and NR5R6, R2 and R3 are independently selected from the group consisting of H, NHR7, OR8, NHC(O)R4, and NO2, or R2 and R3, taken together with the carbon to which they are attached, form a 3- to 5-membered heterocyclic ring containing 1 to 3 heteroatoms, and
- R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when R1 is NR5R6 then R5 and R6 may, together with the nitrogen to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms.
A compound of the following formula:
- wherein R1 is selected from the group consisting of OR4 and NR5R6,
- R4, R5, and R6 are each independently selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when R1 is NR5R6 then R5 and R6 may, together with the nitrogen to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms;
- and
- R10 and R11 are each independently selected from the group consisting of H, alkyl, alkoxy, C(O)R4, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups.
1 more element
A compound of the following formula:
- wherein R1 is selected from the group consisting of H and R4, and
- R2 and R3 are independently selected from the group consisting of H, NHR5, OR6, NHC(O)R7, and NO2,
- or R2 and R3, taken together with the carbon to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms, and
- R4, R5, R6, and R7 are each independently selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups.
1 more element
A compound of the following formula:
- wherein R1 is selected from the group consisting of OR4 and NR5R6,
- R2 and R3 are independently selected from the group consisting of H, NHR7, OR8, NHC(O)R4, and NO2, or
- R2 and R3, taken together with the carbon to which they are attached, form a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms, and
- R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, or when R1 is NR5R6 then R5 and R6 may, together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms.
1 more element
Dependencies are inferred from the claim text.