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US 2001/0041798 A1Published application
Processes and intermediates in the synthesis of 5-(3-{exo-bicyclo{2.2.1}hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6- tetrahydropyrimidin-2(1H)-one
AssigneePfizer Inc.
InventorsThomas G. LaCour, Charles William Murtiashaw, III
Life of this patent
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Abstract
This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.
Claims27
A process for preparing a compound of the formula
- 27
- comprising:
- (a) reacting, respectively, a compound of the formula
- 28
- with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C1-C6)alkyl, to form an intermediate of the formula
- 29
- wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl;
- and then either:
- (b1) isolating said intermediate of formula V or V′ and reacting it with compounds of the formulae NaOZ and Z′OH, wherein Z and Z′ are defined as above;
- or
- (b2) reacting said intermediate of formula V or V′ in situ with compounds of the formula NaOZ and Z′OH, wherein Z and Z′ are defined as above.
8 more elements
A process for preparing a compound of the formula
- 30
- wherein X and Y are the same and are selected from —CN1, —CONH2, —CO2(C1-C6)alkyl and —CONHOH, or X and Y, taken together, form a group of the formula
- 31
- comprising:
- (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is —CN, —CO2(C1-C6)alkyl, —CONH2 or —CONHOH, in the presence of a base, to form a compound of the formula
- 32
- wherein X and Y are the same and are selected from —CN, —CONH2, —CO2(C1-C6)alkyl and —CONHOH;
- or (2) (a) reacting a compound of the formula II wherein X and Y are both —CN with hydrogen peroxide to form the corresponding bis-amide in which both —CN groups are replaced by —CONH2;
- (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate;
- and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic area wherein X and Y, taken together, form a group of the formula
- 33
- and then (3) reacting said compound of formula II formed in step 1 or 2 above with a triaryl ortrialkylphosphine, an azo dicarboxylate, and either R-(+)-endo-norborneol or S-(−)-endo-norborneol, respectively.
9 more elements
A process for preparing a compound of the formula
- 34
- comprising reacting, respectively, a compound of the formula
- 35
- wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl, with compounds of the formulae NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C1-C6)alkyl.
1 more element
A compound having the formula
- 36
- wherein X an Y are the same and are selected from —CO2(C1-C6)alkyl, —CONH2 and —CONHOH, or X and Y, taken together, form a group of the formula
- 37
A compound having the formula
- 39
- wherein R1 and R2 are independently selected from (C1-C6)alkyl and hydrogen.
A process for preparing a compound of the formula
- 40
- wherein X and Y are the same and are selected from —CO2(C1-C6)alkyl, —CONH2 and —CONHOH, or X and Y, taken together, form a group of the formula
- 41
- comprising:
- (1) reacting 3-hydroxy4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is selected from —CO2(C1-C6)alkyl, —CONH2 and —CONHOH, in the presence of a base, to yield a compound of the formula II wherein X and Y are both —CO2(C1-C6)alkyl, —CONH2 or —CONHOH;
- or (2) (a) reacting a compound of the formula II wherein X and Y are both —CN with hydrogen peroxide to form the corresponding bis-amide in which both —CN groups are replaced by —CONH2;
- (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate;
- and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic urea wherein X and Y, taken together, form a group of the formula
- 42
6 more elements
A process for preparing a compound of the formula
- 43
- wherein X and Y are the same and are selected from —CN1—CONH2, CO2(C1-C6)alkyl and —CONHOH, or X and Y, taken together, form a group of the formula
- 44
- comprising reacting a compound of the formula
- 45
- wherein X and Y are the same and are defined as above, with a triaryl or trialkylphosphine, an azo dicarboxylate and either R(+)-endo-norborneol or S-(−)-endo-norborneol, respectively.
3 more elements
A process for preparing a compound of the formula
- 46
- wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl, comprising reacting, respectively, a compound of the formula
- 47
- with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C1-C6)alkyl.
1 more element
A compound of the formula
- 49
- wherein each R2 is independently selected from (C1-C6)alkyl.
Dependencies are inferred from the claim text.