Process and intermediates in the synthesis of...

Details Process and intermediates in the synthesis of... Process and intermediates in the synthesis of...

1999-10-28

2001-08-14

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C560S025000, C560S029000, C562S448000

Reexamination Certificate

active

06274733

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
International Patent Application WO 87/06576, which was published on Nov. 5, 1987, refers to 5-(3-[(2-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, and states that it is useful as an antidepressant. International Patent Application WO 91/07178, which was published on May 30, 1991, refers to the utility of this compound in the treatment of asthma, inflammatory airway diseases and skin diseases.
U.S. Pat. No. 5,270,206, which issued on Dec. 14, 1993, refers to a process for preparing (+)-(2R)-endo-norborneol (also referred to as (2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S,2R,4R)-bicyclo[2.2.1]heptan-2-ol) and (−)-(2S)-endo-norborneol (also referred to as (2S)-endo-bicyclo[2.2.1]heptan-2-ol or (1R,2S,4S)-bicyclo[2.2.1]heptan-2-ol), and to their further conversion into the pharmaceutically active agents 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, depicted below,
and 5-(3-[(2R)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, depicted below,
All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties.
SUMMARY OF THE INVENTION
This invention relates to a compound having the formula
wherein X and Y are the same and are selected from —CN, —CO
2
(C
1
-C
6
)alkyl, —CONH
2
and —CONHOH, or X and Y, taken together, form a group of the formula
This invention also relates to a compound having the formula
wherein R
1
and R
2
are independently selected from (C
1
-C
6
)alkyl and hydrogen.
This invention also relates to compounds of the formulae
wherein each R
2
is independently selected from (C
1
-C
6
)alkyl.
This invention also relates to a process for preparing a compound of the formula
wherein X and Y are the same and are selected from —CN, —CO
2
(C
1
-C
6
)alkyl, —CONH
2
and —CONHOH, or X and Y, taken together, form a group of the formula
comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH
2
CO
2
H, wherein X is defined as above, in the presence of a base, preferably a tertiary amine, to yield a compound of the formula II wherein X and Y are both —CN, —CO
2
(C
1
-C
6
)alkyl, —CONH
2
or —CONHOH; or (2) (a) reacting a compound of the formula II wherein X and Y are both —CN with hydrogen peroxide, preferably basic aqueous hydrogen peroxide, to form the corresponding bis-amide in which both —CN groups are replaced by —CONH
2
; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base (e.g., an alkali metal alkoxide containing from one to six carbon atoms or an alkali metal hydroxide), to form a cyclic urea wherein X and Y, taken together, form a group of the formula “a”, as depicted above.
This invention also relates to a process for preparing a compound of the formula
wherein X and Y are defined as for formula II above, comprising reacting a compound of formula II, as defined above, with, respectively, R-(+)-endo-norborneol or S-(−)-endo-norborneol, a triaryl or trialkyl phosphine and an azo dicarboxylate.
This invention also relates to a process for preparing a compound of the formula
wherein X and Y are the same and are selected from —CN, —CONH
2
, CO
2
(C
1
-C
6
)alkyl and —CONHOH, or X and Y, taken together, form a group of the formula
comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH
2
CO
2
H, wherein X is —CN, —CO
2
(C
1
-C
6
)alkyl, —CONH
2
or —CONHOH, in the presence of a base, preferably a tertiary amine, to form a compound of the formula
wherein X and Y are the same and are selected from —CN, —CONH
2
, —CO(C
1
-C
6
)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 —CONH
2
; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base (e.g., an alkali metal alkoxide containing from one to six carbon atoms), to form a cyclic area wherein X and Y, taken together, form a group of the formula
and then (3) reacting said compound of formula II so formed in step 1 or 2 above with, respectively, R-(+)-endo-norborneol or S-(−)-endo-norborneol, a triaryl or trialkyl phosphine and an azo dicarboxylate.
This invention also relates to a process for preparing a compound of the formula
wherein R
1
and R
2
are independently selected from hydrogen and (C
1
-C
6
)alkyl, comprising reacting, respectively, a compound of the formula
with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C
1
-C
6
)alkyl.
This invention also relates to a process for preparing a compound of the formula
comprising reacting, respectively, a compound of the formula
wherein R
1
and R
2
are independently selected from hydrogen and (C
1
-C
6
)alkyl with compounds of the formulae NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C
1
-C
6
)alkyl.
This invention also relates to a process for preparing a compound of the formula
comprising:
reacting, respectively, a compound of the formula
 with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ are independently selected from hydrogen and (C
1
-C
6
)alkyl, to form an intermediate of the formula
 wherein R
1
and R
2
are independently selected from hydrogen and (C
1
-C
6
)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.
As used herein, the expression “reaction inert solvent” refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product or products.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
Formulae II, and V and V′ above include compounds identical to those depicted but for the fact that one or more hydrogen, carbon, nitrogen or oxygen atoms are replaced by radioactive or stable isotopes thereof. Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
DETAILED DESCRIPTION OF THE INVENTION
The processes of the this invention and methods of preparing the novel compounds of this invention are described in the following reaction schemes and discussion. Unless otherwise indicated, the substituents X, Y, R, R
1
, R
2
, R
3
, and R
4
, group “(a)” and formulae II, III, III′, IV, IV′, V, V′, VI and VI′ in the reaction schemes and discussion t

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