process of making...

Details process of making... process of making...

2000-06-29

2002-03-12

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C568S630000, C568S648000, C568S649000, C568S656000

Reexamination Certificate

active

06355813

ABSTRACT:

The present invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferably, the present invention relates to an improved process for preparing indane carboxylates and cyclopentanopyridine derivatives. Advantageously, the present invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof. Such compounds are described in International Application Number: PCT/US94/04603-International Publication Number WO 94/25013 published on Nov. 10, 1994 and in U.S. Pat. No. 5,389,620, as being useful as endothelin receptor antagonists. Also invented are novel intermediates useful in preparing these compounds.
BACKGROUND OF THE INVENTION
Processes for the preparation of indane carboxylates, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid have previously been described. In particular a multistep process to prepare (+) (1S, 2R, 3S)-3-(2carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 6% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4 -methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in 2% overall yield (not including a racemic separation step) from methyl 3-(prop-1-yloxy)benzoylacetate is reported in International Publication Number WO 4/25013, published Nov. 10, 1994. The syntheses of these molecules are complicated by the presence of three chiral centers in each compound.
Processes for the preparation of cyclopentanopyridine derivatives have previously been described. In particular, multistep processes to prepare cyclopentanopyridine derivatives, in low over all yield, are reported in U.S. Pat. No. 5,389,620.
Thus, there is a need in the art for an economical method to prepare indane carboxylates and cyclopentanopyridine derivatives, specifically (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof.
The numerous advantages of the presently invented process and intermediates will become apparent upon review of the following description.
SUMMARY OF THE INVENTION
This invention relates to an improved process for preparing aromatic ring-fused cyclopentane derivatives.
This invention also relates to novel intermediates useful in preparing aromatic ring-fused cyclopentane derivatives.
This invention relates to an improved process for preparing indane carboxylates.
This invention also relates to novel intermediates useful in preparing indane carboxylates.
This invention relates to an improved process for preparing cyclopentanopyridine derivatives.
This invention also relates to novel intermediates useful in preparing cyclopentanopyridine derivatives.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl) -5-(prop-1-yloxy)indane-2-carboxylic acid.
This invention relates to an improved process for preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt.
This invention relates to novel intermediates useful in preparing (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise defined, the term ‘aromatic ring-fused cyclopentane derivatives’ as used herein, is meant the racemic compounds of Formula (1):
wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom;
R
1
is
where R
3
and R
4
are independently H, OH, protected OH, C
1-8
alkoxy, I, Br, Cl, F, CF
3
or C
1-6
alkyl and R
5
is —OCH
2
CO
2
H or —OCH
2
CH
2
OH;
R
2
is
where R
3
and R
4
are as indicated above and
Z is H, OH, or C
1-5
alkoxy;
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (1) are the compounds of Formula (17):
wherein A, B, C, D, R
1
, R
2
and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
By the term indane carboxylates as used herein is meant the racemic compounds of: Formula (2):
wherein R
1
, R
2
and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (2) are the compounds of Formula (18):
wherein R
1
, R
2
and Z are as described in Formula (1); or a pharmaceutically acceptable salt thereof.
By the term cyclopentanopyridine derivatives as used herein is meant the racemic compounds of Formula (3):
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R
1
, R
2
and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
Preferred among the racemic compounds of Formula (3) are the compounds of Formula (19):
wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and
R
1
, R
2
and Z are as described in Formula (1);
or a pharmaceutically acceptable salt thereof.
In Formula (3) compounds, in Formula (19) compounds and in Formula (1) compounds when one of A, B, C or D is a nitrogen atom, preferably A is nitrogen.
Pharmaceutically acceptable salts of the compounds of Formulas (1), (2), (3), (17), (18) and (19) are formed where appropriate by methods well known to those of skill in the art.
Pharmaceutically acceptable salts of (+) (1S, 2R, 3S)-3-[2-2-hydroxyeth-1-yloxy)-4methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylic acid are formed where appropriate by methods well known to those of skill in the art.
By the term “Pr” as used herein is meant n-propyl.
The term ‘activation reaction’ for use herein refers to the numerous reactions and reaction conditions well known to those skilled in the art to effect the introduction of a Br, I, —OSO
2
CF
3
or a —OSO
2
F substituent.
By the term ‘chiral reduction’ as used herein refers to reagents and reaction conditions that effect an enantioselective reduction, preferably using, a chiral catalyst, most preferably using (R)-3,3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo-[1,2-c][1.3.2]oxazaborole (as used hereinafter and in the claims (R)-MeCBS which is available from the Callery Chemical Co. of Evans City, Pa.).
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as used herein utilizes standard chemical terminology and refers to compound (o)
The term (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl&rs

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