Method for producing 3,3-diarylpropylamines

Details Method for producing 3,3-diarylpropylamines Method for producing 3,3-diarylpropylamines

2003-07-14

2004-10-26

Solola, Taofiq (Department: 1626)

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

Organic compounds

Oxygen containing

C568S708000

Reexamination Certificate

active

06809225

ABSTRACT:

The invention relates to a novel method for producing substituted 3,3-diarylpropylamine derivatives. In particular, it relates to the production of such compounds by hydrocarbonylation/hydroformylation with subsequent reductive amination.
The abovementioned 3,3-diarylpropylamine derivatives are used in the treatment of urinary incontinence and other spasmogenic conditions (see WO 99/58478). The methods described there for producing the 3,3-diphenylpropylamine derivatives are for the most part multi-stage and for the production of optically active compounds require for the most part enantiomer separation.
The underlying object of the invention is, therefore, to provide new methods for the production of substituted 3,3-diarylpropylamine derivatives, that are simpler than the ones described in the state of the art, i.e. involve less stages, and that, apart from this, allow a stereo-selective synthesis of the target compounds.
The object of the invention is a method for producing 3,3-diarylpropylamines of the general formula I
wherein
Ar represents a substituted or unsubstituted aryl radical,
X represents H, OH or OR
3
,
Y represents Cl, Br, I, CN, CHO, CH
2
OR, COOH, COOR, wherein R represents C
1
-C
10
-alkyl or a substituted or unsubstituted aryl radical, or C
1
-C
10
-alkyl,
R
1
, R
2
represents C
1
-C
10
-alkyl or C
3
-C
8
-cycloalkyl, wherein R
1
and R
2
can be linked to form a cyclical structure,
and wherein R
3
represents a radical, that is derived from one of the following compounds:
(i) the amino acids D-proline, L-proline, D-alanine, L-alanine, D-asparagine, L-asparagine, D-asparagine acid, L-asparagine acid, D-glutamine, L-glutamine, D-glutamine acid, L-glutamine acid, D-phenylalanine, L-phenylalanine, D-histidine, L-histidine, D-leucine, L-leucine, D-serine, L-serine, L-threonine, D-threonine, D-tryptophane, L-tryptophane, D-tyrosine, L-tyrosine, D-valine, L-valine, D-cysteine, L-cysteine, D-methionine, L-methionine, D-isoleucine, L-isoleucine, or the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(ii) the amino acids N-diphenylphosphanyl-D-alanine, N-di-phenylphosphanyl-L-alanine, N-diphenylphosphanyl-D-proline, N-diphenylphosphanyl-L-proline, N-diphenylphosphanyl-D-phenylalanine, N-diphenylphosphanyl-L-phenylalanine, and the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(iii) &agr;-hydroxycarboxylic acid derivatives of the general formula
 respectively in the form of both optical antipodes, wherein R
4
represents a linear or branched C
1
-C
10
-alkyl group or cycloalkyl group or a substituted or unsubstituted aryl radical and R
5
represents C
1
-C
10
-alkyl, cycloalkyl, acyl, alkoxycarbonyl, benzoyl, diphenylphosphanyl, dicyclohexylphosphanyl or diarylphosphanyl,
(iv) the compounds of the general formula
 wherein R
6
represents a substituent selected from the group comprising PPh
2
, P(C
6
H
11
)
2
, P(aryl)
2
, alkyl, acyl, alkoxycarbonyl, benzoyl, arylcarbonyl, diarylphosphanyl and dicyclohexylphosphanyl, and their stereoisomers,
(v) the compounds of the general formula
 wherein R
7
represents a linear or branched C
1
-C
10
-alkyl group or a substituted or unsubstituted aryl radical, and stereoisomers of this,
(vi) the acids
 (R)-acetoxyphenylacetic acid,
 (R)- and (S)-1,4-benzodioxane-2-carboxylic acid,
 (R)-(−)- and (S)-(+)-hexahydro-acetoxymandelic acid,
 (2R, 3S)-2,3-O-isopropylidene-2,3-dihydroxybutyric acid and its stereoisomers,
 (+)- and (−)-menthyloxyacetic acid,
 (R)- and (S)-3-phenyl-2-acyloxypropionic acid,
 (R)- and (S)-acetoxymandelic acid,
 (R)- and (S)-&agr;-methoxy-&agr;-trifluoromethylphenylacetic acid,
 (S)-(+)-alpha-methoxyphenylacetic acid,
 (R)- and (S)-5-oxo-tetrahydrofurane-2-carboxylic acid,
 and the alcohols that are produced from these acids by reduction of the carboxylic acid function to the hydroxymethylene unit,
(vii) compounds of the general formula
 wherein R
8
represents a substituted or unsubstituted aryl radical and R
9
a hydrogen or a linear or branched C
1
-C
10
-alkyl radical,
(viii) &agr;-naphthol, &bgr;-naphthol or (R)- or (S)-1-(9-anthryl)-2,2,2-trifluoroethanol,
(ix) 2-methylamino-1-phenyl-propan-1-ol (ephedrine) in all stereomer forms,
or R
3
represents one of the following radicals:
(x) phosphite radicals of the general formula —P(OR
10
) (OR
11
), wherein R
10
and R
11
can be the same or different and represent an if necessary polycyclic or bridged aryl radical,
(xi) C
1
-C
10
-alkyl, branched or linear,
(xii) acyl,
(xiii) benzyl or substituted benzyl radicals,
characterised in that compounds of the general formula (II)
 wherein X, Y and Ar are as defined above, are transformed together with carbon monoxide (CO) and hydrogen (H
2
)in the presence of a transition metal catalyst and the resultant oxo compounds are allowed to react in the presence of a transition metal catalyst with an amine of the general formula HNR
1
R
2
, wherein R
1
and R
2
are as defined above.
In formula I, the substituent X represents hydrogen (H), hydroxy (OH) or the group OR
3
.
Here, the substituent R
3
can have the meaning assigned to substituents R and R′ in claim 1 of patent WO 99/58478.
R
3
preferably represents a radical that is derived from the following compounds and alcohols:
(i) the amino acids D-proline, L-proline, D-alanine, L-alanine, D-asparagine, L-asparagine, D-asparagine acid, L-asparagine acid, D-glutamine, L-glutamine, D-glutamine acid, L-glutamine acid, D-phenylalanine, L-phenylalanine, D-histidine, L-histidine, D-leucine, L-leucine, D-serine, L-serine, L-threonine, D-threonine, D-tryptophane, L-tryptophane, D-tyrosine, L-tyrosine, D-valine, L-valine, D-cysteine, L-cysteine, D-methionine, L-methionine, D-isoleucine, L-isoleucine, or the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit.
 In these amino acid radicals, the bonding to the oxygen atom takes place according to the formula —O—R
3
via the OH group of the abovementioned amino acids, as shown in the following graphic formula:
 bzw. = or
(ii) Furthermore, the substituent R
3
can be derived from the following amino acid derivatives:
 the amino acids N-diphenylphosphanyl-D-alanine, N-diphenylphosphanyl-L-alanine, N-diphenylphosphanyl-D-proline, N-diphenylphosphanyl-L-proline, N-diphenylphosphanyl-D-phenylalanine, N-diphenylphosphanyl-L-phenylalanine, and the alcohols that are produced by these amino acids by reduction of the carboxylic acid function to the hydroxymethylene unit.
(iii) According to a further embodiment R
3
can be derived from the following &agr;-hydroxycarboxylic acids:
 &agr;-hydroxycarboxylic acid derivatives of the general formula
 respectively in the form of both optical antipodes, wherein R
4
represents a linear or branched C
1
-C
10
-alkyl group or cycloalkyl group or a substituted or unsubstituted aryl radical and R
5
represents C
1
-C
10
-alkyl, cycloalkyl, acyl, alkoxycarbonyl, benzoyl, diphenylphosphanyl, dicyclohexylphosphanyl or diarylphosphanyl.
 Preferred examples are (R)- and (S)-acetoxy-phenylacetic acid, (S)-(+)- and R-(−)-alphamethoxyphenylacetic acid, (R)- and (S)-3-phenyl-2-acyloxypropionic acid.
(iv) R
3
can, furthermore, be derived from the carboxylic acids or alcohols shown below:
 wherein R
6
represents a substituent selected from the group comprising PPh
2
, alkyl, acyl, alkoxycarbonyl, benzoyl, arylcarbonyl, diphenylphosphanyl, diarylphosphanyl and dicyclohexylphosphanyl, and stereoisomers of these.
(v) Furthermore, R
3
be derived from the carboxylic acids or alcohols shown below:
 wherein R
7
represents a linear or branched C
1
-C
10
-alkyl group or a substituted or unsubstituted aryl radical, and stereoisomers of this.
(vi) Furthermore, the substituent R
3
can be derived from one of the carboxylic acids

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