Preparation of (R -2-alkyl-3-phenylpropionic acids

Details Preparation of (R -2-alkyl-3-phenylpropionic acids Preparation of (R -2-alkyl-3-phenylpropionic acids

2003-01-02

2004-01-27

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C562S450000, C502S162000, C556S021000

Reexamination Certificate

active

06683206

ABSTRACT:

The invention relates to a stereoselective process for the preparation of (R)-2-alkyl-3-phenyl-propionic acids and intermediate products obtained in the process steps.
In EP-A-0 678 503, &dgr;-amino-&ggr;-hydroxy-&ohgr;-aryl-alkanecarboxamides are described which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing processes described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
In a new process, one starts from 2,7-dialkyl-8-aryl-4-octenoyl amides, whose double bond is simultaneously halogenated in the 5-position and hydroxylated in the 4-position under lactonization, then the halogen is substituted by azide, the lactone amidated and the azide then transferred to the amine group. The desired alkanecarboxamides are obtained with the new process both in high total yields and in a high degree of purity, and selectively pure diastereomers can be prepared. The halolactonization of process step a), the azidation of process step b), and the azide reduction of process step d) are described by P. Herold in the Journal of Organic Chemistry, Vol. 54 (1989), pages 1178-1185.
The 2,7-dialkyl-8-aryl-4-octenoyl amides may correspond for example to formula A,
and especially to formula A1
wherein R
1
and R
2
are, independently of one another, H, C
1
-C
6
alkyl, C
1
-C
6
halogenalkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, or C
1
-C
6
alkoxy-C
1
-C
6
alkyloxy, R
3
is C
1
-C
6
alkyl, R
4
is C
1
-C
6
alkyl, R
6
is C
1
-C
6
alkyl, R
5
is C
1
-C
6
alkyl or C
1
-C
6
alkoxy, or R
5
and R
6
together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH
2
CH
2
O—C(O)— substituted if necessary with C
1
-C
4
alkyl, phenyl or benzyl.
The compounds of formulae A and Al are obtainable by reacting a compound of formula B
as racemate or enantiomer, with a compound of formula C, as racemate or enantiomer,
wherein R
1
to R
4
, R
5
and R
6
are as defined above, Y is Cl, Br or I and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably Br and especially Cl.
The compounds of formula B are known from EP-A-0 678 503. The compounds of formula C may be prepared from amidation of the corresponding carbonic esters, amides, or halides. The formation of carboxamides from carbonic esters and amines in the presence of trialkyl aluminium or dialkyl aluminium halide, for example using trimethyl aluminium or dimethyl aluminium chloride, is described by S. M. Weinreb in Org. Synthesis, VI, page 49 (1988). The carbonic esters are obtainable by the reaction of trans-1,3-dihalogenpropene (for example, trans-1,3-dichlorepropene) with corresponding carbonic esters in the presence of strong bases, for example alkali metal amides.
A satisfactory solution for the stereoselective preparation of compounds of formula B has not yet been found, especially with regard to an industrial process. Surprisingly it has now been found that 2-alkyl-3-phenylpropionic acids can be stereoselectively prepared with high yields in only three process steps. When suitably substituted benzaldehydes are condensed with carbonic esters to form 2-alkyl-3-hydroxy-3-phenylpropionic acid esters, the desired diastereomers are obtainable in surprisingly high yields mostly as crystalline compounds which can be readily isolated. After conversion of the hydroxy group to a leaving group, 2-alkylcinnamic acid esters are then formed by elimination with strong bases with surprisingly high regioselectivity. The carboxylic acids obtained after saponification can in turn be surprisingly hydrogenated in the presence of homogeneous, asymmetric hydrogenation catalysts to form practically enantiomer-pure 2-alkyl-3-phenylpropionic acids. These acids can then be reduced in a manner known per se to form enantiomer-pure alcohols, from which the compounds of formula B are obtainable by halogenation.
The object of the invention is a process for the preparation of compounds of formula I,
wherein R
1
and R
2
are, independently of one another, H, C
1
-C
6
alkyl, C
1
-C
6
halogenalkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, or C
1
-C
6
alkoxy-C
1
-C
6
alkyloxy, and R
3
is C
1
-C
6
alkyl, comprising
(a) the reaction of a compound of formula II
wherein R
1
and R
2
are as defined above, with a compound of formula III,
R
3
−CH
2
−COOR
7
  (III),
wherein R
3
is as defined above, to form a compound of IV,
wherein R
7
is C
1
C
12
alkyl, C
3
-C
8
cycloalkyl, phenyl or benzyl,
(b) the isolation of the crystalline compound of formula IV, the conversion of the OH group to a leaving group, and the reaction of a compound containing a leaving group in the presence of a strong base to form a compound of formula V,
(c) the hydrolysis of carbonic esters of formula V to form the carboxylic acid of formula VI,
(d) the hydrogenation of the carboxylic acid of formula VI in the presence of hydrogen and catalytic quantities of a metal complex as asymmetric hydrogenation catalyst, comprising metals from the group of ruthenium, rhodium and iridium, to which the chiral bidentate ligands are bonded, to form a compound of formula I.
R
1
and R
2
may be a linear or branched alkyl and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
R
1
and R
2
may be a linear or branched halogenalkyl and preferably comprise 1 to 4 C atoms, 1 or 2 C atoms being especially preferred. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
R
1
and R
2
may be a linear or branched alkoxy and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
R
1
and R
2
may be a linear or branched alkoxyalkyl. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
R
1
and R
2
may be linear or branched C
1
-C
6
alkoxy-C
1
-C
6
alkyloxy. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R
1
is methoxy-C
1
-C
4
alkyloxy or ethoxy-C
1
-C
4
alkyloxy, and R
2
is preferably methoxy or ethoxy. Quite especially preferred are compounds of formula I, wherein R
1
is 1-methoxyprop-3-yloxy and R
2
is methoxy.
R
3
may be a linear or branched alkyl and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R
3
in compounds of formula I is isopropyl.
Especially preferred are compounds of formula I wherein R
1
is ethoxy-n-propoxy, R
2
is methoxy and R
3
is isopropyl.
R
7
is preferably C
1
-C
6
alkyl, C
1
-C
4
alkyl being especially preferred; some examples are methyl, ethyl, n-propyl and n-butyl.
The starting compounds of formulae II and III used in process step a) are known or can be prepared in a manner similar to known processes. Compounds of formula II are described in EP-A 0 678 503. The reaction is advantageously carried out at low temperatures, for example 0-40° C., in the presence of at least equivalent quantities of strong bases.

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