Shortened synthesis of 3,3-diarylpropylamine derivatives

Details Shortened synthesis of 3,3-diarylpropylamine derivatives Shortened synthesis of 3,3-diarylpropylamine derivatives

2002-12-09

2004-10-26

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C562S441000, C549S273000

Reexamination Certificate

active

06809214

ABSTRACT:

In particular, the invention relates to a process for the production of a compound of formula II
and to pharmaceutically valuable intermediates.
From U.S. Pat. No. 5,559,269 a process for the production of a compound of formula II is known. This process comprises 11 process steps before this compound is obtained. The R enantiomer is obtained in this process by resolution of racemates with a chiral acid in process step 5.
From PCT/EP99/03212=WO 99/58478, a process for the production of a compound of formula II is known, which comprises 12 process steps. According to this, the resolution of racemates takes place using a chiral base in process step 2.
Both processes have the disadvantages that, owing to the large number of process steps involved in the synthesis, they are very complex and lead to an unsatisfactory yield.
The object of the present invention is therefore to avoid the above-mentioned disadvantages.
Surprisingly, this object has been achieved in that a process is provided which comprises only 6 process steps, in which the necessary resolution of racemates takes place as early as step 1 of the process and which has the features mentioned in the claims.
To produce 3,3-diarylpropylamines of the general formula I mentioned above, 4-hydroxybenzoic acid or its low alkyl esters (PHB esters; para-hydroxybenzoates), preferably its methyl esters according to formula 1, are used as starting compounds,
which are reacted with cinnamic acid to form a compound of the general formula 2
wherein
R has the meaning of hydrogen, straight-chained or branched C
1
-C
6
alkyl, preferably methyl or isopropyl. By conducting the reaction in a particular way, starting from 4-hydroxybenzoates, the free, crystalline acid according to formula 2a can be obtained directly as a reaction product according to the process.
The reaction takes place at elevated temperatures and with catalysis. The preferred solvent is acetic acid. Protonic acids such as sulfuric acid have proved suitable as the catalyst and favourable temperatures are between 50° C. and 117° C., preferably 100° C. The compounds of formula 2a are obtained under the above reaction conditions as crystalline solids in a yield of about 70-78% and in good purity (>90%). The purity is further increased by recrystallisation, e.g. from 2-butanone, acetic acid or N-methylpyrrolidin-2-one.
Crystalline salts are obtained with inorganic or organic bases. Chiral organic bases yield diastereomeric salts, in each of which one enantiomer is noticeably concentrated. If the tertiary, chiral amine cinchonidine is used, the crystalline salt according to formula 2b is obtained in 90% purity, in which the R enantiomer predominates as the acid component at over 95%. By further recrystallisation, an increased optical purity of 99% e.e. is obtainable.
Salts in which the base component is formed from other chiral amines, on the other hand, do not lead to any significant optical concentration.
The free acid according to the compound of formula 3 is isolated by acidification of aqueous solutions or suspensions and extraction with a suitable solvent. According to the invention, ethyl acetate is preferably used.
The pure compound of formula 3 is stable and crystalline. Further recrystallisation leads to high chemical and optical purity of over 99%.
The dextrorotatory compound of formula 3 is converted, after activation, to esters of the general formula 4, in which R has the meaning of straight-chained or branched C
1
-C
6
alkyl, preferably methyl or isopropyl.
According to the invention, the reaction is performed with thionyl chloride or oxalyl chloride via the intermediate step of an acid chloride, which is followed by ester formation with alcohols of the R—OH type, in which R has the meaning of linear or branched-chain C
1
-C
6
alkyl, preferably methyl or isopropyl, in the presence of suitable bases.
The esters obtained, of the lactone type, are in the form of stable, colourless, crystalline substances.
Another aspect of the invention is the targeted utilisation of differing reactivity of the carboxyl groups of the lactone ring and of the aromatic ester towards hydride reagents.
Thus, when these reagents act on compounds of formula 4, preferably diisobutylaluminium hydride or lithium tri-tert.-butoxyaluminium hydride, reduction of the lactone to the lactols of formula 5 (e.g. R=methyl or isopropyl) occurs almost exclusively.
Another aspect of this invention is that, under suitable reaction conditions, the acid lactol of formula 5a is formed from a compound of formula 3 when reduction is carried out with an equivalent excess of hydride reagent.
These lactols of formulae 5 and 5a are suitable substrates for reductive amination with primary, secondary or tertiary amines and lead to compounds of the general formula I. In formula I, R′ and R″ are the same or different and have the meanings of hydrogen, straight-chained or branched C
1
-C
6
alkyl, preferably methyl or isopropyl. R there has the meaning already mentioned above. The hydrogen gas/precious metal system has proved suitable, preferably palladium. Transfer hydrogenation (ammonium formate/precious metal) or reduction with hydride reagents (e.g. cyanoborohydride) can also be used.
Amines of formula I can be obtained both as neutral compounds and as salts, preferably as hydrochlorides, in crystalline form.
Another aspect of the invention is the reduction of the carboxy group of compounds of formula I to hydroxybenzyl alcohols of the structure as reproduced in formula II. Diborane, boron hydride, aluminium hydride, diisobutylaluminium hydride or preferably lithium aluminium hydride are suitable as reducing agents. A compound according to formula II is obtained when R′ and R″ in formula I each have the meaning of isopropyl.
In analogy to the production process mentioned in the document PCT/EP99/03212=WO 99/58478, which was adapted to the present solution to the problem according to the invention, the dextrorotatory enantiomer of a compound of formula II is obtained as a free base. According to the production process for a compound of formula II described with the aid of the following examples, the dextrorotatory enantiomer is obtained. This possesses the R configuration. The hydroxybenzyl alcohol of formula II forms a series of stable, crystalline salts, with hydrochlorides, formates and hydrogen fumarates deserving particular mention.
The hydrogen fumarate salts in particular are highly suitable for the chemically elegant purification of the hydroxybenzyl alcohol.
In particular, the following compounds are produced by the process according to the invention:
(R,S)-4-phenyl-2-chromanone-6-carboxylic acid
(R)-4-phenyl-2-chromanone-6-carboxylic acid cinchonidine salt
(R)-4-phenyl-2-chromanone-6-carboxylic acid
(R,S)-4-phenyl-2-chromanone-6-carbonyl chloride
(R)-4-phenyl-2-chromanone-6-carbonyl chloride
(R,S)-2-oxo-4-phenylchromane-2-carboxylic acid methyl ester
(R)-2-oxo-4-phenylchromane-2-carboxylic acid methyl ester
(R,S)-2-oxo-4-phenylchromane-2-carboxylic acid isopropyl ester
(R)-2-oxo-4-phenylchromane-2-carboxylic acid isopropyl ester
(4R,4S)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid methyl ester
(4R)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid methyl ester
(4R,4S)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid isopropyl ester
(4R)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid isopropyl ester
(4R,4S)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid
(4R)-2-(R,S)-hydroxy-4-phenylchromane-6-carboxylic acid
(R,S)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester—base and hydrochloride
(R)-(−)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester—base and hydrochloride
(R)-(−)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid—base and hydrochloride
(R,S)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol
(R)-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol base, formate and hydrogen fumarate salt
The above-mentioned compounds were obtained a

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