Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-26
2002-02-05
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S556000, C548S550000
Reexamination Certificate
active
06344566
ABSTRACT:
The invention relates to a novel process for the alternative preparation of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, and the novel compounds N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethane] and N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidin-1-yl) -ethane], which are formed as intermediates in this process.
As described by Barber et al. (B. J. Pharmacol. (1994), 113, 1317-1327), both the compound N-methyl-N-[(1S) -1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and its physiologically tolerable salts have valuable pharmacological properties such as an analgesic, anti-inflammatory and aquaretic action, so that they are particularly suitable for the production of medicaments.
It has been found, as described in the Patent Application DE 1 95 23 502 or EP 752 246, that this compound is a particularly efficacious compound which is suitable as a medicament for the treatment of inflammatory intestinal disorders in a very particular manner. In particular, this compound is employable and efficacious in this indication, since it simultaneously alleviates the pain associated with this disorder and, in the acute case of an intestinal occlusion threatening or produced due to the inflammatory intestinal disorder, again normalizes or sets in motion the motor response of the intestine without producing noticeable side effects. Moreover, the compound can be employed in non-inflammatory intestinal disorders such as IBS (irritable bowel syndrome).
The Patent Applications DE 40 34 785 Al and DE 42 15 213 A1 or EP 0 569 802 A1 describe the preparation of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl) ethyl]-2,2-diphenylacetamide by reaction of (2S)-2-N-carboxyethyl-2-phenylglycin-N,N-[(3S)-3-hydroxytetramethylamide with diphenylacetyl chloride. As described in DE 42 15 213, the starting compound (2S)-2-N-carboxyethyl-2-phenylglycin-N,N-[(3S)-3-hydroxytetramethyleneamide, also known as (1S)-[1-N-methylamino-1-phenyl-2-((3S)-3-hydroxypyrrol idino)ethane can be prepared by reacting (1S)-1-amino-1-phenyl-2-chloroethane with (3S)-3-hydroxypyrrolidine and then methylating with methyl iodide. The problems of this preparation method, however, are the solubility of the starting products and that following the synthesis the racemic product mixture obtained, which is contaminated by by-products, has to be laboriously separated. The process known until now for the preparation of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide is therefore laborious and expensive and results in low yields based on the starting compounds employed.
It was therefore the object of the present invention to make available a process, which can be carried out in a simple manner and economically, for the preparation of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or, when using the enantiomeric starting materials, of N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, which starts from economical, readily soluble starting materials which result in a product which is as enantiomerically pure as possible, which can then be isolated and purified in a simple manner.
The object is achieved by a process according to claim 1, either the previously unknown compound N-methyl -N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethane]-yl)etane] being used as a novel intermediate for the preparation of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxypyrrolidin1-yl)ethane] being used as a novel intermediate for the preparation of N-methyl-N-[(1R)-1-phenyl-2-((3R)-3hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.
It has been found that compounds of the formula (III)
in which R and R
2
have the following meanings,
R is H, OR
1
or SR
1
,
R
1
is A, aryl, heteroaryl, Si(R
3
)
3
or COR
3
,
R
2
is H, A, aryl, heteroaryl and Si(R
3
)
3
or COR
3
,
R
3
is H, A, aryl or heteroaryl,
A is a straight-chain or branched alkyl radical having 1 to 6 C atoms,
can be prepared in high yields and in enantiomerically pure form by amidically coupling, depending on the final product desired, (3S)-3-hydroxypyrrolidines or (3R)-3-hydroxypyrrolidines of the formula (II)
in which
R
2
is H, A, aryl, heteroaryl and Si(R
3
)
3
or COR
3
and
R
3
is H, A, aryl or heteroaryl or their salts, formed with HCl, HBr, HI, H
2
SO
4
, H
3
PO
4
or suitable organic acids, with appropriate (S)- or (R)-enantiomeric forms of N-substituted phenylglycines of the formula (I)
in which
R is H, OR
1
or SR
1
,
R
1
is A, aryl, heteroaryl, Si(R
3
)
3
or COR
3
,
R
3
is H, A, aryl or heteroaryl,
M is H or a cation from the group consisting of alkali metal, alkaline earth metal, ammonium or alkylammonium.
Alkyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-or 1,2,2-trimethylpropyl.
Aryl is preferably unsubstituted phenyl or phenyl which is mono- or disubstituted by Hal, OA or alkyl, furthermore, for example, biphenyl or naphthyl.
Heteroaryl is preferably, for example, furanyl, thiophenyl, pyridinyl, pyrrolyl or thiazolyl.
Si(R
3
)
3
is preferably, for example, Si(CH
3
)
3
.
COR
3
is preferably, for example, acetyl or benzoyl.
R is preferably, in particular, for example, methoxy or ethoxy.
R
1
is in particular, for example, methyl, ethyl, propyl, butyl, phenyl, Si(CH
3
)
3
or acetyl.
R
2
is, in particular, for example, H, tert-butyl, Si(CH
3
)
3
, acetyl, benzyl or benzoyl, very particularly preferably it is H.
The amides of the formula (III) prepared can be converted in a simple manner reductively, if appropriate by removal of the protective group from the hydroxyl group of the pyrrolidine in N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl) ethane] or N-methyl -N-[(1R)-1-phenyl-2-((3R)3-hydroxypyrrolidin-1yl)ethane] of the formula (IV).
By reaction with activated carboxylic acids of the formula (V)
in which
R
4
is F, Cl, Br, I, OA or O—CO—A, it is possible to obtain from the free bases of the compounds of the formula (IV)
or from their salts, formed with HCl, HBr, HI, H
2
SO
4
, H
3
PO
4
or suitable organic acids, the enantiomeric compounds of the formula (VI)
in pure form. Preferably, these compounds are prepared as hydrochlorides, the compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide being the known form EMD 61753; but the corresponding salts with the other abovementioned acids can also be prepared analogously.
In particular, N-methyl-N-[(1S)-1-phenyl-2((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylace-amide can be prepared by the last reaction with diphenylacetyl chloride.
The compounds of the formula (IV) synthesized as intermediates can generally be obtained by reaction of compounds of the formula (I) with those of the formula (II). Preferably, compounds of the formula (I) are used in this reaction in which R has the meaning OR
1
where R
1
is A, aryl, heteroaryl, Si(R
3
)
3
or COR
2
and R
2
is H, alkyl, aryl or heteroalkyl, having the preferred meanings indicated above. Surprisingly, in contrast to the use of the corresponding formyl compound, enantiomerically pure reaction products of the formula (III) are obtained. In this manner, the resolution of the racemate can advantageously be omitted.
The reaction of the compounds (I) and (II) can be carried out in any des
Ackermann Karl-August
Bathe Andreas
Budak Jens
Gottschlich Rudolf
Helfert Bernd
Higel Floyd D.
Merck Patent GmbH
Shameem Golam M. M.
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