Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Reexamination Certificate
2002-11-04
2004-11-16
Zucker, Paul A. (Department: 1621)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
C562S579000
Reexamination Certificate
active
06818423
ABSTRACT:
The invention relates to a process for the preparation of chiral &agr;-hydroxycarboxylic acids, which are valuable intermediates for pharmaceutical and agrochemical products, from C
4
-C
6
-ketones.
&agr;-Hydroxycarboxylic acids, such as, for example, 2-hydroxy-2-methyl-3-phenylthiopropionic acid, are employed, for example according to EP 0 100 172, in the preparation of acylanilides, which have anti-androgenic activity. According to EP 0 100 172, these &agr;-hydroxy-carboxylic acids are obtained as a racemate by reaction of the appropriate phenylthioketones with KCN to give the corresponding cyanohydrin and subsequent reaction with aqueous HCl. Yields, purities, and details of the configuration can be taken from EP 0 100 172.
Phenylthioketones which can serve as a precursor for the above reaction, such as, for example, 4-phenylthio-2-butanone, are obtained, for example according to J. Org. Chem. 1995, 60, 2022-2025, by addition of thiophenol to methyl vinyl ketone.
According to J. Org. Chem. 1990, 55, 4643-4647, racemic tert-&agr;-benzyloxy acid esters are in each case cleaved into the corresponding (+)-tert-&agr;-benzyloxy acid ester and the corresponding (S)-&agr;-benzyloxycarboxylic acid by means of lipase OF from
Candida cylindracea
. The desired chiral &agr;-hydroxycarboxylic acids, such as, for example, (S)-2-hydroxy-2-methyl-butyric acid, are then obtained from the (S)-&agr;-benzyloxycarboxylic acids by hydrogenation. The yield in this process is 67%. The ee value of the final product is only 60%.
The object of the present invention was to find a process for the preparation of short-chain C
4
-C
6
-&agr;-hydroxycarboxylic acids which makes possible the preparation of the desired products in high yield and enantiomeric purity.
Unexpectedly, it was possible to achieve this object by means of a process in which low-molecular-weight C
4
-C
6
-ketones derivatized with a chemically removable group are converted into the corresponding &agr;-hydroxycarboxylic acids by reaction with a cyanide group donor in the presence of a hydroxynitrile lyase or by racemic reaction, subsequent acidic hydrolysis, optionally resolution, and cleavage of the group.
The invention accordingly relates to a process for the preparation of chiral &agr;-hydroxycarboxylic acids of the formula (I)
in which R1 is a C
1
-C
2
-alkyl radical optionally substituted by one or more halogen atoms and R2 is a C
2
-C
3
-alkyl radical optionally substituted by one or more halogen atoms, which comprises reacting a compound of the formula (II),
in which R1 is as defined above, R
2
′ is a C
2
-C
3
-alkylene radical optionally substituted by one or more halogen atoms, m can be equal to 0 or 1, R is a C
1
-C
20
-alkyl radical, a C
5
-C
20
-aryl radical, heteroaryl radical or a heterocyclyl radical, where the radicals can optionally be mono- or polysubstituted by substituents from the group consisting of C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
6
-alkylthio, phenyl, benzyl, halogen, hydroxyl, nitro, carboxyl, esters, thioesters, carbonates, carbamates or urethanes, and X can be oxygen, sulfur, sulfinyl, sulfonyl, imino, C
1
-C
6
-alkylimino, xanthate, silyl, or, if m is equal to 0, halogen,
in the presence of a cyanide group donor either enantioselectively with an (R)- or (S)-hydroxynitrile lyase in an organic, aqueous or 2-phase system or in emulsion to give the corresponding (R)- or (S)-cyanohydrin of the formula (III)
in which R1, R
2
′, R, m and X are as defined above, or racemically to give the corresponding racemate of the cyanohydrin of the formula (III), then converting the compound of the formula (III) or its racemate by means of acidic hydrolysis into the corresponding acid of the formula (IV)
in which R1, R
2
′, R, m and X are as defined above, or its racemate, whereupon the elimination of the group of the formula (V)
(R)m-X (V)
takes place, where in the case of the racemate a resolution is first carried out, and isolating the desired chiral &agr;-hydroxycarboxylic acid of the formula (I).
In the process according to the invention, chiral &agr;-hydroxycarboxylic acids of the formula (I)
are prepared.
In the formula (I), R1 is a C
1
-C
2
-alkyl radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, methyl, ethyl, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, etc. A methyl radical optionally substituted by one to 3 fluorine or chlorine atoms is preferred, and an unsubstituted methyl radical is particularly preferred.
R2 is a C
2
-C
3
-alkyl radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, ethyl, difluoroethyl, propyl, pentafluoroethyl, etc. Preferably, R2 is an ethyl radical optionally substituted by one or more fluorine or chlorine atoms, particularly preferably an unsubstituted ethyl radical.
Preferably, in the compounds of the formula (I) R2 has one C atom more than R1.
Examples of compounds of the formula (I) are (R)- or (S)-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-2-hydroxy-2-ethylpentanoic acid, (R)- or (S)-2-hydroxy-2-fluoromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-chloromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-difluoromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-dichloromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-trifluoromethylbutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-fluoromethylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-fluoro-methylbutanoic acid, (R)- or (S)-3-difluoro-2-difluoromethyl-2-hydroxy-butanoic acid, (R)- or (S)-4-difluoro-2-difluoromethyl-2-hydroxybutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-trifluoromethylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-trifluoromethylbutanoic acid, (2S,3S)-3-fluoro-2-hydroxy-2-methylbutanoic acid, (2S,3R)-3-fluoro-2-hydroxy-2-methyl-butanoic acid, (2R,3S)-3-fluoro-2-hydroxy-2-methylbutanoic acid, (2R,3R)-3-fluoro-2-hydroxy-2-methylbutanoic acid, etc.
The starting material used is the compound of the formula (II)
In the formula (II), R1 is as defined above.
R
2
′ is a C
2
-C
3
-alkylene radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, ethylene, propylene, difluoroethylene, pentafluoroethylene, dichloroethylene, pentachloroethylene etc. Preferably, R
2
′ is an ethylene radical optionally substituted by one or more fluorine or chlorine atoms, particularly preferably an unsubstituted ethylene radical.
m can be equal to 0 or 1 and R is a C
1
-C
20
-alkyl radical, a C
5
-C
20
-aryl radical, heteroaryl radical or a heterocyclyl radical.
Alkyl in this case is to be understood as meaning saturated or mono- or polyunsaturated, linear, branched or cyclic, primary, secondary or tertiary hydrocarbon radicals. These are C
1
-C
20
-alkyl radicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, octyl, cyclo-octyl, decyl, cyclodecyl, dodecyl, cyclododecyl etc.
C
1
-C
12
-alkyl radicals and particularly preferably C
2
-C
8
-alkyl radicals are preferred here.
The alkyl group can optionally be mono- or polysubstituted by substituents which are inert under the reaction conditions, from the group consisting of C
1
-C
4
-alkoxy, C
1
-C
6
-alkylthio, phenyl, benzyl, halogen, hydroxyl, nitro, carboxyl, esters, thioesters, carbonates, carbamates or urethanes.
Aryl is preferably to be understood as meaning C
6
-C
20
-aryl groups, such as, for example, phenyl, biphenyl, naphthyl, indenyl, fluorenyl etc.
The aryl group can in this case be optionally mono- or polysubstituted by substituents which are inert un
Mayrhofer Herbert
Neuhofer Rudolf
Poechlauer Peter
Skranc Wolfgang
Wirth Irma
DSM Fine Chemicals Austria NFG GmbH & Co KG
Wenderoth , Lind & Ponack, L.L.P.
Zucker Paul A.
LandOfFree
Process for the preparation of chiral... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of chiral..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of chiral... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3281619