Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-15
2002-07-09
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S319000, C549S321000
Reexamination Certificate
active
06417377
ABSTRACT:
Amino- and hydroxyfuranones are, because of their biological activities, important starting materials for the preparation of compounds with an antibiotic, hypotensive or antitumor effect, and of fungicides, insecticides etc.
Most amino- and hydroxyfuranones having a chiral center are, however, employed only in the form of their racemates. However, normally only one enantiomer in a racemic mixture of a biologically active compound shows the desired effect.
Some syntheses for optically active hydroxyfuranones (tetronic acids) starting from enantiopure cyanohydrins by use of the Blaise reaction have already been described, it being observed that there is partial racemization on synthesis of compounds susceptible to racemization, such as, for example, 5-aryl-4-hydroxytetronic acids (Effenberger, Tetrahedron Asymmetry 9 (1998) 817-825).
Optically active tetronic acids have to date usually been synthesized by Dieckmann cyclization starting from enantiopure hydroxy acids (Effenberger, Tetrahedron Asymmetry 9 (1998) 817-825).
Other methods, starting from hydroxy esters, require low reaction temperatures down to −78° C. (Witiak, J. Org. Chem. 1990, 55, 1112-1114).
Momose, Heterocycles, Vol. 51, 6, 1999 describes the synthesis of optically active 4-hydroxy-2(5H)-furanone derivatives (tetronic acids) by reaction of 2-acyloxy esters with zinc to form the Reformatsky compound and intramolecular ring closure. This is associated with a side reaction in which the resulting alcohol (on ring closure) destroys the Reformatsky compound and consequently the maximum yields are only 50% (Brandange, Acta Chem. Scand., 1995, 49, 922-928).
It is also known from the literature that tetronic acids can be obtained by acid hydrolysis on 4-aminofuranones (C. Veronese, Heterocycles, Vol. 32, No. 11, 1991; Nishide, Tetrahedron Vol. 50, No. 28, 8337-8346, 1994).
The preparation of racemic 4-amino-2(5H)-furanone (aminofuranones), derivatives of cyanohydrins by intermolecular reaction with magnesium enolates is described. In addition, cyclization reactions are carried out on acyloxy nitrites with lithium amides at −78° C. or with NaH in THF at the reflux temperature. However, these reactions are applicable only to aldehyde cyanohydrins (Hiyama, Bull. Chem. Soc. Jpn., 60, 2139-2150, 1987) and only on use of a low reaction temperature is it possible to react enantiopure cyanohydrins without racemization (Ohta, Tetrahedron Letters, Vol. 29, No. 52, pp 6957-6960, 1988). The loss of enantiopurity in cyclizations using NaH is described, for example, in T. Ross Kelly, Tetrahedron Letters, Vol. 26, 18, 2173-2176, 1985.
The cyclization of acyloxy nitrites with zinc at about 60° C. is described for racemic cyanohydrins in yields of about 90% in Chem. Abstr. 109: 110244 (JP 63093774).
It was an object of the present invention to find a process which provides optically active, enantiomer-enriched aminofuranones and subsequently optically active, enantiomer-enriched hydroxyfuranones in high yields and without racemization.
Unexpectedly, it has been possible to find a process by which enantiomer-enriched cyanohydrins are also reacted in good yields after acylation by intramolecular Reformatsky reaction with zinc at 60° C. without racemization to give optically active aminofuranones, which are themselves important compounds (Hiyama, Tetrahedron Letters, Vol. 26, No. 20, 2459-2462, 1985).
The resulting aminofuranones can further be converted into optically active hydroxyfuranones.
The present invention accordingly relates to a process for the preparation of enantiomer-enriched aminofuranones and hydroxyfuranones, which comprises
a) acylating an optically active cyanohydrin using an acylating agent, then
b) at 40 to 90° C. cyclizing, in the presence of zinc or a zinc compound, to the corresponding enantiomer-enriched aminofuranone, which is
c) where appropriate converted by acid hydrolysis into the corresponding enantiomer-enriched hydroxy-furanone.
In stage a) there is acylation of optically active cyanohydrins. Suitable starting compounds in this case are optically active cyanohydrins which are obtained, for example, by reacting an aldehyde or a ketone, a cyanide group donor and a hydroxynitrile lyase.
Aldehydes mean in this connection aliphatic, aromatic or heteroaromatic aldehydes. Aliphatic aldehydes in this connection are saturated or unsaturated aliphatic, straight-chain, branched or cyclic aldehydes. Preferred aliphatic aldehydes are straight-chain aldehydes with, in particular, 2 to 18 C atoms, preferably from 2 to 12, which are saturated or mono- or polyunsaturated. The aldehyde may moreover have both C—C double bonds and C—C triple bonds. The aldehyde may be unsubstituted or be substituted by groups which are inert under the reaction conditions, for example by optionally substituted aryl or heteroaryl groups such as phenyl or indolyl groups, by halogen, ether, alcohol, acyl, carboxylic acid, carboxylic ester, nitro or azido groups.
Examples of aromatic or heteroaromatic aldehydes are benzaldehyde and variously substituted benzaldehydes such as, for example, 3,4-difluorobenz-aldehyde, 3-phenoxybenzaldehyde, 4-fluoro-3-phenoxy-benzaldehyde, also furfural, anthracene-9-carbaldehyde, furan-3-carbaldehyde, indole-3-carbaldehyde, naphthalene-1-carbaldehyde, phthalaldehyde, pyrazole-3-carbaldehyde, pyrrole-2-carbaldehyde, thiophene-2-carbaldehyde, isophthalaldehyde etc.
Ketones are aliphatic, aromatic or hetero-aromatic ketones in which the substituents on the carbonyl carbon atom are not the same. Aliphatic ketones means saturated or unsaturated, straight-chain, branched or cyclic ketones. The ketones may be saturated or mono- or polyunsaturated. They may be unsubstituted or be substituted by groups which are inert under the reaction conditions, for example by optionally substituted aryl or heteroaryl groups such as phenyl or indolyl groups, by halogen, ether, alcohol, acyl, carboxylic acid, carboxylic ester, nitro or azido groups.
Examples of aromatic or heteroaromatic ketones are acetophenone or indolylacetone etc.
The optically active cyanohydrins which are employed contain the (S) or (R) form in a proportion of more than 95% and can be represented by formula (I) as follows:
R1 and R2 are derived from the abovementioned aldehydes and ketones and thus are preferably H, it being possible for only one of the two radicals R1 and R2 to be H; and linear, branched or cyclic C
2
-C
18
-alkyl, C
2
-C
18
-alkylene or C
2
-C
18
-alkylidene, each of which may optionally be substituted one or more times by halogen, ether, alcohol, acyl, carboxylic acid, carboxylic ester, nitro or azido groups or by optionally substituted aryl or heteroaryl groups, or are optionally substituted aralkyl, aryl or heteroaryl.
Particular preference is given to optically active aliphatic and aromatic cyanohydrins such as, for example, (R)- or (S)-3-phenoxybenzaldehyde cyanohydrin, (R)- or (S)-4-fluoro-3-phenoxybenzaldehyde cyanohydrin, (R)- or (S)-3,4-difluorobenzaldehyde cyanohydrin, (R)- or (S)-2-hydroxy-2,3-dimethylbutanonitrile, (R)- or (S)-2-hydroxy-2-methylpentanonitrile, (R)- or (S)-2-hydroxynonanonitrile, (R)- or (S)-2-hydroxy-2-methyl-phenylacetonitrile, (R)- or (S)-mandelonitrile.
The acylation takes place under the usual conditions known from the prior art, for example from Takefumi Momose, Heterocycles, Vol. 51, No. 6, 1999. According to this, the reaction temperature is preferably between 20 and 50° C. The molar ratio of cyanohydrin to acylating agent is preferably between 1:1 and 1:3. Examples of suitable solvents are optionally halogenated hydrocarbons such as, for example, cyclohexane, xylene, toluene, chloroform, dichloromethane, chlorobenzene, ethers, esters, pyridine, etc. or mixtures thereof. The acylation preferably takes place with basic catalysis using pyridine or triethylamine etc. by means of a halo carbonyl halide of the formula IIa
or halo carboxylic anhydride of the formula IIb
where R3 is an aliphatic, linear or branched C
1
to C
18
-alkyl radical or an aryl radical with 6 to 20 C atoms and X is a halide from t
Mayrhofer Herbert
Pöchlauer Peter
Riebel Peter
Wirth Irma
Dentz Bernard
DSM Fine Chemicals Austria Nfg GmbH & Co KG
Wenderoth Lind & Ponack LLP
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