Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-09-03
2003-12-23
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S322000, C568S323000, C568S404000, C568S407000, C568S812000, C568S814000, C549S514000, C549S520000, C546S244000, C546S245000
Reexamination Certificate
active
06667422
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for preparing &agr;-haloketones.
2. Background Art
The preparation of &agr;-chloroketones by reacting an N-protected amino acid with alkyl chloroformates to give the mixed anhydride, reacting the mixed anhydride with diazomethane to give the diazoketone, and subsequently reacting the diazoketone with HCl to give the chloroketone is disclosed, for example, by S. W. Kaldor et al., J. Med. Chem. 1997, 40, 3979-3985. The process employs diazomethane, an explosive and carcinogenic gas which can only be used on the industrial scale at high risk. The preparation of &agr;-chloroketones by reacting an N-protected amino ester with a CH
2
Cl anion at low temperatures is disclosed, for example, by P. Chen et al., TETRAHEDRON LETT. 1997, 38(18), 3175-3178, and by U.S. Pat. Nos. 5,481,011; 5,523,463; U.S. Pat. No. 5,591,885. The process must be carried out at very low temperatures (T<−−80° C.) which limits the general industrial utility and incurs significant cost disadvantages.
The preparation of &agr;-chloroketones by reacting an N-protected amino ester with salts of chloroacetic acid and subsequent decarboxylation is disclosed, for example, by X. Wang et al., Synlett 2000, 902-904, and U.S. Pat. No. 5,929,284. For lithium salts, an industrial low temperature apparatus is again necessary. In the case of magnesium salts, the reaction may be carried out at or above room temperature, but the reaction then delivers only a 52% yield by chromatography.
The preparation of &agr;-chloroketones by reacting an activated N-protected amino acid with alkali metal enolates of acetates to give &bgr;-ketoester derivatives which are then chlorinated selectively in the 2-position in a second step followed by decarboxylation in a third step is disclosed by EP 774 453 and U.S. Pat. Nos. 5,767,316 and 5,902,887. The three stage procedure is accordingly more costly and inconvenient than the previously described processes.
The preparation of &agr;-chloroketones by reacting an activated N-protected amino acid with alkali metal enolates of monohaloacetates to give halogenated &bgr;-ketoester derivatives which are then hydrolyzed and decarboxylated in subsequent steps is described in U.S. Pat. Nos. 5,767,316 and 5,902,887. According to the inventors (EP 774 453 A1, page 5, lines 46-47), the process has to be carried out at −60° C. or lower which again requires an industrial low temperature facility.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an inexpensive process for preparing an &agr;-haloketone from an N-protected amino acid derivative which may be carried out without risk on an industrial scale and which provides higher yields and purities than prior art processes. These and other objects are achieved by reacting a carboxylic acid derivative bearing a leaving group bonded to the carbonyl carbon, with a mono- or dienolate of a silyl ester.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
Thus, the subject invention is directed to a process for preparing an &agr;-haloketone of the general formula (1)
where R
1
is an alkyl, aralkyl or aryl radical in which CH
2
units may be replaced by heteroatoms such as NH, NCH
3
, S or O, and CH units may be replaced by N, and
the R
1
radicals may further be substituted by functional groups, for example a halogen radical, an amino radical, an alkoxy radical or a thioalkyl radical and
R
2
is a hydrogen, alkyl, aralkyl or aryl radical and
X is a halogen radical,
by reacting a carboxylic acid derivative of the general formula (2)
where R
1
is as defined above and
L is a leaving group,
with a mono- or dienolate of a silyl ester of the general formula (3)
where X and R
2
are each as defined above, and R
3
and R
4
are identical or different and are each hydrogen, alkyl, aryl, alkenyl or aralkyl;
and hydrolyzing the reaction product immediately after the reaction and preferably without isolation, by adding acid and decarboxylating to (1).
The leaving group L is preferably a radical which increases the reactivity of a carboxylic acid derivative toward nucleophiles compared to the free carboxylic acid and supports substitution by these nucleophiles at the carbonyl carbon of the carboxylic acid derivative.
R
1
is preferably selected from the group of linear or branched alkyl radicals having from 1 to 25 carbon atoms, aryl radicals having from 6 to 30 carbon atoms and aralkyl radicals having from 7 to 31 carbon atoms, where the CH
2
units of each radical may be substituted by heteroatoms such as NH, NCH
3
, S or O and the CH units by N, and the R
1
radicals may optionally be substituted by non-interfering functional groups including halogen radicals, amino radicals, alkoxy radicals, and thioalkyl radicals. Examples of R
1
include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, isopropyl, isobutyl, t-butyl, 2,2-dimethylpropyl, 3-methylbutyl, phenyl, naphthyl and benzyl radicals.
The leaving group L is preferably selected from among alkoxy radicals having from 1 to 10 carbon atoms, optionally ring-substituted phenoxy or benzyloxy radicals, halogen radicals such as bromine or chlorine radicals, imidazolyl radicals, 1-oxybenzotriazole, and alkoxycarbonyloxy groups such as methoxycarbonyloxy, ethoxycarbonyloxy and isobutoxycarbonyloxy (mixed anhydrides). The leaving group L is preferably a linear alkoxy radical having from 1 to 4 carbon atoms, and is more preferably the methoxy radical.
X is Cl, Br, F or I, more preferably Cl or Br, most preferably Cl.
Preferably, the R
2
radicals are each independently hydrogen radicals, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 11 carbon atoms or alkenyl radicals having from 2 to 10 carbon atoms. A preferred R
2
radical is the hydrogen radical.
The R
3
and R
4
radicals are preferably each independently hydrogen radicals, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms or alkenyl radicals having from 2 to 10 carbon atoms. Examples of SiR
3
R
4
silyl radicals include the dimethylsilyl, diethylsilyl, diisopropylsilyl, di-(t-butyl)silyl, dibutylsilyl, t-butylmethylsilyl, phenylmethylsilyl, diphenylsilyl and divinylsilyl radicals. Preferred silyl radicals are dimethylsilyl and diphenylsilyl radicals. A particularly preferred silyl radical is the dimethylsilyl radical.
Preference is given to carrying out the inventive process at a temperature in the range from −10° C. to 110° C., more preferably from 0° C. to 70° C. The process requires only one process step, requires no low temperature facility and no dangerous chemicals, employs inexpensive silyl radicals, and delivers better yields than the prior art processes.
Preference is given to carrying out the process in the presence of a solvent. In addition to aromatic hydrocarbons such as benzene, toluene or xylene, and aliphatic solvents such as hexane or heptane, preferred solvents include ethers such as t-butyl methyl ether, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, and 1,2-dimethoxyethane.
It has surprisingly been discovered that silyl bis(&agr;-halocarboxylate) esters can form stable enolates at room temperature or even at elevated temperature with selected bases, and that these enolates add onto activated (amino) acid derivatives in the desired manner and give the desired &agr;-haloketones under acidic workup by immediate hydrolysis and in situ decarboxylation. In view of the prior art, it would have been expected that enolates of silyl haloacetates would only be suitable for preparing chloroketones at very low temperatures (T<−60° C.) and even then only in low yields of up to about 50%.
The present invention relates in particular to a process for preparing an &agr;-haloketone of the general formula (5)
where R
2
is as defined above and R
5
is a hydrogen, alkyl, aralkyl or aryl radical in which one or more CH
2
groups may be replaced by O, S,
Heldmann Dieter
Stohrer Juergen
Brooks & Kushman P.C.
Consortium fuer Elektrochemische Industrie GmbH
Richter Johann
Witherspoon Sikarl A.
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