Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-02-21
2003-06-03
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S029000, C560S038000, C564S337000, C564S342000, C564S463000, C564S502000
Reexamination Certificate
active
06573399
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a &bgr;-amino acid ester derivative of value as intermediates of pharmaceutical and agrochemical substances, particularly an optically active &bgr;-amino acid ester derivative, and to a process for producing an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of value as its intermediates.
BACKGROUND ART
As the standard method of producing &bgr;-amino acids from &agr;-amino acids, the process which comprises reacting a mixed acid anhydride of an &agr;-amino acid with diazomethane and causing the resulting &agr;-amino-&agr;′-diazoketone to undergo rearrangement in an alcohol in the presence of a metal catalyst such as silver ion (Liebigs Ann, 1995, pp.1217-122) is known. However, this process requires the use of diazomethane, an explosive and highly toxic substance, for synthesizing said &agr;-amino-&agr;′-diazoketone so that it is unsuited for a commercial operation.
As an alternative technology, there is known a process which comprises reducing an a-amino acid ester derivative with sodium borohydride, mesylating the resulting alcohol, reacting the mesylate with sodium cyanide, and hydrolyzing the resulting nitrile (Org. Prep Proced Int. 1994, 26(5), 599). However, this process involves many reaction steps and, in addition, requires the use of the highly toxic cyanide, thus being not suited for commercial exploitation.
In the above state of the art, the present invention has for its object to provide a commercially profitable process for synthesizing optically active &bgr;-amino acid ester derivatives of value in the pharmaceutical and other fields, starting with readily available optically active &agr;-amino acid esters.
DISCLOSURE OF THE INVENTION
Thus, the present invention is directed to a process for producing a &bgr;-amino acid ester derivative of the following formula (4):
wherein R
1
represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R
3
represents an alkyl group containing 1 to 5 carbon atoms, and P
1
and P
2
each independently represents a hydrogen atom or an amino-protecting group or P
1
and P
2
taken together represents a phthaloyl group, excluding the case in which both P
1
and P
2
are hydrogen atoms,
which comprises reacting an &agr;-amino acid ester derivative of the following formula (1):
wherein R
1
, P
1
and P
2
are as respectively defined above, R
2
represents an alkyl group containing 1 to 5 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms,
with a base and a dihalomethane of the following formula (2):
CH
2
X
1
X
2
(2)
wherein X
1
and X
2
each independently represents a halogen atom, to synthesize an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of the following formula (3):
wherein R
1
, P
1
, P
2
, X
1
and X
2
are as respectively defined above,
reacting this derivative with a lithium amide and an alkyllithium in succession,
and treating the reaction product with an acid in an alcohol.
The present invention is further directed to a process for producing an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of the above general formula (3)
which comprises reacting an &agr;-amino acid ester derivative of the above formula (1) with a base and a dihalomethane of the above formula (2).
In another aspect, the present invention is directed to a process for producing a &bgr;-amino acid ester derivative of the above formula (4)
which comprises reacting an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of the above formula (3) with a lithium amide and an alkyllithium in succession,
and treating the reaction product with an acid in an alcohol.
In a still another aspect, the present invention is directed to an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of the above formula (3) wherein
R
1
is a benzyl group,
X
1
is a bromine atom,
X
2
is a chlorine atom or a bromine atom.
The present invention is now described in detail.
Referring to the above formulas (1), (3) and (4), R
1
represents a substituted or unsubstituted straight-chain, branched-chain or cyclic alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms, or an aryl group containing 6 to 18 carbon atoms. As specific examples, there can be mentioned benzyl, methyl, isopropyl, isobutyl, sec-butyl and phenyl, although these are not exclusive choices. Preferred is benzyl or phenyl.
Referring to the formula (1), R
2
represents an alkyl group containing 1 to 5 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms. As specific examples, there can be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, p-nitrobenzyl and p-chlorobenzyl, among others. Preferred is methyl or ethyl.
In the formulas (1), (3) and (4), P
1
and P
2
each independently represents a hydrogen atom or an amino-protecting group, or P
1
and P
2
taken together represents a phthaloyl group; excluding the case in which both P
1
and P
2
are hydrogen atoms.
The amino-protecting group is not particularly restricted as far as it is a protecting group in routine use for the protection of an amino group. Thus, the groups mentioned in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W. Green, John Willey & Sons), 1990, pp.309-384, e.g. methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, dibenzyl, phthalimido, tosyl, benzoyl, trimethylsilyl, etc., can be employed. Preferred, among these, are carbamate-form protecting groups such as, for example, methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl and t-butyloxycarbonyl. When either one of P
1
and P
2
represents an amino-protecting group, the other preferably represents a hydrogen atom. When P
1
and P
2
taken together represents a phthaloyl group, it may also be regarded as a kind of amino-protecting group.
X
1
and X
2
in the formulas (2) and (3) each independently represents a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom. Preferred is a chlorine atom or a bromine atom. X
1
and X
2
may be the same or different.
R
3
in the formula (4) represents a straight-chain or branched-chain alkyl group containing 1 to 5 carbon atoms. Preferred is methyl, ethyl, n-propyl or the like.
The process for producing an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative in accordance with the present invention is now described.
Thus, an &agr;-amino acid ester derivative of the formula (1) is reacted with a base and a dihalomethane of the formula (2) at −90° C. to 50° C., preferably −10° C. to 30° C., to synthesize an &agr;-amino-&agr;′,&agr;′-dihaloketone derivative of the formula (3).
The &agr;-amino acid constituting said &agr;-amino acid ester derivative of the formula (1) is not particularly restricted but includes phenylalanine, alanine, valine, leucine, isoleucine and phenylglycine, among others. Preferred is phenylalanine or phenylglycine. In the present invention, even when an optically active amino acid is used as the starting compound, the desired compound can be obtained without decreasing in optical activity. Therefore, more preferred amino acid is L-phenylalanine or L-phenylglycine, which is optically active.
The base mentioned above is not particularly restricted but includes alkyllithiums, alkylmagnesium halides, lithium amides, e.g. lithium diisopropylamide, lithium hexamethyldisilazide, etc., and halomagnesium dialkylamides which can be prepared by reacting a Grignard reagent with a secondary amine, e.g. chloromagnesium diisopropylamide, bromomagnesium diisopropylamide and chloromagnesium dicyclohexylamide. These bases can be used independently or in a combination of 2 or more species. Preferred bases are halomagnesium dialkylamides, and particularly preferred base is chloromagnesium diisopropylamide. The amount of use of said
Inoue Kenji
Nishiyama Akira
Connolly Bove & Lodge & Hutz LLP
Kaneka Corporation
Killos Paul J.
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