Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-05-11
2002-02-19
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S014000, C560S021000, C560S024000, C560S027000, C560S106000, C560S107000, C560S110000, C560S112000, C560S250000, C560S252000
Reexamination Certificate
active
06348615
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing (2R,3S)-3-amino-4-phenylbutane-1,2-epoxide (hereinafter also referred to as 3-amino-1,2-oxirane), which is useful as an intermediate for the production of an HIV protease inhibitor.
BACKGROUND ART
The processes so far known for producing said (2R,3S)-3-amino-1,2-oxirane comprise starting with L-phenylalanine, reducing the carboxyl group thereof to an alcohol function, reoxidizing the same to an aldehyde function, and thereafter 1) directly causing formation of the epoxide using a dimethylsulfonium methylide (J. Org. Chem., 1985, 50, 4615; J. Med. Chem., 1992, 35, 2525), 2) converting the aldehyde to the corresponding olefin by the Wittig reaction and epoxidizing the olefin using m-chloroperbenzoic acid (J. Org. Chem., 1987, 52, 1487; J. Med. Chem. 1992, 35, 1685), 3) reacting the aldehyde with trimethylsilylmethylmagnesium chloride, converting the resulting trimethylsilylalcohol to the corresponding olefin by treatment with trifluoroboron and, as in the method 2) mentioned above, conducting epoxidation using m-chloroperbenzoic acid (EP 0532-466 A2, U.S. Pat. No. 5,514,814) or 4) converting L-phenylalanine to the diazoketone form, degradating the same with hydrochloric acid, reducing the resulting &agr;-ketone with NaBH
4
and treating the resulting chlorohydrin with a base to give the epoxide (J. Med. Chem., 1994, 37, 1758), among others.
Meanwhile, there is no precedent technology for producing (2R,3S)-3-amino-1,2-oxirane compounds represented by the general formula (8) starting with a (2S,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane compound or a (2S,3S)-3-amino-1,2-oxirane compound as in the process of the present invention.
Referring to the above known processes, the process 1) is disadvantageous in that it is necessary to use the sulfur compound in large amounts in the step of epoxide formation, the methods 2) and 3) are disadvantageous in that it is necessary to use the peroxide, which is explosive, in large amounts, and the method 4) is disadvantageous in that it is necessary to handle the diazo compound, which is also explosive, and, in addition, the selectivity toward the desired (2R,3S)-chlorohydrin in NaBH
4
reduction is low. Thus, every process comprises a step undesirable from the viewpoint of commercial scale practicing.
SUMMARY OF THE INVENTION
In view of the problems mentioned above, the present inventors made intensive investigations in an attempt to develop a process for producing a (2R, 3S)-3-amino-1,2-oxirane compounds which can be carried out efficiently and on a commercial scale and, as a result, succeeded in developing a novel process for production which starts with a (2S, 3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane compound or a (2S, 3S) -3-amino-1, 2-oxirane compound and involves three steps, namely acyloxylation, sulfonate ester formation and treatment with a base.
Thus, the present invention relates to a process for producing (2R, 3S)-3-amino-4-phenylbutane-1,2-epoxide compounds represented by the general formula (8):
wherein R
1
represents an amino-protecting group, which comprises
treating a (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound represented by the general formula (1) or a (2S, 3S)-3-amino-4-phenylbutane-1,2-epoxide represented by the general formula (2):
wherein R
1
is as defined above and X represents a halogen atom,
wherein R
1
is as defined above,
with a carboxylic acid quaternary ammonium salt represented by the general formula (3) or a carboxylic acid metal salt represented by the general formula (4):
R
3
R
4
R
5
R
6
N
+
OCOR
2
−
(3)
wherein R
2
represents an alkyl, aryl or aralkyl group and R
3
, R
4
, R
5
and R
6
may be the same or different and each independently represents an alkyl or aralkyl group,
R
2
COO
−
M
+
(4)
wherein R
2
is as defined above and M represents a metal atom, and a quaternary ammonium salt represented by the general formula (5):
R
3
R
4
R
5
R
6
N′Y
−
(5)
wherein R
3
, R
4
, R
5
and R
6
are as defined above and Y represents a halogen atom, to give a (2S, 3S) -1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound represented by the general formula (6):
wherein R
1
and R
2
are as defined above,
further treating said (2S, 3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound with a sulfonic acid halide in the presence of an organic base
to give a (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound represented by the general formula (7):
wherein R
1
and R
2
are as defined above and R
7
represents an alkyl, aryl or aralkyl group,
and furthermore treating said (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound with an inorganic base.
The (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound can be synthesized, for example, by N-protection of L-phenylalanine, which is a naturally-occurring and inexpensive substance, followed by esterification, and stereoselective reduction of the haloketone resulting from chain extension (Japanese Kokai Publication Hei-08-823756).
BEST MODES FOR CARRYING OUT THE INVENTION
The starting compound in the present process is the above-mentioned (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound of the general formula (1) or (2S, 3S)-3-amino-4-phenylbutane-1,2-epoxide compound of the general formula (2). In the formulas, R
1
represents an amino-protecting group in common use, such as a methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, acetyl, benzoyl or chloroacetyl group, desirably a t-butoxycarbonyl or benzyloxycarbonyl group, and X represents a halogen atom such as a chlorine or bromine atom.
The acyloxylating agent to be used in the above process is the above-mentioned carboxylic acid quaternary ammonium salt of the general formula (3), or the carboxylic acid metal salt of the general formula (4) plus the quaternary ammonium salt of the general formula (5). In the formula (3), R
2
represents an alkyl, aryl or aralkyl group. The alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl. The aryl group is, for example, phenyl or tolyl. The aralkyl group is, for example, benzyl. A methyl group is preferred as R
2
, however. In the formula (3), M specifically includes, among others, lithium, sodium, potassium, magnesium and calcium, and is preferably sodium or potassium. R
3
, R
4
, R
5
and R
6
each independently represents an alkyl or aralkyl group. The alkyl group includes, among others, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. The aralkyl group is, for example, benzyl. Among these, butyl is preferred. Y is a halogen atom, such as a chlorine or bromine atom.
In the general formula (7) representing the sulfonate ester, R
7
represents an alkyl, aryl or aralkyl group. The alkyl group is, for example, methyl or ethyl. The aryl group is, for example, phenyl, p-methylphenyl or p-nitrophenyl. The aralkyl group is, for example, benzyl. Among them, methyl is preferred.
In accordance with the present invention, the above (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound (6) is first derived from the (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound (1) or (2S, 3S)-3-amino-1, 2-oxirane compound (2) by treatment with the carboxylic acid quaternary ammonium salt (3), for example tetrabutylammonium acetate, or with the carboxylic acid metal salt (4) and quaternary ammonium salt (5), for example calcium acetate or sodium acetate, and tetrabutylammonium chloride or tetrabutylammonium bromide.
The solvent to be used in the above step is not particularly restricted but includes, among others, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and toluene. Among them, acetone, acetonitrile and N,N-dimethylformamide are preferred.
The carboxylic acid quaternary ammonium salt (3) is used generally in an amount of 1.0 to 2.0 moles, preferably 1.2 moles, per mole of the compound (1) or (2). The carboxylic acid metal salt (4) and quaternary ammonium salt
Inoue Kenji
Okuro Kazumi
Kaneka Corporation
Sughrue & Mion, PLLC
Trinh Ba K.
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