Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-17
2002-02-05
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S513000
Reexamination Certificate
active
06344572
ABSTRACT:
“This application is a 371 application of PCT/JP00/00495 filed Jan. 31, 2000.”
TECHNICAL FIELD
The present invention relates to a production method of a threo-1,2-epoxy-3-amino-4-phenylbutane derivative represented by the following general formula (1):
wherein P represents a urethane-type amino-protecting group and the configurations at 2 and 3 positions are (2S,3R) or (2R,3S). The threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1), in particular (2R,3S)-1,2-epoxy-3-amino-4-phenylbutane derivatives, are compounds useful as intermediates for the production of various HIV proteases, as described in Japanese Kokai Publication Hei-05-230095.
BACKGROUND ART
The hitherto-known production technology for threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1), in particular (2R,3S)-1,2-epoxy-3-amino-4-phenylbutane derivatives, includes a method which comprises synthesizing (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane by epoxidizing 2(S)-N-(tert-butoxycarbonyl)amino-1-phenyl-3-butene with m-chloroperbenzoic acid in methylene chloride (e.g. J. Org. Chem., 1987, vol. 52, page 1487; Japanese Kokai Publication Hei-05-230095). Further, there is also known the method for isolating (2R,3S)-1,2-epoxy-3-amino-4-phenylbutane derivatives, which comprises carrying out ether extraction and washing repeatedly, drying the organic phase over anhydrous sodium sulfate, evaporating the solvent, purifying the residue by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) and recrystallizing the product from hexane (Japanese Kokai Publication Hei-05-230095).
However, the prior art methods pose serious problems in carrying out them on an industrial scale; for example, the reaction yield of (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is low, namely about 80 mole percent (J. Org. Chem., 1987, vol. 52, page 1487); it is necessary to use undesirable reagents (e.g. methylene chloride, which is a halogenated hydrocarbon, ether and hexane, which are very inflammable organic solvents, and m-chloroperbenzoic acid, which is a very hazardous peroxide, or the like) ; a plurality of organic solvents are used in large quantities; the procedure is complicated; and the productivity is low.
In the prior art methods, silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) and/or recrystallization from hexane is carried out for purification and isolation of (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane. Such an isolation procedure, however, involves serious problems in carrying it out on a commercial scale; for example, use of large amounts of undesirable reagents, complexity of the process, a waste of time resulting from the complicatedness, increases in the number and capacity of production units, and low yields. A further problem is that the product crystallized from hexane has a low density, hence a large capacity container is required for packaging crystals of the above compound.
In particular, investigations made by the present inventors revealed that the affinity of (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane and other threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1) with various organic solvents is not suitable, which makes it very difficult to isolate high-quality crystals in good yield by crystallization at an appropriate crystallization concentration.
Thus, there is no effective method available in the art for producing a threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1), in particular (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane.
The above threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1) are intermediates for the production of HIV protease inhibitors which need to be ingested in high doses, and, therefore, it is of particular significance to develop a practical method for mass production of said derivatives.
SUMMARY OF THE INVENTION
In view of the above state of the art, it is an object of the present invention to provide a production method of high quality threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1) on a commercial scale in a simple, easy and efficient manner and with very high productivity. Another object of the invention is to develop a method of crystallizing the above derivatives in a high density state.
The present invention thus provides a production method of a threo-1,2-epoxy-3-amino-4-phenylbutane derivative of the above general formula (1)
which comprises treating, with a base, a threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivative of the following general formula (2):
wherein P is as defined above, X represents a halogen atom and the configurations at positions 2 and 3 are (2S,3R) when they are (2S,3R) in the formula (1) or (2R,3S) when they are (2R,3S) in the formula (1), in a polar organic solvent or a solvent composed of a polar organic solvent and water,
and adding the resulting reaction mixture to water to thereby cause the threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) to crystallize out.
The present invention further relates to a synthesis method of a threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1)
which comprises treating, with a base, a threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivative (2) in a polar organic solvent or a solvent composed of a polar organic solvent and water.
The present invention further relates to a purification/isolation method of a threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1)
which comprises adding, to water, a solution of the threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) in a polar organic solvent or a solution of the threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) in a solvent composed of a polar organic solvent and water to thereby cause the threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) to crystallize out.
In the following, the present invention is described in detail.
DETAILED DISCLOSURE OF THE INVENTION
The threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1), which is the desired compound to be produced by the method of the present invention, is a protected form of threo-1,2-epoxy-3-amino-4-phenylbutane having the amino group protected by a urethane type protective group.
In the above general formula (1), the group P attached to the amino group is an amino-protecting group. This amino-protecting group is a group capable of protecting an amino group and includes various routine protective groups such as those described in the relevant monographs or literature available in the art, for example “Protective Groups in Organic Synthesis”, 2nd edition, John Wiley & Sons, 1991. As the protective group P in the above general formula (1), preferred is a urethane type protective group (also referred to as carbamate type protective group). Preferred as such group are, among others, aralkyloxycarbonyl groups and lower alkoxycarbonyl groups (the alkyl moiety having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms). More preferred are benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl. Particularly preferred is tert-butoxycarbonyl.
The configurations at positions 2 and 3 of the above threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) are either (2S,3R) or (2R,3S).
The threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivative of the above general formula (2), which serves as the substrate in the reaction involved in the production method according to the present invention, has the same configuration as the above threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1). Thus, when the above threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) , which is to be obtained, has the (2S,3R) configuration, the above threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivative (2) should have the (2S,3R) configuration. For obtaining the (2R,3S) product, the substrate should be of (2R,3S) configuration.
In the above general formula (2), the group P attached to the amino group is as mentioned above. X represents a halogen atom, such as a chlorine, bromine, fluorine or iodine atom. A chlorine or bromine atom is preferred and a chlorine atom is more p
Maehara Katsuji
Murao Hiroshi
Tokuda Yukinori
Ueda Yasuyoshi
Connolly Bove Lodge & Hutz
Davis Zinna Northington
Kaneka Corporation
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