Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
2001-11-02
2004-05-18
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06737264
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for purification and isolation of (2S,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes of the general formula (1):
(wherein X represents a halogen atom) or (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes of the general formula (2):
(wherein X represents a halogen atom). The above compounds are of great use as production intermediates of medicines, particularly HIV protease inhibitors [e.g. JP 06206857A, JP 08109131A and JP 08225557A].
BACKGROUND ART
(2S,3S)-1-Halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes (1) [hereinafter referred to sometimes as compound (1)] and (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes (2) [hereinafter referred to sometimes as compound (2)] can be respectively produced by diastereo-selective reduction of the oxo group in position-2 of (3S)-1-halo-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes of the general formula (3) [hereinafter referred to sometimes as compound (3)]:
(wherein X represents a halogen atom) using a borane compound or an aluminum compound as a reducing agent (e.g. JP C6206857A, JP 08109131A and JP 08225557A) or by means of a strain of microorganism (e.g. JP 09000285A).
The compound (1) or compound (2) thus obtained usually contains the counterpart diastereomer compound (2) or compound (1) as a byproduct and the unreacted substrate compound (3) as impurity depending on reduction selectivity and conversion rate. Furthermore, the above compound (1) and compound (2) are not sufficiently stable and, therefore, in the course of process leading to final isolation, the loss of yield due to decomposition and the contamination with decomposition products tend to take place depending on conditions. The decomposition products, which are of several kinds, have not been fully identified as yet but at least (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane of the following general formula (4):
[(hereinafter referred to sometimes as compound (4)] and (2R,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane of the following general formula (5):
are known.
Therefore, in order that said compound (1) or compound (2) may be isolated in good yield and with high quality, it is necessary to use a sophisticated purification/isolation procedure insuring a minimum of contamination with said diastereomer compound (2) or (1), said unreacted substrate compound (3), said decomposition product compounds (4) and (5) and other structurally analogous contaminants.
For the purification and isolation of said compound (1), the following methods, among others, are known.
i) After the reduction reaction, the reaction mixture is quenched with KHSO
4
/H
2
O and concentrated to give a yellow solid and this yellow solid is re-slurried with water, washed with hexane, and dried. Then, this dry solid is extracted with hot ethyl acetate and the extract is filtered after treatment with activated carbon and Celite, concentrated, and cooled to give lichenoid brown crystals. Yield 45.5%. (2S,35) compound/(2R,3S) compound=95.6/2.0 (JP 08225557A).
ii) After the reduction reaction, the reaction mixture is quenched with KHSO
4
/H
2
O, extracted with ethyl acetate, dried over MgSO
4
, filtered, and concentrated to give a white solid. This solid is recrystallized from hot ethyl acetate. Yield 50%. (2R,3S) compound content: a few % (JP 06206857A).
iii) After the reduction reaction, the reaction mixture is quenched with KHSO
4
/H
2
O, extracted with ethyl acetate, dried over MgSO
4
, filtered and concentrated to give a grayish white solid. This solid is crystallized from hot ethyl acetate/hexane (50/50) to give needle-like crystals. Yield 53% (JP 08225557A).
For the isolation of said compound (2), the method for isolation by column chromatography, for instance, is known (JP 06206857A). However, there is not known a method for isolating crystals by crystallization procedure only.
Moreover, in these methods, the quality and yield of the product compound cannot necessarily be reconciled. Further, these conventional methods require the use of various reagents unsuitable for commercial-scale operation in substantial amounts and/or involve a concentration—crystallization—filtration procedure which is either time-consuming or complicated, so that none of the methods are fully satisfactory in operability or productivity. In other words, none of the known methods have proved satisfactory for practical mass production.
Under the circumstances, it has a great significance to establish a practical method for the purification/isolation on a mass-production scale of (2S,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes (1) or (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutanes (2), which are useful production intermediates of HIV protease inhibitors.
SUMMARY OF THE INVENTION
In the above state of the art, the present invention has for its object to provide a practical method for the purification and isolation on a commercial scale of said compound (1) or compound (2) in good yield and with high quality.
The present invention, therefore, is concerned with a purification/isolation method of a (2S,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane of the following general formula (1):
(wherein X represents a halogen atom) or a (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane of the following general formula (2):
(wherein X represents a halogen atom)
which comprises, for the purpose of removing contaminant impurity from a mixture containing at least one of said (2S,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (1) and (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (2), causing the objective compound (1) or compound (2) to be crystallized in the presence of a solvent comprised of a hydrocarbon solvent
and collecting the obtained crystals.
DISCLOSURE OF THE INVENTION
The purification/isolation method of the present invention comprises, for the purpose of removing contaminant impurity from a mixture containing at least one of said compound (1) and compound (2), causing the objective compound (1) or compound (2) to be crystallized in the presence of a solvent comprised of a hydrocarbon solvent and collecting the obtained crystals.
In the above general formulas (1), (2) and (3), X represents a halogen atom. The halogen atom includes fluorine, chlorine, bromine and iodine, although a chlorine atom or a bromine atom is preferred in terms of the ease of synthesis. The most preferred is a chlorine atom.
The mixture containing at least one of said compound (1) and compound (2) for use in the present invention can be obtained by, for example, the diastereo-selective reduction of a (3S)-1-halo-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane of the above general formula (3) by means of a reducing agent, such as a borane compound and an aluminum compound, or by means of a strain of microorganism. Specifically, any of the known techniques can be liberally used (e.g. JP 06206857A, JP 08109131A, JP 08225557A and JP 09000285A).
The reducing agent for use in the above reduction reaction is not particularly restricted but includes sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, sodium borohydride, potassium borohydride, tetramethylammonium borohydride; aluminum trialkoxides such as aluminum triisopropoxide and aluminum tri-sec-butoxide; lithium aluminum trialkoxyhydrides such as lithium aluminum tri-tert-butoxyhydride; substituted aluminum alkoxides such as methanesulfonyloxyaluminum diisopropoxide and ethanesulfonyloxyaluminum diisopropoxide; among others [e.g. JP 06206857A, JP 08109131A, JP 08225557A, JP 08099959, Japanese Patent Application H-9-162005, etc.]. These reducing agents are generally effective in preferentially producing said compound (1).
The microorganism for use in the above reduction reaction includes microorganisms belonging to a
Kawano Shigeru
Maehara Katsuji
Ueda Yasuyoshi
Yamaguchi Makoto
Armstrong Kratz Quintos Hanson & Brooks, LLP
Kaneka Corporation
Saucier Sandra E.
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