Single-crystal – oriented-crystal – and epitaxy growth processes; – Processes of growth from liquid or supercritical state – Having growth from a solution comprising a solvent which is...
Reexamination Certificate
2001-12-11
2004-07-20
Kunemund, Robert (Department: 1765)
Single-crystal, oriented-crystal, and epitaxy growth processes;
Processes of growth from liquid or supercritical state
Having growth from a solution comprising a solvent which is...
C117S925000, C117S927000, C549S521000, C549S529000, C549S530000
Reexamination Certificate
active
06764545
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a production method of a crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane and a crystal of (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane.
BACKGROUND OF THE INVENTION
The (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane [the following formula (1), hereinafter sometimes to be referred to as a (2R,3S)-epoxide compound] and (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane [the following formula (2), hereinafter sometimes to be referred to as a (2S,3R)-epoxide compound] are useful as intermediates for pharmaceutical compounds such as HIV protease inhibitor and the like [see, for example, A. A. Malik, The 3rd International Conference on Organic Process Research & Development, Development of a Commercial Process for 2S,3S and 2R,3S-epoxides, Jul. 10-12, 2000, Montreal, T. Archibald et al., Scientific Update Conference Manual, Chiral USA '99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update].
The (2R,3S)-epoxide compound and (2S,3R)-epoxide compound are relatively difficult to crystallize and the development of a method of producing the crystals of these compounds at an industrial scale has been desired. While the production methods of these compounds are disclosed in JP-A-6-206857 (EP0580402), WO99/38855, WO00/44736 and the like, they are not necessarily sufficient as a method for industrially producing the crystals.
For example, JP-A-6-206857 (EP0580402) discloses a method comprising treating (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane with an aqueous KOH solution in ethanol to give (2R,3S)-epoxide compound, removing alkali and the like by extraction, dissolving the compound by refluxing in ethyl acetate and adding hexane to the obtained solution for crystallization. WO99/38855 discloses a method comprising reacting (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-1-butanol with alkylsulfonyl halide compound or arylsulfonyl halide compound in an organic solvent in the presence of a base for sulfonation to give (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-1-methanesulfonyloxybutane, treating the compound with a base and crystallizing the obtained (2R,3S)-epoxide compound from an aliphatic hydrocarbon solvent such as hexane and the like.
According to the above-mentioned methods, however, a complicated step of extraction and the like is necessary to remove alkali and the like remaining in the system after production of the (2R,3S)-epoxide compound. In addition, a poor solvent used (e.g., hexane etc.) dissolves the objective product of the present invention to some extent, and the crystallization ratio tends to decrease. Therefore, crystallization should be conducted at an extremely low temperature of −20° C. (WO99/38855) or −40° C. (JP-A-6-206857) to increase the ratio. As such, these methods are not necessarily sufficient for industrial production.
WO00/44736 discloses a crystallization method comprising treating (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane with aqueous sodium hydroxide solution in acetone to give (2R,3S)-epoxide compound, separating the aqueous phase, dissolving the obtained (2R,3S)-epoxide compound in a mixed solvent of acetone and water and adding the resulting solution to water. According to this method, however, a solution of the objective product is added dropwise to a poor solvent to allow rapid crystallization. As a result, crystals may aggregate or form scales and the like depending on the conditions of the dropwise addition, stirring and the like. In addition, a solution of the objective product needs to be added into a different container containing the poor solvent, which makes the method not entirely suitable for an industrial production.
SUMMARY OF THE INVENTION
The present invention aims at providing a method for industrial scale production of a crystal of (2R,3S)-3-tert-butoxycarbonylamino-1-epoxy-4-phenylbutane and a crystal of (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, which method is free of the above-mentioned problems (e.g., complicated operation, extremely low temperature necessary for crystallization and the like).
According to the present invention, water is added to a solution of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane or an optical isomer thereof, (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, in a polar solvent, to allow crystallization, whereby crystals superior in filtration property and separation property are obtained conveniently in a high yield without requiring an extremely low temperature.
Accordingly, the present invention provides the following.
[1] A method for producing a crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R,3S)-epoxide compound) of the above-mentioned formula (1) or (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2S,3R)-epoxide compound) of the above-mentioned formula (2), which method comprises adding water to a solution of the (2R,3S)-epoxide compound or the (2S,3R)-epoxide compound in a polar solvent to allow crystallization.
[2] The method of the above-mentioned [1], wherein the crystallization comprises a step of starting precipitation of crystals and aging the crystals precipitated.
[3] The method of the above-mentioned [1], wherein the crystallization is conducted at a temperature of not higher than 16° C.
[4] The method of the above-mentioned [1], wherein the polar solvent is one or more kinds of solvent(s) selected from group (A) consisting of methanol, ethanol, 1-propanol and 2-propanol, or a mixed solvent of water and one or more kinds of solvent(s) selected from the group (A).
[5] The method of the above-mentioned [1], wherein the polar solvent is 2-propanol or a mixed solvent of water and 2-propanol.
[6] A method for producing a crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane or (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, which method comprises treating (2R,3S)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4-phenylbutane of the following formula (3)
wherein X is a halogen atom, or (2S,3R)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4-phenylbutane of the following formula (4)
wherein X is a halogen atom, with a base in a polar solvent to give a solution of (2R,3S)-epoxide compound or (2S,3R)-epoxide compound in a polar solvent, and adding water to the obtained solution to allow crystallization.
[7] The method of the above-mentioned [6], wherein X is a chlorine atom.
[8] The method of the above-mentioned [6], wherein the crystallization comprises a step of starting precipitation of crystals and aging the crystals precipitated.
[9] The method of the above-mentioned [6], wherein the crystallization is conducted at a temperature of not higher than 16° C.
[10] The method of the above-mentioned [6], wherein the polar solvent is one or more kinds of solvent(s) selected from group (A) consisting of methanol, ethanol, 1-propanol and 2-propanol, or a mixed solvent of water and one or more kinds of solvent(s) selected from the group (A).
[11] The method of the above-mentioned [6], wherein the polar solvent is 2-propanol or a mixed solvent of water and 2-propanol.
[12] A method for producing a crystal of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane or (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane, which method comprises treating (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane or (2S,3R)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane with a base in a polar solvent to give a solution of (2R,3S)-epoxide compound or (2S,3R)-epoxide compound in a polar solvent, and adding water to the obtained solution to allow crystallization.
[13] The method
Hirose Naoko
Izawa Kunisuke
Onishi Tomoyuki
Suzuki Yuichi
Ajinomoto Co. Inc.
Kunemund Robert
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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