MXPA99002001A - Process for the purification or isolation of (2s, 3r)-1-halo-2-hydroxy-3-(protected amino)-4-phenylthiobutanes or optical antipodes thereof - Google Patents

Abstract

A process for the purification or isolation of (2S, 3R)-1-halo-2-hydroxy-3-(protected amino)-4-phenylthiobutanes of general formula (1) or optical antipodes thereof, which comprises ridding a compound of general formula (1) contaminated with impurities or an optical antipode thereof contaminated similarly by the use of an aromatic hydrocarbon solvent to thereby obtain the compound or the antipode as a crystal. In said formula, X is halogeno;and P1 and P2 are each independently hydrogen or an amino-protecting group, or alternatively P1 and P2 may be united to form an amino-protecting group.

Description

METHOD OF PURIFICATION AND ISOLATION OF ONE (2S, 3R) -1-HALO-2-HYDROXY-3-AMINO-4-PHENYLTIOBUTANE PROTECTED IN THE NITROGEN OR ITS ENANTIOMER FIELD OF THE INVENTION The present invention relates to a method of purification and isolation of a N-protected (2S, 3R) -l-halo-2-hydroxy-3-amino-4-phenyl-or-butane of the following general formula (1) or its enantiomer. The following compound is useful as an intermediate for the production of medicinal compounds, particularly of an HIV protease inhibitor (Viracept ™, already commercially available) which is described, inter alia, in EP 604185 Al. (wherein X represents a halogen atom, one of P1 and P2 represents a hydrogen atom and the REF.29200 other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group).

BACKGROUND OF THE INVENTION N-protected (2S, 3R) -l-halo-2-hydroxy-3-amino-4-f-enyl-1-iobuthane of the general formula (1) above (sometimes referred to as subsequently, in the present as compound (1)) it can be synthesized, for example, by the process described in WO 95/09843 or by the process described in WO 96/23756 or the like. "" In the process in accordance with the WO 95/09843, (2R) -2-N- (benzyloxycarbonyl) amino-3-phenylthiopropanoic acid is first converted to (3 S) -1-diazo-2-oxo-3-N- (benzyloxycarbonyl) amino -4-phenylthiobutane, and then it is converted to the compound of haloketone (3R) -l-chloro-2-oxo-3-N- (benzyloxycarbonyl) aiaino-4-f-en-l-butyl ether and, in turn, is reduced to (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. In accordance with the process described in WO 96/23756, an ester (2R) -2-N- (benzyloxycarbonyl) amino-3-phenyl or opiopane is converted to the haloketone compound (3R) -1- chloro-2 -oxo-3-N- (benzyloxy carboni 1) amino-4-f eni lt iobut an, and then reduced to (2S, 3R) -1-chloro-2-hydroxy-3-N- ( benzyloxycarbonyl) amino-4-phenylthiobutane. The compound (1) thus obtained is not necessarily thermally stable and, in addition, due to the decompositions and secondary reactions involved in the course of production, it is likely that the product contains various contaminants. Particularly, the (2R, 3R) -l-halo-2-hydroxy-3-amino-4-phenylthiolbutane-protected N, of the following general formula (2) (to which reference is sometimes made, hereinafter in the present , as a compound (2)), the N-protected (3R) -1-f-en-lythio-2-hydroxy-3-amino-4-phenylthioethane of the following general formula (3) (to which reference is sometimes made, subsequently herein, as the compound (3)), and the (2R, 3S) -l-haro-2-hydroxy-3-amino-4-phenylthiobutane protected in N of the following general formula (4)) to which sometimes referred to hereinbefore, as the compound (4)) tend to form appreciable amounts of side products such as those of the compound (1) and so that the target compound can be obtained with a high quality should be eliminated In some way, those impurities consisting of products will rise. where X, P1 and P2 are as defined above. The above compound (2) is one tereomeric day of the objective compound (1) and its secondary production is based on the selectivity of the reduction of the precursor (haloketone) (3R) -l-halo-2-oxo-3-amino-4 -phenylthiobutane. The above compound (3) is a compound that is obtained by the substitution of a phenylthio group by the halogen atom of the 1-position of the target compound (1) and its secondary production can apparently be attributed to a substitution reaction involving the phenylthio group released or its equivalent. The above compound (4) is an enantiomer of the objective compound (1) and its secondary production is derived from the haloketone formed as (S) which is present with a precursor (haloketone) of the compound (R), the (3R) -l-halo-2-oxo-3-amino-4-phenylthiobutane which is an enantiomer thereof. This compound formed as (S) can be produced when the optical purity of the acid (2R) -2-N- (benzyloxy carbonyl) amino-3-phenyl thiopropane ico or of the ester (2R) -2-N- (benz 1 oxyi carboni 1) amino-3-phenyl-1-io-propane-ico or the like, which is a starting material of the methods described in WO95 / 09843 or W096 / 23756 mentioned above, is not at all elevated. As is generally known, it is difficult to remove structurally analogous impurities (related compounds) and for those impurities to be eliminated and for a high quality target compound to be provided, effective purification and isolation technology must be established. As a purification technology and c isolation of the above compound (1), for example, the process of WO 95/09843 is known, in which the above compound (1) is purified by two executions of flash chromatography (eluent of the first execution: methylene chloride containing methanol, eluent of the second embodiment: chloroform containing ethyl acetate) and then, crystallized from methylene chloride at a very low temperature of -78 ° C to isolate it. However, the technology has the following disadvantages. (1) Objectable organic solvents (particularly halogenated hydrocarbons such as methylene chloride and chloroform) must be used in large quantities with the consequent disadvantage associated with the disposal of effluents. (2) The process is complicated and time consuming. (3) Expensive production equipment such as a low temperature generator is required which increases the number of units and the capacity of the necessary equipment. (4) Low performance Therefore this technology of purification and isolation has many disadvantages to overcome for its application on a commercial scale. Thus, the prior art has failed to provide a convenient technology for the purification and isolation of the above compound (1), which is an objective compound, through the efficient removal of those compounds (2), (3), and ( 4) on a commercial scale. Furthermore, it is not necessary to mention, that any technology for the purification and isolation of the compound (1) by eliminating the compounds (2), (3) and (4) is a technology for the purification and isolation of its enantiomers as such . Under the circumstances, a task of outstanding importance was to establish a purification and isolation technology for the compound (1) which is an intermediate compound useful for the production of the HIV protease inhibitor.

BRIEF DESCRIPTION OF THE INVENTION In view of the prior art, the present invention aims to provide a convenient and efficient, commercially useful method for the purification and isolation of a (2S, 3R) -1-halo-2-hydroxyl- 3 - amino-4-f eni 11 iobut anion protected in N (1), which is capable of removing the different pollutants, particularly compounds (2), (3) and (4), by the use of a hydrocarbon-based solvent aromatic, by which the problem of instability of the compound (1) can be overcome and a high yield of the product can be ensured. The present invention relates to a method for the purification and isolation of an N-protected (2S, 3R) -1-halo-2-hydroxy-3-amino-4-phenylthio-butane of the general formula (1) : (wherein X represents a halogen atom, one between P1 and P2 represents a hydrogen atom and the other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group) or its enantiomer, which comprises using an aromatic hydrocarbon-based solvent to remove impurities that occur in the compound of general formula (1) or impurities that occur in the enantiomer of the compound of general formula (1) containing the impurities or the enantiomer containing the impurities, and isolating the compound of general formula (1) or the enantiomer, as crystals.

DESCRIPTION OF ALLADA OF THE INVENTION The present invention is now described with such a. The present invention relates to a method for the purification and isolation of the above compound (1) or its enantiomer, which is a method for removing the contaminants found in the above compound (1) or its enantiomer, and to obtain the above compound (1) or its enantiomer, like crystal, in a solvent based on aromatic hydrocarbon. In the general formula (1), which represents the above compound (1), X represents a halogen atom. As the above halogen atom, fluorine, chlorine, bromine, iodine, or the like can be mentioned, and from the standpoint of the ease of their synthesis, the chlorine atom is preferable. In the general formula (1), one of P1 and P2 represents a hydrogen atom and the other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group. The amino protecting group, above, is generally any group that is effective to protect an amino group. Specific amino-protecting groups, which are generally used, can be found in academic publications relevant to the particular field such as in Protective Groups in Organic Synthesis (Second Edition, John Wiley &Sons, 1991).

The amino-protecting group that can be used is not particularly restricted, and includes, but is not limited to, benzyloxycarbonyl, methoxycarbonyl, tert-butyloxycarbonyl, acetyl, trifluoride, benzyl, dibenzyl, tosyl, phthaloyl, benzoyl, and 3-hydroxy-2-methylthiazole (of which 3-hydroxy can be protected, for example, in the alkoxy or ester form). From the point of view of the ease of synthesis of the compound (1), urethane-type protecting groups such as benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-but oxycarbonyl, etc. are preferred, and particularly preferred are benzyloxycarbonyl and tert-but oxycarboni lo. Typical impurities that occur in compound (1) and that can be removed in accordance with the purification and isolation of the present invention are (2R, 3R) -1-halo-2-hydroxy-3-amino-4 - feni lt iobut no (a threo form of impurity, secondarily produced in the reduction er itr o- se 1 ec ti va of the general formula above (2), the (3R) - 1 - phenyl thio-2-hydroxy - 3 - amino-4-f enylthiobutyl of the above general formula (3), and / or the (2R, 3 S) -1-halo-2-hydroxy-3-amino-4-f-enyl-11-aminobutyl the above general formula (4), which is an enantiomer of compound (1) (is derived from the isomer of (2S) -amino acid which is a contamination of the starting material, an ester (2R) -2-N-amino- 3-f eni 1 t iopr opanoi co protected in N) Typical impurities that occur in the form (2R, 3S), an enantiomer of the above compound (1), which can be removed in accordance with the method herein invention, are the (2S, 3 S) - 1 -halo- 2 -hi drox i- 3 -amino-4-phenylthiobutane, (3S) -1-phenylthio-2-hydro i-3-amino-4-phene 11 iobutum and / or the above compound (1). The aromatic hydrocarbon solvent used in the purification and isolation method of the present invention is not particularly restricted to a single species but includes compounds of the following general formula (5), among others. wherein R1 and R2 each independently represents a hydrogen atom, a halogen atom, or an alkyl group of 1 to 4 carbon atoms.) For example, it includes: benzene, toluene, o-xylene, m-xylene, p-xylene, eumeno, ethylbenzene, mesitylene, n-but i lbenzene, sec-but i lbenzene, t-butyl i, benzene, p-cymene, o-diethylbenzene, m-diethylbenzene, p-di eti, benzene, c-lorobenzene , o-chloro aluene, m-chlorocene, p-chloro to luene, o-di-chlorobenzene, m-di chlorobenzene, and p-di chlorobenzene, etc. These solvents can be used alone or in combination of 2 or more speci c es. Particularly, from the point of view of the ease of removal of the solvent from the wet compound and the use in recycles, of the solvent (recovery by distillation), a solvent having a comparatively low boiling point is preferred. The boiling point of that solvent is generally not greater than about 200 ° C, particularly it is up to about 150 ° C, at atmospheric pressure. For example, six-membered monocyclic aromatic hydrocarbon solvents of 6 to 9 carbon atoms, such as benzene, toluene, o-xylene, m-xylene, p-xylene, eumeno, ethylbenzene, and chlorobenzene, may be mentioned. From the point of view of cost and safety, etc., toluene is particularly preferred. The use of this aromatic hydrocarbon solvent can lead to the stabilization and high yield of the compound (1) and to a high purification effect, ie an affective removal of various impurities, particularly of the compound (2), of the compound (3), and of compound (4). The amount of the aromatic hydrocarbon solvent is preferably large enough to maintain the fluidity of the system at the end of the isolation procedure of the compound (1) as crystals. For example, about 5 to 20 times the weight of the compound (1) are used and, in some cases, even larger proportions are used. The appropriate amount of the aromatic hydrocarbon solvent can be easily established through a simple experiment. In the present invention, when the above compound (1) is isolated as crystals, either crystallization by cooling or crystallization by concentration, or a similar method, or preferably the combination of these methods can be used. As other methods, the so-called liquid paste reincorporation process (re-pulp process) can be used. In addition, crystallization by concentration can be carried out by replacing the solution containing a solvent other than aromatic hydrocarbon-based solvents, with the solution containing the aromatic hydrocarbon solvent. When the above compound (1) is isolated as crystals, embryo crystals can be added.

In the present invention, when isolating the above compound (1) as crystals, an auxiliary solvent different from the aromatic hydrocarbon solvent can be used, to improve at least one condition between solubility and yield, concentration of treatment, effect of the purification (effect of removing impurities), and the physical properties of the crystals of the product of the compound (1). The auxiliary solvent may be added to the aromatic hydrocarbon solvent or may be used separately. The auxiliary solvent is not restricted to a particular type. This includes, but is not limited to, acetone, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, methanol, ethanol, 2-propanol, and methylene chloride, etc. These solvents can be used alone or in a combination of two or more species. Particularly, by using at least one solvent selected from the group consisting of ethyl acetate, methylene chloride, and acetonitrile, the solubility can be improved and likewise treatment effects such as the concentration of treatment and the treatment can also be improved. purification effect, etc. The auxiliary solvent may be used with advantage when used in combination with the aromatic hydrocarbon solvent in the optimized amount in accordance with the intended effect and its characteristics. Although the quality of the target compound generally deteriorates when the yield is too great, an appropriate amount of the auxiliary solvent can be easily established by a simple experiment. From the viewpoint of the yield and purification effect, when the weight ratio of the auxiliary solvent to the aromatic hydrocarbon solvent (the auxiliary solvent / the aromatic hydrocarbon solvent) is preferably not greater than 0.5 at the time of completion of the Process for the isolation of the compound of general formula (1) or its enantiomer, as crystals. More preferably, a ratio not greater than 0.3 is used. The purification and isolation method of the invention can be carried out at a temperature close to room temperature. Where necessary, to improve the property of the crystals or to increase the performance thereof, the treatment may be carried out under heating or under cooling, for example, at a temperature not above about 60 °. C, usually about 50 ° C to -20 ° C. Particularly, the temperature condition is preferably used to inhibit the decomposition of the compound (1) by heating. The compound (1) tends to decompose in the presence of moisture or oxygen. To minimize this decomposition, the treatment is preferably carried out in an inert gas atmosphere, for example under nitrogen gas, argon gas, or helium gas. The compound (1) thus obtained is subjected to solid-liquid separation and, where necessary, the cake is washed and dried. The method for solid-liquid separation is not particularly restricted although it includes pressure filtration, filtration under reduced pressure, centrifugation, and other techniques. The preferred method for drying is drying in vacuo (vacuum drying), for example at a temperature, not higher than about 60 ° C, to avoid pyrolysis. To improve the physical properties and ease of handling of the wet crystals, the wet crystals can be washed and replaced with a compound that can be used in the practice of purification and isolation, in accordance with the present invention. According to the present invention, the compound (1) can be isolated conveniently and efficiently, with a yield of not less than 80% and, preferably, not less than 90%. The purification and isolation method described above can be applied, as such, to the enantiomer of compound (1) as such. The above purification and isolation method of the invention is particularly effective to obtain the objective compound (halohydr ina) (2S, 3R) -1-halo-2-n-hydroxy-3-amino-4-phenylthioethane protected in N or its enantiomer, through the reduction of the corresponding haloketone, the compound (3R) -1-halo-2-oxo-3-amino-4-f-11-iobutum or its enantiomer. Particularly the effect of the invention is maximized when the method is applied to the target compound (hal ohidr ina) rich in impurities which has been produced from crude haloketone which has not been purified and isolated by crystallization or solid process. Particularly, the preferred embodiment of this invention is crystallization by the replacement of a solution which substantially contains a solvent other than aromatic hydrocarbon solvents. (preferably, ethyl acetate, etc.) and containing the compound (1) or its enantiomer, with a solution substantially containing toluene or crystallization by cooling a solution containing substantially toluene and containing the compound (1) or its enantiomer (preferably a solution of toluene containing acetonitrile, as the auxiliary solvent, etc.). However, this invention is not limited to these methods.

EXAMPLES "It is intended that the following examples illustrate the present invention in greater detail and in no way be construed as limiting the scope of the invention.

(Reference Example 1) Preparation of (2S, 3R) - 1 - cyclo-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4- f eni 11 Under nitrogen gas, a solution composed of 20.0 g of (2R) -2-N- (benzyloxy carboni 1) amino-3-f-eni-11-methyl-o-opropane, 13.5 g of sodium monochloroacetate, 11. 05 g of magnesium chloride, and 80 ml of THF, is stirred at 25 ° C for 1 hour (Solution A). On the other hand, under nitrogen gas, 23.5 g of di isopropyl 1 amine were added to 116 ml of a solution of n-butyl chloride in THF (2.0 mol / l) for 30 minutes at room temperature and the mixture is further stirred at 50 ° C for 1 hour (Solution B). Solution B is added to solution A for about 1 hour at an internal temperature of about 5 ° C, and after the addition is complete the mixture is stirred for about 10 hours. This mixture is then added to a solution composed of 22.8 g of sulfuric acid, 200 ml of water, and 300 ml of L ethyl acetate and the mixture is stirred for 30 minutes to effect hydrolysis. After phase separation, the organic phase is washed in series with 200 ml of water, 200 ml of hydrogen carbonate or 5% sodium / H20, and 200 ml of 1 N hydrochloric acid and concentrated under reduced pressure. To 21.6 ml of a solution of DIBAH (dihydride of 1 sobutyl aluminum) in toluene (1.02 M) 2.64 g of 2-propanol are added at room temperature, and the mixture is stirred for 1 hour. To this mixture is added (3R) -l-chloro-2-oxo-3-N- (benzyloxycarbonyl) amino-4-phenylthioethane equivalent to 3.96 g obtained by concentration under reduced pressure, and the mixture is stirred at room temperature for 3 hours . Then, using 50 ml of 1 N hydrochloric acid, the hydrolysis reaction is carried out under cooling with ice. This reaction mixture is extracted with 30 ml of ethyl acetate and the extract is washed with 50 ml of 2% sodium hydrogen carbonate / H20 and 20 ml of 2% NaCl / H20, in that order, and concentrated under reduced pressure. The solvent is replaced with ethyl acetate to provide an ethyl acetate solution containing the (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f eni-1-iobut . This solution is concentrated to dryness and further dried in vacuo. The quality of the (2S, 3R) -1-cyro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane thus obtained was as follows. Purity: 79% in area (70% by weight) content of (2R, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.5% content area (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl 1) -amino-4-phene 11 iobutum: 0.2% in content area of (3R) -1-phenylethio- 2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 3.9% area (Reference example 2 Preparation of (2S, 3R) -1-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenyl-thiobutane The mixture is stirred at 40 ° C for 2 hours (Solution A) under nitrogen gas, a solution composed of 25.4 g of (2R) -2-N- (tert-butoxycarbonyl) amino-3-f-enyl-11-iopropane at or of methyl. , and 14.2 g of sodium monochloroacetic acid, 11.6 g of magnesium chloride, and 20 ml of THF. On the other hand, under nitrogen gas, 44.5 g of di-sopropi lamina were added to 197 ml of a solution of n-butyl chloride in THF (1.9 mol / l) for 30 minutes at an internal temperature of 40 ml. ° C and the mixture is further stirred at 40 ° C for 2 hours (Solution B). Solution B is added to solution A for about 1 hour at an internal temperature of about -5 ° C, and after the addition is complete, the mixture is stirred for about 15 hours. This mixture is added to a solution composed of 81.8 g of concentrated hydrochloric acid, 50 ml of water, and 30 ml of ethyl acetate for 2 hours at 5 ° C and the hydrolysis reaction is carried out. After phase separation, the organic phase is washed in series with 200 ml of hydrogen carbonate or 5% sodium / H20 and 200 ml x 2 of water and then concentrated under reduced pressure. To 20.0 ml of a solution (1.02 M) of DIBAH in toluene, 7.1 g of 2-propanol are added at room temperature, and the mixture is stirred for 3 hours. To this mixture is added (3R) -l-chloro-2-oxo-3-N- (tert-butoxycarbonyl) amino-4-phenyl thiobutane equivalent to 2.80 g obtained by concentration under reduced pressure. The mixture is stirred at 5 ° C for 10 hours and then a solution composed of 1.8 g of concentrated hydrochloric acid, 10 ml of water, and 20 ml of ethyl acetate is added over 1 hour, under cooling with ice. The mixture is further stirred for 13 hours to effect hydrolysis. After hydrolysis, the organic phase is washed with 15 ml of hydrogen carbonate or 5% sodium / H20 and 15 ml of water in 3 cycles, and then concentrated under reduced pressure. The solvent is replaced with ethyl acetate to provide an ethyl acetate solution containing the (2S, 3R) -l-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-f eni 1 t iobut anus. This solution is concentrated to dryness and further dried in vacuo. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenyl thiobutane, thus obtained, was as follows. Purity: 85% area (80% by weight) content of (2R, 3R) - 1 -cl gold-2 -hi drox i- 3 -N- (tert-butoxycarbonyl) amino-4-phenyl thiobutane: 3.8% in content area of (2R, 3 S) - l-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenylthiobutane: 0.2% in content area of (3R) - 1 - f eni lt io- 2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenylthiobutane: 3.7% by area (Reference Example 3 Preparation of (2R, 3 S) -1- cyclo-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane Using (2S) -2-N- (benzyloxy carboni 1) amino-3-f-enyl-1-thio-methyl optopane instead of (2R) -2-N- (benzyloxy-carboni-1) amino-3-phenylthiopropanoate of methyl, the procedure of reference example 1 was repeated to provide an ethyl acetate solution containing (2R, 3S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4 -f eni lt iobut anus. This solution was concentrated to dryness and further dried in vacuo. The quality of (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxy carboni 1) amino-4-f-enyltin, thus obtained was as follows: Purity: 78% in area (70% by weight) content of: (2S, 3 S) -1-c-loro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 4.6% in content area of (2S, 3R ) - 1 - cl oro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (3 S) -1- f eni 11 io-2-hydroxy-3-N - (benzyloxycarbonyl) amino-4-phenylthiobutane: 4.0% area.

( Example 1 Under nitrogen gas, 29.9 g of a solution containing 5.44 g of (2S, 3R) -1-chlor or-2-hydroxy-3-N- (benzyloxycarbonyl) are inoculated to ino-4-f-enylthiobutane in _ to lueno / acetoni tri lo (9: 1 (weight / weight)) from an initial internal temperature of 50 ° C, under vigorous agitation (18% treatment concentration (weight of solute / weight of the solution)). The cooling program was 40 minutes descending to an internal temperature of 40 ° C, addition of seed crystals, and 30 minutes of incubation at an internal temperature of 40 ° C. The resulting liquid paste is cooled to an internal temperature of 5 ° C for more than 12 hours and incubated at this internal temperature of 5 ° C for 2 hours. The resulting crystal collection was filtered under reduced pressure, drained completely, and washed 3 times with 13 ml of toluene each time. The crystals were then dried in vacuo (approximately 1 to 10 mm Hg, to 40 ° C, approximately 10 hours) to provide 4.32 g (80% yield) of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxy-carboni-1) amino-4-f-en-1-thiobutane, as crystals. "" The quality of (2S, "3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f-enylthiobutane, before treatment (after concentration to dryness and drying in vacuo) was as follows: Purity: 74% in area (70% by weight) content of: (2R, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 5.2% by area content of: (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.3% in content area of: (3R) -1- f eni 1 thio- 2-Hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 3.5% area The quality of the crystals of (2S, 3R) -l-chloro-2-idroxy-3-N- (benzyloxy-carboni-1) amino-4-phenyl-thiobutane, after the treatment, was as follows. Purity: 98% area (99% by weight) content of (2R, 3R) - 1-cl gold-2-hydrox i -3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in area content of: (2R, 3 S) - 1 - c parrot -2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in content area of: (3R) - 1 - phenyl thio-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.2% by area (E j emp lo 2 r nitrogen gas, a solution of 40 g of ethyl acetate which contained 1.75 g of (2s, 3R) -1-vacuo-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane was concentrated, until 18.0 g r reduced pressure (approximately 100 mm Hg) at an internal temperature of 30 to 40 ° C, with vigorous stirring. Then, r an internal pressure of 5 to 50 mm Hg, with vigorous stirring, the concentrate was further distilled keeping the volume of the mixture constant by addition of toluene, and the solvent was replaced until the content of ethyl acetate had decreased up to 5% by weight (treatment concentration of 10% (weight of solute / weight of the solution)). The pressure was returned to atmospheric pressure, with nitrogen, and r nitrogen gas with vigorous stirring, the solution was incubated at 40 ° C for 1 hour. Then, the solution was gradually cooled to an internal temperature of 5 ° C and incubated at this temperature for 1 hour. The resulting crystal collection was filtered r reduced pressure, drained completely, washed with 10 ml of toluene, and dried in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) provide 1.59 g (91% yield) of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino) 4-phenylthiobutyl, as crystals. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenyl-1-thiobutyrate before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 80% in area (71% by weight) content of: (2R, 3R) -1-C-loro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 5.2% in content area of : (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2 in content area of: (3R) -1-phenylthio-2-hydroxy-3 -N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 3.6% in area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenyl thiobutane, after the treatment, was as follows. Purity: 98% in area (98% by weight) content of: (2R, 3R) - 1 - c, 2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.1% in area content of: (2R, 3 S) - 1 - chloro - 2 - hydroxy - 3 - N - (benzyloxycarbonyl) - amino - 4 - phenylthiobutane: less than 0.1% in content area of: (3R) - 1 - phenyl thio -2-Hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.5% area.

(E j us 3) The procedure of Example 2 was repeated, except that o-xylene was used in place of toluene (treatment concentration of 9% (weight of solute / weight of the solution), content of ethyl acetate of 0% by weight) to provide 1.49 g (85% yield) of crystals of (2S, 3R) - 1 -cl gold- 2 -hi drox i- 3-N- (benzyloxycarbonyl) amino-4-phenyl thiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows . Purity: 78% area (69% by weight) content of: (2R, 3R) - 1 - c, 2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.9% by area content of : (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (3R) -1-phenyl-2-hydroxy-3 -N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 3.9% by area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) to ino-4-phenylthiobutane after of the treatment was as follows. Purity: 98% area (98% by weight) content of (2R, 3R) - 1 - cl gold - 2 -hi drox i- 3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in contained area of (2R, 3 S) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in content area of: (3R) -1- phenylthio-2 -hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.8% by area (E xemplo 4Example 2 was repeated using ethylbenzene in place of toluene (treatment concentration of 7% (solute weight / weight of the solution), ethyl acetate content of 1% by weight) to provide 1.40 g (80% yield) of crystals of (2S, 3R) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 80% area (72% by weight) content of (2R, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.7% content area of ( 2R, 3 S) - 1 -cl gold-2 -hi dro i - 3 -N- (benzyloxycarbonyl) -amino- 4-phenylthiobutane: 0.2% in content area of (3R) -1-pheny11-io-2 -hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 4.0% in area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f-en-1-thiobutane, after the treatment was as follows. Purity: 99% area (98% by weight) content of: (2R, - 3R) - 1 - c, 2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in contained area of (2R, 3 S) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in the content area of (3R) -1-phenylethio- 2-hydroxy-3-N- (benzyloxy carboni 1) amino-4-phenylthiobutane: 0.7% by area (E xemplo 5) The procedure of Example was repeated 2 using chlorobenzene in place of toluene, (treatment concentration of 10% (weight of solute / weight of the solution), content of ethyl acetate of 3% by weight) to provide 1.42 g (81% yield) of crystals of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before the treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 81% in area (73% by weight) Content of (2R, 3R) -1-chloro-2-hydroxy i -3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.4% in area contained in ( 2R, 3 S) - 1 - cl or ro - 2 -hi drox i - 3 -N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.3% in content area of (3R) - 1 - phenyl t io -2 - hydroxy-3-N- (benzyloxy carboni 1) amino-4-phenylthiobutane: 3.8% in area The quality of crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino -4- Phenyl thiobutane after the treatment was as follows. Purity: 99% in area (98% by weight) content of: (2R, 3R) - 1 - c, 2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.1% in content area of : (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -no-4-phenylthiobutane: less than 0.1% in content area of: (3R) -1-f eni 11 io-2 -hidrox i - 3 -N- (benzyloxy carbonyl) amino-4-phenyl thiobutane: 0.3% by area (E xemplo 6) The procedure of Example 2 was repeated using benzene in place of toluene and methylene chloride instead of ethyl acetate (treatment concentration of 8% (solute weight / weight of the solution), methylene chloride content of 0% by weight) to provide 1.44 g (82% yield) of crystals of (2S, 3R) - 1 - chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before the treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 79% area (70% by weight) content of (2R, 3R) - 1 - cl gold-2-hydrox i - 3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.5% in contained area of (2R, 3 S) - 1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (3R) -1-phenyl-t-2-hydroxy - 3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 3.9% in area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane after the treatment was as follows. Purity: 98% in area (98% by weight) content of (2R, 3R) - 1 -cl gold-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.1% in content area of (2R, 3S) - lc-loro-2-hydroxy-3-N- (benzyloxy carboni 1) -amino-4-phenyl thiobutane: less than 0.1% in contained area of (3R) - 1-phenylthio -2-Hydroxy -3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.5% in area Example 7 Concentrate, under nitrogen gas, 70 g of a solution containing 2.21 g of (2S, 3R) -1-chloro-2-hydroxy-3-N- (tert-butoxycarboni-1) amino-f The solvent was added in ethyl acetate to 40 g, under reduced pressure (approximately 100 mm Hg) at an internal temperature of 30 to 40 ° C, with vigorous stirring. Then, the solvent was removed by distillation, under vigorous stirring, under an internal pressure of 50 to 150 mm Hg, keeping the volume of the liquid constant by the addition of toluene until the content of ethyl acetate had reached 3% by weight (Treatment concentration of 6% (solute weight / solution weight)). Then, the pressure was returned to atmospheric with nitrogen gas and the mixture was incubated at 40 ° C with vigorous stirring under nitrogen for 1 hour. The mixture was then cooled gradually to an internal temperature of 5 ° C and further incubated at this temperature for 1 hour. The resulting crystals were filtered under reduced pressure, drained completely, and washed with 10 ml of toluene. This crystal collection was dried in vacuo (approximately 1 to 10 mm Hg, from 20 to 40 ° C, approximately for 10 hours) to provide 1.76 g (80% yield) of crystals of (2S, 3R) -1 -chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -1-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows . Purity: 85% area (80% by weight) content of (2R, 3R) -1-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) -amino-4-phenylthiobutane: 3.8% in area content of (2R, 3 S) -1- cl-2-hydroxy-3-N- (tert-butoxycarbonyl) -amino-4-phenyl thiobutane: 0.2% in content area of (3R) -1- phenylthio-2 - hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenyl thiobutane: 3.7% in area The quality of crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (tert-butoxy) -carbonyl) amino-4-f-enyl thiobutane after the treatment was as follows. Purity: 99% area (99% by weight) content of (2R, 3R) - 1-chloro-2-hydroxy-3-N- (tert-butoxycarbonyl) -amino-4-phenyl thiobutane: 0.1% area content of (2R, 3 S) -1-chloro-2-hydroxy-3-N- (tert-butoxy-carboni 1) -amino-4-phenyl-thiobutane: less than 0.1% in content area of (3R) -1 - Pheni-thio-2-hydroxy-3-N- (tert-butoxycarbonyl) amino-4-phenyl thiobutane: 0.5% by area (E j e plo 8 Concentrate gradually, under nitrogen gas, 149.2 g of a solution containing 1.73 g of (2S, 3R) -1- c, 2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutyl. anion in toluene, up to 20.1 g, under reduced pressure, at an internal temperature of 30 to 40 ° C, with vigorous stirring (treatment concentration of 9% (weight of solute / weight of the solution)). Then, under nitrogen gas and vigorous stirring, the mixture is incubated at an internal temperature of 40 ° C for 1 hour, then gradually cooled to an internal temperature of 5 ° C, and further incubated at this internal temperature of 5 ° C. for 1 hour. The resulting crystals are filtered under reduced pressure, drained completely and washed with 10 ml of toluene. This crystal collection was dried in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) to provide 1.49 g (86% yield) of crystals of (2S, 3R) -1 -cl-gold- 2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 79% area (70% by weight) content of (2R, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.5% area • content of (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (3R) -1-f eni 11 io-2-hydroxy- 3-N- (benzyloxy carbonyl) amino-4-f eni 11 i obut ano: 3.9% in area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f eni-11-butylone, after the treatment, was as follows. Purity: 98% area (98% by weight) content of (2R, 3R) -1- cl gold- 2 -hydrox i- 3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (2R, 3 S) - 1-cl oro-2 -hi drox i- 3 -N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in contained area. of (3R) -1-pheny11-io-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.7% by area (Example 9) The procedure of Example 2 was repeated using (2R, 3S) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -araine-4-phenylthiobutane instead of (2S, 3R) -1-cl gold - 2 -hi-drox i- 3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane, (treatment concentration of 10% (weight of solute / weight of the solution), content of ethyl acetate: 0% by weight) for provide 1.60 g (91% yield) of crystals of (2R, 3 S) -1- ro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane. The quality of (2R, 3 S) - 1 - cio r o -2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 78% area (70% by weight) content of (2S, 3 S) - 1 - cl gold - 2 -hi droxy- 3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 4.6% in contained area of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in content area of (3 S) -1-phenyl-1-t-2-hydroxy - 3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 4.0% in area The quality of the crystals of (2R, 3S) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino- 4-phenylthiobutane, after the treatment, was as follows.

Purity: 98% in area (98% by weight) content of (2S, 3 S) - 1 -cl gold-2 -hi drox i - 3 -N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.21 in contained area of (2S, 3R) -1-chloro-2-hydrox i-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in content area of (3S) -1- phenylthio-2 -hydroxy -3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.7% by area (E j us 10) The crystalline (2S, 3R) -l; chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f-enyltonic acid obtained in Example 2 was treated as in Example 1 (concentration of 20% treatment (weight of solute / weight of the solution), to luene / ace t oni tri 1 or (3: 1, weight / weight)). The yield of the (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane thus obtained was 91%, and the quality of the crystals of the product was as follows. Purity: 100% area (100% by weight) content of (2R, 3R) -1-chloro-2-hydrox i- 3-N- (benzyloxycarbonyl) -amino- 4-phenylthiobutane: less than 0.1% in the content area of (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in content area of (3R) -1- phenylthio- 2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: less than 0.1% by area (E xemplo 11 Cool, under nitrogen gas, 19.2 g of a solution containing 3.66 g of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenyl-thiobutane in toluene / acet. oni tri lo (9: 1 (w / w) from an initial internal temperature of 50 ° C, under vigorous agitation (treatment concentration of 19% (weight of solute / weight of solution)). 1 hour descending to an internal temperature of 40 ° C, and 30 minutes of incubation at an internal temperature of 40 ° C. The resulting liquid paste is cooled to an internal temperature of 5 ° C for more than 12 hours and incubated at that temperature. internal temperature of 5 ° C for 2 hours The resulting crystal collection is filtered under reduced pressure, drained completely, and washed once with 16 ml of toluene, then the crystals were dried in vacuo (approximately 1 to 10 mm of Hg, from 20 to 40 ° C, approximately for 10 hours) to provide 3.29 g (90% yield) of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-f-en-1-thiobutane as crystals. The quality of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 98% area (97% by weight) content of (2R, 3R) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in area contained in ( 2R, 3 S) - 1 - chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 1.5% in content area of (3R) -1-pheny1-t-2-hydroxy-3- N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.7% in area. The quality of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane after the treatment was as follows. Purity: 99% area (98% by weight) content of (2R, 3R) -1-chloro-2-hydrox i- 3 -N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in area content of (2R, 3 S) - 1-cl gold-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% content area of (3R) -1- phenylthio-2 - hydroxy -3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: less than 0.1% by area E xemployment 12) Concentrate, under nitrogen gas, 40 g of a solution containing 3.46 g of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenyl-1-thiobutane in ethyl acetate, to 27.8 g, under reduced pressure (approximately 100 mm Hg) at an internal temperature of 30 to 40 ° C, with vigorous stirring. Then, under vigorous stirring, the solvent is distilled off under an internal pressure of 5 to 50 mm Hg keeping the volume of the liquid constant by the addition of chlorobenzene until the content of ethyl acetate has reached 18% by weight (concentration of treatment of 13% (weight of solute / weight of the solution)). Then, the pressure is returned to atmospheric, with nitrogen gas, and the mixture is incubated at 40 ° C with vigorous stirring under nitrogen for 1 hour. The mixture is then cooled gradually to an internal temperature of 5 ° C and further incubated at that temperature for 1 hour. The resulting crystals are filtered under reduced pressure, drained completely, and washed with 15 ml of toluene, once.

This collection of crystals is dried in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) to provide 3.11 g (90% yield) of crystals of (2S, 3R) - 1 - cl gold- 2 -hi drox i- 3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 98% area (97% by weight) content of (2R, 3R) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% content area of ( 2R, 3 S) - 1-cl gold- 2 -hi drox i- 3 -N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 1.3% in content area of (3R) -1- phenylthio- 2 -hydroxy - 3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.7% area. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane after the treatment was as follows. Purity: 99% area (98% by weight) content of (2R, 3R) -1-chloro-2-hydroxy i-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in contained area of (2R, 3 S) - 1 -chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.3% in area con tained from (3R) -l-phenylthio-2 -hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane less than 0.1% by area (Comparative Example 1) Concentrate one hundred grams (100 g) of a solution containing 2.15 g of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane in methylene chloride, up to 44 g , under reduced pressure (approximately 500 mm Hg) at an internal temperature of 20 to 40 ° C (treatment concentration of 5% (weight of solute / weight of the solution)). The residue is cooled to an internal temperature of 5 ° C and the resulting liquid paste is further cooled, graphically, to an internal temperature of -50 ° C and maintained at that temperature for 1 hour. This liquid paste is further cooled to an internal temperature of -76 ° C and maintained at the same temperature for 1 hour. The resulting crystal collection is filtered under reduced pressure, drained completely, and washed with 10 ml of cold methylene chloride (approximately -70 ° C). The crystals are dried in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) to provide 1.42 g (66% yield) of crystals of (2S, 3R) - 1 -2-hydroxy-3-N (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino- 4-f eni 11-o-butane, before treatment (after concentration to dryness and drying in vacuo) was as follows. Purity: 73% area (75% by weight) content of (2R, 3R) - 1 - cl gold-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 3.9% in content area of (3R) - 1 - phenyltithio-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 4.0% area The quality of the crystals of (2 S), 3R) -l-chloro-2-hydroxy-3-N- (benzyloxy-carboni 1) amino-4-f eni 11 iobut, after the treatment was as follows. Purity: 98% area (97% by weight) content of (2R, 3R) -1-cl-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.2% in area contained in ( 3R) -1-Pheni 11 io-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane: 0.7% by area , 'Comparative Example 2) Gradually concentrate, under nitrogen gas, 71 g of a solution containing 1.50 g of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxy carboni 1) amino- 4-pheni 1-thiut. in 2-propanol up to 10 g, under reduced pressure, at an internal temperature of about 30 to 40 ° C (treatment concentration of 17% (weight of solute / weight of the solution)). After the pressure returns to atmospheric pressure, 10 ml of water are added and the mixture is incubated for a time under nitrogen gas. The liquid paste thus obtained is gradually cooled to an internal temperature of 5 ° C and incubated at that temperature for 1 hour. The resulting crystal collection is filtered under reduced pressure, drained completely, and washed with 10 ml of 2-propane 1 / water. The crystals are then 'dried' in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) to provide 1.23 g (82% yield) of (2S, 3R) crystals - 1-gold-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane The quality of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino- 4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows Purity: 83% in area (75% by weight) content of (2R, 3R) -1-chloro-2- hi drox i - 3-N- (benzyloxycarbonyl) -amino-4-phenyl thiobutane: 3.3% in content area of (3R) -1- phenylthio-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane : 4.0% area The quality of the crystals of (2S, 3R) -l-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane, after the treatment, was as follows: Purity: 87% in area (78% by weight) content of (2R, 3R) - 1 - cl gold-2-hydroxy-3-N- (benzyloxycarboni) l) -amino-4-phenylthiobutane: 2.1% in content area of (3R) -1-f eni 11 io-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane 3.9% in area Comparative example 3) One hundred grams (100 g) of a solution containing 3.21 g of (2S, 3R) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane in methylene chloride, was concentrated to 45 g. , under reduced pressure (approximately 500 mm Hg) at an internal temperature of 20 to 40 ° C (treatment concentration of 7% (weight of solute / weight of the solution)). The residue is cooled to an internal temperature of 5 ° C and the resulting liquid paste is further cooled gradually to an internal temperature of -50 ° C and maintained at this temperature for 1 hour. This liquid paste is further cooled to an internal temperature of -78 ° C and maintained at that same temperature for 1 hour. The resulting crystal collection is filtered under reduced pressure, drained completely, and washed with 11 ml of cold methylene chloride (approximately -70 ° C). The crystals are dried in vacuo (approximately 1 to 10 mm Hg, 20 to 40 ° C, approximately 10 hours) to provide 2.89 g (90% yield) of crystals of (2S, 3R) - 1 -cl gold- 2 -hydrox i -3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane. The quality of (2S, 3R) -1-cyano-2-hydroxy-3-N- (benzyloxycarbonyl) amino-4-phenylthiobutane before treatment (after concentration to dryness and drying in vacuo) was as follows . Purity: 98% area (97% by weight) content of (2R, 3R) -1-chloro-2-hydroxy-3-N- (benzylscarbonyl) -amino-4-phenylthiobutane: 0.2% content area of ( 2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 1.2% by area The quality of (2S, 3R) -1-chloro-2-hydroxy-3 -N- (benzyloxy carboni 1) amino-4-phenylthiobutane after the treatment, it was as if gue. Purity: 99% area (98% by weight) content of (2R, 3R) -1-chloro-2-hydrox i- 3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: less than 0.1% in area content of (2R, 3 S) -1-chloro-2-hydroxy-3-N- (benzyloxycarbonyl) -amino-4-phenylthiobutane: 0.6% by area INDUSTRIAL APPLICABILITY Having the above constitution, the method for purification and isolation of the invention can be conveniently and efficiently carried out on a commercial scale to provide a (2S, 3R) -1 -hal or-2-hydr oxy-3- N-protected amino-4-pheni 11 iobut anen, or its enantiomer, of improved quality, with a good yield.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. A method for the purification and isolation of a (2S, 3R) -1-halo-2-hydroxy-3-amino-4-fyl-1-iobutyl protected N, of general formula (1): (wherein X represents a halogen atom, one of P1 and P2 represents a hydrogen atom and the other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group) or its enantiomer, characterized in that it comprises using an aromatic hydrocarbon solvent to remove an impurity that is present in the compound of general formula (1) or an impurity that is present in the enantiomer of the compound of general formula (1) containing impurities or its enantiomer containing impurities, and isolating the compound of general formula (1) or its enantiomer, as crystals.

2. A method of purification. and isolation, in accordance with the rei indication 1, characterized in that either crystallization by cooling or crystallization by concentration, or both, is used for the isolation of the compound, such as crystals.

3. A method for the purification and isolation of a N-protected (2S, 3R) -1-halo-2-hydroxy-3-amino-4-f enylthiolate according to claim 1 or 2, characterized in that the impurity that occurs in the compound of general formula (1) is at least one selected from the group consisting of a (2R, 3R) -l-halo-2-hydroxy-3-amino-4-phenylthiobutane protected in N, of general formula (2): (2) (wherein X represents a halogen atom, one of P1 and P2 represents a hydrogen atom and the other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group), a (3R ) -l-phenylthio-2-hydroxy-3-amino-4-phenylthiobutane protected in N, of general formula (3): (wherein P1 and P2 are as defined above), and (2R, 3 S) -1-halo-2-hydroxy-3-amino-4-phenyl-1-thiobutane protected in N, of general formula (4) : (where X, are as previously defined]

4. A method for the purification and isolation of an enantiomer of a (2S, 3R) -1-halo-2-hydroxy-3-amino-4-phenylthiobutane protected in N, according to claim 1 or 2, characterized in that the impurity that occurs in the enantiomer of the compound of general formula (1) is at least one selected from the group consisting of (2S, 3S) -l-halo-2-hydroxy-3-amino-4-phenylthio-butane protected in N, a (3 S) -1-f-enyl thio-2-hydroxy-3-amino-4 - feni 11 protected iobutane in N and one (2S, 3R) - l-halo-2-hydroxy-3-amino-4-phenylthio-buthane protected in N.

5. A method of purification and isolation in accordance with the rei indication 1, 2, 3, or 4 characterized in that the aromatic hydrocarbon solvent is a compound of the general formula (5): (5) (wherein R1 and R2 each represents, independently, a monovalent group selected from the group consisting of a hydrogen atom, a halogen atom, and an alkyl group of 1 to 4 carbon atoms).

6. A method of purification and isolation, according to claim 5, characterized in that the aromatic hydrocarbon solvent is toluene.

7. A method of purification and isolation according to claim 1, 2, 3, 4, 5, or 6 characterized in that the isolation as crystals further comprises using an auxiliary solvent to improve at least one condition between solubility, yield, concentration of treatment , purification effect, and physical properties of the crystals of the compound of general formula (1) or its enantiomer.

8. A method of purification and isolation according to claim 7, characterized in that the auxiliary solvent is at least one member selected from the group consisting of ethyl acetate, methylene chloride, and acetonitrile.

9. A method of purification and isolation according to claim 7 or 8 characterized in that the auxiliary solvent is used in an amount such that the weight ratio (of the auxiliary solvent / aromatic hydrocarbon solvent) of the auxiliary solvent to the aromatic hydrocarbon solvent , at the end of the procedure for the isolation of the crystals, it will not be greater than 0.5.

10. A method of purification and isolation in accordance with the claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, characterized in that the method of isolating the crystals is carried out under an inert gas.

11 A method of purification and isolation, according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characterized in that the amino protecting group is a protective group of the urethane type.

12. A method of purification and isolation according to claim 11, characterized in that the amino protecting group is benzyloxycarbonyl or tert-butoxycarbonyl or.

13. A method of purification and isolation in accordance with the rei indication 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, characterized in that the halogen atom represented by X in the general formula (1) is chlorine. SUMMARY OF THE INVENTION The present invention aims to provide a commercially useful, convenient and efficient method for the purification and isolation of a protected (2S, 3R) -1-halo-2-hydroxy-3-amino-4-phenylthiobutane in N, (1 ), or its enantiomer, which is capable of eliminating the different contaminants, particularly the by-products, by means of which the problem of instability of the compound (1) or its enantiomer can be overcome and a high yield of the product can be ensured. The present invention relates to a method for the purification and isolation of a protected (2S, 3R) -l-halo-2-hydroxy-3-amino-4-phenylthio-butane in N, (1): (i) (wherein X represents a halogen atom, one of P1 and P2 represents a hydrogen atom and the other represents an amino protecting group, or P1 and P2 taken together represent an amino protecting group) or its enantiomer, which comprises using an aromatic hydrocarbon solvent to remove impurities that occur in the compound (1) or impurities that occur in the enantiomer of the compound (1) which contains impurities or its enantiomer containing impurities, and isolating the compound (1) or its enantiomer as crystals.