JP2002080470A - Method of producing crystalline epoxide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide (2R,3S) or (2S,3R)-N-carbamate-protected β-amino epoxide (crystals) and a method of producing the same. SOLUTION: The method of producing an N-carbamate-protected β-amino- alcohol comprises the following steps (a)-(d); (a) the step where the (2R,3S) or (2S,3R)-N-carbamate-protected β-amino epoxide including at least the diastereomers as impurities is dissolved in a solvent and the purities are removed; (b) the step where amino alcohol is treated with a base to convert the alcohol to the corresponding N-carbamate-protected β-amino epoxide; (c) the step where the amino epoxide including its diastereomers as impurities is treated with an acid to convert the impurities to oxazolidine-2-one, which is removed, when necessary; and (d) the step where the epoxide product is crystallized in water and/or a mixture thereof with an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a specific configuration (2
The present invention relates to a method for producing an N-carbamate-protected β-aminoepoxide having R, 3S or 2S, 3R) (a purification method) and a method for producing a crystal thereof, and further to a specific configuration (2
R, 3S or 2S, 3R).

[0002]

2. Description of the Related Art General formula (2)

[0003] [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. ]

The N-carbamate-protected β-aminoepoxide represented by is a compound useful as a pharmaceutical intermediate.
For example, (2R, 3S) -N-carbamate protected β-aminoepoxides are known to be useful as intermediates such as HIV protease inhibitors and renin inhibitors (eg, P. Raddatz et al., Journal of Pharmaceutical Sciences, Vol.・ Medicinal Chemistry, Vol. 34, No. 11, p. 3269, 19
91 (J. Med. Chem., 1991, 34, 11, 3269.), or
T. Archibald et al., Scientific Update Conference Manual, Chiral USA '99, Full Scale Chiral Separations Using SM, May 4, 1999, Scientific, San Francisco. Update (Scientific UpdateConference Manual, Chiral U
SA '99, Full Scale Chiral Separations Using SMB, 4
th May 1999, San Francisco, Scientific Update)).

It is known that the N-carbamate-protected β-aminoepoxide represented by the general formula (2) can be synthesized, for example, according to the following route.

[0006] [Wherein, R, A, and * have the same meanings as described above, and X represents a halogen atom. ]

For example, when (3S) -N-carbamate protected α-halomethyl ketone is used as a starting material as a compound represented by the general formula (4), it is reduced to give (2R, 3S) -N-carbamate protected β-
It can be converted to an amino alcohol, and further treated with a base to give (2R, 3S) -N-carbamate protected β
An aminoepoxide can be produced. Similarly,
When (3R) -N-carbamate-protected α-halomethylketone is used as a starting material, it can be reduced to (2S, 3R) -N-carbamate-protected β-aminoalcohol, and further a base (2S, 3R) -N-carbamate-protected β-aminoepoxide can be produced.

Here, when the N-carbamate-protected α-halomethyl ketone represented by the general formula (4) is reduced using a suitable reducing agent, diastereomers are generated as by-products. For example, (3S) -N- represented by the general formula (13)
When the carbamate protected α-halomethyl ketone is reduced, it is a diastereomer as a by-product (2S, 3
S) -N-Carbamate protected β-amino alcohol (7) results. This by-product is a diastereomer of the desired product by performing the following base treatment step (2
(S, 3S) -N-carbamate protected β-aminoepoxide (11) (see scheme below).

[0009] [Wherein, R, A, and X have the same meaning as described above. ]

Specifically, for example, (3S) -3-ter
When t-butoxycarbonylamino-1-halo-4-phenyl-2-butane is reduced with lithium aluminum tri-tert-butoxyhydride in ether, it is a diastereomer, (2S, 3S) -3-tert-. Butoxycarbonylamino-1-halo-2-hydroxy-
4-phenylbutane is the desired (2R, 3S) form 5
It has been reported that it is produced at a ratio of about 1 molar equivalent to 8 molar equivalents (P. Raddatz et al., Journal of Medicinal Chemistry, Vol. 34, No. 11, 32).
69, 1991 (J. Med. Chem., 1991, 34, 11, 3).
269.) or T. Archibald et al., Scientific
Update Conference Manual, Chiral
USA '99, Full Scale Chiral Separations Using SM, May 4, 1999, San Francisco, Scientific Update Conference Man
ual, Chiral USA '99, Full Scale Chiral Separations
Using SMB, 4th May 1999, San Francisco, Scientifi
c Update)). Further obtained by base treatment (2R,
3S) -3-tert-Butoxycarbonylamino-
1,2-Epoxy-4-phenylbutane also contains comparable diastereomers.

According to the above literature, (2R, 3S) -N-carbamate protected β-amino alcohol or (2R, 3S) -N-carbamate protected β is obtained by silica gel chromatography or high performance liquid chromatography.
Disclosed are methods for separating aminoepoxides, but these methods are not industrially suitable production methods because they require the use of large amounts of expensive carriers and solvents, and are complicated and time-consuming. Was.

Also, on page 3 of the latter document, (2)
R, 3S) -N-carbamate-protected β-aminoalcohol or (2R, 3S) -N-carbamate-protected β-aminoepoxide has a lower melting point and higher solubility than its diastereomer. The document states that the ratio of diastereomer to target substance can be reduced to only 94: 6 in purification, and further purification by recrystallization cannot be performed.

Further, the technology for removing other impurities is not always sufficient, and high-purity (2R, 3S)
Alternatively, development of an industrial production method for obtaining (2S, 3R) -N-carbamate-protected β-aminoepoxide has been desired.

[0014]

The present invention relates to (2R, 3
An object of the present invention is to provide a method for industrially producing (S) or (2S, 3R) -N-carbamate-protected β-aminoepoxide (including the crystal) and N-carbamate-protected β-aminoalcohol.

[0015]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found the following knowledge. 1) A (2R, 3S) -N-carbamate-protected β-amino alcohol containing at least its diastereomer as an impurity or an optical isomer thereof is converted into an aromatic hydrocarbon solvent, an aryl halide solvent, or a saturated hydrocarbon solvent. ,
By dissolving in at least one or more solvents selected from aqueous mixed solvents, acetone and 2-propanol and removing insolubles, diastereomers of impurities are highly separated and removed. 2) treating the (2R, 3S) -N-carbamate-protected β-aminoepoxide or its optical isomer containing at least its diastereomer as an impurity with an acid to convert the diastereomer of the impurity to oxazolidin-2;
The -one derivative is separated and removed in water or a water-based mixed solvent, whereby diastereomers of impurities are highly separated and removed. 3) By crystallizing (2R, 3S) -N-carbamate-protected β-aminoepoxide or its optical isomer with an aqueous mixed solvent, crystals of the epoxide with higher purity can be obtained. The present inventors have completed the present invention based on the above findings.

That is, the present invention includes the following contents.

A method for producing an N-carbamate-protected β-aminoepoxide crystal, comprising the following steps (a) to (d):

(A) Formula (1) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents a halogen atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S,
R. The N-carbamate-protected β-amino alcohol represented by the formula (1), wherein at least one or more selected from aromatic hydrocarbon solvents, aryl halide solvents, saturated hydrocarbon solvents, aqueous mixed solvents, acetone and 2-propanol A step of dissolving in a solvent to remove insolubles.

(B) The N-carbamate-protected β-amino alcohol represented by the general formula (1) is treated with a base to give a compound of the general formula (2) [Wherein, R, A, and * have the same meanings as described above,
The configuration of the position is 2R, 3S or 2S, 3R. To a N-carbamate-protected β-aminoepoxide represented by the following formula:

(C) Formula (2) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. N represented by
Treating the carbamate-protected β-aminoepoxide with an acid to give the diastereomer of the impurity with the general formula (3) [Wherein, A and * have the same meanings as described above, and the configuration at the 4- and 5-positions is 4S, 5R or 4R, 5S. A step of separating and removing the oxazolidin-2-one derivative in water or an aqueous mixed solvent, if necessary.

(D) a step of crystallizing the N-carbamate-protected β-aminoepoxide represented by the general formula (2) with an aqueous mixed solvent.

[0022]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In this specification, (2R, 3S) -N-
The carbamate-protected β-amino alcohol is converted to (2R, 3
S) Alcohol and its diastereomer as an impurity may be abbreviated as (2S, 3S) alcohol.

[0023]

The (2S, 3R) -N-carbamate-protected β-aminoalcohol is replaced with a (2S, 3R) alcohol,
The diastereomer serving as the impurity may be abbreviated as (2R, 3R) alcohol.

[0025]

Further, (2R, 3S) -N-carbamate-protected β-aminoaminoepoxide is converted to (2R, 3S) epoxide, and its impurity diastereomer is converted to (2S, 3
S) It may be abbreviated as epoxide.

[0027]

Further, (2S, 3R) -N-carbamate protected β-aminoepoxide is converted to (2S, 3R) epoxide,
The diastereomer serving as the impurity may be abbreviated as (2R, 3R) epoxide.

[0029]

In the formula of the present invention, X represents a halogen atom. As the halogen atom, a chlorine atom and a bromine atom are preferred, and a chlorine atom is particularly preferred.

In the formula in the present invention, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group. R is preferably a lower alkyl group. The lower alkyl group is an alkyl group having 1 to 8 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. For example, a methyl group, an ethyl group, a tert-butyl group and the like can be mentioned.

As R, a tert-butyl group is particularly preferred.

In the formula in the present invention, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, each of which may have a substituent; Represents a group containing a heteroatom in the carbon skeleton. Note that a plurality of substituents and hetero atoms may be present. The substituent having a substituent is not particularly limited as long as it does not adversely affect the reaction of the present invention. Examples thereof include an alkoxy group (preferably having 1 to 7 carbon atoms),
Examples thereof include a nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), and a halogen atom.

Examples of the group containing a hetero atom (nitrogen, oxygen, sulfur atom, etc.) in the carbon skeleton include, for example, methylthioethyl group, t-butylthiomethyl group, tritylthiomethyl group, (p-methylbenzyl) thiomethyl group, (P-methoxybenzyl) thiomethyl group, t-butoxymethyl group,
Examples include a benzyloxymethyl group, a t-butoxyethyl group, a benzyloxyethyl group, a 4- (t-butoxy) phenylmethyl group, a 4-benzyloxyphenylmethyl group, and a phenylthiomethyl group.

Such a group can be introduced, for example, using an amino acid as a raw material. For example, A may be alanine if it is a methyl group, valine if it is an isopropyl group, leucine if it is a 2-methylpropyl group, isoleucine if it is a 1-methylpropyl group, phenylalanine or a methylthioethyl group if it is a benzyl group. For example, it can be introduced by using methionine as a raw material.

A is an amino acid in which the functional group of the amino acid side chain is protected, for example, St-butylcysteine, S
-Tritylcysteine, S- (p-methylbenzyl) cysteine, S- (p-methoxybenzyl) cysteine,
Ot-butylserine, O-benzylserine, Ot-
Butylthreonine, O-benzylthreonine, Ot-
A group introduced using butyl tyrosine, O-benzyl tyrosine or the like as a raw material may be used. A is not limited to a group introduced from a raw material derived from a natural amino acid, and may be a group (eg, a phenyl group or a phenylthiomethyl group) introduced from a raw material derived from an unnatural amino acid.

In the present invention, A is preferably a compound in which A is an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or a group containing a hetero atom in the carbon skeleton. Compounds that are aralkyl groups of the formulas 7 to 20 or groups containing a hetero atom in their carbon skeleton are preferable. Specifically, for example, a compound in which A is a benzyl group, a phenylthiomethyl group, a 4-benzyloxyphenylmethyl group, an isopropyl group, a 2-methylpropyl group, or a 1-methylpropyl group is preferable. , A compound in which A is a benzyl group is particularly preferable.

Step (a) will be described below.

The N-carbamate-protected β-amino alcohol represented by the general formula (1) containing at least its diastereomer as an impurity, ie, (2R, 3
The S) alcohol or the (2S, 3R) alcohol is, for example, each represented by the general formula (13) [Wherein, R, A, and X have the same meaning as described above. (3S) -N-protected α-aminohalomethylketone represented by the formula:
Or the general formula (14) [Wherein, R, A, and X have the same meaning as described above. [3R) -N-protected α-aminohalomethyl ketone represented by the formula:

In the reduction, (2)
It is known that the production ratio between (R, 3S) alcohol and (2S, 3S) alcohol is different, and by selecting an appropriate reducing agent, the ratio of diastereomers as impurities can be suppressed to some extent. (T. Archi
bald et al., Scientific Update Conference Manual, Chiral USA '9
9. Full-Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific UpdateConference Manual, Chiral USA '
99, Full Scale Chiral Separations Using SMB, 4th M
ay 1999, San Francisco, Scientific Update)). The same applies to the ratio of (2S, 3R) alcohol to (2R, 3R) alcohol when (3R) -N-protected α-aminohalomethyl ketone is reduced.

Preferred reducing agents include tri-tert.
-Lithium aluminum butoxy hydride, (+)-B-
Chlorodiisopinocamphenylborane, tri-sec-
Examples thereof include potassium butyl borohydride and the like, and particularly preferred is lithium aluminum tri-tert-butoxyhydride.

Here, (3S) -N-protected α-aminohalomethyl ketone and (3R) -N-protected α-aminohalomethyl ketone can be obtained, for example, by converting an amino group-protected amino acid ester from α-haloacetic acid. Method for reacting with a prepared metal enolate and decarboxylation (International application WO 96/23)
756).

For example, when the reaction mixture obtained by the above-mentioned method is subjected to the step (a) of the present invention, it is preferable that the ratio of the desired (2R, 3S) alcohol or (2S, 3R) alcohol is higher. Of course, for example, if the ratio of these diastereomers is (2R, 3
Even when it is higher than (S) alcohol or (2S, 3R) alcohol, the production method of the present invention can be applied.
For example, in a molar ratio, (2S, 3S) alcohol /
The present invention also applies to a mixture of (2R, 3S) alcohol or (2R, 3R) alcohol / (2S, 3R) alcohol of 100 or less, preferably 1 or less, more preferably 1/2 or less, particularly preferably 1/3 or less. Can be applied.

As the aromatic hydrocarbon solvent used in the step (a), for example, benzene, xylene, toluene, any mixed solvent of these solvents and the like can be mentioned.
In particular, xylene, toluene, and any mixed solvent of these solvents are preferable, and toluene is particularly preferable. As the aryl halide solvent used in the step (a), for example, chlorobenzene, bromobenzene, an arbitrary mixed solvent of these solvents and the like can be mentioned. Particularly, chlorobenzene is preferred. Examples of the saturated hydrocarbon solvent used in the step (a) include n-pentane and n-pentane.
Hexane, n-heptane, n-octane, n-nonane,
Examples thereof include n-decane, isohexane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, petroleum ether, and any mixed solvent of these solvents. Particularly, n-hexane, n-heptane, cyclohexane, methylcyclohexane, and any mixed solvent of these solvents are preferable, and n-heptane is particularly preferable. The aqueous mixed solvent in the step (a) is a mixed solvent of water and an organic solvent miscible with water. Examples of the organic solvent miscible with water include methanol, ethanol, 1-propanol,
-Propanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran and the like. Methanol, ethanol, 2-propanol, acetone and any mixed solvent of these solvents are preferable, furthermore, methanol, ethanol, 2-propanol and any mixed solvent of these solvents are preferable, and 2-propanol is particularly preferable. In the case of acetone and 2-propanol, they can be used alone, but are preferably used in a mixed solvent with water. Although the composition ratio of water and the organic solvent is not particularly limited,
It is preferably 5-95%, more preferably 25-90% (% is indicated by the ratio of the organic solvent in the mixed solvent). Among the above-mentioned solvents used in the step (a), more preferred are an aromatic hydrocarbon solvent and an aqueous mixed solvent, particularly preferably an aromatic hydrocarbon solvent. Among them, 2
-A mixed solvent of propanol and water, toluene and xylene are more preferred, and toluene is particularly preferred. In the solvent used in step (a), another solvent may be added as long as the effect of the present invention is not impaired.

In step (a) of the present invention, at least the diastereomer is contained as an impurity (2
(R, 3S) alcohol or (2S, 3R) alcohol is dissolved in an aromatic hydrocarbon solvent, an aryl halide solvent, a saturated hydrocarbon solvent, acetone, 2-propanol or an aqueous mixed solvent to remove insolubles. . That is, regardless of the operation, if the (2R, 3S) alcohol or the (2S, 3R) alcohol as the target substance is dissolved in these solvents and the diastereomer is in an insoluble state, Good.

For example, (2R, 3S) alcohol or (2S, 3R) alcohol containing at least its diastereomer as an impurity is mixed with an aromatic hydrocarbon solvent, an aryl halide solvent, a saturated hydrocarbon solvent, an aqueous mixed solvent. , Acetone and 2-propanol are added and stirred. At this time, (2
(R, 3S) alcohol or (2S, 3R) alcohol is relatively easily dissolved in these solvents, but these diastereomers are difficult to dissolve and become insoluble, depending on impurity content, amount of solvent, temperature and the like. Usually, it can be in the form of slurry. Alternatively, for example, a solution state may be formed at a high temperature of room temperature or higher, and the solution may be cooled to an appropriate temperature to precipitate diastereomers as impurities.

For example, when subjecting the reaction mixture obtained by the reduction reaction to the step (a) of the present invention, from the viewpoint of purification effect, after stopping the reduction reaction, preferably the reaction solvent is concentrated.
More preferably, after sufficiently distilling off, the above-mentioned solvent is added.

The amount of the solvent to be added is not particularly limited, but is preferably 1 to 1 with respect to the reaction mixture to be subjected to the step (a).
It is 50 times the weight. The temperature at the time of stirring is not particularly limited, and is, for example, a temperature from −20 ° C. to the boiling point of the solvent to be used. The preferred temperature varies depending on the type and amount of the solvent used, but in order to suppress the loss of the target product, for example, when a saturated hydrocarbon solvent is used, an appropriate temperature from room temperature to the boiling point of the solvent (preferably 35 ℃ 70
C.), and the insolubles are preferably filtered while hot. In addition, for example, when an aromatic hydrocarbon solvent or an aryl halide solvent is used, it is preferable that the temperature is set at room temperature or lower to an appropriate temperature (for example, about −20 ° C.), and the insoluble matter is filtered. Further, for example, when an aqueous mixed solvent is used, the mixing ratio varies depending on the mixing ratio of water and the solvent.
What is necessary is just to filter insoluble matter in the range of about ° C. The stirring time is not particularly limited, either, and is preferably 10 minutes to 6 hours. A person skilled in the art can easily and appropriately set more preferable conditions according to the solvent used, based on the description in the present specification.

Next, insoluble matter is removed by filtration or the like. At this time, the impurities (2S, 3S) alcohol or (2S, 3S)
The (R, 3R) alcohol is removed as a solid. By evaporating the solvent of the filtrate, purified (2R, 3S) alcohol or (2S, 3R) alcohol can be obtained. Alternatively, the target substance may be isolated by crystallization, for example, by cooling the filtrate. If necessary, the solvent of the filtrate may be removed azeotropically for the next reaction step. If necessary, the filtrate may be concentrated or used as it is in the next reaction step.

The above-described purification operation may be repeated a plurality of times as necessary, for example, when purifying a mixture having a high impurity content. If necessary, the purification may be carried out in combination with other purification operations known to those skilled in the art. However, as described above, for example, when the target product is synthesized via a reduction reaction, the ratio of diastereomers, which are impurities, can be suppressed to some extent by selecting an appropriate reducing agent. It is possible to obtain a highly purified target substance by operation.

According to the step (a) of the present invention, the desired product (2R, 3S) alcohol or (2R) is obtained by a simple operation.
The (S, 3R) alcohol can be efficiently purified and isolated. For example, it is possible to reduce the content of diastereomer which is an impurity which is impossible in the above literature to less than 6%.

Incidentally, the solid separated as an insoluble matter is usually (2S, 3S) alcohol or (2S, 3S) alcohol containing (2S, 3R) alcohol to some extent, or (2S, 3S) alcohol or (2S, 3S) alcohol.
(R, 3R) A solid mainly composed of alcohol. This solid, for example, a known purification method such as Soxhlet extraction,
The highly purified (2S, 3S) alcohol or (2S, 3S) alcohol is purified by the step (a) of the present invention, or by purifying by using a combination of these methods as necessary, or by repeating these purifying methods as necessary. It is also possible to obtain (2R, 3R) alcohols.

Hereinafter, the step (b) will be described.

The N-carbamate-protected β-aminoalcohol represented by the general formula (1) can be treated with a base to give an intermediate in a more advanced form. -Carbamate-protected β-aminoepoxides can be derived (see supra)

As the base, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-
Examples thereof include butoxide and sodium hydride, and particularly preferred are sodium hydroxide and potassium carbonate. As a reaction solvent, methanol, ethanol, 1-propanol,
2-propanol, 1-butanol, 2-butanol,
Protic solvents such as 1,2-dimethylpropanol and water, or aprotic solvents such as acetone, tetrahydrofuran, and acetonitrile are used alone or as a mixture. Particularly, ethanol, a mixed solvent of ethanol and water, 2- A mixed solvent of propanol and water and a mixed solvent of acetone and water are preferred.

The amount of the base used varies depending on the combination of the base and the solvent used, but is usually 1 to 10 equivalents, preferably 1 to 5 equivalents. Although the reaction temperature also varies depending on the combination of the base and the solvent used, it is usually -10 to 80C, preferably 0 to 60C. The reaction time is not particularly limited, but is preferably about 10 minutes to 50 hours. The reaction is usually carried out with stirring, and after completion of the reaction, the reaction may be stopped by adding an acid. As the acid, hydrochloric acid, sulfuric acid, acetic acid, citric acid, aqueous potassium hydrogen sulfate solution and the like can be preferably used.

The (2R, 3S) epoxide or (2S, 3R) epoxide can be isolated from the reaction solvent by a method such as extraction. Further, in order to further remove diastereomers of impurities, it is preferable to carry out step (c) described below.

When the step (c) or the step (d) is performed subsequently to the step (b), the reaction solvent is concentrated or replaced with a suitable solvent as necessary without performing extraction or the like, and the next step is performed. It may be used. After the step (b), crystallization is performed by the method of the step (d), and after the step (c) is further performed, an N-carbamate-protected β-aminoepoxide crystal is obtained again by the step (d), if necessary. The same step can be performed multiple times.

Hereinafter, the step (c) will be described.

An N-carbamate-protected aminoepoxide represented by the general formula (2) containing at least its diastereomer as an impurity is treated with an acid, and the diastereomer of the impurity is converted into an oxazolidine represented by the general formula (3) −
This is a 2-one derivative, which is separated and removed as necessary in water or an aqueous mixed solvent.

When an N-carbamate-protected β-aminoepoxide represented by the general formula (2), that is, (2R, 3S) epoxide or (2S, 3R) epoxide is treated with an acid, its diastereomer (2S , 3S) epoxide or (2R, 3R) epoxide is relatively quickly converted to an oxazolidin-2-one derivative represented by the general formula (3) (see Reference Examples 4 and 5 described later). However, (2R, 3S) epoxide or (2S, 3R) epoxide has a slow reaction rate, so that the resulting oxazolidine-2-one derivative is removed from the system, whereby the diastereomer as an impurity is preferentially removed. (Tetrahedron Letters, 35
Vol. 28, No. 4939-4942, 1994 Tetr
ahedron Letters, Vol. 35, No. 28, 4939-4942, 1994).

Examples of the acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and acid. Examples include ion exchange resin (ion exchange resin acid catalyst), acid alumina (alumina acid catalyst), acid zeolite (zeolite acid catalyst), and acid clay, but p-toluenesulfonic acid, acid ion exchange resin, acid zeolite, Solid acids insoluble in solvents such as acid clay are preferred. A solid acid that is insoluble in a reaction solvent such as an acidic ion exchange resin, an acidic alumina, an acidic zeolite, and an acid clay is easily removed, and by-products generated by the reaction between the epoxide and the acid can be simultaneously removed by filtration. .

As the reaction solvent, methanol, ethanol, 2-propanol, 1,2-dimethylpropanol, water, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, dichloroethane,
Solvents such as diethyl ether, benzene, toluene, hexane, heptane and the like are used alone or as a mixture, and aprotic solvents such as dichloromethane, toluene, acetone and acetonitrile are particularly preferable.

The amount of the acid used varies depending on the acid used and is not particularly limited, but the desired amount of (2R, 3S) or (2
In view of the quality (purity) and yield of the (S, 3R) epoxide, an appropriate amount can be easily and appropriately set by a person skilled in the art through experiments. For example, when p-toluenesulfonic acid is used, (2S, 3S) or (2R,
It is preferable to use 1 to 5 equivalents to 3R) epoxide. When a strongly acidic ion exchange resin or acidic zeolite is used, preferably 1 to 200% by weight based on the treated (2R, 3S) or (2S, 3R) epoxide.
Good to use.

The reaction temperature varies depending on the combination of the acid and solvent used, but is usually -10 to 120 ° C, preferably 0 to 100 ° C. The reaction time is not particularly limited, but is preferably about 10 minutes to 50 hours. The desired product (2R, 3S) or (2S, 3R) epoxide also reacts with acid slowly but oxazolidine-2.
It is not preferable to carry out the reaction more than necessary because it is converted into a -one derivative. As with the amount of acid used, an appropriate reaction time should be determined by those skilled in the art by monitoring the concentration of diastereomer in the reaction solution in view of the required quality (purity) and yield of the target product. It can be set easily as appropriate.

By the above-mentioned acid treatment, diastereomers contained as impurities are preferentially converted to oxazolidine-2-one derivatives. Since the oxazolidine-2-one derivative is highly water-soluble, it can be easily separated and removed by dissolving it in water or an aqueous mixed solvent. The aqueous mixed solvent is a mixed solvent of water and an organic solvent miscible with water. Examples of the organic solvent include methanol, ethanol, 1-propanol, 2-
Examples thereof include propanol, acetone, 2-butanone, acetonitrile, and tetrahydrofuran. The method of separating and removing the oxazolidin-2-one derivative in water or an aqueous mixed solvent is not particularly limited, but may be by extraction or crystallization. When the step (d) is performed after the step (c),
Since crystallization is carried out with an aqueous mixed solvent, oxazolidine-2
The -one derivative is separated and removed to the mother liquor side. For this reason, oxazolidine-2-oxide is usually extracted by extraction or the like before the step (d).
It is not necessary to remove the on derivative in advance.

The case of performing the extraction will be described below. In this case, water is particularly preferable as the solvent for dissolving the oxazolidin-2-one derivative. For example, in the process of acid treatment,
When an acid soluble in a solvent such as p-toluenesulfonic acid is used as the acid, for example, after an appropriate reaction time, an aqueous base solution such as sodium hydrogencarbonate is added to the reaction solution, and the mixture is stirred if necessary. Stop the reaction. Thereafter, if necessary, the organic layer is distilled off and replaced with a solvent suitable for extraction. Examples of the extraction solvent include toluene, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane and the like, and toluene is particularly preferred in view of the effect of separating and removing the oxazolidin-2-one derivative into the aqueous phase. At the time of extraction, it is preferable that insolubles that are insoluble in the organic layer and the aqueous phase are filtered off in advance. After the extraction operation, the organic layer is separated and preferably further washed with water to efficiently (4S, 5R) or (4R, 5S)
Oxazolidin-2-one can be removed.

For example, when an acid insoluble in a reaction solvent such as an acidic ion exchange resin or an acidic zeolite is used as the acid, the acid can be removed by filtration to stop the reaction. Thereafter, if necessary, the organic solvent is distilled off and replaced with a solvent preferable for extraction. Toluene, te
Examples thereof include rt-butyl methyl ether, ethyl acetate, isopropyl acetate, and dichloromethane. Of these, toluene is particularly preferred from the viewpoint of the effect of separating and removing the oxazolidine-2-one derivative in the aqueous phase. Next, water or an aqueous mixed solvent is added to carry out extraction. At this time, it is preferable that insolubles which are not dissolved in both the organic layer and the aqueous layer are filtered off in advance. After extraction, the organic layer is separated and preferably further washed with water to efficiently (4S, 5R) or (4R,
5S) Oxazolidin-2-one can be removed.

According to the method of the step (c) described above,
Diastereomers, which are impurities, can be efficiently removed. Further, the diastereomer is removed to a higher degree by using this step (c) after the diastereomer is removed in advance by the method of the step (a). 3R) Epoxides can be obtained. Thus, the diastereomer content of the impurities is preferably 3% or less, preferably through the steps (a) and (c) of the present invention, or after these steps and further through the step (d). Is 2% or less, more preferably 1% or less of (2R, 3S) or (2S, 3R) epoxide. The (2R, 3S) or (2S, 3R) epoxide thus obtained can be obtained as a solid by distilling off the organic layer under reduced pressure. Further, if necessary, it may be further purified by an adsorption resin or the like.
However, by performing the step (d) described below, a highly pure (2R, 3S) can be obtained in an industrially advantageous manner.
Alternatively, (2S, 3R) epoxide crystals can be obtained.

Hereinafter, the step (d) will be described.

Crystals of high purity can be obtained by crystallizing (2R, 3S) or (2S, 3R) epoxide with an aqueous mixed solvent.

First, an aqueous mixed solvent is added to (2R, 3S) or (2S, 3R) epoxide. The aqueous mixed solvent is a mixed solvent of water and an organic solvent that is miscible with water, and as the organic solvent, methanol, ethanol, 1-propanol,
Examples include 2-propanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran and the like, and particularly preferred are methanol, ethanol, 2-propanol and acetone. At this time, the composition ratio of water and the organic solvent is not particularly limited, but is preferably 5 to 95%, more preferably 25%.
８５85% (% indicates the proportion of the organic solvent in the mixed solvent.) Usually, (2R, 3S) or (2S, 3R)
Epoxides are unlikely to crystallize even in aqueous solvents that are relatively easy to crystallize compared to other solvents. However, crystallization can be easily performed by inoculating a seed crystal.

The amount of the aqueous mixed solvent is not particularly limited. For example, 2 to 20 ml of the solvent can be used per 1 g of the (2R, 3S) or (2S, 3R) epoxide.

Next, the mixture is cooled to crystallize (2R, 3S) or (2S, 3R) epoxide.

The crystallization temperature is preferably from -40 ° C to 25 ° C, particularly preferably from -20 ° C to 10 ° C. At this time, the crystallization may be performed with stirring or under static conditions, but is preferably performed with stirring. Usually, (2R, 3S) or (2S, 3R) epoxide is hard to be crystallized, and crystallization can be performed more easily by inoculating a seed crystal as needed. Furthermore, if necessary, in order to increase the purification effect, 10 ° C to 40 ° C
After heating to about ℃ to partially dissolve the crystals,
Crystallization can also be performed by cooling to, for example, from 10 to 10 ° C. The obtained crystals are preferably washed with water or the like. By performing this step (d), highly polar impurities are efficiently removed to the mother liquor side, so that a highly pure (2R, 3S) or (2S, 3R) epoxide crystal can be obtained.

As described above, the diastereomer (2S, 3S) or (2R, 3R) epoxide is difficult to be removed by crystallization, so that steps (a) and (b)
Alternatively, by performing step (d) in combination with step (c) or (a), (b) and (c), a higher-purity (2R, 3S) or (2S, 3R) epoxide crystal can be obtained. Obtainable. If necessary, the step (d) may be performed plural times.

Hereinafter, the present invention will be described in more detail by way of examples. Of course, the present embodiment does not limit the present invention at all. All the ratios of the target substance and its diastereomer described in the examples are molar ratios.

[0078]

EXAMPLES Reference Example 1 Production of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Tri-tert. Was added to dehydrated diethyl ether (29.3 ml).
Lithium aluminum tert-butoxyhydride (999 m
g) and cooled to 0 ° C., followed by (3S) -3-ter
A diethyl ether solution (10 ml) of t-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.06 g) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours and 20 minutes. The reaction was quenched with a 5% aqueous solution of potassium hydrogen sulfate, and extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate.
After removing magnesium sulfate, the obtained ethyl acetate solution was analyzed by HPLC, and a diastereomer mixture of 3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane was found to have a total yield of 95. %
Was confirmed. It is an object (2R,
3S) isomer and its diastereomer (2S, 3S)
The body formation ratio is (2R, 3S) :( 2S, 3S) = 8
4.7: 15.3. The solvent was distilled off from the obtained solution under reduced pressure, and crude (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4 was obtained.
-Phenylbutane (1.01 g) was obtained.

Example 1 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane The crude (2R, 3S) obtained in Reference Example 1 -3-tert
-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (199.5 mg, (2R,
3S): (2S, 3S) = 84.7: 15.3)) and n
-Heptane (4 ml) was added to form a slurry, and the mixture was stirred at 55 ° C for 1 hour. The slurry was filtered while hot at 55 ° C. to remove insolubles. The solvent was distilled off from the obtained mother liquor under reduced pressure, and further dried at 40 ° C. under reduced pressure to obtain (2R,
3S) -3-tert-Butoxycarbonylamino-1
Crystals of -chloro-2-hydroxy-4-phenylbutane were obtained (total yield of 148.4 mg of (2R, 3S) form and (2S, 3S) form, 85.2% of total yield). When the dried crystals were analyzed by HPLC, (2R, 3S):
(2S, 3S) = 97.7: 2.3. ¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.38 (s, 9H), 2.91
(dd, J = 8.1, 13.2Hz, 1H), 3.01 (dd, J = 7.1, 13.2Hz,
1H), 3.14 (d, J = 4.0Hz, 1H), 3.53 (s, 1H), 3.55
(d, J = 2.3Hz, 1H), 3.70-3.77 (m, 1H), 3.79-3.89 (m,
1H), 4.88 (bd, 1H), 7.19-7.35 (m, 5H) Mass spectrum m / e: 322 (M + Na ⁺ )

Example 2 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane The crude (2R, 3S) obtained in Reference Example 1 ) -3-ter
t-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (199.7 mg, (2
R, 3S) :( 2S, 3S) = 84.7: 15.3))
Was added to n-hexane (4 ml) to form a slurry.
Stirred at C for 1 hour. The slurry was filtered while hot at 55 ° C. to remove insolubles. The solvent was distilled off from the obtained mother liquor under reduced pressure, and further dried at 40 ° C. under reduced pressure.
A crystal of (R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane was obtained (total yield of (2R, 3S) form and (2S, 3S) form: 145.0 mg). , Total yield 76.1%). When the dried crystals were analyzed by HPLC, (2R, 3
S): (2S, 3S) = 96.0: 4.0.

Example 3 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane The crude (2R, 3S) obtained in Reference Example 1 ) -3-ter
t-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (161.18 mg, (2
R, 3S) :( 2S, 3S) = 84.7: 15.3))
Then, cyclohexane (3.2 ml) was added to the mixture to form a slurry, and the mixture was stirred at 50 ° C. for 1 hour, cooled to room temperature and stirred for 1 hour. The slurry was filtered to remove insolubles. The solvent was distilled off from the obtained mother liquor under reduced pressure, and further dried at 40 ° C. under reduced pressure to obtain (2R, 3S) -3-te.
Crystals of rt-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane were obtained ((2R,
Total yield of the 3S) form and the (2S, 3S) form is 112.6 m.
g, 77.2% total yield). When the dried crystals were analyzed by HPLC, (2R, 3S) :( 2S, 3S) =
96.7: 3.3.

Example 4 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane The crude (2R, 3S) obtained in Reference Example 1 ) -3-ter
t-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (200.6 mg, (2
R, 3S) :( 2S, 3S) = 84.7: 15.3))
Was added to methylcyclohexane (4 ml) to form a slurry, and the mixture was stirred at 55 ° C. for 1 hour. 55 this slurry liquid
The mixture was filtered while hot at 0 ° C. to remove insolubles. The solvent was distilled off from the obtained mother liquor under reduced pressure, and further dried at 40 ° C. under reduced pressure to obtain (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane. (2R, 3S) and (2S, 3
S) Total yield of the compound 155.0 mg, total yield 88.9
%). When the dried crystals were analyzed by HPLC,
(2R, 3S): (2S, 3S) = 96.3: 3.7.

Reference Example 2 (2S, 3R) -3-tert-butoxycarbonyl mixed with (2R, 3R) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Amino-1-chloro-2-hydroxy-4
Preparation of -Phenylbutane Tri-ter in dehydrated diethyl ether (12.6 ml)
Lithium aluminum tert-butoxyhydride (457m
g) and cooled to −20 ° C., then (3R) -3-t
ert-butoxycarbonylamino-1-chloro-4-
A diethyl ether solution (5.3 ml) of phenyl-2-butanone (500 mg) was added dropwise, and the mixture was stirred at -20 ° C for 6 hours. The reaction was quenched with a 5% aqueous solution of potassium hydrogen sulfate, and extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the obtained ethyl acetate solution was analyzed by HPLC, and 3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-.
90% yield of diastereomeric mixture of phenylbutane
Was confirmed. The target (2S,
The formation ratio of the (3R) form and its (2R, 3R) isomer is (2S, 3R) :( 2R, 3R) = 76.9: 2
3.1. The solvent was distilled off from the solution obtained under reduced pressure, and crude (2) used as a raw material in Example 5 below was used.
(S, 3R) -3-tert-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.502 g) was obtained as a solid.

Example 5 Purification of (2S, 3R) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane The crude (2S, 3R) obtained in Reference Example 2 ) -3-ter
t-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (502 mg, (2S, 3
R): (2R, 3R) = 76.9: 23.1)) n-
Hexane (10 ml) was added to form a slurry, and the mixture was stirred at 55 ° C. for 1 hour. The slurry was filtered while hot at 55 ° C. to remove insolubles. The solvent was distilled off from the obtained mother liquor under reduced pressure, and further dried at 40 ° C. under reduced pressure to obtain (2S, 3
R) -3-tert-Butoxycarbonylamino-1-
Crystal 3 of chloro-2-hydroxy-4-phenylbutane
75.5 mg was obtained (yield of the (2S, 3R) form 94.3).
%). When the dried crystals were analyzed by HPLC,
(2S, 3R): (2R, 3R) = 97.2: 2.8.

Example 6 Preparation of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3-te in methanol (2.0 ml)
rt-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (100 mg) and potassium carbonate (91.5 mg) were added, and the mixture was stirred at room temperature for 4 hours. After adding a 10% aqueous citric acid solution (0.204 ml) and water (0.408 ml), the solvent was distilled off under reduced pressure. After water (1 ml) and ethyl acetate (1 ml) were added to the residue for extraction, the organic layer was concentrated under reduced pressure (2R, 3S).
-3-tert-Butoxycarbonylamino-1,2-
Epoxy-4-phenylbutane ((2R, 3S form) yield 81.4 mg, (2R, 3S form) yield 93.5%) was obtained. ¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.38 (s, 9H), 2.59
(bs, 1H), 2.69 (t, J = 4.4Hz, 1H), 2.83-3.04 (m, 3
H), 4.12 (bs, 1H), 4.48 (bs, 1H), 7.17-7.37 (m, 5
H) Mass spectrum m / e: 286 (M + Na ⁺ )

Example 7 Production of Crystals of (2R, 3S) -3-tert-Butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 1 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 300mg, (2S, 3S) body content 6.67m
g) in ethanol (3.40 ml) and water (0.109 m
l) and potassium carbonate (755 mg).
After stirring for an hour, the mixture was further stirred at 30 ° C. for 1 hour. After cooling to 5 ° C., a 17.5% aqueous citric acid solution (3.99 g) was added. After separating at 0 ° C and cooling the ethanol layer to -10 ° C, seed crystals were inoculated and stirred overnight to obtain (2R, 3S) -3-ter.
t-butoxycarbonylamino-1,2-epoxy-4
-Phenylbutane crystallized. By filtering the obtained slurry, (2R, 3S) -3-tert-
Crystals of butoxycarbonylamino-1,2-epoxy-4-phenylbutane were obtained ((2R, 3S) form yield 19).
1 mg, (2R, 3S) form yield 71.6%). When the dried crystals were analyzed by HPLC, (2R, 3S):
(2S, 3S) = 96.8: 3.2.

Example 8 Preparation of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Crystal Obtained in the same manner as in Example 1 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 97.8 mg, (2S, 3S) body content 2.2 m
g) with acetone (0.8 ml) and 2.5 mol / l sodium hydroxide aqueous solution (0.2 ml), and the mixture was added at room temperature for 2 hours.
Stirred for 0 minutes. This was separated and water (1.1) was added to the acetone layer.
After cooling to −10 ° C., seed crystals were inoculated and stirred overnight to obtain (2R, 3S) -3-.
tert-Butoxycarbonylamino-1,2-epoxy-4-phenylbutane crystallized. The obtained slurry was filtered to obtain crystals of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form yield 64.2 m).
g, (2R, 3S) form yield 75%). This dried crystal is
When analyzed by PLC, (2R, 3S): (2S,
3S) = 97.9: 2.1.

Example 9 Production of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 1 (2R, 3S) ) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 40.6g, (2S, 3S) body content 1.66g)
2-propanol (342 ml) and 2.5 mol / l aqueous sodium hydroxide solution (85.8 ml) were added to
Stir for 30 minutes. 13.8% citric acid aqueous solution (9
After adding 9.5 g), 2-propanol was distilled off under reduced pressure. After toluene (342 ml) was added to the residue for extraction, the organic layer was concentrated under reduced pressure to give (2R, 3S) -3-t.
ert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (37.2 g) was obtained ((2R,
(Total yield of 3S) form and (2S, 3S) form 98.3%).
When analyzed by HPLC, (2R, 3S): (2
(S, 3S) = 96.1: 3.9.

Example 10 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 9 (2R, 3S) ) -3
-Tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 44
Toluene (5.4 ml) and p-toluenesulfonic acid monohydrate (25.9 mg) were added to 4.3 mg, (2S, 3S) body content 11.9 mg)), and the mixture was stirred at 18 ° C. for 2 hours. After the reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. When the filtrate was analyzed using HPLC, (2R, 3S) :( 2S, 3S) =
99.6: 0.4 or (2R, 3S) -3-tert
-Butoxycarbonylamino-1,2-epoxy-4-
The recovery of phenylbutane was 77.5%. Part of the filtrate ((2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane 2
29.4 mg (including 29.4 mg) and concentrated, and then separated and purified using a column packed with 29 ml of synthetic adsorption resin CHP20P (Mitsubishi Chemical). The obtained fraction is concentrated,
Extracted with n-heptane. The organic layer was concentrated and (2
R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3
(S) form yield 198 mg, (2R, 3S form yield 86.5)
%) As a solid. When analyzed by HPLC,
(2R, 3S): (2S, 3S) = 99.6: 0.4.

<Example 11> Acid treatment of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3- obtained in Example 9 tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 35.7 g, (2
(S, 3S) body content 1.45 g) and dichloromethane (4
16ml) and Amberlyst 15 ion exchange resin (Ambe
rlyst: registered trademark) (manufactured by Aldrich) (2
5.0 g), and the mixture was stirred at room temperature for 2 hours and 50 minutes. Amberlyst was removed by filtration, and the filtrate was concentrated under reduced pressure to remove the solvent. Toluene (200 ml) and water (200 ml) were added thereto, and insolubles were removed by filtration.
The filtrate was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Further, n-heptane (20
ml) and the solvent was removed under reduced pressure to give (2R, 3S) -3
-Tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form yield 2)
3.4 g, (2R, 3S) body recovery rate 66%) was obtained. H
When analyzed by PLC, (2R, 3S): (2S,
3S) = 99.2: 0.8.

<Example 12> Acid treatment of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by a method similar to that in Example 9 (2R, 3S) ) -3-
tert-Butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 92.
8 mg, (2S, 3S) content 2.2 mg), toluene (2 ml) and Amberlyst 15 ion exchange resin (Am
berlyst (registered trademark) (manufactured by Aldrich)
(28.9 mg) was added, and the mixture was stirred at 40 ° C. for 29 hours. Amberlyst (29.5 mg) was further added, and the mixture was stirred at 60 ° C. for 19 hours. When the reaction solution was analyzed by HPLC, (2R, 3S) :( 2S, 3S) = 99.5: 0.
5, and the recovery of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was 81.3%.

Example 13 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 9 (2R, 3S). -3-
tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 20.
7 mg, (2S, 3S) body content 0.7 mg), dichloromethane (0.6 ml) and zeolite (Zeolist C)
BV90A) (Zeolyst: registered trademark) (manufactured by Zeolyst International) (71)
mg) and stirred at room temperature for 6.5 hours. H
When analyzed by PLC, (2R, 3S): (2S,
3S) = 99.6: 0.4, and (2R, 3S) -3-
The recovery of tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was 80.9%.

Example 14 Production of Crystals of (2R, 3S) -3-tert-Butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 11 (2R, 3S) 3S) -3
-Tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 1
1.1 g, (2S, 3S) body content 75.5 mg, (2
R, 3S) body purity = 95.3%: HPLC area ratio)
Methanol (30.5 ml) and water (20.5 ml) were added. After cooling to −10 ° C., seed crystals were inoculated and stirred overnight to obtain (2R, 3S) -3-tert.
-Butoxycarbonylamino-1,2-epoxy-4-
The phenylbutane crystallized. After adding methanol (17.3 ml) at −10 ° C., the mixture was heated to 0 ° C., stirred for 1 hour, and cooled to −10 ° C. again. The obtained slurry was filtered and washed with 70% methanol (5 ml) at -10 ° C to obtain (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane crystal 6 .78 g ((2R, 3S) form and (2S, 3
(S) total yield of the product 61.1%). When analyzed by HPLC, (2R, 3S) :( 2S, 3S) = 99.5:
0.5 and the purity was 98.0% (HPLC area ratio).

Example 15 Preparation of Crystal of (2R, 3S) -3-tert-Butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3 obtained in Example 14 -Tert-
Butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 2.94 g, (2
Methanol (7.7 ml) and water (5.1 ml) were added to (S, 3S) form content 14.8 mg) and (2R, 3S) form purity = 98.0%: HPLC area ratio). -10 ° C
After cooling, the seed crystals were inoculated and stirred to crystallize (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. Heat to room temperature and add methanol (6.4 ml)
And water (0.9 ml) were added, and the mixture was stirred for 15 minutes.
Cooled to 0 ° C. The resulting slurry is filtered and -10C
Was washed with 70% methanol (6 ml), and (2R, 3
S) -3-tert-Butoxycarbonylamino-1,
2.03 g of crystals of 2-epoxy-4-phenylbutane was obtained (total yield of (2R, 3S) form and (2S, 3S) form, 67.2%). When analyzed by HPLC, (2R,
3S): (2S, 3S) = 99.6: 0.4, and HP
LC purity was 99.3% (HPLC area ratio). ¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.38 (s, 9H), 2.59
(bs, 1H), 2.69 (t, J = 4.4Hz, 1H), 2.83-3.04 (m, 3
H), 4.12 (bs, 1H), 4.48 (bs, 1H), 7.17-7.37 (m, 5
H) mass spectrum m / e: 286 (M + Na +) [α] D 20 = -15.2 ° (c = 1.0, MeOH) mp; 46-47 ° C.

Reference Example 3 Production of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Dehydrated diethyl ether (600 m
To l), lithium aluminum tri-tert-butoxyhydride (28.2 g) was added, and the mixture was cooled to 0 ° C.
S) -3-tert-Butoxycarbonylamino-1-
Chloro-4-phenyl-2-butanone (30.0 g) was added, and the mixture was stirred at 0 ° C for 2 hours and 30 minutes. 1N in the reaction solution
An aqueous hydrochloric acid solution (222 ml) was added to stop the reaction, the organic layer was washed with a 1N aqueous hydrochloric acid solution and saturated saline, and the obtained organic layer was analyzed by HPLC. As a result, 3-tert-butoxycarbonylamino-1- was obtained. It was confirmed that a diastereomer mixture of chloro-2-hydroxy-4-phenylbutane was obtained in a total yield of 92.0%. The formation ratio of the desired (2R, 3S) form and its diastereomer (2S, 3S) form is (2R, 3S) :( 2
S, 3S) = 87.4: 12.6. The solvent was distilled off from the obtained solution under reduced pressure to obtain crude (2R, 3S) -3-t.
tert-butoxycarbonylamino-1-chloro-2-
Hydroxy-4-phenylbutane (33.2 g) was obtained.

Example 16 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane and (2R, 3S) -3-tert-butoxycarbonylamino Production of -1,2-epoxy-4-phenylbutane 33.2 g of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane obtained in Reference Example 3 ( (2R, 3S):
(2S, 3S) = 87.4: 12.6)) and 2-propanol (62.1 ml) and water (20.7 ml) were added.
After stirring at 70 ° C. for 1 hour, the solution was added for 2 hours over 10 hours.
Cooled to 0 ° C. Insolubles generated by cooling were removed by filtration at 20 ° C. 2-Propanol (143 ml) and 3.26 mol / l aqueous sodium hydroxide solution (42.3 ml) were added to the obtained mother liquor, and the mixture was stirred at 4 ° C for 2 hours. When the reaction solution was analyzed by HPLC, the target (2R, 3
The S) form was 93.9% (HPLC area ratio). 1.
After adding a 06% aqueous citric acid solution (279 g) to terminate the reaction, water (73.2 ml) was added. 1. From 27 ° C.
After cooling to −10 ° C. over 5 hours, seed crystals were inoculated and stirred overnight to obtain (2R, 3S) -3-t.
ert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was crystallized. By filtering the obtained slurry, (2R, 3S) -3-ter
t-butoxycarbonylamino-1,2-epoxy-4
20.4 g of -phenylbutane crystals were obtained ((2R, 3
S) Isomeric yield 85.0%). When the dried crystals were analyzed by HPLC, (2R, 3S) :( 2S, 3S) = 9
7.9: 2.1, and the purity of the (2R, 3S) form is 96.
It was 4% (HPLC area ratio).

Example 17 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained by a method similar to that of Reference Example 3 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 3.05 g, (2S, 3S) body content 0.55
g), (2R, 3S): (2S, 3S) = 84.7: 1
5.3)), 2-propanol (8.1 ml) and water (2.7 ml) were added to form a slurry, the mixture was stirred at 60 ° C for 1 hour, and then cooled to 24 ° C over 1.3 hours.
The slurry was filtered at 24 ° C. to remove insolubles.
When the obtained mother liquor was analyzed by HPLC, (2R,
3S) -3-tert-Butoxycarbonylamino-1
-Chloro-2-hydroxy-4-phenylbutane was obtained with a recovery of 91.3% (2.8 g). (2R, 3S):
(2S, 3S) = 97.1: 2.9 and (2R, 3
S) The body purity was 94.4% (HPLC area ratio).

Example 18 Production of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3-obtained in Example 17 tert
-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane ((2R, 3S) form content 2.
2-propanol (12.9 ml) and 6.08 mol /
l Add sodium hydroxide aqueous solution (2.94 g) and add 4 ° C
For 15 hours. When the reaction solution was analyzed by HPLC, the target (2R, 3S) form was 94.0% (HPLC area ratio). 4.4% citric acid aqueous solution (20.9
g) to stop the reaction, then cool from 25 ° C to -10 ° C over 2.3 hours, inoculate with seed crystals, add water (19.2 ml) and stir overnight. Crystallized (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. The resulting slurry was filtered to obtain the desired crystal of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form yield) 96.2%,
(2R, 3S) body yield 2.4 g). This dried crystal is HP
When analyzed by LC, (2R, 3S): (2S, 3S)
S) = 97.1: 2.9, and the purity of the (2R, 3S) form was 95.4% (HPLC area ratio).

Example 19 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained by a method similar to that of Reference Example 3 , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 1.33 g, (2S, 3S) body content 0.34 g,
(2R, 3S): (2S, 3S) = 79.8: 20.
2) acetone (4.68 ml) and water (1.56 ml)
Was added to form a slurry, and the mixture was stirred at room temperature for 2.5 hours. Then, the slurry was filtered at room temperature to remove insolubles. When the obtained mother liquor was analyzed by HPLC, (2
(R, 3S) -3-tert-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane was obtained at a recovery of 74.5% (0.99 g). (2R, 3
S): (2S, 3S) = 96.6: 3.4.

Example 20 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane and (2R, 3S) -3-tert-butoxycarbonylamino Production of -1,2-epoxy-4-phenylbutane (2R, 3S) -3 obtained in the same manner as in Reference Example 3.
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 11.28 g, (2S, 3S) body content 1.55
g, (2R, 3S): (2S, 3S) = 87.9: 1
2.1) 2-propanol (25.3 ml) and water (8.5 ml) were added to form a slurry, potassium chloride (329 mg) was added at 70 ° C., and the mixture was stirred for 15 hours.
Cooled to 20 ° C. over 2.5 hours. The slurry was filtered at 20 ° C. to remove insolubles. 2-propanol (58.7 ml) and water (3.2 ml) were added to the obtained mother liquor.
After cooling to 4 ° C, a 4 mol / l sodium hydroxide aqueous solution (14.1 ml) was added, and the mixture was stirred at 4 ° C for 2.5 hours. When the reaction solution was analyzed by HPLC, the target (2)
(R, 3S) form was 93.6% (HPLC area ratio). The reaction was stopped by adding a 0.85% aqueous citric acid solution (142 g). After cooling from 27 ° C to -10 ° C over 2.5 hours, seed crystals were inoculated and stirred overnight to give (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy- 4-phenylbutane crystallized. The slurry was filtered, water (56.4 ml) was added to the obtained crystals to form a slurry, and the mixture was stirred at 20 ° C. for 1 hour. Then, the slurry was filtered and dried to obtain (2R, 3S) -3-. Crystals of tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane were obtained ((2R, 3S) form yield 80.2%, (2R,
3S) Body yield 7.94 g). When the dried crystals were analyzed by HPLC, (2R, 3S) :( 2S, 3S) =
98.1: 1.9, and (2R, 3S) form purity is 97.
It was 6% (HPLC area ratio).

Example 21 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3-tert obtained in Example 20 −
Butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 7.94 g, (2
(S, 3S) body content 0.15 mg), acetonitrile (48.5 ml) and zeolite (zeolist CBV6)
00) (Zeolyst: registered trademark) (manufactured by Zeolyst International) (4.05 g)
Was added and stirred at room temperature for 24 hours. When the reaction solution was analyzed by HPLC, the target (2R, 3S) form was 87.0%.
(HPLC area ratio). The reaction solution was filtered through celite, water (161 ml) was added to the obtained mother liquor, and the mixture was cooled from 25 ° C. to −5 ° C. over 5 hours, seeded with seed crystals, and stirred overnight (2R, 3S). -3-ter
t-butoxycarbonylamino-1,2-epoxy-4
-Phenylbutane crystallized. This slurry was filtered and dried to obtain (2R, 3S) -3-ter.
t-butoxycarbonylamino-1,2-epoxy-4
Crystals of -phenylbutane were obtained ((2R, 3S) form yield 5.56 g, (2R, 3S) form yield 68.7%). When the dried crystals were analyzed by HPLC, (2R, 3
S): (2S, 3S) = 99.5: 0.5, and (2S, 3S)
The purity of the (R, 3S) form was 97.5% (HPLC area ratio).

Reference Example 4 Production of (4S, 5R) -5-hydroxymethyl-4-phenylmethyloxazolidin-2-one (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy- 4-phenylbutane (2.7
To 5 g), ethanol (27.5 ml) was added, and 29.5 g of a 6.8% aqueous citric acid solution was further added, followed by stirring at 70 ° C for 2 hours. After cooling to room temperature, the ethanol was removed under reduced pressure. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further, a mixed solvent of hexane (2.5 ml) and ethyl acetate (2.5 ml) was added to generate crystals. After the crystals were collected by filtration, hexane / ethyl acetate (1/1) was added.
Washing was performed twice using the mixed solvent of 1). The obtained crystals are dried and the desired (4S, 5R) -5-hydroxymethyl-4-phenylmethyloxazolidin-2-one (1.
79 g) was obtained in a yield of 80%. ¹ H-NMR (DMSO-d6, 300 MHz) δppm: 2.73-2.86 (m, 2
H), 3.20 (dt, 1H, J = 12.3, 5.1 Hz), 3.30-3.41 (m, 1
H), 3.80 (ddd, 1H, J = 5.7, 5.7, 5.7 Hz), 4.13-4.18
(ddd, 1H, J = 5.7, 5.7, 5.7 Hz), 5.01 (dd, 1H, J = 5.
7, 5.7 Hz), 7.17-7.37 (m, 5H) ¹³ C-NMR (DMSO-d6, 300 MHz) δppm: 40.4, 54.1, 61.
9, 80.5, 126,7, 128,5, 129,7, 136.6, 158.1 Mass spectrum m / e: 208 (M + H ⁺ ) [α] _D ²⁰ = -47.2 ゜ (c = 1.0, MeOH)

Reference Example 5 Production of (4S, 5R) -5-hydroxymethyl-4-phenylmethyloxazolidin-2-one (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy- 4-phenylbutane (112
mg), toluene (2.24 ml) and p-toluenesulfonic acid monohydrate (81 mg) were added, and the mixture was stirred at 40 ° C for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was analyzed using HPLC and (4S, 5R) -5-hydroxymethyl-4-phenylmethyloxazolidine-
It was confirmed that 2-one (88.1 mg) was obtained quantitatively.

Example 22 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained by the same method as in Reference Example 3 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 0.818 g, (2S, 3S) body content 0.162
g), (2R, 3S): (2S, 3S) = 83.4: 1
6.6)) was added with toluene (5.0 ml) to form a slurry, and the mixture was stirred at 70 ° C for 0.5 hour, and then cooled to 10 ° C over 10 hours. The slurry was filtered at 10 ° C. to remove insolubles. When the obtained mother liquor was analyzed by HPLC, (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4 was obtained.
-Recovery of 91.1% of phenylbutane (0.745 g)
I got it. (2R, 3S): (2S, 3S) = 98.8:
1.2.

Example 23 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained by the same method as in Reference Example 3 , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 1.59 g, (2S, 3S) body content 0.22
g), (2R, 3S): (2S, 3S) = 88.0: 1
2.0)), chlorobenzene (14.0 ml) was added to form a slurry, and the mixture was stirred at 70 ° C. for 0.5 hour, and then stirred.
Cooled to 10 ° C. over time. This slurry liquid was added to 10
The mixture was filtered at ℃ to remove insolubles. The obtained mother liquor is HPL
When analyzed by C, (2R, 3S) -3-tert
-Butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane was recovered at 94.9% (1.5%).
1g). (2R, 3S): (2S, 3S) = 9
8.4: 1.6.

Example 24 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained in the same manner as in Reference Example 3 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 1.59 g, (2S, 3S) body content 0.22
g), (2R, 3S): (2S, 3S) = 88.0: 1
2.0)), xylene (a mixture of 10% ortho-xylene, 70% meta-xylene, 10% para-xylene, and 10% ethylbenzene) (14.0 ml) was added to form a slurry, and 0.5% at 70 ° C. After stirring for 10 hours, the mixture was cooled to 10 ° C. over 10 hours. The slurry was filtered at 10 ° C. to remove insolubles. When the obtained mother liquor was analyzed by HPLC, (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-
83.5% recovery of 4-phenylbutane (1.33 g)
I got it. (2R, 3S): (2S, 3S) = 98.7:
1.3.

Example 25 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane Obtained in the same manner as in Reference Example 3 (2R, 3S) , 3S) -3
-Tert-butoxycarbonylamino-1-chloro-
2-hydroxy-4-phenylbutane ((2R, 3S)
Body content 1.59 g, (2S, 3S) body content 0.22
g), (2R, 3S): (2S, 3S) = 88.0: 1
2.0)) was added with benzene (14.0 ml) to form a slurry, and the mixture was stirred at 70 ° C for 0.5 hour, and then cooled to 10 ° C over 10 hours. The slurry was filtered at 10 ° C. to remove insolubles. When the obtained mother liquor was analyzed by HPLC, (2R, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-
89.9% recovery of 4-phenylbutane (1.43 g)
I got it. (2R, 3S): (2S, 3S) = 97.0:
3.0.

Example 26 Production of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane Obtained by the same method as in Example 22 (2R, 3S) )-
3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane ((2R, 3
S) Body content 5.99 g, (2S, 3S) body content 80 m
g), the solution containing 2-propanol (3
0.8 ml) and water (10.3 ml) were added, and the mixture was cooled to 4 ° C. 4mol / l sodium hydroxide aqueous solution (7.7ml)
Was added and stirred at 4 ° C. for 70 minutes. When the reaction solution was analyzed by HPLC, the target (2R, 3S) form was 97.1%.
(HPLC area ratio). After adding 1.5% aqueous citric acid solution (44.3 g) to stop the reaction, the mixture was cooled to -3 ° C, inoculated with seed crystals, stirred for 30 minutes, and cooled to -10 ° C over 1 hour. (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was crystallized by stirring for an additional 2 hours. This slurry liquid was filtered, and the obtained crystals were slurried with water (61.6 ml) and added at room temperature for 30 minutes.
After stirring for minutes, the mixture was filtered. Water (61.6 m) was added to the obtained crystals again.
l) was added to form a slurry, and the mixture was stirred at room temperature for 30 minutes. The slurry was filtered and dried to obtain the desired (2R,
3S) -3-tert-Butoxycarbonylamino-
Crystals of 1,2-epoxy-4-phenylbutane were obtained ((2R, 3S) form yield 93.5%, (2R, 3S) form yield 4.92 g). When the dried crystals were analyzed by HPLC, (2R, 3S): (2S, 3S) = 98.
5: 1.5, and the purity of the (2R, 3S) form is 98.3%
(HPLC area ratio).

Example 27 Purification of (2R, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2R, 3S) -3-tert obtained in Example 26 −
Butoxycarbonylamino-1,2-epoxy-4-phenylbutane ((2R, 3S) form content 2.46 g, (2
(S, 3S) body content 37.5mg), acetonitrile (15ml) and zeolite (zeolist CBV400)
(Zeolyst: registered trademark) (Zeolyst International) (2.50 g) was added, and the mixture was stirred at 25 ° C for 5.5 hours. When the reaction solution was analyzed by HPLC, the target (2R, 3S) form was 78.7%.
(HPLC area ratio). The reaction solution was filtered through celite, and the celite was washed with acetonitrile. The obtained mother liquor was concentrated to obtain an oil. Acetonitrile (1
1.5 ml) and water (38.5 ml).
After cooling to 4 ° C. over 4 hours, seed crystals were inoculated and stirred for 3 hours to give (2R, 3S) -3-tert.
-Butoxycarbonylamino-1,2-epoxy-4-
The phenylbutane crystallized. The slurry was filtered, and the obtained crystals were slurried by adding water (25 ml). After stirring at room temperature for 30 minutes, the crystals were filtered and dried to obtain (2R, 3S) -3-tert-butoxy. Crystals of carbonylamino-1,2-epoxy-4-phenylbutane were obtained (1.56 g of ((2R, 3S) form),
(2R, 3S) isomer yield 63.2%). This dried crystal is
When analyzed by PLC, (2R, 3S): (2S,
3S) = 99.7: 0.3, and the purity of the (2R, 3S) form was 98.8% (HPLC area ratio).

As described above, according to the production method of the present invention, high purity (2
(R, 3S) or (2S, 3R) -N-carbamate protected β-aminoepoxide, or (2R, 3S) or (2
(S, 3R) -N-carbamate protected β-amino alcohol can be efficiently produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) // C07B 57/00 350 C07B 57/00 350 C07M 7:00 C07M 7:00 (31) Claim number of priority Japanese Patent Application No. 11-245645 (32) Priority date August 31, 1999 (August 31, 1999) (33) Priority claiming country Japan (JP) (72) Inventor Takashi Nakano Suzuki, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture 1-1 Ajinomoto Co., Inc. Amino Science Research Laboratories (72) Inventor Hiroshi Honda 1-1 Suzukicho, Kawasaki-ku, Kawasaki City, Kanagawa Prefecture Ajinomoto Co., Inc. Amino Science Research Laboratories (72) Inventor Masakazu Nakazawa Kanagawa 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi Ajinomoto Co., Inc. (72) Inventor Kunisuke Izawa 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc. Roh Science Institute in the F-term (reference) 4C048 AA01 BB19 CC01 KK08 UU03 XX02 XX03 XX04 4H006 AA02 AC83 AD17 BB11 BB12 BB14 BB15 BB16 BB21 BB31 RA08 RA10

Claims (31)

[Claims] 1. A method for producing an N-carbamate-protected β-aminoepoxide crystal, comprising the following steps (a) to (d): (A) General formula (1) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents a halogen atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S,
R. The N-carbamate-protected β-amino alcohol represented by the formula (1), wherein at least one or more selected from aromatic hydrocarbon solvents, aryl halide solvents, saturated hydrocarbon solvents, aqueous mixed solvents, acetone and 2-propanol A step of dissolving in a solvent to remove insolubles. (B) N-carbamate protected β represented by the general formula (1)
-Treating an amino alcohol with a base, to obtain a compound represented by the general formula (2): [Wherein, R, A, and * have the same meanings as described above,
The configuration of the position is 2R, 3S or 2S, 3R. To a N-carbamate-protected β-aminoepoxide represented by the following formula: (C) general formula (2) containing at least its diastereomer as an impurity [Wherein, R, A, and * have the same meanings as described above,
The configuration of the position is 2R, 3S or 2S, 3R. The N-carbamate-protected β-aminoepoxide represented by the general formula (3) [Wherein, A and * have the same meanings as described above, and the configuration at the 4- and 5-positions is 4S, 5R or 4R, 5S. A step of separating and removing the oxazolidin-2-one derivative in water or an aqueous mixed solvent, if necessary. (D) N-carbamate protected β represented by the general formula (2)
-Crystallizing the aminoepoxide with an aqueous mixed solvent. 2. The method according to claim 1, wherein A is a benzyl group. 3. The method according to claim 1, wherein R is a tert-butyl group. 4. In step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene, xylene, and benzene, and the aryl halide solvent is at least one solvent selected from chlorobenzene and bromobenzene. Solvent, and the saturated hydrocarbon solvent is n-
Hexane, n-heptane, cyclohexane, at least one solvent selected from methylcyclohexane, wherein the aqueous mixed solvent is at least selected from methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran The method according to claim 1, wherein the solvent is a mixed solvent of at least one organic solvent and water. 5. In the step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene and xylene, the aryl halide solvent is chlorobenzene, and the saturated hydrocarbon solvent is n-heptane. The method according to claim 1, wherein the aqueous mixed solvent is a mixed solvent of water and at least one or more organic solvents selected from methanol, ethanol, and 2-propanol. 6. The method according to claim 1, wherein the solvent in the step (a) is a mixed solvent of 2-propanol and water, toluene or xylene. 7. The method according to claim 1, wherein in step (c), the acid is a solid acid insoluble in a solvent. 8. In step (d), the aqueous mixed solvent is acetone, methanol, ethanol, 2-propanol,
2. The method according to claim 1, wherein the solvent is a mixed solvent of at least one or more organic solvents selected from acetonitrile and water. 9. A method for producing an N-carbamate-protected β-amino alcohol, comprising the following step (a): (A) General formula (1) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents a halogen atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S,
R. Is dissolved in at least one selected from aromatic hydrocarbon solvents, aryl halide solvents, saturated hydrocarbon solvents, aqueous mixed solvents, acetone and 2-propanol. And removing insolubles. 10. The method according to claim 9, wherein A is a benzyl group. 11. The method according to claim 9, wherein R is a tert-butyl group. 12. In the step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene, xylene and benzene, and the aryl halide solvent is at least one solvent selected from chlorobenzene and bromobenzene. Solvent, and the saturated hydrocarbon solvent is n
-Hexane, n-heptane, cyclohexane, at least one solvent selected from methylcyclohexane, and the aqueous mixed solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile, and tetrahydrofuran. The method according to claim 9, wherein the solvent is a mixed solvent of at least one or more organic solvents and water. 13. In the step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene and xylene, the aryl halide solvent is chlorobenzene, and the saturated hydrocarbon solvent is n-heptane. 10. The method according to claim 9, wherein the aqueous mixed solvent is a mixed solvent of at least one or more organic solvents selected from methanol, ethanol, and 2-propanol and water. 14. The method according to claim 9, wherein the solvent in the step (a) is a mixed solvent of 2-propanol and water, toluene or xylene. 15. A method for producing an N-carbamate-protected β-aminoepoxide, comprising the following steps (a) and (b): (A) General formula (1) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents a halogen atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S,
R. The N-carbamate-protected β-amino alcohol represented by the formula (1), wherein at least one or more selected from aromatic hydrocarbon solvents, aryl halide solvents, saturated hydrocarbon solvents, aqueous mixed solvents, acetone and 2-propanol A step of dissolving in a solvent to remove insolubles. (B) N-carbamate protected β represented by the general formula (1)
-Treating an amino alcohol with a base, to obtain a compound represented by the general formula (2): [Wherein, R, A, and * have the same meanings as described above,
The configuration of the position is 2R, 3S or 2S, 3R. To a N-carbamate-protected β-aminoepoxide represented by the following formula: 16. The method according to claim 15, wherein A is a benzyl group. 17. The method according to claim 15, wherein R is a tert-butyl group. 18. In the step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene, xylene and benzene, and the aryl halide is at least one solvent selected from chlorobenzene and bromobenzene. Wherein the saturated hydrocarbon solvent is at least one solvent selected from n-hexane, n-heptane, cyclohexane and methylcyclohexane, and the aqueous mixed solvent is methanol, ethanol, 1-propanol, 2-propanol, acetone, The production method according to claim 15, which is a mixed solvent of water and at least one or more organic solvents selected from 2-butanone, acetonitrile, and tetrahydrofuran. 19. In the step (a), the aromatic hydrocarbon solvent is at least one solvent selected from toluene and xylene, the aryl halide solvent is chlorobenzene, and the saturated hydrocarbon solvent is n-heptane. The method according to claim 15, wherein the aqueous mixed solvent is a mixed solvent of water and at least one or more organic solvents selected from methanol, ethanol, and 2-propanol. 20. The method according to claim 15, wherein the solvent in the step (a) is a mixed solvent of 2-propanol and water, toluene or xylene. 21. A method for producing an N-carbamate-protected β-aminoepoxide crystal, comprising the following steps (c) and (d). (C) general formula (2) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. N represented by
Treating the carbamate-protected β-aminoepoxide with an acid to give the diastereomer of the impurity with the general formula (3) [Wherein A and * have the same meanings as described above, and the configuration is 4
S, 5R or 4R, 5S. A step of separating and removing the oxazolidin-2-one derivative in water or an aqueous mixed solvent, if necessary. (D) N-carbamate protected β represented by the general formula (2)
-Crystallizing the aminoepoxide with an aqueous mixed solvent. 22. The method according to claim 21, wherein A is a benzyl group. 23. The method according to claim 21, wherein R is a tert-butyl group. 24. The method according to claim 21, wherein in step (c), the acid is a solid acid insoluble in a solvent. 25. The process according to claim 21, wherein in step (d), the aqueous mixed solvent is a mixed solvent of at least one organic solvent selected from acetone, methanol, ethanol, 2-propanol, and acetonitrile with water. Method. 26. A method for producing an N-carbamate-protected β-aminoepoxide crystal, comprising the following step (d). (D) General formula (2) [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. N represented by
-A step of crystallizing the carbamate-protected β-aminoepoxide with an aqueous mixed solvent. 27. The method according to claim 26, wherein A is a benzyl group. 28. The method according to claim 26, wherein R is a tert-butyl group. 29. The method according to claim 26, wherein the aqueous mixed solvent is a mixed solvent of at least one organic solvent selected from acetone, methanol, ethanol, 2-propanol, and acetonitrile with water. 30. A method for producing an N-carbamate-protected β-aminoepoxide, which comprises the following step (c ′). (C ′) a compound of the general formula (2) containing at least its diastereomer as an impurity [Wherein, R represents a lower alkyl group, a benzyl group or a fluorenylmethyl group, and A represents an optionally substituted alkyl group having 1 to 10 carbon atoms and an aryl group having 6 to 15 carbon atoms. Or an aralkyl group having 7 to 20 carbon atoms or a group containing a hetero atom in the carbon skeleton thereof;
Represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. N represented by
-Treatment of the carbamate-protected β-aminoepoxide with a solid acid insoluble in the solvent to give the diastereomer of the impurity of the general formula (3) [Wherein A and * have the same meanings as described above, and the configuration is 4S, 5R or 4R, 5S. A step of separating and removing the oxazolidin-2-one derivative in water or an aqueous mixed solvent, if necessary. 31. A crystal of N-carbamate-protected β-aminoepoxide represented by the general formula (2) obtained according to the process of claim 1, 21 or 26.