JP2002326982A - Method for producing sulfonamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an economical and efficient method for producing a specific N-carbamate type protected benzenesulfonamide derivative which is suitable for industrial production, the specific benzenesulfonamide derivative and its salt derived from the aforesaid derivative and a method for producing a crystal of the benzenesulfonamide derivative salt. SOLUTION: An N-carbamate type protected β-aminoalcohol or an N- carbamate type protected β-aminoepoxide is reacted with N-isobutyl-3- nitrobenzenesulfonamide in the presence of a base to obtain the N-carbamate type protected benzenesulfonamide derivative. In the benzenesulfonamide derivative in which a protecting group of the amino group is benzyloxycarbonyl group, the protecting group is removed by reacting methanesulfonic acid. An impurity is efficiently separated and removed into the mother liquor by crystallizing a methanesulfonate of the benzenesulfonamide derivative containing at least a diastereomer thereof as the impurity from an alcohol or an alcoholic mixed solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an N-carbamate-type protected benzenesulfonamide derivative from an N-carbamate-type protected β-amino alcohol or an N-carbamate-type protected β-aminoepoxide. Furthermore, the present invention relates to a method for producing a benzenesulfonamide derivative or a salt thereof from the N-carbamate-type protected benzenesulfonamide derivative. Further, the present invention relates to a method for producing a specific benzenesulfonamide derivative salt crystal.

[0002]

2. Description of the Related Art General formula (4) [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, R represents an alkyl group or a benzyl group, * represents an asymmetric carbon atom, and the configuration at the 2- and 3-positions is 2R, 3S or 2
S, 3R. The N-carbamate-type protected benzenesulfonamide derivative represented by the formula [1] is a compound useful as an intermediate of a pharmaceutical compound such as an HIV protease inhibitor.

[0003] For example, the international application WO95 / 06030 discloses a production method shown by the following scheme.

[0004]

A method for producing a tetrahydrofuryl carbamic acid derivative is disclosed in JP-A-9-124630.
Discloses a manufacturing method shown by the following scheme.

The method disclosed in Japanese Patent Application Laid-Open No. 9-124630 is different from the method disclosed in WO95 / 06030 in that
This is a simple production method in that an N-isobutylbenzenesulfonesulfonamide group can be introduced in the process, but according to studies by the present inventors, N- (2-hydroxyalkyl) -4-nitrobenzenesulfonamide is present in the presence of a base. It has been found that the rearrangement proceeds and 2-hydroxyalkyl-4-nitrophenylamine is by-produced. Regarding the rearrangement reaction of N- (2-hydroxyalkyl) -4-nitrobenzenesulfonamide, for example, KG Kleb, Angevante Chemie International Edition Vol. 7, No. 4,
No., p.291, 1968 (Angew. Chem. Internat. Edi
t. 7 (1968), 4, 291.). Since this reaction is not highly reactive, the starting material N-isobutyl-
An excessive amount of 4-nitrobenzenesulfonamide is required, and purification by silica gel column chromatography or the like is required to remove raw materials and impurities (see JP-A-9-12).
No. 4630, Example 5). As a result, the yield is not high, and the production method is not necessarily industrially suitable.

[0007]

SUMMARY OF THE INVENTION The present invention provides an economical and efficient process for producing a specific protected N-carbamate-type protected benzenesulfonamide derivative suitable for industrial production, and a specific process derived from the derivative. An object of the present invention is to provide a benzenesulfonamide derivative and a salt thereof, and a method for producing a crystal of the benzenesulfonamide derivative salt.

[0008]

The present inventors have conducted intensive studies on a method for producing an N-carbamate-type protected benzenesulfonamide derivative having a nitro group at the meta position (3 position) of a phenyl group. By reacting N-carbamate-type protected β-amino alcohol or N-carbamate-type protected β-aminoepoxide with N-isobutyl-3-nitrobenzenesulfonamide in the presence of a base, the problem of the rearrangement reaction can be reduced in one step. Not
It has been found that N-carbamate-type protected benzenesulfonamide derivatives can be obtained in good yield. In addition, it has been found that the benzenesulfonamide derivative, in which the protecting group for the amino group is a benzyloxycarbonyl group, can be deprotected in good yield by the action of methanesulfonic acid. Furthermore, they have found that the methanesulfonate of a benzenesulfonamide derivative containing at least its diastereomer as an impurity can be efficiently separated and removed from the mother liquor by crystallization from an alcohol or an alcohol-based mixed solvent. The present inventors have completed the present invention based on the above findings.

That is, the present invention includes the following contents.

General formula (1) [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, R represents an alkyl group or a benzyl group, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2S, 3S or 2
R and 3R. An N-carbamate-type protected β-amino alcohol represented by the general formula (2): [Wherein, A, R and * have the same meanings as described above, and the configuration at the 2-position and 3-position is 2S, 3S or 2R, 3R. ]
In the presence of a base, an N-carbamate-type protected β-aminoepoxide represented by the following formula (3) Reacting with N-isobutyl-3-nitrobenzenesulfonamide represented by the general formula (4): [Wherein, A, R and * have the same meaning as described above, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. ]
A method for producing an N-carbamate-type protected benzenesulfonamide derivative represented by the formula:

After the N-carbamate-type protected benzenesulfonamide derivative represented by the general formula (4) is obtained by the above-mentioned production method, the carbamate-type protecting group of the N-carbamate-type protected benzenesulfonamide derivative is deprotected. General formula (5) characterized by the following: [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2
R, 3S or 2S, 3R. ] The method for producing a benzenesulfonamide derivative or a salt thereof represented by the formula:

General formula (6) [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2
R, 3S or 2S, 3R. Wherein the benzyloxycarbonyl-protecting group is deprotected by reacting methanesulfonic acid with the N-benzyloxycarbonyl-protected benzenesulfonamide derivative represented by the general formula (5): [Wherein, A and * have the same meanings as described above, and the configuration at the 2- and 3-positions is 2R, 3S or 2S, 3R. ] The method for producing a benzenesulfonamide derivative or a salt thereof represented by the formula:

Formula (7) containing at least its diastereomer as an impurity [Wherein, * represents an asymmetric carbon atom;
The configuration of the position is 2R, 3S or 2S, 3R. A methanesulfonate of a benzenesulfonamide derivative represented by the following formula: is crystallized from an alcohol or an alcohol-based mixed solvent, and impurities are separated and removed from a mother liquor.
A method for producing crystals of the benzenesulfonamide derivative methanesulfonate.

[0014]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

In the formula in the present invention, A is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aryl group having 7 to 15 carbon atoms, each of which may have a substituent.
20 represents an aralkyl group or a group containing a hetero atom in the carbon skeleton of these groups. The substituent in the case of having a substituent is not particularly limited as long as it does not adversely affect the reaction of the present invention. For example, an alkoxy group (preferably having 1 to 6 carbon atoms), a nitro group, an alkyl group (preferably Represents a carbon atom having 1 to 6) and a halogen atom.

Examples of the group containing a hetero atom (nitrogen, oxygen, sulfur atom, etc.) in the carbon skeleton include a methylthioethyl group, a 4-benzyloxyphenylmethyl group, a phenylthiomethyl group and the like.

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

A may be a group introduced from an amino acid in which the functional group of the amino acid side chain is protected, such as O-benzyltyrosine.

A is not limited to a group introduced from a raw material derived from a natural amino acid, but may be a group introduced from a raw material derived from an unnatural amino acid (for example, a phenyl group or a phenylthiomethyl group).

A is particularly preferably benzyl.

In the formula of the present invention, R represents an alkyl group or a benzyl group. The 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.

R is particularly preferably tert-butyl and benzyl.

The N-carbamate-type protected β-amino alcohol represented by the general formula (1) or the N-carbamate-type protected β-aminoepoxide represented by the general formula (2) used as a raw material in the present invention is known. A compound,
For example, it can be produced by a known method such as reducing the N-carbamate-type protected α-chloromethyl ketone represented by the general formula (8) followed by treatment with a base (for example, see International Application WO00 / 44706).

[0024] [Wherein, A, R and * have the same meanings as described above, and the configuration at the 2-position and 3-position is 2S, 3S or 2R, 3R. ]

In the present invention, N-
Isobutyl-3-nitrobenzenesulfonamide (formula (3)) is described in, for example, Japanese Patent Application Laid-Open No. 9-507762, ML Carmellino et al., Boll. Chim. Farm. 1983, 122,
It can be manufactured by a known method as described in 10, 485.

Hereinafter, N-carbamate-type protected β-amino alcohol (general formula (1)) or N-carbamate-type protected β-aminoepoxide (general formula (2)) is reacted with N-isobutyl-3-amine in the presence of a base. A method for producing an N-carbamate-type protected benzenesulfonamide derivative (general formula (4)) by reacting with nitrobenzenesulfonamide (formula (3)) will be described.

As the base, for example, lithium hydride, sodium hydride, potassium hydride, calcium hydride,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Potassium carbonate, cesium carbonate, sodium methoxide,
Sodium ethoxide, sodium butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, dicyclohexylmethylamine,
N-methylmorpholine, pyridine, 2,6-lutidine,
N, N-dimethylaminopyridine and the like can be mentioned. Especially sodium hydroxide, potassium hydroxide, sodium carbonate,
Potassium carbonate or cesium carbonate is preferred, and potassium carbonate is most preferred. Each of these bases may be used alone or
Mixtures of more than one species may be used.

Examples of the reaction solvent include methanol, ethanol, 1-propanol, 2-propanol and 1-propanol.
Protic solvents such as butanol, 1,2-dimethylpropanol and water, or acetone, 2-butanone, methyl isobutyl ketone, toluene, tetrahydrofuran,
Aprotic solvents such as 4-dioxane, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like. Particularly, acetone, 2-butanone, methyl isobutyl ketone or toluene is preferred, and 2-butanone is most preferred. These reaction solvents may be used alone or in combination of one or more.

The amount of the base used varies depending on the type of the base and the solvent used, but is usually 1 to 10 equivalents, preferably 1 to 6 equivalents. The reaction temperature also varies depending on the type of base or solvent used, but is usually -10 to 150 ° C, preferably 50 to 130 ° C, particularly preferably 70 to 130 ° C.
100 ° C. The reaction temperature may be changed during the course of the reaction. The reaction time is not particularly limited, but is preferably about 10 minutes to 50 hours.

The reaction is usually carried out with stirring.
The reaction may be stopped by adding an acid. Hydrochloric acid as the acid,
Sulfuric acid, acetic acid, citric acid, an aqueous solution of potassium hydrogen sulfate and the like can be preferably used. Thereafter, if necessary, water or an organic solvent such as ethyl acetate, isopropyl acetate, diethyl ether, tert-butyl methyl ether, dichloromethane, chloroform, toluene, acetone, 2-butanone, and methyl isobutyl ketone are added to the reaction solution to separate the layers. By doing so, a solution of the benzenesulfonamide derivative (general formula (4)) can be obtained. Further, if necessary, the solution is concentrated, and the solution is heated in the range of about 25 ° C. to about 100 ° C., and a poor solvent such as hexane, heptane, a lower alcohol aqueous solution, or water is added. Crystallization is performed by cooling or the like to obtain a benzenesulfonamide derivative (general formula (4)).
The target substance can also be isolated using a means such as chromatography. Also, without performing extraction, the reaction solution is concentrated if necessary, and directly cooled and crystallized under the above conditions,
By washing the obtained crystal with water or the like, a crystal of a benzenesulfonamide derivative (general formula (4)) can be obtained.

Next, the N-carbamate protected benzenesulfonamide derivative (general formula (4)) is deprotected to give a benzenesulfonamide derivative (general formula (5))
A method for obtaining the following will be described.

The deprotection reaction conditions differ depending on the type of N-carbamate protecting group (for carbamate-type protecting groups, for example, Protecting Groups in
Organic Chemistry 2nd Edition, John Willie and Sons, 1991 (Protecting Group
s in Organic Chemistry 2nd edition (John Wiley & So
ns, Inc. 1991)).

For example, in the case of a tert-butoxycarbonyl group (Boc group), deprotection can be performed by the action of an acid (for example, PL Beaulieu et al., Journal of Medicinal Chemistry, 43).
Volume, 1094, 2000 (J. Med. Chem., 2000, 4
3, 1094.) or International Application WO 99/48885).

When the protecting group is a benzyloxycarbonyl group (C
In the case of (bz group), deprotection is usually performed by hydrogenation, but in the case of N-Cbz protected sulfonamide derivative (general formula (6)), reduction of the nitro group proceeds as a side reaction, which is not preferable. Further, although a method of deprotection by the action of a hydrobromic acid / acetic acid solution is known, it is not always industrially satisfactory due to problems such as the side reaction progressing. Kaihei 9-1944
No. 44, Example 22).

Under such a technical background, the present inventors surprisingly surprisingly remove the Cbz group by reacting methanesulfonic acid on the N-Cbz-protected sulfonamide derivative (general formula (6)). I found something that could be protected.

The amount of methanesulfonic acid to be used is not particularly limited, but is preferably 0.1-10 to 1 g of the N-Cbz-protected benzenesulfonamide derivative (general formula (6)).
Use ml. Although the reaction temperature is not particularly limited, it is preferably 0-80 ° C. Although the reaction time is not particularly limited, it is preferably 10 minutes to 50 hours. As an additive, for example, cation scavenge such as thioanisole, m-cresol, ethanedithiol, etc.
It is also preferable to add r), and particularly preferable to add thioanisole. Further, any solvent such as dichloromethane, dichloroethane and the like may be added as long as the reaction is not inhibited.

The benzenesulfonamide derivative (general formula (5)) obtained by the deprotection can obtain high purity crystals by crystallization from alcohol or an alcohol-based mixed solvent as a salt.

First, an alcohol or an alcohol-based mixed solvent is added to the salt of the benzenesulfonamide derivative (general formula (5)). Examples of the alcohol include alcohols having 1 to 6 carbon atoms such as methanol, ethanol, 1-propanol and 2-propanol. Particularly, methanol or ethanol is preferable. The alcohol-based mixed solvent refers to a mixed solvent of water or an organic solvent miscible with an alcohol and an alcohol. Examples of the organic solvent miscible with the alcohol include toluene, ethyl acetate, isopropyl acetate, ether, methyl tert-butyl ether, dichloromethane, chloroform, dichloroethane, acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, and the like. As the alcohol-based mixed solvent, a mixed solvent of alcohol and water is particularly preferable. At this time, the composition ratio of the alcohol and another solvent (for example, water) is not particularly limited, but is preferably 5 to 9
It is 9%, more preferably 25-95% (% is indicated by volume ratio of alcohol in the mixed solvent).

The amount of the alcohol or the alcohol-based mixed solvent is not particularly limited, but for example, 2 to 20 ml of the solvent can be used per 1 g of the salt of the sulfonamide derivative (general formula (5)).

The salt of the benzenesulfonamide derivative may be desalted as necessary, and then added to another acid to form another salt of the benzenesulfonamide derivative.

Next, the reaction mixture is cooled to crystallize a salt of a benzenesulfonamide derivative (general formula (5)).

The crystallization temperature is preferably from -10 ° C to 25 ° C. At this time, the crystallization may be carried out with stirring or under static conditions, but preferably with stirring. Further, if necessary, in order to increase the purification effect, 30 ° C.
After heating to about 80 ° C. to partially dissolve the crystals, the crystals can be cooled again to −10 ° C. to 25 ° C. for crystallization. The obtained crystals can be further washed with alcohol, an alcohol-based mixed solvent or water, or an organic solvent such as methyl tert-butyl ether, ethyl acetate, isopropyl acetate or dichloromethane. By performing crystallization, impurities are efficiently removed to the mother liquor side, so that a crystal of a salt of a highly pure benzenesulfonamide derivative (general formula (5)) can be obtained.

In particular, N- (3-amino-2-hydroxy-
In the methanesulfonate of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide (formula (7)), when crystallized from an alcohol or an alcohol-based mixed solvent, diastereomers as impurities are present in the mother liquor. Since it is efficiently separated and removed, it is an excellent purification method from an industrial viewpoint.

Hereinafter, the present invention will be described in more detail with reference to examples. Of course, the present embodiment does not limit the present invention at all.

Reference Example 1 Production of N-isobutyl-3-nitrobenzenesulfonamide Dichloromethane (270 ml) was added to N-isobutylamine (19.72 g) and cooled to 0 ° C. 1 in this solution
After adding a 5% aqueous sodium carbonate solution (225.8 g), 3-nitrobenzenesulfonyl chloride (59.6) was added.
A solution of 4 g) in dichloromethane (100 ml) was added dropwise over 15 minutes. After completion of the dropwise addition, the reaction temperature was raised to 20 ° C., and the mixture was further stirred for 2 hours and 30 minutes.
Was added to perform extraction. Dichloromethane (80m
After l) was added and re-extraction was performed, the dichloromethane layer was concentrated under reduced pressure. Hexane (143 ml) and ethyl acetate (71.5 ml) were added thereto, and recrystallization was performed. The crystals obtained by filtration were dried under reduced pressure, and 67.6 g of crystals of N-isobutyl-3-nitrobenzenesulfonamide were obtained (yield 97).
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.89 (d, J = 6.6 Hz, 6H), 1.69
-1.82 (m, 1H), 2.84 (dd, J = 6.3, 6.3Hz, 2H), 4.97
(t, J = 6.3Hz, 1H), 7.76 (dd, J = 8.1, 8.1Hz, 1H), 8.2
1 (ddd, J = 8.1, 1.8, 1.2Hz, 1H), 8.43 (ddd, J = 8.1,
2.4, 1.2Hz, 1H), 8.70-8.72 (m, 1H) Mass spectrum m / e: 257.06 (MH ⁻ ) Melting point; 90 ° C.

Example 1 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N
Preparation of -isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (500
mg), N-isobutyl-3-nitrobenzenesulfonamide (490 mg) and potassium carbonate (262 mg) were added with acetone (5.0 ml), and the mixture was stirred at 60 ° C for 23 hours. This was filtered to remove potassium carbonate, and acetone was distilled off under reduced pressure. Dichloromethane (10m
l), water (10 ml) was added for extraction, and the dichloromethane layer was concentrated. The obtained crystals were treated with hexane (4 m
l), washed with a mixed solution of ethyl acetate (1 ml), dried under reduced pressure, and treated with (2R, 3S) -N- (3-ter
827 mg (84% yield) of crystals of t-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide were obtained. ¹ H-NMR (CDCl ₃ ) δppm: 0.88 (d, J = 6.6Hz, 6H), 1.36
(s, 9H), 1.82-1.96 (m, 1H), 2.85-2.98 (m, 2H), 3.01
(d, J = 7.8Hz, 2H), 3.21 (d, J = 6.3Hz, 2H), 3.70-3.9
0 (m, 3H), 4.63 (bs, 1H), 7.20-7.34 (m, 5H), 7.72
(dd, J = 7.8, 7.8Hz, 1H), 8.10 (d, J = 7.8Hz, 1H), 8.4
2 (d, J = 7.8 Hz, 1H), 8.63 (s, 1H) Mass spectrum m / e: 522.36 (MH ⁺ ) [α] _D ²⁰ = 2.97 ゜ (c 1.0, CHCl ₃ ) Melting point; 114 ° C.

Example 2 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl)-
Preparation of N-isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (500
mg), N-isobutyl-3-nitrobenzenesulfonamide (490 mg) and potassium carbonate (525 mg), and 2-butanone (2.5 ml) was added.
Stir for 8 hours. After adding water (10 ml), the obtained crystals were collected by filtration and analyzed by HPLC.
S) -N- (3-tert-butoxycarbonylamino-
926.1 m of 2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide
g (93% yield).

Example 3 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl)-
Preparation of N-isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (5.0
0 g), N-isobutyl-3-nitrobenzenesulfonamide (4.90 g), and potassium carbonate (5, 25 g) were added with methyl isobutyl ketone (25 ml), and the mixture was stirred at 90 ° C. for 6 hours. After cooling the reaction solution to room temperature, methyl isobutyl ketone was distilled off under reduced pressure. Water (30 ml) was added to the obtained crystals, and the crystals were collected by filtration. The crystals were further washed with water (20 ml) and dried under reduced pressure.
(2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N
8.34 g of crystals of -isobutyl-3-nitrobenzenesulfonamide were obtained (yield 84%).

Example 4 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl)-
Preparation of N-isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (300
mg), N-isobutyl-3-nitrobenzenesulfonamide (295 mg) and potassium carbonate (316 mg) were added with toluene (1.5 ml), and the mixture was stirred at 90 ° C for 21 hours. The solution was cooled to room temperature, and dichloromethane (10 ml) was added to the obtained slurry solution to dissolve the crystals. As a result of analysis by HPLC, (2R, 3S) -N-
459 mg of (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide (yield 77)
%) Was confirmed to have been obtained.

Example 5 (2R, 3S) -N- (3-amino-2-hydroxy-
Production of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (2R, 3S) -N- (3-
Ethanol (49.4 ml) was added to tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide (5.01 g), and the mixture was stirred at 65 ° C. Methanesulfonic acid (0.768 ml) was added thereto, and the mixture was stirred for 1 hour and 30 minutes. The reaction solution was cooled to 20 ° C., and the crystals were collected by filtration. The crystals were washed twice with methyl-tert-butyl ether (25 ml, 25 ml). The obtained crystals were dried under reduced pressure to give (2R, 3S) -N- (3-
Amino-2-hydroxy-4-phenylbutyl) -N-
3.90 g (yield 95%) of crystals of isobutyl-3-nitrobenzenesulfonamide methanesulfonate were obtained. ¹ H-NMR (DMSO-d ₆ ) δppm: 0.76 (d, J = 6.6 Hz, 3H), 0.8
3 (d, J = 6.6Hz, 3H), 1.80-1.95 (m, 1H), 2.30 (s, 3
H), 2.73-3.13 (m, 5H), 3.33-3.51 (m, 2H), 3.86-3.9
5 (m, 1H), 5.57 (d, J = 5.7Hz, 1H), 7.24-7.40 (m, 5
H), 7.76-7.89 (bs, 3H), 7.90 (dd, J = 7.8, 7.8Hz, 1H),
8.24 (m, 1H), 8.50 (m, 2H) Mass spectrum m / e: 516.32 (MH ⁻ ) [α] _D ²⁵ = 8.02 ゜ (c 2.0, MeOH) Melting point: 235-26.2 ° C.

Reference Example 2 Method for producing (2S, 3S) -3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3S) -3-tert-butoxycarbonylamino-
1-chloro-4-phenyl-2-butanone (2.08
g) in toluene (4.2 ml) and ethanol (16.7).
ml), and sodium borohydride (1
33 mg) and stirred for 1 hour and 40 minutes. Acetic acid (0.40 ml) was added to the reaction solution to stop the reaction. The mixture was heated to 60 ° C. over 1 hour, and further stirred at 60 ° C. for 30 minutes. Then, it cooled to -10 degreeC over 1 hour and 50 minutes, and also stirred at -10 degreeC for 6 hours. The obtained crystals are collected by filtration,
After washing with toluene (10.4 ml), further washing with water at 0 ° C., and drying under reduced pressure, the desired (2S, 3S)
-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52
g) was obtained. When the dried crystals were analyzed by HPLC, (2S, 3S): (2R, 3S) = 99.2: 0.8.
Quality crystals.

Example 6 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl)-
Production of N-isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3- obtained by the same method as in Reference Example 2.
tert-butoxycarbonylamino-1-chloro-2
-Hydroxy-4-phenylbutane (12.6 g, (2
(S, 3S) :( 2R, 3S) = 99.2: 0.8) and acetone (100 ml) was added. Further, a 10% aqueous sodium hydroxide solution (27.8 g) was added, and the mixture was stirred at 30 ° C. for 1 hour and 30 minutes. After cooling to room temperature, liquid separation was performed to remove the aqueous layer, and acetone was distilled off under reduced pressure. Methyl isobutyl ketone (37.9 ml) was added, and the solvent was distilled off under reduced pressure. Methyl isobutyl ketone (55.5 ml), potassium carbonate (11.6 g),
N-Isobutyl-3-nitrobenzenesulfonamide (10.9 g) was added, and the mixture was stirred at 90 ° C. for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Ethanol (55.5 ml) and water (150 ml) were added, the mixture was stirred at room temperature for 5 hours, and the solution was filtered. The obtained crystals were dried under reduced pressure to give (2R, 3S) -N- (3-ter
t-butoxycarbonylamino-2-hydroxy-4-
23.1 g of a crystal of phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide ((2R, 3
S): (2S, 3S) = 99.2: 0.8, yield 89
%)Obtained.

Example 7 (2R, 3S) -N- (3-amino-2-hydroxy-
Preparation of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (2R, 3S) -N- (3-
Ethanol (55.7 ml) was added to tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide (5.00 g), and the mixture was stirred at 70 ° C. Further, methanesulfonic acid (0.958 ml) was added, and the mixture was stirred for 3 hours. Further, methanesulfonic acid (0.372 m
l) added and stirred for 3 hours. After cooling to 20 ° C., the crystals were collected by filtration, and methyl-tert-butyl ether (26 ml,
10 ml) twice. The obtained crystals were dried under reduced pressure to obtain crystals of (2R, 3S) -N- (3-amino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate. .20 g ((2R, 3S): (2S, 3S) = 10
0: 0, yield 99%).

Example 8 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N
Production of -isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3- obtained in the same manner as in Reference Example 2.
tert-butoxycarbonylamino-1-chloro-2
-Hydroxy-4-phenylbutane (1.90 g, (2
S, 3S): (2R, 3S) = 99.2: 0.8), N
-Isobutyl-3-nitrobenzenesulfonamide (1.64 g) and potassium carbonate (4.37 g) were added with methyl ethyl ketone (9.5 ml).
Stir for 9 hours. After cooling to 50 ° C., water (6.3 ml) was added, and the mixture was separated to remove an aqueous layer. As a result of analysis by HPLC, (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide was 3.00 g (yield 91%). ) I confirmed that it was obtained. Hexane (45 ml) was added to the reaction solution at 50 ° C.
Was added dropwise over 15 minutes and then stirred at 50 ° C. for 1 hour.
The mixture was cooled to 0 ° C over 5 hours and stirred at 0 ° C for 1 hour. The obtained crystals were collected by filtration, and methyl ethyl ketone: hexane =
Washed with a 1: 6 mixture (7 ml) and hexane (3 ml). The obtained crystals were dried under reduced pressure to give (2R, 3
1. Crystals of S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide
88 g ((2R, 3S): (2S, 3S) = 99.2:
0.8, 89% yield, two steps).

Example 9 (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N
Production of -isobutyl-3-nitrobenzenesulfonamide (2S, 3S) -3- obtained in the same manner as in Reference Example 2.
tert-butoxycarbonylamino-1-chloro-2
-Hydroxy-4-phenylbutane (1.90 g, (2
S, 3S): (2R, 3S) = 99.2: 0.8), N
-Isobutyl-3-nitrobenzenesulfonamide (1.64 g) and potassium carbonate (4.37 g) were added with methyl ethyl ketone (9.5 ml).
Stir for 9 hours. After cooling to 50 ° C., water (6.3 ml) was added, and the mixture was separated to remove an aqueous layer. As a result of analysis by HPLC, 3.00 g (91% yield) of (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide was obtained. ) I confirmed that it was obtained. At 50 ° C, add methanol (6 ml)
Was added, and water (9 ml) was added dropwise over 10 minutes.
Stir at 50 ° C for 1 hour, cool to 0 ° C over 5 hours,
Stirred at 0 ° C. for 1 hour. The obtained crystals were collected by filtration and washed with a mixed solution of methyl ethyl ketone: hexane = 1: 6 (7 ml) and hexane (3 ml). The obtained crystals were dried under reduced pressure to obtain (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide as crystals. 81 g ((2R, 3S): (2
S, 3S) = 99.2: 0.8, yield 85%, two steps)
Obtained.

Example 10 (2R, 3S) -N- (3-amino-2-hydroxy-
Production of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (2S, 3S) -3- obtained by the same method as in Reference Example 2.
tert-butoxycarbonylamino-1-chloro-2
-Hydroxy-4-phenylbutane (30.0 g, (2
S, 3S): (2R, 3S) = 99.2: 0.8), N
-Isobutyl-3-nitrobenzenesulfonamide (2
5.9 g) and potassium carbonate (69.1 g) were added with methyl ethyl ketone (150 ml), and the mixture was stirred at 80 ° C. for 19 hours. After cooling to 50 ° C., water (100 ml) was added, and the mixture was separated to remove an aqueous layer. As a result of analysis by HPLC, (2R, 3S) -N- (3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl)
It was confirmed that 47.4 g (yield 91%) of -N-isobutyl-3-nitrobenzenesulfonamide was obtained. After distilling off methyl ethyl ketone under reduced pressure,
Ethanol (568 ml) was added and stirred at 75 ° C. Further, methanesulfonic acid (11.8 ml) was added,
The mixture was stirred for 7 hours and 45 minutes. After heating to 80 ° C, 20 ° C
And cooled. The obtained crystals were collected by filtration and methyl-tert.
-Washed with butyl ether (284 ml). The obtained crystals were dried under reduced pressure to obtain (2R, 3S) -N- (3-amino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate crystals. 0.0 g ((2R, 3S): (2
S, 3S) = 100: 0, yield 85%, two steps).
Ethanol (440 ml) was added to the obtained crystals to give 70
After heating to ° C., water (65.9 ml) was added. The solution was cooled from 70 ° C. to 15 ° C. over 3 hours and 40 minutes, stirred overnight, and the crystals were collected by filtration. Methyl-tert-butyl ether (264 ml) was added to the obtained crystals, and the mixture was stirred at room temperature for 1 hour, and then filtered. The obtained crystals were dried under reduced pressure to give (2R, 3S) -N- (3-amino-2
-Hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide 39.4 g of crystals of methanesulfonate ((2R, 3S) :( 2S, 3
S) = 100: 0, yield 76%, 3 steps) were obtained.

Example 11 (2R, 3S) -N- (3-amino-2-hydroxy-
Preparation of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (2R, 3S) -N in methanesulfonic acid (2.5 ml)
-(3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide (500 mg) was added, and the mixture was stirred at room temperature for 7 hours. Water (2.5 m
l) was added and the crystals were collected by filtration. The obtained crystals were dissolved in water (1.
(0 ml, 1.0 ml, 1.0 ml). The crystals were dried under reduced pressure to give (2R, 3S) -N-
(3-amino-2-hydroxy-4-phenylbutyl)
360 mg of crystals of -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (yield 77)
%)Obtained.

Example 12 (2R, 3S) -N- (3-amino-2-hydroxy-
Preparation of 4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate (2R, 3S) -N- (3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl) -N-isobutyl -3-nitrobenzenesulfonamide (300
mg), 1,2-dichloroethane (1.5 ml) was added, methanesulfonic acid (0.105 ml) and thioanisole (0.127 ml) were further added, and the mixture was stirred at 70 ° C for 7 hours. Ethanol (1.5m
After adding l), the mixture was stirred at 0 ° C for 30 minutes. The obtained crystals were collected by filtration and ethanol (1.0 ml, 1.0 ml)
Was performed twice. The crystals were dried under reduced pressure, and (2R, 3
258 mg of crystals of S) -N- (3-amino-2-hydroxy-4-phenylbutyl) -N-isobutyl-3-nitrobenzenesulfonamide methanesulfonate
(Yield 92%).

[0059]

According to the present invention, a specific N-carbamate-type protected benzenesulfonamide derivative, a specific benzenesulfonamide derivative derived from the derivative and a salt thereof, and a methanesulfonate of the benzenesulfonamide derivative Can be industrially efficiently produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07M 7:00 C07M 7:00 (72) Inventor Naoko Hirose 1-1 Suzukicho, Kawasaki-ku, Kawasaki-shi, Kawasaki, Kanagawa Prefecture Sinoko Oka 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Inside the AminoScience Laboratory, Nonomoto Co., Ltd. (72) Kunisuke Izawa, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture 1-1 Ajinomoto Co., Inc. Amino Science Laboratory F-term (reference) 4H006 AA02 AC61 AC80 AC81 AC83 AD15 BA92 BB11 BB16 BD70 BE10 BE12

Claims (7)

[Claims] 1. General formula (1) [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, R represents an alkyl group or a benzyl group, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2S, 3S or 2
R and 3R. An N-carbamate-type protected β-amino alcohol represented by the general formula (2): [Wherein, A, R and * have the same meanings as described above, and the configuration at the 2-position and 3-position is 2S, 3S or 2R, 3R. ]
In the presence of a base, an N-carbamate-type protected β-aminoepoxide represented by the following formula (3) Reacting with N-isobutyl-3-nitrobenzenesulfonamide represented by the general formula (4): [Wherein, A, R and * have the same meaning as described above, and the configuration at the 2-position and 3-position is 2R, 3S or 2S, 3R. ]
A method for producing an N-carbamate-type protected benzenesulfonamide derivative represented by the formula: 2. A is a benzyl group and R is tert-
2. The production method according to claim 1, wherein the production method is a butyl group or a benzyl group. 3. The N-carbamate-type protected benzenesulfonamide derivative represented by the general formula (4) is obtained by the production method according to claim 1, and then the N-carbamate-type protected benzenesulfonamide derivative is carbamate-type protected. General formula (5), characterized in that the group is deprotected [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, * represents an asymmetric carbon atom, and the configuration at the 2-position and 3-position is 2
R, 3S or 2S, 3R. ] The method for producing a benzenesulfonamide derivative or a salt thereof represented by the formula: 4. The method according to claim 3, wherein A is a benzyl group and R is a tert-butyl group or a benzyl group. 5. General formula (6) [Wherein, 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, or a carbon skeleton of these groups. Represents a group containing a hetero atom, R represents an alkyl group or a benzyl group, * represents an asymmetric carbon atom, and the configuration at the 2- and 3-positions is 2R, 3S or 2
S, 3R. Wherein the benzyloxycarbonyl-protecting group is deprotected by reacting methanesulfonic acid with the N-benzyloxycarbonyl-protected benzenesulfonamide derivative represented by the general formula (5): [Wherein, * represents an asymmetric carbon atom;
The configuration of the position is 2R, 3S or 2S, 3R. ] The method for producing a benzenesulfonamide derivative or a salt thereof represented by the formula: 6. The method according to claim 5, wherein A is a benzyl group. 7. A compound of the formula (7) containing at least its diastereomer as an impurity. [Wherein, * represents an asymmetric carbon atom;
The configuration of the position is 2R, 3S or 2S, 3R. A methanesulfonate of a benzenesulfonamide derivative represented by the following formula: is crystallized from an alcohol or an alcohol-based mixed solvent, and impurities are separated and removed from a mother liquor.
A method for producing crystals of the benzenesulfonamide derivative methanesulfonate.