JPH09124630A - Production of tetrahydrofuryl carbamate derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain the above compound having HIV protease inhibitory activity useful as a preventive medicine or therapeutic agent or their intermediate for acquired immune deficiency syndrome by using a partially new starting compounds, etc. SOLUTION: This tetrahydrofurylcarbamate derivative of formula III [the comformation of (R) marked C is R conformation] is obtained by carrying out of reaction of an epoxy derivative of formula I [the conformation of (S) marked C is S conformation] with a N-isobutyl-benzenesulfone amide, a partially new compound, of formula II (A is a nitro, an amino and an amino group having a protective group). The compounds which has NH2 as A in compounds of formula III is useful as a preventive medicine or therapeutic agent for acquired immune deficiency syndrome. The epoxy derivative of formula I is obtained, for example, by carrying out the cyclization reaction of a sulfonic acid ester derivative of formula IV (B is methyl, phenyl, methoxyphenyl, etc.) in an alkyline condition.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a carbamic acid tetrahydrofuryl ester derivative or a production intermediate thereof which is useful as a medicine.

More specifically, the present invention has an activity of inhibiting HIV protease and is useful as a prophylactic or therapeutic agent for acquired immunodeficiency syndrome.

[0003]

Embedded image

In the formula, the arrangement of carbon atoms with (R) indicates the R configuration, and the arrangement of carbon atoms with (S) indicates the S configuration. N-[(1S, 2R ) -3- (4-
Amino-N-isobutylbenzenesulfonamide) -1
-Benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester or a production intermediate thereof.

[0005]

PRIOR ART As a method for producing a carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I),

[0006]

Embedded image

A carbamic acid tetrahydrofuryl ester derivative represented by the formula (wherein (R) and (S) have the same meanings as described above) is reacted with 4-nitrobenzenesulfonyl chloride to give a compound of the formula

[0008]

[Chemical 6]

After preparing a carbamic acid tetrahydrofuryl ester derivative represented by (wherein (R) and (S) have the same meanings as described above), the nitro group of this derivative is catalytically hydrogenated to give an amino group. A manufacturing method for conversion is known (WO94 / 05639).

That is, according to the above-mentioned production method, the carbamic acid tetrahydrofuryl ester derivative represented by the above formula (II) into which an isobutylamino group is introduced is produced and then reacted with 4-nitrobenzenesulfonyl chloride to give N- This is a production method in which an isobutylbenzenesulfonamide group is introduced.

[0011]

DISCLOSURE OF THE INVENTION The present invention has a carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I), which has an HIV protease inhibitory activity and is useful as a preventive or therapeutic agent for acquired immunodeficiency syndrome. An object of the present invention is to provide a manufacturing method capable of easily manufacturing.

[0012]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to efficiently produce the carbamic acid tetrahydrofuryl ester derivative represented by the formula (I), the formula

[0013]

Embedded image

((S) in the formula has the same meaning as above)
In the presence of a basic substance, the epoxy derivative represented by

[0015]

Embedded image

By reacting an N-isobutylbenzenesulfonamide derivative represented by the formula (A in the formula is a nitro group, an amino group or an amino group having a protecting group), a compound of the general formula

[0017]

Embedded image

It was found that a carbamic acid tetrahydrofuryl ester derivative represented by the formula (A, (R) and (S) in the formula have the same meanings as described above) can be produced, and the present invention has been completed.

That is, the production method of the present invention is the above formula (I
A method for producing a carbamic acid tetrahydrofuryl ester derivative represented by the general formula (VI), which comprises introducing an N-isobutylbenzenesulfonamide group into the epoxy derivative represented by V) in one step. is there.

In the present invention, the amino group having a protective group means an amino group protected by a general amino group-protecting group such as acetamido group, phthalimido group or benzyloxycarbonylamino group.

Examples of the basic substance used in the production method of the present invention include organic tertiary amines such as triethylamine and N-methylmorpholine, and metal hydrides such as sodium hydride, lithium hydride and calcium hydride. it can.

In order to preferably carry out the production method of the present invention,
The N-isobutylbenzenesulfonamide derivative represented by the general formula (V) is dissolved in an organic solvent such as tetrahydrofuran, and 0.1 to 3 times equivalent of a basic substance is added, and then the compound represented by the formula (IV) is used. The resulting epoxy derivative is added and the mixture is heated at 50 to 100 ° C. for 10 to 30 hours. After completion of the reaction, it is isolated by extraction with an organic solvent such as ethyl acetate, and then recrystallized to give the compound of the general formula (VI) above.
A carbamic acid tetrahydrofuryl ester derivative represented by

When the basic substance is a metal hydride, a metal salt of the N-isobutylbenzenesulfonamide derivative represented by the general formula (V) is prepared in advance, and the metal salt is used to prepare the metal salt. You may implement the manufacturing method of invention.

In the above-mentioned production method, when the N-isobutylbenzenesulfonamide derivative of the general formula (V) in which A is an amino group is used as the starting material, the carbamic acid represented by the above formula (I) is used. The tetrahydrofuryl ester derivative can be directly produced.

In the above production method, when A of the N-isobutylbenzenesulfonamide derivative of the general formula (V) is a nitro group or an amino group having a protecting group as a starting material, it is obtained by the above production method. A carbamic acid tetrahydrofuryl ester represented by the above formula (I) useful as a medicine by converting the nitro group of the obtained product into an amino group by a conventional method or removing the protecting group of the amino group by a conventional method. It can lead to derivatives.

For example, when A is a nitro group and the amino group having a protective group is a benzyloxycarbonylamino group, the product obtained by the above-mentioned production method is treated with a suitable catalyst,
For example, hydrogenation in the presence of platinum dioxide, palladium carbon, or the like can lead to a carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I), which is useful as a drug.

When the amino group having a protective group of A is an acetamide group, the product obtained by the above-mentioned production method is treated with an acid, for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an alcohol solution of hydrogen chloride. This leads to a carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I), which is useful as a drug.

Further, when the amino group having a protective group of A is a phthalimido group, it is useful as a medicine by treating the product obtained by the above production method with an organic amine such as hydrazine monohydrate. It can lead to a carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I).

The epoxy derivative represented by the above formula (IV), which is the starting material for the production method of the present invention, can be prepared by

[0030]

Embedded image

(B in the formula is a methyl group, a phenyl group, 4-
Methoxyphenyl group, 4-methylphenyl group or 2-
It is a nitrophenyl group, and (S) has the same meaning as described above), and can be produced by reacting a sulfonic acid ester derivative represented by the formula (1) under an alkaline condition to perform ring closure.

The sulfonic acid ester derivative represented by the above general formula (VII), which is the starting material of the above-mentioned production method, is, for example, a compound represented by the formula:

[0033]

Embedded image

((S) in the formula has the same meaning as above)
The diol derivative represented by N-succinimidyl-
(S) -tetrahydrofuran-3-yl carbonate is reacted to give a compound of the formula

[0035]

Embedded image

((S) in the formula has the same meaning as above)
After the diol derivative represented by

B-SO ₃ H (X)

It can be produced by reacting a sulfonic acid derivative represented by the formula (B has the same meaning as described above) or a reactive functional derivative thereof.

The diol derivative represented by the above formula (IX) has the formula

[0040]

Embedded image

((S) in the formula has the same meaning as above)
The amino acid ester derivative represented by the formula is reacted with N-succinimidyl- (S) -tetrahydrofuran-3-yl carbonate to give a compound of the formula

[0042]

Embedded image

((S) in the formula has the same meaning as above)
It can also be produced by producing an amino acid ester derivative represented by and then reducing the ester group with a reducing agent such as lithium borohydride.

The N-isobutylbenzenesulfonamide derivative represented by the above general formula (V), which is a starting material for the production method of the present invention, contains a part of a novel compound, but it is similar to the method described in the literature or similar thereto. It can be easily manufactured by the method.

The carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I) obtained by the production method of the present invention has HIV protease inhibitory activity and is useful as a preventive or therapeutic agent for acquired immunodeficiency syndrome. Is. According to the production method of the present invention, the carbamic acid tetrahydrofuryl ester derivative represented by the formula (I) can be easily and efficiently produced.

[0046]

According to the production method of the present invention, the carbamic acid tetrahydrofuryl ester derivative represented by the above formula (I), which is useful as a medicine, can be easily produced and is a very useful method. is there.

[0047]

BEST MODE FOR CARRYING OUT THE INVENTION The contents of the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited to these contents. All melting points of the compounds in Reference Examples and Examples are uncorrected.

[0048]

【Example】

Reference Example 1 (2S, 3S) -3-Amino-4-phenylbutane-
1,2-diol hydrochloride (2S, 3S) -3- (tert-butoxycarbonylamino) -4-phenylbutane-1,2-diol 6.
0 g was dissolved in 10 ml of methanol saturated with hydrogen chloride. The reaction solution was stirred at 50 ° C. for 2 hours, the solvent was evaporated under reduced pressure, and white crystals of (2S, 3S) -3-amino-4-
4.6 g of phenylbutane-1,2-diol hydrochloride was obtained.

NMR (DMSO-d ₆ , ppm) δ: 2.81 (dd, 1H, J = 8.1, 14.3H)
z), 2.97 (dd, 1H, J = 5.8, 14.3H)
z), 3.35 to 3.5 (m, 3H), 3.7 to 3.8.
(M, 1H), 4.9 to 5.1 (br, 1H), 5.4
7 (d, 1H, J = 4.0 Hz), 7.2-7.4
(M, 5H), 7.92 (s, 3H) IR (KBr): 3367, 3150, 3030, 29
00 cm ⁻¹ melting point 114 to 116 ° C.

Reference Example 2 (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1,2-diol (2S, 3S) -3-amino-4 -Phenylbutane-
1,2-diol hydrochloride 1.24 g was added to ethanol 20
Dissolve it in ml and stir at room temperature to add triethylamine 0.9.
5 ml was added dropwise, followed by N-succinimidyl-
1.57 g of (S) -tetrahydrofuran-3-yl carbonate was added little by little. After stirring at room temperature for 3 hours, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was recrystallized from ethyl acetate, and (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1,2- Diol 1.
47 g were obtained.

NMR (CDCl ₃ , ppm) δ: 1.9 to 2.0 (m, 1H), 2.1 to 2.2
(M, 1H), 2.85-3.0 (m, 2H), 3.0
5 to 3.15 (m, 2H), 3.4 to 3.5 (m, 1
H), 3.65-4.0 (m, 7H), 4.84 (d,
1H, J = 8.7 Hz), 5.15 to 5.2 (m, 1
H), 7.2-7.4 (m, 5H) IR (KBr): 3340, 1680 cm ^-1 Melting point 149-150 ° C.

Reference Example 3 (2S, 3S) -3-Amino-2-hydroxy-4-phenylbutyric acid methyl hydrochloride (2S, 3S) -3-Amino-2-hydroxy-4-phenylbutyric acid 500 mg methanol 4. 1.5 ml of methanol dissolved in 5 ml and saturated with hydrogen chloride
Was added and the mixture was stirred at 60 ° C. for 3 hours. Then, the reaction solution was concentrated to dryness under reduced pressure to give (2S, 3S) -3-amino-2.
-Hydroxy-4-phenylbutyric acid methyl hydrochloride 442m
g was obtained as a colorless amorphous.

NMR (DMSO-d ₆ , ppm) δ: 2.85-2.9 (m, 2H), 3.27 (s, 3)
H), 3.7 to 3.8 (m, 1H), 4.48 (d, 1)
H, J = 2.6 Hz), 7.2 to 7.35 (m, 5
H), 8.40 (br, 3H) IR (KBr): 3346, 3030, 1743 cm
^-1

Reference Example 4 (2S, 3S) -2-Hydroxy-4-phenyl-3-
Methyl [(S) -tetrahydrofuran-3-yloxycarbonylamino] butyrate (2S, 3S) -3-amino-2-hydroxy-4-phenylbutyric acid methyl chloride 442 mg was added to methylene chloride 20.
14 ml of saturated aqueous sodium hydrogen carbonate solution
1 was added and the mixture was stirred at room temperature. To this suspension, 427 mg of N-succinimidyl- (S) -tetrahydrofuran-3-yl carbonate was added little by little over 10 minutes, and the mixture was stirred at room temperature for 5 hours. Saturated saline was added to the reaction mixture,
After neutralizing with 2N hydrochloric acid, it was extracted with methylene chloride. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from hexane to give white crystals of (2S, 3S) -2-hydroxy-4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]. Methyl butyrate 5
01 mg was obtained.

NMR (CDCl ₃ , ppm) δ: 1.95 to 2.2 (m, 2H), 2.75 to 2.8
5 (m, 2H), 3.21 (d, 1H, J = 5.2H
z), 3.61 (s, 3H), 3.69 (d, 1H, J
= 10.3 Hz), 3.8 to 3.95 (m, 3H),
4.35 to 4.45 (m, 2H), 5.06 (d, 1
H, J = 9.0 Hz), 5.15 to 5.2 (m, 1)
H), 7.15 to 7.35 (m, 5H) IR (KBr): 3325, 1735, 1695 cm.
^-1 melting point 129-130 ° C

Reference Example 5 (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1,2-diol (2S, 3S) -2-hydroxy-4 -Phenyl-3-
618 mg of methyl [(S) -tetrahydrofuran-3-yloxycarbonylamino] butyrate was dissolved in 6 ml of tetrahydrofuran, and 129 mg of lithium borohydride was added little by little thereto with stirring. 12 ml of ethanol was added to the resulting suspension, and the mixture was stirred at room temperature for 2 hours. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was further stirred for 30 minutes, diluted with water and extracted with ethyl acetate. The organic layer was saturated with saline 2
After washing twice and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1: 3) to give (2S, 3S) -4-phenyl-3-.
397 mg of [(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1,2-diol was obtained. The physical property values were in agreement with those of Reference Example 2.

Reference Example 6 (2S, 3S) -2-Hydroxy-4-phenyl-3-
[(S) -Tetrahydrofuran-3-yloxycarbonylamino] butyl methanesulfonate (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1,2-diol 338 mg was dissolved in 7 ml of pyridine, and 98 μl of methanesulfonyl chloride was added dropwise little by little while stirring under ice cooling. After stirring for 6 hours under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (7:10) to give white crystals of (2S, 3S) -2-hydroxy-4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butyl. Methanesulfonate 210
mg was obtained.

NMR (CDCl ₃ , ppm) δ: 1.9 to 2.0 (m, 1H), 2.1 to 2.2
(M, 1H), 2.85 to 2.95 (m, 1H), 2.
99 (dd, 1H, J = 4.8, 14.2 Hz), 3.
08 (s, 3H), 3.2 to 3.45 (m, 1H),
3.68 (d, 1H, J = 10.7 Hz), 3.75-
4.05 (m, 5H), 4.24 (dd, 1H, J =
6.4, 10.8 Hz), 4.33 (dd, 1H, J =
3.3, 10.8 Hz), 4.83 (d, 1H, J =
7.2 Hz), 5.15 to 5.2 (m, 1H), 7.2 to 7.35 (m, 5H) IR (KBr): 3340, 1695, 1355 cm.
^-1 melting point 131-132 ° C

Reference Example 7 (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
1,2-epoxybutane (2S, 3S) -2-hydroxy-4-phenyl-3-
100 mg of [(S) -tetrahydrofuran-3-yloxycarbonylamino] butyl methanesulfonate was dissolved in 1.6 ml of tetrahydrofuran, and 176 μl of 5N sodium hydroxide aqueous solution was added dropwise while stirring under ice cooling. Then, the mixture was vigorously stirred for 3 hours under ice cooling, the reaction mixture was poured into water, and the mixture was extracted with methylene chloride. The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent ethyl acetate: methylene chloride = 1: 4), and white crystals of (2S, 3S)-
4-phenyl-3-[(S) -tetrahydrofuran-3
66 mg of -yloxycarbonylamino] -1,2-epoxybutane was obtained.

NMR (CDCl ₃ , ppm) δ: 1.9 to 2.0 (m, 1H), 2.05 to 2.2
(M, 1H), 2.7 to 3.05 (m, 5H), 3.7
~ 3.9 (m, 5H), 4.55 to 4.75 (m, 1
H), 5.15 to 5.25 (m, 1H), 7.2 to 7.
35 (m, 5H) IR (KBr): 3340,1695 cm < ^-1 > Melting point 104-105 [deg.] C.

Reference Example 8 (2S, 3S) -2-Hydroxy-4-phenyl-3-
[(S) -Tetrahydrofuran-3-yloxycarbonylamino] butyl 4-methoxybenzenesulfonate (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino] butane-1, 1.30 g of 2-diol was dissolved in 15 ml of pyridine, and 1.01 g of 4-methoxybenzenesulfonyl chloride was added with stirring at 0 ° C. After stirring at 0 ° C for 3 hours,
Ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 20% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to give (2S, 3S) -2-hydroxy-4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]. 1.70 g of butyl 4-methoxybenzenesulfonate was obtained.

NMR (CDCl ₃ , ppm) δ: 1.9 to 2.0 (m, 1H), 2.05 to 2.2
(M, 1H), 2.85 to 2.95 (m, 2H), 3.
10 (br, 1H), 3.65 (d, 1H, J = 100)
Hz), 3.75 to 3.95 (m, 5H), 3.89
(S, 3H), 3.95 to 4.05 (m, 1H), 4.
05 to 4.15 (m, 1H), 4.75 (d, 1H, J
= 7.6 Hz), 5.1 to 5.2 (m, 1H), 702
(D, 2H, J = 8.8 Hz), 7.15 (d, 2H,
J = 7.1 Hz), 7.2 to 7.35 (m, 3H),
7.83 (d, 2H, J = 8.8Hz) IR (KBr): 3330, 1680, 1360, 12
60,1160 cm ⁻¹ Melting point 107-109 ° C.

Reference Example 9 (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
1,2-epoxybutane (2S, 3S) -2-hydroxy-4-phenyl-3-
[(S) -Tetrahydrofuran-3-yloxycarbonylamino] butyl 4-methoxybenzenesulfonate (100 mg) was dissolved in tetrahydrofuran (3 ml), and 5N aqueous sodium hydroxide solution (1 ml) was added with stirring at room temperature. After stirring for 3 hours, ethyl acetate was added to the reaction mixture,
The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino].
59 mg of -1,2-epoxybutane was obtained. The physical property values were in agreement with those of Reference Example 7.

Example 1 N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl Ester (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
70 mg of 1,2-epoxybutane was dissolved in 1 ml of anhydrous tetrahydrofuran, and 57 mg of 4-amino-N-isobutylbenzenesulfonamide and triethylamine 105 were dissolved.
μl was added, and the mixture was heated under reflux with stirring. After 20 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 1), and N-[(1S, 2
R) -3- (4-Amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester 33 mg was obtained.

NMR (CDCl ₃ , ppm) δ: 0.87 (d, 3H, J = 6.6 Hz), 0.92
(D, 3H, J = 6.4 Hz), 1.75 to 2.0
(M, 2H), 2.0 to 2.15 (m, 1H), 2.7
6 (dd, 1H, J = 6.8, 12.2Hz), 2.8
~ 3.05 (m, 4H), 3.14 (dd, 1H, J =
7.3, 15.4 Hz), 3.61 (d, 1H, J = 1
0.3 Hz), 3.7 to 3.9 (m, 6H), 4.15
(S, 2H), 4.8 to 4.95 (m, 1H), 5.0
1 to 5.15 (m, 1H), 6.68 (d, 2H, J =
8.3 Hz), 7.2 to 7.35 (m, 5H), 7.5
4 (d, 2H, J = 8.3 Hz) IR (KBr): 3506, 3397, 1719, 13
07,1142 cm ⁻¹ melting point 130-132 ° C.

Example 2 N-[(1S, 2R) -3- (4-acetamido-N-
Isobutylbenzenesulfonamide) -1-benzyl-
2-Hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
70 mg of 1,2-epoxybutane was dissolved in 1 ml of anhydrous tetrahydrofuran, 69 mg of 4-acetamido-N-isobutylbenzenesulfonamide and 9 mg of 4-acetamido-N-isobutylbenzenesulfonamide disodium salt were added, and the mixture was heated under reflux with stirring. After 13 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent).
Purified with ethyl acetate: hexane = 1: 1), N-[(1
S, 2R) -3- (4-Acetamido-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-
22 mg of 3-furyl ester was obtained as white crystals.

NMR (CDCl ₃ , ppm) δ: 0.87 (d, 3H, J = 6.6 Hz), 0.91
(D, 3H, J = 6.6 Hz), 1.75 to 1.85
(M, 1H), 1.85 to 1.95 (m, 1H), 2.
05-2.2 (m, 1H), 2.23 (s, 3H),
2.80 (dd, 1H, J = 6.5, 13.2Hz),
2.85 to 3.05 (m, 4H), 3.13 (dd, 1
H, J = 8.3, 15.0 Hz), 3.62 (d, 1)
H, J = 10.2 Hz), 3.7 to 3.9 (m, 6)
H), 4.87 (d, 1H, J = 8.6 Hz), 5.1
-5.2 (m, 1H), 7.2-7.35 (m, 5
H), 7.46 (br, 1H), 7.67 (d, 2H,
J = 8.8 Hz), 7.72 (d, 2H, J = 8.8H)
z) IR (KBr): 3340, 3320, 1690, 11
54 cm ⁻¹ melting point 116 to 118 ° C.

Reference Example 10 N-[(1S, 2R) -3- (4, amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl Ester N-[(1S, 2R) -3- (4-acetamido-N-
Isobutylbenzenesulfonamide) -1-benzyl-
266 mg of 2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester was dissolved in 3 ml of ethanol and 0.2 ml of concentrated hydrochloric acid, and the mixture was stirred at 80 ° C. for 4 hours. After returning to room temperature, the reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was recrystallized from ethyl acetate-hexane, and N-[(1S, 2R) -3-
(4-Amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester 1
49 mg was obtained as white crystals. The physical properties were in agreement with those of Example 1.

Example 3 N-[(1S, 2R) -1-benzyl-2-hydroxy-3- (4-phthalimido-N-isobutylbenzenesulfonamido) propyl] carbamic acid (3S) -tetrahydro-3-furyl Ester (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
70 mg of 1,2-epoxybutane was dissolved in 1 ml of anhydrous tetrahydrofuran, 95 mg of 4-phthalimido-N-isobutylbenzenesulfonamide sodium salt was added, and the mixture was heated under reflux with stirring. After 18 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 1) and N-[(1S, 2R) -1-benzyl-2-hydroxy-3-). (4-phthalimide-N
37 mg of (isobutylbenzenesulfonamide) propyl] carbamic acid (3S) -tetrahydro-3-furyl ester were obtained as white crystals.

NMR (CDCl ₃ , ppm) δ: 0.9 (d, 3H, J = 6.6 Hz), 0.94
(D, 3H, J = 6.6 Hz), 1.8-1.95
(M, 1H), 1.9 to 2, 0 (m, 1H), 2.05
-2.1 (m, 1H), 2.87 (dd, 1H, J =
6.7, 13.4 Hz), 2.85 to 2.95 (m, 1
H), 2.95 to 3.1 (m, 3H), 3.19 (d
d, 1H, J = 8.5, 15.1 Hz), 3.63
(D, 1H, J = 10.6 Hz), 3.7 to 3.95
(M, 6H), 4.94 (d, 1H, J = 8.4H
z), 5.14 (br, 1H), 7.2 to 7.35.
(M, 5H), 7.71 (d, 2H, J = 8.7H
z), 7.8 to 7.9 (m, 2H), 7.90 (d, 2)
H, J = 8.7 Hz), 7.95 to 8.05 (m, 2
H) IR (KBr): 3340, 2970, 1730, 17
00,1160 cm ⁻¹ melting point 72 to 74 ° C.

Reference Example 11 N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl Ester N-[(1S, 2R) -1-benzyl-2-hydroxy-3- (4-phthalimido-N-isobutylbenzenesulfonamide) propyl] carbamic acid (3S) -tetrahydro-3-furyl ester 76 mg in methanol 3
Dissolve in ml, add 18 mg of hydrazine monohydrate,
Stir at room temperature. After 2 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 1).
1), N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3
52 mg of S) -tetrahydro-3-furyl ester were obtained. The physical properties were in agreement with those of Example 1.

Example 4 N-[(1S, 2R) -1-Benzyl-3- (4-benzyloxycarbonylamino-N-isobutylbenzenesulfonamide) -2-hydroxypropyl] carbamic acid (3S) -tetrahydro- 3-furyl ester (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
70 mg of 1,2-epoxybutane was dissolved in 1 ml of anhydrous tetrahydrofuran, 106 μl of triethylamine and 92 mg of 4-benzyloxycarbonylamino-N-isobutylbenzenesulfonamide were added, and the mixture was heated under reflux with stirring. After 25 hours, add ethyl acetate to the reaction mixture,
The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 2).
Purified with N-[(1S, 2R) -1-benzyl-3-
24 mg of (4-benzyloxycarbonylamino-N-isobutylbenzenesulfonamide) -2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester was obtained as white crystals.

NMR (CDCl ₃ , ppm) δ: 0.88 (d, 3H, J = 6.6 Hz), 0.90
(D, 3H, J = 6.6 Hz), 1.75 to 1.85
(M, 1H), 1.85 to 2.0 (m, 1H), 2.0
~ 2.15 (m, 1H), 2.80 (dd, 1H, J =
6.8, 13.5 Hz), 2.85 to 3.05 (m, 4
H), 3.12 (dd, 1H, J = 8.2, 15.3H)
z), 3.62 (d, 1H, J = 10.6 Hz), 3.
70 (br, 1H), 3.75 to 3.9 (m, 5H),
4.84 (d, 1H, J = 7.9 Hz), 5.12 (b
r, 1H), 5.23 (s, 2H), 6.92 (s, 1
H), 7.15 to 7.35 (m, 5H), 7.35
7.45 (m, 5H), 7.54 (d, 2H, J = 8.
8 Hz), 7.70 (d, 2H, J = 8.8 Hz) IR (KBr): 3350, 2970, 1720 cm
^-1 melting point 149-151 ° C

Reference Example 12 N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl Ester N-[(1S, 2R) -1-benzyl-3- (4-benzyloxycarbonylamino-N-isobutylbenzenesulfonamide) -2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester 70
mg was dissolved in 5 ml of methanol, 10 mg of 10% palladium carbon powder was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 2 hours, the catalyst was filtered off, the solvent was distilled off under reduced pressure,
55 mg of N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester were obtained. The physical properties were in agreement with those of Example 1.

Example 5 N-[(1S, 2R) -1-Benzyl-2-hydroxy-3- (4-nitro-N-isobutylbenzenesulfonamido) propyl] carbamic acid (3S) -tetrahydro-3-furyl Ester (2S, 3S) -4-phenyl-3-[(S) -tetrahydrofuran-3-yloxycarbonylamino]-
70 mg of 1,2-epoxybutane was dissolved in 1 ml of anhydrous tetrahydrofuran, 0.1 ml of triethylamine and 187 mg of 4-nitro-N-isobutylbenzenesulfonamide were added, and the mixture was heated under reflux with stirring. 15 hours later,
Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 1) and recrystallized from ethyl acetate-hexane to give N-[(1S, 2R) -1. -Benzyl-2-hydroxy-3- (4-nitro-N-isobutylbenzenesulfonamide) propyl] carbamic acid (3S) -tetrahydro-3-furyl ester 79 mg
I got

NMR (CDCl ₃ , ppm) δ: 0.87 (d, 3H, J = 6.5 Hz), 0.8
9 (d, 3H, J = 6.5 Hz), 1.8 to 2.0
(M, 2H), 2.05 to 2.2 (m, 1H), 2.7
5 to 3.1 (m, 4H), 3.1 to 3.25 (m, 2
H), 3.60 (br, 1H), 3.66 (d, 1H,
J = 10.6 Hz), 3.7 to 4.0 (m, 5H),
4.85 (d, 1H, J = 7.1 Hz), 5.30 (b
r, 1H), 7.15 to 7.45 (m, 5H), 7.9.
5 (d, 2H, J = 8.7 Hz), 8.35 (d, 2)
H, J = 8.7 Hz) IR (KBr): 3550, 33
30, 2950, 1680, 1530, 1340, 11
60 cm ⁻¹ melting point 158-159 ° C.

Reference Example 13 N-[(1S, 2R) -3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2-hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl Ester N-[(1S, 2R) -1-benzyl-2-hydroxy-3- (4-nitro-N-isobutylbenzenesulfonamido) propyl] carbamic acid (3S) -tetrahydro-3-furyl ester 140 mg and methanol 5 ml
And dissolved in a mixed solvent of 1 ml of methylene chloride, 15 mg of 10% palladium-carbon powder was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 21 hours, the catalyst was filtered off, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 2: 1), and N-[(1S, 2R)- 3- (4-amino-N-isobutylbenzenesulfonamide) -1-benzyl-2
96 mg of -hydroxypropyl] carbamic acid (3S) -tetrahydro-3-furyl ester were obtained. The physical properties were in agreement with those of Example 1.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hideki Takeuchi 1-2-34 Nozomi Woodwork, Matsumoto City, Nagano Prefecture

Claims (1)

[Claims] (1) Formula (1) In the epoxy derivative represented by (the arrangement of carbon atoms with (S) in the formula shows the S arrangement) in the presence of a basic substance,
General formula (Wherein A is a nitro group, an amino group or an amino group having a protecting group) is reacted with an N-isobutylbenzenesulfonamide derivative represented by the general formula: (A in the formula is a nitro group, an amino group or an amino group having a protecting group, the carbon atom with (R) has the R configuration, and the carbon atom with (S) has the S configuration. The method for producing a carbamic acid tetrahydrofuryl ester derivative represented by