JPH09136885A - Thiyran derivatives and methods for producing them - Google Patents

Abstract

(57) [Summary] (Modified) SOLUTION: A 2-aminomethylthiirane derivative represented by the general formula (I) and the formula (1) or (2)
A method for producing a compound of general formula (I), which comprises hydrolyzing the compound of claim 1 in water or a mixed solvent of water and an organic solvent by further adding an acid such as hydrochloric acid. [In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic heterocyclic group. And X represents a halogen atom. [Effect] The 2-aminomethylthiirane derivative is a novel compound, and these compounds themselves are useful as intermediates for pharmaceutical production. Moreover, the 2-aminomethylthiirane derivative can be efficiently obtained by a simple method by the production method.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a 2-aminomethylthiirane derivative useful as an intermediate for the production of pharmaceuticals and a method for producing the same.

[0002]

2. Description of the Related Art Nitrogen-containing heterocyclic compounds, particularly 2-aminomethylthiirane derivatives, are known to have physiological activity. For example, Japanese Patent Application Laid-Open No. 4-257975 describes a 2-aminomethylthiirane derivative having anti-HIV activity.

In addition, Izv. Akad. Nauk SS
SR, Ser. Khim. 2 in 733 (1986)
-Amino-5-bromo-5,6-dihydro-4H-1,
3-thiazine, 2-amino-5-bromomethyl-4,5
It is described that 2- (cyanoaminomethyl) thiirane can be obtained by reacting -dihydro-1,3-thiazole under basic conditions with sodium hydroxide, sodium methoxide and the like.

General formula

[0005]

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(In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic hetero group. Represents a ring group, and X represents a halogen atom.)
The 4H-5,6-dihydro-1,3-thiazine derivative (Compound 1) represented by

[0007]

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(Wherein R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic hetero group. It can be produced by reacting a thioimidic acid allyl ester represented by a ring group) with a halogenating reagent in a suitable solvent (Japanese Patent Application No. 7-22).
2968).

In addition, the general formula

[0010]

[Chemical 6]

(In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic hetero group. Represents a ring group, and X represents a halogen atom.)
The trans-4,5-dihydro-1,3-thiazole derivative (Compound 2) represented by

[0012]

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(Wherein R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic hetero group. Represents a ring group, and X represents a halogen atom.)
Trans-4H-5,6-dihydro-1,3 represented by
-The thiazine derivative can be produced by an intramolecular thermal rearrangement reaction (described in Japanese Patent Application No. 7-296375).

[0014]

DISCLOSURE OF THE INVENTION The inventors of the present invention conducted extensive research into a method for producing a nitrogen-containing heterocyclic compound,
A 4-aminomethylthiirane derivative is selectively produced by hydrolyzing a 4H-5,6-dihydro-1,3-thiazine derivative and a 4,5-dihydro-1,3-thiazole derivative with an acid such as hydrochloric acid. As a result, they have completed the present invention.

[0015]

According to the present invention, there are provided a 2-aminomethylthiirane derivative useful as an intermediate for producing pharmaceuticals, and a method for producing the same.

The general formula of the compound of the present invention

[0017]

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(In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic hetero group. 2-aminomethylthiirane derivative represented by a ring group) is produced by hydrolyzing Compound 1 or Compound 2 in water or a mixed solvent of water and an organic solvent with addition of an acid such as hydrochloric acid. You can

Any organic solvent may be used as long as it is miscible with water, and examples thereof include tetrahydrofuran, dioxane, ethanol, methanol and dimethyl sulfoxide. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid and the like. The amount of acid is 0.1 equivalent to 1 equivalent based on the reaction substrate. The reaction temperature is −10 to 150 ° C., and the reaction time is 5 minutes to 5 days. After the reaction,
The target compound can be obtained by usual treatment.

In this specification, the alkyl group is a linear or branched saturated hydrocarbon having 1 to 5 carbon atoms such as methyl group, ethyl group or propyl group. The aryl group is a phenyl group, a 1-naphthyl group or a 2-naphthyl group.
When it has a substituent, suitable substituents include a lower alkyl group such as methyl, ethyl, propyl and isopropyl, a hydroxy group, a lower alkoxy group such as methoxy, ethoxy, propoxy and isopropoxy, and a halogen such as fluorine, chlorine and bromine. Examples include an atom, an amino group, a lower alkylamino group such as methylamino and dimethylamino, an alkylcarbamoyl group, a carbamoyl group, a lower alkoxycarbonyl group such as methoxycarbonyl, a nitro group, an acylamino group such as acetylamino and propionylamino, and the like. Aromatic heterocyclic groups are thiophene, oxazole, thiazole, furan, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline,
A monovalent group composed of isoquinoline and the like can be mentioned. A halogen atom is chlorine, bromine or iodine.

[0021]

INDUSTRIAL APPLICABILITY The 2-aminomethylthiirane derivative of the present invention is a novel compound, and these compounds themselves are useful as an intermediate for the production of pharmaceuticals.

Further, the production method allows a 2-aminomethylthiirane derivative to be efficiently obtained by a simple method.

[0023]

The present invention will be described in more detail with reference to the following examples.

Example 1 (2R ^* , 1'S ^* )-2- (1-benzoylamino-1)
Synthesis of -phenyl) methylthiirane

[0025]

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Trans-5-bromo-2,4-diphenyl-4H-5,6-dihydro-1,3-thiazine 97.
0 mg (0.288 mmol) of THF 6 ml and water 2 m
It was dissolved in 1 and 1 equivalent of hydrochloric acid was added. The mixture was heated to reflux for 15.0 hours. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, the residue was eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 by silica gel column chromatography. After concentrating the eluate (2R ^* , 1 '
S ^* )-2- (1-benzoylamino-1-phenyl)
Methyl thiirane as colorless crystals, 44.0 mg (0.1
63 mmol) was obtained (yield 57%).

¹ H-NMR (CDCl ₃ , 270 MHz) 2.35 (1 H, d, J = 6.5, 1.8), 2.54
(1H, d, J = 6.1, 1.8), 3.40 to 3.5.
0 (1H, m), 5.79 (1H, dd, J = 7.9,
2.4), 6.71 (1H, brd, J = 8.5) 7.
20 to 7.55 (8H, m), 7.70 to 7.80 (2
H, m).

Example 2 (2R ^* , 1'S ^* )-2- (1-benzoylamino-1)
Synthesis of -phenyl) methylthiirane

[0029]

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Trans-5-bromo-2,4-diphenyl-4H-5,6-dihydro-1,3-thiazine 637
mg (1.92 mmol) 10 ml THF and 20 m water
It was dissolved in 1 and 1 equivalent of hydrobromic acid was added. The mixture was heated under reflux for 1.5 hours. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, silica gel column chromatography showed that hexane: ethyl acetate = 5:
It was eluted with the mixed solvent of 1. After concentrating the eluate (2R ^* ,
302 mg (1.S ^* )-2- (1-benzoylamino-1-phenyl) methylthiirane as colorless crystals (1.
12 mmol) was obtained (yield 58%).

1H-NMR was consistent with that shown in Example 1.

Example 3 (2R ^* , 1'S ^* )-2- (1-benzoylamino-1)
Synthesis of -phenyl) methylthiirane

[0033]

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Trans-5-bromomethyl-2,4-diphenyl-4,5-dihydro-1,3-thiazole 10
8 mg (0.321 mmol) of THF 6 ml and water 2 m
It was dissolved in 1 and 1 equivalent of hydrochloric acid was added. The mixture was heated to reflux for 30.0 hours. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, the residue was eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 by silica gel column chromatography. After concentrating the eluate, (2R ^* ,
57.0 mg of 1'S ^* )-2- (1-benzoylamino-1-phenyl) methylthiirane as colorless crystals.
(0.212 mmol) was obtained (yield 66%).

1H-NMR was consistent with that shown in Example 1.

Example 4 Synthesis of (2R ^* , 1'S ^* )-2- (1-benzoylamino) propylthiirane

[0037]

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Trans-5-bromo-4-ethyl-2-
Phenyl-4H-5,6-dihydro-1,3-thiazine (440 mg, 1.55 mmol) was dissolved in THF (15 ml) and water (15 ml), and 1 equivalent of hydrochloric acid was added. The mixture was heated under reflux for 6.0 hours. After cooling to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, silica gel column chromatography showed that hexane: ethyl acetate = 5:
It was eluted with the mixed solvent of 1. After concentrating the eluate, (2
166 mg (0.750 m) of R ^* , 1 ′S ^* )-2- (1-benzoylamino) propylthiirane as colorless crystals.
mol) was obtained (yield 48%).

¹ H-NMR (CDCl ₃ , 270 MHz) 1.07 (3H, t, J = 7.3), 1.60 to 1.9
1 (2H, m), 2.20 (1H, dd, J = 6.1,
1.8), 2.44 (1H, dd, J = 6.8, 1.
8), 3.20 to 3.28 (1H, m), 4.60 to
4.70 (1H, m), 6.08 (1H, brd, J =
7.9) 7.38 to 7.51 (3H, m), 7.70 to
7.74 (2H, m).

Example 5 Synthesis of (2R ^* , 1'S ^* )-2- (1-benzoylamino) propylthiirane

[0041]

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20.5 g (0.0753 mmol) of trans-5-bromomethyl-4-ethyl-2-phenyl-4,5-dihydro-1,3-thiazole was added to 1 ml of THF.
And dissolved in 1 ml of water, and 1 equivalent of hydrochloric acid was added. 10.0
Heated to reflux. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and distilling off the solvent, silica gel column chromatography showed that hexane: ethyl acetate =
Elution was performed with a mixed solvent of 5: 1. After concentrating the eluate, (2
10.0 mg (0.045) of R ^* , 1 ′S ^* )-2- (1-benzoylamino) propylthiirane as colorless crystals.
2 mmol) was obtained (yield 60%).

1H-NMR was consistent with that shown in Example 4.

Example 6 Synthesis of (2R ^* , 1 ′S ^* )-2- (1-phenyl-1-propionylamino) methylthiirane

[0045]

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Trans-5-bromo-2-ethyl-4-
Phenyl-4H-5,6-dihydro-1,3-thiazine (400 mg, 1.41 mmol) was added to THF (5 ml) and water (1).
It was dissolved in ml and 1 equivalent of hydrochloric acid was added. Heated to reflux for 15 minutes. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, the residue was eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 by silica gel column chromatography. After concentrating the eluate, (2R ^* , 1 '
S ^* )-2- (1-Phenyl-1-propionylamino) methylthiirane as colorless crystals (140 mg, 0.
630 mmol) was obtained (yield 45%). ¹ H-NMR (CDCl ₃ , 270 MHz) 1.14 (3H, t, J = 7.3), 2.22 (2H,
q, J = 7.3), 2.24 (1H, dd, J = 6.
1, 1.8), 2.49 (1H, dd, J = 6.1,
1.8), 3.29 to 3.35 (1H, m), 5.57
(1H, dd, J = 9.2, 3.1), 5.94 (1
H, brd, J = 9.2) 7.28 to 7.45 (5H,
m).

Example 7 Synthesis of (2R ^* , 1 ′S ^* )-2- (1-phenyl-1-propionylamino) methylthiirane

[0048]

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140 mg (0.493 mmol) of trans-5-bromomethyl-2-ethyl-4-phenyl-4,5-dihydro-1,3-thiazole was dissolved in 2 ml of THF and 2 ml of water, and 1 equivalent of hydrochloric acid was added. It was The mixture was heated under reflux for 30 minutes. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and distilling off the solvent, silica gel column chromatography showed that hexane: ethyl acetate = 5: 1.
It was eluted with a mixed solvent of. After concentrating the eluate, (2R ^* ,
95.0 mg of 1 ′S ^* )-2- (1-phenyl-1-propionylamino) methylthiirane as colorless crystals.
(0.429 mmol) was obtained (yield 87%).

¹ H-NMR was consistent with that shown in Example 6.

Example 8 (2R ^* , 1′R ^* )-2- (1-benzoylamino-1)
Synthesis of -phenyl) methylthiirane

[0052]

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Cis-5-Bromo-2,4-diphenyl-
4H-5,6-dihydro-1,3-thiazine 35.0 m
g (0.104 mmol) was dissolved in 1 ml of THF and 1 ml of water, and 1 equivalent of hydrochloric acid was added. The mixture was heated under reflux for 3.0 hours. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and evaporating the solvent, the residue was eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 by silica gel column chromatography. After concentrating the eluate (2R ^* , 1'R ^* )
21.0 mg (0.0780) of 2- (1-benzoylamino-1-phenyl) methylthiirane as colorless crystals
mmol) was obtained (yield 75%).

¹ H-NMR (CDCl ₃ , 270 MHz) 2.50 (1 H, d, J = 5.5, 1.2), 2.57
(1H, d, J = 6.1, 1.2), 3.32 to 3.4.
0 (1H, m), 5.12 (1H, dd, J = 7.9,
7.3), 6.62 (1H, brd, J = 6.7) 7.
25 to 7.54 (8H, m), 7.50 to 7.80 (2
H, m).

Claims (3)

[Claims] 1. A compound of the general formula (In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic heterocyclic group. 2-aminomethylthiirane derivative represented by 2. A compound of the general formula (In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic heterocyclic group. And X represents a halogen atom.) 4
2. The H-5,6-dihydro-1,3-thiazine derivative is hydrolyzed under acidic conditions.
-A method for producing an aminomethylthiirane derivative. 3. A compound of the general formula (In the formula, R ₁ represents an alkyl group or an aryl group which may have a substituent, and R ₂ represents an alkyl group or an aryl group which may have a substituent or an aromatic heterocyclic group. Wherein X represents a halogen atom), and the trans-4,5-dihydro-1,3-thiazole derivative represented by the formula (2) is hydrolyzed under acidic conditions. Method for producing derivative.