JP2001089449A - Production of 4,7-dioxo-5-azaspiro[2,4]heptane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an intermediate for an anti-bacterial medicine. SOLUTION: This method for producing a compound expressed by a general formula (III) (R1 is a blocking group for amino group) is provided by halogenating a compound expressed by a general formula (I) to obtain a compound expressed by a general formula (II) (X1 is a halogen atom) and then ring-opening it.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an antibacterial compound and an intermediate for producing the compound.

[0002]

2. Description of the Prior Art 7- (7-Amino-5-azaspiro [2,4] heptane-5-yl) -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acids (see JP-A-2-231475) are known as compounds having high antibacterial activity. As an intermediate for producing this antibacterial agent, a compound represented by the general formula (III)

[0003]

Embedded image (Wherein, R ¹ represents a protecting group for an amino group) (hereinafter, referred to as compound (III).
Compounds represented by other general formulas are similarly represented. ) Is useful. The following method has been known as a method for producing compound (III) (see JP-A-5-221947).

[0004]

Embedded image (In the formula, Bn means a benzyl group.) In this production method, after the carbonyl group is protected, a step of protection / deprotection is required to perform a halogenation reaction.
There are many steps and there is room for improvement as an industrial production method.

Japanese Patent Application Laid-Open No. 5-286933 discloses that 1-acetyl-1-benzylaminocarbonylcyclobutane is brominated (treated with bromine in 1,4-dioxane) to give 1-benzylaminocarbonyl-1-butane. After obtaining bromomethylcarbonylcyclobutane, the ring is closed to give 6-benzyl-5,8-dioxo-6-azaspiro [3,4].
A process for obtaining octane is described. However, when brominating 1-acetyl-1-benzylaminocarbonylcyclopropane by the method described in this publication, the compound was decomposed and the desired product could not be obtained.

[0006]

DISCLOSURE OF THE INVENTION The present invention is a useful method as an industrial production method for producing an important compound as an intermediate of an antibacterial drug in a shorter step than conventional methods.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a compound of the general formula (I)

[0008]

Embedded image (Wherein, R ¹ represents a protecting group for an amino group), and the compound represented by the general formula (II) is halogenated.

[0009]

Embedded image (Wherein X ¹ represents a halogen atom, R ¹ represents a protecting group for an amino group), and then ring-closing, wherein the compound is represented by the general formula (III):

[0010]

Embedded image (Wherein, R ¹ represents a protecting group for an amino group).

Further, the present invention relates to a method for producing a compound represented by the general formula (II), comprising halogenating the compound represented by the general formula (I). Furthermore, the general formula (I
The present invention relates to a method for producing a compound represented by the general formula (III), wherein the compound represented by I) is closed.
Alternatively, the general formula (IV)

[0012]

Embedded image Wherein X ² represents a halogen atom and R ¹ represents a protecting group for an amino group. The compound represented by the general formula (II-1):

[0013]

Embedded image (Wherein, X ² represents a halogen atom, and R ¹ represents an amino-protecting group).

Further, the present invention relates to a compound represented by the general formula (II-1). Further, the present invention relates to the above production method, wherein the halogenation is performed in an alcohol. Further, the present invention relates to the above-mentioned production method, wherein the deprotection is performed with perchloric acid.

The definition of the substituent used in the general formula of the present invention will be described below. R ¹ means an amino-protecting group, but the amino-protecting group is not particularly limited as long as it is a group usually used in this field. Examples of the amino-protecting group include a benzyl group and a phenylethyl group (each of which may have a substituent on the benzene ring, for example, a lower alkoxyl group such as a p-methoxy group, a p-nitro group, etc.). And an optionally substituted aralkyl group, trityl group, benzhydryl group, lower alkyl group and the like. R ¹ is preferably an aralkyl group which may have a substituent, particularly preferably a benzyl group. The halogen atom of X ^1, a bromine atom. As the halogen atom for X ² , a chlorine atom or a bromine atom is preferable. Next, each step of the manufacturing method according to the present invention will be described in detail.

Step of converting compound (I) to compound (II) In this step, compound (II) can be obtained by halogenating compound (I). The halogenation can be carried out by treating compound (I) with a halogenating reagent in a solvent, particularly in an alcohol. As a solvent that can be used, any solvent can be used as long as it is inert to the reaction, but alcohols such as methanol, ethanol, propanol, isopropanol, and t-butanol are preferable. Further, two or more alcohols may be used in combination. As the alcohol, methanol and ethanol are preferable. As the halogenating reagent,
Chlorine, bromine, pyridinium tribromide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) and the like can be mentioned, with bromine being particularly preferred. The halogenating reagent may be used in a range of 1 equivalent to a large excess with respect to compound (I), and preferably 1 equivalent to 2 equivalents. The reaction temperature is usually −78 ° C.
To the boiling point of the solvent, preferably from 0 ° C to 30 ° C. The reaction time depends on the reaction temperature, but is usually in the range of 30 minutes to 24 hours, preferably 1 hour to 5 hours.
Time range.

Conversion of compound (II) to compound (III)
Step Compound (II) is closed to give compound (II)
I) can be obtained. The ring closure may be carried out by treating compound (II) with a base in a solvent. As a solvent that can be used, any solvent can be used as long as it is inert to the reaction. For example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dimethoxyethane, and 1,4-dioxane; chloroform, methylene chloride ,
Examples include halogenated hydrocarbon solvents such as ethylene chloride; amide solvents such as dimethylformamide (DMF) and dimethylacetamide (DMAC); and nitrile solvents such as acetonitrile and propionitrile. Further, a mixed solvent obtained by combining two or more of the above solvents may be used. As the solvent, ether solvents and amide solvents are preferable, and particularly, tetrahydrofuran (TH
F), dimethylformamide (DMF) is preferred.

As the base, either an inorganic base or an organic base can be used. Examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydride, sodium hydride, potassium hydride, and the like. Can be. As the organic base, diisopropylethylamine, 1,8
Amines such as -diazabicyclo [5.4.0] -7-undecene; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium ethoxide; n-butyllithium, methyllithium, t-butyl Alkyl lithiums such as lithium and sec-butyllithium; and lithium diisopropylamide (LDA). The base used in this step is preferably an alkoxide-based or alkyllithium-based organic or inorganic base, and particularly preferably sodium hydride. The base may be used in the range of 1 equivalent to a large excess with respect to compound (II), and preferably 1 equivalent to 2 equivalents. The reaction temperature is usually in the range of -78 ° C to the boiling point of the solvent, preferably -20 ° C.
In the range of 30 ° C to 30 ° C. The reaction time depends on the reaction temperature, but is usually in the range of 5 minutes to 24 hours, preferably in the range of 5 minutes to 2 hours. Compound (II), which is an intermediate in the method for producing compound (III) of the present invention, is a novel compound, and compound (II) can also be produced from compound (IV).

From compound (IV) to compound (II-1)
The compound (II) is deprotected to give the compound (II)
-1) can be obtained. Deprotection is carried out using compound (IV)
May be treated with an acid in a solvent. As a solvent that can be used, any solvent can be used as long as it is inert to the reaction. For example, alcohol solvents such as methanol, ethanol, propanol, isopropanol, and t-butanol; diethyl ether (abbreviated simply as ether); tetrahydrofuran (THF), dimethoxyethane, 1,4-
Ether solvents such as dioxane; halogenated hydrocarbon solvents such as chloroform, methylene chloride and ethylene chloride; amide solvents such as dimethylformamide (DMF) and dimethylacetamide (DMAC); nitrile solvents such as acetonitrile and propionitrile Ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; and water. Further, a mixed solvent obtained by combining two or more of the above solvents may be used.
As the solvent, a halogenated hydrocarbon solvent is preferable,
Particularly, chloroform and methylene chloride are preferred.

As the acid, either an inorganic acid or an organic acid can be used. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, and perchloric acid. Examples of the organic acid include acetic acid, trifluoroacetic acid, tosylic acid, tosylic acid monohydrate, pyridinium p-toluenesulfonate, and trifluoromethane. Sulfonic acid, camphormethanesulfonic acid and the like can be mentioned, but perchloric acid is particularly preferred. The acid may be used in the range of 1 equivalent to a large excess with respect to compound (II-1), and preferably 1 equivalent to 10 equivalents. The reaction temperature is generally in the range of 0 ° C to the boiling point of the solvent, preferably in the range of 0 ° C to 30 ° C. The reaction time depends on the reaction temperature, but is usually in the range of 1 hour to 24 hours, preferably in the range of 1 hour to 5 hours. The obtained compound (II-1) was isolated without isolation.
Compound (III) can be obtained by performing the same reaction as in the step of converting to (III). Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

[0021]

Example 1 1-benzylaminocarbonyl-1-bromoacetyl
Clopropane 1-acetyl-1-benzylaminocarbonylcyclopropane (5.00 g) was dissolved in ethanol (25 mL), and bromine (1.42 mL) was added to the solution while stirring at 0 ° C.
Minutes. Then, the mixture was brought to room temperature and stirred for 3 hours. After the reaction, water (25 mL) was added, and the mixture was stirred for 30 minutes. After evaporating the solvent under reduced pressure and adding ethyl acetate (25 mL), insoluble materials were removed by suction filtration. Ethyl acetate (25
After adding (mL), a liquid separation operation was performed to separate an organic layer and an aqueous layer. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (2
5mL), water (15mL) and saturated saline (10mL)
Was sequentially washed. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3.63 g of a residue. After the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 3: 1) and ¹ H-NMR was measured, the following peaks were observed for the title compound. ¹ H-NMR (CDCl ₃ ) d: 1.60 (m,
2H), 1.94 (m, 2H), 3.79
(S, 2H), 4.49 (d, J = 5.6
Hz, 2H), 7.24-7.39 (m, 5
H), 8.55 (br s, 1H).

Example 2 5-benzyl 4,7-dioxo-5-azaspiro [2.
4] Sodium heptane (20 mg) was suspended in dimethylformamide (1.5 mL), and 1-benzylaminocarbonyl-1-bromoacetylcyclopropane (200 mg) in tetrahydrofuran was stirred at 0 ° C. (1.5 mL) solution was added. After stirring for 15 minutes,
Water (2.0 mL) was added to the reaction solution. Ethyl acetate (3m
After extraction with L), the aqueous layer was extracted again with ethyl acetate (1.5 mL). All organic layers were washed with saturated saline (1.5m
After washing with L), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 107 mg of a residue. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1), and ¹ H-NMR was measured. As a result, the following peaks were observed for the title compound. ¹ H-NMR (CDCl ₃ ) d: 1.62 (m, 2H), 1.75 (m, 2H), 3.80
(s, 2H), 4.68 (s, 2H), 7.25-7.41 (m, 5H).

Example 3 1-benzylaminocarbonyl-1-chloroacetyl
Clopropane 1-benzylaminocarbonyl-1- (2-chloro-
1,1-Ethylenedioxyethyl) cyclopropane (3.00 g) was dissolved in methylene chloride (30 mL), and a 70% aqueous solution of perchloric acid (4.37 mL) was added while stirring at 0 ° C. Was. After stirring for 30 minutes, the mixture was brought to room temperature and further stirred for 2.5 hours. After the reaction, water (5.63 mL) and methylene chloride (20 m
L) was added. After performing a liquid separation operation to separate an organic layer and an aqueous layer, the aqueous layer was re-extracted twice with methylene chloride (first time: 20 mL, second time: 10 mL). All organic layers were washed twice with water (first time: 20 mL, second time: 10 mL), and then washed with saturated saline (15 mL). After drying over sodium sulfate, the solvent was distilled off under reduced pressure.
Obtained. When ¹ H-NMR of the obtained residue was measured,
The following peaks were observed for the title compound. _{^{1 H-NMR (CDCl 3)}} d: 1.56 (m,
2H), 1.90 (m, 2H), 4.03
(S, 2H), 4.49 (d, J = 5.9
Hz, 2H), 7.23-7.41 (m, 5
H), 8.48 (brs, 1H).

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C204 AB02 BB04 CB10 DB30 EB03 FB08 GB01 4H006 AA02 AC30 AC45 BB14 BD70 BE53 BJ20 BM10 BR20 BV62

Claims (7)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ represents a protecting group for an amino group), and the compound represented by the general formula (II) is halogenated. (Wherein, X ¹ represents a halogen atom, and R ¹ represents a protecting group for an amino group).
General formula (III) characterized by ring closure (Wherein, R ¹ represents a protecting group for an amino group.) 2. A compound of the general formula (I) (Wherein R ¹ represents a protecting group for an amino group), characterized in that the compound represented by the general formula (II) is halogenated. (Wherein, X ¹ represents a halogen atom, and R ¹ represents a protecting group for an amino group.) 3. A compound of the general formula (II) Wherein X ¹ represents a halogen atom, and R ¹ represents a protecting group for an amino group. A compound represented by the general formula (III): (Wherein, R ¹ represents a protecting group for an amino group.) 4. Formula (IV) (Wherein, X ² represents a halogen atom, and R ¹ represents a protecting group for an amino group). A compound represented by the general formula (II-1): Formula 8 (Wherein, X ² represents a halogen atom, and R ¹ represents a protecting group for an amino group). 5. A compound of the general formula (II-1) (Wherein, X ² represents a halogen atom, and R ¹ represents a protecting group for an amino group.) 6. The process according to claim 1, wherein the halogenation is carried out in an alcohol. 7. The method according to claim 6, wherein the deprotection is carried out with perchloric acid.