JP2000256311A - Production of 3-methylamino-azetidine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a synthetic intermediate compound of various medicines in an industrially applicable simple method by reacting a specific azetidine with a sulfonic halide derivative in the presence of a base. SOLUTION: This compound represented by formula IV is obtained by reacting (A) N-benzyl-3-hydroxyazetidine of formula I (Bzl is benzyl group) with (B) a sulfonic halide derivative (suitably methane sulfonyl chloride) in the presence of a base (e.g. triethylamine) to obtain a compound of formula II (Ra is a sulfonic acid residue), reacting the compound of formula II with N-methylamine to obtain a compound of formula III and removing benzyl group in the compound of formula III. Preferably, the compound of formula II is isolated or directly subjected to the next reaction without isolating.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing 3-methylamino-azetidine, which is important as an intermediate compound for the synthesis of various pharmaceuticals.

[0002]

2. Description of the Related Art Recently, azetidine compounds having a nitrogen atom-containing four-membered ring structure have attracted attention and have been variously used as side chain modifying groups of various pharmaceutical compounds. For example, 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine is used as a side chain substituent at the 2-position of a carbapenem antibiotic having a strong antibacterial activity (for example, Patent No. 2666118
No.), and 3-methylamino-azetidine has been used as a side chain modifying group of a new quinolone synthetic antibacterial agent [for example, Newcurrent, 9 (3), p34 (199).
8)].

In order to industrially produce these azetidine compounds at low cost, the following formula (II):

[0004]

Embedded image

(Wherein Bzl represents a benzyl group) is a basic synthesis intermediate represented by the formula (I), and the present inventors have previously described this N-benzyl-3-hydroxyazetidine. For benzyl-3-hydroxyazetidine, the present invention provides a simple production method that has a short production process, does not require a complicated reaction treatment, and is satisfactory in yield.

[0006]

The present invention has further developed this N-benzyl-3-hydroxyazetidine,
Of 3-methylamino-azetidine used as a side chain modifying group of the above-mentioned new quinolone synthetic antibacterial agent,
It is an object to provide a simple production method which can be applied industrially.

[0007]

In order to solve the above problems, the present invention provides the following production method as a specific embodiment. That is, the following formula (II):

[0008]

Embedded image

(Wherein Bzl represents a benzyl group), and N-benzyl-3-hydroxyazetidine represented by the formula:
Reacting with a sulfonic acid halide derivative in the presence of a base,
The following formula (III):

[0010]

Embedded image

(Wherein ^Ra represents ^a sulfonic acid residue,
Bzl represents a benzyl group. ) Is obtained,
The resulting compound of formula (III) is reacted with N-methylamine to give the following formula (IV):

[0012]

Embedded image

(Wherein Bzl represents a benzyl group), and then removing the benzyl group of the compound of the formula (IV), the following formula (I):

[0014]

Embedded image

A method for producing 3-methylamino-azetidine represented by the formula:

In the present invention, the compound of the formula (IV) obtained in the intermediate by the above-mentioned production method is a novel compound which has not been known so far. Accordingly, the present invention provides, in still another aspect, such an N-benzyl-formula represented by the formula (IV).
It also provides 3-methylaminoazetidine itself.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The process for producing 3-methylamino-azetidine provided by the present invention is based on N-benzyl-3 of formula (II) obtained by a simple synthesis method provided by the present inventors.
-Hydroxyazetidine as a starting material, the reaction is carried out under severe high pressure or high temperature, without using expensive reagents and solvents, etc. This is particularly excellent as an industrial production method capable of producing 3-methylamino-azetidine.

Hereinafter, the method for producing 3-methylamino-azetidine provided by the present invention will be described in more detail.

The process for producing 3-methylamino-azetidine provided by the present invention is basically based on the N-formula represented by the formula (II).
A first step of reacting a sulfonic acid halide derivative with -benzyl-3-hydroxyazetidine to derive a compound represented by the formula (III), and a compound of the formula (III) obtained in the first step. The second step of converting the sulfonic acid residue at the 3-position to a methylamino group and deriving the compound of formula (IV), and removing the benzyl group of the compound of formula (IV), -Methylamino-azetidine.

In this case, the first production step of reacting N-benzyl-3-hydroxyazetidine represented by the formula (II) with a sulfonic acid halide derivative to induce the compound represented by the formula (III) Is specifically implemented as follows. That is, it is carried out by dissolving N-benzyl-3-hydroxyazetidine of the formula (II) in a suitable organic solvent and adding a sulfonic acid halide derivative in the presence of a base.

The organic solvent used in the reaction is not particularly limited as long as it is inert to the reaction. For example, aromatic hydrocarbon solvents such as benzene and toluene are preferably used. The base to be present in the reaction solution may be any as long as it captures an acid by-produced in the reaction between the N-benzyl-3-hydroxyazetidine of the formula (II) and the sulfonic acid halide derivative. Specific examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; and organic bases such as trimethylamine, triethylamine, and pyridine. N-benzyl-3
It is better to use a slightly excessive equivalent to hydroxyazetidine. Among them, using toluene as a solvent,
Use of triethylamine as a base gave good results.

The sulfonic acid halide derivative to be reacted with N-benzyl-3-hydroxyazetidine of the formula (II) includes lower alkylsulfonyl halide and arylsulfonic acid halide. In this case, examples of the lower alkylsulfonyl halide include methanesulfonyl chloride and ethanesulfonyl chloride, and examples of the arylsulfonic acid halide include toluenesulfonic acid chloride and p-toluenesulfonic acid chloride. Can be. Among them, methanesulfonyl chloride is preferably used,
It is preferable to use a slightly excessive equivalent of the compound of the formula (II).

The reaction is carried out under cooling, specifically at a temperature of 15 ° C. or less, preferably about 5 ° C.
In a reaction solvent in which the compound and the base were present, under stirring, a sulfonic acid halide derivative was added by means such as dropping,
After completion of the addition, the reaction is carried out by further stirring until the reaction is completed.

The formula (II) produced by the first step
After completion of the reaction, the compound represented by I) can be converted to a free base, for example, by employing a general processing means commonly used in organic chemistry such as filtration, liquid conversion, concentration, extraction, phase transfer, salt formation, and the like. Alternatively, it can be isolated as a hydrochloride. When methanesulfonyl chloride is used as the sulfonic acid halide derivative, the compound of the formula (III) can be isolated as a hydrochloride by crystal. Further, without isolating the formed compound of the formula (III) from the reaction system, the compound can be directly subjected to the next second step using a reaction solvent which has been appropriately treated.

Formula (III) produced as described above
Is reacted with N-methylamine to give a compound of formula (IV)
In the third step for deriving the compound of the formula (II),
The compound of I) is dissolved in a suitable organic solvent, and N
The reaction is carried out by adding an aqueous solution of -methylamine and appropriately performing stirring or the like until the reaction is completed.

In the second step, the reaction solution containing the compound of the formula (III) obtained in the first step can be used as it is, and an aqueous solution of N-methylamine can be added thereto. And the compound of formula (III) obtained by isolation in the first step. In this case, if the compound of the formula (III) is in the form of a salt, it is possible to carry out the second step with a free base or with the salt as it is.

The amount of N-methylamine used is determined by the formula (I)
It is preferable to use an excess amount based on the compound of II). Therefore, even when a salt of the compound of the formula (III) is reacted, the salt is converted into a free base by N-methylamine and reacted.

After completion of the reaction of the second step, the reaction solution is appropriately filtered, subjected to liquid conversion, concentration, extraction, phase transfer, salt formation, etc., by adding ordinary processing means commonly used in organic chemistry. The desired compound of formula (IV) can be isolated, for example, as a free base or as a hydrochloride.

Next, the benzyl group at the 1-position in the compound of the formula (IV) thus obtained is removed, and the target compound of the present invention, 3-methylamino- represented by the formula (I), is removed.
The third step for deriving azetidine is carried out by a debenzylation reaction commonly used in organic chemistry. Specifically, Raney nickel, palladium oxide, palladium
-It can be preferably carried out by a hydrogenation reaction using a catalyst such as carbon.

Thus, the compound represented by formula (I) of the present invention
-Methylamino-azetidine can be produced in high yield. The 3-methylamino-azetidine represented by the formula (I) of the present invention can be isolated as a free base or as a salt such as a hydrochloride in a crystalline form.

Further, according to the study of the present inventors, the formula (I)
3-methylamino-azetidine represented by the following formula (V) proposed by the present applicant:

[0032]

Embedded image

1-azabicyclo [1.1.
0] butane was reacted with N-methylamine. In this case, the reaction is carried out, for example, by reacting the compound of formula (V) with an excess amount of an aqueous solution of N-methylamine in an inert solvent such as tetrahydrofuran or dioxane at room temperature under stirring and the like. Will be implemented. Also in this reaction, the 3-methylamino-azetidine represented by the formula (I) of the present invention can be isolated in a crystalline state as a free base or as a salt such as hydrochloride.

The thus produced 3-methylamino-azetidine of the formula (I) of the present invention is, for example, 1- (6-amino-3,5) which is one of new quinolone synthetic antibacterial agents.
-Difluoropyridin-2-yl) -8-bromo-6-
Used as the side chain of fluoro-7- (3-methylaminoazetidin-1-yl) -1,4-dihydroquinoline-3-carboxylic acid.

[0035]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which, however, are not intended to limit the scope of the present invention. This modification is also included in the scope of the present invention.

Embodiment 1

[0037]

Embedded image

A solution of 163.2 g (1 mol) of N-benzyl-3-hydroxyazetidine in 1.6 L of toluene was added to
While cooling to 5 ° C., 106 g (1.05 equivalent) of triethylamine was added, and then methanesulfonyl chloride was added.
A solution of 0.2 g (1.05 equivalents) in 400 ml of toluene was added dropwise over 80 minutes. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 30 minutes, and the precipitated salt was separated by filtration. The obtained filtrate was cooled to 0 ° C, and 4 mol / L hydrochloric acid-
250 ml of a dioxane mixed solution was added, and the mixture was stirred for 1 hour. The precipitated crystals are collected by filtration, washed with toluene and dried, and 306.5 g of the desired hydrochloride of N-benzyl-3-methanesulfonyloxyazetidine (yield: quantitative)
I got

¹ H-NMR (400 MHz; CD ₃ OD)
δ: 3.21 (s, 3H), 4.33-4.65 (m,
4H), 4.82 (s, 2H), 5.36-5.39.
(M, 1H), 7.48 (m, 5H).

Embodiment 2

[0041]

Embedded image

Under a nitrogen gas stream, 32.6 ml (420 mmol) of methanesulfonyl chloride was added to a solution of 65.2 g (400 mmol) of N-benzyl-3-hydroxyazetidine and 58.6 ml (420 mmol) of triethylamine in 600 ml of toluene at 5 ° C. ) Toluene 10
0 ml solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then 300 ml of water was added to the reaction solution to wash the toluene layer. The thus-obtained toluene solution containing the desired N-benzyl-3-methanesulfonyloxyazetidine was directly used in the next reaction.

To the toluene solution obtained above, 200 ml (2323 mmol) of a 40% aqueous methylamine solution was added, and the mixture was stirred at 40 to 45 ° C. overnight. After the reaction,
The organic layer was separated, and the aqueous layer was further diluted with 100 ml of toluene.
It was extracted twice, combined with the toluene layer and concentrated to obtain a yellow liquid containing a colorless precipitate. After removing the precipitate by filtration, the precipitate was washed with a small amount of toluene, and the toluene layer was concentrated again to obtain a yellow liquid. This was dissolved in 400 ml of isopropyl alcohol, 66 ml of concentrated hydrochloric acid was added to this solution at 0 ° C., and the mixture was stirred.
00 ml was added all at once and stirred for 20 minutes. The precipitated crystals were collected by filtration, dried, and treated with the desired N-benzyl-
83.1 g (yield: 83.4%) of 3-methylaminoazetidine hydrochloride was obtained as white crystals.

¹ H-NMR (CD ₃ OD) δ: 2.74
(B, 3H), 4.30-4.70 (m, 7H), 7.
43-7.62 (m, 5H).

Embodiment 3

[0046]

Embedded image

The hydrochloride of N-benzyl-3-methylaminoazetidine obtained in Example 2 above was 19.8 g (79.4 m
mol) of methanol (119 ml) and water (2 ml), 3.96 g of 10% palladium-carbon (containing 50% water).
At a temperature of 50 to 55 ° C. under a hydrogen gas flow (normal pressure).
Hydrogenation was performed for hours. After completion of the reaction, the catalyst was separated by filtration, the filtrate was concentrated, 50 ml of isopropyl alcohol was added to the obtained residue, and the mixture was concentrated again. 50 ml of isopropyl alcohol was again added to the selected residue, and the mixture was concentrated to obtain a colorless solid, which was then dried and 12.6 g of the desired hydrochloride of 3-methylamino-azetidine (yield: 99.4%). Obtained.

¹ H-NMR (CD ₃ OD) δ: 2.73
(S, 3H), 4.32-4.53 (m, 5H).

The free base of 3-methylamino-azetidine was produced as follows using the hydrochloride of 3-methylamino-azetidine obtained above. That is, 13.2 g (83 mmol) of 3-methylamino-azetidine hydrochloride obtained above was treated with 67.5 ml of methanol.
7.47 g of sodium hydroxide (187 m
mol), and the mixture was stirred for 30 minutes, the precipitate was removed by filtration, and the precipitate was washed with 10 ml of tetrahydrofuran.
And washed. The filtrate and the washing solution were combined, concentrated, 25 ml of tetrahydrofuran was added to the obtained residue, and 12 g of molecular sieves 4A in pellet form was further added.
Left for 2 hours. By filtration, molecular sieves and other precipitates were removed, and tetrahydrofuran 10m
l. The filtrate and washings were combined and concentrated to give a yellow oil. This oily substance was subjected to distillation under reduced pressure to give a boiling point of 79-.
A fraction at 84 ° C. (65 mmHg) was collected to give 3.98 g (yield: 54.5%) of 3-methylamino-azetidine as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.37
(S, 3H), 3.37-3.42 (m, 2H), 3.
58-3.66 (m, 1H), 3.70-3.77
(M, 2H).

Embodiment 4

[0052]

Embedded image

At room temperature, 1-azabicyclo [1.1.
[0] 200 ml of a 40% N-methylamine aqueous solution was dropped into 200 ml of a tetrahydrofuran solution containing 5.6 g (100 mmol) of butane, and after the dropping was completed, stirring was performed at the same temperature for 18 hours. After the completion of the reaction, the reaction solvent was concentrated, and the obtained residue was subjected to distillation under reduced pressure as it was to obtain 1.6 g of the desired 3-methylamino-azetidine as a colorless oil (yield: 18.6%). Obtained. NM of this product
The R spectrum was obtained from 3-methylamino-
Perfectly matched that of azetidine.

[0054]

As described above, according to the production method provided by the present invention, the extremely inexpensive compound (II) previously provided by the present inventors can be converted to a specially expensive reagent or solvent. Of the desired formula (I) in high yield without using
Of 3-methylamino-azetidine can be produced. In addition, the isolation of the target compound in each step can be isolated as a crystal from the reaction solution, and the operation is simple, which is particularly excellent as an industrial production method. .

Claims (6)

[Claims] 1. The following formula (II): (In the formula, Bzl represents a benzyl group.)
Benzyl-3-hydroxyazetidine is reacted with a sulfonic acid halide derivative in the presence of a base to give the following formula (II)
I): embedded image (Wherein ^Ra represents ^a sulfonic acid residue and Bzl represents a benzyl group), and the obtained compound of the formula (III) is reacted with N-methylamine to give the following formula ( IV): embedded image (Wherein Bzl represents a benzyl group), and then removing the benzyl group of the compound of the formula (IV), comprising the following formula (I): A method for producing 3-methylamino-azetidine represented by the formula: 2. N-benzyl-3 represented by the formula (II)
The process according to claim 1, wherein the compound of the formula (III) obtained by reacting -hydroxyazetidine with a sulfonic acid halide derivative is isolated or directly subjected to the next reaction without isolation. 3. The method according to claim 1, wherein the sulfonic acid halide derivative is methanesulfonyl chloride. 4. The following formula (II): (In the formula, Bzl represents a benzyl group.)
By reacting benzyl-3-hydroxyazetidine with a sulfonic acid halide derivative in the presence of a base,
The following formula (III): (Wherein, ^Ra represents ^a sulfonic acid residue, and Bzl represents a benzyl group). 5. The method according to claim 4, wherein the sulfonic acid halide derivative is methanesulfonyl chloride. 6. The following formula (IV): (Where Bzl represents a benzyl group)
-Benzyl-3-methylaminoazetidine compound.