JP2000001474A - Method for producing N-benzyl-3-hydroxyazetidine - Google Patents

Abstract

(57) [Summary] [PROBLEMS] N- is an important intermediate for the synthesis of various pharmaceuticals.
Provided is a process for industrially applicable production of benzyl-3-hydroxyazetidine. SOLUTION: Epichlorohydrin is added to a reaction aqueous solution containing benzylamine, and crystallized from the reaction mixture, the following formula (II): (In the formula, Bzl represents a benzyl group.) A crystal of the compound represented by the formula (II) is collected, and the crystal of the compound represented by the formula (II) is subjected to a heat treatment with an alkali metal hydrogencarbonate in an organic solvent. By collecting as free base or, if desired, the hydrochloride, the following formula (I): (In the formula, Bzl represents a benzyl group.)
A method for producing benzyl-3-hydroxyazetidine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing N-benzyl-3-hydroxyazetidine, which is important as a synthetic intermediate compound for various pharmaceuticals.

[0002]

2. Description of the Related Art The following formula (I):

Embedded image (In the formula, Bzl represents a benzyl group.)
Benzyl-3-hydroxyazetidine is an important compound as a synthetic intermediate for various pharmaceuticals.

For example, a benzyl group substituted on the nitrogen atom of this N-benzyl-3-hydroxyazetidine (I) is replaced with a 1,3-thiazolin-2-yl group, and a hydroxyl group at the 3-position is further substituted with a mercapto group. 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine, which is derived by substituting the above, is used as a side chain substituent at the 2-position of a carbapenem antibiotic having a strong antibacterial activity. (See, for example, Japanese Patent No. 2666118).
No.), 3-methylamino-azetidine obtained by removing a benzyl group on a nitrogen atom and replacing the hydroxyl group at the 3-position with a methylamino group is used as a raw material for the synthesis of a new quinolone-based synthetic antibacterial agent [for example, New current, 9
(3), p34 (1998)].

[0004] Therefore, N-benzyl-3-
Various methods for synthesizing 3-hydroxyazetidine derivatives, including hydroxyazetidine (I), have been provided. However, in the production thereof, the number of steps is large, the reaction yield is low, and the reaction is considerably complicated. However, it is not satisfactory as an industrial production method, such as using expensive raw materials even in a production method with a small number of steps.

[0005]

SUMMARY OF THE INVENTION Accordingly, the present invention provides an industrially applicable method for producing N-benzyl-3-hydroxyazetidine, which is important as a synthetic intermediate for various pharmaceuticals, and has a short production process. It is another object of the present invention to provide a simple production method which does not require a complicated reaction treatment, and which can use an inexpensive raw material and can satisfy the yield.

[0006]

In order to solve the above problems, the present invention provides the following production method as a specific embodiment. That is, epichlorohydrin is added to a reaction aqueous solution containing benzylamine under cooling and stirring, and after completion of the addition, the mixture is further stirred at room temperature until the reaction is completed, and crystallized from the reaction mixture by the following formula ( II):

[0007]

Embedded image (In the formula, Bzl represents a benzyl group.)

After collecting crystals of the compound represented by
Subsequently, the obtained crystal of the compound represented by the formula (II) is subjected to a heat treatment with an alkali metal hydrogencarbonate in an organic solvent, wherein the following formula (I):

[0009]

Embedded image (In the formula, Bzl represents a benzyl group.)

The present invention also provides a method for producing N-benzyl-3-hydroxyazetidine represented by the formula:

Therefore, in the production method provided by the present invention, as another specific embodiment, the compound represented by the above formula (I) is obtained by heating and reacting a compound represented by the formula (II) with an alkali metal hydrogencarbonate in an organic solvent. The present invention also provides a method for producing N-benzyl-3-hydroxyazetidine represented by the following formula:

In particular, in the present invention, after completion of the heating reaction between the compound represented by the formula (II) and the alkali metal hydrogencarbonate, insolubles are separated by filtration, and the filtrate is appropriately stirred to give the compound of the formula (I)
By isolating the compound of formula (I) as free crystals, or introducing hydrochloric acid gas into the filtrate, or adding an organic solvent containing hydrogen chloride to isolate the compound of formula (I) as crystals of the hydrochloride. To provide a simple manufacturing method.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION N-benzyl-
The method for producing 3-hydroxyazetidine uses inexpensive compounds such as benzylamine and epichlorohydrin as starting materials, and uses severe high pressure or high temperature heating as reaction conditions, and also uses expensive reagents and solvents. This is particularly excellent as an industrial production method in which the desired N-benzyl-3-hydroxyazetidine can be produced in a high yield by an extremely simple operation without performing the same.

That is, the reaction between benzylamine and epichlorohydrin in the production method of the present invention is carried out in an aqueous solution, and by gradually adding epichlorohydrin to the benzylamine under low-temperature conditions,
Crystallizing the compound of the formula (II) insoluble in water as a crystal in the reaction solution, and further performing a ring-closing reaction using the crystal of the compound of the formula (II) in an inert organic solvent. By simply heating with an alkali metal salt, the target substance, N-benzyl-3-hydroxyazetidine, can be isolated from the reaction solution in the form of a free base, or can be isolated from the reaction solution as a hydrochloride. It can be said that this method is particularly excellent as an industrial manufacturing method.

[0015] N-benzyl-3 provided by the present invention will be described below.
-The method for producing hydroxyazetidine will be described in more detail. The method for producing N-benzyl-3-hydroxyazetidine provided by the present invention is basically a first step for producing a compound represented by the formula (II) by a reaction of benzylamine with epichlorohydrin, It comprises a second step of subjecting the compound of the formula (II) obtained in one step to a ring-closure reaction to derive the desired N-benzyl-3-hydroxyazetidine.

In this case, the first step for producing the compound represented by the formula (II) by reacting benzylamine with epichlorohydrin is specifically carried out as follows. That is, benzylamine is dissolved in an aqueous solution, and the solution is cooled and stirred,
Epichlorohydrin is added at a temperature of not more than 5 ° C., preferably at a temperature of not more than 5 ° C., more preferably at a temperature of about 3 ° C. to 5 ° C. After completion of the addition, stirring is further continued at room temperature until the reaction is completed. It is implemented by performing.

In the first step, the amounts of benzylamine and epichlorohydrin used in the reaction are theoretically 1 mol to 1 mol. However, 1.05 mol of benzylamine and 1 mol of epichlorohydrin are equivalent to 1 mol of epichlorohydrin. It has been found that it is preferable to use the above excess amount.

It is preferable that epichlorohydrin is added to benzylamine in a dropwise manner or intermittently under the above temperature conditions. When adding intermittently, for example, it is preferable to divide the total amount of epichlorohydrin to be added into an appropriate ratio and to add the epichlorohydrin at intervals of, for example, about 30 minutes to 1 hour. The time of addition of epichlorohydrin to benzylamine is not particularly limited, but it has been found that the total addition time should be about 1.5 to about 4 hours.

After the addition of epichlorohydrin to the reaction solution under the above low temperature conditions is completed, the reaction mixture is brought to room temperature, preferably about 20 ° C. to 30 ° C., more preferably about 2 ° C.
The temperature is returned to about 5 ° C., and the reaction mixture is stirred under such temperature conditions until the reaction is completed. According to the addition of epichlorohydrin to benzylamine in the first step, the desired crystal of the compound of the formula (II) is insoluble in water in the reaction solution, and thus gradually crystallizes as a crystal. Generally, it is preferable to stir for about 20 hours.

The crystals crystallized in the reaction solution are collected by filtration and dried under reduced pressure to obtain the desired crystals of the compound of the formula (II) in a high yield of 90 to 95% or more. Can be.

The crystals of the compound of the formula (II) produced as described above are used and subjected to a ring-closing reaction to give the N-benzyl-3-hydroxyazetiate of the formula (I) which is the object compound of the present invention. The step 2 for deriving gin is specifically carried out by subjecting a crystal of the compound of the formula (II) to heat treatment with an alkali metal hydrogencarbonate in an organic solvent.

Examples of the alkali metal hydrogencarbonate used in the ring closure reaction include sodium hydrogencarbonate and potassium hydrogencarbonate. Among them, sodium hydrogencarbonate is preferred. As the amount of use, the formula (II)
It is preferable to use at least about twice the molar equivalent of the compound of the formula (1).

The organic solvent that can be used in the reaction includes:
Examples include organic solvents inert to the reaction, such as acetonitrile, t-butanol, dioxane, and the like. Of these, alcohols having a bulky substituent and polar organic solvents are preferable, and acetonitrile and dioxane are particularly preferable.

Accordingly, as a particularly preferable reaction means, it is preferable to use sodium hydrogen carbonate as an alkali metal hydrogen carbonate and to carry out the reaction in dioxane or acetonitrile as an organic solvent.

Although the amount of the organic solvent to be used is not strictly limited, it is preferable to carry out the reaction at a relatively low concentration. For example, the concentration of the compound of the formula (II) in the reaction solution is not more than 5 molar. , Preferably 2 mol or less, particularly preferably 1 mol or less.

The ring closure reaction is carried out under heating conditions, particularly by heating and refluxing at a temperature near the boiling point of the organic solvent used. The reaction time is not particularly limited by the organic solvent used, but when dioxane is preferably used, it is sufficient to heat and reflux for about 10 to 20 hours. When acetonitrile is used, it is sufficient to heat and reflux for about 5 to 15 hours. In addition, it is also possible to add a stirring operation if desired.

After the completion of the ring-closing reaction, insoluble substances such as alkali metal bicarbonate mixed in the reaction solution and alkali metal chlorides generated as the reaction proceeds are filtered off, and the filtrate is appropriately concentrated. By adding a suitable organic solvent to the obtained residue and performing a treatment such as stirring, the N-benzyl-3-hydroxyazetidine represented by the formula (I) is isolated as crystals in a free base state. can do.

On the other hand, a hydrochloric acid gas is introduced into the filtrate obtained by filtering the reaction solution obtained after the completion of the ring closure reaction, or a small amount of a mixed solvent of an organic solvent and hydrogen chloride used for the reaction is used. The desired hydrochloride of N-benzyl-3-hydroxyazetidine represented by the formula (I) of the present invention can be crystallized as crystals by adding and stirring appropriately.

Thus, the N of the present invention represented by the formula (I)
-Benzyl-3-hydroxyazetidine can be produced as crystals in high yield.

As an example of applying the thus-produced N-benzyl-3-hydroxyazetidine of the formula (I) of the present invention to pharmaceuticals, for example, one of the new quinolone synthetic antibacterial agents, 1- (6-) Amino-3,5-difluoropyridin-2-yl) -8-bromo-6-fluoro-7-
(3-methylaminoazetidin-1-yl) -1,4-
There is 3-methylamino-azetidine, the side chain of dihydroquinoline-3-carboxylic acid. This compound can be obtained by activating the hydroxyl group of the compound of the formula (I), converting it to a methylamino group, and then subjecting the N-benzyl group to an appropriate debenzylation reaction such as catalytic reduction. .

[0031]

As described above, according to the production method provided by the present invention, benzylamine and epichlorohydrin, which are very inexpensive industrial reagents, can be produced in only two steps in a production process and in addition to specially expensive reagents or The desired N-benzyl-3-hydroxyazetidine of the formula (I) can be produced in high yield without using a solvent. 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. It is understood that.

[0032]

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.

Example 1 92.5 g (1 mol) according to the method of the first step described above.
And 112.5 g (1.05 mol) of benzylamine in a solvent volume of 1 L under the following conditions to obtain a crystal of the compound of formula (II) in the right column of the following table. Obtained in the yield indicated.

[0034]

[Table 1]

Example 2 According to the method of the above-mentioned second step, compound (II) was added to 20
Using 0 g (1 mol), the reaction was carried out under the following conditions in a solvent amount of 1 L. After completion of the reaction, insolubles were separated by filtration, and the hydrochloride of the formula (I) was isolated as crystals from the filtrate, and produced in the yield shown in the right column of the following table.

[0036]

[Table 2]

Comparative Example 1 The reaction was carried out under the following conditions and using the same dosage as in Example 1, and the results shown in the right column of the following table were obtained.

[0038]

[Table 3]

Comparative Example 2 The reaction was carried out under the following conditions and using the same dosage as in Example 2, and the results shown in the right column of the following table were obtained.

[0040]

[Table 4]

Example 3 Compound (II) (22.9 g, 114.7 mmol) and sodium hydrogencarbonate (19.3 g, 229 mmol) were combined with 2
The mixture was refluxed for 6 hours in 30 ml of acetonitrile. Then, after cooling to room temperature, the reaction solution was filtered, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain a colorless oil. 115 ml of heptane was added to the obtained residue, and the mixture was stirred to precipitate crystals. The precipitated crystals were collected by filtration and dried to obtain 17.9 g of the desired free crystals of the compound (I) (yield: 9).
5.8%). ¹ H-NMR (CDCl ₃ ) δ: 3.89-3.98
(M, 2H), 3.57-3.63 (m, 4H), 4.
35-4.45 (m, 1H), 7.20-7.35
(M, 5H).

Example 4 Compound (II) (643.7 g, 3.22 mol) and sodium hydrogencarbonate (542 g, 6.45 mol) were obtained.
The mixture was added to 6.4 L of acetonitrile, and stirred under reflux for 7 hours. After allowing to cool for one day, the precipitated salt was separated by suction filtration, and the obtained filtrate was concentrated under reduced pressure to 0.6 kg. After 300 ml of ethyl acetate was added to the obtained residue and stirred for 1 hour, 3.2 L of heptane was further added and stirred for 1 hour to precipitate a crystal. The precipitated crystals were collected by filtration and extracted with ethyl acetate 5
After washing with a mixture of 0 ml and 450 ml of heptane,
After drying, the desired free crystals of the compound (I) were obtained in 519.
8 g (purity: 93.9%; yield: 92.9%) was obtained. ¹ H-NMR (400 MHz; CDCl ₃ ) δ: 2.93
-2.97 (m, 2H), 3.59-3.63 (4H,
m), 4.39-4.45 (1H, m), 7.23-
7.33 (5H, m).

Claims (13)

[Claims] 1. An epichlorohydrin is added to a reaction aqueous solution containing benzylamine under cooling and stirring, and after completion of the addition, the mixture is further stirred at room temperature until the reaction is completed, and crystallized from the reaction mixture. The following formula (II): (In the formula, Bzl represents a benzyl group.) After collecting crystals of the compound represented by the formula (II),
Wherein the compound of formula (I) is subjected to heat treatment with an alkali metal hydrogen carbonate in an organic solvent. (In the formula, Bzl represents a benzyl group.)
A method for producing benzyl-3-hydroxyazetidine. 2. The process according to claim 1, wherein benzylamine is used in excess of 1.05 mol or more relative to 1 mol of epichlorohydrin. 3. The method according to claim 1, wherein the reaction between the aqueous reaction solution of benzylamine and epichlorohydrin is carried out at a temperature of 10 ° C. or less. 4. The process according to claim 1, wherein the alkali metal hydrogencarbonate salt is used in an amount of at least 2 mol equivalent to 1 mol equivalent of the crystal of the compound of the formula (II). 5. The organic solvent for heating the crystal of the compound of the formula (II) and the alkali metal hydrogencarbonate is acetonitrile, t-butanol or dioxane.
Production method described in 1. 6. The method according to claim 1, wherein the alkali metal hydrogencarbonate is potassium hydrogencarbonate or sodium hydrogencarbonate. 7. The method according to claim 1, wherein the organic solvent for heating the crystal of the compound of the formula (II) and the alkali metal bicarbonate is dioxane or acetonitrile, and the alkali metal bicarbonate is sodium bicarbonate. Manufacturing method. 8. After the heating reaction of the crystal of the compound of the formula (II) with the alkali metal hydrogencarbonate, the insoluble matter is separated by filtration, and hydrochloric acid gas is introduced into the filtrate or the organic solvent containing hydrogen chloride is added. 2. The process according to claim 1, wherein the compound of formula (I) is obtained as crystals of the hydrochloride by the addition. 9. The following formula (II): A method for producing N-benzyl-3-hydroxyazetidine represented by the formula (I) according to claim 1, wherein the compound represented by the formula (I) is subjected to a heat treatment with an alkali metal hydrogencarbonate in an organic solvent. . 10. The process according to claim 9, wherein at least 2 mole equivalent of the alkali metal hydrogencarbonate is used per 1 mole equivalent of the compound of the formula (II). 11. The organic solvent for heating the compound of the formula (II) and the alkali metal hydrogencarbonate is acetonitrile,
The production method according to claim 9, wherein t-butanol or dioxane is used, and the alkali metal hydrogencarbonate is potassium hydrogencarbonate or sodium hydrogencarbonate. 12. After the heating reaction between the compound of the formula (II) and the alkali metal hydrogencarbonate, insoluble substances are separated by filtration, and hydrochloric acid gas is introduced into the filtrate, or an organic solvent containing hydrogen chloride is added. 10. The process according to claim 9, wherein the compound of the formula (I) is obtained as crystals of the hydrochloride. 13. The process according to claim 9, wherein the compound of the formula (II) is used in a crystalline state.