JPH0967339A - Production of 3-aminoazetidinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in a simple operation in high yield the subject compound useful as an intermediate for various cephalosporin-based antibiotics by continuously carrying out deacylation and chlorination during the deacylation process without isolation and purification of the products in the respective reactions. SOLUTION: An azetidinone derivative of formula I [R<1> is a (substituted)aryl, arylmethyl or aryloxymethyl; R<2> is a carboxyl-protective group; R<3> is a (substituted)aryl] is reacted with phosphorus pentachloride in an organic solvent in the presence of a hydrogen chloride scavenger to form an iminochloride form, which is then reacted with a chlorinating agent to form a chloroimino chloride form of formula III, which is, in turn, reacted with an alcohol to form a chloroiminoether form of formula IV (R<4> is an alkyl, etc.), which is then hydrolyzed to obtain the objective compound of formula V [e.g. p- methoxybenzyl-2-(3-amino-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-ch loromethyl-3- butenoate].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a 3-aminoazetidinone derivative represented by the general formula (5) and a salt thereof. The 3-aminoazetidinone derivative represented by the general formula (5) produced in the present invention is an important known compound that can be a synthetic intermediate for various cephalosporin antibiotics. For example, the following general formula (6)

[0002]

[Chemical 6]

(In the formula, R ² has the same meaning as described above.) It becomes an important synthetic intermediate for cephalosporin antibiotics and has extremely high utility value in the pharmaceutical manufacturing industry.

[0004]

2. Description of the Related Art Known analogues of the derivative represented by the general formula (5) according to the present invention include, for example, JP-A-58-8.
It is disclosed in Japanese Patent No. 5894 and Japanese Patent Laid-Open No. 59-164771. All of these compounds are represented by the following general formula (7)

[0005]

[Chemical 7]

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), and the amino group is in a form protected by an acyl group. Therefore, in order to obtain the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention, deacylation must be performed later, which is not industrially advantageous.
Further, known synthesis reactions of the 3-aminoazetidinone derivative represented by the general formula (5) include, for example, JP-A-5-
78373, JP-A-5-65268 (reaction formula A), JP-A-3-147539 and JP-A-5.
-51361 gazette (reaction formula B) is mentioned.

[0007]

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[0008]

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In the reaction formula A, it is necessary to isolate the product for each reaction, and in the reaction formula (B), the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention is used. In order to obtain the above, it is necessary to cleave the side chain at the 3-position of azetidinone again, which is not industrially advantageous.

[0010]

In view of the above facts, the present inventors have earnestly studied a method for producing a 3-aminoazetidinone derivative represented by the general formula (5) and a salt thereof in high yield. As a result, the iminochloro compound represented by the general formula (2) obtained by reacting the azetidinone derivative represented by the general formula (1) with phosphorus pentachloride in the presence of a hydrogen chloride scavenger in an organic solvent was obtained. , Reacting with a chlorinating agent in the state of the reaction solution as it is to produce a chlorinated iminochloro compound in a high yield, and further, reacting the reaction solution with an alcohol to produce a chlorinated iminoether produced. By hydrolyzing the body, it was found that the 3-aminoazetidinone derivative and its salt can be produced in high yield by a simple continuous operation, and the present invention was completed.

[0011]

That is, the present invention provides the following general formula (1):

[0012]

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(Wherein R ¹ represents a substituted or unsubstituted aryl group, an arylmethyl group or an aryloxymethyl group, and R ² represents a protecting group for a carboxyl group,
R ³ represents a substituted or unsubstituted aryl group) and is reacted with phosphorus pentachloride in the presence of a hydrogen chloride scavenger in an organic solvent to give a compound represented by the following general formula (2):

[0014]

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(In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) The first step for producing an iminochlore compound, and then the iminochlore compound is reacted with a chlorinating agent,
The following general formula (3)

[Chemical 12]

(Wherein R ¹ , R ² and R ³ have the same meanings as defined above), a second step for producing a chlorinated iminochlore compound, and then the product is reacted with alcohol. The following general formula (4)

[0017]

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(Wherein R ¹ , R ² and R ³ have the same meanings as described above,
R ⁴ represents an alkyl group or an alkyl group having one or more hydroxyl groups. ) The third step of producing a chlorinated imino ether body, and then the chlorinated imino ether
The following general formula (5) is characterized by comprising the fourth step of hydrolyzing the telluride.

[0019]

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The present invention relates to a novel method for producing a 3-aminoazetidinone derivative represented by the formula (wherein R ² and R ³ are as defined above) and salts thereof. Hereinafter, the present invention will be described in detail. The method for producing a 3-aminoazetidinone derivative represented by the general formula (5) and a salt thereof according to the present invention is
As mentioned above, it basically consists of four reaction steps. It is characterized by the fact that, though four steps are involved in the reaction formula, deacylation and chlorination of the starting material can be carried out continuously without isolation and purification of the product of each reaction. It is in. In the manufacturing method of the present invention, the second
The following general formula (12) obtained by deacylation without the chlorination reaction in the step

[0021]

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Even if the compound represented by the formula (wherein R ² and R ³ are as defined above) is chlorinated, the object of the present invention is hardly obtained. The azetidinone derivative of the general formula (1) used as a starting material in the present invention is
For example, JP-A-50-129590 and JP-A-59-
It is a compound already disclosed as an important synthetic intermediate of various cephalosporin antibiotics, which is disclosed in JP 164771 B and JP 5-51361 A.

In the present invention, specific examples of R ^{1 in} the compound represented by the general formula (1) include, for example, phenyl group, tolyl group, p-chlorophenyl group, p-nitrophenyl group, p-methoxyphenyl group and the like. Substituted or non-substituted aryl group, benzyl group, tolylmethyl group, naphthylmethyl group, p-methoxybenzyl group, p-nitrobenzyl group, phenyldichloromethyl group, etc. Substituted or non-substituted arylmethyl group Group, a phenoxymethyl group, a p-chlorophenoxymethyl group, a p-nitrophenoxymethyl group and the like, or an aryloxymethyl group having no substituent.

Examples of the carboxylic acid protecting group for R ² include halogen such as methyl group, ethyl group, propyl group, butyl group, tert-butyl group, 2,2,2-trichloroethyl group and 2-chloroethyl group. An optionally substituted lower alkyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a 3,4,5-trimethoxybenzyl group, a diphenylmethyl group or the like or an arylmethyl group having no substituent, Substituted or unsubstituted aryl groups such as phenyl group and p-methoxyphenyl group can be mentioned.

Specific examples of R ³ include phenyl group, tolyl group, xylyl group, p-methoxyphenyl group,
Examples thereof include substituted or unsubstituted aryl groups such as p-nitrophenyl group and p-chlorophenyl group. In the first step, the azetidinone derivative represented by the general formula (1) is reacted with phosphorus pentachloride in an organic solvent in the presence of a hydrogen chloride scavenger to produce an iminochlore body represented by the general formula (2). It is the process of making.

The organic solvent used in the present invention includes lower halogenated hydrocarbons, aromatic hydrocarbons, di-lower alkyl ethers, cyclic ethers, lower dialkoxyethanes, aliphatic amides, etc., and is selected from these. 1 fork is 2
Used as a mixed solvent of at least one species. For example, chloroform, dichloromethane, dichloroethane, lower halogenated hydrocarbons such as carbon tetrachloride, aromatic hydrocarbons such as benzene and chlorobenzene, dilower alkyl ethers such as diethyl ether and dimethyl ether, tetrahydrofuran,
Cyclic ethers such as dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1,2-dibutoxyethane,
Examples thereof include lower dialkoxyethane such as 1,2-dibenzyloxyethane and aliphatic amide such as dimethylformamide. The hydrogen chloride scavenger, for example, pyridine, picoline, tertiary amines such as triethylamine, propylene oxide, epoxides such as butylene oxide,
Examples thereof include carbonates of alkali metals such as soda carbonate, calcium carbonate and soda bicarbonate.

The reaction conditions in the first step differ depending on the physical properties of the raw materials, the type of solvent and the hydrogen chloride scavenger, but the reaction temperature is usually -30 to 10 ° C, preferably -2 to.
It is 4 ° C., and the reaction time is usually 0.5 to 10 hours, preferably 1 to 3 hours. The amount of phosphorus pentachloride and hydrogen chloride scavenger used with respect to the azetidinone derivative of compound (1) is not particularly limited, but usually phosphorus pentachloride is 1 to 5 times mol, preferably 1 to 3 times mol of compound (1). 1 mole to 10 moles, and preferably 1 mole to 3 moles of the hydrogen chloride scavenger are suitable.

Next, the second step is a step of reacting the reaction solution of the iminochlore compound obtained above with a chlorinating agent in an organic solvent to produce a chlorinated iminochlore compound represented by the general formula (3). . Examples of the chlorinating agent include chlorine gas and t
-BuOCl, may be mentioned Cl ₂ O or the like. Chlorine gas can also be reacted as a solution of a gaseous or an inert organic solvent, for example, a lower halogenated hydrocarbon such as carbon tetrachloride, dichloromethane, chloroform and the like. The amount of the chlorinating agent used is not particularly limited, but is usually 1 to 5 times, preferably 1 to 2 times the mol of the compound (1). In the chlorination of this step, the methyl group of the general formula (2) is chlorinated with the above chlorinating agent, but this chlorination does not proceed with the phosphorus pentachloride used in the previous step.

In the second step, by using an organic solvent, the iminochloro compound represented by the general formula (2) can be easily chlorinated without using a hydrogen chloride scavenger, and at low temperature. The chlorinated iminochloro compound represented by the general formula (3) can be obtained in a high yield by carrying out the reaction in (1). The organic solvent used in this step is the same as those listed above, but is selected from the group consisting of lower halogenated hydrocarbons, aromatic hydrocarbons, di-lower alkyl ethers, cyclic ethers and aliphatic amides. Two or more kinds of organic solvents are preferable, and a mixed solvent of a lower halogenated hydrocarbon and a cyclic ether is particularly preferable, and dioxane 1 to 3 is usually added to 1 (volume) of dichloromethane.
A mixed solvent of (volume), preferably dioxane 2 (volume) is most suitable.

The reaction temperature in this step is usually -15 to -4.
It is 0 ° C., preferably −20 ° C. or lower. Reaction temperature is -2
At 0 ° C. or higher, other chloro compounds are likely to be by-produced in addition to the formation of the target compound represented by the general formula (3). For example, when R ¹ is an arylmethyl group, chlorination proceeds further, and the methyl group at the 3-position is chlorinated by the following general formulas (13) and (14).

[0031]

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[0032]

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(In the formula, R ² and R ³ have the same meanings as described above.) By-products and the like represented by the formula are easily produced. However, even in the case of the compounds represented by the general formulas (13) and (14), the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention and its derivative are obtained by the subsequent alcohol treatment and hydrolysis. It is also possible to make salt.

Next, in the third step, the reaction liquid of the chlorinated iminochloro compound obtained above is reacted with alcohol to produce a chlorinated iminoether compound represented by the following general formula (4). It is a reaction. Examples of the alcohol to be used include lower alcohols such as methanol, ethanol, n-propanol and n-butanol, polyhydric alcohols such as ethylene glycol, propylene glycol and glycerin. Examples thereof include alcohol. The reaction conditions vary depending on the type of alcohol, but the reaction temperature is usually -50 to 50 ° C, preferably -30 to 20 ° C, and the reaction time is usually 0.5 to 24 hours, preferably 0.5 to 5. 10 hours. The amount of alcohol used is not particularly limited, but is usually 10 to 100 V / W, preferably 10 to 50 V / W with respect to the compound (1).
Is appropriate.

Next, in the fourth step, the reaction solution of the chlorinated imino ether compound represented by the general formula (4) obtained in the previous step is hydrolyzed to obtain the desired product of the present invention. This is a step of obtaining an aminoazetidinone derivative and a salt thereof. The reaction product can be obtained by reacting the reaction liquid obtained in the previous step with water. The reaction time is usually 0.5 to 5 hours, preferably 0.5 to 1 hour. The reaction temperature may be room temperature or lower, but it is preferable to carry out the reaction at a temperature as low as possible in order to suppress decomposition of the product. After completion of the reaction, a hydrophobic solvent such as dichloromethane, 1,2-dichloromethane, chloroform, carbon tetrachloride, benzene, chlorobenzene, ethyl acetate, ethyl formate, dichloroethane, an organic layer extracted by adding an extraction solvent such as ethoxyacetate Separate from the aqueous layer.

Further, the separated organic layer is washed with water and then dehydrated with, for example, anhydrous magnesium sulfate or anhydrous sodium sulfate. Then, it is concentrated at a temperature below room temperature to obtain a hydrochloride of the 3-aminoazetidinone derivative. Further, the free amino compound of the 3-aminoazetidinone derivative can be obtained by adjusting the pH to around neutral, and inorganic acids and organic acids such as inorganic acids such as sulfuric acid and phosphoric acid, tosylic acid, benzenesulfonic acid and the like can be obtained. It is also possible to obtain a salt corresponding to those acids by further reacting with an organic acid. The thus-produced compound of the present invention can be easily isolated and purified by a usual separation and purification means, but the compound of the present invention is purified to induce the compound represented by the general formula (6). It is also possible to do without doing,
It is industrially advantageous.

[0037]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below in detail with reference to Examples. Example 1 Preparation of [p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] (first step) with stirrer A 0.5 liter 4-necked flask was replaced with nitrogen, and 15 g of phosphorus pentachloride (0.072
M) and 100 ml of dichloromethane were charged to 30 to 35
After dissolution at ℃, cooled to -2 to -5 ℃, pyridine 5.8
7g (0.073M) is slowly added dropwise. -2--5
After reacting at ℃ for about 20 minutes, p-methoxybenzyl-2- (3-
Phenylacetamido-4-benzenesulfonylthio-
20 g (0.033 M) of 2-azetidinone-1-yl) -3-methyl-3-butenoate are added. The reaction was completed in about 2 hours (1 to 2 hours) to obtain an iminochlor body.

(Second step) The obtained iminochlore body reaction solution was cooled to -20 ° C., 200 ml of dioxane was added, and 36 g of dichloromethane containing 7.9% chlorine (chlorine content 2.86 g at a temperature of -20 ° C. or lower). (0.04 M) was added dropwise, and the mixture was reacted with stirring at a temperature of -20 ° C or lower for 0.5 hour to obtain a chlorinated iminochloro compound.

(Third step) A 1-liter four-necked flask equipped with a stirrer prepared separately was replaced with nitrogen, 400 ml of dehydrated methanol was charged, and after cooling to -20 ° C, the chlorinated iminochlore body obtained above was obtained. Add the reaction solution all at once,
Reaction was carried out at about 0 ° C. for 1 to 2 hours to obtain a chlorinated imino ether compound.

(Fourth step) The chlorinated iminoether reaction solution obtained above was cooled to -10 ° C, and distilled water (140 m) was added.
1 was added, and the mixture was reacted at a temperature of -10 to 0 ° C for about 20 minutes, and then extracted with 100 ml of dichloromethane. Further, the organic layer was dehydrated with anhydrous sodium sulfate and then concentrated to obtain a pale yellow mixed solution of aminoazetidinone. The obtained mixed liquid was crystallized from isopropyl alcohol and dried to obtain 16.3 g of a pale yellow solid. By instrumental analysis such as NMR, MS, IR, p-methoxybenzyl-2- (3-amino-4-)
Benzenesulfonylthio-2-azetidin-1-yl)
It was confirmed to be -3-chloromethyl-3-butenoate / hydrochloride. The yield was 89%.

(1) 400 MHz ¹ H-NMR δppm (DMSO: CDCl ₃
1: 1) 3.81 (s, 3H, OMe) 4.06 (d, 1H, -CH 2 Cl, J = 16.0Hz), 4.39 (d, 1H, -CH 2 C
l, J = 16.0Hz) 4.29 ( s, 1H, -CH (-COO -) - C) 4.98 (s, 1H, = C = CH 2), 5.01 (s, 1H, = C = CH 2) 5.14 ( d, 1H, -OCH _2- , J = 16.0Hz), 5.20 (d.1H, -OCH _2- ,
J = 16.0Hz) 5.24 (d, 1H, lactam, J = 4.0Hz), 6.01 (d, 1H, lactam, J = 4.
0Hz) 6.94 (d, 2H, J = 8.0Hz), 7.32 (d, 2H, J = 8.0Hz) 7.59 (t, 2H, J = 8.0Hz), 7.71 (t, 1H, J = 8.0Hz) 7.84 ( d, 2H, J = 8.0Hz) (2) MS (FAB): 511 m / z (M + H) ⁺ (3) IR (KBr): ν3400, 2950, 2840, 1785, 174
0, 1515, 1330, 1245, 1170, 1140, 580 cm ^-1

Example 2 Preparation of [p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] (first step) A 100 ml four-necked flask equipped with a stirrer was purged with nitrogen, charged with 3.5 g of phosphorus pentachloride (0.017 M) and 24 ml of dichloromethane, dissolved at 30 to 35 ° C., and then cooled to −2 to −5 ° C. , Pyridine 1.35 g (0.3
017M) is slowly added dropwise. About 20 at -2 to -5 ℃
After reacting for a minute, 5.0 g (0.0084 M) of p-methoxybenzyl-2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate is added. Reaction is almost 2
The reaction was completed in 1 hour (1 to 2 hours), and an iminochloro body was obtained.

(Second step) The obtained iminochloro body reaction solution was cooled to -20 ° C.
48 ml of a double volume of dioxane was added, and 10.0 g of chlorine containing 7.9% chlorine (chlorine content 0.8 g = 0.011 M) was added dropwise at −20 ° C. or lower, followed by stirring reaction at 0 ° C. for 0.5 hours. A chlorinated iminochlore was obtained.

(Third step) A 0.5-liter four-necked flask equipped with a stirrer, which was separately prepared, was purged with nitrogen, charged with 100 ml of dehydrated methanol, cooled to -20 ° C., and then reacted with a chlorinated iminochlore body. Add the liquid all at once, about 0 ℃
The aging reaction was carried out for 1 hour to obtain a chlorinated imino ether compound.

(Fourth step) The obtained chlorinated iminoether body reaction liquid was cooled to -10 ° C, 35 ml of pure water was added, and after reacting for 20 minutes, it was extracted with dichloromethane, cooled with heavy soup water, and washed with water. After that, the organic layer was dehydrated and dried with anhydrous magnesium sulfate 10 g and then concentrated to obtain a yellow mixed liquid. The obtained yellow mixed liquid was subjected to normal phase (Wako gel C-300, 450 g) column chromatography to remove impurities with ethyl acetate, and a fraction containing a target substance was recovered with methanol. The collected liquid was concentrated and the reverse phase (COSMOSIL 75C18, 50
0g) Chromatographic acetonitrile: water =
Purification with a 1: 1 solvent gave 1.9 g of a yellow liquid. Free p- by instrumental analysis of NMR, MS, IR
It was confirmed to be methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate.
Yield was 45%.

(1) 300 MHz ¹ H-NMR δppm (DMSO: CDCl ₃ ) 3.78 (s, 3H, OMe) 4.07 (d, 2H, -CH ₂ Cl) 4.64 (d, 1H, lactam, J = 4.8Hz ) 4.93 (s, 1H, -CH (-COO-)-C) 5.09 (d, 1H, -OCH _2- , J = 12.0Hz), 5.13 (d, 1H, -OCH
_{2 -, J = 12.0Hz) 5.16} (s, 1H, = C = CH 2), 5.29 (d, 1H, = C = CH 2) 5.69 (d, 1H, lactam, J = 4.8Hz) 6.90 (d , 2H, J = 9.6Hz), 7.29 (d, 2H, J = 9.6Hz) 7.52 (t, 2H, J = 9.8Hz), 7.63 (t, 1H, J = 9.8Hz) 7.88 (d, 2H, J = 9.8Hz) (2) MS (FAB): 511 m / z (M + H) ⁺ (3) IR (neat): ν3400, 2960, 1780, 1740, 161
5, 1520, 1445, 13721330, 1250, 1175, 1145, 1075, 5
90 cm ^-1

Example 3 Preparation of [p-Methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] Example 1 A yellow mixed solution was obtained as a result of the same procedure as in Example 1 except that 200 ml of dimethylformamide was used instead of dioxane in the two steps. The obtained yellow mixed liquid was crystallized in the same manner as in Example 1 to obtain 11.7 g of a hydrochloride. The yield was 64%.

[0048]

As described in detail above, according to the production method of the present invention, the 3-aminoazetidinone derivative and its salt can be continuously obtained in a high yield by a simple operation. The feature is that deacylation and chlorination are continuously performed in the deacylation step without isolation and purification of the product of each reaction, which is industrially advantageous.

Claims (2)

[Claims] 1. The following general formula (1): (In the formula, R ¹ represents a substituted or unsubstituted aryl group, an arylmethyl group or an aryloxymethyl group, R ² represents a protecting group for a carboxyl group, and R ³ represents a substituted or substituent group. An azetidinone derivative represented by the following general formula (2) embedded image is reacted with phosphorus pentachloride in the presence of a hydrogen chloride scavenger in an organic solvent. (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) The first step of forming an iminochlore compound, and then reacting the iminochlore compound with a chlorinating agent to give the following general formula: (3) [Chemical Formula 3] (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A second step of forming a chlorinated iminochlore compound, and then reacting the product with an alcohol (4) [Chemical 4] (Wherein R ¹ , R ² and R ³ have the same meanings as described above, R ⁴ represents an alkyl group, and an alkyl group having one or more hydroxyl groups.) To form a chlorinated imino ether compound. A third step, followed by a fourth step of hydrolyzing the chlorinated iminoether body, represented by the following general formula (5): (In the formula, R ² and R ³ have the same meanings as described above.) A process for producing a 3-aminoazetidinone derivative and a salt thereof. 2. The reaction in the second step comprises one or more organic solvents selected from the group consisting of lower halogenated hydrocarbons, aromatic hydrocarbons, di-lower alkyl ethers, cyclic ethers and aliphatic amides. The method according to claim 1, which is carried out in the presence of