JPH0853462A - Production of aminomethylpenam derivative and triazolylmethylpenam derivative - Google Patents

Abstract

PURPOSE:To obtain an aminomethylpenam derivative expressed by a specific formula, useful as a starting material for triazolylmethylpenam derivatives to be used as synthetic intermediates for antibiotics, and freed from problems concerning the reaction for obtaining the subject compound, namely, safety, low selectivity and low yield. CONSTITUTION:This compound, an aminomethylpenam derivative, is expressed by formula I (X<1> and X<2> are each H or a halogen; R<1> is H or a carboxylic acid-protecting group; (n) is 0-2), e.g. 2beta-aminomethyl-2alpha-methylpenicillanic diphenylmethyl ester. It is recommended that this derivative of formula I is obtained, for example, by reaction between a compound of formula II and sodium azide to form an azide compound which is, in turn, reduced in the presence of methylene chloride, lead chloride and aluminum powder. The other objective triazolylmethylpenam derivative of formula III is obtained, preferably, by reaction between the compound of formula I and a hydrazone derivative of formula IV (e.g. 2,2'-dichloroacetaldehyde-p-toluenesulfonyl hydrazone) under neutral or basic conditions.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel aminomethylpenam derivative and a novel method for producing a triazolylmethylpenam derivative using the same as a starting material. The triazolylmethylpenam derivative obtained in the present invention is an antibiotic or β-
It is useful as an intermediate for pharmaceutical products such as lactamase inhibitors.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a triazolylmethylpenam derivative represented by the formula (3), a method of reacting an azidomethylpenam derivative represented by the formula (4) with acetylene under high pressure, Alternatively, a method of reacting a chloromethylpenam derivative represented by the formula (5) with 1,2,3-triazole is known.

[0003]

[Chemical 4] [In the formula, X ¹ , X ² , R ¹ and n are the same as defined above. ]

[0004]

[Chemical 5] [In the formula, X ¹ , X ² , R ¹ and n are the same as defined above. ]

In the method of reacting an azidomethylpenam derivative (4) with acetylene, since a large amount of acetylene is reacted under high pressure, the explosive property of acetylene is a problem.
This is a manufacturing method that is difficult to put to practical use. Further, the method of reacting chloromethylpenam derivative (5) with 1,2,3-triazole has a low reaction selectivity and a low yield of the target triazolylmethylpenam derivative (3). was there.

[0006]

DISCLOSURE OF THE INVENTION The object of the present invention is to produce a triazolylmethylpenam derivative which solves the problems of the known production method such as safety of reaction, low selectivity of reaction and low yield. To provide the law.

Another object of the present invention is to provide a novel aminomethylpenam derivative useful as a synthetic intermediate for a triazolylmethylpenam derivative.

[0008]

The present invention relates to an aminomethylpenam derivative represented by the formula (1).

[0009]

[Chemical 6]

[Wherein X ¹ and X ² are hydrogen atoms or halogen atoms, R ¹ is a hydrogen atom or a carboxylic acid protecting group, and n is an integer of 0 to 2]. ]

The compound (1) is prepared, for example, by converting the azido group into an amino group by a reduction reaction of the compound (4). In the formula (1) of the present invention, X ¹ and X ^{2 each} represent a hydrogen atom or a halogen atom, one of which may be a hydrogen atom and the other of which may be a halogen atom. Specific examples of the halogen atom include chlorine, bromine, iodine and the like. R ¹ represents a hydrogen atom or a carboxylic acid protecting group.

Examples of the carboxylic acid protecting group for R ¹ include "Prote
ctive Groups in Organic Synthesis "by Theodora
The protecting groups of Chapter 5 of W. Greene can be widely used, and specific examples thereof include benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trimethoxybenzyl, t-butyl, methoxyethoxymethyl, and the like.
Examples thereof include piperonyl, ditolylmethyl, trimethoxydichlorobenzyl, trichloromethyl and bis (p-methoxyphenyl) methyl groups.

Examples of the reduction reaction of the compound (4) include a method of reducing with aluminum in the presence of lead chloride.
In addition, “Experimental Chemistry Course 20” (edited by the Chemical Society of Japan, 19
56, Maruzen), "New Experimental Chemistry Course 15 Organic Synthesis III"
The method for reducing an azide compound to an amine described in (Chemical Society of Japan, Maruzen, 1977) can be widely used. As a specific example, a method using tin (I) chloride, zinc / hydrochloric acid, aluminum amalgam, catalytic reduction (platinum, palladium, Raney nickel, etc.), lithium aluminum hydride, hydrohalic acid, etc. can be used.

The present invention is also characterized by reacting the aminomethylpenam derivative represented by the formula (1) with the hydrazone derivative represented by the formula (2) under neutral or basic conditions. ) Also relates to a method for producing a triazolylmethylpenam derivative.

[0015]

[Chemical 7]

[Wherein Y is a halogen atom, R ² is a lower alkyl group optionally substituted with a halogen atom, or the benzene ring is at least one substituent selected from a halogen atom, a lower alkyl group or a lower alkoxy group] Represents a phenyl group which may be substituted with. ]

[0017]

Embedded image [In the formula, X ¹ , X ² , R ¹ and n are the same as defined above. ]

In the compound (2), Y in the formula represents a halogen atom. R ² represents a lower alkyl group optionally substituted with a halogen atom or a phenyl group optionally substituted with at least one substituent selected from a halogen atom, a lower alkyl group or a lower alkoxy group on the benzene ring. . Examples of the halogen atom include chlorine, bromine, iodine and the like. Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-
Examples thereof include an alkyl group having 1 to 4 carbon atoms such as a butyl group. Examples of the lower alkoxy group include alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups. The amount of compound (2) used with respect to compound (1) is usually 1 to 50 times equivalent, preferably 1 to 10 times equivalent.

Examples of the base used in the present invention include basic ion exchange resins, alkali bicarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate and potassium carbonate, and alkali carbonates, ammonia or methyl, Examples thereof include tertiary amines substituted with lower alkyl groups such as ethyl, propyl, isopropyl and t-butyl groups, and quaternary ammonium salts thereof. The amount of the base used with respect to the compound (1) is usually 1 to 100 times equivalent, preferably 1 to 30 times equivalent. Further, these bases may be mixed arbitrarily. Further, the basicity of the compound (1) may be used without the presence of a base.

The ion exchange resins used in the present invention include Diaion WK-10, WK-11 and WK-2.
0, WA-10, WA-11, WA-20, WA-2
1, WA-30, Amberlite IRA-35, IRA
-93ZU, IRA-94S, Levatit MP-62,
Examples thereof include MP-64, AP-49, CA-9222, and the like, but other types can be used as long as they are basic ion exchange resins.

The solvent used in the present invention is the compound (1)
Any solvent can be used alone or as a mixture as long as it dissolves the compound (2) and the basic substance to some extent and does not inhibit the reaction. However, the ion exchange resin does not have to dissolve. For example, acetone,
Ketones such as methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone, esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, methanol, ethanol, propanol, etc. Ether-based solvents such as aliphatic alcohols, diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane, halogenated solvents such as dichloromethane, dibromomethane, chloroform, bromoform, carbon tetrachloride, nitromethane, nitroethane, nitropropane, etc. Nitroalkanes, nitriles such as acetonitrile, propionitrile, butyronitrile, valeronitrile and the like, other organic solvents and water can be mentioned. In particular,
Halogenated solvents and lower alcohols are preferred. The amount of the solvent used is usually 1 to 100 parts by weight with respect to the compound (1),
It is preferably 5 to 20 times by weight.

The reaction of the present invention is usually carried out at normal pressure, but it may be pressurized if necessary. The reaction temperature is usually -2.
The temperature is 0 to 110 ° C, preferably 0 to 80 ° C. The reaction time in the present invention depends on the reaction temperature, the substrate concentration, the number of equivalents and the like and cannot be generally stated, but is usually 0.1 to 24 hours, preferably 1 to 8 hours.

In the present invention, the method for mixing the compound (1) with the compound (2) and the basic substance is not particularly limited. For example, when an ion exchange resin is used, the compound (1) is uniformly dissolved, and a solution in which the compound (2) is dissolved is added thereto. However, it is not necessary to completely dissolve the compound (1) and the compound (2). The reaction system may be a homogeneous system or a heterogeneous system. The reaction of the present invention is carried out in a closed container or a non-closed container, after the completion of the reaction, the precipitated salt is removed by filtration, the filtrate is concentrated, and then purified by recrystallization or distillation or column chromatography to obtain the objective. The compound (3) can be obtained efficiently.

[0024]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to the following Examples without departing from the gist thereof.

Reference Example 1 Synthesis of glyoxal-p-toluenesulfonylmonohydrazone A 500 ml four-necked flask equipped with a thermometer and a stirrer was charged with 41.5 g of p-toluenesulfonylhydrazine and 280 ml of propionic acid and stirred under suspension. 25 g of dichloroacetaldehyde are added as a solid and stirring is continued for 1 hour at 15 ° C. Then cool to 0 ° C and let stand for 3 hours,
The crystals were filtered and dried to obtain 35.0 g of the desired compound.

Example 1 Synthesis of 2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester 2β-chloromethyl-2α-methylpenicillanic acid diphenylmethyl ester and 8.00 g of azide compound obtained by sodium azide 30 ml of methylene chloride and lead chloride
1.0 g, aluminum powder 2.0 g, methanol 10 ml
Was charged into a 100 ml four-necked flask, and 15 ml of 20% ammonium chloride solution was added to the flask, and the internal temperature was adjusted to 28 to 35 ° C.
And continue stirring for 3 hours. After confirming the disappearance of the azide as a raw material by HPLC, the reaction solution is washed twice with 30 ml of water and separated, and methylene chloride is concentrated. The obtained oil is separated and purified by silica gel chromatography using ethyl acetate / hexane as a developing solvent to obtain 2.16 g of the desired compound.
(Yield 45%). The NMR and IR data of 2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester are as follows. NMR, CDCl ₃ (ppm); 1.29 (3H, s), 3.2
1 (1H, dd, J = 1.8Hz, 16.2Hz), 3.61
(1H, dd, J = 4.2Hz, 16.2Hz), 4.31
(2H, s), 5.01 (1H, s), 5.28 (1H, d
d, J = 4.2 Hz, 1.8 Hz), 6.93 (1 Hz, s),
7.32-7.39 (10H, br) IR (cm ^-1 ); 3200 (br), 1783, 1630,
1297, 1200, 697

Example 2 Synthesis of 1,1-dioxide-2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester Obtained with 2β-chloromethyl-2α-methylpenicillanic acid diphenylmethyl ester and sodium azide. After oxidizing the azide compound to a sulfone with potassium permanganate / acetic acid system, reduction treatment is performed in the same manner as in Example 1 to prepare 1,1-dioxide-2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester. To do.
NMR of 1,1-dioxide-2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester, I
The R data is as follows. NMR, CDCl ₃ (ppm); 1.15 (3H, s), 3.5
1 (1H, dd, J = 2.4Hz, 16.2Hz), 3.60
(1H, dd, J = 4.2Hz, 16.2Hz), 4.31
(2H, s), 5.13 (1H, s), 5.28 (1H, d)
d, J = 3.9 Hz, 2.4 Hz), 7.02 (1 Hz, s),
7.30-7.37 (10H, br) IR (cm ^-1 ); 3200 (br), 1781, 1648,
1290, 1207, 710

Example 3 Synthesis of 2β-triazolylmethyl-2α-methylpenicillanic acid diphenylmethyl ester 2β-synthesized in Example 1 in a 100 ml four-necked flask.
Aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester (4.28 g) and methanol (20 ml) were charged, and the mixture was adjusted to 20 ° C. and stirred. Then, 2.81 g of 2,2-dichloroacetaldehyde-p-toluenesulfonylhydrazone prepared in Reference Example 1 was suspended in 15 ml of methanol and added dropwise. The temperature of the liquid is 15-
Keep at 25 ° C and continue stirring for 2 hours. After the reaction, methanol is concentrated, the concentrated residue is dissolved in methylene chloride, and the precipitated salt is filtered off. The obtained solution was concentrated and then crystallized with a mixed solvent of ethyl acetate: hexane = 1: 1 to obtain 4.22 g of the target diphenylmethyl 2-triazolylmethylpenicillanate (yield 87%). . The structure of this compound was identified by comparing the NMR and IR spectra with a separately synthesized standard product.

Example 4 1,1-dioxide-2β-triazolylmethyl-2α
Synthesis of Diphenylmethyl Ester of Methylpenicillanic Acid 1,1 synthesized in Example 2 in a 100 ml 4-necked flask.
-Dioxide-2β-aminomethyl-2α-methylpenicillanic acid diphenylmethyl ester (4.50 g) was treated and treated in the same manner as in Example 3 to give the desired 1,1-dioxide-2β-triazolylmethyl-2α-. 3.83 g of methylpenicillanic acid diphenylmethyl ester was obtained (yield 9
5%). The structure of this compound was identified by comparing the NMR and IR spectra with a separately synthesized standard product.

[0030]

INDUSTRIAL APPLICABILITY According to the present invention, a novel aminomethylpenam derivative useful as a synthetic intermediate for a triazolylmethylpenam derivative is used as a starting material, and the reaction safety, which is a problem of the known production method, is improved. It is possible to provide a method for producing a triazolylmethylpenam derivative that solves low selectivity and low yield of the reaction.

Claims (2)

[Claims] 1. An aminomethylpenam derivative represented by the formula (1). Embedded image [In the formula, X ¹ and X ² represent a hydrogen atom or a halogen atom, R ¹ represents a hydrogen atom or a carboxylic acid protecting group, and n represents an integer of 0 to 2. ] 2. A formula (3) characterized by reacting an aminomethylpenam derivative represented by the formula (1) with a hydrazone derivative represented by the formula (2) under neutral or basic conditions. A method for producing the represented triazolylmethylpenam derivative. Embedded image [Wherein Y is a halogen atom, R ² is a lower alkyl group which may be substituted with a halogen atom, or the benzene ring is substituted with at least one substituent selected from a halogen atom, a lower alkyl group or a lower alkoxy group. Represents a phenyl group which may be present. ] [Chemical 3] [In the formula, X ¹ , X ² , R ¹ and n are the same as defined above. ]