JPH01110689A - Production of 2beta-halogeno substituted methylpenicillin derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an intermediate for beta-lactamase inhibitors and a cephalosporin based antibiotic in high purity and high yield, by reacting an azetidinone disulfide derivative with a hydrohalogenic acid in the presence of a nitrite, etc. CONSTITUTION:An azetidinone disulfide derivative expressed by formula I (R represents carboxyl-protecting group; R<1> and R<2> represent H, phthalimide, halogen or acylamino; R<3> represents nitrogen-containing heterocyclic group) [example; 2-oxo-4-(benzothiazol-2-yl)dithio-alpha-isopropenyl-1-azetidine acetic acid p-nitrobenzyl ester] is reacted with a hydrohalogenic acid (example; hydrochloric acid) in the presence of a nitrite (example; sodium nitrite) and/or an ester of nitrous acid to afford the aimed compound expressed by formula II (X represents halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing 2β-halogeno-substituted methylpenicillin derivatives. , R1
and R2 are the same or different and represent a hydrogen atom, a phthalimide group, a hydrogen atom or an acylamino group. The present invention relates to an improvement in a method for producing a 2β-halogeno-substituted methylpenicillin derivative represented by

Prior Art The above 2β-halogeno-substituted methylpenicillin derivative (I)
is a known compound useful as a β-lactamase inhibitor or an important intermediate for cephalosporin antibiotics.

Conventionally known methods for producing 2β-halogeno-substituted methylpenicillin derivatives (I) include the methods disclosed in JP-A-49-81380 and JP-A-58-4788, and Tetrahedron Le
tt, ), 1973. The method described in No. 3001 is known.

That is, these are -Sakura [where R-R', R2 and R3 are the same as above. ] By reacting the disulfide derivative represented by chlorine, bromine, metal chloride or metal bromide, known 2β
- A method for obtaining a halogeno-substituted methylpenicillin derivative (I).

Problems to be Solved by the Invention 2β-halogeno-substituted methylpenicillin derivative (I) is
It is a particularly unstable compound among penicillin derivatives,
For example, the Tetrahedron letter (Tetrahedron letter)
Lett, ), 1973. It is known that cephalosporins are readily isomerized to 3β-halogeno-substituted cephalosporins as described in 3001. Thus, the unstable 2β-halogeno-substituted methylpenicillin derivative CI
), it is desirable that the reaction time be short and the amount of by-products be small, and that the post-treatment etc. be simple.

However, in conventional methods using halogen gases such as chlorine and bromine, it is difficult to control the reaction and by-products are likely to be produced. Furthermore, methods using metal halides such as copper chloride and copper bromide (a) involve problems in stirring and the like in large-scale synthesis because of the non-uniform reaction system. (b) There are difficulties in filtering the slurry-like metal complex of the mercapto derivative and metal ion produced in the reaction; (C) The residue also poses problems such as pollution as industrial waste; (d) The solvent used is There remain problems in scale-up, such as the need for an anhydrous solvent, and it is difficult to say that this method is industrially satisfactory.

An object of the present invention is to provide a novel method for producing a 2β-halogeno-substituted methylpenicillin derivative (I) that does not have the above-mentioned problems.

Means for Solving the Problems As a result of intensive search for a new method that can be applied to the industrial production of 2β-halogeno-substituted methylpenicillin derivative (I) from disulfide derivative (II), the present inventor has found that disulfide derivative (II) We have discovered that 2β-halogeno-substituted methylpenicillin derivative (I) can be efficiently produced with high purity and high yield by a simple procedure of reacting n) with hydrohalic acid in the presence of nitrite or nitrite ester, and this book The invention was completed.

That is, the present invention relates to the general formula [wherein R represents a carboxyl protecting group, R1 and R2 are the same or different and represent a hydrogen atom, a phthalimide group, a halogen atom or an acylamino group, and R3 is a nitrogen-containing heterocyclic group] By reacting an azetidinone disulfide derivative represented by and X represents a halogen atom. ] This relates to a method for producing a 2β-halogeno-substituted methylpenicillin derivative, which is characterized by obtaining a penicillin derivative represented by the following.

In this specification, in particular, the above general formulas (I) and (II)
The groups represented by R5R1, R2, R3 and X are as follows.

The carboxyl protecting group represented by R may be any commonly known one, and specifically, for example, JP-A No. 49-813
Publication No. 80 and H., E., Frain, eds. Cephalosporins and Penicillins, Chemistry and
Biology (1972, published by Academic Press)
Any of those listed can be used. Preferred R groups include, for example, methyl, ethyl, propyl, butyl, t-
Substituted or unsubstituted alkyl groups such as butyl, trichloroethyl; substituted or unsubstituted aralkyl groups such as benzyl, diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxy Acyloxyalkyl groups such as methyl, pivaloyloxyethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl; methoxymethyl,
Alkoxyalkyl groups such as ethoxymethyl and benzyloxymethyl; other examples include a tetrahydropyranyl group and a dimethylaminoethyl group.

In this specification, examples of the halogen atom represented by R or R2 include a chlorine atom, a bromine atom, and
As the acylamino group, an acylamino group derived from an organic carboxylic acid that is linear or branched, cyclic or acyclic and may contain an unsaturated bond, nitrogen, oxygen, sulfur atom, etc. is used. For example, generally penicillin An acylamino group substituted at the 6-position of the derivative and at the 7-position of the cephalosporin derivative is used. Examples of suitable acylamino groups include phenylacetamino group, phenoxyacetamino group, 2-thienylacetamino group, furylacetamino group, and formylamino group.

Further, the nitrogen-containing heterocyclic group represented by R3 is a heterocyclic group containing 1 to 4 nitrogen atoms as a hetero atom, and these may further contain one sulfur atom as a hetero atom. . Examples include benzothiazolyl group, tetrazolyl group, thiadiazolyl group, pyridyl group, and pyrimidyl group. Moreover, these nitrogen-containing heterocyclic groups may have 1 to 3 lower alkyl groups, particularly alkyl groups having 1 to 4 carbon atoms, as substituents. Particularly preferred nitrogen-containing heterocyclic groups include benzothiazolyl group, 1-
Examples include lower alkyl-tetrazol-5-yl groups.

Disulfide derivative (I) used as a raw material in the method of the present invention
I) is, for example, a tetrahedron letter (Tetrahe
Dron Lett, ), 1973. 300
It can be synthesized by the method described in 1. That is, a compound represented by the following general formula and the general formula R35H (IV) [wherein R3 is the same as above]. ] It is obtained by reacting the compound represented by these under heating. Compounds of the above general formula (III) and general formula (IV)
) are all known compounds.

Examples of the hydrohalic acid used in the production method of the present invention include hydrochloric acid and hydrobromic acid.

Further, as the nitrite, any salt that does not affect the reaction can be used, but preferably alkali metal salts such as sodium, potassium, and lithium, alkaline earth metal salts such as calcium and magnesium, and the like are used. Further, the nitrite ester is not particularly limited, but examples thereof include lower alkyl nitrite esters having an alkyl moiety having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, etc. . A nitrite and a nitrite ester can also be used in combination.

The usage ratio of the disulfide derivative of the above general formula (II) and the hydrohalic acid is about 1 to 50 moles, preferably about 2 to 10 moles, per 1 mole of the disulfide derivative (■). Bye. The amount of nitrite and/or nitrite ester to be used is preferably about 0.2 to 50 moles, usually about 0.5 to 6 moles, per 1 mole of the disulfide derivative (■). The reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and various organic solvents or mixed solvents of organic solvents and water can be used. Examples of organic solvents include halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane, ether solvents such as ethyl ether and diisopropyl ether, aromatic solvents such as benzene and toluene, and esters such as ethyl acetate. Examples include hydrocarbon solvents such as hydrocarbon solvents, hexane, and petroleum ether, which may be used alone or in combination of two or more. Particularly in the present invention, it is preferable to use a two-phase solvent consisting of the above organic solvent and water. Although the reaction temperature is not particularly limited,
The reaction is usually carried out at a temperature of -20°C to 60°C, preferably -10°C to room temperature, and the reaction time is 30 minutes to 20 minutes.
Although the reaction time is about 4 hours, the reaction usually completes in about 30 minutes to 5 hours.

After the reaction is completed, the organic layer can be separated if necessary, and the desired product can be easily isolated by processing it by conventionally known methods such as recrystallization or chromatography.

Effect of the invention According to the present invention, the following excellent effects are achieved.

(1) The desired 2β-halogeno-substituted methylpenicillin derivative of general formula (I) can be produced with high purity and high yield.

(2) The reaction time is relatively short, usually about 30 minutes to 5 hours, and there are few by-products, and the purification process is simple, so isomerization and decomposition of unstable target products can be minimized.

(3) Compared to methods using metal halides such as copper chloride and copper bromide, there are no problems with stirring during mass synthesis;
There are no problems with filtration or disposal of the slurry-like metal complex of the mercapto derivative and heavy metal ions produced in the reaction.

(4) A two-phase solvent of water and an organic solvent can be used.

(5) It is easy to scale up and is industrially advantageous.

Example Next, examples will be shown to explain the present invention more specifically.

Example 1 Preparation of 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2-oxo-4-(benzothiazol-2-yl)dithio-α-impropenyl-1-azetidine acetic acid p- Two volumes of 15% hydrochloric acid were added to a solution of 251 mg of nitrobenzyl ester in dichloromethane, and an aqueous solution of 38 mg of sodium nitrite dissolved in 0.5 InlG of water was added dropwise over 30 minutes while stirring under water cooling.

After stirring for 1 hour under water cooling, the precipitate was filtered, and the organic layer of synovial fluid was separated, washed twice each with water, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate.

After filtration, the synovial fluid was concentrated under reduced pressure, and the residue was dissolved in a small amount of acetone. Insoluble materials were filtered off, the synovial fluid was concentrated under reduced pressure, and the residue was crystallized from ether. Melting point 104-105°C. Yield 98%.

Infrared absorption spectrum (KBr) νmax (Cm-') = 1780.1775 Nuclear magnetic resonance spectrum (CD (1!3') δ (ppm) = 1.49 (3H, s) 3.15, 3.63 ( 2H, AB-X.

J=16.1Hz, 4.2Hz, 1.7Hz) 3.60 (2H,s) 5, 12 (IH,s) 5.30 (2H,s) 5, 37~5.43 (LH,m ) 7, 57 (2H, d, J-8, 3Hz) 8.
26 (2H, d, I=8.3Hz) Example 2 Preparation of 2β-bromomethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2-oxo-4-(benzothiazol-2-yl)dithio- α-isopropenyl-1-azetidine acetic acid p-nitrobenzyl ester 5.01 g dichloromethane 2
10% hydrobromic acid was added to the solution, and an aqueous solution of 1.43 g of sodium nitrite dissolved in 10 g of water was added dropwise over 30 minutes while stirring under water cooling. After stirring for 1 hour at room temperature, the precipitate was filtered, and the organic layer of synovial fluid was separated, washed twice each with water, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the synovial fluid was concentrated under reduced pressure, and the residue was dissolved in a small amount of acetone. Insoluble materials were separated, the synovial fluid was concentrated under reduced pressure, and the residue was crystallized from ether. Melting point: 80-82°C. Yield 77%.

Infrared absorption spectrum (KBr) νmax (cm-') = 1790.1760 Nuclear magnetic resonance spectrum (CDCρ3) δ (ppm) = 1.53 (3H, s) 3.15.3.65 (2H, AB-X .

J=16.1Hz, 4.2Hz, 1.7Hz) 3.57 (2H,s) 5.18 (IH,s) 5.31 (2H,s) 5.40~5.46 (IH,m ') 7.57 (2H, d, J=8.9Hz) 8.26 (
2H, d, J = 8.9 Hz) Example 3 Preparation of 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2-oxo-4-(1-methyltetrazol-5-yl)dithio -α-isopropenyl-1-azetidine acetic acid
12 mQ of 5% hydrochloric acid was added to a solution of 1.19 g of p-nitrobenzyl ester in 8 mQ of dichloromethane, and the mixture was cooled with water and stirred.
An aqueous solution prepared by dissolving 0.43 g of sodium nitrite in 3 parts of water was added dropwise over 30 minutes. The mixture was stirred at room temperature for 5 hours, and the precipitate was filtered, and the organic layer of the furnace solution was separated, washed twice each with water, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the synovial fluid was concentrated under reduced pressure, and the residue was dissolved in a small amount of acetone. Separate insoluble matter by furnace,
After concentrating the furnace solution under reduced pressure, the residue was subjected to silica gel chromatography (developing solvent: benzene:acetone = 7:1) to obtain the desired product. Yield 61%. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained here matched those of the compound obtained in Example 1.

Example 4 Preparation of 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2-oxo-4-(benzothiazol-2-yl)dithio-α-impropenyl-1-azetidine acetic acid p- 2.51 g of nitrobenzyl ester to 1 part of dichloromethane
After dissolving the mixture in 5 mQ of water and adding 22% hydrochloric acid under water cooling, a solution of 650 mg of isoamyl nitrite in dichloromethane was added dropwise. After returning to room temperature and stirring for 1 hour, the precipitated insoluble matter was removed, and the organic layer of the furnace solution was separated, washed twice each with water, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the furnace liquid was concentrated under reduced pressure,
The residue was crystallized from ether. Yield 95%. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound obtained here matched those of the compound obtained in Example 1.

Example 5 Preparation of 2β-chloromethyl-2α-methyl-6β-phenylacetamidopenam-3α-carboxylic acid p-nitrobenzyl ester 2-oxo-3-(phenylacetamido)-4-(benzothiazol-2-yl ) dithio-α-isopropenyl-1-azetidine acetic acid p-nitrobenzyl ester 15% in 295 mg dichloromethane 51TIQ solution
Add 2 liters of hydrochloric acid and add 38 m of sodium nitrite while stirring under water cooling.
g to 0.g of water. An aqueous solution dissolved in 5 mQ was added dropwise over 30 minutes. After stirring for 1 hour under water cooling, the precipitate was filtered, and the organic layer of the furnace solution was separated, washed twice each with water, an aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the synovial fluid was concentrated under reduced pressure, and the residue was dissolved in a small amount of acetone. Separate insoluble matter by furnace? After concentrating the P solution under reduced pressure, the residue was subjected to silica gel chromatography (developing solvent: benzene:ethyl acetate = 9:1) to obtain the desired product. Yield 91%.

Infrared absorption spectrum (CHCρ3) νmax (cm”) = 3410. 178017
75.1680 Nuclear magnetic resonance spectrum (CDCρ3) δ (ppm) = 1.62 (3H, s) 3.37 (2H, s) 3.59 (2H, s) 5.02 (IH, s) 5.14 (2H, s) 5.45-5.70 (2H, m) 6.38 (IH, d, J=8Hz) 7.27 (5H, s) 7, 32 (5H, s) Examples 6-15 Thereafter, the reaction was carried out in the same manner as in Example 1. The physical properties of the obtained compound of general formula (I) are shown in Table 1 below.

In addition, in Table 1, rBhJ is a benzhydryl group, rPMB
J represents a varamethoxybenzyl group, and "rPNB" represents a varanitrobenzyl group. Regarding the infrared absorption spectra in Table 1, Examples 9 and 12 were measured using the KBr method, and the other Examples were measured using CHCρ3.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) [In the formula, R represents a carboxyl protecting group, R^1 and R^
2 are the same or different and represent a hydrogen atom, a phthalimide group, a halogen atom, or an acylamino group, and R^3 represents a nitrogen-containing heterocyclic group] and a hydrohalic acid are combined into nitrite. And/or by reacting in the presence of nitrite ester, the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R, R^1 and R^2 are the same as above, X
indicates a halogen atom. ] A method for producing a 2β-halogeno-substituted methylpenicillin derivative, which comprises obtaining a penicillin derivative represented by the following.