KR820000630B1 - Process for preparation of azetidinone mercury sulfides - Google Patents

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Description

Method for preparing azetidinone mercury sulfides

The present invention relates to a process for the preparation of an azetidinone compound of formula (I) used for the synthesis of cephalosporin derivatives.

N is 0 or 1 in the above structural formula,

X is chlorine or bromine,

R is hydrogen or a carboxylic ester protecting group.

The bicyclic structures of penicillins and cephalosporins are largely β-lactam or azetidinone residues. Because of the presence of β-lactam residues in the structures of these active antibiotics, many chemists in this field have used β-lactam ring as the parent nucleus. Of course, efforts to convert to penicillin-cephalosporins have found many types of β-lactam intermediates, both mono- and bicyclic. These intermediates were derived from penicillins and cephalosporins, while other intermediates were made by fully synthesizing.

In the Dutch Kingdom Patent Application No. 7,600,950 (August 3, 1976) an example of the above description is given which discloses the reaction of an azetidinone compound with salts of silver, mercury, copper, cadmium and zinc. In this reaction, 3-acylamino azetidinone (Example 6) is obtained by using thiazolin azetidinones as starting materials.

The azetidinone compound of formula (I) according to the present invention is prepared as follows. That is, the compound of formula (II) is 1.0 to 1.2 equivalents of halogenated secondary mercury of HgX ₂ (X = Cl, Br) with at least an equivalent primary or secondary alkyl of 1 to 8 or 1 to 8 carbon atoms The azetidinone compound of formula (I) is prepared by reacting in an acyclic organic solvent in the presence of diol of 8.

N is 0 or 1 in the above structural formula,

X is chlorine or bromine,

R is hydrogen or a carboxylic ester protecting group,

R ₁ is a) alkyl of 1 to 4 carbon atoms, halo-alkyl of 1 to 4 carbon atoms,

b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, benzhydryloxy, 4-methoxy benzyloxy

c) 1,4-cyclohexadienyl, phenyl or chlorine, bromine, urethra, hydroxy, alkoxy of 4 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, nitro, cyano, trifluoromethyl 1 or 2 substitution R ₂ group consisting of phenyl,

d) an arylalkyl group of the formula R _2- (O) m CH _2- , wherein R ₂ is as defined above and m is 1 or 0,

e) Heteroarylmethyl of formula R ₃ CH ₂ -wherein R ₃ is 2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl, 4-isoxazolyl Group.

In the above definition, the term "alkyl of 1 to 4 carbon atoms" means methyl, ethyl, isopropyl, n-prephyll, isobutyl, n-butyl, and the term "alkoxy of 1 to 4 carbon atoms" refers to methoxy. Oxy, isopropoxy, tert-butoxy, n-propoxy, and the term "halo-C1-4 alkyl" means chloromethyl, bromomethyl, iodoethyl, 2-chloropropyl, 3- Bromopropyl, 2-iodobutyl, 3-chlorobutyl, 1-chlorobutyl and the like.

The term “carboxylic acid ester group” refers to an ester group used to protect a carboxylic acid functional group when a reaction occurs at another functional group in the compound, and these protecting groups are easily removed from the carboxy group by a method such as hydrolysis or hydrocracking. It should be one that can liberate the corresponding carboxylic acid. Examples thereof include tert-butyl, 1-methyl cyclohexyl, benzyl-4-methoxybenzyl, alkanoyloxymethyl of 2 to 6 carbon atoms, 2-iodoethyl, 2-bromoethyl, 4-nitrobenzyl, di Phenyl (benzhydryl), phenacyl, 4-halofenacyl, dimethylallyl, 2,2,2-trichloroethyl, succinimido methyl, alkoxy-methyl having 1 to 3 carbons. Other carboxylic acid protecting groups are described in the following references. [E. Haslam in Protective Groups in Organic Chemistry J. F.W. Mcomie, Ed., Plenum Press, New York, 1973, Chapter 5.]

The nature of such a protection group is not a problem as long as it is stable under the conditions of this procedure. Preferred carboxylic acid protecting groups are tert-butyl, 4-methoxybenzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl.

When R ₂ is substituted phenyl, representative examples of the R ₁ group include 4-chlorophenyl, 2-chlorophenyl, 3-methyl-4-bromophenyl, 4-alkoxy-2-chlorophenyl, 4-hydroxyphenyl, 3-nitrophenyl, 4-cyanophenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 3-methyl-4-n-butoxyphenyl, 4-nitro-3-chlorophenyl, 2-hydroxy 4-methoxyphenyl.

Examples of R ₁ when R ₁ is of the formula R _2- (O) m CH ₂ -group include benzyl, phenoxymethyl, 1,4-cyclohexadienylmethyl 4-chlorophenoxymethyl, 2-methyl-4- Hydroxybenzyl, 3-nitrobenzyl, 2-bromophenoxymethyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 2,4-dichlorophenoxymethyl, 3-cyano-4-e Oxybenzyl.

Thiazoline azetidinone, which is used as a starting material in preparing the compound of formula (I), is a known compound obtained by reacting penicillin sulfoxide ester with trimethylphosphite at high temperature.

The preparation of this compound is well documented in the following references.

Compounds obtained from 6-phenylacetamido and 6-phenoxy acetamido penicillin sulfoxide esters are preferred as starting materials.

Another method of the present invention is carried out by stirring the mixture of the substrate thiazolin azetidinone, halogenated di mercury, alcohol or glycol well in a room temperature, inert organic solvent. The reaction temperature is not critical and is preferably within the range of room temperature (20 ° to 30 ° C.).

The inert organic solvent used as the medium is an organic solvent which does not react with the reactants or products under the present reaction conditions, and aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, chloroform, methylene chloride, carbon tetrachloride, 1 Halogenated aliphatic hydrocarbons such as, 2-dichloroethane (ethylene chloride), 1,1,2-trichloroethane, 1,1-dibromo-1,2-chloroethane, esters such as ethyl acetate and methyl acetate Ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether and 1,2-dimethoxy ethane, nitriles such as acetonitrile and propionitrile, nitromethane, dimethylformamide and dimethylacetamide There is acetone. Preference is given to double halogenated aliphatic hydrocarbons, in particular methylene chloride.

As the second mercury halide, mercury chloride and mercury bromide are preferable, and mercury chloride is even more preferable.

When mercuric chloride is used, the product is obtained with azetidinonethio mercurychloride hydrochloride of formula (I), and when mercury bromide is used the product is azetidinonethio mercury bromide bromide Obtained with hydrochloride.

At least one chemical equivalent of the second mercury halide is used to complete the reaction. If an amount of less than 1 molar amount is used, the yield of the product is poor, and unreacted starting material remains. 1.0 to 1.2 moles of the second mercury halide are preferably used for each mole of starting material thiazolin azetidinone.

As mentioned above, this reaction is essential to be carried out in the presence of an alcohol or diol (glycol).

Preference is given to primary or secondary alcohols of 1 to 8 carbon atoms or diols of 1 to 8 carbon atoms. Examples of suitable primary C1-C8 alcohols include methanol, ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, benzyl alcohol and isooctyl alcohol. Examples of suitable secondary alcohols are isopropanol, Secondary-butanol, 2-hydroxypentane, cyclohexanol, 2-hydroxyoctane. Representative examples of diols include ethylene glycol, propylene glycol, 2,2-dimethyl-1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-butene-1,4 -Diol, 1,2-cyclohexanediol and 1,3-cyclohexanediol.

It is preferable to use diols because the yield is much better when diols are used than when alcohols are used.

If the alcohol or diol to be used should be at least chemical equivalent (1 mole per mole), it is preferable to use about 2 to 10 moles of alcohol or diol per mole of thiazolin azetidinone. However, as mentioned above, it is necessary to note that the structure of the product according to the invention does not depend on the alcohol or diol and properties used.

The reaction time is not critical and the reaction starts to occur when the reactants start contacting and proceeds at different reaction rates depending on the nature of the substrate, the reaction temperature and the solvent used.

After the reaction, thin layer chromatography is performed. The reaction time is usually in the range of 30 minutes to 12 hours, particularly 3 to 6 hours.

As a specific example, the compound of the following formula (a) comprises 1,2-dichloro with 2.2 equimolar amount of mercury bromide and 2 equimolar amounts of thiazolin azetidinone of the following formula (b) and 10 equimolar secondary butanol It can be obtained by reacting at room temperature in ethane. When mercuric chloride is used, the corresponding mercury chloride hydrochloride is obtained.

Examples of representative compounds according to the invention are as follows.

[[1- [1- (benzylhydroxycarbonyl) -2-methyl-prop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercury hydrochloride,

[[1- [1- (1-methylcyclohexyloxycarbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] -mercury chloride hydrochloride ,

[[1- [1- (phenacycloxycarbonyl) -2-methyl-2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] -mercury chloride hydro Chloride,

[[1- [1- (2,2,2-Trichlorethoxy carbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio]- Mercury bromide hydrobromide,

[[1- [1- (4-nitrobenzyloxycarbonyl) -2-methyl-prop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercury bromide hydrobromide,

[[1- [1-benzyloxycarbonyl-2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercury chloride hydrochloride,

[[1- [1- (4-methoxybenzyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercury chloride hydrochloride and

[[1- [1- (2-iodoethoxycarbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercuric chloride hydrochloride.

The product prepared according to the invention can be separated by conventional laboratory methods such as filtration, crystallization, recrystallization, chromatography, etc., and in general, the product is crystallized in the reaction mixture, separated by filtration.

Compounds of formula (I) are useful as intermediates in preparing known cephalosporin antibiotics, which react with excess chlorine in an inert organic solvent such as chloroform, methylene chloride, ethyl acetate, dimethylformamide and the like A mixture of 6-amino-2-chloromethyl-2-methylphena-3-carboxylate and 7-amino-3-chloro-3-methylcepam-4-carboxylate is produced.

The mixture is acylated by a conventional acylation reaction, separated by column chromatography to give the corresponding 6-acylamino-3-chloro-3-methylcepam-4-carboxylate.

Treatment of the 3-chloro-3-methylcepam derivative with an organic base such as pyridine or triethylamine in methylene chloride results in dehydrohalogenation reaction to give the desacetoxy cephalosporin of formula (c).

In the above structural formula

R ′ is an acyl group derived from carboxylic acid,

R is hydrogen or a carboxylic ester protecting group.

The ester protecting group R can be removed according to a known method, and when the carboxylic acid protecting group is benzhydryl, tert-butyl, 4-methoxybenzyl, 1-methylcyclohexyl, the ester is trifluorinated in the presence of anisole. Treatment with an acid such as acetic acid to de-esterify. 2-iodoethyl, 2-bromoethyl, 4-nitrobenzyl, 2,2,2-trichloroethyl protecting group can be removed by treatment with an acid such as zinc and acetic acid or hydrochloric acid. The 4-nitrobenzyl protecting group may be removed by hydrogenation in a carrier or suspension of barium sulfate, carbon alumina or the like in the presence of Pd, Pt, Rh or a compound thereof.

이고, R=이다)으로 임상적으로 널리 사용되고 있는 화합물이다.The antibiotic effect of cephalic acid is well known, and one of these cephalic acids is cephalexin (R '

And R =).

The following examples illustrate the invention in more detail.

Example 1

[[1- [1- (4-nitrobenzyl oxycarbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercuric chloride hydrochloride

56.22 g (120 mmol) 2-phenoxymethyl-7- [1- (4-nitrobenzyl oxycarbonyl) -2-methylprop in 603 ml methylene chloride suspension containing 35 g (130 mmol) of mercuric chloride 2-enyl-1,3,6-diazabicyclo [3,2,0] hept-2-en-5-one is added.

67 ml (53.6 g, 720 mmol) of isobutanol are then added and the mixture is stirred at room temperature for 5.5 hours. Once the product crystallizes, it is filtered off, washed with methylene chloride and dried.

Yield: 40.45 g (54%): nmr (DMSO-d ₆ ) δ 1.86 (bis, 3, CH ₃ ), 4.83 (1, d, J = 4 Hz, C ₂ -H), 4.96 (s, 1,- CHCOO-), 5.1 (bis, 2, = CH ₂ ), 5.40 s, 2, ester CH ₂ ), 5.76 (1, d, J = 4 Hz, C ₃ -H), 7.4-8.8 (g, 4, ArH ), And 8.76 (bis, 2, NH ₂ -HCl).

Example 2

[[1- [1- (4-nitrobenzyl oxycarbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercuric chloride hydrochloride

(A) 9.2 g (20 mmol) 2-phenoxymethyl-7- [1- (4-nitrobenzyl oxycarbonyl) -2-methylprop-2-enyl) -1,3,6-diazabicyclo -3,2,0] Hept-2-en-5-one, 5.8 g (21.5 mmol) of mercuric chloride, 100 ml methylene chloride, a mixture of 18.75 ml (120 mmol) and 2-ethylhexanol at room temperature Stir for hours.

When the title compound falls into the crystals, it is filtered off, washed with methylene chloride and dried. Yield: 8.14 g (65%)

The process is repeated with other alcohols and diols instead of 2-ethyl hexanol. The following are the properties and amounts of alcohols or diols used and the yields of the materials produced.

(B) 1,3 propanediol (4.35 ml, 60 mmol);

Yield 11.41 g (91.3%)

(C) 1,3-butanediol (5.36 ml, 60 mmol);

Yield 9.69 g (77.5%)

(D) 2,2-dimethyl-1,3-propanediol (60 mmol);

Yield: 12527 g (98%)

(E) propylene glycol (1,2-propanediol) (60 mmol);

Yield: 11.30 g (90.4%)

(F) methanol (60 mmol);

Yield: 8.10 g (64.8%)

(G) n-butanol (60 mmol);

Yield: 7.22 g (57.8%)

Example 3

[[1- [1- (2,2,2-trichloroethoxycarbonyl) -2-methylprop-2-enyl] -3-amino-4-oxo-2-azetidinyl] thio] mercury Chloride hydrochloride

2.9 g (10.7 mmol) of mercuric dichloride was added to 4.6 g (10 mmol) of 2-phenoxy-methyl-7- [1- (2,2,2-trichloroethoxycarbonyl) -2-methylprop- 2-enyl] -1,3,6-diazabicyclo [3,2,0] is added in a mixture of 50 ml methylene chloride, 10 ml methanol, 5 ml water containing hept-2-en-3-one. The mixture is stirred at room temperature overnight, and when crystals precipitate, the mixture is filtered, washed with methanol and dried under vacuum at 50 ° C.

Yield: 3.7 g (63%); nmr (DMSO-δ ₆ ) δ 1.9 (bis, 3, (CH ₃ ), 4.73 (d, 1, J = 4 Hz, C ₂ -H), 4.95 (bis, 2), 5.0 (s, 1), 5.76 (d, 1, J = 4 Hz, C ₃ -H), 8.73 (bis, 2, -NH ₂ -HCl).

Claims (1)

The compound of formula (II) is reacted in an inert organic solvent with a halogenated second mercury of HgX ₂ of 1.0 to 1.2 equimolar amounts in the presence of an equimolar amount of 1 to 8 primary or secondary alcohols or diols. Method for preparing the compound of I).

Wherein n is 0 or 1, X is chlorine or bromine, R is hydrogen or a carboxylic acid protecting group, R ₁ is a) alkyl of 1 to 4 carbon atoms, halo-alkyl of 1 to 4 carbon atoms, b) benzyloxy , 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, benzhydryloxy, 4-methoxybenzyloxy, c) 1,4-cyclohexadienyl, phenyl, or R ₂ group consisting of phenyl once or twice substituted with a group selected from chloro, bromo, ureth-do, hydroxy, nitro, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms _{, d) R 2 - (O} ) m-CH 2 - aryl-alkyl group (R ₂ is as defined above, m is 0 or _{1), e) R 3 CH} 2 - heteroaryl methyl group of ( R ₃ is 2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl, 4-isoxazolyl).