CS236799B2 - Processing of halogenmethyl-6-(2-fenylacetamide)penicillinyloxymethyl-carbonyl - Google Patents

Description

(54) A method for producing halomethyl 1-6- (2-phenylacetamido) penicilanoyloxymethyl carbonate

The present invention provides a process for the preparation of novel lialogenomethyl-6- (2-phenylacetamido) penicilanoyloxymethyl carbonates bearing a residue at the 2-position of the acetamide moiety that can be easily converted to an amino group. These compounds are useful as starting materials for the preparation of antibacterially active 6- (2-amino-2-phenylacetamido) penicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl carbonate, which is the subject of our co-pending U.S. Patent No. 236,779.

Accordingly, the present invention provides a process for the preparation of compounds of formula IV '

in which

R @ ¹ represents a hydrogen atom, a hydroxyl group, a formyloxy group, a C2 -C7 alkanoyloxy group, a C2 -C7 alkoxycarbonyloxy group or a radical of the formula

R ² C ⁶ H ⁴ COO in which

R ² is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorine, bromine, iodine, or cyano,

Q is azido, benzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino; and

X represents a halogen atom, characterized in that the compound of formula (IV) -W

CHCONH i

GL

N, ^CH3

COOM

Í / Z) in which

R ¹ and Q are as defined above and M represents a salt-forming cation at the carboxyl group, reacted with a compound of the formula wherein:

X is as defined above,

The process for the preparation of the compounds of the formula IV according to the invention can be described by the following reaction scheme

XCH2OCOOCH2X

in which

R ¹ , M, Q and X are as defined above.

The reaction is carried out by reacting the amine-protected benzyl piperilecillin salt of formula (IV) with at least an equimolar amount, but preferably with an excess of up to 10-fold molar excess, bis-halomethyl carbonate in the presence of an inert organic solvent at a temperature of about -20 to 60 ° C, preferably at a temperature of 0 to 30 ° C. Among the solvents that can be used successfully in this reaction are relatively polar organic solvents, the use of which reduces the required reaction time to a minimum. Typical usable solvents include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, dichloromethane, chloroform, acetone, and hexamethylphosphoric triamide. The time required for the reaction to proceed virtually completely varies depending on a number of factors, such as the nature of the reactants, the reaction temperature and the solvent.

Carboxylic acid salts of formula (IV) are prepared from the corresponding carboxylic acids. In a preferred process for preparing those salts in which M is an alkali metal, such as sodium or potassium, the corresponding 2-ethylhexanoic acid salt is used as the base. Typically, the carboxylic acid of formula IV ', in which M is hydrogen, is dissolved in ethyl acetate, an equimolar amount of sodium or potassium 2-ethylhexanoate is added with stirring, and the precipitated salt of formula IV' is isolated by filtration.

Appropriate salts of the general formula IV 'in which M is tetrabutylammonium ion can be obtained from the corresponding acids, for example by neutralization with an aqueous solution of tetrabutylammonium hydroxide in the presence of a water-immiscible organic solvent, preferably in the presence of chloroform. The solvent layer was separated and the product was isolated by evaporation of the solvent. Alternatively, the sodium or potassium salt of formula IV 'is reacted with an equimolar amount of an aqueous solution of tetrabutylammonium hydrogen sulfate in the presence of a water-immiscible solvent, the precipitated alkali metal hydrogen sulfate is filtered off and the product isolated by evaporation of the solvent.

The corresponding carboxylic acids, which are precursors of these intermediates of formula (IV), can be obtained, for example, according to the methods described in U.S. Pat. No. 4,053,360 by acylating 6-aminopenicillanic acid corresponding to the acid of formula (I) in which:

R ¹ and Q are as defined above, or an activated derivative thereof, for example an acid chloride or a mixed anhydride formed by reaction with ethyl chloroformate.

Bis-chloromethyl carbonate is prepared photochemically. by chlorination of dimethyl carbonate according to the method of Kling et al., Compt. rend. 170, 111, 234 (1920); Chem. Abstr. 14, 1304 (1920).

Bis-bromomethyl carbonate and bis-iodomethyl carbonate are obtained from the bis-chloromethyl derivative by reaction with, for example, sodium bromide or potassium iodide using methods known in the art.

The invention relates to a process for the preparation of penicillanic acid derivatives corresponding to a structural formula

In penicillanic acid derivatives, the intermittent bond (.......) of the substituent to the bicyclic nucleus indicates that the substituent is above the plane of the nucleus. Such a substituent is referred to as a substituent having an α-configuration.

In contrast, enhanced bonding of the substituent to the bicyclic nucleus means that the substituent is located above the plane of the nucleus and is referred to as the β-configuration. Binding of the substituent to the bicyclic nucleus by normal solid line

means that this substituent can be in both the n-configuration and the β-configuration.

The compounds of formula (IV ') are named as diesters of carbonic acid. Thus for example the compound of formula IV 'in which R ¹ represents hydrogen, Q represents an azido group and X is iodo is designated JEKO iodomethyl-6- (2-azido-2-fenylacetamidoj Peni cilanoyloxymethyl carbonate.

Furthermore, whenever reference is made herein to compounds of the general formula IV se or IV ', these are always (unless otherwise indicated) compounds in which the substituent of the formula chconh

Θ in which

R ¹ and Q are as defined above, having the D-configuration.

The invention is illustrated by the following non-limiting examples. NMR spectra were measured for solutions in deuterochloroform or DMSOd and positions ^of: gnálů are expressed in ppm-values versus tetramethylsilane. Signal shapes are indicated by the following abbreviations:

šs = broad singlet s = singlet d = doublet t = triplet q = quartet m = multiplet

Preparation

Bis-chloromethyl carbonate

The method used essentially corresponds to that described by Kling et al. in Compt. rend. 170, 111-113, 234-236 (1920),

Chem. Abstr. 14, 1304 (1920).

A solution of 59 ml of dimethyl carbonate in 120 ml of carbon tetrachloride was cooled in ice and chlorine gas was bubbled into it under irradiation with a daylight bulb until most of the starting material had reacted. Excess chlorine was removed by a stream of nitrogen, the solvent was evaporated and the residue was distilled at 50 psi using a short distillation column equipped with a distillation head. The desired product boils at 95-100 ° C / 6.7 kPa.

Yield 68 g.

Preparation

Tetrabutylammonium-6- (2-benzyloxycarbonylamino-2- [4-hydroxyphenyl] acetamido] penicillanate

To a vigorously stirred mixture of 1.0 g of 6- (2-benzyloxycarbonylamino-2- [4-hydroxyphenyl] acetamido) penicillanic acid, 30 mL of dichloromethane and 20 mL of water was added an aqueous solution of terabutylammonium hydroxide to a pH of 8.0. The mixture was stirred at pH 8.0 for a further 30 minutes, then the layers were separated. The aqueous layer was extracted with dichloromethane, the combined dichloromethane solutions were dried over sodium sulfate and evaporated in vacuo. This gave 1.1 g of the title compound.

236793

NMR (perdeuterodimethylsulfoxide, δ in ppm):

0.70-1.80 (m, 34H),

2.90-3.50 (m, 8H),

3.93 (s, 1 H),

5.10 (s, 2H).

5.23-5.50 (m, 3H)

6.76 (d, 2 H),

7.20 (d, 2H).

7.40 (s, 5H);

7.76 (d, IH)

8.6 (d, 1 H).

Example 1 bis-iodomethyl carbonate

To a solution of 10.7 ml (15.9 g 0.1 mol) bis (chloromethyl) carbonate in 400 ml acetone was added 75 g (0.5 mol) sodium iodide, and the mixture was heated under reflux for 2 hours under nitrogen. The mixture is then allowed to stand overnight at room temperature and filtered. The filtrate is concentrated in vacuo, 500 ml of methylene chloride are added to the residue, and the mixture is filtered. The filtrate is concentrated to a volume of 200 ml, 200 ml of water are added to the concentrate and the aqueous phase is adjusted to pH 7.5. Aqueous sodium thiosulfate solution was added to remove iodine, the organic phase was separated and dried over sodium sulfate. The dried methylene chloride solution is concentrated in vacuo to an oily residue which darkens on standing. The oily product is stirred with a mixture of 35 ml of hexane and 6 ml of diethyl ether at 0 DEG C., the precipitated crystals are filtered off and washed with hexane and dried. There were obtained 10.0 g (29%) of a yellowish crystalline product, m.p. 49-51 ° C.

@ 1 H-NMR (CDCl3, < 5 ppm):

5.94 (s).

IR (nujol): 1756, 1775 cm @ ^-1 .

Example 2

Iodomethyl-6- [D- (2-azido-2-phenylacetamido)] penicilanoyloxymethyl carbonate

To a solution of 2.43 g (7.1 mmol) of bis-iodomethyl carbonate in 16 mL of chloroform cooled to 0 ° C was added dropwise a solution of 2.19 g (3.5 mmol) of tetrabutylammonium 6- [D- (2 (azido-2-phenylacetamido) -penicillanate in 10 ml of chloroform. After the addition was complete, the reaction mixture was allowed to warm to room temperature and allowed to stand at room temperature overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using methylene chloride / ethyl acetate (8: 1 by volume) as eluent. 822 mg (40%) of the desired product is obtained.

1 H-NMR (CDCl 3, δ in ppm):

1.52 (s, 3H);

1.65 (s. 3H);

4.45 (s, 1 H),

5.04 (s, 1H),

5.65 (m. 4H);

5.92 (s, 2H).

7.34 (s, 5H).

IR (chloroform): 1770 cm @ ^-1

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of halomethyl 6- (2-phenylacetamido) penicilanoyloxymethyl carbonates of the general formula IV- ^R -CHCONH GL COOCH, OCOCH, X of || (IV 1 in which R @ ¹ represents a hydrogen atom, a hydroxyl group, a formyloxy group, a C2 -C7 alkanoyloxy group, a C2 -C7 alkoxycarbonyloxy group or a radical of the formula RWldCOO in which R ² is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, fluorine, chlorine, bromine or iodine, or cyano, Q is azido, benzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino; and X represents a halogen atom, characterized in that the compound of formula (IV ') in which R ¹ and Q are as defined above and M represents a salt-forming cation on the carboxyl group, reacted with a compound of formula XCH2OCOOCH2X in which X is as defined above, in an inert organic solvent; at temperatures from -20 to 60 ° C. 2. A process according to claim 1, wherein R @ ¹ is a hydrogen atom or a hydroxyl group and the remaining radicals are as defined above. 3. A process according to claim 1, wherein M is sodium, potassium or tetrabutylammonium and the remaining general symbols are as defined above.