CH650494A5 - METHOD FOR PRODUCING CARBONIC ACID ESTERS. - Google Patents

Description

650494

PATENT CLAIM Process for the preparation of carboxylic acid esters of the general formula I

R-C-O-R 'II

O

(I)

O

II

R-C-OH

(II)

in which R has the above meanings, with an N-chlorocarbonyl-sec.-amide of the general formula III

,1

Cl-C-N

r

n o

in which

X1 and X2 for Q-Qalkyl or X1 + X2 for Cj-Cßalkylene or for -CH2CH-S-C (CH3) -CH-

-N-

0 0

«II

R-C-O-C-N x "

tl

0

The present invention relates to a new process for the preparation of carboxylic acid esters of the general formula I.

R-C-O-R 'II

O

(I)

in which R is a residue of an organic acid, selected from a (1-6 Qalkyl, a cycloalkyl with up to 6 C atoms, an aryl, an aralkyl with up to 5 C atoms in the alkyl residue or a heterocyclic residue which is unsubstituted or can be substituted with other functional groups, and R 'is a (1-6 Qalkyl, a cycloalkyl having up to 6 carbon atoms, an aryl or an aralkyl having up to 5 carbon atoms in the alkyl radical, which is unsubstituted or can be substituted with halogen, alkoxy or nitro, or represents an enamine radical, characterized in that a carboxylic acid of the general formula II

(III)

in which R is a residue of an organic acid, selected from a (1-6 Qalkyl, a cycloalkyl with up to 6 C-io atoms, an aryl, an aralkyl with up to 5 C-atoms in alkyl residue or a heterocyclic residue, which can be unsubstituted or substituted with other functional groups, and R 'is a (1-6 Qalkyl, a cycloalkyl having up to 6 C atoms, an aryl or an aralkyl i5 having up to 5 C atoms in the alkyl radical, which may be unsubstituted or substituted with a halogen, alkoxy or nitro, or represents an enamine radical.

The compounds of the formula (I) are known and many of them are used to a large extent in the pharmaceutical industry, since they include Penicillin esters and the corresponding sulfoxides, which are important intermediates for the synthesis of cephalosporin and other β-lactam antibiotics, include.

It is already known that esters of very sensitive organic carboxylic acids, e.g. Carboxylic acid (ß-lactams), by the reaction of alcohols with mixed anhydrides, which in turn can be obtained from chlorocarbonic acid (DE-OS 1 795 413).

It is also known that esters of sensitive carboxylic acids starting from alcohols and carboxylic acids via an intermediate complex formed from N, N-disubstituted acid amides and carbonyl dichloride, or generally by the action of a halogenating agent, e.g. Thionyl chloride (DE-OS 2 233 519) or alkyl chloroformate 35 (DE-OS 2 233 520) are accessible.

It has now been found that carboxylic acid esters of the formula (I) can be obtained by the selective alcoholysis of mixed anhydrides of the general formula IV

40

COCH3

stand,

in the presence of an inert, water-immiscible organic solvent and in the presence of an organic tert. Base at a temperature of -10 ° to +10 ° C in a mixed anhydride of the general formula IV

X1

0 0

II II '

R-C-O-C-N, "2nd

9 «

0

(XV)

in which R, X1 and X2 have the meaning given in the claim, with an alcohol of the general formula V

(IV)

H-O-R '

(V)

in which R, X1 and X2 have the meaning given above and this is a selective alcoholysis with an alcohol of the general formula V

H-O-R '

(V)

55 in which R 'has the above meanings.

The reaction is carried out in the temperature range from -5 ° C to + 5 ° C, most advantageously at a temperature of about 0 ° C. If necessary, an inert organic solvent such as methylene chloride is used. 60 The mixed anhydride of formula IV is by the reaction of a carboxylic acid of general formula II

in which R 'has the above meaning, at a temperature of -5 ° to + 5 ° C.

65

O

II

R-C-OH

(II)

in which R has the above meanings, with an N-chlorocarbonyl-sec.-amide of the general formula III

3rd

650 494

O x1

Cl-C-H x2 ("D

VCL —- /

II

0

in which X1 and X2 have the meaning given above. This reaction is carried out in an inert water-immiscible organic solvent, most advantageously in methylene chloride or tetrahydrofuran, with the addition of an organic tert. Base, preferably pyridine or triethylamine. The reaction takes place at a temperature from -10 ° C to +10 ° C, most advantageously at about 0 ° C.

The reaction time in the preparation of the intermediate compound (IV) can be 5 to 30 minutes, while the selective alcoholysis is completed in 30 to 60 minutes, in each case with stirring.

In both reaction stages, the reagents are advantageously used in stoichiometric amounts, but in each case an excess of up to 10 mol% of the N-chlorocarbonyl-sec.-amide, the alcohol or the tert. Base, based on the carboxylic acid, can be used.

The carboxylic acid ester (I) obtained is isolated and purified from the reaction mixture in a conventional manner, for. B. by adding water, separating the organic layer, washing with water and subsequent drying and evaporation of the solvent. Alternatively, the solvent can be evaporated immediately after the reaction, after which the residue is dissolved in an organic water-immiscible solvent, e.g. is dissolved in methylene chloride or ethyl acetate and stirred with water. The organic layer can optionally be washed with a NaHCO 3 solution and repeatedly with water and finally processed in the manner indicated above.

The following examples are intended to illustrate the invention, but in no way limit it. (Unless otherwise noted, "%" means percent by mass.)

Example 1 Ethyl phenylacetate Phenylacetic acid (6.8 g, 50 mmol) is dissolved in methylene chloride (50 ml), triethylamine (5 g, 50 mmol) is added and the solution is cooled to 0.degree. A solution of N-chlorocarbonyl-pyrrolidin-2-one (7.35 g, 50 mmol) in methylene chloride (30 ml) is then added to the above solution and the reaction mixture is stirred for 30 minutes. Then ethanol (2.3 g, 50 mmol) is slowly added and the reaction solution is stirred for 1 hour. After adding water (60 ml), the layers are separated and the organic layer is washed with water, dried and the solvent is evaporated.

Yield: 7.2 g (87.5%) of an oily product IR spectrum (film): 1730 (vs) cm-1 (C = 0, ester) JH NMR spectrum (CDC13) 5: 1.24 (t , J = 6 Hz, CH3), 3.58 (s, PhCH2CO), 4.21 (q, J = 6 Hz, OCH2), 7.3 (s, C6H5).

Example 2

Phenylacetic acid (2,2,2-trichloroethyl ester)

A solution of phenylacetic acid (6.8 g, 50 mmol), pyridine (4 g, 50 mmol) and methylene chloride (50 ml) is added dropwise with a solution of N-chlorocarbonyl-pyrrolidin-2-one (7.35 g, 50 mmol) in methylene chloride (20 ml) with stirring at a temperature of 0 ° C. The reaction solution is stirred for 20 minutes, then with

2,2,2-trichloroethanol (7.47 g, 50 mmol) was added and stirring was continued for 30 minutes. The reaction product is isolated as mentioned in Example 1.

Yield: 11.4 g (85%) of an oily product IR spectrum (film): 1755 (vs) cm-1 (C = 0, ester).

Example 3

6-phenoxyacetamido-penicillanic acid (2,2,2-trichloroethyl ester)

A solution of 6-phenoxyacetamido-penicillanic acid (7 g, 20 mmol), pyridine (1.6 g, 21 mmol) and methylene chloride (60 ml) is mixed within 10 to 15 minutes with a solution of N-chlorocarbonyl-pyrrolidin-2 -one (2.95 g, 20 mmol) in methylene chloride (15 ml) was added with stirring at 0 ° C. The reaction mixture is stirred for 15 minutes, then a solution of 2,2,2-trichloroethanol (3.3 g, 22 mmol) in methylene chloride (15 ml) is added dropwise and the mixture is stirred for a further hour. Water (50 ml) is added, stirred for 2 minutes, the organic layer is separated, washed with water (25 ml) and dried. After evaporation of the solvent, an oily residue remains.

Yield: 7.9 g (82.5%) of a product whose IR and * H NMR spectra are identical to those cited in the literature [J. Org. Chem. 36 (1971) 1259],

Example 4

Benzyl 6-phenoxyacetamidopenicillanate

A solution of 3-chlorocarbonyl-8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3.2, 1] octan-2-one (2.77 g, 10 mmol) in methylene chloride (50 ml) is mixed with pyridine (0.79 g, 10 mmol) and immediately afterwards 6-phenoxyacetamidopenicillanic acid (3.5 g, 10 mmol) is added and the mixture is stirred at 0 ° C. for 15 minutes. A solution of benzyl alcohol (0.972 g, 9 mmol) in methylene chloride (5 ml) is added dropwise to the reaction mixture within 15 minutes and stirring is continued at 5 ° C. for 1 hour. Then the solvent is evaporated and the residue is dissolved in a mixture of ether (50 ml) and water (50 ml), the organic layer is separated and the aqueous layer is repeatedly extracted with ether (20 ml). The combined ether extracts are washed with a saturated NaHC03 solution and water and dried. Evaporation of the ether leaves an oily residue.

Yield: 3.40 g (77%) of a product whose IR spectrum is identical to the literature [J. Org. Chem. 27 (1962) 1381].

Example 5

6-phenylacetamido-penicillanic acid (2,2,2-trichloro-ethyl ester)

A solution of pyridine (1.6 g, 21 mmol) in methylene chloride (70 ml) is mixed with 6-phenylacetamido-penicil-lanoic acid potassium salt (7 g, 19 mmol) and then a solution of N-chlorocarbonyl-pyrrolidine 2-one (2.95 g, 20 mmol) in methylene chloride (15 ml) was added dropwise with stirring at 0 ° C. The reaction mixture is stirred for 10 minutes, then a solution of 2,2,2-trichloroethanol (3.3 g, 22 mmol) in methylene chloride (10 ml) is added and stirring is continued for 1 hour. The product is isolated in the manner described in Example 3. The remaining product is crystallized with the addition of ether. Yield: 6.71 g (76.7%) of the product, mp. 158-160 ° C IR and XH NMR spectra are identical to the literature [J. Org. Chem. 36 (1971) 1259],

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650 494

In a solution of 6-phenylacetamido-penicillanoic acid (1-oxide) (630 mg, 1.8 mmol), pyridine (160 mg, 2.02 mmol) and methylene chloride (10 ml) is a solution of N-chlorocarbonyl-pyrrolidine -2-one (295 mg, 2 mmol) in methylene chloride (5 ml) at + 5 ° C within 10 minutes. The mixture is stirred for 30 minutes, then a solution of p-nitrobenzyl alcohol (337 mg, 2.2 mmol) in methylene chloride (10 ml) is added and the mixture is stirred for a further 1.5 hours.

Example 6

p-nitrobenzyl-6-phenylacetamidopenicillinate (l-oxide)

touched. After adding cold water (25 ml), the mixture is stirred for 5 minutes, the layers are separated and the organic layer is washed with a 5% NaHCO 3 solution (10 ml) and water (15 ml), dried and the solvent is evaporated.

Yield: 745 mg (85.3%) of a product whose IR spectrum is identical to the literature (DE-OS io 2 064 107).

In a solution of 6-phenoxyacetamido-penicillansäu-re (l-oxide) (660 mg, 1.8 mmol), pyridine (160 mg, 2.02 mmol) and tetrahydrofuran (10 ml) is a solution of N-chlorocarbonyl -pyrrolidin-2-one (295 mg, 2 mmol) in tetrahydrofuran (5 ml) at a temperature of -10 ° C within 15 minutes and then the reaction mixture is stirred for 15 minutes. Then it is mixed with 2,2,2-trichloroethanol (330 mg, 2.2 mmol) and stirring is continued for 30 minutes. The solvent becomes Example 7

2,2,2-trichloroethyl-6-phenoxyacetamidopenicillinate (l-oxide)

evaporated under reduced pressure and the residue is dissolved in methylene chloride (20 ml) and water (20 ml), then stirred for 5 minutes, the organic layer is separated, dried and the solvent is evaporated. Digesting the residue in ether gives the product with an mp of 143-145 ° C.

20 Yield: 721 mg (80%) of a product whose IR and 1H NMR spectra are identical to the literature data [J. Org. Chem. 36 (1971) 1263],

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