CH623589A5 - Process for the preparation of cephalosporin esters - Google Patents

Abstract

Cephalosporin esters with pharmacological activity and the formula I <IMAGE> in which R is a phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2- or 3-thienyl or a dihydrophenyl group, X is an acetoxy, carbamoyloxy or a heterocyclic thio group and R<1> is hydrogen or methoxy, are prepared by reacting the corresponding cephalosporanic acid with phthalaldehydic acid or its reactive derivative which is capable of esterification.

Description

The invention relates to a process for the preparation of cephalosporin esters of the general formula I and their pharmacologically acceptable acid addition salts

30th

R — CH — CO — NH

H H

R -

CH - CO

I.

nh2 -

NH-j

0 ^ ~

fl «

■ Kks ^ —CH2X

COOH

or their reactive esterifiable derivative, in which R and X have the abovementioned meanings, with a compound of the general formula III

(in)

50

or their reactive esterifiable derivative, in which Rl and R2 have the meanings given above, and in which the reactive amino and / or hydroxy groups can be intermediately protected.

2. The method according to claim 1, characterized in that X is the (2-methyl-l, 3,4-thiadiazol-5-yl) thio-, (1-methyl- (lH) -l, 2,3,4 -tetrazol-5-yl) - or the (1H-l, 3,4-triazol-5-yl) thio group.

3. The method according to claim 1 for the preparation of 7 - [(D-a-aminophenyl-acetamido) -3- (2'-methyl-l ', 3', 4'-thiadia-

55

60

I.

NH,

\!

H "

i / \ -c ^ NCH.

35

■ nXc ^ c-ch2x

(I)

40

45

co.o.

CQC,

S

in which R is a phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2- or 3-thienyl or a dihydrophenyl group, X is an acetoxy, carbamoyloxy or a heterocyclic thio group and R1 and R2 represent hydrogen atoms or methoxy groups, provided that when R1 and R2 are both hydrogen atoms and X is the acetoxy group, R is not a phenyl group.

Suitable acid addition salts of the compounds of general formula I are inorganic salts, such as the sulfate, nitrate, phosphate, borate, and also the hydrohalides, such as the hydrochloride, hydrobromide and the hydroiodide, and organic salts such as the acetate, oxalate, tartrate, maleate, citrate, Succinate, benzoate, acorbate and the methanesulfonate.

3rd

623 589

Examples

N-N N. N> f

-s-O '-S ~ IJ -

m

N-N

N-N

O

N-N

~ sJ S,

ch2co2h

GH,

N-N

-t0 ^ ~

CH-

N-N

N N

Cî ^ COgH

S- ^ s ^ -JCH2C02H

The radical X is preferably the (2-methyl-l, 3,4-thiadia-zoI-5-yl) thio-, the (l-methyl- (lH) -l, 2,3,4-tetrazole-5 -yl) -thio-, the (2-methyl-l, 3,4-oxadiazol-5-yl) thio or the (1H-1,3,4-30 triazol-5-yl) thio group.

With regard to the prior art, Swiss Patent Nos. 577,514 and 587,265 by the applicant are to be mentioned, in which processes for the production of a large class of lactone esters of penicillins and cephalosporins are described. Although the compounds produced by the present process according to the invention,

R - CH - CO

where X is acetoxy, are within the scope of the general formulas in the aforementioned patents, they are not specifically mentioned there. Furthermore, the methods of the aforementioned patents do not relate to the preparation of compounds which have heterocyclic methyl or carbamoyloxymethyl substituents in the 3-position of the cephalosporin core.

The compounds of the general formula I are prepared according to the invention in that a compound of the general formula II

NH,

or its reactive esterifiable derivative, where R and X have the meaning given above, with a compound of the general formula III

(II)

(II)

50

55

(in)

(ni)

or its reactive esterifiable derivative, in which R1 and R2 have the meanings given above, and whose amino and / or hydroxyl group can be protected as an intermediate. Furthermore, obtained compounds of formula I in which X is acetoxy can be used to prepare compounds of formula I in which X is a heterocyclic thio group by reaction with a compound HX in which X is a heterocyclic thio group.

60

65

COOH

Reactive esterifiable derivatives with regard to the compound of the general formulas II and III are understood to mean derivatives of the compounds II and III which, when reacting with one another, take part in a reaction with the subsequent formation of an ester bond of the general formula I. Numerous processes for esterification are known from the literature. For example, the above-mentioned esterification action can be achieved by reacting a cephalosporanic acid of the general formula II which has protective groups on the nitrogen atom or its salt with a 3-halophthalide or a 3-halo gene-5,6-dimethoxyphthalide. Examples of suitable salts are alkali metal salts, such as the sodium and potassium salts, or a trialkylammonium salt, such as the triethylammonium salt.

The a-amino group in the side chain of the compound of general formula I is preferably protected from the esterification reaction. In these cases, any, from the literature in the synthesis of «-aminobenzyl-peni-

623 589

cillin or a-aminobenzyl-cephalosporanic acid known amino protective groups, such as the following.

Examples of amino protecting groups are also the protonated amino group (NH + s) which is well known per se for this purpose and which can be converted into the free amino group by simple neutralization after the acylation. Further examples are the tert-butyloxycarbonyl or the benzyloxycarbonylamino group and the substituted benzyloxycarbonylamino groups, which can subsequently be converted into the amino group by catalytic hydrogenation. Furthermore, numerous groups can be used as protective groups, which can be converted into the amino group after the acylation by weakly acidic hydrolysis. Alkaline hydrolysis is generally not advantageous since hydrolysis of the ester group also takes place under alkaline conditions.

Examples of amino protecting groups known per se, which can subsequently be converted into the amino group by weakly acidic hydrolysis, are enamine groups of the general formula IV or their tautomeric modifications, and also a-hydroxyarylidene groups of the general formula V or their tautomeric modifications:

10th

IS

20th

25th

Acetoxy group from the corresponding 3-acetoxymethyl compound of the general formula I - d. H. = Acetoxy - are produced using a nucleophilic thiol compound.

The examples illustrate the invention.

example 1

(a) 7-D-a-tert-butyloxycarbonyl-aminophenyI-acetamido

3- (2'-methyl-l ', 3', 4'-thiadiazol-5'-yl-thiomethyl) -eeph-3-em-

4-carboxylic acid phthalidyl ester

3.00 g of 7-Da-tert-butyloxycarbonyl-phenylaeetamido-3- (2'-methyl-l ', 3', 4'-thiadiazol-5'-yl-thiomethyl) -eeph-3-em-4- carboxylic acid are dissolved at 0 to 5 ° C in 30 ml of anhydrous dimethylformamide and treated with 0.96 ml of triethylamine and then mixed with 1.62 g of bromophthalimide, which is dissolved in 10 ml of dimethylformamide. After 30 minutes at 0 to 5 ° C and 60 minutes at 20 ° C, the solution is poured into 800 ml of water. The solid precipitate is washed well with water and dissolved in ethyl acetate. This solution is washed with sodium bicarbonate solution and water, then dried and evaporated. Precipitation with a mixture of ethyl acetate and petroleum ether gives the desired ester as a brown-yellow solid in a yield of 2.3 g (= 47 percent of theory).

This solid is used without further purification.

CH

(IV)

'V /

No

(V)

F

I l

H

45

50

In formula IV and V, the dashed lines are hydrogen bonds. In formula IV, Rs 40 is a lower alkyl radical, R4 is either a hydrogen atom or together with R3 a carbocyclic ring R5 is a lower alkyl, lower alkoxy or an aryl radical. In the formula V, Z represents the residue of a substituted or unsubstituted benzene or naphthalene ring.

An example of a known amino protective group that can be converted into the amino group after esterification is the azido group. In this case, the final conversion to the amino group can be accomplished either by catalytic hydrogenation or by an electrolytic reduction. If appropriate, the amino group can be blocked as a nitro group, which can later be converted into the amino group by reduction.

In the above process, the esterification can cause the double bond to shift to the 2-position of the cephem nucleus, thereby producing a mixture of 2-cephem and 3-cephem isomers. If this occurs, this mixture can be converted into the 3-cephem isomer by oxidizing the mixture into the sulfoxide with subsequent reduction. Of course, this is a standard process for the production of 3-Ce-phemes from 2-cephemes, such as. B. is described in GB-PS 1 280 693. One of these procedures is treatment with triphenylphosphine and acetyl chloride.

After using the process according to the invention, compounds of the general formula I in which X is a heterocyclic thio radical can be replaced by replacing the

60

65

CHCls: max

3380, 1785 (b), 1700 (shoulder), 1690, 1485, 1160, 980 cm- '.

30th

C2H5-OH: v max

<5 (CDCU):

228nm <£ = 18590) and 268nm (£ = 12620).

1.40 (s, 9H, Bu-H), 2.71 (s, 3H, Thiadia-35 zolyl-CHs), 3.5-4.4 (m, 4H total,

S-CH2), 4.9 (d), 5.2 (m) and 5.7 (m) (Ca, C6 and Cj-H), 7.3-8.0 (m, Ar-H, O -CH-O and NH).

(b) 7-Da-aminophenyl-acetamido-3- (2'-methyl-1 ', 3', 4'-thiadiazol-5'-yl-thiomethyl) -ceph-3-em-4-carboxylic acid phthalate lidyl ester

1.50 g of the tert-butoxycarbonyl derivative are treated for 60 minutes at 5 to 10 ° C. with 15 ml of a 98 percent aqueous trifluoroacetic acid. The solution is then evaporated. The residue is triturated with ether to give 1.4 g of the essentially pure trifluoroacetate.

CHCI3: 3400-2600, 1785 (b), 1700 (shoulder), 1675, 'max 1620, 1540, 1190, 1140, 980 cm-1.

C2H5-OH:

Max

227nm (£ = 16690) and 268nm (£ = 12020).

55

Neutralizing the trifluoroacetate provides the free amino ester.

Example 2

The procedures described in Example 1 are repeated using 3-bromo-5,6-dimethoxyphthalide instead of 3-bromophthalide. The following compounds are obtained.

7- (D-a-Amino-p-hydroxyphenyl-acetamido) cephalospo-ranoic acid 5 ', 6'-dimethoxyphthalidyl ester,

7- [Da-aminophenylacetamido-3- (2-methyl-l ', 3', 4'-thia-diazol-5-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid-5 ', 6' -di-methoxyphthalidyl ester.

5

623 589

Example 3

(a) 7-D-a-tert-Butyloxycarbonyl-aminophenyl-acetamido-3- (l'-methyl-l'-H-tetrazol-5'-yl-thiomethyl) -ceph-3-em-4-carboxylic acid phthalidyl ester

2.4 g (4.1 mmol) of the sodium salt of 7-Da-tert-butyloxy-carbonyl-aminophenyl-acetamido-3- (l'-methyl-l'-H-tetrazol-5'-yl-thiomethyl) -ceph-3-em-4-carboxylic acid are stirred into 30 ml of anhydrous dimethylformamide and 0.85 g (4 mmol) of bromophthalide are added while cooling with ice. After 3 hours at 20 ° C the mixture is poured into 300 ml of ice water. The solid is filtered off.

A solution of the solid in ethyl acetate is washed with dilute sodium bicarbonate solution and water, then dried and evaporated. Precipitation of the residue from a mixture of ethyl acetate and petroleum ether provides 2.0 g (= 74 percent of theory) of the desired ester, which is processed without further purification.

a main zone in biochromatography: R {= 0.85 in an n-butanol-ethanol-water mixture.

C2H5-OH:

Max

CHCls: max

270nm (e = 7750);

3400, 1790, 1740, 1700 (b), 1495, 1165, 980 cm-1.

If necessary, the crude product can be separated into its three epimers by chromatography on silica gel.

(b) 7-D-a-Aminophenyl-acetamido-3- (l'-methyl-l'-H-tetrazol-5'-yl-thiomethyl) -ceph-3-em-4-carboxylic acid phthalic dylester

2.5 g (3.6 mmol) of the abovementioned tert-butyloxycarbonyl derivative are stirred for 45 minutes at 10 ° C. with 25 ml of trifluoroacetic acid. After the trifluoroacetic acid has been evaporated off, the residue is triturated with anhydrous ether. 2.48 g (= 97 percent of theory) of the crude trifluoroacetate of the desired compound are filtered off and washed well with ether. The product shows

10th

15

20th

30th

Nujol:

V

max Ò (DMSO):

C2H5OH: max

1785, 1680, 1200 cm-1.

3.4-4.1 (m, 2H, C2-H), 3.77 and 3.92 (2s, 3H, tetrazolyl-CHs), 4.1-4.6 (m, 2H, CH2S), 4 , 8-6.1 (m, 3H, C6, C7 and Ca-H), 7.2-8.2 (m, 10H, Ar-H + OCHO), 8.9 (bs, 3H, NH + s) , 9.4-10.0 (m, NH).

270nm (, - = 7410).

Example 4

(a) 7-D-a-tert-Butyloxycarbonyl-aminophenyl-acetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid phthalidyl ester

2.1 g (4 mmol) of sodium salt of 7-Da-tert-butyloxy-carbonylaminophenyl-acetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (cf. British Patent Application No. 49 423/74) are described in 30 ml of anhydrous dimethylformamide suspended and treated with 0.84 g (0.39 mmol) of bromophthalide with ice cooling. After 60 minutes at 20 ° C, 300 ml of ice water are added. The precipitate that has precipitated is filtered off. A solution of the precipitate in ethyl acetate is washed with dilute sodium bicarbonate and water and then dried and evaporated. Precipitation of the residue from a mixture of ethyl acetate and petroleum ether gives 1.9 g of the desired ester, which is used without further purification.

(b) 7-D-o-Aminophenyl-acetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid phthalidyl ester

1.6 g of the aforementioned crude ester are treated with 15 ml of cooled trifluoroacetic acid over 40 minutes. 35 After evaporation and trituration with ether, 1.5 g of the aforementioned compound are obtained as trifluoroacetate. This compound shows a main zone in biochromatography (Rf = 0.75 in n-butanol-water).

M

Claims (4)

623 589 2nd PATENT CLAIMS 1. Process for the preparation of cephalosporin esters of the formula I or their pharmaceutically acceptable acid addition salts R CH CO NH I. NH " zol-5'-yl) thiomethyl] ceph-3-em-4-carboxylic acid phthalidyl ester or 7- (D-a-amino-p-hydroxyphenyl-acetamido) -cepha-losporanoic acid phthalidyl ester. 4. The method according to claim 1 for the preparation of 7- (Da-aminophenyl-aeetamido) -ephalosporansäure-5 ', 6'-dime-thoxyphthalidylester or 7- (Da-Amino-p-hydroxyphenyl-acetamido) -cephalosporansäure-5', 6'-dimethoxy phthalide ester. 5. The method according to claim 1 for the preparation of 7- [Da-aminophenyl-aeetamido-3- (2'-methyl-l ', 3', 4 ', thiadiazol-5'-yl) -thiometh.yI] -eeph- 3-em-4-earbonic acid 5 ', 6'-dimethoxy-phthalidyl ester, 7- [Da-aminophenyl-acetamido-3- (l'-methyl-l'-H-tetrazoI-5'-yl) thiomethyl} -eeph-3-em-4-eirbonic acid phthalidyl ester or 7-Da-AminophenyI-aeetamido-3-carba-moyloxy-methyl-ceph-3-em-4-carboxylic acid phthalidyl ester. 6. Use of a compound of formula I, in which X is acetoxy, obtained according to the process of claim 1, characterized in that it is reacted with a compound of formula H-X, in which X is a heterocyclic thio radical, one Compound of formula I in which X is a heterocyclic thio group is obtained. in which R is a phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2- or 3-thienyl or a dihydrophenyl group, X represents an acetoxy, carbamoyloxy or a heterocyclic thio group and R1 and R2 represent hydrogen atoms or methoxy groups, provided that R is not a phenyl group if R1 and R2 are both hydrogen atoms and X is the acetoxy group, characterized in that a compound of the general formula 25th