DK144886B - METHOD OF MANUFACTURING CEPHALOSPORINESTERS - Google Patents

Description

(19) DENMARK

I VRB.

||| (12) PUBLICATION MANUAL OR M886 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5587/73 (51) | ntCI.3 C 07 D 501 / OA

(22) Submission day 4 Oct. 1973 (24) Race day 4 Oct. 1973 (41) Aim. available Apr 6 1974 (44) Submitted 28 Jun. 1982 (86) International application no.

(86) International Filing Day (85) Continuation Day ”(62)

(30) Priority Oct. 5 1972, 46063/72, GB

(71) Applicant LEO PHARMACEUTICAL PRODUCTS LTD. A / S (LOVE CHEMICAL FACTORY

PRODUCTION SHARE COMPANY), 2750 Ballerup, DK.

(72) Inventor Ernst Torndal Binderup, DK.

(74) Plenipotentiary - (54) Procedure for the preparation of cephalosporin esters.

The present invention relates to a particular process for the preparation of cephalosporin esters of the general formula I

(7) / aX

h-hn-hc— ch (6) (2) ch2 O-C - N. (3) 0 E1 1

g (ioOC ^ OCOCCH ^ A

30 '4 · J [wherein R is hydrogen or an acyl group, R is an organic r

Q

N is an integer from 0 to 5 and A is an alkyl group having from 1 to 6 carbon atoms or a phenyl group.

Acycloxymethyl esters of this type with an acylamino group at the 7-position have been found to be valuable therapeutic agents because they are generally well-resorbed from the gastrointestinal tract and, after resorption, are enzymatically hydrolyzed to form the corresponding free acids which are antibiotically active.

Such compounds, which at the 7-position have a free amino group, are important intermediates in the preparation of these antibiotics.

Such esters have so far been prepared by reacting a salt of the cephalosporin in question with a chloromethyl ester, as described in J.Med.Chem. 9, 74l (1966) and in J. Antibiotics 24, 767 (197l) ·

This reaction involves a migration of the double bond from the 3 2 2 Δ - to Δ position and therefore leads to mixtures of Δ - and 3 Δ-cephalosporin esters.

2

Since the Δ-cephalosporins are biologically inactive, it is necessary either to separate the two isomers or to convert the 2 3 Δ isomer to the Δ isomer. The separation process is cumbersome, and since the Δ isomer is usually the predominant one in the mixture,

ISLAND

the yield of the desired Δ-isomer is low. A process for converting the Δ isomer to the corresponding Δ isomer is described in J.Org.Chem. 2430 (l970). Briefly, the method is that the mixture of the two isomers is subjected to an oxidation process, 2 o 2, thereby forming a mixture of Δ - and Δ-sulfoxides. The Δ-sulf-3 oxide derivatives are readily rearranged to the corresponding Δ-sulfoxide isomers when treated with an alcohol, and in a reduction process 3 the Δ-cephem esters are obtained without the double bond migrating. In this process, the desired compounds can be obtained in a pure state, but the two process steps (an oxidation and a reduction) cannot be carried out without a substantial loss of substance and in several cases involve additional steps to protect any. substituents which are sensitive to oxidation and reduction processes.

It has been desirable to find a method by which the migration of the double bond can be avoided and the present invention relates to such a particular method.

The process according to the invention is characterized in that a salt of a cephalosporanoic acid of the general formula III

U4886 3

(T) / tlK

K-HN-HC-CH (6) '(2) j) H2 U1 ^ (? KS4> ^' b1 shows i

wherein R and R are as defined above, reacted with a compound of formula II

I-CH 0 CO (CH) A II

2 2 'n where n and A have the above meanings. Preferably, alkali metal salts or tertamine salts are used, but other salts can also be used. Surprisingly, by using iodine methyl esters instead of chloromethyl esters, the reaction proceeds so rapidly that no double bond migration occurs. Therefore, the isolation of the reaction products is very simple and the desired β-derivatives are obtained in high yields. The process is preferably carried out by cooling teeth and in matching inert organic solvents such as dimethylformamide.

The process is generally useful in preparing esters of the above-mentioned types of compounds.

Among these compounds derived from formula I may be mentioned those having at the 3-position a methyl, acetoxymethyl, alkylthiomethyl, or heterocyclic substituted methyl substituent, and which at the 7-amino group has a hydrogen atom or is substituted by a group having one of the following partial formulas: 4 · ρ3 RV = y - Λ · Λ 1-— CH-CO- L CH-CO- or "j 2 where R is hydrogen, a free or protected amino group or a 3 Λ azido group, and R and R is hydrogen, hydroxy or chlorine, which substituents are intended to exemplify but not limit the utility of the process of the invention.

As is well known, the corresponding free cephalosporanoic acids have a broad spectrum of antibiotic activity in Vitro, but their use in human treatment is limited due to their inadequate resorption after oral administration. However, it has been found that this disadvantage can be eliminated by the administration of said cephalosporanoic acids in the form of esters of formula I, which are better resorbed and distributed in the organism and give satisfactory therapeutic concentrations of the corresponding acids 4 U4886 ± blood and tissue. as a result of an enzymatic cleavage of the esters.

The compounds of formula II are novel compounds with the exception of the iodomethyl acetate. They are prepared with almost quantitative yield from the corresponding chloromethyl esters by treatment with sodium iodide. They are less stable than the corresponding chlorine and bromomethyl esters at room temperature, but can be stored at lower temperatures.

The process of the invention is described in detail in the following examples.

Example 1 o

Pivaloyloxymethyl-7-phenylacetamido-3-methyl-A-cephem-4-carboxylate To an ice-cooled suspension of 18 g of potassium 7-phenylacetamido

ISLAND

3-methyl-A-cephem-4-carboxylate in 200 ml of dimethylformamide was added 13 g of iodomethyl pivalate. The mixture was stirred for 10 min. with continued cooling, diluted with 800 ml of ethyl acetate and washed with water, aqueous sodium bicarbonate, and water. The organic phase was dried and evaporated in vacuo. Upon addition of cyclohexane, the product crystallized. Yield 18.5 g. Melting point 162-162.5 ° C. The starting material iodine methyl pivalate can be prepared as follows s

Jodmethylpivalat.

A solution of 1200 g of sodium iodide in 3500 ml of acetone was stirred at room temperature under a nitrogen atmosphere. 300 g of chloromethyl pivalate were added and stirring was continued for 3 hours at room temperature. The precipitated sodium chloride was filtered off and the acetone evaporated in vacuo. The residue was extracted with petroleum ether and the colored extract shaken with aqueous sodium thiosulfate until the color disappeared. The colorless extract was dried, filtered and the petroleum ether evaporated in vacuo. The residual crude product was distilled in vacuo, with nitrogen being bubbled during distillation. Yield 403 S (93f °) of a slightly yellowish liquid. Boiling point 71-73 ° C / l2 mm Hg.

Analysis: CgHH I IO₂

C Η I

Calculated: 29.77 4.58 52.43%

Found:, 30.18 4.68 51993% 5 144886

Example 2

ISLAND

Pivalovloxymethyl-7- (D-a-azidophenylacetamido) -3-methyl-Λ-cephem-4-carboxylate.

This compound was prepared following the procedure described in Example 1, replacing potassium 7-phenylacet-πamido-3-methyl-A-cephem-4-carboxylate with potassium 7- (Da-azidophenylacetamido) -3- methyl-N, -cephem-4-carboxylate. Melting point 111-112 ° C.

[α] D = -21 ° (c = 1, CHCl3). Yield $ 85.

Example 3

Acetoxymethyl 7- (2-tbienylacetamido) cephalosporanate.

A suspension of 21 g of sodium 7- (2-thienylacetamido) cephalo-sporanate in 200 ml of dimethylformamide was cooled in ice and 11 g of iodomethyl acetate was added. After stirring for 15 min. under cooling, the mixture was diluted with 800 ml of ethyl acetate and washed with water, aqueous sodium bicarbonate and water, respectively. The organic phase was dried and evaporated in vacuo to give a solid which crystallized from methylene chloride / diisopropyl ether in a yield of 20 g of the desired compound. Melting point 137-139 ° C · [oc] J; O = + 39 ° (c = 1, CHCl3).

The starting material iodomethyl acetate can be prepared as follows:

Jodmethylacetat.

This compound has previously been prepared from acetyl iodide and paraformaldehyde (J. Am, ChemSoc, KJ, 2989 (1925) and Acta.

Chem. Scand. 20, 1273 (1966)). In this case it was prepared from chloromethyl acetate as described above in connection with the preparation of iodomethyl pivalate. The compound is a yellowish liquid. Boiling point 51-53 ° C / l2 mm Hg.

Example 4

Acetoxymethyl-7- (D-G-azidophenylacetamido) -cephalosporanat.

A suspension of 200 g of potassium 7- (D-a-azidophenylacetamido) cephalosporanate in 1700 ml of dimethyl formaraide was cooled in ice and 93 »6 g of iodomethyl acetate was added. The mixture was stirred for 5 min. under cooling, diluted with 6800 ml of ethyl acetate and washed with water, aqueous sodium bicarbonate and water. The organic phase was dried and evaporated in vacuo. The remaining partially crystalline product was recrystallized from methanol / water. Yield: 182.2 g. Melting point 100-101 ° C.

6 144886

Example 5

Pivalovloxymethyl-7- (D-Q> azidophenylacetamido) cephalosporanate.

Following the procedure described in Example 4, however, using iodo methyl pivalate instead of iodo methyl acetate, the desired compound was prepared as a foam.

The NMR spectrum (CDCl3, TMS as internal standard) showed signals at S = 1.23 (s); 2.07 (s); 3.42 (d); 3.59 (d); 4.84 (d); 5.11 (d); 5.01 (d); 5.13 (s); 5.75 (m); 5.89 (d); 5.93 (d) j 7.18 (d) and 7.42 (s).

Example 6

Benzoyloxymethyl-7- (D-CT-azidophenvlacetamido) -cephalosporanat.

To an ice-cooled suspension of 172 g of potassium 7- (D-a-azido-phenylacetamido) cephalosporanate in 1,400 ml of dimethylformamide was added 100 g of iodomethylbenzoate. The cold mixture was stirred for 5 min, diluted with 56ΟΟ ml of ethyl acetate and washed with water, aqueous sodium bicarbonate, and water. The organic phase was dried and evaporated in vacuo. The partially crystalline residue was recrystallized from ethyl acetate-cyclohexane. Yield: 142 g. Melting point 144-142 ° C.

[cc] p ° = -38 ° (c = 1, CHCl3).

Analysis: C ^ gHHN NO₂S

C Η N S

Calculated: 55.21 4.10 12.39 5.68

Found: 55.23 4.24 12.39 5.77

The starting material iodine methyl benzoate is novel and was prepared from chloromethyl benzoate in the same manner as described above in connection with the preparation of iodine methyl pivalate. Boiling point 92-93 ° C / 0.55 mm Hg.

Example 7

Acetoxymethyl-7- (D-a-amino-p-hydroxyphenylacetamido) -cephalosporanat. hydrochloride.

10.8 g of sodium 7- (D-α-tert-butoxycarbonylamino-p-hydroxy-phenylacetamido) cephalosporanate and 80 ml of dimethylformamide were cooled in ice and 4.4 g of iodomethyl acetate was added. The mixture was stirred for 10 min. under cooling and then diluted with 320 ml of ethyl acetate. After washing several times with water, the organic phase was dried and evaporated in vacuo. The residue was dissolved in ice-cold trifluoroacetic acid and stirred for 5 min. during ice cooling. Then, the mixture was evaporated in vacuo and the residue was treated with ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated and washed with water. The organic phase was stirred with water while hydrochloric acid was added to pH: 2.5. The aqueous phase was separated and lyophilized to give the desired compound as an amorphous powder.

The NMR spectrum (CD 1 OD, TMS as internal reference) showed peaks at <5 = 2.03 (s); 2.08 (s); 3.45 (d) J = 19; 3.57 (d) Jsl9; 4.77 (d) J = 13; 5.01 (d) J = 13 | 5.03 (s); 5.08 (d) J = 5; 5.83 (d) J = 5; 5.82 (d) J = 5.5; 5.93 (d) J = 5.5; 6.90 (d) J = 8.5; 7.35 (d) J = 8.5.

Example 8

Ace toxymethyl-7- (D-cx-amino-m-chloro-p-hydroxyphenylace tamido) - cephalosporanate, hydrochloride.

This compound was prepared by following the procedure described in Example 7, replacing sodium 7- (D- (X-tert-butoxycarbonylamino-p-hydroxyphenylacetamido) cephalosporanate with sodium 7- (Da-tert-butoxycarbonylamino) m -chloro-p-hydroxyphenyl-acetamido) -cephalosporanate The compound was isolated as an amorphous powder whose NMR spectrum (CD 3 OD, TMS as internal reference) showed peaks at (5 = 2.03 (s); 2.08 ( s); 3.47 (d) J = 19; 3.58 (d) J = 19; 4.78 (d) J = 13; 5.02 (d) J = 13j 5.05 (s) j 5 , 08 (d) J = 5; 5.83 (d) J = 5; 5.82 (d) J = 5.5} 5.92 (d) J = 5.55 6.9 - 7.6 ( m).

Example 9

Acetoxymethyl 7-aminocephalosporanate hydrochloride.

A suspension of 4.6 g of potassium 7-aminocephalosporanate in 80 ml of dimethylformamide was cooled in ice and 3.3 g of iodomethyl acetate was added. The mixture was stirred for 8 min. under cooling, diluted with 320 ml of ethyl acetate and washed with 4 x 4θ ml of water. The organic phase was extracted with ice cold 0.1 N hydrochloric acid. The aqueous phase was separated and made alkaline by the addition of aqueous sodium bicarbonate. The oil which was separated was taken up in ethyl acetate and the solution was dried over MgSO4 and filtered.

Upon addition of 1N hydrochloric acid in 2-propanol to the ethyl acetate solution, the desired hydrochloride crystallized. The crystals were filtered off and recrystallized from methanol-ether. Melting point> 170 ° C (dec.).

[+ x] + = 64 ° (c = 1, 0.1 N HCl)