DE2065718A1 - PROCESS FOR THE PREPARATION OF 3-CHLORO OR BROMOMETHYL DELTA HIGH 3-CEPHALOSPORINE SULFOXIDE ESTER - Google Patents

Description

PATENT LAWYERS .--, .. ·

DR. I. MAAS j '·''? ■ /?' ■■ '- ^ - ZfY'ϊ ~

DFiG. Mockery "'* ~ /' Ov

οοοο Γ /? ^: ";: · -Γ"·;-; · -.μ 40

GCHLElSSi ifiUvl ^ Fu / ra 209
TEL. 35922GI / 2Ü5

83 680 Div

Eliminated from P 20 52 531.9

Eli Lilly and Company ,. Indianapolis, Indiana, V.St.A.

Process for the preparation of 3-chloro or bromomethyl / cephalosporin sulfoxide ester

The invention is a process for the production of 3-chloro or bromomethyl / cephalosporin sulfoxide esters of formula I.

Il.

R-NH-CH-CH

I I

CO-N.

COOR ¹

wherein R is C1 -C6 alkanoyl, C1 -C6 chloroalkanoyl or acyl

PBIGINAL INSPECTED

509829/0904 V

the formula

R ³

_Ar fCH ₂ ^ --- Ζ- (έ) _η CO-.,

ι "

.R ⁴

stands / in which Ar stands for 2-thienyl, m is an integer ■ is from 0 to 4, η is an integer from 1 to 4, Z Means oxygen, sulfur or a chemical bond,

3 4

R and R stand for hydrogen or methyl, or if

3 4

R is hydrogen, R is also an N-protected amino, namely an, N- £ bert *. r-butoxycarbonyl) amino, N- (benzyloxycarbonyl) amino, N- (allyloxycarbonyl) amino, N- (cyclopentyloxycarbonyl) amino or N- (2-methoxycarbonyl-1-methylvinyl) amino,

Can be 4 and η has the value 1, and / or if R 'for N-protected Amino stands, Ar also a group of the formula

can mean in which Y is hydrogen or fluorine, chlorine, bromine, iodine, C -C -alkyl, C -C -alkyloxy, N-protected alpha-amino-C ..- C_-alkyl, butoxycarbonyl, nitro, cyanoq or trifluoromethyl and w is 1 or 2, X is chlorine or bromine, and R is 2,2,2-trichloroethyl, C.-Cg-tert.-alkyl, Cc-C -tert.-alkenyl, C ₅ -C-- is tert-alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl, phthalimidomethyl, or succinimidomethyl.

The process for the preparation of these compounds is characterized in that a 3-hydroxymethyl

509829/0904

-cephalosporinsulfoxidester in the presence of a tertiary amine in a practically anhydrous liquid diluent

a) at temperatures from about -75 to about -25 ° C with a approximately equimolar amount of phosphorus tribromide or phosphorus

trichloride, or

b) at temperatures from about -75 to about 50 C with phosphorus pentachloride, Phosphorus pentabromide, phosphorus oxychloride or

Phosphorus oxybromide converts.

The 3- chloro- or -bromomethyl- / \ -cephalosporin esters according to the invention are advantageous intermediates for the production of new and known nitrogen- and sulfur-containing 3- (Nucleophil-Muethyl) - ZS -cephalosporin antibiotics and can be used to produce 3- (nucleophilmethyl) - / S> -cephalosporins can be used without oxidation and reduction conditions having to be applied.

The method according to the invention eliminates the difficulties circumvented or avoided, which in some cases result after the conversion of a 3-bromomethyl- ^ A>. -cephalosporin esters into a 3- (nucleophil-methyl) - /! - S -cephalosporin ester can when the nucleophilic group contains an oxidizable nitrogen or sulfur atom.

The method according to the invention is carried out in detail in the same way as in DT-OS 2015 317 (DT-PS).

If 7-aminocephalosporanic acid (7-ACA) is used as the starting material should be used, 7-amino protecting groups are preferred

509829/0904

added, which not only easily combine with the 7-amino nitrogen, but can also be easily removed after the desired sequence of reactions at the methyl group in the 3-position has ended. In such cases the preferred 7-amino-can a simple C.-C _fi alkanoyl, for example formyl, acetyl, propionyl, butanoyl or hexanoyl, or a C ~ C ^ -Chloralkanoylgruppe, particularly an alpha-Chloralkanoylgruppe , for example a 2-chloroacetyl group. These groups are attached by reacting 7-ACA with the corresponding acid chloride. If the chosen overall route to the cephalosporin antibiotic requires acylation of 7-ACA, an ™ ester of 7-ACA, 7-ACA-sulfoxide or a 7-ACA-sulfoxide ester with the final acyl group, one can, for example, with an activated form of N - Acylate protected phenylglycine. Such an activated form can consist of the mixed anhydride which is formed by the reaction of isobutylchloride and 2 ~ £ N- (tert-butoxycarbonyl) amino-7 ~ 2-phenylacetic acid.

The symbol R in the above formula I means an ester group, as defined in DT-OS 2015 317 (DT-PS).

The 3-chloro-or-bromomethyl- ₍₍ A5 -cephalosporin esters h of the formula I are suitable as intermediates for the direct preparation of antibiotically active cephalosporins by removing the ester group by various known methods, as described in the above-mentioned DT-OS (DT- PS) is specified.

The compounds of the formula I are mainly used for the production of known and new antibiotic cephalosporins of importance for what. Reference is also made to the above DT-OS (DT-PS).

509829/0904

The invention is illustrated in more detail by means of the following examples .

example 1

The amino group of 7-aminocephalosporanic acid (7-ACA) is linked to a formyl group by reacting 7-ACA with the mixed anhydride, which is formed by the addition of formic acid to acetic anhydride; protected with formation of the 7-formamido-3-acetoxymethyl - ^ / \ -cephem-4-carboxylic acid. This N-protected 7-ACE is esterified in the manner described in Example 1 with formation of the tert-butyl-7-formamido-3-acetoxymethyl- £ ± -cephem-4-carboxylate ester. This / \ -Cephalosporin ester is as described in Example 1 to tert-butyl ^ -formamido-S-acetoxymethyl- Δ. -cephem-4-carboxylate-1-oxide oxidized. This / \ -Cephalosporinsulfoxidester is hydrolyzed with citrus acetylesterase to tert-butyl-7-formamido-3-hydroxymethyl- ^ S -cephem-4-carboxylate-i-oxide, which serves as a starting material for the process according to the invention.

Following the procedure of Example 7 (...) of DT-OS 2015 (DT-PS.), Phosphorus tribromide is combined with tert-butyl-7-form-

p
amido-3-hydroxymethyl-Δ-cephem-4-carboxylate-i-oxide converted to tert-butyl-7-formamido-3-bromomethyl-cephem-4-carboxylate according to the invention.

This compound is useful as an intermediate for the manufacture of known and new cephalosporin antibiotics. For example, this compound can be reacted with methanol to give tert-butyl-7-formamido-3-methoxymethyl- / S> -cephem-4-carboxylate-1-oxide; the sulfoxide ester can be converted to tert-butyl-7 with potassium iodide / acetyl chloride -formamido-3-bromomethyl- / ^ s cephem-4-carboxylate are reduced, and the formyl group

£ 09829/0904

came with mineral acid at -15 to 100 degrees C with formation of the V-amino-S-methoxymethyl- / \ -cephem-4-carboxylate ester nucleus. This core ester can be acylated with any acyl group known to contribute to the formation of a cephalosporin compound with significant antibiotic activity. For example, the core ester can be mixed with an activated N-protected form of D-phenylglycine with formation of tert-butyl-7- / D-2- (N-protected amino) -2'-phenyl-acetamido_7-3-methoxymethyl-Δ. -cephem-4-carboxylate ester are acylated. The N-protecting group and the Estergruppe can according to known methods to form the 7- / ~ D-'2 ^{l -amino-2-l} -phenylacetamido7-3 methoxyraethyl- _/ A _{s.-Cephem-4-carboxylic} acid, a known Äntibioticums, removed. .

S09829 / 0904

Claims (1)

PATENT CLAIM Process for the preparation of 3-chloro- or -bromomethyl / cephalosporinsulfoxide esters of formula I. R-NH-CH-CH I I CO-N Il COOR ¹ wherein R is C. ~ Cg-alkanoyl, C ^ Cg-chloroalkanoyl or acyl der formula R ³ > _n co- R ⁴ in which Ar is 2-thienyl, m is an integer is from 0 to 4, η is an integer from 1 to 4, Z is oxygen, sulfur or a chemical bond, 3 4
R and R stand for hydrogen or methyl, or if 3 4 R is hydrogen, R is also an N-protected amino, namely a. N-tert-butoxycarbonyl) amino, N- (benzyloxycarbony1) amino, N- (AlIyloxycarbonyl) amino, N- (Cyclopentyloxycarbony1) amino or N- (2-methoxycarbony1-1-methylvinyl) amino can and η has the value 1 and / or, if R stands for N-protected amino, Ar also a group of the formula -B- (Y) can mean in which Y is hydrogen or fluorine, chlorine, bromine, iodine, C ₁ -C ₉ alkYl, C ₁ -C ₃ alkYloXy, N-dashed alpha-amino-C ₁ -C ₇ alkYl, C ₁ - C ₃ -AIkYlOXY, N-protected alpha-amino-C ..- C_-alkyl, butoxycarbonyl, nitro, cyano or trifluoromethyl and w stands for 1 or 2, X stands for chlorine or bromine, and R 2,2,2 -Trichloroethyl, C ₄ -Cg-tert.-alkyl, C _c -C -tert.-alkenyl, C _c -C_ -tert.-alkynyl, benzyl, methoxy-P benzyl, nitrobenzyl, phenacyl, phthalimidomethyl or succinimidomethyl means, characterized in that a 3-hydroxymethyl- / ^ -cephalosporinsulfoxidester in the presence of a tertiary amine in a practically anhydrous liquid diluent a) at temperatures of about -75 to about -25 ° C with an approximately equimolar amount of phosphorus tribromide or phosphorus tri- chloride, or b) at temperatures from about -75 to about 50 ° C. with phosphorus pentachlorodide Phosphorus pentabromide, phosphorus oxychloride or fc converts phosphorus oxybromide.