DE2052531A1 - 3 halomethyl delta to the power of 3 cephalosporin esters - Google Patents

Description

PAT L- "· 'f, Λ M γι;, j _c

ü .v; U :: ■ Z H -ι. ;% j 2 3

hGi; -it .; j, j ?, ϋί,. VuL. 3ö Ü2 36 83 680

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

■ 2

3-halomethyl / cephalosporin ester

Addition to patent P 20 15 317.7

The invention relates to the further development of the object from patent P 20 15 317.7.

The invention relates to 3-halomethyl- / \ -cephalosporin esters the formula .. ■.

¹ R-NH-CH-CII

CH,

t <

CO-N. C-CH ₀ X

, 2

• COOR ¹
or

It

¹¹ R-NH-CH-CH OH ₀

If I ^C

COOR ¹

209808/1866

wherein R is a C 1 -C 6 alkanoyl radical, a C ₂ -C 6 chloroalkanoyl radical or an acyl group of the formula

H ⁵

00-,

E ⁴ ■ ·

where Ar is a 2-thienyl radical, m is an integer from 0 to 4, η is an integer from 1 to 4, £ oxygen or sulfur or a chemical bond is

3 4 ···
indicates that R and R are hydrogen atoms or methyl radicals, or, when R is a hydrogen atom, f R is also an N-protected amino group, namely an N-tert.-butoxycarbonyl) amino, N- (benzyloxycarbonyl) amino, N- (allyloxycarbonyl ) amino, N- (cyclopentyloxycarbonyl) amino or N- (2-methoxycarbonyl-1-methylvinyl) amino group and η can have the value 1 and / or, if R denotes the N-protected amino group, Ar also a group the formula '.

may mean in which Y is hydrogen or fluorine, chlorine, bromine, iodine, C- | -C2-alkyl radicals, Cj-C2-alkyloxy radicals, N-protected alpha-amino-C ^ -Cj-alkyl create, butoxycarbonyl radicals, nitro groups, cyano groups or trifluoromethyl radicals as substituents on the phenyl ring carbon atoms and w is an integer from 1 to 2, X is chlorine, fluorine or iodine and R is 2,2,2-trichloroethyl, C.-Gg-tert.-alkyl, Cc-C, -tert-alkenyl, Cc-C ₇ -tert-alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl, phthalimidoaethyl or succinimidoaethyl radical.

20 9 80 8 / 18.6 6

The process for the preparation of these compounds is characterized in that one of the following Phosphorus compounds

(1) phosphorus trichloride or phosphorus tribromide or

(2) phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybromide;

• ar

with a 3-HydroxymethyI- A -cephaloaporinaulfoxidester in the presence of a tertiary amine in a practically anhydrous liquid diluent at a temperature of about -75 degrees \ Q to about 50 degrees C and the product is the corresponding

■ 2

(1) 3- _{Halomethyl ~ / \ L} -cephalosporin ester when using an equiaolar amount of phosphorus chloride or phosphorus tribromide and temperatures above about -25 degrees C or

(2) 3-Halomethyl-A -CQPhaloBporine sulfoxide ester when using an approximately equal amount of phosphorus tribromide or phosphorus trichloride and from temperatures below about -25 degrees C or

(3) 3-halomethyl-A-cephaloeporine sulfoxide ester generated when using phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybroaid.

One of the particular advantages of / \ -desacetoxycephalosporin compounds is that they can be prepared from penicillin sulfoxide esters by the process of US Pat. No. 3,275,626.

209808/1866

• χ

The 3-halomethyl-A-cephalosporin esters according to the invention are advantageous intermediates for the production of new and known nitrogen and Sulfur-containing 3- (Nuceliophil-methyl) - / \ -cephalosporin antibiotics and can be used to generate

• z

3- (Nucleophilmethyl) - / \ -cephalosporinen incorporated without the need to apply oxidation and reduction conditions.

The method according to the invention eliminates the difficulties circumvented or avoided, which in some cases after the conversion., of a 3-bromomethyl-, A-

cephalosporin ester into a 3- (nucleophile-methyl) - ^ \ cephalosporin ester can result if the nucleophilic group is an oxidizable nitrogen or sulfur atom contains.

The process according to the invention is carried out in detail in the same way as in the main patent is described. .,

If 7-aminocephalosporanic acid (7-ACA) is to be used as the starting material, preference is given to 7-amino protecting groups, which not only combine easily with the 7-amino nitrogen, but can also be easily removed after the desired sequence of reactions on the methyl group In such cases, the preferred 7-amino protective group can be a simple Cj-Cg -alkanoyl group, for example a formyl, aetyl, propionyl, butanoyl or hexanoyl group, or a C 1-6 chloroalkanoyl group, in particular an alpha-chloroalkanoyl group, for example a 2-chloroacetyl group, These groups are converted into the corresponding acid chloride by the reaction of 7-AOA

2 09808/1 8.6 6

appropriate. If the chosen overall procedural route on the Cephalosporinaritibioticum an acylation of 7-ACA, an ester of 7-AGA, of 7-ACA-sulfoxide or one of them 7-AGA sulfoxide ester with the final Acy! Group requires, you can use an activated

; Acylate form of N-protected phenyl glycine. One.

• ^; such an activated form can consist of the mixed anhydride which is formed by the reaction of isobutyl chloroformate and 2 - ^ - (tert-butoxyoarboryl) amino ^ 2 ~ phenyl-phenylgic acid.

The symbol R in formulas I and II given above means an ester group), as defined in the main patent is.

The 3-halomethyl- ^ Λ, -cephaloaporlnester obtained of formula I are available as intermediates for direct production of antibiotic gephalosporin compounds advantageous by removing the ester group by various known methods, as in the main patent is specified. . .

The compounds of formula I and II are mainly used for the production of known and new antibiotic active cephalosporin compounds of importance, as already explained in the main patent.

Through the following examples showing the implementation of the process and typical manufacturing methods of the new Compounds, the invention is explained in more detail.

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example 1

A '

* * z

7-Aoetamido-3-acetoxymethyl-A -cephem ^ -carboxylic acid is produced by reacting 7-aminocephalosporanic acid (7-AGA) with Acetylchlorld '. The 7-acetamido • 3-acetoxymethyl- ^ -cephem-4-oarboxylic acid is

} ■ treatment with oxalyl chloride in the presence of a small amount of Ν, Ν-dimethylformamide converted into the corresponding acid chloride. This acid chloride of 7-acetamido-3-acetoxymethyl- ^ -oephem-4-carboxylic acid is dissolved in methylene chloride and the solution is treated with tert-butanol

^ and triethylamine treated, to the tert-butyl-7-acetamido-3-acetoxymethyl- ^ -cephem ^ -carboxylate ester.

The tert-butyl-7-acetamido-3-acetoxymethyl - / \ -cephem-4-carboxylate is with a peracid, for example m-chloroperbenzoic acid in a mixture of isopropanol and methylene chloride to the tert-butyl-7-acetamido-3-acetoxymethyl- ^ -cephem-4-carboxylate-i-oxide oxidized.

The tert-butyl-7-aoetamido-3-acetoxymethyl-A -cephem-4-carboxylate-1-oxide is treated according to known methods with Citrusacetyleateraee to tert-butyl-7-acetamido-3-hydroxymethyl - / \ - to obtain cephem ^ -carboxylate-i-oxide

The tert-butyl-7-acetamido-3-hydroxymethyl-A-oephem-4-carboxylate-1-oxide is treated with phosphorus tribromide according to the procedure of Example 7 of the main patent, whereby the product tert-butyl ^ -aoetamidoO-bromomethyl- -cephem-4-carbpxylate-i-oxide is obtained.

209808/186 6

This product can be used as an intermediate for the production of various known and novel Cepha- ₄ losporinantibiotica. For example, this product can be converted into the 3-methoxymethyl analogue by treatment with methanol or into the 3-methylthiomethyl analogue with methyl mercaptan. Such compounds can then be reduced to the sulfide state, treated in a known manner with PClc / CH ^ OH / HgO to split off the 7-acetyl group and acylated again with any acyl group known to give the cephalosporic acid obtained. For example the tert-butyl-7-amino-3-methylthiomethyl- / y-cβphem-4-carboxylate8ter "core" compound can be acylated with a mixed alkyl anhydride of an ND- (tert-butoxycarbonylamido) phenylglycine, and then the tert. -Butoxycarbonyl protective group and the tert-butyl ester groups are removed by known methods, whereby the 3-Methylthiomethy1-7- ^ 0-2'-amino-2 * -pheny! Acetamido ^ 7 - / \ -cephem-4-carboxylic acid zwitterion (inner SaI ^, a well-known antibiotic, is obtained .

Example 2

The amino group of 7-aminocephalosporanic acid (7-ACA) is reacted with a formyl group by the reaction of 7-ACA with the mixed anhydride formed by addition of formic acid to acetic anhydride, to give the 7-Pormamido-3-acetoxymethyl - / \ - cephem -4-carbonic acid protected. This N-protected 7-ACA is converted in the manner described in Example 1 with the formation of the tert-Bitty 1-7-formamido-3-acetoxymethyl- / \ -cephem-4-carboxylate ester. This ^ \ -Cephaloeporin-

209 808/1 86 6

Ester is oxidized as described in Example 1 to tert -butyl-T-formamido-J-acetoxymethyl - / ^ -cephem-4-carboxylate-1-oxide. This / \ -Cephalosporinsulfoxidester is with Citrusacetylesterase to tert-butyl-7-formamido-3-hydroxymethyl-A -cephem-4-oarboxylat-1-oxide hydrolyzed, which serves as starting material for the novel process.

Following the procedure of Example '7 of the main patent Phosphorus tribromide with tert-butyl-T-formamido-J-hydroxymethyi- ^ y-cephem - ^ - carboxylate-i-oxide to tert-butyl-7-formamido-3-bromomethyl- -cephem-4-carboxylate implemented.

This compound is used as an intermediate for the manufacture of known and new cephalosporin antibiotics advantageous. For example, this compound can be combined with methanol to give tert-butyl - ^ - formamido-O-methoxymethyl- -cephem-4-carboxylate-i-oxide are converted, the

Sulphoxide ester can be added with potassium iodide / acetyl chloride

Λ 3

tert-Butyl ^ -formamido ^ -bromomethyl - / ^ -cephem-4-carboxylate can be reduced, and the formyl group can with
Mineral acid at -15 to 100 degrees G with formation of the 7-amino-3-methoxymethyl- / \ _i -oepheia-4-carboxylate ester "nucleus" are split off. 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 with an activated N-protected form of D-phenylglycine to form tert-butyl-7- / D-2- (N-protected amino) -2'-phenyl-acetamidoj ⁷ "3-methoxymethyl- ^ The N-protective group and the ester group can be acylated by known methods with formation of the Ί- / Ώ-2 ^1- amines'-phenylacetamide-7-3-methoxymethyl- / N _i ⁵ -oephem-4-carboxylic acid , a known antibiotic, must be removed.

209808/1866

Claims (8)

Claims Jt Further formation of the 3-halomethyl / cephalosporin esters according to patent P 20 15 317.7 »marked; is characterized by the formula · ■ -NH-CH-OIi ^ Ί3 I CO-N C-CH ₉ X CO OR ¹ or 11 R-NH-CH-CH CH ₂ COOR ¹ wherein R is a Cj-Cg alkanoyl group, a Cg-Cg alkanoyl group or an acyl group of the formula Ar tCHg ^ tr Z- (C-k CO- d m. , η where Ar is a 2-thienyl radical, m is an integer from 0 to 4 »n is an integer from 1 to 4» Z is oxygen or 209808/1866 - ίο - "5 4 sulfur or a chemical bond and Ir and R , Mean hydrogen atoms or methyl radicals, or, if H is hydrogen, R also an N-protected amino group, namely an N-tert.-butoxycarbonyl) -amino-, N- (benzyloxycarbonyl) amino-, N- (allyloxy- · 'Carbonyl) amino-, N- (cyclopentyloxycarbonyl) amino- or N- (2-methoxycarbonyl-1-methylvinyl) amino group can and η can have the value 1 and / or, if R denotes an N-protected amino group, Ar also one Group of formula may mean in which Y is hydrogen or fluorine, chlorine, bromine, iodine, Cj-Cg-alkyl radicals, Cj - ^ - alkyloxy radicals, N-protected alpha-amino-C «-C, -alkyl radicals, butoxycarbonyl groups, nitro groups, cyano groups or trifluoromethyl radicals as Substituents on the phenyl ring carbon atoms and w is an integer from 1 to 2, X is chlorine, fluorine or iodine and R is 2,2,2-trichloroethyl, C ^ -Cg alkyl, Cc-C ₇ -tert.-alkenyl , Cc-C ^ tert-alkynyl, benzyl, methoxybenzyl-j nitrobenzyl, phenacyl, phthalimidomethyl or succinimidomethyl radical. 2. A compound according to claim 1 of the formula II, characterized in that X is bromine, R is acetyl and R is C.-Cg-tert-alkyl. 209808/186 6 3. A compound according to claim 1 of the formula II, characterized characterized in that X is bromine, R is formyl and E is C ^ -Cg-tert-alkyl means. 4. A compound according to claim 2 or 3, daduroh in that R is t-butyl. 5. Process for the preparation of compounds of the formula I and II, characterized in that one of the following phosphorus compounds (.1) Phosphorus trichloride or phosphorus tribromide, or V (2) phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybromide, a tertiary amine in a substantially water-free liquid diluent is reacted with a 3-hydroxymethy1-Λ -cephalosporinsulf oxidester in the presence of at a temperature of about -75 degrees C to about 50 degrees C and as a product of the corresponding (1) 3-halomethyl - / ^ -cephalosporin ester when used at least an equimolar amount of phosphorus trichloride or phosphorus tribromide and temperatures above about -25 degrees C or (2) 3-halomethyl - ^ [\ -cephalosporinsulfoxide ester when using an approximately equimolar amount of phosphorus tribromide or phosphorus trichloride and temperatures below about -25 degrees C or 2098Ö8 / 1866 \ 5) 3-Halomethyl-A -oephalosporinsulfoxidester generated when using phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride or phosphorus oxybromide. 6. The method according to claim 5, characterized in »that the phosphorus compound used is phosphorus tribromide. 7. The method according to claim 5 »daduroh characterized in that one phosphorus tribromide as phosphorus compound and as 3-hydroxymethyl / \ -oephaloaporinsulfoxidester- tert-butyl-3-hydroxymethyl-7-aoetaaiido- _i / ^ -cephea-4-carboxylate-i oxide used and to tert-butyl-J-broauaethyl-T-acetaaido- implements. 8. The method according to claim 5 »daduroh characterized, that as phosphorus compound phosphorus tribromide and as 3-hydroxymethyl- ^ -oephalosporinsulfoxidester tert-butyl-3-hydroxymethyl-7-formamido-Zy-cephem-4-carboxylate-ioxide used and zu.tert.-Butyl-3-chloromethy1-7-formamido-2 ^ -cephem ^ -oarboxylate-i-oxide converts. 209808/1866