DE2351375A1 - PROCESS FOR THE PREPARATION OF 7-ACYLAMIDO-7-ALKOXYCEPHALOSPORINES - Google Patents

Description

TEL. a sy 22 Ol / 205

Χ-3673

BIi Lilly and Company »Indianapolis» Indiana »V.St.A.

Process for the preparation of 7- "acylamido-7'-alkoxycephalosporins

The invention relates to a process for the production of 7-Aeylamldö-7-alköxycephalösporinen by reacting 7- (B-Amino-S-earboxyvaleramido) »* 7-methoxy cephalosporin» whose amino and acid groups are protected with PCl ₅ or a other 'to form a iminohalides suitable means to implement then the Iminohalogenids thus obtained under substantially anhydrous conditions with a primary Alkanoi having 1 to 4 carbon atoms or with methane-d ^ -ol> to obtain a core with a 7-alkoxy group of the primary low Alkanoi or the methane-d ^ oi native "the results in in situ acylation of the core then 7-Aeylamidö-7» alkoxyeephalösporine in good yield "These products can bu _t are the corresponding acids esterified affect the antibacterial.

In J * Am »etern * Sog» 93: 9 (1971) new antibiotics are already introduced the following structural formulas:

409817/1132

OCHa

HOOC-CH (CHa) a CONH NHa

and

COOH

CHaOCCHs

HOOC-CH (CHa) sCONH NHa

OCHa

CHsOCNHa

COOH

These antibiotics are called 7- (S-amino-S-carboxyvaleramldo) ■ 7-methoxycephalospora acid and 7- (5-amino-5-carboxyvalerami do) -7-methoxy-3-carbanoyloxyiaethyl-3-cephem-4-carboxylic acid designated. Optionally, they are also named as antibiotics A16884 and A168861 (see BE-PS 754 424 and 754 693). The last-mentioned antibiotic is also described in BE-PS 764 160, and it is there as Designated antibiotic 842A.

In BE-PS 764 160 there is also an antibiotic 81OA mentions that has the following formula:

409817/1132

235137a

OCHa
HOOC-CH (CHb) ₃ CONH.

NHb. I 0

CHaOC-C = CH- / f j \ OH

OCH ₃ \ s ^ J /

cooH y ^ zz /

This antibiotic is called 7- (S-amino-S-carboxyvaleramido) -7-methoxy-3- (alpha-methoxy-p-hydroxycinnamoyl- oxymethyl) -3-cepheIn-4-carboxylic acid.

Like other cephalosporins, so can these antibiotics to produce a core with cleavage of the 7-acyl group by the PCl ^ process. The one with it obtained core can if desired with introduction reacylate another 7-acyl group. However, there has now been an improved method of cleavage and reacylation of the above * mentioned antibiotics and other modifications found in position 3. This procedure can additionally be used in the antibiotics mentioned above or their corresponding modifications in position instead of the original 7-methoxy group another To introduce a 7-alkoxy group or a 7-methoxy-d ~ group.

The invention accordingly relates to a process for the preparation of a compound of the formula:

£ 098 17/1132

HeN

CHe-R ¹

COOR '

in which R is primary alkyl of 1 to 4 carbon atoms or methyl-d., R is acetoxy, carbamoyloxy, alpha-methoxy-p-hydroxycinnamoyloxy, Propionyloxy, benzoyloxy, methoxy, methylthio, 1-methyl-1,2,3,4-tetrazol-S-ylthio or

5-methyl-1,3 _/ 4-thiadiazol-2-ylthio means and R ^2A means water

2 2

hydrogen or a radical R, where R is alkyl with 1 to 6 carbon atoms, 2,2,2-trichloroethyl, 2-iodoethyl, tert-alkenyl with 5 to 7 carbon atoms, tert-alkynyl with 5 to 7 carbon atoms, benzyl, arylnitrobenzyl, tetrahydropyranyl, Succinimidomethyl, phthalimidomethyl, arylmethoxybenzyl, Aryl, aryl-dimethoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitrophenyl, bis (p-methoxyphenyl) methyl, Triphenylmethyl, diphenylmethyl, benzyloxymethyl, lower alkanoyloxymethyl of 3 to 6 carbon atoms or phenacyl, which is characterized in that an iminohalide of the formula

OCHa

^{R, for example,} OOC-CH (CHa) ₃ -C = N-

CHa-R ¹

COOR '

Λ098 1 7/1 132

where X stands for bromine or chlorine, R has the above meaning,

*? R 2

R for the above-mentioned radical R, lower alkanoyl with up to 4 carbon atoms or a radical of the formula

R-Si

stands in which the substituents R are each the same or are different and are alkyl with 1 to 4 carbon atoms, Mean fluorine, chlorine, bromine or iodine, but at least

3
one of the substituents R must stand for lower alkyl,

4th
and where R is an acylamido group in which the acyl group is for

Alkanoyl of 1 to 4 carbon atoms _B

Benzoyl,

Naphthoyl,

Alkoxycarbonyl with 2 to 5 carbon atoms,

Cycloalkoxycarbonyl with 6 to 7 carbon atoms,

Benzyloxycarbonyl,

Naphthyloxycarbonyl _β

where the above-mentioned groups can be substituted one to three times by halogen, nitro, Alkoxy with 1 to 4 carbon atoms, cyano and, in the case of benzoyl, naphthoyl, benzyloxy or naphthyloxy, also by alkyl having 1 to 4 carbon atoms, or for

Phthalyl stands,

with an alcohol of the formula R ° -OH. under practically anhydrous Implements conditions.

409817/113 *

The imino halide used as the starting product is preferably prepared in situ by reacting a compound the formula

OCHo

R ^ED OOC-CH (CHa) aCONH • ⁴

C.
R.

-M. Λ CHa-R ¹

X) QR ^

with PCl ₅ or another acid halide.

The product obtained in this way, namely a compound of the formula

HaN

H2-R ¹

COOR

is then preferably carried out in situ with a compound of the formula

X-R *

or CHR)

reacylated, where X is halogen, preferably bromine or chlorine, and R _{5 is}

409817/1132

stands.

Alkanoyl with 1 to 8 carbon atoms "Azidoacetyl,
Cyanoacetyl,
Haloacetyl,

Ar-CH ₂ -O-, where Ar is phenyl, thienyl, furyl, pyrrolyl or one to three times by fluorine, chlorine, bromine iodine, tri fluorine thy I, protected amino, protected hydroxy, alkyl with 1 to "3 carbon atoms, alkoxy denotes phenyl substituted with 1 to 3 carbon atoms, cyano or nitro,

Ar * -Y-CH ₂ -C-, where Ar ^{1 is} phenyl, pyridyl _s or substituted phenyl of the type mentioned above and Y is oxygen or sulfur “ for

BO

in.

Ar-CH-C-, wherein Ar has the above meaning and B stands for protected amino, protected hydroxy, protected carboxy -CN ₂ or -N ₃ or for

2- (3-sydnone) acetyl or
2- (IH-tetrazol-1-yl) acetyl

The protected amino preferably carries protective groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, alkoxycarbonyl with 2 to 5 carbon atoms, cycloalkoxycarbonyl with 6 to 7 carbon atoms, tripheriylmethyl or 2,2,2-trichloroethoxycarbonyl. The protected hydroxy group is preferably a group of the formula

Il

or HGO-.

The protected carboxy group is preferably with such Providing protective groups, such as the corresponding carboxy group in the starting products.

2A The reacylated compounds in which R is hydrogen have an antibacterial effect. If with these · connections the substituent R is any of those specified in detail Means ester groups, or if other protective groups are present are, then the reacylated compounds can be deesterified, or the other protective groups can be removed and you get connections here as well with antibacterial effect.

The compounds of the formula used as Äusgarigsprodukte

R ^eÖ OÖC-p (CHa) 3-Cöm R *

CHe-R ¹

can be produced by known processes. The antibiotics A16 884, A16 8861 or 81OA are in particular implemented by (1) protecting the amino group, (2) protecting the acid groups and, in the case of the antibiotic 81QA, (3) protects the hydroxy group.

The amino group is best protected by reaction the antibiotics A16884, A168861 or 81OA with an appropriate one Acyl halide, anhydride or ketene with formation of an acylamido group. The identity of the acylamido group formed is not critical. Suitable acylamido groups are for example those with the following Äcylrests

Alkanoyl with 1 to 4 carbon atoms, Benzoyl,

Naphthoyl,

Alkoxycarbonyl with 2 to 5 carbon atoms "cycloalkoxycarbonyl with 6 to 7 carbon atoms _t benzyloxycarbonyl,

Naphthyloxycarbonyl,

wherein the abovementioned groups may be substituted one to three times by halogen "Nitro _ρ alkoxy - with 1 to 4 carbon atoms, cyano, and, in the case of benzoyl, naphthoyl, benzyloxy or naphthyloxy, by alkyl having 1 to 4 carbon atoms or

Phthaloylo

Halogen is understood to mean the substituents bromine, chlorine, “iodine or fluorine”. Typical suitable groups are formyl, acetyl, propionyl, chloroacetyl, “ dichloroacetyl, benzoyl, p-nitrobenzoyl, phthaloyl _? p-methoxybenzoyl, cyclohexyloxycarbonyl _r terto-butoxycarbonyl, phenoxycarbonyl or benzyloxycarbonylο For better separation of the compound protected on the amino group, a corresponding salt can be prepared therefrom »

409817/1132

In one embodiment, the carboxyl groups are protected by esterification. The ester group used in each case is: not critical. In general, groups which can be easily split off after the protection has ceased to be suitable are suitable. If the esterification is carried out as a separate process step, the following typical groups are suitable, for example: alkyl with 1 to 6 carbon atoms, 2 _f 2 _y 2-trichloroethyl _f 2-iodoethyl, tert.-alkenyl with 5 to carbon atoms, tert.-alkynyl with 5 to 7 carbon atoms f benzene t aryl-nitrobenzyl, tetrahydropyranyl, succinimiclcethyl, phthalimidomethyl, aryl-methoxybenzyl, aryl, aryldimetfaoxybenzyl, cyanomethyl, nitrophenyl, dinitrophenyl, 2,4,6-trinitrophenyl, 2,4,6-trinitrophenyl, tripheny-1) methyl, bis-Cp-methoxyphenyl ! methyl, benzyloxymethyl, lower alkanoyloxynsethyi with 3 to 6 carbon atoms or phenacyl.

A second and often preferred method is used the protection of the carboxyl groups in the form of a first part of the cleavage reactions by either having one to form a mixed anhydride capable reactant or a silane compound is used. The mixed anhydride is produced by conventional methods, for example by reacting the antibiotic with an acyl halide. The acid halide used for this purpose and its corresponding remainder in the case of the mixed anhydride are not critical. Suitable groups are, for example, the lower alkanoyl radicals and those radicals, the substituents exhibit. However, because of their ease of manufacture the simple lower alkanoy groups preferred, for example those with 2 to 4 carbon atoms,

The tin protection of the carboxyl groups used silane compound is conveniently a compound of the formula

R ³

₃ \ 3
R-Si-R

R ^3/409 817/1132

in which the radicals R ^{3 are} each identical or different and represent alkyl with 1 to 4 carbon atoms, fluorine, chlorine, bromine or iodine, but at least one of the substituents R ^{3 is} halogen and at least one of the substituents R ^{3 is} lower alkyl must stand »A preferred silane compound is trimethylchlorosilane. Other suitable compounds are dimethyldichlorosilane, Methyltrichiörsiläni ,. Diethyldiflüorsiiän or Bromotrimethylsilän *

The protecting group of the formula

can also be introduced by using the Sntibiöüieum with a SiIylamid, SiIy! urea or Siiyluretiiaa, as described in BE-PS 737 761

Both when using the Siiylesterschutzgruppeiii and of the fished anhydride protecting groups become these groups in the implementation of the imittöhälGgöiSiids according to the invention removed with alcohol, and you get a core in the free acid.

Optionally, the carboxyl and amino acids can be deir alpha-aminoadipoyi side chain also through ring formation be blocked, for example durcii Bilduiig eüie'äf dazölylringes.

In the case of the antibiotic 81OA, sicii ά ± € can easily be protected by known "procedures: _{t for} example by reaction with GhlormethyMethyiather or with p-bromophenacyl bromide (Fieser & Wi & sGt _f Röägents for Örgäöiö

40981: 7/1

Synthesis, John Wiley & Sons, New York 1968, Volume I, Page 133, or Volume III, page 34).

Those starting products in which R is propionyloxy, Benzoyloxy, methoxy, methylthio, 1-methyl-1,2,3,4-tetrazol-5-ylthio or 5-methyl-1,3,4-thiadiazol-2-ylthio can be prepared according to BE-PS 768 528. The corresponding Compounds can then, as already described above, protected at their amino or acid groups will.

regardless of how you get to your respective starting product reaches in detail, the resulting compound of the formula

R ^8B OOC-pH (CHs) a-CONH

then with one to form an amino halide Appropriate "means implemented. For this purpose phosphorus peritachloride is used preferred. However, other acid halides can also be used. These other suitable agents include phosphorus oxychloride, Phosphorus trichloride, thionyl chloride, phosgene, Oxalyl chloride and those from o-dihydroxybenzoi and phosphorus trichloride complex compound formed *

409817/1132

O D ί

The starting product and the iminohalide forming agent are reacted together in any suitable manner "Good results are generally obtained then _s by reacting the reactants as _B that 1 mol of the Äusgangsverbindung and 2 to 5 moles used of the iminohalide forming agent. The reaction can be carried out at temperatures from -50 to 50. ⁰ C made "but preferably is carried out at room temperature; Preferably the reaction is in the presence of a tertiary amine _g performed, for example, triethylamine, pyridine or dimethylaniline "

Through the above-mentioned implementation gives a iminohalide following formula

R ⁸⁸ OOC-CH (CHe) ₃ -O = N

OCHs

COOR *

'that then without prior separation of the erfindungsge is subject to moderate implementation.

It has been found that this _e-for the treatment of Iminohalogenids with an alcohol directly to the desired core of the formula

HbN

receives.

CHaR

COOR "

409817/1132

By using an alcohol according to the invention one in contrast to the known method for the implementation not to use water. This eliminates the risk of the core degrading under aqueous conditions seems to be less stable.

In addition to the advantages already mentioned above, the use of an alcohol according to the invention provides at the same time also a method of introducing another 7-alkoxy group or for the introduction of the methoxy-d - group. Of the exact heaction mechanism is not known by the treatment according to the invention with an alcohol is obtained however, a ring which has an alkoxy group in position 7, which is different from the alkane used! derives. If you want to have a 7 ™ methoxy group, then for the implementation used alcohol.

The introduction of the 7-alkoxy group from the alcohol is with associated with a certain epimerization in position 7 it is believed that Antibiotics & 16884, Al68861 and 81OA "(as well as its other derivatives in position 3) in the 7-alpha-Methoxykonfigurati © B occur, whereby the 7- (5-amino-5-carboxyvaleramido) group is in the ß-configuration. Reacylated compounds prepared according to the invention occur in the form of a mixture of alpha and beta alkoxy compounds »The exact ratio of these compounds varies depending on the Acy! rest used.

For this stage of the process according to the invention one can use any primary alcohol with 1 to 4 carbon atoms, for example methanol, ethanol, n-propanol, n-butanol or isobutanol, or the alcohol can also be methand ^ -ol be. For the reaction, the alcohol is added to a solution which contains the iminohalide intermediate. In order to get good yields, the solution should be practical

409817/1132

be anhydrous and also be kept practically anhydrous until the core is reacylated. The reaction is zweckraäüigerweise carried out at temperatures between -70 and + 5O ⁰ C ₁ wherein one initially but preferably is carried out at 0 C, then warmed for a few minutes at room temperature and finally cooled again to 0 ° C.

The proportions of the iminohalide and the alcohol are not critical and they vary depending on the reaction and the reactants. The reaction of the imino halide with the cabbage should require 2 moles of alcohol per mole of imino halide. However, additional alcohol is consumed by excess PCl _{5 or other acid halides.} Are the acid groups by a «jeiaic-

tes anhydride or through a silyl group <R »lower alkanoyl or the group

protected, then it also comes through these groups consumption of alkanol. In general, good results are obtained if the alcohol is used in a fairly large amount Excess is used, for example 5 to 10 moles of alcohol per mole of imino halide.

The product of the formula obtained according to the above procedure

HaN-

\ K ^

CH R ¹

COOR *

409817/1132

can, if desired, be separated from the reaction mixture. Such a separation should, however, be carried out under slightly basic conditions. Better results are obtained when the product is reacylated in situ. The reacylation is carried out by reaction with a compound of the Formula X-R or O-fR) ", in which X and R have the above meaning to have. The acylation is carried out in the customary manner. The compounds of the formula obtained in this way

R ^e -NH

CHbR ¹

COOR ^loc

are interesting insofar as those compounds in which R stands for an ester group to the free

2A
Can hydrolyze acids (R = H). The free acids with the group -OR ° in the alpha configuration are interesting antibacterial agents (cf. BE-PS 768 528). If the compounds are in the form of their β-OR ° epimer, then these esters can be treated according to the invention and a mixture of alpha and beta-alkoxy esters is obtained, the alpha-alkoxy epimers likewise being very, as already described above are useful.

The invention is further illustrated by the following examples explained. In numerous syntheses of these examples, solvents as well as other reactants, which have nothing to do with the actual reaction partners, deuterated compounds are used to thus the products obtained in each case can be identified by means of NMR spectroscopy. The use of such deuterated compounds is therefore not critical for the process according to the invention.

409817/1132

B e i s ρ i e 1 1

7-Amino-7-methoxy cephalosporanic acid methyl ester

7- (S-Phthalimido-S-carboxyvaleramido) -7-methoxycephalosporanic acid dimethyl ester (6Q, 4 mg, 0.1 mmol) is treated at room temperature with methylene chloride-d »(0.5 ml), pyridine-dg (21 mg , 0.25 mmol) and phosphorus pentachloride (42 mg, 0.2 mmol) mixed. The mixture is left, the reaction mixture as it is about 1 hour, then cooled to 0 ⁰ C and keeps it for a further hour at this temperature. Methanol-d (50 mg, 1.44 mmol) is then added. The reaction mixture is allowed to stand for 1/2 hour and then the desired methyl 7-Äraino-7-methoxycephalosporanate is obtained in situ.

In a typical reaction of the type mentioned above, the reaction mixture is monitored by NMR spectroscopy. The addition of phosphorus pentachloride results in a downfield shift of the signal for the alpha-methylene group the valeramido side chain. Before the phosphorus pentachloride is added, there is a broad range at about 2.35 ppm. 4 proton resonance. After the addition (but before the addition of methanol) there is a 2 proton trip at 2.74 ppm (J ** ^ 7 cps) lett, which indicates the formation of the iminochloride. After adding the methanol, the triplet disappears and you receives a 4 proton resonance centered at 2.35 ppm.

Example 2 7-Phenoxyacetamido-7-methoxycephalosporanic acid methyl ester

The mixture prepared according to Example 1 and containing 7-amino-7-methoxycepha- * losporanic acid methyl ester is treated with chloroform-d (0.5 ml), pyridine-d ₅ (127 mg, 1.52 mmol) and

409817 / 113Γ2

Phenoxyacetyl chloride (131 mg, 0.77 mmol) was added at 0 ⁰ C. The mixture is kept at 0 ^° C. for 15 minutes and then warmed to room temperature for 10 minutes. The reaction mixture is then worked up in the customary manner. The measures used for this purpose are practically the same as described in Example 9 later, starting with the addition of dry methanol, with the exception of the use of methylene chloride instead of the chloroform used in Example 9. The methylene chloride phase obtained is examined by thick layer chromatography using benzene / ether 7: 3 as developer and acetone as eluent. A main peak at 450 is obtained in the mass spectrum, which agrees with the calculated molecular weight (450.4) for the expected methyl 7-phenoxyacetamido-7-methoxycephalosporic acid ester.

The compound obtained is also examined in a high-resolution mass spectrograph, and a parent ion with the mass 450.1106 is obtained (the theoretical mass for the formula ^C 2o ^H 22 ^N 2 ° 8 ^{S is} 9 ^t 450.1097).

The product prepared by a typical process of the type described above is also examined in the NMR spectrum, the following results being obtained: CDCl ₃ = S 2.05, (s, 3H, 3-CH ₂ OCOCH ₃ ); 3.41 (two q, 2H, 2-CH ₂ )? 3.51 and 3.54 (two s, 3H, 7-OCH ₃ two epimers); 3.87 (s, 4-COOCH ₃ ); 4.08 (broad, 2H, 0OCH ₂ CONH); 4.96 (two q, 2H, 3-CH ₂ OCOCH ₃ ); 5.12 (s, «0.15H, 6-H of 7-alpha-OCH ₃ epimer); and 5.23 ppm (s, fvO, 85H, 6H of 7-6-OCH ₃ epimer). ·

409817/1132

Example 3

T-amino ^ -methoxycephalosporanic acid

8- (S-Phthalimido-S-carboxyvaleramido) -7-methoxycephalosporanic acid (57.6 mg, 0.1 mmol) is mixed with 0.5 ml of methylene chloride-d_, and the resulting mixture is cooled to O C. Then Dimethy ! aniline (80.5 mg, 0.72 mmol) and Äcefcylchlorid-d- (28.5 mg, 0.35 mmol) was added to give further holding the reaction mixture at 0 ⁰ C and vibrates. All substances dissolve within 15 minutes. After 1 hour, phosphorus pentachloride (73 mg, 0.35 mmol) is added and the reaction mixture continues to vibrate in a similar manner. The phosphorus pentachloride dissolves within 25 minutes, and the reaction mixture is then kept at the specified conditions for several hours. The reaction mixture is then stored in dry ice for 2 hours and then brought to 0 ° C. Then it is mixed with methanol-d (96 mg, 3.0 mmol}, vibrated and after 5 minutes brought to tree temperature. This gives the desired 7-amino-7-methoxycephalosporanic acid in situ.

Example 4 T-Phenoxyacetamido -? - methoxycephalosporanic acid

The final reaction mixture produced according to Example 3 (276 mg, 3.5 mmol) at ⁰ ° C with chloroform-d (0.5 ml), pyridine-d ₅ and phenoxyacetyl chloride (273 mg, 1.6 mmol) was added, followed by the reaction mixture vibrates. After 20 minutes, 0 _v 5 ml of chloroform and 96 mg of methanol (3.0 mmol) are added. The reaction mixture obtained is diluted to 10 ml with chloroform, extracted twice with 15 ml of sodium bicarbonate solution each time, and the sodium bicarbonate solutions are washed with 20 ml of chloroform. The chloroform and sodium bicarbonate layers are separated from each other, and the

4098 17/1132

- 2O -

50 ml of chloroform are added to the sodium bicarbonate layer and then acidified to pH 2.5 with phosphoric acid and finally separates the chloroform layer. The solution obtained is extracted again with 20 ml of chloroform. The last two chloroform layers obtained from the acidified bicarbonate solution are combined and evaporated, and a total of 35.2 mg of 7-phenoxyacetamido-7-methoxycephalosporanic acid is obtained.

Example 5 7-Phenoxyacetamido-7-methoxycephalosporic acid

7-Phenoxyacetamido-7-methoxycephalosporanic acid is prepared by the same method as in Examples 3 and 4, but with the exception of 7- (S-chloroacetamido-S-carboxyvaleramido) -7-methoxycephalosporanic acid (52.2 mg, O , 1 mmol) was used as the starting product. In addition, the other original starting materials used are methylene chloride-d ₂ (0.5 ml), N, N-dimethylaniline (80.5 mg, 0.72 mmol) and acetyl chloride-d- (28.5 mg, 0.35 mmol) . In the further procedure, phosphorus pentachloride (73 mg, 0.35 mmol) is then added. The then following reactants and the respective amounts as well as the work-up procedures correspond to those of Examples 3 and 4. 454 mg of T-phenoxyacetamido -? - methoxycephalosporanic acid are obtained.

409817/1132

Examples 7-Amino77 ^ methoxy-d ₃ -cephalosporanic acid methyl ester

7- (S-Phthalimido-S-carboxyvaleramido) -7-methoxycephalosporanic acid dimethyl ester (60.4 mg, 0.1 mmol), methylene chloride-d- (0.5 ml) and pyridine-d ₅ (21 mg, 0, 31 mmol) are mixed at room temperature and then phosphorus pentachloride (42 mg, 0.2 mmol) is added. The reaction mixture is maintained for about 5 hours at these conditions, after which it is cooled to 0 ⁰ C, and (52 mg, 1.44 mmol) and methane-d ~ ol-d are added. In this way, the desired 7-amino-7-methoxy-d ₃ -cephalosporanic acid methyl ester is obtained in situ.

Example 7 7-Phenoxyacetamido-7-methoxy-d ₃ -cephalosporanic acid methyl ester

The reaction mixture obtained according to Example 6 is admixed with chloroform-d (0.5 ml), pyridine-d ₅ (127 mg, 1.52 mmol) and phenoxyacetyl chloride (131 mg, 0.77 mmol). The reaction mixture is then treated further as described in Example 9. Customary work-up gives 18 mg of the 7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycephalosporahic acid dimethyl ester, 16.2 mg of 7- (5-phthalimido-5-carbomethoxy-d, -valeramido) - 7-methoxycephalosporanic acid methyl ester, 111 mg phenoxyacetic acid methyl-d ₃ -ester and 19 mg of the desired 7-phenoxyacetamido-7-methoxy-d ₃ -cephalosporanic acid methyl ester. The investigation of the 7-phenoxyacetamido-7-methoxy-

409817/1132

d - ^ - cephalosporanic acid methyl ester in a high resolution The mass spectrometer gives a trunk peak with a mass of 453.1277

(The theoretical mass calculated from the gross formula C ₂₀ D ₃ H ₁₉ N ₂ OgS is 453.1285). The following values are obtained in the NMR spectrum (CDCl ₃ ): cf 2.09 (s, 3H _f 3 -CH ₂ OCOCH ₂ ); 3.45 (m, 2H, 2-CH _2); 3.91 (t, 3H, 4-COOCH ₃ ); 4.61 and 4.62 (2 sharp peaks, total 2H, 0OCH ₂ CONH); 4.98 (q, 2H, 3-CH ₂ -OCOCH ₃ ); and 5.15 and 5.26 ppm (2 sharp peaks, O, 3H and 0.7H, 6-H of 7-alpha-OCH ₃ and 7-B-OCH ₃ epimers, respectively).

Example 8 7-3 ^ mino-7-methoxycephalosporanic acid benzhydryl ester

7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycephalosporansäure-dibenzhydryl ester (910 mg, 1 mmol) is dissolved in 5 ml of methylene chloride, and the solution is stirred at O ⁰ C. The mixture thereby obtained is mixed with pyridine ( 0.198 g, 0.20 ml, 2.5 mmol) and then with phosphorus pentachloride (0.42 g, .2.0 mmol). The reaction mixture is stirred for 1.5 hours at room temperature. Are then added methanol (0.46 g, 0.59 ml, 14.4 mmol), whereupon it is stirred for 1O minutes at 0 ⁰ C and then for 5 minutes at room temperature * The reaction mixture thereby obtained, which includes the desired 7-amino Contains 7-methoxycephalosporanic acid benzhydryl ester, is ^{cooled again to 0 0} C and divided into two parts.

409817/1132

Example 7-phenoxyacetamido-7-methoxycephalosporic acid benzfaydry ester

A portion of the reaction device produced according to Example 8 above, which contains 7-amino-7-methoxycephalosporanoic acid benzhydryl ester, is mixed with chloroform (2.5 ml) which contains (0.6O ml, 7.6 μmol) pyridine. The reaction mixture is stirred for 5 minutes and phenoxyacetyl chloride (0.68 g, 3.85 mmol) is added. The mixture is ^{stirred for 15 minutes at 0} ° C. and then for 10 minutes at room temperature. Dry methanol (0.3 ml) is then added and stirring is continued for 5 minutes at room temperature. The reaction mixture is then poured into ice water, the chloroform phase is washed with dilute hydrochloric acid and then with several volumes of water, whereupon it is dried over sodium chloride iamd "over magnesium sulfate. The chloroform is then removed on a rotary evaporator, and 1.14 g of one is obtained Oil.

The oil obtained in this way is worked up by chromatography, the fraction containing the 7-phenoxyacetamido-.7-Hiethoxycephalosporanic acid benzhydryl ester being separated off and _{examined in the NMR spectrum (CDCl 3} ): S 1.97, 1.98 (two b, 3H, 3-CH ₂ OCOCH ₃ ); 3.4 (two q, 2H, 2-CH ₃ ); 3.54 (broad, 3H, 7-OCH ₃ ); 4.56 (two S, 2H, 0OCH ₂ CONH); 4.9 (two q _f 2H, 3-CH ₂ OCOCH ₃ ); X 5.11 (s, 0.4H, 6-H of 7-alpha-OCH ₃ epimer); and 5.24 ppm (s, 0.6H, 6-H of 7-B-OCH ₃ epians),

The same fraction is separated into two parts by chromatography, one of which is the 7-ß-Methoxy-Stereoisosaer C32 mg), and the other 7-alpha-methoxy- and 7-ß-methoxy episode (57 mg) contains.

.4.0981.7 / 1 132

Example 10

7-ß-phenoxyacetamido-7-alpha-methoxycephalosporanic acid

The fraction prepared according to Example 9, which Contains 7-alpha-methoxy and 7-ß-methoxy epimers to the splitting off of the Benzhydry! group. For this the fraction is dissolved in a 1: 1 mixture of trifluoroacetic acid / formic acid (0.2 ml). Leave it for 5 minutes stand at room temperature, methylene chloride (4 ml) is added and the reaction mixture is evaporated at room temperature on the rotary evaporator to dryness. Ethyl acetate is added to the residue and the resulting mixture is extracted one with dilute sodium bicarbonate solution. The sodium bicarbonate extract is washed with ethyl acetate, and then acidified to pH 1.5 under ethyl acetate. Then one separates the phases, and the. Ethyl acetate extract is dried over magnesium sulfate, filtered and evaporated to dryness.

The alpha-epimer is obtained according to the above procedure of 7-ß-PhenQxyacetamido-7-alpha-inethoxycephalosporanic acid with the following characteristics in the NMR spectrum (CDCl-):

S 2, O6 (s, 3H, 3-CH ₂ OCOCH ₃ ); 3.36 (g, 2H, 2-CH ₂ ; 3.54 (s, 3H, 7-OCH ₃ ); 4.61 (broad, 2H, OOCH ₂ CONH); 5.04 (q, 2H, 3- CH ₂ OCOCH ₃ ); and 5.12 ppm (s, 1H, 6-H).

Example 11 7-Acetamido-7-methoxycephalosporanic acid benzhydryl ester

The second portion of the reaction mixture prepared according to Example 8, which 7-amino-7-methoxycephalosporanic acid benzhydryl ester contains, is acylated with acetyl chloride. The procedures used other than the acyl halide and

4 0 9 8 17/1132

Reaction components are the same as in Example 9. In this way the 7-acetamido-7-raethoxycephalosporanic acid benzhydryl ester is obtained, the investigation of which in the NMR spectrum (CDCl ₃ ) shows the following characteristics:

<f 1.96 and 1.97 (two s, 6H, 3-CH _{2 OCOCH 3} and 7-CH ₃ CONH} r 3.38 (q, 2H, 2-CH ₃ ); 3.50 (broad, 3H , 7-OCH ₃ ); 4 _r 81 (two q, 2H, 3-CH ₂ OCOCH ₃ ); - 5.10 (s coming from another signal, 6-H from 7-alpha-OCH ₃ epimer); and 5.20 ppm (s, 0.6H, 6-H of 7-B-OCH ₃ epimer).

A0 9817 / Ί 132

Claims (10)

P a te η ta claim Τ. ·. Process for the preparation of 7-acylamido-7-alkoxycephalosporins the formula OR ' HsN- COOR ^8A CHe-R ¹ , In which R is primary alkyl of 1 to 4 carbon atoms or methyl-d., R is acetoxy, carbamoyloxy, alpha-methoxy-p-hydroxyclnnamoyloxy, Propionyloxy, benzoyloxy, methoxy, methylthio, 1-methyl-1 ^, S ^ -tetrazol-S-ylthio or 5-methyl-1,3,4-thiadiazol-2-ylthio is and R ^{2A is} 2 2 Is hydrogen or a radical R, where R is alkyl with 1 to 6 carbon atoms, 2,2,2-trichloroethyl, 2-iodoethyl, tert-alkenyl with 5 to 7 carbon atoms, tert-alkynyl with 5 to 7 carbon atoms, benzyl, aryl-nitrobenzyl, tetrahydropyranyl, Succinimidomethyl, phthalimidomethyl, arylnethoxybenzyl, 7uryl, aryl-dimethoxybenzyl, cyanomethyl, nitrophenyl, Dinitrophe.nyl, 2, 4, 6-trinitrophenyl, bis (p-methoxyphenyl) methyl, Triphenylmethyl, diphenylmethyl, benzyloxymethyl, lower alkanoyloxymethyl of 3 to 6 carbon atoms or phenacyl, characterized in that an iminohalogonide of the formula R ⁸⁸ OOC-QH (CHe) 3 OCHs COOR 4098 17/1132 wherein X stands for bromine or chlorine, R has the above meaning, R ^2B for the above-mentioned radical R, lower alkanoyl with up to 4 carbon atoms or a radical of the formula R ³
R ³ -Si- stands in which the substituents R are each identical or different are and alkyl with 1 to 4 carbon atoms, Mean fluorine, chlorine, bromine or iodine, but at least 3
one of the substituents R must stand for lower alkyl, - and wherein R is an acylamido group in which the Acyl group for Alkanoyl with 1 to 4 carbon atoms, Benzoyl, ■ Naphthoyl, Alkoxycarbonyl with 2 to 5 carbon atoms, Cycloalkoxycarbonyl with 6 to 7 carbon atoms, Benzyloxycarbonyl, Naphthyloxycarbonyl, where the above-mentioned groups can be substituted one to three times by halogen, nitro, Alkoxy having 1 to 4 carbon atoms, cyano and, in the case of benzoyl, naphthoyl, benzyloxy or Naphthyloxy, also by alkyl having 1 to 4 carbon atoms or for Phthaloyl stands, with an alcohol of the formula R ° -OH under practically anhydrous Implements conditions. 4 0-9 8 1.7 / 11-3 = 2 ^: * 28 - 2. The method according to claim 1, characterized in that the substituent R is acetoxy. 3. The method according to claim 1, characterized in that that the substituent R is carbamoyloxy. 4. The method according to claim 1, characterized in that that the product obtained is then in situ with a compound of the formula XR ⁵ or CHR ⁵ J ₂ converts, wherein X is halogen, preferably bromine or Is chlorine, and R ^{5 is} , ·, _v . ,, Alkanoyl with 1 to 8 carbon atoms, azidoacetyl,
Cyanoacetyl,
• halogen acetyl, Il Ar-CH ₂ -C-, where Ar is phenyl, thienyl, furyl, pyrrolyl or one to three times by fluorine, chlorine, bromine, iodine, trifluoromethyl, protected amino, protected hydroxy / alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 Carbon atoms, cyano or nitro- ^ substituted phenyl means for Ar'-Y-CH ₉ -C-, where Ar ^{1 is} phenyl, pyridyl, or substituted phenyl of the type mentioned above and Y is oxygen or sulfur, for 40 98 177 1132 BO
Ar-CH-C- f where Ar has the above meaning and- B stands for protected amino, protected hydroxyl, protected carboxy "CN ₂ or -N ₃ , or - for 2- (3-sydnone (acetyl) or 2- (1H-tetrazol-1-yl) acetyl stands. 5. The method according to claim 4, characterized in that that the substituent R is acetoxy. 6. The method according to claim 4, characterized in that that the substituent R is carbamoyloxy. 7. T-Acylamido ^ -alkoxycephalosporins of the formula OCD ₃ HaN- CHbR ¹ COO-R * ^A where R is acetoxy, carbamoyloxy, alpha-methoxy-p-hydroxycinnamoyloxy, Propionyloxy, benzoyloxy, methoxy, methylthio, 1-methyl, 1,2,3,4-tetrazol-S-ylthio or 5-methyl-1,3,4-thia- 2A
diazol-1-ylthio, R is hydrogen or the substituents 09817/1132 2 2 R denotes and R denotes alkyl with 1 to 6 carbon atoms, 2,2,2-trichloroethyl, 2-iodoethyl, text.-alkenyl with 5 to 7 carbon atoms, tert.-alkynyl with 5 to 7 carbon atoms, benzyl, aryl-nitrobenzyl, Tetrahydropyranyl, succinimidomethyl, phthalimidomethyl, aryl-methoxybenzyl, aryl, aryl-dimethoxybenzyl , cyanomethy1, nitropheny1, dinitropheny1, 2,4,6-trinitrophenyl, bis (p-methoxyphenyl) methy1-triphenyl-3-methyl, benzoxyphenylmethoxy-3-methyl, benzyloxyethyl to 6 carbon atoms or phenacyl. 8. Compounds according to claim 7, characterized in that that the substituent R is acetoxy. 9. Compounds according to claim 7, characterized in that that the substituent R is carbamoyloxy. 10. Compounds according to claim 7, characterized in that 2A that the substituent R stands for hydrogen. 409817/1132