CA1115692A - Oxygen analogs of cephalosporins - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention provides oxgen analoques of 7-aminocephalosporanic acid having the formula as well as oxygen analogs of cephalsporins having the formula where R' is an organic nucleophile, R" is hydrogen or a pharma-ceutically acceptable blocking group and R''' is an organic elec-trophile. The compounds are biologically active.

Description

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This invention relates to derivatives of cephalosporin and more particularly, to oxygen analogs of 7-aminocephalosporanic acid and biologically active derivatives thereof.
This application is a divisional application of copend-ing application No. 232,812 filed August 5, 1975.
Following the discovery of the penicillins and their synthesis, perhaps one of the most important advances in medical research was the discovery of the cephalosporin antibiotics and their use in clinical medicine. The cephalosporin antibiotics, though not penicillins, have a structure quite similar to the structure of the penicillins and the two can be coproduced in the fermentation of a cephalosporium organism. Because of this similarity in structure and a similarity in chemical reactivity, considerable research has been devoted to the formation of deriva-tives of cephalosporins using, to a large extent, chemical reac-tions useful for the formation of penicillin derivatives. For example, 7-aminocephalosporanic acid (7-ACA) may be obtained by mild acid hydrolysis of Cephalosporin C. The 7-ACA compound is then available for formation of a multitude of derivatives. For example, reacylation of 7-ACA with phenylacetyl chloride gives a derivative that has antibacterial activity approximately 100-fold greater than Cephalosporin C. Many other reactions of the amino group of 7-ACA are known and reported in the literature.
Thus, acyl groups, isocyanates, isothiocyanates, halogen compounds methylisoureas, ethylene oxide, ethylene imine and the like have been introduced into the 7-amino group of 7-ACA to form both biologically active and biologically inactive derivatives.

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In addition to the above, there have been reactions of both the ~-lacta~ ring system and the dihydrothiazine ring system of the cephalosporins. ~or example, with regard to the ~-lactam ring system, C-7 epimers may be formed by treatment of cephalothin sulfoxide with triethylamine in refluxing chloroform.
With regard to the dihydrothiazine ring system, there is the possibility of reaction of the double bond, the C-3 substituents and the carboxyl group to form a vast number of derivatives.
Reactions of the cephalosporins, as described above, are reported in part by R. B. Morin and B. G. Jackson, "Chemistry of Cephalosporin Antibiotics", Progress in the Chemistry of Organic Natural Products XXVIII, Wein, Springer-Verlag, 1970.
For brevity, the commonly accepted abbreviation "7-ACA"
will be used for the term 7-aminocephalosporanic acid throughout the balance of this specification.
Summary of the Invention The present invention provides a wide variety of new derivatives of the cephalosporins and is based upon the discovery of certain esters of 7-oxocephalosporanic acid and methods for the formation of said esters. The esters of this invention are intermediates useful for the formation of the biologically active oxygen analog (7~-hydroxycephalosporanic acid) of 7-ACA. This oxygen analog may be used to form a wide variety of biologically active derivatives analogous to the derivatives of the 7-ACA.
Thus, the invention provides novel esters of 7-oxocephalosporanic acid, the oxygen analog of 7-ACA, derivatives of said oxygen analog and methods for the formation of the aforesaid.
The esters of 7-oxocephalosporanic acid are formed by esterifyino the acid group of 7-ACA with a pharmaceutically acceptable hlocking group, diazotization of the amino group, and contact of the diazo compound so formed with a hypohalous acid and a base in a water miscible organic solvent.

1~1569~

The oxygen analog of 7-aminocephalosporanate is formed by reducin~ the a~esaid ester to a corresponding 7~-hydroxy-cephalosporanate, Thereafter, derivatives of the oxygen analog can be formed by any suitable hydroxyl group modification reaction such as acylation or other derivatizations analogous to those of 7-aminocephalosporanate. The pharmaceutically acceptable blocking-group can then be removed regeneratiny the free ac~d.
Description of the Preferred Embodiments The first step in the formation of the esters of 7-oxo-cephalosporanic acid is the formation of an ester of 7-ACA by an esterification reaction whereby the carboxyl group is protected with a pharmaceutically acceptable blocking group. This is neces-sary to prevent reaction through the reactive carboxyl group which could interfere with the desired reaction.
The formation of such an ester is a well known procedure and is common practice in the art. It ~s used in the formation of derivatives of 7-ACA as well as in the formation of derivatives of 6-amino penicillanic acid (6-APA). Preferably, for purposes set forth herein, the benzhydryl ester is formed by reaction with diphenyldiazomethane, though any other pnarmaceutically acceptable blocking group may be used provided the group is read;ly removable when desired.
Using the benzhydryl ester for purposes of illustration only, the ester of 7-ACA is diazotized by contact for between lO
and 60 minutes with nitrous acid, generated most conveniently by addition of a nitrite salt to an acidified solution of the amine.
Common nitrite salts, MN02, include but are not limited to salts where M is potassium, sodium, ammon;um or the like. Most common acids including perchloric, sulfuric, sulfonic, haloic ~D

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and tetrafluoroboric, etc. have found use in this acidification.
Alkyl nit~ites such as i~soamyl nitrite alone or in combination with trifluoroacetic acid are employed as d~azotization agents ln an-hydrous organic media. This reaction is performed in a solution ~referably cooled below ambient temperature, more preferably to about 0C. The diazo compound is isolable by extraction followed by drying and concentrating the extract until only the oily diazo compound remains.
The diazo compound is converted to the ketone -- e.g. a 7-oxocephalsporanate by contact with about an equimolar amount of a hypohalous acid dissolved in a water miscible organic solvent containing aqueous base. Preferably, the reaction is cooled down to a temperature of no more than room temperature and more preferably, to a temperature within the range of from 0VC to -25C. The time of reaction should not exceed two hours and typi-caly requires from about 15 minutes to 45 minutes.
Hypohalous acids for use in the above transformation may be conveniently generated in situ via hydrolysis of N-halo-amines. The N-haloamide used preferably conforms to the formula O R
Il I
R - C - N - X
where X is halogen, preferably chlorine or bromine, and most preferably bromine. Iodine and fluorine are uncommon in this reaction and consequently less preferred. R and Rl are not critical and may be selected from the group of hydroaen, a hydro-carbon radical having up to about 8 carbon atoms such as methyl, ethyl, propyl and the like, aryl or acylradicals together, or R and R' may form part of a heterocyclic ring system having up to a total of six atoms. Examples of N-haloamides within the scope ~r - 5 -~ 156~2 of the invention include N-bromoacetamide, N-chloroacetamide, N-bromosuccinamide, N-chlorosuccinamide and the like.
The mechanism of this reaction is proposed to be as follows:
O R O R
R - C - N - X + H2O > R - C - NH2 + HOX

HO-X

B-: ~ R' -BB ~ ~ R' C2R" C2R"

~ ~ R' C2R" C2R"

~ -HX (HX + B~ BH + X ~) H

O~ ~S~

O ~ ~ N

Hypohalous acid is generated upon hydrolysis of an N-haloamide. This reactant is both a source of halonium ion to effecta halogenation and also of hydroxide ion for solvolytic displacement of N2 . The unstable hydroxyhalo intermediate is transformed to the 7-oxocephalosporanate via rapid elimination ~S692 of hydrohalic acid. This acid is neutralized by the base present in the reaction mixture.
The base employed in this neutralization can be any common organic or inorganic base known in the art. Examples of bases used within the scope of this invention include sodium bicarbonate, sodium carbonate, pyridine, dimethyl aniline and the like.
In the aforesaid reaction, the reactants are dissolved in a suitable organic solvent to which water in an amount of at least 5%, and preferably from 10 to 35%, by volume of soivent has been added. The water is necessary for formation of the ketone. The organic solvent is not critical provided it is a solvent for the reactants, is water miscible to the extent that water is present, and is non-reactive with the reactants.
Organic solvents such as but not limited to dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran and dioxane are suitable solvents for this purpose.
The reaction sequence for the formation of the ester of 7-oxocephalosporanic acid, using the benzhydryl ester as an example, for purposes of illustration only, is as follows:

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H H
H2N ~/ S

0 " N ~ R' ~ Ph2CH-N- N:

H H

2 ~ ~
"L___N ~ R' C02CH Ph2 ¦ NaN02 ~ HC104 H H
~N
R~
o 20 CO2CH Ph2 CH3CONHBr aq- cH3cOcH3 , ~ NaHC03 ~S

~ N ~ R' C02CHPh2 30R' in the above reaction sequence will be defined below.

As noted above, the aforesaid reaction sequence for the formation of the benzhydryl 7-oxocephalosporanate may be used for the formation of other esters of 7-oxocephalosporanic acid by different pharmaceutically acceptable blocking group. In this respect, for purposes of this invention, a general formula for the ester of 7-oxocephalosporanic acid is as set forth below:
(I) ~ Lr s ~

~ 2 CO R"
: where R' is an organic nucleophile selected from the group of hydrogen, halogen hydroxyl, alkoxy, aryloxy, alkylamino, aryl-amino, carboxyl, organic carbonyl, organic sulfonyl, carbamyl, thiocarboxyl and other analogous functionalities. R" represents a pharmaceutically acceptable, readily removable protective group.
Such groups include: (1) alkyl, cycloalkyl, aryl, alkaryl and aral-kyl as illustrated by me-thyl, benzyl, p-nitrobenzyl, p-methoxy-benyyl, benzhydryl and ~ -trichloroethyl, (2) phenacyl with or without substitution on the ring such as p-methoxyphenacyl and 2,5-dimethoxyphenacyl, (3) salts such as sodium, potassium, N-ethylpiperidine and dicyclohexylamine and (4) organo silicon groups such as trimethyl silyl. It should.be understood that some of the aforesaid groups may be more difficult to remove than others, but most are groups heretofore used as protective groups in ana-logous reactions for both penicillins and cephalosporins and are removed in accordance with recognized procedures dependent upon the particular group involved.

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The 7~-oxy~en analog o~ 7-ACA is ~ormed by reduct~on of the ester of 7-~xocephalosporanic acid (~) above, Reduction of such a reactiye ~ diketone can '~e accomplished by myriad techni-ques well known in the art. Such reducing agents include potassium borohydride, sodium borohydride, alkylated borohydrides, lithium aluminum hydride and its alkylated derivatives, well known hydro-genation catalysts, zinc dust in acetic acid and the like. The reduction is preferably carried out in an aqueous alcoholic solu-tion at room temperature of below -- e.g., down to about 0C.
The blocking group can be readily removed there~y forming the free acid by such procedures as hydrogenation of hyrolysis with tri-fluoracetic acid (TFA) or by using other methods known to the art.
The reaction sequence for forming the 7~ hydroxy-cephalosporic acid from 7-oxocephalosporanate ester for illustration purposes only is as follows:

~lS~

o~
0 ~ LN ~ ~1~/ R

C2R"

1 4/aq alcohol IlO '~ Y~ S
II "

C02R"

H H
III HO - C~/~RI

The free acid (III) is the oxygen analog of 7-ACA. It is biologically active which is unexpected since prior art had taught that a ~ Nitrogen substituent was essential to this activity.
Both the ester of 7~-hydroxycephalosporanic acid (II) and the acid itself(III) can be used for the formation of other biologically active derivatives of 7-ACA. In this respect, a wide variety of funct.ional groups can be introduced into the 1~156~

hydroxyl group thus making it ~os~ible to pxoduce ~ wide variety of oxy~en an~ s o~ ce~hal~sp4rin, In this respect, typical side chain modificat~ons'include ~or example,' formyl, acetyl, phenylacetyl, phenoxyacetyl, carbo~ethoxy, carbobenzyloxy, p-nitrocarbobenzyloxy, carbophenoxy, p-chIorocarbophenoxy, methane-sulfonyl, benzylsulfonyl, p-chlorobenzylsulfonyl~ phenylsul~onyl,' or p-aminophenylsulfonyl. Although the halide, especially chloride and bromide, or anhydride of the functionalizing agent'isparticu-larly suitable for this modification, other agents may also be used. Such agents include mixed anhydrides, acid azides, lactones, particularly ~-lactones, "activated esters" such as thiol esters and phenolic esters, carboxylic acids with carbodiimides or alkoxy-acetylenes, thiolactones, particularly ~-thiolactones, and acylated enols.
Other groups can also be introduced into the hydroxy group of (II) or (III) to provide additional types of oxygen ana-logs by means of such reagents as: isothiocyanates, for example, phenylisothiocyanate and ethylisothiocyanate, to convert the hydroxy group to a substituted thiocarbamate, reactive halogen compounds, such as triphenylmethyl chloride which forms the trityl ether derivative; methylisourea which converts the hydroxyl group to an isourea group; ethylene oxide and ethyleneimine, which add to the hydroxyl group with ring opening andothers known to the art. Further exemplification of the akove and additional groups can be found by reference to Naylor, Proc. R. Soc. Lond, B 179, pp. 357-367, 1971, wherein reactions of 6-aminopenicillanic acid are described. These are very analogous to the reactions of 7-hydroxycephalosporanic acid.

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With further reference to the above reaction scheme, it should be noted that the free acid (III) can be esterified in conventional manner to further alter the structure of the derivatives such as by formation of the methyl ester by reaction with diazomethane. Thus, by selection of the appropriate functionalization agent for reaction with the hydroxyl group and with the carboxyl group of 7~-hydroxycephalosporanic acid (III), a multitude of derivatives of the ~ygen analogs can be formed having the formula:
H H S
R"' O ~ ~
(IV) ~ l l R' N ~/

where Rl and R" are as above defined. R"'is an organic electro-phile produced during the ~-hydroxy modifications defined above.

Specific examples of R' and R"'are set forth below in the following Table:

--H, -C l, -Br, -OH, -O-CH 3, --o-CH2-CH3 ~ --- @~
0 ~31 CH 3 ~+

_ o - C - NH2 ¦¦ CH3 - o - C - N<H

l O

N N
Il 11 .
- S~S ~ CH

-,~ -14-6~ 1 ".
i' o .
_ C - CH2 - C6H5 ,., ,o, .
, 5 - C - CH2 - O - C6H5 . - C - CH - C6H5 Ot CO~H
~0 11 ,0~

~5 - O ---- -,f ' ' O -' . .
- C~- C~2 - S--~ ~o - --N N
,' . ..... _~ot ,_ ~ ,,, ,_ .
- C - H, -C - CH3, --O ' '~
,5 ~ H2, - ~ ~n O
_ ~ ~X -C~I3, _ ~ - ~H3 ~156~:
Example 1 Benzhydryl 7-aminocephalosporanate -- A suspension of 7-ACA (13.6g, 0 05 mole3 in methanol (20 ml) and dichloromethane (70 ml) was stirred overnight with diphenyldiazomethane (15 7g) s prepared accordin~ to the method set forth in Fieser and Yieser, ~'~ Organic Reagents, pg. 338, Wiley Interscience, 1967. The violet color was discharged at the end of the reaction. Ethyl ether (200 ml) was added to precipitate the unreacted 7-ACA. Filtration and evaporation of the solvents gave a crystalline product which was recrystallized from a mixture of dichloromethane and ethyl ether. The first crop weighed 9.5 g (43~) and had the following properties: mp. 128.5-129.5; nmr (DCC13,ppm): 7.39 (S,lOH), 7.00 (S, lH), 5.19-4.62 (M, 4H), 3.50 (D, 2H), 2.05 (S, 3H), 1.84 (S, br, 2H); ir (film, cm 1): 3400, 1770, 1730, 1655, 1390, 1225.
Example 2 Benzhydryl 7-diazocephalosporanate -- senzhydryl 7-amino-cephalosporanate prepared as in Example 1 (3g, 6.85 mole) was dis-solved in dichloromethane(90 ml) and stirred at 0C. Sodium nitrite (0.7g, 1.5eg), dissolved in H2O (10 ml), was added to the cooled stirred solution and 1.01 N perch]oric acid (10.5 ml, 1.5 eg.) was àdded dropwise. The mixture was stirred at 0~C for 1 hr. and diluted with additional dichloromethane, washed twice with ice cold water and once with an ice cold sodium chloride solution.
The dichloromethane layer was then dried and evaporated to a yel-low oil. It had the following properites: nmr (DCC13,ppm):
7.39 (S,lOH), 7.00 (S, lH), 5.40 (S, lH), 5.08-4.52 (Q, 2H), 3.35 (S, br, 2H), 1.98 (S, 3H); ir (film cm 1): 2090, 1780, 1735, 1235.
Example 3 _ . .
i B ~ 1_7-oxocephalosporanate -- Benzhydryl 7-diazo-cephalosporanate prepared from 3g of benzhydryl 7-amino-cephalo-sporana~e in the manner of Example 2 was used without further puri-fication. It was dissoved in a 10% aa. acetone (90 ml) solution , ~D

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and cooled in an ice-acetone~odium chIoride bath ~-15C). Sodium bicarbonate (3~] and N-bromoacetamide (0,945g) were pouxed into the stirred cold solution. A~ter 45 ~inutes, the reaction mix-ture was diluted with dichloromethane and water. Extraction with dichloromethane was repeated three`times. The organic layer was washed once with cold water and once with cold sodium chloride solution. Dryiny and evaporation of solvent gave about 3g of yellow oil which was purified by column chromatography on silicic acid and eluted with 1:9 ethyl ether-dichloromethane. The yield was 50~ from benzhydryl 7-amino-cephalosporanate. The properites were as follows: nmr (DCCl3,ppm): 7.39 (S, lOH), 7.00 (s~lH)~
5.21 (S, lH), 5.10-4.65 (Q, 2H), 3.48 (Q, 2H), 2.01 (S, 3H);
ir (film, cm 1): 1825, 1785, 1730, 1230.
Example 4 Benzyhydryl 7~-hydroxycephalosporanate -- Crude benzhydryl 7-oxocephalosporanate (2.95g) was dissolved in ethanol (150 ml).
~o this cooled and stirred solution, there was added a solution of potassium borohydride (0.74g) in a 1:1 ethanol-water mixture (150 ml). The reaction was quenched after 2 minutes by addition of lN HCl to pH 2. The reaction mixture was diluted with water and extracted twice with dichloremethane. The organic layer was washed once with sodium bicarbonate solution and once with sodium chloride solution. Drying and evaporation gave a yellow oil which was chromatographed to give 1.2g solid product. The product was recrystallized from benzene. Its properties are as follows: mp. 122-3; nmr (DCC13,ppm): 7.39 (S, lOH), 7.00 (S, lH) 5.29 (d, lH, J = 4.5), 5.20-4.62 (m, 3H, J=4.5 and 13), 3.90 (S, br., lH); 3.45 (d, 2H), 2.04 (S, 3H); ir (CH2C12, cm ): 3540, 1785, 1735, 1225.
Example 5 7~-hydroxycephalosporanic acid -- Benzhydryl 7~-hydroxy-cephalosporanate (0.3g, 0.68 m moles) was dissolved at 0C in a ~I~ - 17 -~1156~2 mixture of tr~fluoroacetic acid (7 ml) and anisole (1 ml). After , 1 hr., the solvents ~ere eva~orated under vacuum. The residual ;~ yellow material was washed with petroleum ether and then dissolved s in ethyl acetate. Treatment with charcoal for half an hour and evaporation of the solvent gave a solid produce, 0.17~ (99%). It was recrystallized from ethyl acetate. Its properties were as follows: mp 132 (decomp). nmr (acetone d6,ppm): 5.40 (d, lH, J=4.8Hz), 5.15-4.80 (m, 3H, J=4.8 and 13 Hz), 3.55 (d, 2H), 2.04 s (S, 3H); ir (Kbr, cm ): 3439, 3100, 1780~1700, 1625, 1380, 1220.Bioassay results (minimum inhibitory concentration in Mg~ml):
S.aureus (75), B subtilis (75) E.coli(50), K. Pneumoniae (200).
Example 6 Benzhydryl 7~-phenoxyacetoxycephalosporanate -- Benzyhydryl 7B-hydroxycephalosporante (0.8g), (1.82 m moles) and phenoxy-acetyl chloride (0.42g, 1.5eq.) were dissolved in dichlormethane (50 ml). Pyridine (0.15 ml, 1.5eq.) was added to the cooled stirred solution. After stirring for three hours at room temperature, the dichloromethane solution was washed with water, sodium ~icarbonate solution, and sodium chloride solution. Drying and evaporation gave a yellow oily product which was chromatographed on silicic acid using a 1:20 ethyl ether/dichloromethane mi~ture to yield 0.85g of a pale yellow oil, 88% yield. Its properties are as follows: nmr(DCC13,ppm): 7.54-6.80 (m, 16H), 6.10 (d, lH, J=4.8Hz) 5.20-4.65 (q, 3H, J=4.8 and 14hZ), 4.75 (S, 2H), 3.38 (s, br., 2H), 1.98 (S, 3H); ir (film, cm 1): 1785, 1730, 1600, 1495, 1380, 1225.
Example 7 7~ phenoxyacetoxycephalosporanic acid -- The procedure of Example 5 was repeated with a product yield of 93%, the product having the following properties: nmr (acetone-d6,ppm): 8.10 (br, IH), 7.42-6.87 (m, 5H), 6.32(d, +H, J=4.8Hz), 5.25 (d, lH, J=4.8Hz), 5.28-4.70 (q, 2H, J=14Hz), 4.92 (S, 2H), 3.60 (d, 2H), 2.02 (S, 3H): ir (film, cm 1):3580, 3520-2500, 1785-1690, 1635, ~iS~i~2 ... .
1600, 1495, 138Q~ 1230 Bloasaay results (minimum inhibitory concentxation In Mg/~l): S.aureus (I2~5), s.subtilis (25), E. Coli (200)~ K. pneumoniae (200).
Example 8 Benzhydryl 7~-(2-thienyl)'a'cetoxycephalosporana'te --Benzhydryl 7~-hydroxycephalosporanate (0.45g, 1.02 m moles), 2-thienylacetic acid (0.21g, 1.5eq.), and pyridine (0.1 ml~l.2eq.) ~ were dissolved in dichloromethane (50 ml) at 0. To this solution ,~ was added diisopropyl carbodiimide (0.13g~1eq.). The cold solu-tion was stirred one hour and then allowed to stand 17 hours under refrigeration. The solid urea formed was separated by filtration and the filtrate was diluted with dichloromethane and washed with cold dilute hydrochloric acid, sodium bicorbonate solution, and sodium chloride solution. Drying and evaporation gave a yellow oil which was chromatographed on solicic acid in a 1:20 mixtùre of ethyl ether and dichloromethane to yield 0.6g product (>95~) having the following properties: nmr. (DCC13ppm): 7.54-6.90 (m, 14H), 6.05 (d, lH, J=4.8Hz), 5.20-4.60 (d on q, 3H, J=4.8Hz and 14 Hz), 3.91 (S, 2H), 3.36 (S, br, 2H), 1.98 (S, 3H); ir (film, cm 1): 1785, 1330, 1360, 1235.
Example 9 7~ (2-thienyl)acetoxycephalosporanic acid -- The proce-dure of Example 5 was used to yield a productobta'ined by freeze drying from benzene. The yield was 98~ and the product had the following properties: nmr (DCC13,ppm): 7.73(S, br, lH), 7.40-7.20 (m, 2H), 7.00 (d, lH), 6.19(d, lH, J=4.8Hz), 5.38-4.82(d on q, 3H, J=4.8Hz and 15Hz), 4.00 (S, 2H), 3.48 (S, br., 2H), 2.13 (S, 3H);
ir (film, cm ); 3560-2540, 1780, 1725, 1380, 1225. Bioassay results (minimum inhibitory concentration in Mg/ml): S~aureus (12.5), S. Fecalis (200), B, subtilis (6.25), P. Mirabilis (200), P. vulgaris (200), K pneumoniae (100).

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Claims (17)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS;

1. A process for the formation of an oxygen analog of 7-aminocephalosporanic acid having the formula (I) where R' is an organic nucleophile selected from hydrogen, halogen, hydroxy, alkoxy, aryloxy, alkaryloxy, alkylamino, arylamino, carboxyl, organo, carbonyl, organo, sulfonyl, carbamyl, thiocarboxyl, alkylthiocarboxyl, aryl thio-carboxyl, alkyl thiadiazoyl-thio, the radical -S-C-NH2 - or the radical said process comprising subjecting an ester of 7-oxocephalosporanic acid of the formula II

where R' is as above and R'' is a pharmaceutically acceptable blocking group to the action of a reducing agent.

2, The process of claim 1, where the reducing agent is selected from the group of potassium borohydride, sodium boro-hydride, alkylated borohydrides, lithium aluminum hydride, alkyl-ated lithium aluminum hydrides, zinc dust-acetic acid and hydrogen.

3, The process of claim 1, where R' is selected from the group of hydrogen, halogen, hydroxyl, alkoxyl, aryloxy, alkyl-amino, aryl-amino, carboxylic acid radicals, carbonic acid radicals and sulfonic acid radicals, and R" is selected from the group of alkyl, cycloalkyl, aryl, alkaryl, aralkyl, phenacyl, salts and organo silicon groups.

4. The process of claim 3, where R' is hydrogen.

5. The process of claim 3, where R' is acetoxy

6, The process of claim 3, where R' is halogen,

7. The process of claim 3, where R' is hydroxyl.

8. The process of claim 3, where R' is pyridinium.

9. The process of claim 3, where R' is carbamoyloxy.

10. The process of claim 3, where R" is benzyl.

11. The process of claim 3, where R" is benzhydryl.

12. The process of claim 3, where R" is methoxyphenacyl.

13. The process of claim 3, where R" is .beta.,.beta.,.beta.-tri-chloroethyl.

14. The process of claim 3, where R" is p-nitro benzyl.

15. The process of claim 3, where R" is p-methoxy benzyl.

16. An oxygen analog of 7-aminocephalosporanic acid having the formula where R1 is an organic nucleophile selected from hydrogen, halogen, hydroxy, alkoxy, aryloxy, alkaryloxy, alkylamino, arylamino, carboxyl, aminocarboxyl, organo carbonyl, organo sulfonyl, carbamyl, thiocarboxyl, alkylthiocarboxyl, aryl thio carboxyl, alkyl thia-diazoyl-thio, the radical or the radical whenever prepared or produced by the process as claimed in claim 1 or 2, or an obvious chemical equivalent thereof.

17. An oxygen analog of 7-aminocephalosporanic acid of formula I given in claim 1, where R1 is selected from the group of hydrogen, halogen, hydroxyl, alkoxyl, aryloxy, alkyl, amino, aryl amino, carboxylic acid radicals, carbonic acid radicals, and sulfonic acid radicals, whenever prepared or produced by the process as claimed in claim 3, or an obvious chemical equivalent thereof.