CA1061330A - Process for the acylation of 6-aminopenicillanic (6-apa), 7-aminocephalosporanic (7-aca) and 7-aminodesacetoxycephalosporanic (7-adca) acids and their derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the acylation of 6-aminopenicillanic, aminocephalosporanic, and aminodesacetoxycephalosporanic acids and their derivatives to prepare the corresponding penicillins and cephalosporins. The process comprises reacting in the presence of an inert solvent a compound of the formula:

(I) where R1 and R2 are hydrogen or low molecular weight alkyls, X
is an element selected from the halogen group and R is a further group selected from a low molecular weight alkyl, phenyl, halogen and dimethylamin, with a carboxylic acid in the form of a tertiary organic base salt in methylene chloride at temperature between -15 and +20°C for a period of form 15 to 120 min, to obtain a mixture of active species with a relative proportion of acid halide, N-acyl-2-oxazolidinone and 2-acyloxy-.DELTA.2-oxazoline, and further reacting the mixture with a solution of a compound of the formula:

(II)

Description

" ~61330 ~ he present invention relates to a novel process for the acylation of 6-aminopenicillanic (6-AP~), 7-aminocephalosporanic (7-ADCA) acids and their de~ivatives, such as 7-aminodesacetoxycepha-losporanic-3-thio-(2-thiadia~olyl-5-methyl) (7-ACA-TD), ~-pyridi- i methyl-aminodesacetoxycephalosporanic acid (7-ACA-PYRIDY~) and 6-APA phthalidyl ester, to prepare the corresponding penicillin~
and cephalosporins.
The process comprises preparing a solution of activated carboxylic acid using as starting products tertiary organic base salts of carboxylic acids, prepared immediately prior to their use. These are made to react with a phosphonium or quasi-phosphonium salt derived from a 2-oxazolidinone. ~he resulting activated acid solution is reacted with a further solution prepared with an aminopenicillanic or aminocephalosporanic acid, to form respective penicillins or cephalo~porins. These are then isolated by known techniques, described in scientlfic or technical literature, as pharmaceutically applicable acids, esters or non-toxic salts.
One widespread practical way of conducting the acylation process is related to the preparation of a solution of a carboxylic acid in methylene chloride, by way of an organic base equivalent to give a salt which is added over a suspension or solution of a 3-substituted-2-oxazolidinone having the ~ollowing formula;
' ~ R (_) (I) O N - P _ R c X

where R1 and R2 are low molecular weight alkyls or hydrogen, X
may be an element selected from the halogens and R is a further group selected from among a low molecular weight alkyl, phenyl, -1- ~ ., ,; . .

~ L~36~33~
halogen and dimethyla~ino, which are preferable among others such as diethylamino, diphenylamino, N-morpholino or methylphenylamino.
The resultin~ mixture i8 reacted with a further solution of a compound ~elected from the group comprising 6-APA, 7-ACA, 7-ADCA and their derivatives, represented by the following formula:

(C)n (II) /
(H)1 OOR~
where n may be 1 or 2, (H~2 may be 0 or 2 atoms o~ hydrogen or a methyl group, (H)1 may be 0 or 1 atom of hydro~en, R4 an element selected from the group comprising hydrogen, alkali metals, trime-thylsilyl, phthalidyl and R3 may represent methyl azidomethyl, acyloxymethyl, thiomethyl, thiadia~olylmethyl, cyanomethyl, chloro-methyl, methoxymethyl, to prepare a penicillin or cephalosporin.
Compounds com~rising the purpose of the invention ~nd represented by Formula I, that is, the phosphonium or quasi-phosphonium salts, following Kosolapoff and Maier's differential nomenclature tOrganic Phosphorous Compounds, Vol. 2 and 6, Wiley Intra. New York, respectively, page 189-1972 and page 579-1973) are ~pecifically halides of 3-trichlorophosphonium-2-oxazolidinone (CP0), 3-tribromophGsphonium-2-oxazolidinone (BP0) and 3-tridimethyl-aminopho~phonium-2-oxazolidinone (HP0) which could also be called phosphoranes, ~or example, TP0 would be chloro-N-oxazolidin-triphenylphosphorane. These substances are used in suspension or in solution in an appropriate inert solvent, such as methylene chloride, ~0 carbon tetrachloride, chloroform, 1,2-dimethoxyethane, acetonitrile and nitromethane.
The carboxylic acid comprised in the invention may be ~ 06~330 selected from the group comprising the aliphatic, alicyclic, aromatic, alkanoaromatic, heterocyclic, alcanoheterocyclic acids and condensated nuclei and dis~olved in methylene chloride.
Examples of representative acids appropriate for the purposes of the invention are tetrazolyl acetic, cyanacetic, thienyl acetic, pyridincarboxylic, alpha-carboxyindanyl-phenyl acetic acid~, derivatives of alpha-carboxy phenyl acetic and alpha-azido phenyl acetic acids, those corresponding to the isoxazolyl-4-carboxylic acid group, a benzoic acid, quinoxaline, etc. and also the organic 10 base may be triethylamine, pyridine, picolines, lutidines, N- -ethylpyperidine, ~-methylmorpholine, tributylamine, triprop~lamine, with the cheapest and most easily obtainable on the market being chosen.
The compound~ of Formula II are grouped in a large number of aubstances having the characteristic of supporting an amino group in their structure. This re~ers equally to products prepared by semi-synthesis or complete ~ynthesis methods known and described in the literature. The expression "semi-synthesis"
is applied when the preparation proceeds directly from penicillins or cephalosporins and the expression "synthesis" is used for those using the fundamental nuclei of 6-APA, 7-ACA and 7-ADCA or their derivatives, such as, e.g., 7-ACA-~D resulting from the reaction between 7-amino-3-methylthiol-~ ~-cephem-4-carboxylic acid and

2-chloro-5-methyl-thiadiazol, 6-APA-phthalidyl prepared by reacting 6-APA hydrochloride chloride with 2-carboxy benzaldehyde in its hemiacetal cyclic form.
The reaction of an activated acid with CP0, BP0, TP0 or HP0 and a compound of Formula II, the latter as a triethyla~ine alkali salt, silyl ester or ester derivative for acylationJ is conducted by gradual addition of the acid previously activated with a compound of Formula I over a solution containing an amino-penicillanic or aminocephalosporanic acid at a temperature of from

-3-' "''.

.... . . . . . . . .
: ,........ . . . . . ~ .

6~330 -15 to +20~C, with the pEI of the medium controlled to from 4 to 6.8, by way of a tertiary organic base or a salt, e.g., a triethyla-mine salt of acetic, pivalic or 2-ethylhexanoic acid, with the reaction time being extended up to 120 min.
The expression "activated acid" as used in this specification means the reaction between an acid an a compound of ~ormula I to obtain a solution containing active species which thereafter participate in the acylation process. Some examples of active species were disclosed in Spanish patents nos. 411.867 and 421,660, although it has now been discovered that these species ~ay be controlled with CPO, BPO, TPO and HPO, although the proportion thereof, that is of the acid halides, of N-acyl-2-oxazolidinone and of 2-acyloxy-~ 2-oxazoline (~ 2-oxazoline ester), depends on the structure o~ the reagent and of the acid. It has been possible to prove the presence of these substances by IR spectrography and isolation.
Acid halides are known to be active as acylating agents.
The activity of the N-acyl-2-oxazolidinones was disclosed in Spanish patent n 411.867 and it has now been discovered that ~ 2-oxazoline es-ters also have this property. It thus happens that the reaction medium between a carboxylic acid salt and a compound of Formula I is constituted by acylating reagents, ac-tive specie~ o~ the carboxylic acid.
For example, the triethylamine salt of 3,5-dinitrobenzoic acid produces an 80% mixture of N-3,5-dinitrobenzoyl-2-oxazolidinone and 2-(3,5-dinitrobenzoyloxy) ~ 2-oxazoline with CPO, whereas with TPO the oxazoline ester is obtained with virtually quantitatiYe yield. On the other hand, with CPO, thienyl acetic and cyanacetic acid give mainly the acid chlorides and ~ 2-oxazoline esters are produced with alpha-substituted phenyl acetic acids and 3-(0-chlorophenyl)-5-methylisoxazolyl-4-carboxylic acid~ Essen~ially, TPO and HPO cause the formation o ~ 2-oxazoline esters, the presence ... .

-4-~ ~016133~
of acid chloride being insignificant or non-existen-t.
~ hese active species may be isolated from the solutions prepared by reacting a carboxylic acid with a compound of ~ormula I by evaporation of the solvent or precipitation and they may be used in the acylation process. Nevertheless, for the purposes of the invention, it is obviously preferable to use the solution resulting from activation of the acid, without having recourse to further complications caused by isolation and which cause losses. Direct use makes the process more expensive, particularly since mixtures of active species a:re formedO
The novel acylation process of the invention allows an appropriate Formula I compound to be selected for a particular carboxylic acid and, consequently, it will be hard to find an acid which may not be activated under extraordinarily moderate conditions. In other words i~ allows a large ~umber of penicillin~ and cephalosporins to be prepared.
No alteration, decomposition or racemisation phenomena have been observed either with sensitive or optically active acids. Moreover, when ~ 2-oxazoline esters are used, acylation is performed at temperatures from 0~ to 20C, with the consequent power saving and no additional auxiliary consumption of tertiary organic base i9 required, since ~trong inorganic acids are not produced in the reaction medium.
The process is also outstanding with respec-t to the more stringent requiraments for control of impurities in antibiotics particularly impurities coming directly from the products involved in the preparation of penicillins and cephalosporins and which may possibly be harmful for the health. All the compounds resulting from the reaction with CP0, BP0 and HP0 are water soluble and easily eliminated, like the phosphorous compounds (metabolisable) and 2-oxazolidinone itself~ which is harmless.
In the case of TP0, the triphenylphosphine oxide is very soluble

-5-~6133~
in methylene chloride and the sodium salt form of the antibiotic is water soluble, both being easily separable.
All these results may be considered to be surprising in view of the advantages mentioned and of the new active species, -oxazoline esters, which cannot be formed by conventional processes.
Wi-th a view conveniently to illustrate the description~
a serieg of non-limiting examples are described Some of these are complemented with the use of isolated ~ 2-oxazoline esters, with a view to showing the effectiveness of these active species produced in the activation of acids in the new acylation process for the preparation of penicillins and cephalosporins. ~he initials corresponding to the phosphonium halides given in the examples refer to the chloride in the case of CP0 and to the bromide in the case of BP0, TP0 and HP0. Any other halide i9 specified, such as IIP0 chloride or 'rP0 chloride, for exarnple.

EXAMP~ES

1. D(-) alpha-azidobenzyl penicillin_(Via CP0~ -~

A solution of D(-) alpha-azidophenylacetic acid (20 ml, 2 cmole~ 3.543 g) with triethylamine (2 cmole, 2.80 ml) in methylene chloride (20 ml) is added gradually over a suspension of CP0 (1 cmole; 2.590 g) in methylene chloride (20 ml) with cooling to -1 oQc . Thereafter the mixture i9 allowed to rise to rooM
temperature while stirring i9 continued for 120 min. After this time the pH is adjusted to 4 with triethylamine (approximately 1.5 ml). ,r"
~hereafter it is poured gradually (30 min) over a further solution prepared from 6-APA ~2 cmole; 4.347 g), methylene chloride (30 ml), triethylamine (2 cmole; 2.80 ml), ~MS0 (3 trimethylsilyl-2-oxazolidinone, 5.0 ml) and pi~alic acid (3 cmole;
3.06 g) previously cooled to 15C, prior to proceeding to acylation.

` ~0~:~33~
The reaction is controlled to from -l5~ to -1 oQc during the addition of the activated acid and the pH is adjusted to between 4 and 5 with triethylamine~ ~hereafter the mixture is stirred for 90 min at oQc.
The resulting solution is washed with wa-ter (15 ml) and HCl is added to pH = 1 (1.5 to 2.0 ml), the organic phase is decanted of~, is washed with water and dried with sodium sulphate.
Thereafter a solution of sodium 2-e-thylhexanoate in MIC (44~0;
10 ml) is added and precipitation starts. The resulting mass is diluted with n-heptane at 409C (400 ml) with good stirring.
After 15 min the white product is isolated by filtration, washed with n-heptane and dried to give the sodium salt of -the compound of the title (7.34 g; Y = 93% [~¦D = ~ 180.58 (C 1~ H20). IR
spectrum the same as tha-t of a pure sample.

n,0-meth lphen~l-carbamoyl)-benzyl penici.llin (Vla CP0) . First phenylmalonic acid hemi-o-toluide (2 cmole; 5.386g) and gradually triethylamine (2 cmole; 2~80 ml) in methylene chloride (20 ml) i9 added to the CP0 (1cmole) suspension prepared according to Example 1. The temperature is then allowed to rise to room temperature (20~C) and stirring is continued for 120 rnin.
Thereafter the process is conduc-ted in exactly the same way as in Example 1 to give the sodium salt of the compound of the title, a white product (9.40 g; Y _ 94~ ~<) 20 _ ~ 142.0Q
(c = 1%, H20) with identical IR sepctrum to that of ~ pure sample.

3. 3(0-chloro~hen~1)-5-methyl-4-isoxazolyl penicillin lVia GP0) Following Example 1, but using 3(.0-chlorophenyl)-5-methyl-4-isoxazolylacarboxylic acid (2 cmole; 4.752 g) instead of the D(-) alpha-azidophenyl acetic acid, the pH is adjusted to 5.2-5.5 after 120 min. Dilute in n-heptane and isolate the white precipitate to obtain the sodium salt of the compound of the title : , .:.. . . . . . .. . .

6:~331D
(9~03 g; Y = 96~80%)~ [~) 20 = ~ 170~3 (c ~ o in D~IS0; crystallised in MIC). ~he IR spectrum is indentical to that of a pure sample.

4. Alpha-carbox~-5-in_anyl bens~l penicillin (Via CP0) ~ ollowing Example 2, but using phenylmalonic acid 5-indanyl half ester (2 cmole; 5.928 g) instead of the acid described therein, a solution is produced which is adjusted to pH = 4.9-5.2. This is poured gradually over a further solution of 6 APA prepared as described in Exampel 1. To isolate the penicillin, instead of diluting over n-heptane, isopropanol (250 ml) is added and after removal of the methylene chloride by evaporation at reduced pressure, the mixture is allowed to rest overnight.
~he white precipitate is filtered and dried to give the sodium salt of the compound of the title (8.29 g; Y = 80~o) ~ [~) 20 =
170.0~ (c , 1%, ~120) with indentical IR spectrum to that of a pure sample.

5. Alpha-carboxy~henyl benzyl penicillin (Via BP0) Following Exarnple 4 and using monophenyl phenylmalonate (2 cmole; 5.120 g) instead of phenylmalonic 5-indanyl monoester and BP0 (1 cmole; 4.360 g) instead of CP0, the resulting mixture from the reaction is wa~hed in water and the organic phase is dried and adjusted to pH = 6 with sodium 2-ethylhexanoate. It is then concentrated at reduced pressure and diluted with n-heptane. ~he white precipitate is filtered and dried to give the sodium salt of the compound of the title with almost quantitative yield (9.20 g). The IR spectrum is indentical to that of a pure sample.

0 6. 7-(phenoxyacetamido)-desacetoxycephalosporanic acid (Via BP0~

A solution of phenoxyacetic acid (3 cmole; 4.560 g) with N-methylmorpholine (3 cmole; 3.033 g) in methylene chloride , ._ .. _ ; ......................... . . . ........ ~ . .
. ' ~

1~i3L33~
(20 ml) is added gradually to a suspension of BP0 (1.5 c~ole;
6.540 g) in methylene chloride (50 ml) with cooling to -15C. The temperature is then allowed to rise to room temperature and stirring is continued for 120 min. After adjusting to pH = 4 with methyl-morpholine, the solution is added over a further trimethylsilyl ester solution prepared with 7-A~CA (3 cmole; 6.429 g) in methylene chloride (30 ml). Thereafter acetic acid (2.25 ml) and triethylamine ~4.2 ml) in methylene chloride ~10 ml) is added and stirring is continued for 60 min, at a temperature of-from 0- to 5QC.
Then 20 ml water are poured in and the mixture is adjusted to pH = 1 with HCl. lhe organic phase is decanted off, washed three times with water and then dried with sodium sulphate anhydride.
It is then concentrated at reduced pressure, ethyl acetate (25 ml) is added to the resulting solution which is then concentrated to produce crystallisation. The compound o~ the title is isolated by filtration with a virtually quan-titative yield (9.409 g), m.p. =
170-184QC; recrystallised in ethyl acetate, m.p. = 184-6QC. IR
spectrum identical to that of a pure sample.
..... .. .. .

7. 7-(alpha-chlorophen~lacetamido)-¢ephalosporanic acid (Via BP0) Follow ~xample 6, but using a solution of alpha-chloro-phenylace-tic acid (1 cmole; 1.705 g) and N-ethylpipexidine (1 cmole; 1.1~2 g) in methylene chloride (10 ml) and a ~uspension of BP0 (0,5 cmole; 2.180 g) in carbon tetrachloride ~20 ml). Then replace the 7-ADCA tximethylsilyl es-ter with 7-ACA (1 cmole;
3,040 g) in methylene chloride (30 ml), the reaction being conducted in a similar way. After washing with water and drying, concentrate at reduced pressure and the re~idue i9 diluted with n-heptane until it turns turbid, whereafter it is allowed to rest for crystallisation.~ ~he compound of the tit}e is isolated ~4~00 g;
Y = 87.6%), m.p. = 88-90~C. Neutralisation equivalent: calculated 424.5; found: 415; IR spectrum identical to that of a pure sample.

_9_ .. . , ~ , . ~ . . .

- 106~33~

8. 7-(alpha-chlorophenylacetamido)-desacetoxycephalo~poranic acid (Via BP0) Follow Example 6 but use alpha-chlorophenylacetic acid (3 cmole; 5,115 g) and tributylamine (3 cmole; 5.560 g) instead of the phenoxyacetic acid and M-methylmorpholine, respectively.
The organic phase is isolated, washed and extracted with water (90 ml), ammonium hydroxide i9 added to give an alkaline pH to phenolphthalein. ~he water phase is drawn off ~d treated with HCl to give a white solid which, when filtered and dried, gives the compound of the title (9.900 g; Y = 86.4~), m.p. = 152-4C.
Neutralization equivalent, calculated: 366.5; found: 367. IR
spectrum equivalent to that of a pure sample.

9. 7~ (1H)-tetrazolylacetamido)-cephalosporanic acid sodium salt (Via CP0) _ __ ~ he reaction is conducted in a similar way to Example 6, with CP0 (1.5 cmole; ~.88~ g), 1-(1H~-tetrazolyl acetic acid (3 cmole; 3.840 g), beta-picoline (3 cmole; 2.700 g) and 7-ACA
(3cmole; 9.120 g) instead of BP0, phenoxyacetic acid, N-methyl-morpholine and 7-A~CA, respectively. The mixture resulting from the operation i~ ~iluted with an equal volume of isopropanol and 100 ml water, followed by ad~ustment to pH = 2.2. ~he organic phase is decanted off and the methylene chloride is evaporated at reduced pressure. After concentration a sodium 2-e-thylhexanoate solution is added. lhe white precipitate is filtered, washed with isopropanol-water (80~ and dried to give the compound of the title (11.17 g; Y = 90.0%), m.p. = 175-~QC (d). IR spectrum identical to that of a pure sample.

10, 7-(1-(lH)-tetrazolylacetamido)-3-(5-methyl-1,3,4-thiadiazolyl-2-thiomethyl) ~ 3-cephem-4-carboxylic acid (Via CP0) ~61330 A solution of 1-(1H)-tetraæolylacetic acid (3 cmole;
3.840 g) and triethylamine (3 cmoles; 4.20 ~l) in methylene chloride (60 ml) is added quickly with good stirring to a ~uspension of CP0 (1,5 cmoles; 3~885 g) in ~ethylene chloride (60 ml) at -15QC. After 60 min at 25~C it is added gradually over a further solutibn, chilled in an ice-water bath, of 7-A~A-TD (3 cmoles;
10.333 g) (7-amino-3-(5-methyl-1,3,4-thiadiazolyl-2-thiomethyl) ~ 3-cephem-4-carboxylic acid) as trimethylsilyl ester (prepared with 3-trimethylsilyl-2-oxazolidinone) in methylene chloride (60 ml).
Stirring i8 continued for 60 min and the evolution of the reaction is controlled by adjusting to pH = 4 with a triethylamine pivalate solution. The resulting mixture is washed with a sodium chloride ~olution and then extracted with water and sodium hydroxide, the water phase being dr~wn off. lhe water pha.se is chilled in an ice-water bath, HCl is added and the white precipitate is filtered, washed and dried to give the compound of the title (12.00 g;
Y = 88.0%), on recry3tallisation has m.p. = 196-9gC(d) and IR
spectrum identical to that of a pure sample.
The 7-ACA-~D was prepared by heating a solution of 7-(alpha-chlorophenylacetamido)-3-thiomethyl ~ 3-cephem-4-carboxylic acid trimethylsilyl ester (3 cmoles; 11.960 g), 2-chloro-5-methyl-thiadiazol (3 cmoles; 4.035 g) in dimeth~lformamide with pH adjusted with quinolein to 70QC. The 7-ACA-~D group was then released with thiourea, following the process described in Spanish patent n 431.484.

11. 7-(thien~lacetamido)-cephalosporanic acid (Via cPo?

Following Example ~ and u~ing thienylacetic acid (3 cmoles; 4.323 g) instead of the tetrazolylacetic acid, evaporation of the ~olvent gives a precipitate which, after isolation by filtra-tion~ gives the compound of the title (10.20 g; Y = 85.2%) identi-fied by IR spectrum, identical to that of a pure sample; m.p.

-1 1 - '.

~, , ' . . , . ! .
'~ ' " ' ' '~ .; ' " "' 106~L33C~
l69-172C (d). ` ;

12. 7-(thienylacetamido)-3-pyridylmethyl) ~ 3-cephem-4-carboxylate (Via CPO) Thienylacetic acid (1 cmole; 1.442 g) i~ activated with CPO (0,5 cmole) according to Example 11. Thereafter it is added over 7-ACA-pyrimidyl (1 cmole; 2.913 g) (7-amino--3-pyridyl-methyl)--cephem-4-carboxylate) in methylene chloride 30 ml) with ~tirring in an ice bath and with pH controlled to 5. After 60 minutes the solvent i~ removed by evaporation and the re~idue is treated first with moist methylisobutylketone and then with water (7ml) and then left to crystallise in an ice bath. ~he precipitate is filtered and dried and the treatment i8 repeated with the mother liquor, to give the compound of the title (3.05 g; Y = 73.2%) identified by its IR sepctrum, identical to that o~ a pure ~ample.
Optical aotivity +47.0P ~c =1~, H20)

13. 7-(3,5-dinitrobenzoylamido)-3-azidomethyl ~ 3-cephem-4~carboxylic acid. (Via ~PO) A solution of 3,5-dinitrobenzoic acid (1 cmole; 2.121 g) and triethylamine (1 cmole; 1.42 ml) in methylene chloride (10 ml) i~
added over a further solution of lPO ~1 cmole; 4.282 g) in methylene chloride (20 ml) with cooling in an ice water bath. After stirring for 15 min, it is added over 7-amino 3-azidomethyl ~ ~-cephem-4-carbo~ylic acid trimethylsilyl ester, prepared with the 3-azido derivative of 7-ADC~ (1 cmole; 2.552 g), ~-trimethylsilyl-2-oxazoliai-none (2.5 ml) in methylene chloride (20 ml) with adjustement to pH = 6 with triethylamine acetate. The mixture is stirred at room tempe-rature (20QC) for 30 min. me resulting solution is adjusted to pH = 2 and washed with water (10 ml) several times, the organic phase i3 then extracted with more water ~10 ml) and ammonium hydroxide until the pH is alkaline with phenolphthalein. ~he ' , ~: ' .' :" . . . ~ . :

aqueou~ liquors are cooled in an ice bath and precipitated with dilute HCl. The product is filtered and dried to give the compound of the title (4.10 g; Y = 91.2%); identified by its IR spectrum with characteri~tic bands due to the beta-lactam nucleus and the azido and nitro functions in the usual position~.

14, 7-(3,5-dinitrobenzoylamino)-desacetoxycephalosporanic acid.

(Via 2-(3,5-dinitrobenzoylox~) ~ 2-oxazoline).
, . .
~irst triethylamine piv~late (0.5 cmole; 0.545 g pivalic acid and 0.70 ml base) and thereafter 2-(3,5-dinitrobenzoyloxy) ~ 2-oxazoline (1 cmole; 2.812 g) prepared from CP0 and 3,5-dinitrobenzoic aoid 2,4-lutidine ~alt i~ added to a solution of 7-ADCA (1 cmole;
2.142 g) prepared in methylene chloride (30 ml) in the trimethyl-8ilyl ester form. After 15 min stirring at 20C, wa-ter i~ added, the organic phase is decanted off and extracted with an ammonium hydride aqueou~ solution. This is cooled and the compound of the title (3.074 g; Y = 75.3~) is precipitated out with HCl. It i8 identified by its IR sepctrum and shows the corresponding bands due to the beta-lactam nucleus and nitro groups.
i~ 1

15. 6l3-(2,6-dichlorophenyl)-5-methylisoxazolyl-~-carboxyamido~-penicillanic acid sodium salt. (Via 2 ~-(2,6-dichlorophenyl)-5-methylisoxazolyl-4-carbonyloxy,¦ ~ 2-oxazollne).
, A solution of 6-APA (1 cmole; 2.162 g) trimethylsilyl ester i8 prepared in methylene chloride ~10 ml) with triethylamine (1 cmole; 1.40 ml) and 3-trimethylsilyl-2-oxazolidinone (200 ml).
Then pivalic acid (1 cmole; 1.10 g) followed by the ~2-oxazoline ester of the title (1 cmole; 3.411 g) are added. The mixture is stirred for 15 min at 20QC. The resulting solution is first washed wlth water, then adjusted to pH = 2, the organio phase is deoanted off, dried and adju~ted to pH - 6.5 ~4 to 5 ml of a 44% ~odium 2-ethylhexanoate solution in methylisobutylketone). A~ter concentration " ., ~. . . .
~ . ' ' .

~6133~

at reduced pres3ure, the liquor~ are first diluted with isopropanol and then with n-heptane (200 ml) to produce a white precipitate which i~ i~olated and washed. Once dry it gives the compound o~
the title with an almost quantitative yield (4.770 g). ~he optical activity i~ +134 tc = 1%, H20), crygtallised from methylisobutyl-ketone, it ha3 m.p. 212-214QC (d) and IR sepctrum identical to that of a pure sample.
Th ~ 2-oxazoline ester isolated from the reaction between HPO and the acid triethylamine salt has m.pO 209-211G and characteri~tic readings in IR with intense bands at i785 cm 1 and 1728 cm 1 (BrK).

16. 6 ~3-(2-ohlorophenyl)-5-methyli~oxazolyl-4-carboxyamido~- penicil-lanic acid sodium aalt. (Via 2~3-(2-chlorophenyl)-5-methylisoxazolyl-4-carbonyloxy~1 ~2-oxazoline).

.. _ _ . . . . . . . . . . .

Operating in a similar way to Example 15 and replacing the 4 -oxazoline e~ter with the corresponding ester of the title (1 cmole; 3.066 g), the penicillin i5 produced with comparable yield. In IR it has a ~pectrum identical to that of a pure sample.
me~ 2-oxazoline e~ter, with ~.p. 115-119C, give~ inten3e IR
spectrum readings at 1795 cm 1 and 1730cm 1 (BrK).

17, 6L3-(2-fluor-5-chlorophenyl)-5-methylisoxazolyl-4-carboxyamido~~
penicillanic acid sodium salt. (Via 2~3-(2-fluor-6-chlorophenyl)-5-methylisoxazol-4-carbonyloxy,1 ~ 2-oxazoline).

Operating in a similar way to Example 15 and replacing the~ 2-oxazoline a~ter with the corresponding ester of the title (1 cmole; 3.247 g), the penicillin i8 proauced with comparable yield. In IR it ha~ a ~pectrum identical to that of a pure 3ampleO ~ i ~h ~ 2-oxazolln~ ester gives i~tense IR spectrum reading~ at 1795 cm 1 and 1729 cm 1 (BrK).

18. 7~1-(1H)-tetrazolylacetamido1 3-(5-methyl-1,3,4-thiadiazolyl-2-L06~L33~
thiomethyl)~3-cephem-4-carboxylic acid sodium salt. ~Via 2~-(1H)-tetrazolylacetyloxy,~- ~2-oxazoline).

A solution of 7-ACA-TD (3 cmoles; 10.332 g~ is prepared in water (50 ml) and sodium hydroxide is added until the solution is alkaline to phenolphthalein. ~hereafter ethanol (50 ml) and the /~2-oxazoline ester of the title ~3 cmoles; 5.916 g) are added.
~e mixture is held with good stirring at a temperature of 10C for 30 min and then mixed with further ethanol (75 ml) and allowed to crystallise in ice bath. The white precipitate produced is filtered, washed with ethanol and dried to give the compound of the title (10.75 g; ~ - 75.1%) m.p. 185QC and IR spectrum identical to that of a pure sample. Ihe~2-oxazoline ester gives characteristio inten~e IR readings at 1800 cm 1 ~d 1730 cm 1 (BrK).

19. 7-(cyanacetamido)~cephalosporanic acid sodium salt. (Via 2-(cyanacetiloxy) ~ 2-oxazoline).
.
Following Example 18 and replacing the 7-ACA-~D with 7-ACA (3 cmoles; 8.166 g), the ethanol with isopropanol and the /\2-oxazoline ester with the correspondin~ ester of the title (3 cmoles; 4.623 g) and operating in a similar way, the compound of the title is isolated with a comparable yield. ~he IR spectrum gives aII identioal reading to that of a pure sample. ~he liquid -oxazoline ester gives characteristic IR readings at 1798 cm 1 and 1732 cm 1, apart from the one due to the nitrilo group.

20. 7-(3,5-dinitrobenzoylamido~-3-methylthiol-~3-cephem-4- carboxglic acid. (Via 2-(3,5-~initrobenzoyloxy)-~2-oxazoline ester~.

~ollowing Example 14 and replacing the 7-ADCA with 7-amino-~-methylthiol-/~3-cephem-4-carboxylic acid (1 cmole; 2.463 g), the compound of the title i~ isolated with comparable yield Identi-fied by its IR spectrum lhe~2-oxazoline ester has mcp. 216C and :.

33~
gives intense characteristic readings in IR at 1805 c~ 1 and 1745 cm 1 (KBr), as well a~ those corre~ponding to the nitro group.
~he 7-amino~3~thiomethyl~3-cephem-4-carboxylic acid wa~ prepared either by reaction of the corresponding chloromethyl derivative and sodium monosulphide solution in dime-thylformamide solution or, alternatively, by treatment of 7-(alpha-chlorophenyl-acetamido)-3-chloromethyl~3-cephem-4-carboxylic acid in acetoni-trile with thiourea~ as de~cribed in Spanish patent n 431.585, with release of the correspollding thiomethyl derivative.

21. 7-(alpha-bromophenylacetamido)-3-chloromethyl-~3-cephem 4-carboxylic acid. ~Via HPO chloride) Operate in a similar way to E~cample 13 replacing the 3,5-dinitrobenæoio acid with alpha-bromophenylacetic acid (1 cmole;
2.150 G), the TPO with HPO chloride (1 cmole; 2.847 g) and the 7-amino-3-azidomethyl~3-oephem-4-carboxylic acid with the corresponding 3-chloromethyl derivative (1 cmole; 2.487 g). Isolation conduct~ to the compound of the title (3.660 g; Y = 82.15~), identified by its IR spectrum, neutrali~ation equivalent and iodometric evaluation, with 98.2% purity.

22. 7-(cyclohexylcarboxyamido)-3-methoxymethyl~3-cephem-4-carboxylic acid. (Via ~-tri~dimethylaminophosphonium-4-methyl-2-oxazolidinoIle (HPO-4-methyl) bromide~ _ t Operating in a similar way to Example 13 and replacing the 3,5-dinitrobenzoic acid with cyclohexanecarboxylic acid (1 cmole;
1.281 g), the TPO with HPO-4-methyl (1 cmole; 3.431 g~ and the azidomethylcephalosporanic acid with 7-amino-3-methoxym~thyl-~3-cephem-4-carboxyllc acid (1 cmole; 2.442 g), the compound of the 30 title i~ produced (2.481 g; Y a 70 0%) identified by its IR spec-trum and beta lactam nucleus. Iodometric evaluation shows it to be 94,3~6 pure.

', ~. . ' . . : '' 1~6~33C~

23. 7-(quinoxalin-2-carboxyamido~-3-cyanomethyl ~ ~-cephem-4- -carboxylic acid. (Via 3-trisdimethylaminophosphonium-5- methyl-2-oxazolidinone chloride fHP0-5-meth l chloride).

Following Example 6 and replacing the BP0 with HP0-5-methyl chloride (1 cmole9 2.987 g), the phe~oxyacetic acid with quinoxalin~2-carboxylic acid (1 cmole; 1.741 g) and the 7-ADCA with 7-amino-3-cyanomethyl ~ 3-cephem-4_~arbOxylic acid, the result i3 the compound of the title with almost quantitative yield (3.954 g).
Identified by its IR sepctrum9 beta lactam nucleus and nitrilo group;
neutralisation equivalent and iodometric evaluation (more time than usual required during treatment with alkali - 90 min).

24. 6-(pyridin-3-carboxyamido)-penicillanic acid phthalidyl e~ter.
(Via 3-triohlorophosphonium-4-methyl-2-oxazolidinone chloride CP0 ~ th l~
( - -me y ,. - _ Nicotinic acid t1 cmole; 1.231 g) i~ treated with CP0-4-methyl (0.5 cmole; 1.415 g) in a similar way to Example 1, followed by gradual addition over 6-aminopenicillanic acid phthalidyl ester (1 cmole; isolated from hydrochloride, 3.848 g) in 40 ml methylene chloride with the temperature controlled by ice bath. After 60 min stirring, water (10 ml) is added, p~ is adjusted to 6, the or~anic phase i~ decanted off, washed with water, dried and concentra-ted at reduced pressure. Thereafter the mixture is saturated with hydrogen chloride, diluted with n-heptane and left in the refrige-rator. The product9 filtered and washed with n-heptane and dried, gives the compound of the title as the hydrochloride (4.223 g;
Y 80.3~). Identified by It~ IR spectrum with the characteristic bands corresponding to the beta-lactam nucleus, aromatic and pyridine nucleus; iodometric evaluation - 94.6% and bioa~say 895 ~0 ,~glg.
The 6-APA phthalidyl ester wa~ prepared by react:ing 6-APA hydrochloride ohlor~de (2 c~ole; 5.438 g) in methylene chloride 6~33(~
~40 ml) with 2-carboxybenzaldehyde cyclic hemiacetal (2.5 cmole;
3.753 g) with stirring in a water-ice bath for 120 min. Thereafter the product wa~ filtered and dried~ ~he purity wa3 evaluated with standardi~ed sodium hydroxide solution.

25. 6-(5-nitrofuryl-2-carboxyamido)-penicillanic acid sodium salt.
(Via 3-trichlorophosphonium-4,5-dimethyl-2-oxazolidinone chloride (CPO-4,5-dimeth~

Following Example 1 exactly and replacing the CPO with CPO-4,5-dimethyl (1 cmole9 3.070 g), the alpha-azidophenylacatic acid with 5-nitro-2-furoic acid (2 cmoles; 3.141 g) and the triethylamine with pyridine, the result is the compound of the title t7.409 g; Y = 98.2%). Characterised by the IR ~pectrum bands and thin layer chromatography (developed with a concentrated NaOH
~olution in methanol-acetone), with identical Rf to that o~ a pure sa~ple.

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the acylation of aminopenicillanic, aminocephalosporanic, and aminodesacetoxycephalosporanio acids and their derivatives, characterised in that a compound of the following formula:
(I) where R1 and R2 are hydrogen or low molecular weight alkyls, X may be an element selected from the halogen group and R is a further group selected from a low molecular weight alkyl, phenyl, halogen and dimethylamin, is reacted with a carboxylic acid in the form of a tertiary organic base salt in methylene chloride at temperatures between -15 and +20°C for a period of from 15 to 120 min, to obtain a mixture of active species with a relative proportion of acid halide, N-acyl-2-oxazolidinone and 2-acyloxy-.DELTA.2-oxazoline, and further reacting the mixture in an inert solvent with a compound of the following formula :

(II) where n may be 1 or 2, (H)2 may be 0, 2 atoms of hydrogen or a methyl group, (H)1 is 0 or 1 atom of hydrogen, R4 an element selected from the group comprising hydrogen, alkali metals, trimethylsilyl, phthalidyl and R3 selected from the group comprising methyl, azidomethyl, acyloxymethyl, thiolmethyl, 5-methylthiadiazolyl-2-thiomethyl, cyanomethyl, chloromethyl, methoxymethyl, to prepare a penicillin or cephalosporin.

2. A process according to claim 1, wherein a compound of Formula I, where R1 and R2 are hydrogen, X and R have the meaning given above, is reacted in an inert solvent with a carboxylic acid salt, selected from the group comprising aliphatic, alicyclic, aromatic, alkanoaromatic, heterocyclic, alkanoheterocyclic acids and condensed nuclei, with tertiary organic bases of the group comprising pyridine, picolones, lutidines, triethylamine, tributylamine, N-ethyl piperidine and N-methylmorpholine and the resulting mixture is made to react with a further solution of compound II in methylene chloride to obtain a penicillin or cephalosporin.

3. A process according to claim 1, wherein a compound of Formula I where R1 and R2 are hydrogen, X and R have the meaning given above, is made to react in an inert solvent with a tertiary organic base salt and carboxylic acid, the acid being selected from the group comprising benzoic, phenylacetic, acetic, pyridincarboxylic, quinoxalincarboxylic, isoxazolylcarboxylic acids and the resulting mixture is reacted with a further solution of a compound of formula II in methylene chloride to obtain a penicillin or cephalosporin.