CA1184898A - Process for the preparation of penicillanic acid esters - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a method of preparing a liquid for radiopharmaceutical application comprising a radioisotope by eluting a radioactive daughter isotope from a parent isotope which is adsorbed on an adsorbent by means of a physiological solution, in which a fission-produced parent isotope is used and the eluate comprising a daughter isotope is purified with a cation-exchange material. By using the method according to the invention a liquid containing a radioisotope having an exceptionally high chemical, radiochemical and radio-nuclidic purity is obtained in a high yield.
The invention also relates to an isotope generator system suitable for use of the said method and to a reservoir for said generator system.

Description

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The present invention relates to useful intermediates in preparing compounds with readily hydrolyzable esters which degrade in iVO
into beta-lactam antibiotics and the beta-lactamase inhibition penicillanic acid sulfone.
This application is divided from applicants copending application Serial No.398,978 filed March 22, 1982, the latter application also being directed to intcrmediates useful in preParing simila.r compounds with hydrolyzable esters.
Despite the wide use and acceptance o:E penicillins and cephalosporins, beta-lactum antibiotics, in combatine bacterial infections, there are certain members within the group that are not active against resistant microorganisms because of the oreanism's ability to produce a beta-lactamase enzyme which reacts with beta-lactam antibiotic to produce Products devoid of anti-bacterial activity. However, certain substances have the ability to inhibit beta-lactamases. and when used in combination with a Penicillin or cephalos-porin can increase or enhance the antibacterial effectiveness of the antibiotic against certain beta-lactamase producine microorganisms.
West German Offenle~un~sschrift No. 2,824,535 nublished December 14, lg78 teaches that penicillanic acid sulfone is such an ef-fective beta-lactamase inhibitor. In addition, it is taueht in said a~plication that certain esters of penicillanic acid sulfone are readily hydrolyzable in iVO
giving high blood levels of this beta-lactamase inhibitor. Further, U.K.
Patent Application 2~044,255 and United States Patent 4.244,951 also teaches that halomethyl esters of penicillanic acid sulfone can be coupled through the carboxy group of an antibacterial Penicillin to ~ive compounds with readily hydrolyzable esters which degrade in vivo into anti-bacterial penicillins and the beta-lactamase inhibitor penicillanic acid sulfone.

-U.K. Patent Application 2,C44,255 further teaches that the inLermediate chloromethyl penicillanate sulfone can be prepared by coupling the potassium salt of peni-cillanic acid sulfone with chloroiodomethane in the presence of a catalytic amount of tetrabutylammonium .sulfatev In addition it is reported that the tetra-bu~ylammonium salts of certain penicillanic antibacterial agen~s can be coupled with alpha-haloalkyl penicillanate sùlfones to give compounds ~ith readiiy hydrolyzable esters which degrade in vivo into antibacterial peni-___ _ , cillins and penicillanic acid sulfone.

The process of aforementioned application Serial No.39$~978 is for the preparation of a compound of the formwla H H (O) _ _ ~ ~n ~liCH3 /f ---N , 3 'C021::H2Cl .wherein n is an integer of 0 or 2, R is a) hydrogen b) R~ ~ CHCONH- or ~ ~CO
c) R2~CH ~-HN J-CH
C~3 3 wherein R2 is hydrogen or hydroxy and R1 is azido, amino~
l-methoxycarbonylpropen-2-ylamino or carboben~yloxy- -amino, which comprises contacting one mole of a com-pound of the formula ~ ~ ~ C~13 wherein R3 is alkyl of one to four carbon atomsJ with at least one mole of indochloromethane or bromochloromethane at from about -20C. to about 25C. with the proviso that when _ is 2, R is hydrogen.
A preferred feature of the process is the use of excess bromochloromethane.
An especially preferred feature of the claimed process is the preparation of those compounds where R is hydrogen, R3 is n-butyl and n is 2, and where R is R2 ~ CICONH-where R2 is hydrogen, n is 0, R3 is n-butyl and Rl is azido, amino or l-methoxycarbonylpropen-2-ylamino.
The products of the above process are useful intermediates in preparing compounds with readily hydrolyzable esters which degrade in vivo into beta-lactam antibiotics and the beta-lactamase inhibitor penicillanic acid sulfone.
According to the present invention, there is provided a process for the preparation of a compound selected from those of the formula C02CH~02C ;

i 3~

wherein X is selected from the group consisting of a) R2 ~ CHCONH-, and ----R
r~ C
b) R2 ~ ~ C~ N-wherein Rl is selected from the group consisting of a~ido, amino, carbobenzyloxyamino and l-methylcarbonylpropen-2-ylamino and R2 i.s selected from the group consisting of hydrogen and hydroxy, which comprises:
(a) contacting one mole of a compound selected from those of the formula:

~ CH3 /i-- /f/Co2CH2 -Y

wherein ~ is selected from the group consisting of chloro, bromo and iodo, with at least one mole of a compound selected from those of the formula H H

X ~ ~ CH3 O ~C02N(R3)~

wherein R3 is alkyl having from one to four carbon atoms in a reaction-iner-t solvent at ambient temperatures, or (b) contacting one mole of a compound selected from those of the formula ~ " S ~ ~\GH3 )/ - N ~ C113 O C02CH2-y with at least one mole of a compound selected from those of the formula ~ \
~ N I ~ CH3 O '~, C02N(R3)~1 wherein R3 is alkyl having from one to four carbon atoms and Y is selected from the group consisting of chloro, bromo and iodo, in a reaction-inert solvent at from about 0~ to about 60C.
A preferred feature of the process is the use of acetone or dimethylformamide as the reaction-inert solvent.
An especially preferred feature of this process is the preparation of those compounds wherein X is R2_ ~ CHCONH-wherein R2 is hydrogen, Y is iodo or chloro respectively in parts ~a) and (b) R3 is n-butyl and Rl is azido, amino or l-methoxycarbonylpropen-2-ylamino.
Those products wherein R2 is as defined and Rl is azido, l-methoxycarbonylpropen-2-ylamino or carbobenzyloxyamino are useful intermediates to those compounds wherein Rl is amino as taught by the herein described procedures. In addition, compounds of the structure wherein X is R ~ ~

and R2 is as defined contain a readily hydroly~able ester rnoiety which in vivo gives a beta-lactam antibiotic and the beta-lactamase inhibitor penicillanic acid sulfone.
'~hile United Kingdom Application Z,044,255 teaches the coupling of chloroiodomethane with the potassium salt of penicillanic acid sulfone in the presence of a catalytic amount of tetrabutylammonium sulfate to give chloromethyl penicillanate sulfone~ the processes of the present invention employ equimolar amounts of the tetraalkylammonium salts of the appropriate acid and requisite halide, and pro-vide unexpectedly higher yields of the condensed products.
The process of the present invention~ part (a), is readily carried out by contacting one mole of a halomethyl ester of penicillanic acid sulfone of the formula S ~CH
._ , ~ ,~ 3 -r ~CH3 ~ ~// C02CH2-Y

wherein Y is as previously de~ined, with at least one mole of a compound of the formula H S~ CH3 ~ ``~ C~l ~ "~2N(R3)4 wherein X and R3 are previously defined, in a reaction-inert solvent.
The reaction-inert solvent or mixtures thereof for this process of the present invention should solubili~e the reactan-ts without reacting to any appreciable extent with either the reactants or the product under the conditions of the reaction. The preferred solvent for said reaction is acetone, althowgh a wide variety o~ other aprotic, water-miscible solvents including ethyl acetate, acetonitrile, dimethylformamide and hexamethylphosphoramide are also operable.
Reaction time is dependent on concentration, reaction tempera-ture and reactivity of the starting reagents. When the reaction is conducted at the preferred temperature of about 25C. the reaction is usually complete in 30-60 minu~es.
For optimum yield of product at least one mole of the tetra-alkylammonium salt is employed per mole of halomethyl ester. In addition, as much as a 10-20% excess of the salt can be employed without markedly affecting the quality of the product produced.
On completion of the reaction the solvent is removed, usually in vacuo, and the residual product is purified by chromatographing on silica gel.
I`he tetraalkylalmnonium penicillanate salts and the halomethyl penicillanate sulfones are prepared by the herein described procedures.
The process of the present invention part (b) is carried out ~ 3~

by contacting one mole of a halomethyl penicillanate of the formula H
~CH

wherein X and Y are as previously defined, with at least one mole of a compound of the formula ~,S ~\CH3 ~ C2N(R3)~

wherein R3 is as previously defined.
The reaction is carried out in a reaction-inert solvent, which should solubilize the reactants without reacting to any appreciable extent with either the reactants or the product under the conditions of said reaction. The preferred solvent for this reaction is acetone, although other highly polar water miscible, aprotic solvents, such as dimethylformamide and hexamethyl phosphoramide, can also be employed.
Reaction time is a function of concentration, temperature and reactivity of the starting reagents. Reaction is conducted at 0C. to 60C.
with a preferred temperature of about 25C. to about 60C. The reaction time for the preferred temperature is about 0.5-~ hours. For convenience, the reaction is frequently allowed to proceed overnight without a detrimental affect on the product.

On completion of the reaction it is diluted with water and a water immiscible solvent. The organic phase is concentrated and the product purified by column chromatography.
As previously indicated, the com~ounds oE the present invention of the formula ~1 H 2 X = 3 CH ~

'i C02C~1202C ~" o wherein X is R2 - ~ CHCONH-where R2 is as defined and Rl is amino, when administered to a host suffering from a bacterial infection are readily hydrolyzed into a beta-lactam antibiotic and the beta-lactamase inhibitor penicillanic acid sulfone. Those compounds wherein R2 is as defined and Rl is azido, 1-methoxycarbonylp:ropen -2-ylamino or carbobenzyloxyamino are useful intermediates which can be converted to those compounds wherein Rl is amino.
Reduction of those compounds oE the above formula wherein Rl is azido can be carried out by shaking the intermediate dissolved in an appropriate solvent or solvents, such as a lower allcanol and methylene chloride in the presence of a catalytic amount of a noble metal, such as palladium-on-charcoal, in a hydrogen atmosphere at an initial pressure of about 10-50 psi. On completion of the reduction the spent catalyst is filtered and filtrate concentrated to give the desired product.
Similarly, those compounds of this process wherein Rl is carbo~enzyloxyamino can be reduced to provide those products wherein Rl is amino. The hydrogenolysis reaction is readily carried out by shaking a mixture of the intermediate, dissolved in a lower alkanol and methylene chloride, and a catalytic amount of a noble metal in a hydrogen atmosp~ere at an initial pressure of 5-50 psi. On completion of the reaction the catalyst is filtered and the product isolated from the filtrate by evaporation.
Compounds of the above structure wherein Rl is amino can be obtained from those wherein Rl is l-methoxycarbonylpropen-2-ylamino by treatment of a solution of the latter with at least an equivalent amount of an acid. Lf a non-aqueous reaction inert solvent, such as ethyl acetate, is employed it is preferred that at least 1-5% (v:v) of water be present in said solvent in order to facilitate the hydrolysis of the enimine. Acids suitable for the hydrolysis include inorganic mineral acids as well as organic sulfonic acids. The hydrolysis product is isolated as the corresponding acid addition salt by filtration from the reaction solvent.
United Kingdom Patent Application 2,0~,255 teaches that the halomethyl penicillanate sulfones, products of the presently claimed process, can be coupled with a variety of beta-lactam antibiotics to provide in vivo antibacterial agents which result from the absorption and subsequent hydrolysis of the coupled product to give high blood and tissue levels of penicillanic acid sulfone and the beta-lactwm an-tibiotic resulting from said hydrolysis. In addition, the aforementioned ~nited Kingdom application teaches how to use the produc-ts resulting from a coupling of penicillanic acid sulfone and a beta-lactam antibiotic.
Specific preparations will now be described, by way of example only, and relate to the process of copending application Serial No.398,978 and that of the present invention.
Nuclear magnetic resonance spectra ~NMR) were measured at 60 ~1 for solutions in deuterochloroform (CDC13), perdeutero dimethyl sulfoxide ~DMSO-d~) or deuterium oxide (D20) or are noted otherwise, and peak positions are expressed in parts per million (ppm) downfield from tetra-methylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for peak shapes are used:
b, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

4~

Chloromethyl 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyljPenicillanate .
To a suspension of 1.56 g. of 6 (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl penicillanic acid ~J.
. Chem~, 31, 897 (1966)] in 20 ml. of methylene chloride and 20 ml. of water was added sufficient tetrabutylanmonium hydxoxide to give a pH of 8.5. The organic layer was separated and the aqueous washed ~2 x 20 ml.) with methylene chloride. The or~anic layers were comhined, dried over sodium sulfate and concen-trated to give 2.3 g. o~ a foam.
The residual tetrabutylammonium salt was added to 15 ml. of chloroiodomethane and the reaction mixture allowed to stir at room temperature overnight. The reaction mixtuxe was chromatographed on lOO g. of silica gel usi~g ethyl acetate/hexane (1:1 v:v) as the eluent, taking 14 ml. cuts every 30 sec. Cuts l9S-230 were combined and concentrated to dryness to give 440 mg. of the desired product.
The NMR spectrum (CDC13) showed absorption at 1.5 ~sr 3H), 1.58 (s, 6E), 1.72 (s, 3H), 4.58 (s, lH~, 4.67 (s, lH), 4.73 (d, 1~), 5~54 (d, lH) and 7.2-7.6 (m, 5H) ppm.
Using the same procedure, and starting with 6-~2,2-diméthyl-5-oxo-4~t~-hydroxyphenyl]-1-imidazolidinyl)-penicillanic acid tJ. Chem. Soc., 1920 (1971~J, chloro-methyl 6-(2,2-dimethyl~5-oxo-4-tp-hydroxyphenyl] 1-imidazolidinyl)peni.cillanate is prepared.

.

Chloromethyl 6-(alpha-aminophenylacetamido?-penicillanate : ~
_ A suspension of 4.03 g~ of 6-(alpha-aminophenyl-acetamido)penicillanic acid trihydrate in 30 ml. ofmethylene chloride and 30 ml. of water was treated with sufficient tetrabutylammonium hydroxide to give a pH of 8.5. The methylene chloride layer was separated and the aqueous further extracted (2 x 30 ml~) with fresh - 10 methylen chloride.- The organic extracts were com-bined, dried over sodium sulfate and concentrated in vacuo to give 6.0 g. the desired tetrabutyla~nonium salt.
Five and three-tenths grams of the above salt was added to 35 ml. of chloroiodomethane and the resulting - reaction mixture allowed to stir at room temperature for 3 hoursO The reaction was chromatographed on 200 g. of silica gel using ethyl acetate as the eluent~
and taking :L0 ml. cuts every 0,8 min. Cuts 115-139 were combined and concentrated in vacuo to a white foam.
The NMR specturm (CDC13) showed absorption at 1.55 (s, 3H), 1.65 (s, 3H), 2.6-3.2 ~s~ 2H), 4.~2 (s, lH~, 5.3-5.8 (m, 3H), 5.7 ~dd, 2H), 7.3 (s, 5H) and - 25 7.9 (d, lH) ppm.
Starting with the tetramethylammonium salt of 6-(alpha-amino-p-hydroxyphenylacetamido3penicillanic acid, and employing the above procedure, chloromethyl ; 6-(alpha-amino-p-hydroxyphenylacet~nido)penicillanate is preparcd.
.

.
.

3~

EXAMPLE _3 Chloromethyl 6-~alpha-azidophenylacetamido)-penicillanate . . . ~
A mixture of 3.97 g~ of 6-(alpha-azidophenylacet-amido)penicillanic acid sodium salt in 75 ml. of ethyl acetate ànd 35 ml. of water was treated with sufficienk 6N hydrochloric acid to give a pH of 1.7. The organic phase was separated and the aqueous layer further extracted (2 x 50 ml ) with fresh ethyi acetate. The ethyl acetate layers were combined, dried over sodium sulfate and concentrated under vacuum to give 3.8 g.
of a foam. The residue was taken up in 50 ml. of methylene chlor.ide to which was added 35 ml. of water.
The pH was adjusted to 8.5 with 40% aqueous tetrabutyl-ammonium hydroxide, and organic phase separated. The aqueous was further extracted with fresh methylene chloride (2 x 50 ml.) and the combined organic layers dried o~er sodium sulfate and concentrated to give 6~2 g. of the desired tetrabutylammonium salt.
In a Elask fitted with a magnetic stirrer and stopper were combined 6O2 ~. of tetrabutylammonium 6-(alpha-azidophenylace-tamido)penicillanate and 35 ml.
of chloroiodomethane, and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was chromatographed on 40 g. of silica gel using ethyl acetate/hexane (1:1 v:v) a~ the- eluent, 12 ml. cuts being taken every 36 sec. Cuts 34-68 were combined and concentrated in vacuo to give 4.05 g. of the desired product as a light yellow oil.
The NMR specturm (CDC13) showed absorption at 1.58 (s, 3H?, 1.68 (s, 3H), 4.45 (s, lH), 5.1 (s, lH), 5.5-5.9 (dd m, 4H), 7.2 (d, lH) and 7.4 (s, 5H) ppm.

, ., ~ 3~

The above procedure is repeated, starting with sodium 6 (alpha-azido p-hydroxyphenylacetamido)peni-cillanate and tetrapropylammonium hydroxide to give chloromethyl 6-(alpha-azido-p-hydroxyphenylacetamido~
penicillanate.
E~AMPLE 4 Chloromethyl pe*icillanic acid l,l-aioxide A mixture of 4.66 ~. of penicillanic acid 1,1-dioxide in 50 ml. of methylene chloride and 35 ml. of water was txeated with sufficient tetrabutylammonium hydroxide (40~ in water) to give a pH of 6Ø ~he methylene chl~ride layer was separated and the aqueous phase extracted with fresh methylene chloride (2 x 50 ml.). The organic layers were combined; dried over sodium sul~ate and concentrated to give 10~1 g~ of the desired intermediate.
The above tetrabutylammonium penicillanate suifone was added to S0 ml. of chloroiodomethan~ and the re-action mixture allowed to stir at ambient temperatures overnight. The reaction mixture was concentrated to half volume in vacuo, and chromatographed on 200 g. of silica gel using ethyl acetate~hexane as the eluent, 12 ml. cuts being ta~en every 30 sec. Fractions 41-73 were combined and concentrated to dryness to give 3.2 g of the desired product.
The NMR spectrum (CDC13) showed absorption at 1.5 (s, 3H), 1.66 ~s, 3H), 3.42 (d, 2H), 4.38 (s, lH), 4.6 (t, lH) and 5.7 (dd, 2H) ppm Chlorometh~l 6-alpha-carbobenzyloxyamino-p-hydroxyphenylacetamido)penicillanate ......
To 12.57 g. of 6-(alpha-amino-p-hydroxyphenyl-S acetamido)penicillanic acid trihydrate in 75 ml. of water and 75 ml. of acetone cooled to 0C. was added sufficient 2N sodium hydroxide solution to give a pH of 8.5. To the resulting ha~y solution was added dropwise 4.28 ml. of carbobenzylo~y chloride over a 5 min.
period. ~he pH of 8.0 was maintained by the periodic addition of 2N sodium hydroxide. After 20 min. the reaction mixture was extracted with diethyl ether (2 x 150 ml.), the aqueous layer over-layed with ethyl acetate and the pH adjusted to 1.5 with 6N hydrochloric acid. The ethyl acetate layer is sepa;rated~ washed successively with water (2-x 50 ml.) and dried-over sodium sulfate. The solvent is removed in vacuo to give the desired 6-(alpha-carboben~yloxyaminophenyi-acetamido)penicillanic acid intermediateO
One gxam of the above intermediate in 30 ml. of methylene chloride and 20 ml. of water was treated with sufficient tetrabutylammonium hydroxide (40~ in water) until the pH was 8~0. The organic phase was separated and the aqueous layer extracted with fresh methylene chloride (2 x 30 ml.). The methylene chloride extracts were combined, dried over s~dium sulfate and concen-trated in vacuo to give 1.4 g. of the corresponding tetrabutylammonium salt.

-~ - 16 One gram of the above salt is added to 7.5 ml.
of chloroiodomethane and the resulting reaction mixture allowed to stir at room temperature o~ernightO
The reaction mixture is chromatographed on 25 y. of silica gel using ethyl acetate/hexane (1 0.5 v:v), cuts of 10 ml. being taken every 30 sec. The cuts containing the product are combined and concentrated under vacuum to give the requisite chloromethyl 6-[alpha-carbobenzyloxyamino-~-hydroxyphenylacetamido]-penicillanate.
In a similar manner, starting with 6~(alpha-amino-phenylacetamido)penicillanic acid and tetramethyl-ammonium hydroxide, chloromethyl 6-(alpha-carbobenzyl-oxyaminophenylacetamido)penicillanate is prepared.

, Iodomethyl penicillanate l,l-dioxide .. . . . . ~ .. .
To a solution of 7.9 g. of chloromethyl peni-cillanate l,l-dioxide in 100 ml. of dry acetone main-tained under a nitrogen atmosphere was added 21.0 g.of sodium iodide, and the reaction mixture allowed to -stir overnight at room temperature. The reaction was concentxated in acuo, and the residue was dissolved in 150 ml. ethyl acetate and 150 ml. water. The - 10 organic layer was separated and the aqueous extracted with fresh ethyl acetate. The organic extracts were combined, washed with water ~1 x 50 ml.) and brine (1 x 50 ml.) and dried over sodium sulfate. Removal of the solvent gave 10.5 ~. of product, m.p. 100-102C.
The NMR spectrum (CDC13) showed absorption at 1.55 ~s, 3H), 1.68 (s, 3H~, 3.5 (d, 2H), 4.4 (s, 1H?
4.65 (t, lH) and 6.0 (dd, 2H) ppm.
.

, - 18 -6'~(alpha-Amino-p-hydroxyphenylacetamide)-penicillanoyloxymethyl penicillanate l-,l-dioxide .
6'-(alpha-carbobenzyloxyamino-p-hydroxyphenyl-phenylacetamido)penicillanoyloxymethyl - penicil-lanate l,-l-dioxide _~ e _ To 9.5 g. of tetrabutylammonium 6-~(alpha-carbo-benzyloxyamino~p-hydroxyphenylacetamido)penicillanate in 50 ml. of dry acetone was added 4.78 g. of iodomethyl penicillanate l,l-dioxide, and the reaction mixture allowed to stir at room temperature for 3~ min. The reaction mixture was concèntrated in vacuo and chroma-tographed on 200 g of silica gel using ethyl acetate/
_ 15 methylene chloride (1:1 v:~)/ 25 ml. cuts being made.
~ractions 29~49 were combined and concentrated to give 6.5 g. of the desired product as a yellow foamO
The NM~ spectrum (DMSo-D6j showed absorption at 1.4~ ~s, 3H), 1~52 (s, 3H), 1.6 (s, 3H), 3.1-3.9 ~m, 2H), 4.45 (s, lH), 4.58 (s, lH), 5.08 (s, 2H), 4.98-5.7 (m, 4H), 5~95 (s, 2H), 6.6B (d, 2H), 7.2 (d, 2H) and 7.35 (s, 5H) ppm.

B.
6'-~alpha-amino-p-hydroxyphenylacetamido)-penicillanoyloxymethyl penicillanate l,1-dioxid To 6 4 g. of 6'-~alpha-carboben~yloxyamino-~-hydroxyphenylacetamido)penicillanoyloxymethyI peni-cillanate l,l-dioxide in 70 ml. of methylene chloride . .

.

and 70 ml. of isopropanol was added 6.S g. of 10%
palladi~-on-charcoal and the resulting mixture shaken in a hydrogen atmosphere at an initial pressure of 50 psi for 45 min. An additional 3.0 g. of catalyst was added and the hydrogenation'continued for 30 min. This procedure of adding 3.0 of catalyst was repeated three times. The reaction ~as filtered and spent catalyst was washed with methylene chloride/isop~opanol (1:1 v:v). The filtrate and washings were combined and concentrated to near dryness. Diethyl ether (200 ml.) ~ - was added to the white suspension and the'mixture al-lowed to stir for 15 min. The solids were ~iltered and dried to give 4.Y g. of product. 'The soiids were dis-solved in 35 ml. of dimethylformamide and added drop-wise to 1500 ml. of chloroform. The precipitated solids were filtered and dried, 2.35 g. Additional second crop product was isolated'by diluting the fil-. trate with 2 1. of hexane, 1.75 g.
- The NMR spectrum (DMSO-D6) showed absorption at 20 1.42 (s, 6~), 1.55 (s, 6H), 3.1-3.95 (m, 2H), 4.42 (s, lH), 4~57 (s, lH), 4.9-5.3 (m, 2H), 5.4-5.75 (m, 2H), 5.95 (s, 2~), 6.82 (d, 2H), 7.35 (d, 2H) and 8.7-9.7 (m, 3H~ ppm.

C . . . _ 6'-(alpha-amino-p-hydroxyphenylacetamido)-penicillanoyloxymethyl penicillanate l,l-dioxide _ _hydrochloride To 35 ml. of O.lN hydrochloric acid cooled to 0C.
was added 2.15 g. of 6'-(alpha-amino-p-hydroxyphenyl-acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide. The solution was filtered and freeze dried to give 2.1 g. of the desired product.

The NMR spectrum (DMSO~D6) sho~ed absorption at 1.38 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (s, lH), 4.48 (s, lH), 4.9-5.2 (m, 2H)~ 5.38-5.64 (m, 2H), 5.84 (s, 2H), 6.7 (d, 2H), 7.24 (d, 2H), 8.3-g.2 (bs, 5 4H) and 9.4 ~d, lH) ppm~
In a similar manner, following the procedures of Example 7A-~ and starting with tetramethylammonium 6-(alpha-car~obenzyloxyaminophenylacetamido)penicil-lanate and iodomethyl penicillanate l,l-dioxide, 6'-(alpha-aminophenylacetamido)penicillanoyloxymethyl - penicillanate ljl-dioxide hydrochioride is produced.

3~3~

XP~1PLE 8 6'-(alpha-Aminophenylacetamido)peniclllanoyloxymethyl penicillanate l,1-dioxide A~
6'-(alpha-azidophenylacetamido)penicillanoyloxy-methyl penicillanate -l,l-dioxide ... . .... . _ ~
To a slurry of 5.0 g. of ~etrabutylammonium 6-(alpha-azidophenylacetamido)penicillanate in 75 ml. of _ acetone under a nitrogen atmosphere was added 3.0 g.
of iodomethyl penicillanate l,l-dioxide in 20 ml. of acetone, and the resulting reaction mixture allowed to stir at room temperature for 30 minutes. The reac~ion mixture was concentrated to a yellow oil, which was chromatographed on 80 g. of silica gel using ethyl acetate/methylene chloride (1:4 v:v) as the eluent.
Fractions comprised of 75 ml. were collected~ Fractions

2-6 were combined and concentrated in vacuo to give the desirecl compound, 4.53 g.
The NklR spectrum (CDC13) showed absorption at 1.44 (s, 3Et), 1~52 (s, 3H), 1 6 (s, 3H), 1.66 (s, 3H~,

3.4 (d, 2H), 4.4 (s, lH), 4.46 (s, lH), 4.6 (t, lH), 5~1 (s, lH), 5O4 5~7 (m, 2H), 5.88 (s, 2H), 7.18 (d, lH) and 7~37 (s, 5H) ppm.
.
B.
6'-(alpha-aminophenylacetamido)penicillanoyl-oxymethyl penicillanate 1,l-dioxide . . _ A mixture of 500 mg. of 6l-(alpha-azidophenyl-acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide and 500 mg. o 10% palladium-on-charcoal in 25 ml. of isopropanol and 12 ml. of methylene chloride ~4~3B

was sha]ced in a hydrogen abmosphere at an initial pressure of 50 psi at room temperature. After 30 min.
the reaction mixture was filtered and the filtrate concentrated to give 362 mg. of desired product as an amorphous solid.
The NMR spectrum (CDCl3) showed absorption at 1.5 (d, 5H), 1.6 (d, 6H), 3.55 (d, 2H), 4.45 ~s, lH), 4.55 (s, lH), 4.6-4.75 (m, 2H),. 5.5~5.7 (m, 2H), 5~9 (q, 2H), 7.4 (s, 4H) and 8.1 (d, lH, J=6 Mz) ppm.
In a similar manner, starting with tetrapropyl-- ammonium 6-(alpha-azido p-hydroxyphenylacetamido~peni-cillanate and chloromethyl penicillanate l,l-dioxide and following the procedures of Example 8A-B, 6'-(alpha-aminophenylacetamido)penicillanoyloxymethyl penicillanate l,l-dioxde is prepared.
.

6'-(alpha-Aminophenylacetamido)penicillanoyloxy-methyl penicillanate l,l-dioxide ~ _ . . . .
- To 3.1 g. of tetrabutylammonium Ç-(alpha-amino-phenylacetam~do)penicillanate in 20 ml. of ethyl acetate and 5 ml. of methylene chloride was added 2.0 g. of iodomethyl penicillanate l,l-dioxide in 10 ml. of ethyl acetate, and the reaction mixture allowed to stir at room temperature for 30 min. The - 10 methylene chloride was removed in vacuo and the re-sulting suspension filtered. The filtrate was treated with 25 ml. of water and the pH adjusted to 2.5 with lN
hydrochloric acid. The aqueous layer was retained and organic phase again extracted with fresh water at pH
2.5. The aqueous layers were combined, saturated with salt and extracted with methylene chloride. The organic phase was separated, dried over sodium sulfate and concentrated under- YaCuum to about 10 mI. The residual ~olution was then added to diethyl ether with stirring, and the resulting precipitate filtered and dried, 370 mg. The product was indistinguishable from that isolated in Example 8B. -Starting with tetramethylammonium 6-~alpha-amino-~-hydroxyphenylacetamido)penicillanate and chloromethyI
~5 penicillanate l,l-dioxide, and employing the above pro cedure of Example 9, 6'-~alpha-amino-p-hydroxyphenyl-acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxde is prepared.

- 2~ -E~PLE 10 6'-(2,2-Di~methyl-5-oxo-4-phenyl-1-imidazolidinyl)-peniclilanoyloxymethyl penicillanate l,1-dioxide , A solution of 470 mg. of chloro~ethyl penicil-lanate l,l-dioxide in 7 ml. of ethyl acetate is added aIl at once to a solution of 1.0 g. of tetrabutyl~
ammonium 6-t2~2-dimethyl-5-oxo-4-phenyl-l-imidazolidinyl) penicillanate in 10 ml. o ethyl acetate and 3 ml. of methylene chloride, and the resulting reaction mixt~re allowed to stir at ambient temperatuxes for 45 min.
The reaction mixture is washed successively with water and a saturated brine solution and dried over sodium sulfate. The organic phase is then chromatographed on 75 g. o silic~ gel using ethyl acetate/hexane (1:1 v:v~ as the eluent, 14 ml. cuts being taXen every 30 sec. Fractions 195-230 are combined and concentrated to give the desired product.
- By a similar procedure, st rting wi~h 646 mg. of tetrabutylammonium 6-~2,2-dimethyl-5-oxo-4-[~-hydroxy-phenyl]-l-imidazolidinyl)penicillanate and 281 mg. of iodomethyl penicillanate l,l-dioxide, 210 mg. of 6'-(2,2-dimethyl-5-oxo-4-~-hydroxyphenyl]-1-imidazolidinyl)-penicillanoyloxymethyl penicillanate l,l-dioxide was prepared.
The NMR spectrum (CDC13) showed absorption at 1.4-1.8 (m, 18H), 3.48 (d, 2H), 4.4-4.9 (m, 5H), 5.56 (d, lH), 5.9 (s, 2H), 6.64 ~d, 2H) and 7.18 (d, 2H) ppm.
.

~4~9~

' EXAMeLE 11 6'-(alpha-Azidophenylacetamido)penicillanoyl-ox~methyl pen_c_l~anate l,l--diox de To 5 ml. of dry dimethylformamide was added 424 mg.-of chloromethyl 6-(alpha-azidophenylacetamido) penicillanate followed by 474 mg. of tetrabutylammonium penicillanate l,l-dioxide, and the resul,ing reaction mixture allowed to stir at room temperature overnight~
The reaction mixture was diluted with 50 ml. of ethyl _ 10 acetate and subsequently washed with water ~3 x 15 ml.) and a saturated salt solution (1 x lS ml.). The organic -phase was dried over sodium sulfate and concentrated to a foam, which was su~sequently chromatographed on 40 g.
of silica gel using methylene chloride/ethyl acetate t4:1 v:v) as the eluent, 8 ml. fractions being col~
lected every 30 sec. Fractio~s 13~29 were combined and concentrated in vacuo to give 320 mg. of the desîre~
product which was indistinguishable from the product prepared in Example ~.

EX~PLE 12 Starting with the appropriate chloromethyl 6-substituted penicillanate from Examples 1-5 and a tetraalkylammonium penicillanate l,l-dioxide and em-ploying the procedure of ~xample 11, the following compounds are prepared:
~ '-(alpha-azido-~-hydroxyphenylacetamido~penicil-lanoyloxymethyl penicillanate l,l-dioxi-de;
6'-(alpha-caxbobenzyloxyaminophenylacetamido)peni-cillanoyloxymethyl penicillanate l,l-dioxide;
6'-(alpha-carbobenzyloxyamino-p-hydroxyphenyl-acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide;
6'-(alpha-aminophenylacetamido3penicillanoyloxy-methyl penicillanate l,l-dioxide;
~'-(alpha-amino-~-hydroxyphenylacetamido)peni-cillanoyloxymethyl penicillanate l,l-dioxide;
61-(2,2-dimethyl-5-oxo-4-phenyl-l~imidazolidinyl)-penicillanoyloxymethyl penicillanate l,l-dioxide; and 6'-(2,2-dimethyl-5-oxo-4-[~-hydroxyphenyl]-1-imidazolidinyl)penicillanoyloxymethyl penicillanatel,l-dioxide.

, .

6'-(alpha-Aminophenylacetamido)penicillanoyl-- oxymethyl penicillanate l,l-dioxide p-toluene sulfonate . .

A.
6'-(alpha-N-~l-methoxycarbonylpropen-2-yl]aminophenylacetamido)penicillanoyl-oxymethyl penicillanate 1,l-dioxide To 125 ml. of methylene chloride and 50 ml. of water was added 8.06 g. of 6-(alpha-aminophenylaceta-mido)perlicillanic acid txihydrate and the pH adjusted to 8.5 by the addition of a 40~ tetrabutylammonium hy-droxide solution in water. The methylene chloride layer was separated and the aqueous layer was extrac~ed with fresh methylene chloride (2 x 30 ml.). The methylene chloride layers were combined and dried over magnesium sulfate.
The mixture was filtered and the filtrate concen-trated in vacuo. Chloroform (300 ml.), methyl aceto-acetate (2.16 ml.) and magnesium sulfate (20 g.) was added to the residue and the mixture heated to reflux for 30 minutes. The magnesium sulfate was filtered and the filtrate concentrated under reduced pressure to give ,a, yellow foam. Treatment of the residue with 150 ml~ of-ethyl acetate gave a white solid which was filtered, washed with ethyl acetate t3 x 25 ml.~ and diethyl ether ~ x 50 ml.) and dried under nitrogen to give 6.5 g. of the tetrabutylammonium 6-(alpha-l-methoxycarbonylpropen-2-ylaminophenylacetamido)penicil-lanate~

To 1.38 g. of the above tetrabutylammonium salt in 10 ml. of dry acetone was added 1.04 g. of iodo-methyi penicillanate l,l-dioxide, and the mixture allowed to stir for 10 minutes at room temperature.
S The mixture was concentrated in vacuo and the residue chromatographed on 75 g~ of silica gel using ethyl acetate~hexane (1:1, v:v) as the eluent, 10 ml. fractions being taken every 9 minutes. Fractions 11 19 were combined and concentrated under vacuum to give 970 mg.
o the desired product.
The NMR spectrum (CDC13) showed absorption at 1.42 (s, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 1.6-5s, 3H), 1.9 (s, 3H), 3.48 (d, 2H), 3.66 (s, 3H~, 4.43 (s, lH), 4.~6 (s, lH~, 4.56-4.7 (m, 2H), 5.13 (d, lH), 5.4-5.75 (m, 2H), 5.9 (s, 2H), 6.78 (d, lH), 7.42 (s, 5H) and 9.38 ~d, lH) ppm.
B.
6l-(a~pha-aminophenylacetamido)penicillanoyl-oxymethyl penicillanate l,l-dioxide p-toluenesullonate To 346 mg. of 6'-(alpha-N-[l-methoxycarbonylpropen~
2-yl]aminophenylacetamido)penicillanoyloxymethyl peni-cillanate 1~1 dioxide in 20 ml. of ethyl acetate was added 95 mg. of p toluenesulfonic acid hydrate in 5 ml.
of ethyl acetate and 0.5 ml. of water. After several minutes the precipitate which formed was filtered, washed with ethyl acetate and dried, 290 mg.
The NM~ spectrum (DMSO-D6) showed absorptlon at 1.38 (s, 6H), 1.5 ~s, 6H~, 2.3 (s, 3H? ~ 3-05-3 9 (m, 2H),

4.4 (s, lH), 4.5 (s, lH), 4.95-5.3 (m, 2H), 5.35-5.7 (m, 2H), 5.9 (s, 2H), 7.08 (d, 2H), 7.55 (d, 2H), 7.44 (d, 2H), 8.6-9.0 (ds, 3H) and 9.4 (d, lH) ppm.

6'-(alpha-Amino-p-hydroxyphenylacetamido)-penicillanoyloxymethyl penicillanate - l,l-dioxide hydrochloride A.
6'-(alpha-N-[l-methoxycarbonylpropen-2-yl]amino p-hydroxyphenylacetamido)peni-cillanoyloxymeth~l peniclllanate l~l-dioxide To 300 ml. of methylene chloride was added 41 9 g.
of 6~(alpha-amino-p-hydroxyphenylacetamido~penicillanic acid and 50 ml. of water, and the pH adjusted to 8.5 with 40% aqueous tetrabutylammonium hydxoxide. The mixture was placed in a separatory funnel and the aqueous layer removed, saturated with sodium sulfate - -and extracted with methylene chloride from the separatory funnel and the methylene chloride extracts were combined, dxied over sodium sulfate and concen-trated to an oil which crystallized on trituration with acetone to give 44~6 g. of tetrabutylammonium 6-(alpha-amino~p-hydxoxyphenylacetamido)penicillanate~
The above salt was added to 150 ml. of methyl aceto-acetate, and the suspension heated at steam bath tempera-ture for 8 mlnutes. The mixture was allowed to cool, and the resulting precipitate was filtered and washed with methyl acetoacetate (3 x 25 ml.) and diethyl ether, ~9.25 g.
To 47 5 g. of the above salt in 250 ml. of dimethyl-formamide at 0C. was added with stirring 18~26 g. of iodomethyl penicillanate l,l-dioxide in 50 ml. of the same solvent was added over a 20 minute period. Ten 31~ 1 minutes after completion of the addition the reaction mixture was poured into 3 1. of ethyl acetate and the resulting precipitate was filtered. The precipitate was washed with ethyl acetate (100 ml~) of the washings combined ethyl acetate was washed successively with a hrine solution (4 x 500 ml.~, water (4 x 500 ml.) and a brine solution ~2 x 500 ml.) and dried over sodium sulfate. The residue remaining after the solvent was removed was chromatographed over 750 g. of silica gel using ethyl acetate as the eluent. The fractions (250 ml. each) 2-5 were combined and concentrated to give the product, 31.2 gO
The NMR spectrum (DMSO-D6, lH 100.1 M Hz) showed absorption at 1.37 (s, 3~), 1.38 (s, 3H), 1.48 (s, 3H), 1.57 (s, 3H), 1.76 (s, 3H), 3.14-3.82 (m, 2H), 3.51 (s, 3H), 4.42 (s, lH), 4.44 (s, lH), 4.54 (s, lH), 5.1-5.22 (m, lH), 5.3-5.64 (m, 3H), 5.9 (s, 2H), 6.7 (d, 2H), 7ql4 (d, 2H), 9.02 td, lH), 9.24 (d, lH) and 9.34-9.54 (bs, lH) ppm.

~.
6'-(alpha-amino-~-hydroxyphenylacetamido)-penicillanoyloxymeth~l penicillanate 1,1-_ dioxide hydrochloride~
To 31.1 g. of 6'~alpha-N-~l-metho~ycarbonyl-propen-2-yl~amino-p-hydroxyphenylacetamido)penicil-lanate l,1-dioxide in 250 ml. o acetone cooled to 0C.
was added 439 ml. of 0.1 N hydrochloric acid. After 5 minutes of stirring the acetone was removed in vacuo and the a~ueous was extracted ~ith diethyl ether (3 x 700 ml.). The aqueous layer was separa-ted, filtered through super cel and freeze dried to give 23.1 g. of the desired product.

The NMR spectrum (DMSO-D6) showed absorption at 1.38 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (sr lH), 4.48 (s, lH) 409-5.2 (m,.2H), 5.35-5.64 (m, 2H3,

5.87 (s, 2H), 6.7 (d, 2H), 7.24 (d, 2H3, 8.3-9.2 (bs, 4H3 and 9.4 (d, lH) ppm.

9~ I

EX~MPLE 15 67~(alpna-Aminophenylacetamido~penicillanoyl-oxymethyl penicillanate l,l-dioxide p-tGluene-sul~onate .. . . . .. . .

A~
chloromethyl 6-(alpha-1-methoxycarbontyl-propen~2-ylaminophenylacetamido)-_ penicillanate _ .
~ To 125 ml. of methylene chloride and 50 ml. of water was added 8.06 g. of 6 (alpha-aminophenylaceta-mido)penicillanic acid trihydrate and the pH adjusted to 8.5 by the addition of a 40~ tetrabutylammonium hy-droxide solution in water. The methylene chloride layer was separated and the aqueous layer was extracted with fresh methylene chloride ~2 x 30 ml.). The methylene chloride layers were combined and dried over magnesium sulfate.
The mixture was filtered and the filtrate concen-trated in vacuo. Chloroform (300 ml.), ethyl aceto-.
acetate ~2.16 mlD ) and magnesium sulfate (20 g.) was added to the residue and the mixture heated to reflux for 30 minutes. The magnesi~m sulfate was filtered and the filtrate concentrated undex reduced pressure to give a yellow oam. Treatment of the residue with 150 ml. of~ethyl acetate gave a white solid which was filtered, washed with ethyl acetate (3 x 25 ml.) and diethyl ether (2 x 50 ml.) and dried under nitrogen to give 6.5 g. of the tetrabutylammonium 6-(alpha-1-methoxycarbonylpropen~2-ylaminophenylacetamido)peni-cillanate.

3~3 To 15 ml. of chloroiodomethane was added 1.38 g of the tetrabutylammonium salt, and the resulting mix-ture allowed to stir for one hour at xoom temperature.
The reaction soluticn was subseque~tly chromatographed on 75 g. silica gel using ethyl acetate/hexane (1:1, v:v) as the eluent, 50 mlO cuts being made. Fractions 4-6 were combined and concentrated to give 800 mg. of the desired product The NMR spectrum (CDC13) showed absorption at 1.5 (s, 3H), 1.57 (s, 3H), 1.9 (s, 3H), 3065 (s, 3H), 4.4 (s, 1~)l 4.65 (s, lH), 5.12 (d, lH), 5.42-5.7 (m, 2H), 5.75 (dd, 2H), 6.8 (d, lH), 7.4 (s, 5H) and 9.35 (d, lH) ppm.

B.

6'-(alpha-Aminophenylacetamido)penicillanoyl-o~ymethyl penicillanate l,l-dio;xide p-toluenesulfonate , A mixture of 496 mg. of chloromethyl 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenylacetamido~peni-cillanate and 750 mg. of sodium iodide in 10 ml. of acetone was allowed to stir at room temperature over-night. The solvent was removed in vacuo and the residue extracted with 40 ml. of ethyl acetate. The extract was washed successively with water (3 x 10 ml.) and an aqueous saturated sodium chloride solution ~2 x 5 ml.), and then dried over sodium sulfate. lhe oil xemaining (700 mg.) after the solvent was removed was triturated with petroleum ether to give iodomethyl 6-(alpha l-methoxycarbonylpropen-2-ylaminophenylacetamido) penicillanate as a solid.
A mixture of 590 mg. of iodomethyl 6-(alpha-1-methoxycarbonylpropen-2-ylaminoacetamido)penicillanate - 3~ -and 474 mg. of tetrabutylammonium penicillanate sulfone was allowed to stir in 10 ml. of acetone for 20 minutes.
The reaction mixture was concentrated to dryness and the residue treated with 40 ml. of ethyl acetate. The resulting precipitate was filtered, and the filtrate washed with water ~3 x 10 ml.) and a brine solution (2 x 5 ml.). The dried organic phase was concentrated to about 20 ml. and was treated with 190 mg. of p-toluenesulfonic acid monohydrate and 2-drops of water in 5 ml. of ethyl acetate. Stirring was continued for 3-4 minutes at which time a precipitate formed. After stirring for 10 minutes the desire~ product is filtered and dried, 520 mg.
The product is indistinguishable from that obtained in Example 13.

3~
. .
EX~MPLE 16 Chloromethyl 6-~alpha-1-methoxycarbonylpropen-2-ylaminophenylacetamido)penicillanate To 400 ml. of bromochloromethane at -10C. was added 20 g. of tetrabutylammonium 6-(alpha-1-methoxy-carbonylpropen-2-ylaminophenylacetamido3penicillanate and the reaction mixture allowed to stir at -10 to 0C.
for 6 hours and allowed to stand at room temperature overnight. The mixture was concentra~ed in vacuo and ~ 10 the residue chromatographed on 500 g. of silica gel using ethyl acetate-hexane (80:20, v:v) of the eluent~
~he fractions containing the product were combined and concentrated to a oam, 14.4 g.
- The product was essentially the same as that pre-pared in Example 15A.
Starting with bromochloromethane in place o~ iodo-chloromethane in Examples l through 5 gives the corres-ponding chlorometn~l esters.

' ,

Claims (13)

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

1. A process for the preparation of a compound selected from those of the formula wherein X is selected from the group consisting of a) and b) wherein R1 is selected from the group consisting of azido, amino, carbobenzyloxy-amino and 1-methylcarbonylpropen-2-ylamino and R2 is selected from the group consisting of hydrogen and hydroxy, which comprises (a) contacting one mole of a compound selected from those of the formula wherein Y is selected from the group consisting of chloro, bromo and iodo, with at least one mole of a compound selected from those of the formula wherein R3 is alkyl having from one to four carbon atoms in a reaction-inert solvent at ambient temperatures, or (b) contacting one mole of a compound selected from those of the formula with at least one mole of a compound selected from those of the formula wherein R3 is alkyl having from one to four carbon atoms and Y is selected from the group consisting of chloro, bromo and iodo, in a reaction-inert solvent at from about 0° to about 60°C.

2. A process for the preparation of a compound selected from those of the formula wherein X is selected from the group consisting of a) and b) wherein R1 is selected from the group consisting of azido, amino, carbobenzyl-oxyamino and 1-methylcarbonylpropen-2-ylamino and R2 is selected from the group consisting of hydrogen and hydroxy, which comprises contacting one mole of a compound selected from those of the formula wherein Y is selected from the group consisting of chloro, bromo and iodo, with at least one mole of a compound selected from those of the formula wherein R3 is alkyl having from one to four carbon atoms in a reaction-inert solvent at ambient temperatures.

3. The process of claim 2, wherein the reaction-inert solvent is selected from the group consisting of acetone and dimethylformamide.

4. The process of claim 3, wherein X is wherein R2 is hydrogen, Y is iodo and R3 is n-butyl.

5. The process of claim 4, wherein R1 is azido.

6. The process oE claim 4, wherein R1 is amino.

7. The process of claim 4, wherein R1 is methoxycarbonylpropen-2-ylamino.

8. A process for the preparation of a compound selected from those of the formula wherein X is selected from the group consisting of a) and b) wherein R1 is selected from the group consisting of azido, amino, carbonemzyloxyamino, and 1-methoxycarbo]lylpropen-2-ylamino and R2 is selected from the group consisting of hydrogen and hydroxy, which comprises contacting one mole of a compound selected from those of the formula with at least one mole of a compound selected from those of the formula wherein R3 is alkyl having from one to four carbon atoms and Y is selected from the group consisting of chloro, bromo and iodo, in a reaction-inert solvent at from about 0° to about 60°C.

9. The process of claim 8, wherein the reaction-inert solvent is selected from the group consisting of acetone and dimethylformamide.

10. The process of claim 9, wherein X is wherein R2 is hydrogen, R3 is n-butyl and Y is chloro.

11. The process of claim 10, wherein R1 is azido.

12. The process of claim 10, wherein R1 is amino.

13. The process of claim 10, wherein R1 is 1-methoxycarbonylpropen-2-y-lamino.