A convenient method for the esterification of cephalosporanic acids

Letters NO. 33, pp 2915 - 2916, lm.

‘fetr&edron

A CONVENIENT

METROD

Pergunon Pceee. printed in Great Britain.

FOR THE ESTERIFICATION

CEPHALOSPORANIC

Shigeo

Satoru

Seki,

Nakabayashi:

and Shunzo Central

OF

ACIDS

Niehihata,

Ken

Nobuo

Ito

Fukatsu

Research

Laboratories,

Morooka,

Kohoku,

Heiji

Yokohama

Seika

Kaisha

Ltd.,

222, Japan

(Received in Japan 2 June 197; reoeived in UK for publication r(Jme Eeterification associated A3-ester

with

double

converted

to the A3 -estera

communication isomerization.

A3 -esters

sulphur

dioxide,

acid salt anions

solution)

in high

strongly

yield

present

the products

desirable.

for preparing

A3-ester

as solvent

activated

of base

equilibrium

dioxide,

alkyl

is

waa added

identified

halides

and

in liquid

and refluxed

to A3-esters

authentic

for 2%5

and probed

eamplea.(TLC

bond

Wh en

is ieomerized

exess

bases

in the esterification

to

and NMR)

by cephem

that

of the pure

hand,

mixture

A3-esters

were

obtained,

isomerization

in dichloromethane

did not proceed

carbo-

and cephaloeporanic (ex. in DMF

free of any A2-isomers. 3)

such as triethylamine,

mixtures

on the other

noteworthy

halides

without

for eeterifi-

alkyl

acid and triethylamine

double

are largely

solutions

It

and

In this

dioxide, we assumed, the base and acid anion solvated 4) and so do not cause ieomeriaation of the double

A2-A3

can be

so, an efficient

sulphur

two equivalents

with

and A2-eaters

is clearly

dioxide

halide

with

or base. 1),3)

dichloromethane

sulphur

were

that the cephem itself

When

bases.

And

must

in the table.

with

or DBN,

chromatography

eulphur

by a comparison

are never

In liquid

be isolated

salts with

eq. of alkyl

are summarized

It is known

of the

isomers

in good yield.

1.2*2.0

The products

The results

acid

problems

in a mixture

a new method

liquid

presents

A3 -cephem

of A3 -esters

to report

often

resulting

the eulphoxide.2)

of cephalosporanic

be free of A2 -esters

acid

via

Thus we used

To a solution

xylic

or elution

of A3 -cephaloeporanic

obtained

hrs.

The desired

for preparation

we wish

acid salts

ieomerixatlon

crystallization

procedure

cation

bond

and the A2-ester.i)

by fractional

simple

of A3 -cephaloeporanic

1977)

after

2915

were

stirred

are bond.

at -10'~

A-dimethylaminopyridine respectively. did not occur

esterification

a day and when

In liquid with of acid

the equivalent

these salts

2916

a.

volume

of liquid

started

dioxide

was added

in the solution

the reaction

immediately.

It seems high

sulphur

33

that such strong

solubility

-75.5"~)~)

of organic

make

sulphur

of cephalosporanic

ionizing

compounds

dioxide

power,5)

and broad

suitable

highly

liquid

solvent

selective

range

solvation,

(b.p.-10°C

% m-p.

for use of esterification

acids.

R’ Table

A3-Cephalosporanic

NO

Acid

R"X

R'

R

Esters')

(halide)

Yield%

m.n.

Oc

OAc

(C6H5)2CHC1

"85

173-175

OAc

(C6H5)2CHC1

89

142-143

3

p-CH30~C6H4'CH2C1

59

150-151

4

p-02N'C6H4'CH2Br

47

154-156

5

C6H5COCH2Br

74

177

6

CH3C02CH2Br

60

144-145

7

CH3C02CH21

84

(C6H5)3CC1

68

181

CH30CH2C1

98

110-111

C6H5COCH2Br

82

171

1

H02C~~H(CH2)3C0

2

8

C6H50CH2C0

H

9 10

*

di-ester

References

1)

'%ephalosporins New York.,

2)

G.V.Kaiser,

3)

P.H.Bentley,

4)

N.Tokura, S.G.Smith,

6)

All

and E.M.Van G.Brooks

Synthesis,

R.E.Koehler,

Heyningen,

ed., Academic

639

C.F.Murphy,

.J.Org.Chem., 35

and I.I.Zomaya,

A.H.Fainberg

compounds

E.H.Flynn,

Press,

~172

R.D.G.Cooper,

I.G.Wright

5)

and penicillins",

1972.

Tetrahedron

J.A.Webber, 2430

(1970)

Lett.,

3739

(1976)

(1971) and S.Winstein,

had satisfactory

analytical

J.Amer.Chem.Soc., and spectroscopic

-83 618 (1961) data.