Synthesis of 7α-substituted cephalosporins Part IV. Novel synthesis of 7α-methylcephalosporins

Tetrahedron Letters No. 21, pp 1815 - 1816, 1976. Per-on

SYKTHESIS

OF 7a-SUASTITUTEU

NOVEL

SYKTHESIS

Hiroaki Central

Research

Press.

Printed in Greai.Britain.

CEPHALOSPCRINS

PART

IV.

OF 7a-MRTHYLCEPHALOSPORINS

Yanagisawa

Laboratories,

and Hideo

Sankyo

Kakao

Co., shinapawa,

Tokyo,

Japan

(Received in Japan If March 1976; received in UK for pubzication 12 April 1976) In the search vestigating

for useful

the reaction

At this

time we would

derived

from

tion

C-7

attack

conjugated

water

acetate

in I, and not on the cephcm

and then

with

afforded

in acetone

the mixture

products

gel column

of the amines,

by silica gel column chromatography , [20.2-A from I; dLDCl 3 1.54 (C-7 CH3), 4.52

1.43

(C-7 CH3),

chloride

gave

4.54

(C-4 H)] 1

IVa and IVb, respectively:

(C-6 H)] ; IVb [83$; dCDCl 3 methyl

group

of IVa with

1.53

1723,

1700 cm

-1

chromatography

;d DMS"-d6

with

(ethyl bases

acetate

(IIa

3n' hydrochloric

and IIIb, which

IVa [95:O;o/cDc1 3 5.06

acid

(C-6 H)J .

afforded

- benzene):

were JIIa

phenylacetyl

1.82

1.93

(C-7 CH3),

Removal

4.77

of diphenyl-

7ti-methyl-7-phenylacet-

61$, mp 103+135'(d);

(C-7 CH3),

1815

Schiff

wasbinp

(C-C, H)] ; IIIb c4.6;: from I;dCDC'3

acid 2c) [Va; 1.63

IIIa

(ethyl

acetate,

of IlIa and IIIb with

(C-7 CH3),

t,rifluoroacetic

amido-3-deacetoxycephalosporanic 1775,

Acylation

the

in THF at -7t3' for

of 7u- and 7F-methyl

separated

with

on the quinoidal

ethyl

of IIa an d IIb was hydrolyzed

to give the mixture

al!iyl

nucleus.

of the reaction by silica

of

deals

nucleophile,

bromide

The mixture

58%).

bark

1 eq. of mcthylmagnesium

purification

method 2) for prepara-

substitution

Cur present

a strong

in-

nucleophiles 1)

various

known

electronhilic

reagent,

- benzene)

and IIb;

employed

been

of 7-methylcephalosporins

The previous

reagent.

of a Grignard

by dilution

(I) with

the synthesis

car'sanions.

of Ia with

1 hr followed

crpl~nlosporir~s, ~%'ehave

derivative

cephalosnorin

system

Treatment

acid

like to report

I and a Grignard

with

selective

with

of a quinoid

of 7-atkylcephalosporins

halides

7-substituted

(C-3 CH3)?

JEiiol 3.29

3300,

(C-2 H),

1816

No. 21

3.49

(C6HsCY2),

4.78

Configuration major

product

(C-h H), 7.22

at C-7 was

(IVa) gave

C-7 NH interactions,

(C6Y5CH2),

confirmed

8.62

respectively,

while

values

by IOE

17 and 0% ?;OE values

(NH)). of IVa and IVb.

The

for C-6 H - C-7 CH3 and C-6 H -

IVb gave

5 and 4% h:OEs for the same

intera,ctions. By this methylation CH3), were

4.82

sequence

Vc [mp

(C-G H)] and Vd [powder,

successively Compounds

Staphylococcus

dDMSoed6

145-146'(d),

dDMSo-d6

1.66

(C-7 CH3),

1.64 4.87

(c-7 (C-6 H)]

produced.

Va, Vc and Vd showed aureus

209P,

WIC

of 200, 25 and 12.5 g/ml against

respectively.

References

1)

H. Panagisawa, 2735

2)

M. Fukushima,

A. Ando and H. Nskao,

H. E. Applegate,

Gougoutas,

Chem.

J. Amer.

n. Schelechow,

Sot., 93,

D. B. K. Johnston

(c)

(1972).

E. H. W. Bohmc,

Y. S. Puar

Funke,

B. Toeplitz, 4324

J. E. Dolfini

(1971).

and B. G. Christensen,

J. Org.

Tetrahedron

J. R. Ewing,

H. E. Applegate,

and J. E. Dolfini,

“IN 0

Chem.,

33,

230

m

CHIR

N

COOCHPh,

EL:

III

T-: a:

R=H;

c :

R=OAc

7y-CH, ;

7&-CH

1

b:

R=

d:

R=

H

:

and J. 2.

(b) R. A. Firestone,

C”J

c

Lett.,

jhiti., 259 (1976).

(1975);

(a) h. H. W. Bohme,

375

Tetrahedron

R’ = CHPh, R’=

H

76 - CH,

ri--N -s$% kH,

;

7=-C”,

P. T.

(1973).

Lett.,