6-Substituted penicillin derivatives, VI

?etrahedron

Letters

Fo. 2, pp 145 - 148,

6-SDBSTITUTED

(:ieceived in TSA 13 October In the course

can be generated Schiff

This

condensation

nucleophilic

to give after

or mono-substituted(')

preparation

of additional

a carbon

N,N-diisopropylethylamine

which

turned

major

isomer

6, cm_,:

after

isolated

through

ba-cyanoethyl downfield, upfield,

found pounds

three

Pen-V,

before

with

IIIa

structure

(14% yield)

nitrile

Ib were crystalline

(m.p. 188-191°

identical

Ib).

lack the absorption

but have new absorption

containing

characteristic

M_=N-;

of the vinyl

near 4.6 ppm as well as complex

afforded 5-H;

from

sodium 2.38m

the column

Michael

respectively) spectra

hydrogen

phenoxyacetyl-

3.19s and 3.21s

eluted

(CDc13)

ir

carried

(4)

downfield,

CHHCH-ICN;

The

M+. 492,

when

ester

the expected

The nmr

chroma-

Ib (nmr, T-60,

base reversal,

and 231-233',

145

structure

which were

solution

compounds.

This material

0.77s

in t-butanol

upon fractional

of the benzyl

(8% yield)

mass spectra.

the

the side-chain

blue-green

5-H and 8.92s,

materials

and after

in which

of acrylonitrile

product

3-H; 2.05s upfield,

isomeric

unsub-

We here report

gave an initially

[nmr, D20, ppm from DOH:

The other

to have nearly

an excess

5.68s,

3-H;

alkylation

the corresponding

and was assigned

and then hydrogenolysis

0.445 upfield,

C(CHH)2].

isomeric

site

state.

described (132) steps of Schiff

(495)

aromatic;

immediately product

consistent

to undergo

derivatives

The reaction

15 minutes.

(18%) was a glass

the previously

ation to give IIa

with

nucleophilic

(7-aminocephalosporanic

reactions

oxidized

reacted

2.77s, cH_22cH_2CN;4.58s,

and other nmr peaks

or 7-ACA

penicillin

penicillins

of the nitrobenzaldehyde

can be induced

subsequent

as a catalyst

gel) afforded

6a-substituted

alkyl APA or ACA derivatives.

Ia when

using

(silica

center

6-substituted

base

yellow

VI

that a reactive

treatment

acid)

atom in a more highly

The Schiff

tography

by base

(6-aminopenicillanic

stituted(')

contains

toward preparing

(l-3) it was found

at these positions

acid) esters. (192)

DERIVATIVES,

1972; received in 9'K for publication 11 I!ecember 1972)

of work directed

cephalosporins

base of 6-APA

or aldol

PENICILLIN

Printed in !%eat Britain.

Press.

G. H. Rasmussen, G. F. Reynolds and G. E. Arth Chemical Research Department, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065

Synthetic

and 7a-substituted

Perymon

1973.

addition

and were of these com-

of the Schiff

absorption

base

in the region

No.

146

2.5-3.5

ppm.

(partially

For both compounds

obscured

and another

structure

by the 3-H singlet)

single proton

and deuterium

exchange

IV.

the hydrogen

(atN3.0

was found

(6)

These

each pair,

the orientation stituents

respectively)

on the pyrrolidine afforded

and 2.10d downfield, 1.3-2.4m

upfield,

aromatic;

0.85s

Pen-V

9.62s,

-m-O;

of formaldehyde formyl

5-H;

4.65s,

tained by the corresponding Condensation Ids)

which

purified

was converted

and acetyl

(8)

when

subjected

upfield,

G-trimethylsilyl

additional

in

to

2.59d

3-H + N-of-; derivative

show highly

compounds

in which

of alcohols

Thus,

oxidation

bicarbonate

the added

obtained

oxidation

has given (2)

Pen-V,

IIIc,

product

of the benzyl

IIb

[nmr, 6,

CDCl

3

:

VIb has been ob-

(435)

Via.

(2)

derivative

which

could be

group of IIb in the presence

gave sodium 6a-(a-hydroxyethyl) 5-H;

Ia

of pyridine-

the crude a-hydroxyethyl

to the intermediate

0.81s downfield,

via -

of 6-hydroxy

of the 7a-hydroxymethylcephalosporin

Hydrogenolysis (2)

6-formyl

The analogous

-cHtol.

interesting

with the Schiff base

derivatives.

afforded

in two steps

by chromatography.

[nmr, D20, ppm from DOH:

C(CH,)2;

1.42,

of the two sub-

ppm from DOH:

0.43s+m

(2) and acetaldehyde

of la with acetaldehyde

of one mole of sodium

product

of

do not differ

dimethyl sulfoxide (DMSO) in the presence

and triethylamine

5.87s,

5-H;

The oxidation

withdrawing.

(2) with (IIIb)

sulfur trioxide

(1.43, 1.56;

they probably

and 7-methoxycephalosporins

we were led to prepare

afforded the corresponding methyl

in the nmr position

4.43 and 5.16~1.

was electron

aldol condensation

by spin decoupling

groups

crystalline

downfield,

an NH

the Spiro-pyrrolidine

V [nmr, D20-NaHCC3,

cX2CJ-iand 3.15s upfield,

activity

with both

but only in the orientation

The major

ring.

As 6-methoxypenicillins

functionality

for each compound

the zwitterionic

had M+' of 516; ir, mull:

antibiotic

data suggest

and -gem-dimethyl

(1,2,7)

of the 6-nitrogen

hydrogenolysis

to be coupled

as there is only a small difference

the 5-H (5.54 and 5.37 ppm, respectively) 1.57 ppm;

in the region of 4.6 ppm

and 3.36 ppm, respectively)

experiments.

Inasmuch

absorbing

0.42s upfield,

3-H;

Pen-V,

IIId,

3.22s upfield

DMSO oxidation of IIId failed, but the chromium C(Cli,) and 3.39d, J = 7Hz, CHCH3]. 2 (9) oxidized IIb in near quantitative trioxide-pyridine complex in methylene chloride (495) yield to give 11~. Pen-V, CH&Q@;

IIIe,

Hydrogenolysis

[nmr, D20, ppm from mH;

0.35s upfield,

2

as described

above

1.18s downfield,

3-H; 2.29s upfield,

cH_3cO;

then gave sodium

5-H;

6a-acetyl

0.13s downfield,

3.17s and 3.23s upfield,

147

No. 2

wq21.

The corresponding

to give compound

steps have been carried

out in the cephalosporin

series

VIc.

Reaction propylethylamine

of Ia with methyl

as base

resulted

chloroformate

in acetonitrile

in a crude mixture

from which

with N,N-diiso-

impure

Id

(5)

could

(495) be isolated which

by chromatography.

could be further

acidification 5-H;

of reactions

[nmr, 6,

has been assumed isomers

Ia and benzyl

downfield,

of all introduced

in the examples

some bioactivity

The penicillins

IIIg

5.58s,

[nmr, D20, ppm

5-H, 1.31s upfield,

substituents

above

in the cases cited above

presented although

elsewhere.

p-isomers.

supports

III have

Compound more active

However,

the supposition

all been activity

tested

yields

have resulted

of a-side

against

in

attack.

B. subtilis

by the agar

is III‘cwIIIe

The cephalosporin

than the corresponding

No

the fact that the final

of the compounds

V is inactive.

(1,2,7)

the low isolated

of IIIf and IIIg could possibly

The relative

IIIb>IIIfXIIIg>IIId. and VIc are slightly

Pen-V,

0.52s upfield,

on the arguments

the preparation

disc assay.

7.lm, aromatic;

; M+' 4081. A similar 2 chloroformate gave the corresponding

6-carboxy

aromatic;

of the less favored

have

disodium

then gave after

c(CH,)~].

were found

the separation

with

to be a- based

with

CDC13:

starting

The orientation

diffusion

IIIf,

1.75s and 1.64s, C((X3)

3-H and 3.13s upfield,

products

Pen-V,

of Id gave IId

Hydrogenolysis

3.92s, "_3o;

2.10 to 2.90m

experienced

by chromatography.

and final product,

Ie,

other

transformations

%";

(495) IIe(4,5) from DOH:

purified

6a-carbomethoxy

4-55s*

series

Subsequent

penicillins

>IIIa%

derivatives

VIb

111~ and IIIe.

References 1.

R. A. Firestone, hedron --

2.

Paper

Letters,

4.

Letters,

and B. G. Christensen,

Tetra-

R. A. Firestone

and B. G. Christensen,

for publication.

T. R. Beattie

and B. G. Christensen,

J. Am. Chem. z., _--

(1972).

The materials They were

S. M. Schmitt,

submitted

L. D. Cama, W. J. Lean%, 94, 1408

D. B. R. Johnston

375 (1972).

D. B. R. Johnston,

V;

Tetrahedron 3.

N. Schelechow,

isolated

also uniformly

at this stage exhibited pure as judged

satisfactory

nmr and ir spectra.

by thin layer chromatography.

No. 2

5.

These materials

gave the appropriate

showed fragmentation mass

spectrographic

isomers 6.

analysis

IV verified

Data were obtained Arisen

7.

of

characteristic

for carrying

E. H. W. B&me,

molecular

of penicillin

of the molecular

the elemental

on a HR-100

2,

4324

8.

J. R. Parikh

and W. van E. Doering,

9.

R. Ratcliffe

and R. Rodehorst,

R

We are indebted

to Dr. B.

J. E. Dolfini

and J. J. Gougoutas,

(1971). J. Am. Cbem. E., ---

J. -Org.

Chem., 2,

4000

2,

5505

(1967).

(1970).

R I

R !

C6H50CH2CONH

p02NC6H4

resolution

these experiments.

B. Toeplitz,

s.,

High

and

of these materials.

spectrometer.

out and interpreting

J. Am. e. --

derivatives.

spectrometer

ions of Ib-c, IIa-e and both

composition

Varian

H. E. Applegate,

ion in the mass

v

CO2CH2C6H5

C02H or Na

C02CH2C6H5 IaR=H b R = CH2CH2CN c R = CHOHCH 3 d R = C02CH3 e R = C02CH2C6H5

IIa b c d

R R R R

= = = =

CH2CH2CN CHOHCH3 COCH3 C02CH3

e R = C02CH2C6H5

IIIa R = CH2CH2CN b R = CH20H c R = CHO d R = CHOHCH3 e R = CKH3 f R = C02CH3 g R = C02Na

NC

NC

H2NC6n4

02NC6H4

IV

C02H

V Via R = CH20H b R = CHO c R =

co3 3