Peniciline Metode de obinere

1. Biogeneza penicilinelor naturale i biosinteza dirijat

HOOC-CH-CH2-CH2-CH2-COOH NH2 acid alfa-aminoadipic

NH2 CH COOH

SH

+
H2N

CH3 CH CH3 COOH L-valina

L-cisteina

HOOC-CH-CH2-CH2-CH2-CO-NH NH2 transacilare Adicilina N O

CH3 CH3 H COOH penicilinamidaze

R-CO-NH

CH3 CH3 H N O COOH peniciline naturale

precursori ai catenei H2N laterale O

S N

CH3 CH3 H COOH

6-aminopenicilin
1

2. Sinteza total: - teoretic:

R-CO-NH CHO O OH HS CH3 CH3 H2N H COOH - H2O

R-CO-NH O N H

CH3 CH3

DCCI Penicilina

acid penaldic

D-penicilamina C6H11-N=C=N-C6H11

OH acid peniciloic

- H2O H COOH

DCCI - diciclohexil-carboiimida

- n realitate:
H3C CH3 COOH O N O 1. N2H4 2. HCl CH-CHO + HS H2N CH3 1. CH3-COONa CH3 2. separarea izomerilor H COOH O N O C6H5-O-CH2-COCl trietilamina S C6H5-O-CH2-CO-NH-CH (CH3)3COOC C6H5OCH2CO-NH KOH DCCI N H S NH CH COOC(CH3)3 CH3 CH3 COOH

COOC(CH3)3 H3C CH3 COOH S NH

D-penicilamina

H2N CH COOC(CH3)3 HCl piridina

CH3 CH3 H COOK

S C6H5-O-CH2-CO-NH-CH N COOH H

CH3 CH3 COOH

N O Penicilina V (sare potasica)

3. Semisinteza penicilinelor Dezacilarea enzimatic: penicilinamidaza Dezacilarea chimic:

C6H5-O-CH2-CO-NH N O fenoximetilpenicilina ClSi(CH3)3 PCl5 C6H5-O-CH2-C=N Cl O C6H5-O-CH2-C=N OC4H9 O N S CH3 CH3 H COOSi(CH3)3 N S CH3 CH3 H COOSi(CH3)3 H2O H2N N O S CH3 CH3 H S CH3 CH3 H COOH tautomerie C6H5-O-CH2-C=N OH O N S CH3 CH3 H COOH

n C4H9OH

COOH acid 6-aminopeniciloic

Acilarea a acidului 6-aminopenicilanic:

RCOOCOR1 RCO-Cl R-CO-NH N DCCI RCOOH 3 O S CH3 CH3 H COOH

H2N N O

CH3 CH3 H COOH

acid 6-aminopeniciloic

Stabilitatea i reactivitatea Degradri enzimatice

H H penicilinamidaze H H R-CO-NH N O S CH3 CH3 H COOH H2N N S CH3 CH3

H O COOH acid 6-aminopenicilanic H H CH3 CH3 H COOH

penicilinaze

R-CO-NH O OH N H

acid peniciloic

Degradarea n mediu alcalin

R-CO-NH N O R-CO-NH CHO O + OH - CO2 S CH3 CH3 H COOH HS H2N CH3 CH3 H COOH OHR-CO-NH N H S CH3 CH3 H+ t0C

H O OH COOH acid peniciloic

acid penaldic

D-penicilamina R-CO-NH-CH2-CHO peniloaldehide

Degradarea n mediu acid

S N CH3 CH3 S N H CH3 CH3 H COOH

C6H5-CO-NH O

H+ stomac

H COOH Penicilina G COOH N S N acid penilic CH3 CH3 H COOH

C6H5-CO-NH O

OH acid peniciloic

OH C6H5-C=N O OH N H S

C6H5

CH3 CH3 H COOH

C6H5 O

N N

HS

CH3 CH3 H COOH

C6H5 O

N N H

CH3 CH3 H COOH

O acid penicilenic

Identificarea chimic
Reacia cu ninhidrina
S N O CH3 CH3 H COOH O OH + O ninhidrina O OH OH O + 2 NH3 + HO O - 3 H2O O N NH4O colorant indaminic (violet) O OH O hidrindantina O O OH + NH3 + CO2 + R-CO-NH HCl O CHO + OH HS H2N CH3 CH3 H COOH

R-CO-NH

Penicilina HS H2N CH3 CH3 H COOH

acid penaldic O

D-penicilamina CH3 CH3 CHO

HS

D-penicilamina

Reacia de formare a acizilor hidroxamici

S N O Penicilina S CH3 CH3 H COOH CH3 CH3 H COOH Fe FeCl3 S CH3 CH3

R-CO-NH

OH-

R-CO-NH

H+ NH2OH CH3 CH3 H COOH

N H O OH H COOH acid peniciloic R-CO-NH N O NH O S

R-CO-NH

N H O NH-OH

acid hidroxamic

violet