Sản xuất chất kháng sinh CEPHALOSPORIN

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Nội dung Text: Sản xuất chất kháng sinh CEPHALOSPORIN

III. Sản xuất chất kháng sinh
CEPHALOSPORIN
1. Giới thiệu chung
2. Phân loại Cephalosporin

Cephalosporin thế hệ 1

Cephalosporin thế hệ 2

Cephalosporin thế hệ 3

“Cephalosporin thế hệ 4”
3. Cơ chế tác dụng
4. Sản xuất cephalosporin


• Sinh tổng hợp

• Bán tổng hợp
Sinh tổng hợp từ
Cephalosporium acremonium




Cephalosporin C được sx bởi Paecilomyces persicinus
(Amato et al, 1976); Steptomyces clavuligerus
(Aharonowitz and Demain, 1977); Acremonium chemostat
(Karaffa et al, 1996)
Bán tổng hợp
Bán tổng hợp


• 1. Từ penicilin




• 2. Từ Cephalosporin C
7-ADCA. The old process
• In the old process the penicillin nucleus is
obtained via fermentation.
• Six chemical transformations were
necessary to selectively convert peniccilin
G into 7-amino-desacetoxy-cephalosporic
acid.
1st generation 7-ADCA proces:
step 1
1970-1990


OH
O

NH
+ S CH3
micro-organism, i.e. O

a " multi-enzyme reactor "
MOLASSES CH3
N
O
+
O
N,S NUTRIENTS HO




Penicillin G is produced by fermentation in the presence of
phenylacetic acid (This side -chain makes isolation easier than the
natural side-chain)
Step 2. Oxidation of sulfur

-
O
NH NH +
S S
CH3 CH3
O O

CH3 C H3
N N
O O
peracetic acid
O O
HO HO



Oxidation of sulfur with peracetic acid to create the sulfoxide.
This is necessary to create a leaving group.
Step 3. Acid protection

-
O
-
O NH +
NH S CH3
+ O
S CH3
O
CH 3
N
CH3
N
O
O
trimethylsilyl chloride O
H3C
O O
H3C
in dichloromethane
HO Si
H3C




To prevent intereference of the acidic group in the next chemist ry
it is protected as a trimethylsilyl ester.
Treatment with water will restore the acid group.
Step 4. Ring expansion

-
O
NH NH
+
S S
CH3
O O

CH3
N N CH 3
pyridine HBr
O O
CH3
O O
H3C H3C
Si
O O
H3C
Si H3C
H3C



The rearrangment of the sulfoxide to the ring -expanded product is
catalysed by a very mild acid: pyridinium.HBr salt.
The catalyst ends up in the waste stream.
Step 5. Conversion of amide
into chloroimidate

N
NH
S
Cl
S
O
PCl5 CH2Cl2
N
N CH3
CH 3 -40 °C O
O CH3
CH3 O
H3C
O
H3C Si
Si O
O
H3C
H3C




To split off the amide group a selective reaction is needed that can
discriminate between the amide group and the beta -lactam (a cyclic
amide) group.
Stap 6. Reaction with BuOH
H3C


H3C



O
NH
N
S
S O
Cl

N
N CH3 C H3
O
O
CH3
CH3
O
O H3C
Butanol,
H3C Si
Si O
O
dichloromethane, - 40 C H3C
H3C




It is still not possible to hydrolyse the chloro -imidate selectively. It
needs to be converted into a highly labile ortho ester derivativ e
which can be hydrolysed at low temperature ( -40 °C).
Step 7. Hydrolysis
H3C H3C


H3C
H3C



O OH
NH
O
S
O
O
H2N
S
N
CH3
O
CH3 N
Water, butanol,
O C H3
H3C
Si O
dichloromethane
O
H3C O
HO


•Addition of water hydrolyses both the ortho -ester, as well as the
trimethylsilyester.
•Phenylacetic acid, butanol and the trimethylsilyl rest go to waste.
2nd Generation 7-ADCA process:
Use of an enzyme saves 2 steps
1990-2000


OH
NH
S O
O H2N
S
N
CH 3
O N
C H3
O O
HO
O
HO
Improvement of steps 5 - 7, including recycle of
phenylacetic acid for Pen-G fermentation:
in water; immobilized enzyme (acylase)


•Use of a hydrolytic enzyme immediately generates 7 -ADCA.
•An additional advantage is that the phenylacetic acid can now be
recycled.
3e Generation 7-ADCA proces:
Use of a GMO avoids 3 more steps
>2000 OH
OH

O
O
Expandase introduced in
+ MOLASSES
microorganism replaces
steps 1-4
+ N,S NUTRIENTS NH
S
O
OH
O
N
C H3
O

O
HO


•Fermentation using a genetically modified organism (GMO) leads t o the
immediate formation of N-adipyl 7-ADCA.
•The genome of the penicillin strain has been supplemented with t he gene
for an “expandase” enzyme. This enzyme fulfills the role of chemical
steps 2 and 4.
Overview > 2000 7-ADCA
proces OH



O

OH
GMO
OH
O
O



H2N
NH
S
S
O

N
N ENZYME C H3
CH3
O
O
O
HO
O
HO


•Only 2 steps in water as solvent!
•Adipic acid can be recycled.
•No large chemical waste streams.
•New process is both more economic as well as environmentally fri endly.
20
40
60
80




0
100
Number of
solvents



Amount of
solvents



Other chemicals
In waste stream




Green process
Electricity




Steam



CO2 – via energy
consumption



CO2 -from
7-step old process




fermentation
Green 7-ADCA process




Waste water
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