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Commercial Processes for Antibiotic Fermentation.

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Oxidation and Elimination Reactions of the
Diazomethane-2,2-Bi-( 1,4-naphthoquinone)
Adduct
By A . Zeeck [*I
Both half-molecules of 2,2’-bi-(1,4-naphthoquinone) react
with diazomethane in a cycloaddition yielding the adduct
( I ) 111. This compound can be stabilized in three ways, each
of which involve attack o n the bonds from C-9a and C-9’a
and aromatization:
mined by these methods. Since (5) contains the structural
units of o-aroylbenzoic acids, ring-chain tautomerism also
occurs. Reaction with diazomethane yields the normal dimethyl ester, whereas acetylation or reduction result in ring
closure in both halves of the molecule to yield 1,l’-diacetyl4,4’-bis(3-acetoxyphthalid-3-yl)-5,5’-bipyrazoleor 4,4’-bis(phthalid-3-y1)-5,5’-bipyrazole,respectively.
The parent of (5), namely, 3,3‘- or 5,5’-bipyrazole (7) (m.p.
259 “C) is obtained on decarboxylation of the dicarboxylic
acid (6); it is formed, with benzoic acid, in an alkali melt at
160 OC.
1. Warming the adduct in anhydrous toluene gives 3,3’-dimethyl-2,2’-bi-(l,4-naphthoquinone)(2) (thermal elimination
of nitrogen).
Lecture at Gottingen on December 15th, 1966
[VB 56 IE]
German version: Angew. Chem. 79,477 (1967)
2. In the presence of electrophilic agents disproportionating
fragmentation occurs, yielding benzLflindazole-4,9-quinone
(3) and its hydroquinone (4). The latter is rapidly oxidized
by air to the former. (3) and (4) can be identified in admixture by means of acetic anhydride/pyridine (with exclusion
of air) when the N-acetyl derivative of ( 3 ) , and the leucotriacetate derivative of (4) are obtained. In a side reaction,
( I ) loses half of its nitrogen before the two molecular fragements have separated; a nitrogenous quinone of molecular
weight 352 but unknown structure results.
Organisch-Chemisches Institut der Universitat
Windausweg 2
34 Gottingen (Germany)
[I] Oxidative degradation of diazomethane adducts of type (f]
can be used for determination of the structure of biquinones. H . Brockmann, K.van der Merwe, and A . Zeeck, Chem. Ber. 97,
2555 (1964); H . Brockmann, A. Zeeck, K. van der Merwe, and
W. MuNer, Liebigs Ann. Chem. 698, 209 (1966).
3. Oxidation in 2 to 4 N alkali hydroxide solution leads to (a)
decoupling of the C-9a/C-9’a bond, yielding two molecules
of (3), or (b) fission of the C-9/C-9a and the C-9’1C-9a
bonds, yielding 4,4’-bis(2-carboxybenzoyl)-5,5’-bipyrazole
(5). Use of hydrogen peroxide as oxidizing agent gives
mainly (3) [I], and use of potassium hexacyanoferrate(n1)
gives (energetically more favorable) mainly ( 5 ) . Both reactions are expected to occur by way of an dianion of ( I ) and a
Commercial Processes for Antibiotic Fermentation
[*I Dr. A. Zeeck
By R. KreutzfeldtI*l
Industrial fermentation has recently achieved increased importance, principally by production of antibiotics. Some 1000
antibiotics have been discovered in the last 25 years, of which
about 50 have acquired economic significance, notably the
penicillins, tetracyclins, and streptomycins. About 3000 tons
of antibiotics were prepared in USA in 1964 (ca. 50 % of the
world production), at a value of ca. $400 million. The world
production of penicillins can be estimated as about 1500 tons
a year.
In spite of many years’ experience, penicillin production
remains one of the most difficult and most sensitive. Fleming
achieved yields of 2-10 units/ml in his first fermentations:
today 10000 units/ml are considered normal. The fermentations are carried out in a technically similar way for all
antibiotics, and the technique for penicillin fermentation
alone will be described more closely here.
The penicillin-forming mold is preserved as a permanent
culture in the anhydrous state at about -5 “ C in order t o
exclude any metabolism. From this permanent culture subcultures are made on the laboratory scale, and further cultures are grown in prefermenters. The amount of inoculum
for the main fermenter is chosen to be between 2 and 20%
of the amount to be harvested; larger amounts of inoculum
shorten the fermentation time.
OH
I
radical anion, which either splits into two parts or, when
attacked by hydroxide ions a t C-9 or C-9’, initiates another
reaction path (oxidative-hydrolytic scission of two C-C
bonds).
The structures of (5) and some of its derivatives can be
proved by IR, NM R , and mass spectrometry. The position
of the hydrogen atom in the pyrazole rings cannot be deter-
470
The fermenters are fitted with a n aeration system, a stirrer,
and a cooling system that keeps the temperature constant
within t 0.5”C. Provision of oxygen and formation of
penicillin are closely related. Fermenters in commercial use
today may have a capacity of 400 m3.Antibiotic fermentations
must be carried out without admission of foreign infections :
Only sterilization by steam (at least 120°C for at least 20
min) comes into consideration for large-scale production.
Fermentation conditions: 7 Days a t 25 ;? 0.5OC; 0.3 m3 of
air per min per 1 m3 of liquor. The following are required
for production of 100 kg (4.3 % yield) of penicillin-Na: 1200
kg of carbohydrate, 60 kg of animal and vegetable fats, 770
kg of corn steep liquor, 220 kg of inorganic substances (as
buffer, and as source of sulfur and phosphorus), and 100 kg
of phenylacetic acid for formation of penicillin G.
The material balance of penicillin production from these
quantities (input 2350 kg of raw materials) is: 100 kg of
penicillin-Na (4 wt-x), 825 kg of mould mycelium (35 %),
660 kg of residual substances in the culture solution (28 %),
765 kg of COz (33 %).
Angew. Chem. internat. Edit. 1 Vol. 6 (1967)
1 No. 5
The energy change of penicillin fermentation is as follows
(heats of combustion of raw materials and of the metabolic
products are compared : mechanical energy, e.g. heat generated by stirring of the culture liquor, is not considered):
Energy contained in
I kcal
1
%
~
Penicillin-Na
Mycellium
Residual substances in liquor
Heat of combustion evolved
586000
2 805 000
1923 000
3 147000
7
33
23
37
Total consumption of energy of the
raw materials
8461 000
100
Further, every 100 kg of penicillin require: 3000 kWh of
electrical energy (mainly for stirring), 4 tons of steam
(sterilization and sealing), 50000 Nm3 of crude air, 900 m3
of cooling water (cooling of the sterilized solution, removal of
the heat produced by stirring and by biochemicalcombustion).
Costs of penicillin production (exclusive of amortization) can
be divided as follows: for raw materials 50 %, for energy
20 %, for repairs 10 %, personel costs 15 %. other costs 5 %.
These complicated biological processes are very liable to
disturbance and require detailed supervision and exact
analytical control. Even with fermentation processes that
have been well established variations of yield amounting
to % 15 % are to be expected. In general, the following
factors are responsible for this: variation of the penicillium
strain or of the quality of raw materials; infection by foreign
molds; errors in servicing and technical disturbances. The
quality of the raw materials is decisive for fermentation yields,
and as these materials are mostly of natural origin they are
subjected to analytical and biological control.
The sulfur sorption layer can be easily placed o n any platinum
catalyst, including platinum black, e.g. by treatment with
hydrogen sulfide. It is stable at anodic regions up to 600 mV;
oxidation to sulfur dioxide begins only at higher potentials.
The degree of coverage of the platinum surface has a large
effect o n the reaction rate of carbon monoxide or formic
acid; the rate is a maximum when about one third of the
total surface platinum atoms is covered with sulfur.
[VB 6 6 IEI
Lecture at Essen (Germany) on February loth, 1967
German version: Angew. Chem. 79, 477 (1967)
Dr. H. Binder, A. Kohling, and Dr. G. Sandstede
Battelle-Institut
Wiesbadener Str.
6 Frankfurt/Main (Germany)
Specific Oxidation of Phenols by
Dipotassium Nitrosobissulfate
By H.-J. Teuber[*]
Reaction of 2,3-phenanthrenediol with dipotassium nitrosobissulfate, O N ( S O ~ K ) Z , yields 3-hydroxy-1,2-phenanthraquinone, which is obtained as the colorless dimer ( I )
whose UV spectrum corresponds substantially to that of
3,4-dihydro-l(2H)-phenanthrone but not to that of 2,3-dihydro-4(2H)-phenanthrone. The (dimeric) 2-hydroxy-3,4phenanthraquinone is thus not formed.
0
[VB 57 IEl
Lecture at Frankfurt am Main on October Zlst, 1966
German version: Angew. Chem. 79,478 (1967)
[*I Dr. R. Kreutzfeldt
0
Farbwerke Hoechst A.G.
Pharma-Fabrik/Antibiotika-Betriebe
6230 Frankfurt/(M)-Hochst, Postfach 70 (Germany)
Electrochemical Oxidation of Formic Acid and
Carbon Monoxide on Platinum Catalysts in Acid
Electrolytes
In the formation of p-quinones from monohydric phenols,
substituents may be eliminated from the para-position; not
merely COOH, OCH3, and C1 but even C H 3 may be eliminated, so that blocking of para-positions by methyl
groups cannot always be reliably accomplished :
By H.Binder, A . Kohling, and G. Sandstede[*I
Fuel cells containing acid electrolytes are advantageous for
electrochemical oxidation of carbon-containing fuels because
the resulting carbon dioxide is obtained as a gaseous combustion product, whereas in alkaline electrolytes it remains
dissolved as carbonate. In addition to hydrocarbons and
methanol, other carbon-containing fuels are carbon monoxide (which can be obtained mixed with hydrogen on conversion of hydrocarbons or coal) and also formic acid. Their
use has hitherto been restricted because they poison platinum
catalysts, the electrodes becoming strongly polarized and the
output of the cells lowered. When the platinum surface is
partially covered with sulfur, the anodic oxidation to carbon
dioxide is greatly accelerated. This result could lead to development of fuel cells utilizing either carbon monoxide and
hydrogen, or formic acid.
O n a Raney platinum catalyst that is partially covered with
a monatomic sulfur sorbate, carbon monoxide in 3 N sulfuric acid at 9 0 ° C leads to a potential of 250 mV (at a
current density of 200 mA/cmz) against a hydrogen reference
electrode in the same solution. Anodic oxidation of formic
acid (the hydrate of carbon monoxide) is still more strongly
accelerated, so that under similar conditions a current density of 200 mA/cmz is obtained, even at 30 OC. At 90 OC the
current density reaches a stationary value of ca. 2 A/cmz. At
a n untreated Raney platinum electrode, however, a current
density of less than 1 mA/cmz is obtained.
Angew. Chem. interitat. Edit.
Vol. 6 (1967) / No. 5
Formation of the N-methyliminobissulfate, H~C-N(SO~K)Z,
during demethylating oxidations has been demonstrated.
Lecture at Hamburg on January loth, 1967
[VB 59 IE]
German version: Angew. Chem. 79, 426 (1967)
[*I Prof. Dr. H.-J. Teuber
Institut fur Organische Chemie der Universitat
Robert-Mayer-Str. 719
6 Frankfurt/Main (Germany)
[l] Cf. H.-J.Teuber and G. Steinmetr, Chem. Ber. 98, 666 (1965);
H.-J. Teuber, P. Heinrich, and M. Dietrich, Liebigs Ann. Chem.
696, 64 (1966).
47 1
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