METHODE DE PREPARATION DE CIPROFLOXACINE

PROCESS FOR PREPARING CIPROFLOXACINE

Abrégé anglais

The invention is concerned with a process for
preparing ciprofloxacine of the formula
(see fig.I)
based on the reaction of 1-(2,4-dichloro-5-fluoro-
phenyl)-1,3-butanedione with ethyl orthoformate, to give
an enol ether which is reacted with cyclopropylamine,
resulting in an enaminone, the cyclization of which
provides a compound which is reacted with N-ethoxycar-bonylpiperazine,
producing an intermediate, whose oxidation
leads to an acid which provides ciprofloxacine by
means of alkaline hydrolysis and neutralisation. Ciprofloxacine
is a highly affective bactericidal agent
against gram-positive and gram-negative bacteria.

Revendications

-19-
The embodiments of the invention in which an
exclusive property or privilege is claimed are
defined as follows:
1. A process for the preparation of
1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
quinoline-3-carboxylic acid of formula (I):
<IMG>
and pharmaceutically acceptable acid addition salts
or hydrates thereof, which comprises the steps of:
a) reacting 1-(2,5-dichloro-5-fluorophenyl)-1,3-
butanedione of formula (VI):
<IMG>
with methyl or triethyl orthoformate in the presence
of acetic anhydride to produce an enol ether having
the formula (VII):
<IMG>
wherein R1 is a methyl or ethyl group;

-20-
b) adding cyclopropylamine to the enol ether of
formula (VII) to produce an enaminone having the
formula (VIII):
<IMG>
c) cyclizing the enaminone of formula (VIII) by
heating in an organic solvent and in the presence of
a base, to produce a compound having the formula
(IX):
<IMG>
d) reacting the compound of formula (IX) with
N-ethoxycarbonylpiperazine of formula (X):
<IMG>
to produce an intermediate having the formula (XI):

-21-
<IMG>
e) oxidizing the intermediate of formula (XI) in an
alkaline medium to obtain an acid having the formula
(XII):
<IMG>
f) subjecting the acid of formula (XII) to an
alkaline hydrolysis and neutralization, to obtain
the desired compound of formula (I); and
g) if desired, converting the compound of formula
(I) thus obtained into a corresponding pharmaceutically
acceptable acid addition salt or hydrate.
2. The process of claim 1, characterized in
that in step (a) the butanedione of formula (VI) is
reacted with trimethyl orthoformate in the presence
of acetic anhydride.
3. The process of claim 2, characterized in
that said reaction is conducted initially at the
reflux temperature of the mixture for a period of
one to three hours after which, after removal by

-22-
distillation of part of the more volatile
by-products, the mixture is maintained at a temperature
comprised between 110° and 150°C for a period of
from thirty minutes to three hours.
4. The process of claim 2 or 3, characterized
in that the butadione of formula (VI) is reacted
with an excess of 1 to 2 mols of trimethyl
orthoformate in the presence of an excess of 2 to 3
mols of acetic anhydride, per mol of butadione of
formula (VI), the molar amount of acetic anhydride
being at least the sum of the molar amount of the
trimethyl orthoformate and the molar amount of the
compound of formula (VI).
5. The process of claim 1, characterized in
that the compound of formula (VI) is prepared from
acetophenone of formula (V):
<IMG>
by reaction with acetic anhydride in the presence of
boron trifluoride or complexes thereof with ethyl
acetate or acetic acid.
6. The process of claim 5, characterized in
that the acetophenone of formula (V) is reacted with
an excess of 2 to 4 mols of acetic anhydride in the
presence of an excess of 3 to 6 mols of boron
trifluoride, per mol of acetophenone of formula (V).
7. The process of claim 1, characterized in
that the reaction in step (a) is carried out at a
temperature between 110° and 150°C and using 2 to 4

-23-
mols of acetic anhydride per mol of compounds of
formula (VI).
8. The process of claim 1, characterized in
that the reaction in step (b) is carried out at a
temperature between 0° and 50°C in an inert organic
solvent.
9. The process of claim 8, characterized in
that said inert organic solvent is selected from the
group consisting of ethanol, methanol, isopropanol,
methylene chloride, chloroform, benzene and toluene.
10. The process of claim 1, characterized in
that cyclization in step (c) is conducted by heating
in an organic solvent in the presence of a base and
at a temperature between 80° and 180°C.
11. The process of claim 10, characterized in
that said base is selected from the group consisting
of potassium carbonate, sodium carbonate, sodium
methoxide, potassium tert-butoxide and sodium
hydride.
12. The process of claim 1, characterized in
that the reaction in step (d) is carried out using
an excess of two to four mols of the compounds of
formula (X), in an organic solvent and at a
temperature between 80° and 150°C.
13. The process of claim 10 or 12,
characterized in that said organic solvent is
selected from the group consisting of
N,N-dimethylformamide, N,N-dimethylacetamide and
di-methylsulphoxide.

-24-
14. The process of claim 1, characterized in
that the oxidation in step (e) is effected in an
alkaline aqueous medium or mixture thereof with a
water miscible organic solvent, by the action of an
alkali hypohalite.
15. The process of claim 14, characterized in
that said organic solvent is methanol or ethanol and
said alkali hypohalite is sodium hypochlorite.
16. The process of claim 14, characterized in
that said organic solvent is 1,4-dioxane or
tetrahydrofurane and the said alkali hypohalite is
sodium hypochlorite or sodium hypobromite.
17. The process of claim 1, characterized in
that the hydrolysis in step (f) is carried out in an
aqueous medium or in a mixture of water with a low
molecular weight alcohol, at the reflux temperature
of the alcohol and in the presence of an alkali
hydroxide.
18. The process of claim 17, characterized in
that the said alkali hydroxide is sodium or
potassium hydroxide.

Description

- 1. -
1340~~~.
A PROCESS FOR PREPARING CIPROFLOXACINE
D E S C R I P T I 0 N
The invention refers to a process for preparing 1-cyclo-
propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-
-3-carboxylic acid (ciprofloxacine) as per formula I)
0
COOH
~t~ N ( I ~
the pharmaceutically acceptable acid addition salts and
hydrates, thereof.
The subject compound is a bactericidal agent, recently
introduced in therapeutics in certain countries and is highly
effective against both gram-positive and gram-negative
bacteria.
Spanish Patent No. 516.921 discloses a process for the
preparation of the formula I compound) wherein starting from
2,4-dichloro-5-fluarobenzoyl chloride as per formula II
F / COC1
II
C1 C1

140 Q61
- 2 -
the formula I compound is obtained by means of a sequence of
reactions involving seven steps, the first of which consists
of acylation of diethyl malonate with theacid chloride of
formula II in the presence of magnesium ethoxide prepared "in
situ" from anhydrous ethanol and magnesium metal. There is
also described the preparation of the Formula II starting
material, which is not commercially available, starting from
2,4-dichloro-5-methylaniline using another synthetic route
involving 5 steps.
Later, German Patent n~ 3.435.392 discloses a process
for preparing 2,4-dichloro-5-fluorobenzoic acid as rer formula
III,
F / 00;i
C1 ~1 (III)
starting from 2,4-dichlorofluorobenzene as per formula IV,
F
C ~' C1
(IV)
a commercially available product, by means of a two phase
sequence consisting of the acylation of the formula IV
compound with acetyl chloride and subsequent oxidative degra-
dation of the resulting 2,4-dichloro-5-fluoro-acetophenone
to achieve the said formula III acid. Finally the formula II
acid chloride is obtained by the action of thionyl chloride

13406:1
- 3 -
in a three phase sequence starting from 2,4-dichlorofluoroben-
zene (IV), which represents an overall synthetic route of ten
steps to obtain the formula I compound starting from the
formula IV compound.
Thus, it has now been possible to establish a new process
for preparing the formula I compound which is represented in
the following reaction scheme:

1340~ti1
0 0
i~ i~
;: / CCH2CCH~ HC(OR~ )~ r C~'C~C~CH
A~ 0 / i 'CH 3( VII )
C1 ~ C1 ( VI ) R ~=Et, Me C'- ~ C1 ~ ORS
D-~~z
0 0 0 0
(I
r ~ ~CH3 / C'C~C~CH
i 1 Dr~F ( n
C1 ~ N base C1 ~ 1 C\~vH (VIII)
(IX)
E.t00C- ~H (X)
0 0
0
I I C 'R / 00 H
L l ~I
N ~ IV ~ ~ t! N
N uiN J
Et04C
R = CEi3 (XI) (I)
R - Ou (xII)

1340b1.
- 5 -
I.e., the process in accordance with the invention is
characterized by the following steps:
a) reacting 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione
as per formula VI,
0 0
F / CH2CCH3
C1 ~C1
(VI)
with trimethyl or triethyl orthoformate in the presence of
an excess of acetic anhydride to give an enol ether as per
formula VII,
0 0
CwC.~CwCE~
3
~~H (VII)
C1 ~C1 ~' Oftl
R1 being a methyl or ethyl group.
b) adding cyclopropylamine to the thus obtained enol ether,
to give the enaminone as per formula VIII
0 0
(VIII)
1
C ~C'C NCH
CH
C ~ C
c) cyclization of the enamine by heating in a high boiling
point organic solvent in the presence of a base) to give the
compound of formula IX)

13~0~~1
ll (i
F
C ~C'_
(IX)
C1
d) reacting the thus obtained compound with N-ethoxycarbonyl
piperazine as per formula X,
Et00C- ~H (X)
whereby the intermediate is obtained as per formula XI,
0 0
F ~ ~ ~1
~~ 3
.~ 1 I
~N h
(XI)
NJ
E t00C ~
e) oxidising of the intermediate in an alkaline medium to
obtain the acid as per formula XII,
0
F ~ COOH
~N
N J (XII)
E 100C ~
and f) alkaline hydrolysis and neutralization whereby formula
I compound is obtained.
The starting material for this new process) 1-(2,4-dichlo-
ro-5-fluorophenyl)-1,3-butanedione of formula VI, has not been

.. 134056.1
-
described in scientific literature and was ubt;ained by cunden-
sation of N-acetyl-2-pyrrolidine with 2,4-dichloru-5-fluuru-
-acetophenone of formula V;
F / COCH3
C1 ~Cl (V)
in the presence of a base such as sodium hydride in an inert
solvent, for example ethyl ether, in accordance with the pro-
cedure described by H. Stetter and W. Steinbeck for the
synthesis of 1-phenyl-1,3-butanedione (See Chem. Ber., 103)
1088-1094 (1970)).
Alternatively) the butanedione as per formula VI was also
prepared by acylation of the formula V compound with an excess
of 2 mots of acetic anhydride in the presence of boron tri-
fluoride ethyl acetate or acetic acid complexes thereof,
in accordance with the procedure indicated in literature (See
J. Am. Chem. Soc. 75, 5030 (1953)).
It has been found) in particular, that if the Formula V
acetophenone is acylated in the preparation of the Formula VI
starting material at moderate temperatures with an excess of
two to four mols of acetic anhydride and in the presence of an
exces of three to six muls of 40 wt~o boron trifluoride-acetic
acid complex) excellent yields of Formula VI butanedione are
obtained. Because of its simplicity, yield and high purity of
the compound obtained, the use of this method is recommendable
for the preparation of the said Formula VI starting material.
9

I340 ~b1
_8_
It may also be prepared by means of a Claisen
condensation between formula V acetophenone and an
excess of ethyl acetate in the presence of a base such
as sodium methoxide, sodium ethoxide, sodium or
s potassium tert-butoxide, sodium amidide or sodium
hydride, at temperatures of between -10 and 60~C. This
process, however, gave lower yields than the method
indicated in the previous paragraph.
2,4-dichloro-5-fluoroacetophenone as per formula V
~o is a compound known in scientific literature (See Zh,
Obshch Khim., 32, 3131 (1962), C.A. 58, 1l243 g), and is
obtained by Friedel-Crafts acylation of 2,4
dichlorofluorobenzene, which is commercially available.
The proces of the invention affords advantages
~5 compared to methods indicated in the previously
mentioned patents. First of a11, a 1,3-dicarbonyl
substrate is obtained, capable of being condensed with
trimethyl or triethyl orthoformate in only two steps
starting from the formula IV 2,4-dichlorofluorobenzene,
zo while with the other process mentioned in the previous
patents, the analogous objective requires an elaborate
five step sequence of reactions. Secondly, the number of
steps necessary for obtaining ciprofloxacine (I) as from
the formula IV compound is reduced to eight.
2s From an industrial viewpoint, both aspects
represent a saving in power and manpower, as well as an
improvement in the overall yield of the synthesis. On
the other hand, the use of magnesium metal is avoided,
which means greater manufacturing safety and adequacy,
3o particularly when working with much larger amounts.

- g _
Finally, a11 the reactants used in this novel process can
be acduired freely on the market without the need for prior
preparation of any of them.
The first step of the process for preparing the formula I
compound, i.e. the condensation of formula VI 1-(2,4-dichloro-
5-fluorophenyl)-1,3-butanedione and an excess of triethyl
urthoformate in the presence of more than two mols of acetic
anhydride per mol of the initial compound) is conducted at
temperatures of from l20~- to 15O~-C for a period of time of
from one to three hours, in accordance with generally used
methodology in reactions between alkyl orthoformates and 1,3-
dicarbonyl compounds (See Methoden Organische Chemische, 4th
Ed., Vol. VII, Page 49). After low pressure evaporation of the
volatile material and the excess of reactants, the enol ether
of formula VII is obtained which, without subsequent
purification, is reacted with cyclopropylamine (step b) a~
temperatures of 0~- to 50~-C, in an inert solvent such as
ethanol, methanol, isopropanol) methylene chloride,
chloroform, benzene, toluene, etc., in order to obtain the
formula VIII enaminone with an excellent yield.
When trimethyl orthoformate is used in step a), it is
preferable for the Formula VI butanodione to be reacted with
an excess of said trimethyl orthoformate in the presence of an
excess of acetic anhydride to provide the corresponding enol
ether in this case. The reaction occurs initially at the
reflux temperature of the mixture for a period of time between
one and three hours, after which) after distilling off some of

~3~O~b1
- 10 -
the more volatile by-products, the mixture is held at a
temperature between 110~C and 150~C for from thirty
minutes to three hours. Removal of the remaining
volatile material by evaporation provides the enol ether
s which, with the addition of cyclopropylamine under the
conditions cited for step b), gives the Formula VIII
enaminone. The trimethyl orthoformate excess should
preferably lie between one and two moles and the acetic
anhydride excess between two and three moles per mol of
~o formula butanodione, with the molar amount of acetic
anhydride being, at least, the sum of the other two
components in the reaction.
This alternative possibility, relating to the use
of trimethyl orthoformate, may represent savings on an
~s industrial scale, considering the lower cost of the
trimethyl orthoformate than the triethyl orthoformate
and considering the reduction of over 25% of the amount
of the formerto be used in comparison with the latter,
due to the molecular weight thereof.
zo Cyclization of formula VIII compound is carried out
to obtain the formula IX compound (step c) by heating in
a high boiling point organic solvent, such as N,N-
dimethylformamide, N,N-dimethylacetamide or dimethyl-
sulphoxide, in the presence of a base such as potassium
2s carbonate, sodium carbonate, sodium methoxide, potassium
tert-butoxide or sodium hydride, preferably potassium
carbonate, at temperatures between 80~C and 180~C.
The 3-acetyl-4-oxo-quinoline of formula IX is
condensed

- 11 - 1340e1
(step d) with an excess of 2 to 4 cools ref N-ethuxycarbunyl-
piperazine as per formula X, in the presence of an organic
solvent of the same characteristics as those mentioned in ',;he
previous paragraph) at temperatures lying between 80Q and 150~C
and reaction times lying between two and 10 hours, whereby
formula XI intermediate is obtained with excellent yield.
The oxidation (step e) of the formula XI compound is
carried out in water, or in mixtures thereof with miscible
organic solvents, such as 1,4-dioxane or tetrahydrofurane) by
the action of alkaline aqueous solutions of metal hypohalites,
such as sodium hypochlorite or hypobromite, at temperatures
between -10~- and 90~-C.
The oxidation may preferably be carried out by the action of
an aqueous solution of commercial sodium hypochlorite on a
solution of the said intermediate XI in a low molecular weight
alcohol, fur example) methanol ur ethanol) at temperatures
close to room temperature and reaction times lying between one
and six hours.
Finally, hydrolysis of XII in the presence of an aqueous
solution of alkaline hydroxide such as sodium hydroxide ur
potassium hydroxide, leads to formula I compound being
obtained with good yields. Water or mixtures thereof with a
low molecular weight alcohol can be used as reaction solvent.
Reaction is carried out at reflux temperature of the solvent
used) over a time of between one and four hours.
In order to provide a clear understanding of a11 the
foregoing) hereunder some non-limiting examples of the
inventive process are described.

134n~~~.
- 12
EXAi~fPLE 1. Preparation of starting material:
1-(2,4-dichloru-5-fluruphenyl-1,3-butanP~iune (VI).
31.05 g (0.15 mul) of 2,4-dichluru-5-fluuroacetophenone
(V) were added at room temperature to 112.7 g of a 40 wt%
solution of boron trifluuride in acetic acid (IiF3-2 CH3COOH
complex). The solution was stirred for one hour at room
temperature and 45.9 g (0.45 mol} of acetic anhydride were
added over 10 minutes. The mixture was heated at 40oC fur 8
hours and then held for a further 16 hours at room temperature
with stirring. The crystalline slurry was filtered in an inert
atmosphere and well drained. Approximately 46 g of the boron
difluoride complex VI were obtained. The moist solid was
poured over a solution of 73.8 g of anhydrous sodium acetate
dissolved in 6?5 ml of water and the mixture was heated at
reflux for 90 minutes. It was extracted three times with n-
hexane (200, 120 and 100 ml) and the organic extract was
washed with 1S0 ml of a saturated sodium bicarbonate solution.
It was dried with anhydrous sodium sulphate, filtered and the
solvent was evaporated off to give 24,7 g of the compound of
Formal a VIII .
After 5 days at room temperature) the reaction liquors
had deposited a further 6.65 g of the boron difluoride complex
VI which) when treated in the same way as the main fraction,
gave a further 3.8 g of the compound of the title, therefore,
28.5 g of VI (Yield 76~0} in the form of a whitish-pink solid.
The spectroscopic data show that the formula VI compound
is totally enolised, both in solid state and in solution.
A sample crystallised from n-hexane gave a melting point
of 68-69''C.

- 13 - .3405b1
EXAMPLE 2
Preparation of starting material: 1-(2,4-dichloro-5-fluorophe-
nyI)-1,3-butanedione (VI).
1l,8 g (0.295 mols) of 60% sodium hydride in mineral oil,
and 80 mI of n-hexane were placed in a 500 ml three necked
spherical flask, fitted with an addition funnel, reflex refri-
Berated and nitrogen blanket. After stirring for ten minutes
the solvent is poured off. The procedure was repeated twice
again with 80 m1 of n-hexane on each occasion, and thereafter
100 ml of absolute ethyl ether were added and the solvent
was poured again. 230 ml of absolute ethyl ether were added
and over the slurry a mixture of 30,3 g (0,146 mols) of 2,4-
dichloro-5-fluoracetophenone and 18,6 g (0,146 mols) of N-
acetyl-2-pyrrolidone were added dropwise at room temperature.
The mixture was stirred at room temperature for an hour and
then heated to reflex for three hours. It was then cooled to
-5~C and 65 ml of 30% acetic acid were carefully added. The
ethereal phase was decanted) washed with 100 ml of a 5%
sodium bicarbonate solution and then with 50 ml of water then
dried with anhydrous sodium sulphate. After filtration and
evaporation of the solvent, the resulting residue was purified
by low pressure distillation. The fraction.distilling at
118-133~-C and 0,15 mm was collected) whereby 27,7 g (yield
76%) of 2,4-dichloro-5-fluorophenyl)-1,3-butanedione were
obtained with sufficient purity for it to be used in the
following steps.
L' V A M T7 T L' 7
Preparation of 3-(2,4-dichloro-5-fluorobenzoyl)-4-ethoxy-3-
buten-2-one (VII). (R1=Et)

- 14 -
A three necked spherical flask fitted for a
distillation were placed with 27.4 g (0.l1 mol) of 1-
(2,4-dichloro-5-fluorophenyl)-1,3-butanedione, 23.7 g
(0.16 mol) of triethyl orthoformate and 27.5 g. (0.25
s mol) of acetic anhydride. The mixture was heated slowly,
distilling at the same time the volatile reaction
products until internal temperature reached 140~C. This
temperature was held for two hours, and then left to
cool and the residual volatile components were distilled
io off at 95-100~C and 2-3 mm Hg. In this way 33.5 g of a
crude residue were obtained, corresponding to the tital
compound and usable in the following phase without any
purification whatsoever. (Yield 99.8%).
EXAMPLE 4
15 Preparation of 4-cyclopropylamine)-3-(2,4-dichloro-5-
fluorobenzoyl)-3-buten-2-one (VIII)
6,3 g (0.11 mol) of cyclopropylamine were added,
dropwise with stirring to a solution cooled to 0~C of
33.5 g (0.11 mol) of crude 3-(2,4-dichloro-5-
zo fluorobenzoyl)-4-ethoxy-3-buten-2-one in 100 ml of
absolute ethanol in such a way that the temperature did
not exceed 20~C. When the addition was over an abundant
precipitate forms. The suspension was stirred at room
temperature for 2 hours and then 80 ml of water were
z5 slowly added and it was cooled to 0~C. The mixture was
then filtered and the solid washed with 30 ml of a
mixture of equal parts of ethanol and water. 32 g of
compound VIII were produced (yield 92%).

1340~~i1
- 15 -
rvnn~rnr r. c
Preparation of 3-(2,4-dichloru-5-fluorobenzuyl)-4-methoxy-3-
buten-2-one (VII, R1 - Me5.
In a three necked spherical flask were placed 23 g (92.3
mmols) of 1-(2,4-dichloro-5-fluorophenyl)-1,3-butanedione,
14.7 g (138.5 mmols) of trimethyl orthoformate and 23.6 g (231
mmols) of acetic anhydride. The mixture was heated under
reflux for 2 hours, A mixture of methyl acetate and acetic
acid were distilled until an internal temperature of 130oC was
reached. This temperature was held for one hour, after which
heating was removed and vacuum (1-2 mmHg) was applied to
remove the volatile residues. 26.1 g (Yield 97~) of the
compound of the title were obtained in form of a dark brown
oil, used unpurified in the following step.
FXAMPT.F F,
Preparation of 4-cyclopropylamino)-3-(2,4-dichloro-5-fluoro-
benzoyl)-3-buten-2-one (VIII).
The oil obtained in the previous step (26.1 g, 89.6
mmols) was dissolved in 50 ml of methanol. The solution was
cooled to 5oC and 5.4 g (94,5 mmols) of cyclopropylamine were
added dropwise while the temperature was held to not exceed
15QC. The crystalline suspension was stirred for one hour at
room temperature. It was cooled to OoC and held at this
temperature for30 minutes. It was filtered) washed with 10 ml
of cold methanol and dried in a current of air. 21.5 g (Yield
76io) of a crystalline solid were obtained, with m.p.
122-124uC) corresponding to the Formula VII compound.

... 1340W1
- 16 -
EXAMPLE 7
Preparation of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-
1 4-dihydro-4-oxoquinoline (IX).
A mixture of 36 g (113.8 mmols) of the compound of
formula VIII, 17.4 g (126 mmols) of finely divided
anhydrous potassium carbonate and 110 ml of N,N
dimethylformamide was stirred and heated at 130~C for 2
hours. It was cooled to room temperature and 32 ml of
water were added dropwise. The slurry was cooled 15~C
to and filtered. The moist solid (58 g) was suspended in
200 ml of water and stirred at room temperature for 15
minutes . It was filtered again and washed with 50 ml of
water. It was dried under a current of air to give 27 g
(Yield 85%) of the compound of the title, under the form
Of a brown solid, with m.p. 177-179~C.
EXAMPLE 8
Preparation of 3-acetyl-1-cyclopropyl-7-(4-ethoxycar-
bonyl-1-piperacinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline
XI
zo A mixture of 20 g (7l.5 mmols) of the Formula IX
intermediate, 80 ml of N,N-dimethylacetamide and 42 g
(266 mmols) of N-ethoxycarbonylpiperazine (X) were
heated at 150~C for 15 hours. The mixture was cooled to
10-15~C and 340 ml of water were added at this
z5 temperature, with vigorous stirring, causing
crystallization. The precipitate was filtered, was
washed with water and dried. 24 g of the raw compound of
Formula XI were obtained (Yield 84%) in the form of a
brown solid which was purified by filtration through
3o silica gel, using a mixture of chloroform-methanol
(15:1) as eluent.
X

~.~40~~1
- 17 -
EXAMPLE 9
Preparation of 1-cyclopropyl-7-(4-ethoxycarbonyl-1-pip-
erazinyl)-6-fluoro-1,4-dihydro-4-oxoctuinoline-3-
carboxYlic acid (XII).
120 ml of a 15% aqueous solution of sodium
hypochlorite were added over 30 minutes with stirring to
a solution of 20 g (49.8 mmols) of the intermediate of
Formula XI in 160 ml of absolute ethanol, the
temperature being held to between 20~C and 25~C. The
~o reaction mixture was stirred for a further 3 hours at
the same temperature, 400 ml of water were added and the
major portion of ethanol was removed by low pressure
distillation, without the temperature of the mixture
being allowed to exceed 35~C. The insoluble material was
5 removed by filtration and washed with water. 10 ml of a
40% aqueous solution of sodium bisulfate were added to
the remaining solution and the solution was acidulated
with concentrated HC1. The precipitate was filtered,
washed with water and dried. 12.4 g (Yield 64%) were
zo obtained of the compound of Formula XII, in the form of
a yellowish solid having a melting point of 296-304~C
with decomposition.
EXAMPLE 10
Preparation of 1-cvclopropyl-7-(1-piperacinyl)-6-fluoro
zs 1 4-dih~dro-4-oxoauinoline-3-carboxylic acid (I) (Cipro
floxacine).
l0 g (25 mmols) of the acid of Formula XII were
added to a solution of 5.6 g (90 mmols) of 90% potassium
hydroxide in 140 ml of water. The mixture was stirred
3o and heated under reflux for 4 hours. It was allowed to
cool and the solution
y..

- 18 - 13~~,ri~
was stirred fur half an hour with 2 g of activated carbon. It
was filtered and 160 ml of 1N HC1 were added to the filtrate.
The opalescent solution was clarified by filtration and the pH
was adjusted to 7.2 by addition of 10% ammonium hydroxide. The
precipitate was cooled to S-lOoC for 2 hours) was filtered
and dried at 80oC under Vacuum. 4.1 g of ciprofloxacine (I)
were obtained as a solid, with m.p. 250-255oC with
decomposition (Yield 52/).