METHOD OF SYNTHESIS OF FERROQUINE
BY CONVERGENT REDUCTIVE AMINATION
The present invention relates to a new method of synthesis of ferroquine
particularly useful for the treatment and/or prevention of malaria.
Malaria is one of the primary infectious causes of mortality in the world and affects
annually more than 500 million people, among whom 3 million die each year.
Four types of parasites of the genus Plasmodium, carried by Anopheles
mosquitoes, spread malaria. Plasmodium falciparum, widespread in Africa, is the most
virulent parasite among them and is responsible for the deadly forms of the disease.
Among the active principles against Plasmodium falciparum, chloroquine is an
antimalarial of the family of the 4-aminoquinolines, widely used, but for which resistances
have developed since the 1960s. Artemisinin then made its appearance and proves
effective against forms of Plasmodia resistant to chloroquine. However, since 2006, the
WHO noted the risk of resistance of the parasite to this molecule. It was in this same year
2006 that a new molecule, ferroquine (SSR97193), was discovered, displaying efficacy
against the strains of Plasmodium falciparum resistant to chloroquine described in
Malaria Journal 2006, 5:1 1 and Malaria Journal 2007, 6: 8 1.
Ferroquine is an organometallic complex of iron. In particular, it is a derivative of
4-aminoquinoline coupled to a ferrocene nucleus.
Ferroquine, also called ferrocene-chloroquine or ferrochloroquine, corresponds to
7-chloro-4-[(2-N,N-dimethyl-aminomethyl)ferrocenylmethylamino]quinoline. It can be in
the form of free base, but also in the form of salt, of hydrate or of solvate (these last being
defined as associations or combinations of ferroquine with, respectively, one or more
molecules of water or of solvent). Advantageously, ferroquine is used in the form of free
base.
Ferroquine of formula (F) in the form of free base and its principal metabolite (Fm)
are represented below in scheme 1.
Ferroquine is described in patent WO 96/35698, as well as in scientific articles
such as J. Med. Chem., 1997, 40, 3715-3718, Antimicrob. Agents Chemother., 1998, 42,
540-544, J. Org. Chem., 1999, 589, 59-65 and J. Organometallic Chem., 2004, 689,
4678-4682.
Scheme 1
The known method for the manufacture of ferroquine, partially represented in
scheme 2 below, consists in synthesizing firstly 1-[(dimethylamino)methyl]-2-formylferrocene
from (dimethylamino)methyl-ferrocene with a yield of about 85%, then in
preparing the corresponding intermediate oxime, and finally in carrying out reduction of
this oxime which leads to obtaining 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene
which can be isolated in the form of dihydrochloride. The yield of synthesis of the
dihydrochloride 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene relative to 1-
[(dimethylamino)methyl]-2-formyl-ferrocene is 55-65%.
Scheme 2
Ferroquine
This latter reaction sequence comprises firstly the condensation reaction of 1-
[(dimethylamino)methyl]-2-formyl-ferrocene with the reagent hydroxylamine to lead to
production of the corresponding oxime. Then, reduction of the oxime function to amine by
the metal hydride LiAIH4 is carried out in rigorously anhydrous medium in order to form
after hydrolysis 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene, isolated in the form
of dihydrochloride. The latter hereinafter is also called dihydrochloride of diamino
ferrocene which is a salt of 1-(aminomethyl)-2-[(dimethylamino)methyl]-ferrocene, itself
hereinafter called diamino ferrocene or diamino ferrocene in the form of free base.
Once diamino ferrocene in the form of free base, or its salt of
dihydrochloride SSR244090A is obtained, the latter can be reacted in the presence of (i)
a base, such as for example soda or triethylamine and (ii) of 4,7-dichloroquinoline in
order to synthesize ferroquine by aromatic nucleophilic substitution. This stage of the
synthesis of ferroquine, known and described, is transposable to diamine ferrocene in the
form of free base. The ferroquine thus obtained can then undergo a purification in order
to obtain pure ferroquine.
However, there are many drawbacks connected with this method. In fact, the risks
associated with the use of reagents such as hydroxylamine (unstable and explosive) and
LiAIH4 (inflammable and very reactive in damp conditions), as well as the use of an
intermediate such as the oxime SSR244089, (thermally unstable) do not allow envisaging
the production of ferroquine in adequate conditions of hygiene and safety from an
industrial standpoint.
Moreover, the use of particularly expensive reagents, such as for example LiAIH4,
and the low productivity of this method (large number of stages, dilutions) contribute
significantly to the cost of manufacture of Ferroquine. Now, with the aim of permitting
access to ferroquine for the greatest number in poor countries, which moreover have the
greatest need for it, it is essential to minimize the cost of manufacture of an active
principle such as this in order to reduce significantly the cost price of antimalarial
treatment.
The applicant has now found a new method of synthesis of ferroquine of formula
(F) or of its metabolite of formula (Fm) making it possible to form said ferroquine or said
metabolite directly from aldhehyde-amino ferrocene of formula (III), in which R represents
a hydrogen atom or a methyl group (Me), and from 7-chloroquinolin-4-amine.
The method according to the invention therefore consists in coupling the
aldhehyde-amino ferrocene of formula (III) with 7-chloroquinolin-4-amine according to a
reaction of reductive amination, called convergent, represented in scheme 3.
Scheme 3
The reaction of reductive amination therefore takes place in a single stage but in
several steps:
• Firstly, 7-chloroquinolin-4-amine reacts with the carbonyl function of
aldehyde-amino ferrocene of formula (III), to form an imine function (which can be
protonated to iminium if the reaction mixture is acid) according to a reaction of
condensation, with liberation of a molecule of water;
· Secondly, the imine function of the imino ferrocene intermediate of formula
(II), or if applicable of the iminium, is then reduced by a hydride donor.
• Thirdly, the reaction mixture is hydrolyzed in the presence of an aqueous
solution of ammonia or else of citric acid, in order to destroy the excess hydride employed
and permit isolation of ferroquine (F) or of its metabolite (Fm).
The imino ferrocene intermediate of formula (II) or the corresponding iminium, not
shown, does not to be isolated in contrast to the oxime-amino ferrocene (SSR244089) of
the prior art represented above. The reaction of convergent reductive amination
according to the present invention can therefore be carried out as a so-called one pot
process. Moreover, the imino ferrocene intermediate of formula (II) not being stable in
conditions of analysis by liquid phase chromatography, its formation can be followed
qualitatively by thin-layer chromatography or in situ by Infrared analysis.
Rev 1 The invention therefore relates to a method of synthesis of ferroquine of
formula (F) or of its metabolite of formula (Fm):
comprising a reaction of reductive amination, in which reaction:
(i) the aldhehyde-amino ferrocene of formula (III),
e
(III)
in which R represents a hydrogen atom or a methyl group, is condensed with 7-
chloroquinolin-4-amine
(ii) the product of condensation thus obtained of formula (II),
( )
is reduced,
with R representing a hydrogen atom or a methyl group,
(iii) the reaction mixture is hydrolyzed.
After hydrolysis, the ferroquine of formula (F) and its metabolite of formula (Fm)
are isolated.
Rev 2 According to the present invention, said compounds 7-chloroquinolin-4-amine and
aldehyde-amino ferrocene of formula (III) are advantageously present in stoichiometric
proportion.
Rev 3 The reaction of reductive amination according to the invention takes place
in the presence of at least one reaction solvent suitable both for said stage of
condensation and for said stage of reduction. This reaction solvent is selected from the
protic and aprotic solvents, such as for example ethanol, isopropanol, toluene, THF,
dichloromethane and mixtures thereof. The protic solvents are particularly advantageous.
We may thus mention ethanol and/or isopropanol, advantageously isopropanol, as
reaction solvent permitting particularly advantageous yields of reductive amination to be
obtained.
The stage of condensation
Rev 4 The stage of condensation of 7-chloroquinolin-4-amine with the aldehydeamino
ferrocene of formula (III) takes place in the presence of:
• at least one Lewis acid, or
• at least one Br0nsted base or a Br0nsted acid.
This stage can preferably take place under azeotropic distillation of the reaction
solvent of said stage of condensation or in the presence of at least one drying agent.
The stage of condensation of 7-chloroquinolin-4-amine with aldehyde-amino
ferrocene of formula (III) can take place in the presence of at least one Lewis acid such
as Ti(OiPr) 4, TiCI4, FeCI3, ZnCI2, AICI3 and BF3. The Lewis acid BF3 can be in the form of a
complex such as for example BF3.OEt2 and BF3.S(Me)2.
Rev 5 Thus, in the method according to the invention, the Lewis acid is selected
from Ti(OiPr) 4, TiCI4, FeCI3, ZnCI2, AICI3, BF3, BF3.OEt2 and BF3.S(Me)2.
Rev 6 According to a particularly advantageous embodiment, the Lewis acid is
Ti(OiPr) 4.
Rev 7 The Lewis acid can be used in stoichiometric amount or in excess.
Rev 8Advantageously, the Lewis acid is used in an amount between 1 and 2
equivalents, even more advantageously the Lewis acid is present at the level of 1
equivalent.
According to a particularly advantageous embodiment of the stage of
condensation in the presence of the Lewis acid Ti(OiPr)4, 7-chloroquinolin-4-amine, the
aldehyde-amino ferrocene of formula (III) and said Lewis acid are present at a level of 1
equivalent each. In this case, the reaction solvent is preferably isopropanol.
Rev 9The stage of condensation of 7-chloroquinolin-4-amine with aldehyde-amino
ferrocene of formula (III) can take place in the presence of at least one Br0nsted acid or a
Bransted base selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic
acid, H2S0 4, H3P0 4, HN0 3, piperidine and proline.
Rev lOAdvantageously it is para-toluenesulfonic acid or piperidine, even more
advantageously it is para-toluenesulfonic acid.
According to an embodiment particularly relating to the stage of condensation in
the presence of a Bransted acid, advantageously para-toluenesulfonic acid, said stage of
condensation takes place under azeotropic distillation of the reaction solvent. In this
case, the reaction solvent is preferably toluene.
Since the stage of condensation of an equivalent of 7-chloroquinolin-4-amine with
an equivalent of aldehyde-amino ferrocene of formula (III) is accompanied by the
liberation of an equivalent of water, it is conceivable to trap the water thus formed by
means of a drying agent or to evacuate this water from the reaction mixture by carrying
out an azeotropic distillation with a suitable reaction solvent such as for example the
protic and aprotic solvents enumerated above. This azeotropic distillation can be effected,
for example by means of a Dean-Stark, during said stage of condensation, with the aim of
displacing the equilibrium toward formation of the imino ferrocene intermediate (II), or
iminium if applicable. Said azeotropic distillation can optionally take place at reduced
pressure, for example, at a pressure in the range from 100 to 300 mbar.
The stage of condensation of 7-chloroquinolin-4-amine with the aldehyde-amino
ferrocene of formula (III) can therefore take place in the presence of at least one drying
agent or Rev 11 can take place under azeotropic distillation of the reaction solvent from
said reaction of condensation.
Rev 12 As drying agent mention may be made of alumina, a molecular sieve 3A,
MgS0 4 and Na2S0 4.
Rev 13 Advantageously, it is a molecular sieve 3A.
The stage of reduction
The stage of reduction of the intermediate obtained at the end of the stage of
condensation between 7-chloroquinolin-4-amine with the aldehyde-amino ferrocene of
formula (III), Rev 14 is carried out in the presence of at least one hydride donor.
The hydride donors known in the state of the art, particularly advantageous for
said reaction of reduction, are hydrogen in the presence of a catalyst (transition metal,
optionally in the form of complex) and metal hydrides. The metal hydrides are selected
from borohydrides of sodium, of potassium, of lithium or of zinc and are optionally
coupled to at least one additive selected from LiCI, CaCI2, MgCI2, ZnCI2 and NEt3. Said
borohydrides of sodium, of potassium, of lithium or of zinc are selected from
NaBH(OAc) 3, NaBH3CN, NaBH4, KBH4, LiBH4 and Zn(BH4)2 coupled or not to said
additive.
NaBH4, KBH4 and LiBH4, coupled or not to said additive prove particularly
advantageous for carrying out the reaction of reduction of the imino ferrocene
intermediate of formula (II), if necessary of the corresponding iminium, not shown.
Hydrolysis
Rev 24 The stage of hydrolysis takes place in the presence of an aqueous
solution of ammonia or of citric acid.
When Ti(OiPr) 4 is used as Lewis acid during the stage of condensation, hydrolysis
of the reaction mixture in the presence of an aqueous solution of citric acid is a
particularly advantageous embodiment since it permits removing the titanium salts at the
level of the aqueous phases and thus permits avoiding very difficult filtration of these
salts.
Rev 19 According to one embodiment of the method of the invention, the stage of
condensation takes place in the presence of toluene as reaction solvent, optionally under
azeotropic distillation, for example by means of a Dean-Stark. In this embodiment, the
stage of reduction preferably takes place in the presence of NaBH4. Rev 19
Rev 20 According to one embodiment of the method of the invention, the stage of
condensation takes place in the presence of molecular sieve 3A as drying agent. In this
embodiment, the stage of reduction preferably takes place in the presence of NaBH4.
Rev 2 1According to one embodiment of the method of the invention concerning the stage
of condensation in the presence of a Bransted acid, advantageously para-toluenesulfonic
acid, said stage of condensation takes place under azeotropic distillation of the reaction
solvent. This solvent is advantageously toluene. In this embodiment, the reaction of
reduction preferably takes place in the presence of NaBH4.
According to one embodiment of the method of the invention concerning the stage
of condensation in the presence of toluene as reaction solvent, said stage of
condensation takes place under azeotropic distillation. In this embodiment, the stage of
reduction preferably takes place in the presence of NaBH4.
According to one embodiment of the method of the invention concerning the stage
of condensation in the presence of a Lewis acid, advantageously titanium tetraisopropylate,
Rev 22 the reaction solvent is preferably isopropanol.
According to one embodiment of the method of the invention, the stage of
condensation takes place in the presence of 1 to 2 equivalents of Ti(OiPr) 4 in ethanol
and/or isopropanol as reaction solvent. In this embodiment, the stage of reduction
preferably takes place in the presence of LiBH4 and/or of NaBH4 and/or of KBH4 and the
stage of hydrolysis preferably takes place in the presence of an aqueous solution of citric
acid.
Rev 23 According to one embodiment, the stage of condensation takes place in
the presence of 1 equivalent of Ti(OiPr) 4 in ethanol and/or isopropanol as reaction solvent
and the stage of reduction preferably takes place in the presence of LiBH4 and/or of
KBH4.
At the end of this reaction of reductive amination, ferroquine (F) or its metabolite
(Fm) is formed in the form of free base or of salt, for example of salt of
dihydrochloride.
Ferroquine in the crude form can be isolated and purified according to techniques
known by a person skilled in the art. The isolation of crude ferroquine at the end of the
method of synthesis according to the invention, can be done by crystallization in a
suitable solvent. Acetone, toluene, isopropanol or methyl ethyl ketone may be mentioned.
Advantageously, it is acetone or toluene, even more advantageously it is toluene.
The method of synthesis according to the invention has the advantage relative to
the prior art of being shorter if we consider the number of reaction stages and having
better performance in terms of yield and productivity. Accordingly, it makes it possible to
lower the final cost price of ferroquine through (i) the use of inexpensive reagents, (ii) a
reduction in the number of reaction stages relative to the route of synthesis currently used
and represented in scheme 1 above and (iii) obtaining particularly advantageous reaction
yields: the isolated yield of crude ferroquine is about 70-75 mol% relative to the starting
aldehyde-amino ferrocene of formula (III).
Moreover, it offers the advantage of being safer with the absence of reagents or
intermediates that may prove dangerous to handle.
The invention will now be described in more detail.
The following procedures and examples describe the preparation of intermediates
of ferroquine and of ferroquine according to the invention. These procedures and
examples are not limiting and their only purpose is to illustrate the present invention.
In the procedures and examples below:
- The NMR (nuclear magnetic resonance) spectra are obtained with a Fourier
transform spectrometer (BRUKER), at a temperature of 300°K (exchangeable protons not
recorded);
- s = singlet,
- d = doublet,
- m = multiplet,
- br = broad signal,
- = triplet,
- q = quadruplet,
- DMSO-d6 = deuterated dimethylsulfoxide,
- CDCI3 = deuterated chloroform;
The NMR spectra confirm the structures of the compounds obtained according to
examples below.
In the examples given below, the following abbreviations are used:
MTBE: Tert-Butyl-Methyl-Ether
LiBH4: lithium borohydride
NaBH4: sodium borohydride
KBH4: potassium borohydride
Ti(OiPr) 4: tetraisopropoxy-titanium
DMF: N,N-dimethylformamide
4,7-DCQ: 7-chloroquinolin-4-amine
MeOH: methanol
EtOH: ethanol
MEK: methyl ethyl ketone
tBuLi: t-butyllithium
DCM: dichloromethane
RT: room temperature
pTSA: para-toluenesulfonic acid
MP: melting point in°C
The mixtures of solvents are quantified in volume ratios, ml signifying milliliter.
In the following procedures, the starting compounds and the reagents, when their
method of preparation is not described, are commercially available or are described in the
literature, or else can be prepared according to methods described or known by a person
skilled in the art.
PREPARATIONS
1. Preparation of the compounds of formula (III)
Preparation of 1-[(dimethylamino)methyl]-2-formyl-ferrocene.
Charge an inertized reactor with 39.6 g of 1-[(dimethylamino)methyl]-ferrocene
and 360 ml of MTBE. Distil about 160 ml of MTBE (4V) at atmospheric pressure. Cool the
solution to -10°C and slowly add 98.2 ml of a solution of t-BuLi in heptane (titer 16%). Stir
the reaction mixture at -10°C for 2 hours and then at 0°C, slowly add 25.2 ml of DMF.
Continue stirring the reaction mixture at 20°C for 2 hours then at 5°C, slowly add 135 ml
of 1.5N aqueous HCI. Continue stirring the reaction mixture at 5°C for 30 min, then at
20°C for 30 min. Leave the reaction mixture to settle and withdraw the aqueous phase
then the MTBE phase. Counter-extract the aqueous phase with 125 ml of MTBE. Filter
the combined MTBE phases on activated charcoal then concentrate to 120 ml under
vacuum. Add 80 ml of isopropanol then distil 420 ml of solvent to constant volume, under
vacuum, by regular addition of isopropanol. At the end of distillation, dilute the reaction
mixture to 280 ml with isopropanol. 39.9 g of the expected compound is obtained in
solution in isopropanol.
2. Preparation of 7-chloroquinolin-4-amine
2.1 Preparation of 7-chloroquinolin-4-amine.
Stir a mixture of 100 g of 4,7-DCQ and 1 liter of 5% solution of ammonia in
methanol at 160°C for at least 15 hours. After complete conversion of the 4,7-DCQ,
concentrate the reaction mixture to 300 ml then slowly add 400 ml of a dilute aqueous
solution (3.2%) of soda. Filter the suspension on a Buchner and rinse the cake with
100 ml of a water / MeOH mixture (70/30, v/v), then with 100 ml of water. Dry the beige
solid in a stove at 100°C under vacuum. 85.5 g of the expected compound is obtained.
MP = 187° (with decomposition).
2.2 Purification of 7-chloroquinolin-4-amine.
Heat a mixture of 85 g of the compound obtained in the preceding stage and
550 ml of toluene under reflux until complete dissolution then cooled slowly to 20°C. Filter
the suspension on a Buchner. Rinse the cake with 85 ml of toluene then dry in a stove at
100°C under vacuum. 76.8 g of the expected product is obtained.
EXAMPLES
The following procedures and examples describe the preparation of crude
ferroquine from 7-chloroquinolin-4-amine and of 1-[(dimethylamino)methyl]-2-formylferrocene
(example 1 to 6) as well as the purification of said crude ferroquine (example
7).
Example 1:
Heat a mixture of 0.5 g of the compound from preparation 2.2, 0.76 g of the
compound from preparation 1, 25 mg of ApTS and 5 ml of toluene under reflux and
remove the water by azeotropic distillation for 16 h. Concentrate the reaction mixture
under vacuum and take up in 10 ml of absolute EtOH. Add 0.21 g of NaBH4 and stir the
reaction mixture for 16 h. Concentrate the reaction mixture under vacuum then take up in
40 ml DCM and a mixture of 20 ml of water and 2 ml of ammonia 25%. Leave the mixture
to settle then extract the aqueous phase 4 times in 20 ml of DCM. Combine and
concentrate the organic phases under vacuum, and crystallize the residue in 20 ml of
acetone. Filter the solid cold on a Buchner, rinse with 2 times 5 ml of cold acetone then
dry in a stove under vacuum. 0.37 g of the expected compound is obtained. A second
crystallization stream is recovered from the mother liquor and the wash liquor, from which
crystallization stream 0.1 1 g of the expected compound is obtained.
MP = 197°C.
1H-NMR (DMSOd6, 500 MHz): 2. 15 (s, CH3, 6H), 2.92 (d, NCH2, 1H), 3.82 (d, NCH2,
1H), 4.05 (t, CH, 1H), 4. 17 (s, CH, 5H), 4. 19 (dd, CH, 1H), 4.28 (dd, NCH2, 1H), 4.31 (dd,
CH, 1H), 4.38 (dd, NCH2, 1H), 6.67 (d, CH, 1H) 7.48 (dd, CH, 1H), 7.75 (dd, NH, 1H),
7.78 (d, CH, 1H), 7.85 (d, CH, 1H), 8.42 (d, CH, 1H).
Example 2:
Put 3.3 g of the compound from preparation 2.2, 5 g of the compound from
preparation 1 and 50 ml of isopropanol in a flask. Add 10.9 ml of Ti(OiPr) 4. Stir the
reaction mixture at RT for 24h. Cool the reaction mixture to 0°C and add 0.4 g of LiBH4 in
portions at 0°C. Stir the reaction mixture allowing the temperature to rise to RT for 16h,
then dilute with 50 ml of DCM. Pour this solution onto 40 ml of an aqueous solution of
® ammonia at 12.5%. After 30 minutes of stirring, filter the suspension on Clarcel . Then
rinse the cake with 6 times 20 ml of DCM. Wash the organic phase with 30 ml of 1N soda
then concentrate under vacuum to 40 ml. Effect a change of solvent DCM/acetone by
distillation at constant volume. Cool the suspension under reflux of the ketone at 5°C.
Filter the solid on a Buchner, rinse with 2 times 9 ml of cold acetone and dry in a stove
under vacuum. 4.2 g of the expected compound is obtained.
Example 3:
Put 13.4 g of the compound from preparation 2.2 and 152.2 g of the compound
from preparation 1 at 13.5% in isopropanol in a reactor. Add 42.8 g of Ti(OiPr) 4. Stir the
reaction mixture at 25°C for at least 20h. Then put 5.7 g of finely divided NaBH4 and
60 ml of isopropanol in a second reactor and cool to 0°C. Slowly pour the solution of
imine intermediate onto this suspension of NaBH4 at 0°C. Stir the reaction mixture at
25°C for at least 20 h, concentrate under vacuum then dilute with 150 ml of DCM. Cool
the solution obtained to 0°C then hydrolyze at 0°C with 60 ml of an aqueous solution of
ammonia at 25%. Return the suspension to 20°C then filter on Clartex. Rinse the cake
with 5 times 20 ml of DCM. Concentrate the organic phase under vacuum to 200 ml.
Effect a change of solvent DCM/acetone by distillation at constant volume. Cool the
suspension under reflux of the ketone at 5°C. Filter the solid on a Buchner, rinse with 2
times 20 ml of cold acetone and dry in a stove under vacuum. 23.1 g of the expected
compound is obtained.
Example 4:
Put 13.2 g of the compound from preparation 2.2 and 125 g of a 16% solution of
the compound from preparation 1 in isopropanol in a reactor. Add 42.0 g of Ti(OiPr) 4. Stir
the reaction mixture at 25°C for at least 20 hours. Put 8.0 g of KBH4 and 60 ml of
isopropanol in a second reactor and cool to 0°C. Slowly pour the solution of imine
intermediate onto this suspension of KBH4 at 0°C. Stir the reaction mixture at 25°C for at
least 20 h, concentrate under vacuum then dilute with 130 ml of DCM. Cool the solution
obtained to 0°C then hydrolyze at 0°C with 60 ml of an aqueous solution of ammonia at
25%. Allow the temperature of the suspension to rise to 20°C then filter on textile fiber;
rinse the cake with 5 times 20 ml of DCM. Concentrate the organic phase under vacuum
to 100 ml. Effect a change of solvent DCM/acetone by distillation at constant volume.
Cool the suspension under reflux of the ketone at 5°C. Filter the solid on a Buchner, rinse
with 2 times 20 ml of cold acetone and dry in a stove under vacuum. 23.1 g of the
expected compound is obtained.
Example 5:
Put 26.3 g of the compound from preparation 2.2 and 227 g of a solution of the
compound from preparation 1 at 17.4% in isopropanol in a reactor. Add 83.8 g of
Ti(OiPr) 4. Stir the reaction mixture at 40°C for at least 5 hours.
Put 15.9 g of KBH4 and 120 ml of isopropanol in a second reactor and cool to 0°C. Slowly
pour the solution of imine intermediate onto this suspension of KBH4 at 0°C. Then stir the
reaction mixture at 25°C for at least 20 h, then heat at 50°C for at least 3 h. Hydrolyze the
reaction mixture at 20°C by slowly adding 500 g of an aqueous solution of citric acid at
11.3%, then 75 g of an aqueous solution of ammonia at 20%. Add 400 ml of toluene, stir
the reaction mixture at 50°C for 30 min. Leave the organic phase to settle at 50°C, wash
at 50°C with 3 times 120 ml of water then filter on activated charcoal. Concentrate the
organic phase under vacuum to 400 ml, then distil under vacuum to constant volume by
adding 1 liter of toluene. Heat the toluene phase at 90°C until completely dissolved then
cool to 5°C. Filter the solid on a Buchner, rinse with 40 ml of cold MEK and dry in a stove
under vacuum. 47.5 g of the expected compound is obtained.
Example 6:
Put 26.3 g of the compound from preparation 2.2 and 217 g of a solution of the
compound from preparation 1 at 18.4% in isopropanol in a reactor. Add 4 1.9 g of
Ti(OiPr) 4. Stir the reaction mixture at 40°C for at least 8 h. Put 15.9 g of KBH4 and 120 ml
of isopropanol in a second reactor and cool to 0°C. Slowly pour the solution of imine
intermediate onto this suspension of KBH4 at 0°C. Stir the reaction mixture at 20°C for at
least 20 h, then heat at 50°C for at least 3 h. Hydrolyze the reaction mixture at 20°C by
slowly adding 320 g of an aqueous solution of citric acid at 13.2%, then 56 g of an
aqueous solution of ammonia at 20%. Add 400 ml of toluene, then stir the reaction
mixture at 50°C for 30 min. Leave the organic phase to settle at 50°C, wash at 50°C with
3 times 120 ml of water then filter on activated charcoal. Concentrate the organic phase
under vacuum to 400 ml, then distil under vacuum to constant volume by adding 1 liter of
toluene. Heat the toluene phase at 90°C until completely dissolved then cool to 5°C. Filter
the solid on a Buchner, rinse with 2 times 40 ml of cold MEK and dry in a stove under
vacuum. 50.7 g of the expected compound is obtained.
Example 7:
Put 24.0 g of crude ferroquine and 345 ml of MEK in a reactor and heat to 78°C.
Cool the solution to 67°C and initiate by adding 0.24 g of ferroquine in suspension in
1.2 ml MEK. Stir the mixture for 1 hour at 67°C then cool to 10°C. Filter the suspension at
10°C on a Buchner then wash the cake with 48 ml of MEK. Dry the solid in a stove under
vacuum. 20.2 g of the expected compound is obtained.
CLAIMS
A method of synthesis of ferroquine of formula (F) or of its metabolite of
formula (Fm):
comprising a reaction of reductive amination, in which reaction:
(i) the aldhehyde-amino ferrocene of formula (III),
e
(III)
in which R represents a hydrogen atom or a methyl group, is condensed with 7-
chloroquinolin-4-amine
(ii) the product of condensation thus obtained of formula (II),
is reduced,
with R representing a hydrogen atom or a methyl group,
(iii) the reaction mixture is hydrolyzed prior to isolation of the ferroquine of
formula (F) or of its metabolite of formula (Fm).
2. The method as claimed in claim 1, wherein said compounds 7-chloroquinolin-4-
amine and aldehyde-amino ferrocene of formula (III) are in stoichiometric
proportion.
3. The method as claimed in either one of claims 1 and 2, characterized in that
the reaction of reductive amination takes place in the presence of at least one
reaction solvent selected from ethanol, isopropanol, toluene, THF,
dichloromethane and mixtures thereof.
The method as claimed in any one of claims 1 to 3, characterized in that the
stage of condensation of 7-chloroquinolin-4-amine with aldehyde-amino
ferrocene of formula (III) takes place in the presence of:
■ at least one Lewis acid, or
■ at least one base or a Bransted acid.
The method as claimed in any one of claims 1 to 4, characterized in that the
stage of condensation of 7-chloroquinolin-4-amine with aldehyde-amino
ferrocene of formula (III) takes place under azeotropic distillation of the reaction
solvent of said stage of condensation or in the presence of at least one drying
agent.
6. The method as claimed in claim 4, characterized in that the Lewis acid is
selected from Ti(OiPr) 4, TiCI4, FeCI3, ZnCI2, AICI3, BF3, BF3.OEt2 and
BF3.S(Me)2.
7. The method as claimed in claim 6, characterized in that the Lewis acid is
Ti(OiPr) 4.
8. The method as claimed in any one of claims 4 to 7, characterized in that the
Lewis acid is used in stoichiometric amount or in excess.
9. The method as claimed in any one of claims 4 to 8, characterized in that the
Lewis acid is used in an amount between 1 and 2 equivalents.
10. The method as claimed in claim 4, characterized in that the stage of
condensation takes place in the presence of at least one Bransted acid or a
Bransted base selected from acetic acid, trifluoroacetic acid, methanesulfonic
acid, para-toluenesulfonic acid, H2S0 4, H3P0 4, HN0 3, piperidine and proline.
11. The method as claimed in claim 10, characterized in that the stage of
condensation takes place in the presence of para-toluenesulfonic acid or of
piperidine.
12. The method as claimed in claim 5, characterized in that the drying agent is
selected from alumina, molecular sieve 3A, MgS0 4 and Na2S0 4.
13. The method as claimed in any one of claims 1 to 12, characterized in that the
stage of reduction takes place in the presence of at least one hydride donor
selected from hydrogen in the presence of a catalyst and metal hydrides.
14. The method as claimed in claim 13, characterized in that the metal hydrides
are selected from the borohydrides of sodium, of potassium, of lithium or of
zinc, coupled or not to at least one additive selected from LiCI, CaCI2, MgCI2,
ZnCI2 and NEt3.
15. The method as claimed in either of claims 13 and 14, characterized in that the
borohydrides of sodium, of potassium, of lithium or of zinc are selected from
NaBH(OAc) 3, NaBH3CN, NaBH4, KBH4, LiBH4 and Zn(BH4)2, coupled or not to
said additive.
16. The method as claimed in claim 15, characterized in that the reduction reaction
takes place in the presence of NaBH4, KBH4 and LiBH4, coupled or not to said
additive.
17. The method as claimed in any one of claims 1 to 5 and characterized in that
the stage of condensation takes place in the presence of para-toluenesulfonic
acid, under azeotropic distillation of the reaction solvent.
18. The method as claimed in claim 17, characterized in that the stage of
condensation takes place in the presence of toluene.
19. The method as claimed in either one of claims 17 and 18 characterized in that
the stage of reduction takes place in the presence of NaBH4.
20. The method as claimed in any one of claims 1 to 5 characterized in that the
stage of condensation takes place in the presence of titanium tetra-isopropylate
and of isopropanol as reaction solvent.
21. The method as claimed in any one of claims 1 to 5, characterized in that the
stage of condensation takes place in the presence of 1 equivalent of Ti(OiPr) 4
in ethanol and/or isopropanol as reaction solvent and the stage of reduction
takes place in the presence of LiBH4 and/or of KBH4.
22. The method as claimed in any one of claims 1 to 5, characterized in that the
stage of hydrolysis takes place in the presence of an aqueous solution of citric
acid.