Note: Descriptions are shown in the official language in which they were submitted.
CA 02789373 2012-08-08
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PROCESS FOR PREPARING CHEMICAL COMPOUNDS OF INTEREST BY
NUCLEOPHILIC AROMATIC SUBSTITUTION OF AROMATIC CARBOXYLIC
ACID DERIVATIVES SUPPORTING AT LEAST ONE ELECTRO-
ATTRACTIVE GROUP
Field of the invention
This invention relates to the field of chemical synthesis, and in particular
the
invention proposes a new process enabling to perform a nucleophilic aromatic
substitution on aromatic carboxylic acid derivatives bearing at least one
electron
withdrawing group other than the leaving group, in the absence of a catalyst
and
without a step of protection/deprotection of the acid function of the starting
compound.
Prior art
Nucleophilic aromatic substitution is a reaction whose the interest is well
known, and which is widely used in industry. However, it has disadvantages,
which
are widely reported, in particular the requirement to use catalysts, and the
requirement to protect/deprotect the carboxyl function (CO2H), necessary as a
carbon
anchoring point for subsequent chemical functionalization.
The use of catalysts is restrictive because they have to be trapped and
removed at the end of the reaction. They are polluting residues and are also
susceptible of leaving traces of heavy metals in the reaction products (see,
for
example, Kônigsberger et al, Organic Process Research & Development 2003, 7,
733-742, or Pink et al. Organic Process Research & Development 2008, 12, 589-
595).
The need for protection/deprotection of the carboxyl function (CO2H) is
considered as a limiting requirement of nucleophilic substitution. It is
indeed
generally accepted that the CO2H function reacts with organometallic compounds
to
lead to ketone derivatives, generally undesired (Jorgenson, M. J. Org. React.
1970,
18, 1. Ahn, T.; Cohen, T. Tetrahedron Lett. 1994, 35, 203). Therefore, the
protection
of the carboxylic function at the start of the nucleophilic substitution
reaction appears
to be an compulsory step. The protective groups used are generally sterically
bulky
and are considered to promote nucleophilic substitution.
CA 02789373 2012-08-08
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The ability to overcome these requirements for catalysis and
protection/deprotection is therefore a constant technical problem in the
chemical and
pharmaceutical industry.
In the application FR 1051226, the Applicant discloses a process of
nucleophilic aromatic substitution on an industrial scale and with a high
yield, and an
optimized number of steps. In this process, the nucleophilic aromatic
substitution
reaction is performed on a carboxylic acid derivative or a sait thereof, said
derivative
being not substituted by an electron withdrawing group other than the leaving
group.
The Applicant, in pursuing his work, observed surprisingly that the use of
carboxylic acid derivatives substituted by at least one electron withdrawing
group
other than the leaving group, in particular difluorobenzoic acids, as starting
compound, enabled him to avoid any nucleophilic attack on the carboxylate,
nevertheless unprotected. As a consequence, ketone formation becomes very
minor
when the experimental conditions are well chosen and the ipso-substitution
products
of interest are predominantly obtained. In particular, the presence of a first
fluorine
atom in ortho position of the carboxyl function and a second fluorine atour in
position 4 or 6 of the aromatic ring renders the carobxylate inert to
nucleophilic
attack. This invention therefore makes it possible to minimize the formation
of by-
products.
General description
Thus, the invention relates to a selective process for preparing aromatic
carboxylic acid derivatives by nucleophilic aromatic substitution, wherein the
following are reacted:
an aromatic carboxylic acid derivative bearing a carboxyl function and a
single one, or a sait thereof, preferably a lithium sait, a sodium sait, a
potassium sait
or a zinc sait, preferably a benzoic acid derivative or a sait thereof,
- said carboxylic acid derivative has, in ortho position of the carboxyl
function, a leaving group, which is a fluorine or chlorine atour or a chiral
or non-
chiral alkoxy group, and in this latter case, a methoxy group is preferred;
- said carboxylic acid derivative is substituted on a position of the ring
that is
not that occupied by the leaving group, by at least one electron withdrawing
group,
preferably a fluorine atom,
CA 02789373 2012-08-08
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with a MNu reactant, wherein M is a metal and Nu is a chiral or non-chiral
nucleophile,
given that:
- if the leaving group is a fluorine atom, and there is a bromine atom in para
position, and the other positions are substituted by hydrogen atoms, then NuM
is not
iBuMgCl or NuMgBr where Nu is the ethyl or isobutyl or cyclopentenyl group,
- if the leaving group is a fluorine atom, and there is a halogen in the other
ortho position, and there is a fluorine atom in para position as well as in
the meta
position adjacent to the leaving group and the other meta position is
substituted by a
hydrogen atom, then NuM is not an alkylating agent wherein Nu is C1_6 alkyl,
- if the starting compound is 2,3,4,6-tetrafluorobenzoic acid, then NuM is not
MeMgBr,
said nucleophilic aromatic substitution reaction is performed without catalyst
and without step of protection/deprotection of the acid function of the
starting
compound,
this process being selective in that the reaction leads to the very minor
formation of ketone derivatives during the reaction.
Preferably, the aromatic carboxylic acid derivative, starting product of the
reaction, is a benzoic acid derivative of general formula (II):
RI
R2
R6 #Rl
R5 R4 (II)
wherein
-RI is CO2H,
- R2 is a fluorine or chlorine atour or a chiral or non-chiral alkoxy group,
preferably OCH3
- R3 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl or an amine
substituted or not by one or two alkyl groups or an electron withdrawing
group, or
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R3 is a substituent capable of reacting in presence of a base and a metal to
form MNu,
or R3 may form a ring with R4,
- R4 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an
amine substituted or not by one or two alkyl groups or an electron withdrawing
group, or is a substituent capable of reacting in presence of a base and a
metal to
yield MNu, or R4 may form a ring with R3 or R5,
- R5 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an
amine substituted or not by one or two alkyl groups or an electron withdrawing
group, or is a substituent capable of reacting in presence of a base and a
metal to
yield MNu, or R5 may form a ring with R4 or R6,
- R6 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an
amine substituted or not by one or two alkyl groups or an electron withdrawing
group, or is a substituent capable of reacting in presence of a base and a
metal to
yield MNu, or R6 may form a ring with R5
given that at least one of R3, R4, R5 and R6 is an electron withdrawing group,
which is reacted with
a compound (III) of general formula NuM wherein Nu is a nucleophile, and
M is a metal, preferably Li, Mg, Zn, Cu or an organomagnesium derivative MgX
wherein X is a halogen atom or an alkoxy group, preferably OCH3,
said nucleophilic aromatic substitution reaction is performed without catalyst
and without step of protection/deprotection of the acid function of the
compound (II),
to selectively obtain a compound of general formula (I), which corresponds to
general formula (II) wherein at least R2 has been substituted by Nu,
given that:
- if the leaving group is a fluorine atom, and the para position is
substituted
by a bromine atom and the other positions are substituted by hydrogen atoms,
then
NuM is not iBuMgCl or NuMgBr wherein Nu is the ethyl or isobutyl or
cyclopentenyl group,
- if the leaving group is a fluorine atom, and there is a halogen in the other
ortho position, and there is a fluorine atom in para position as well as in
the meta
position adjacent to the leaving group, and the other meta position is
occupied by a
hydrogen atom, then NuM is not an alkylating agent wherein Nu is C1_6 alkyl,
CA 02789373 2012-08-08
- if the starting product is 2,3,4,6-tetrafluorobenzoic acid, then NuM is not
MeMgBr.
According to a preferred embodiment, at least one of R4 or R6 is an electron
5 withdrawing group, and the other being as defined above, and in this
embodiment
- according to a first alternative, when R6 is an electron withdrawing group,
and when R4 and R5 do not form a ring, then R3 and R4 may form together an
aromatic ring or not, or a heterocycle, optionally substituted, in particular
by a
functional group
- according to a second alternative, when R6 is an electron withdrawing group,
and when R3 and R4 do not together form a ring, then R4 and R5 may form
together
an aromatic ring or not, or a heterocycle, optionally substituted, in
particular by a
functional group
- according to a third alternative, when R4 is an electron withdrawing group,
then R5 and R6 may form together an aromatic ring or not, or a heterocycle,
optionally substituted, in particular by a functional group.
According to an embodiment, when R3 is a substituent capable of reacting in
presence of a base and a metal to afford MNu, then the substitution of the
leaving
group R2 by NuM leads to an intramolecular reaction.
According to an embodiment, R4, R5 or R6 is a substituent capable of
reacting in presence of a base and a metal to form MNu when one of the
adjacent
positions thereof is occupied by a substituent capable of acting as a leaving
group,
leading to an intramolecular reaction.
Procedure
Advantageously, the reaction is performed between -78 C and solvent reflux.
Preferably, the reaction is performed in a polar aprotic solvent, preferably
anhydrous
THF (tetrahydrofuran) or diethyl ether, benzene, toluene or a hydrocarbon such
as
pentane, hexane, heptane or octane.
Advantageously, NuM compound is preferably added dropwise, at a
temperature between -78 C and solvent reflux.
Preferably, the solution is stirred, and then hydrolyzed with water.
Advantageously, the hydrolysis is performed at low temperature. pH is adjusted
to 1
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with an aqueous chlorhydric acid solution (2N) and the solution is extracted
with an
appropriate solvent, for example ethyl acetate. The organic phase is then
dried and
concentrated under vacuum. The raw product is recrystallized or
chromatographied.
According to an embodiment of the invention, at least one equivalent of NuM
is used for one equivalent of starting aromatic carboxylic acid derivative.
Advantageously, in addition to this equivalent, one equivalent of NuM is added
per
leaving group of the starting molecule to be substituted.
According to another embodiment of the invention, at least one equivalent of
a metallic base, preferably butyllithium, sodium hydride, potassium hydride or
lithium hydride is used for one equivalent of starting aromatic carboxylic
acid
derivative in order to form the metal sait corresponding to the acid function
of the
aromatic carboxylic acid derivative, and at least one equivalent of NuM is
added per
leaving group of the staring molecule to be substituted.
The reaction is selective because the ketone is formed in a very minor amount
(< 10%). Expected yields for the reaction process according to the invention
are
between 45 and 100%, preferably 45 to 90%, and more preferably 60 to 90%.
Specific cases cases
Presence of an asymmetric carbon
According to a preferred embodiment, an asymmetric carbon is present on
said aromatic carboxylic acid derivative, preferably on said benzoic acid
derivative
of general formula (II) and/or on the nucleophile, and the compound of general
formula (I) obtained is asymmetric. Very advantageously, aromatic carboxylic
acid
derivative, preferably said benzoic acid derivative of general formula (1I),
has at least
one chiral leaving group.
Use of a chiral ligand
In a specific embodiment, a chiral ligand is added to the reaction mixture;
this
ligand is intended to provide chirality to the product (I) of the reaction of
the
invention.
According to the invention, said chiral ligand may be selected from chiral
diamines, chiral diethers, chiral aminoethers, multi-point binding chiral
aminoethers
CA 02789373 2012-08-08
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and bisoxazoline ligands. Examples of chiral ligands capable of being used are
depicted in table 1.
Example of chiral diamine H N
N Fi
Example of chiral diether PhPh
MeO OMe
Example of chiral aminoether Ph--N -
Me2N O
MeO
Example of multi-point binding chiral aminoether Me2N_
(OOfl
NMe2 Me2N
Example of bisoxazoline ligand
0 0
U~'y'
N
Table 1
Specific cases wherein R2 is a fluorine or chlorine atom
According to a first embodiment, when R2 is a fluorine or chlorine atom, then
Nu is not a substituted or non-substituted amine, in particular Nu is not an
aniline
derivative.
According to a second embodiment, when R2 is a fluorine or chlorine atom,
then Nu is not a substituted or non-substituted amine.
According to a third embodiment, R2 is a fluorine or chlorine atom, and the
nucleophile of the compound of general formula NuM is an aniline derivative.
In this
embodiment, according to a first aspect, compound NuM is obtained according to
the
synthesis routes described below, given that NuM is not the product of
reaction
between the nucleophile and a metallic base selected from lithium hydride,
sodium
hydride, potassium hydride, calcium hydride, lithium diisopropylamide, lithium
amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide,
CA 02789373 2012-08-08
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potassium tert-butoxide, magnesium ethoxide and LiHMDS. In this embodiment,
according to a second aspect, compound NuM is obtained by a reaction of
nucleophile and butyllithium.
Specific cases of difluorobenzoic acids
According to a specific embodiment of the process of the invention, the
compound of general formula (II) is such that:
- R1 is CO2H,
- R2 and R6 are each independently a fluorine atom, and
- R3, R4, R5 are each independently a hydrogen atom.
The reaction of this specific compound with a nucleophile NuM affords only
the mono- or di-substituted product. The corresponding ketones are not formed
and
the carboxyl function does not undergo nucleophilic attacks.
Thus, the following mono-substituted product or a mixture of mono- and di-
substituted products is obtained:
COZH CO'H CO2H
F NuM F Nu Nu Nu
H H
According to another specific embodiment of the process according to the
invention, the compound of general formula (II) is such that:
- R1 is CO2H,
- R2 and R4 are each independently a fluorine atom, and
- R3, R5, R6 are each independently a hydrogen atom
The reaction of this specific compound with a nucleophile NuM produces the
mono-substituted product only. The corresponding ketones are not formed and
the
carboxyl function does not undergo nucleophilic attacks.
The mono-substituted product or a mixture of mono- and di-substituted
products is obtained.
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CO2H CO2H C02H
H F NuM H Nu H Nu
F F Nu
Obtaining the NuM compound (III)
According to a first embodiment, compound NuM may be obtained by direct
synthesis (Carey & Sundberg, Advanced Organic Chemistry, Part A Chapter
7, "Carbanions and Other Nucleophilic Carbon Species", pp. 405-448).
According to a second embodiment, compound NuM may be obtained from
lithium salts and anion radicals (T. Cohen et al. JACS 1980, 102, 1201; JACS
1984,
106, 3245; Acc. Chem. Res, 1989, 22, 52).
According to a third embodiment, compound NuM may be obtained by
metal-halogen exchange (Parham, W. E.; Bradcher, C. K. Acc. Chem. Res. 1982,
15,
300-305).
According to a fourth embodiment, compound NuM may be obtained by
directed metallation (V. Snieckus, Chem. Rev, 1990, 90, 879; JOC 1989, 54,
4372).
According to a preferred embodiment of the invention, compound NuM is
obtained by reaction of the nucleophile and n-BuLi.
According to a preferred embodiment of the invention, compound NuM is
obtained by reaction of the nucleophile and a base, in particular a metallic
or an
organometallic base. According to a first embodiment, the base is not LiNH2.
According to a second embodiment, the metallic base is not selected from the
group
consisting of lithium hydride, sodium hydride, potassium hydride, calcium
hydride,
lithium diisopropylamide, lithium amide, sodium amide, potassium amide, sodium
methoxide, sodium ethoxide, potassium tert-butoxide, magnesium ethoxide, and
LiHMDS. According to a third embodiment, the base is butyllithium, and in this
embodiment, advantageously, compound NuM is obtained by reaction of
nucleophile
and n-BuLi. According to a fourth embodiment, the base is chiral and induces
chirality to NuM.
Preferably, Nu is a nucleophile selected from those depicted in tables 2, 3
and
4.
CA 02789373 2012-08-08
Nu M
Alkyl, preferably CH3 or C2H5 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
alkenyl, optionally substituted Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
Alkynyl optionally substituted Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
Aryl optionally substituted Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
s-Bu Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
t-Bu Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
n-Bu Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
4-MeOC6H4 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
2-MeOC6H4 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
2,5-diMeC6H4 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
4-Me2NC6H4 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
2-MeC6H4 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
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NI Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
N Li, Mg, Cu, Zn, or MgX wherein X is a
halo en or an alkoxy
~~ or g N N Li, Mg, Cu, Zn, or MgX wherein X is a
i - halo en or an alkoxy
or g Li, Mg, Cu, Zn, or MgX wherein X is a
y wherein Y is O, N or S halogen or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a
Q-Y3 halo alkox
wherein Y is O, N or S gen or an Y
P(Aryl)2 Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
PArylAlkyl Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
O(C1.6alkyl) Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
S(C1_6alkyl) Li, Mg, Cu, Zn, or MgX wherein X is a
halogen or an alkoxy
NH2 Li, Mg, Cu, Zn, or MgX wherein X is a
R18 Rt8
halogen or an alkoxy
i
R18 R18
R18 wherein R18 is a
hydrogen atom, an alkyl group,
an alkoxy group, an aryl or an
amine substituted or not by one or
two C1_12alkyl groups
Table 2
Nu M
N(C1-6alkyl)2 Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
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NH(C1-6alkyl), in Li, Mg, Cu, Zn, or MgX wherein X is a halogen
particular NH(tBu) or an alkoxy
NEt2 Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a halogen
NJ or an alkoxy
N(iPr)2 Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
N
Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
N(CH2CH2)2NMe Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy y
NMeBn Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
NBn2 Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
NMePh Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
NHt-Bu Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
NPh2 Li, Mg, Cu, Zn, or MgX wherein X is a halogen
or an alkoxy
Table 3
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According to a first preferred embodiment of the invention, in tables 2 and 3,
M is Li or Mg.
According to a preferred embodiment, M is Li, Mg, Cu, Zn, or MgX wherein
X is a halogen or an alkoxy and Nu is N(C1-6alkyl)2, NH(C1-6alkyl), NEt2,
N(CH2CH2)2NMe, NMeBn, NBn2, NMePh, NHt-Bu or NPh2.
Advantageously, in tables 2 and 3, when M is MgX and X is a halogen, then
the halogen is selected from F, Br, Cl. Advantageously, when M is MgX and X is
an
alkoxy, then the alkoxy is OCH3 or OC2H5. According to a preferred embodiment
of
the invention, M is MgBr or MgOCH3.
The preferred chiral NuM compounds according to the invention are
exemplified in table 4 below.
Nu M
Li, Mg
Li, Mg
~k Li, Mg
vw
Li, Mg, Cu, Zn
r I * Li, Mg, Cu, Zn
Li, Mg, Cu, Zn
N
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14
Nu m
N * Li, Mg, Cu, Zn
~N l * Li, Mg, Cu, Zn
Li, Mg, Cu, Zn
N
Li, Mg, Cu, Zn
i N * Li, Mg, Cu, Zn
I N * Li, Mg, Cu, Zn
~N * Li, Mg, Cu, Zn
wv
N Li, Mg, Cu, Zn
Li, Mg
y wherein Y is O, S or N
Li, Mg
Y wherein Y is O, S or N
Li, Mg
Y wherein Y is O, S or N
Li, Mg
Y wherein Y is O, S or N
NR R wherein R and R are each Li, Mg
independently a hydrogen atom, an alkyl
CA 02789373 2012-08-08
Nu M
group, an alkoxy group, an aryl, or an
amine substituted or not by one or two Ci
_
12alkyl groups.
SiR R 14 R wherein R13, R14 and R15 Li, Mg
are each independently a hydrogen atom,
an alkyl group, an alkoxy group, an aryl,
or an amine substituted or not by one or
two C1_12alkyl groups.
OR 16* wherein R 16 is a hydrogen atom, an Li, Mg
alkyl group, an alkoxy group, an aryl, or
an amine substituted or not by one or two
C1_12alkyl groups.
SR 17* wherein R 17 is a hydrogen atom, an Li, Mg
alkyl group, an alkoxy group, an aryl, or
an amine substituted or not by one or two
C1_12alkyl groups.
Table 4
chiral element
According to a specific embodiment of the invention, each non-substituted
5 position of an aromatic ring depicted in one of tables 2 to 4 may be
substituted by a
hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an amine
substituted or
not by one or two C 1-12alkyl groups.
Preferably, M is Li or MgBr; preferably, Nu is n-Bu, s-Bu, t-Bu, methyl,
phenyl, 2-McC6H4, 2-McOC6H4, 4-McC6H4, 4-McOC6H4 or naphthalene.
10 The preferred NuM compounds are n-Buli, s-Buli, t-Buli, MeLi, PhLi,
PhMgBr, 2-MeC6H4Li, 2-MeOC6H4Li, 4-MeC6H4Li, 4-MeOC6H4Li, 1-
LiNaphthalene, 2-LiNaphthalene.
Definitions
15 In the sense of this invention, the term "aryl" means a mono- or polycyclic
system of 5 to 20, and preferably 6 to 12, carbon atoms having one or more
aromatic
CA 02789373 2012-08-08
16
rings (when there are two rings, it is called a biaryl) among which it is
possible to
cite the phenyl group, the biphenyl group, the 1-naphthyl group, the 2-
naphthyl
group, the tetrahydronaphthyl group, the indanyl group and the binaphthyl
group.
The term aryl also means any aromatic ring including at least one heteroatom
chosen
from an oxygen, nitrogen or sulfur atom. The aryl group may be substituted by
1 to 3
substituents chosen independently of one another, among hydroxyl group; linear
or
branched alkyl group comprising 1, 2, 3, 4, 5 or 6 carbon atoms, in particular
methyl,
ethyl, propyl, butyl; alkoxy group or halogen atom, in particular bromine,
chlorine
and iodine.
The terra "catalyst" refers to any product involved in the reaction for
increasing the speed of said reaction, but regenerated or removed during or at
the end
of the reaction.
By "protecting the carboxyl function (CO2H)", we mean adding to said
function a group destroying the reactivity of the carboxyl function with
regard to the
nucleophiles; this group may be oxazoline; numerous chemical groups other than
the
oxazoline function have been used to protect the CO2H function: 2,6-di-tert-
butyl-4-
methoxyphenylic ester (Hattori, T.; Satoh, T.; Miyano, S. Synthesis 1996, 514.
Koshiishi, E.; Hattori, T.; Ichihara, N.; Miyano, S. J. Chem. Soc., Perkin
Trans. 1
2002, 377), amide (Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.;
MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.;
Springer,
M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella,
A.; Henry,
K.; Lineberger, J.; Schleif, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett.
2005, 15(8),
2129), alkylamide (Guo, Z.; Schultz, A. G. Tetrahedron Lett. 2001, 42(9),
1603),
dialkylamides (Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis
2000), 1-imidazolyles (Figge, A.; Altenbach, H. J.; Brauer, D. J.; Tielmann,
P.
Tetrahedron: Asymmetry 2002, 13(2), 137), 2-oxazolyles (Cram, D. J.; Bryant,
J. A.;
Doxsee, K. M. Chem. Lett. 1987, 19), 2-thiazolyles, etc.
By "leaving group" we mean a group that leads the two electrons of the
sigma bond binding it with the aromatic carbon atom during the substitution
reaction
with the nucleophile; according to the invention, the leaving group may be
chiral or
non-chiral; according to a preferred embodiment of the invention, the leaving
group
is chiral; according to the invention, the leaving group may be electron
withdrawing
or non- electron withdrawing.
CA 02789373 2012-08-08
17
By "alkyl", we mean any saturated linear or branched hydrocarbon chain,
with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably
methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
By "alkoxy", we mean any O-alkyl or 0-aryl group.
By "alkenyl", we mean any linear or branched hydrocarbon chain having at
least one double bond, of 2 to 12 carbon atoms, and preferably 2 to 6 carbon
atoms.
By "alkynyl", we mean any linear or branched hydrocarbon chain having at
least one triple bond, of 2 to 12 carbon atoms, and preferably 2 to 6 carbon
atoms.
By "amine", we mean any compound derived from ammonia NH3 by
substitution of one or more hydrogen atoms with an organic radical. According
to the
invention, a preferred amine is an aniline derivative.
By "functional group", we mean a sub-molecular structure including an
assembly of atoms conferring a reactivity specific to the molecule that
contains it, for
example an oxy, carbonyl, carboxy, sulfonyl group, and so on.
By "nucleophile", we mean an acyclic or cyclic compound, of which the
characteristic is to include at least one atom with a free electron pair,
charged or not.
According to a preferred embodiment of the invention, we mean by "nucleophile"
an
acyclic or cyclic compound of which the characteristic is to include at least
one atom
with a charged free electron pair, preferably negatively charged.
By "nucleophile that may be chiral", we mean a nucleophile with at least
one asymmetric carbon.
By " electron withdrawing group" we mean a functional group having the
ability to attract electrons, in particular if it is a substitutent of an
aromatic group, for
example a group in particular of the NO2, CN, halogen, CO2R, CONR2, CH=NR,
(C=S)OR, (C=O)SR, CS2R, SO2R, SO2NR2, SO3R, P(O)(OR)2, P(O)(R)2, or B(OR)3
type wherein R is an alkyl, an aryl or a hydrogen atom. Amines and alkoxy
groups
are not electron withdrawing groups.
By "heterocycle", we mean a ring with 5- or 6-membered ring containing 1 to
2 heteroatoms selected from O, S, N, optionally substituted with an alkyl.
By "MNu", we mean a reactant wherein M is a metal and Nu is an
independent nucleophile or a substituent of the aromatic ring of the benzoic
acid
derivative of general formula (II), said substituent being capable of reacting
in
presence of a base and a metal to form MNu. When Nu is a substituent of the
CA 02789373 2012-08-08
18
aromatic ring of (II), the nucleophilic aromatic substitution reaction occurs
intramolecularly between the MNu function formed on the substituent and the
leaving group in ortho position to carboxylic acid function.
The invention may be better understood in view of the following examples,
which illustrate the process according to the invention in a non-limiting
manner.
Examples
All of the reactions are done under inert atmosphere with anhydrous solvents
(Gordon, J. A.; Ford, R A. The Chemist's Companion, Wiley J. and Sons, New
York,
1972). The THF is distilled by means of an anhydrous THF GTS 100 station
(Glass
Technology). Alkyllithium derivatives are periodically titrated with N-
benzylbenzamide (Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem.
1997, 542, 281)
S-butyllithium (1.4 M in solution in cyclohexane), n-butyllithium (1.6 M in
solution in hexane), t-butyllithium (1.7 M in solution in pentane) and
phenyllithium
(1.8 M in solution in dibutylether) are sold by Acros Chemicals and Aldrich
Chemical Company.
Nuclear magnetic resonance spectra of the proton 'H (400 MHz or 200 MHz)
and of the carbon 13C (50 MHz or 100.6 MHz) were recorded on a Bruker AC 400
or
DPX 200 apparatus. The chemical shifts ô are expressed in parts per million
(ppm).
Tetramethylsilane (TMS) is used as an internal reference when CDC13 is used
as a solvent. In the case of acetone-d6 and DMSO d6, chemical shifts are given
with
respect to the signal of the solvent. Coupling constants are expressed in
Hertz (Hz).
The following abbreviations are used to describe the NMR spectra: s (singlet),
d
(doublet), dd (double doublet), t (triplet), q (quadruplet), m (multiplet),
sept
(septuplet)
The mass spectra were recorded in chemical impact mode or in field
ionization mode on a high-resolution spectrometer (GCT First High-Resolution
Micromass). The precision obtained for the precise mass measurements is four
digits.
Elemental analyses were performed by the microanalysis center of ICSN of -
Gif sur Yvette. Infrared spectra were recorded on a Nicolet Avatar 370 DTGS
spectrometer. Melting points were measured on a Büchi Melting Point B-540
apparatus.
CA 02789373 2012-08-08
19
Example 1 - Preparation of 2-n-butyl-6-fluorobenzoic acid
CO2H
F n-Bu
n-BuLi (6.9 mL, 11 mmol, 1.6 M in solution in hexane) is added at -78 C to
a solution of 2,6-difluorobenzoic acid (791 mg, 5 mmol) in anhydrous THF (30
mL).
The reaction mixture is stirred at this temperature for 2h, and then
iodomethane (1.25
mL, 12 mmol) is added. The solution is hydrolyzed at room temperature with
water
(20 mL) and the two phases are separated. The aqueous phase is washed with
ethyl
acetate (3x40 mL). The aqueous phase is then acidified to a pH of 1 and
extracted
with ethyl acetate (3x40 mL). The combined organic phases are dried over MgSO4
and concentrated under vacuum. The residue is purified by chromatography on
silica
gel (cyclohexane: ethyl acetate 95: 5) to afford 2-butyl-6-fluorobenzoic acid
(425
mg, 2.17 mmol, 43%) as a yellow oil Addition of iodomethane before hydrolysis
does not modify the outcome of the reaction. 'H NMR (400 MHz, CDC13) 6: 11.04
(s
large, 1 H), 7.35 (td, JHF = 5.7 Hz, J = 8.0 Hz, 1 H, H5), 7.05 (d, J = 7.6
Hz, 1 H, H4),
6.97 (dd, J = 8.2 Hz, JHF = 9.6 Hz, 1 H, H6), 2.81 (t, J = 7.8 Hz, 2H), 1.62
(m, 2H)
1.38 (m, 2H), 0.93 (t, J= 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) & 171.6, 160.3
(d, J = 253 Hz), 144.2 (d, J = 1.3 Hz), 131.9 (d, J = 9.2 Hz), 120.0 (d, J =
14.3 Hz),
125.5 (d, J= 3.2 Hz), 113.4 (d, J= 21.8 Hz), 33.5, 33.2, 22.5, 13.8. IR (ATR,
cm-'):
2960, 2873, 2662, 2873, 1704, 1615, 1576, 1467, 1405, 1293, 1125, 805, 775.
HRMS [M+NH4]+ calculated for CI IHI7NO2F: 214.1243, measured: 214.1246.
Example 2 - Preparation of 2,6-di-sec-butylbenzoic acid
COZH
s-Bu s-Bu -ic
CA 02789373 2012-08-08
This compound is prepared from 2,6 - difluorobenzoic acid (791 mg, 5 mmol)
and s-BuLi (10.7 mL, 15.0 mmol, 1.4 M in solution in cyclohexane) according to
the
procedure of example 1. The reaction mixture is stirred at 0 C during 4h.
Purification by recrystallization (cyclohexane / ethyl acetate) yielded 2,6 di-
sec -
5 butylbenzoic acid (650 mg, 2.77 mmol, 55%) as a white solid (mp 125-126 C).
Addition of iodomethane before hydrolysis does not modify the outcome of the
reaction. 'H NMR (400 MHz, CDC13) O. 7.36 (t, J = 7.8 Hz, 1 H), 7.13 (d, J =
7.8 Hz,
2H), 2.73 (sext, J = 7.0 Hz, 2H), 1.75-1.55 (m, 4H), 1.27 (dd, J = 1.6 Hz, J =
6.8 Hz,
6H), 0.85 (t, J= 7.4 Hz, 6H). 13C NMR (100 MHz, CDC13) &. 176.2, 143.2, 133.4,
10 129.5, 122.8, 38.7, 30.9, 22.0, 12.1. IR (ATR, cm'): 2955, 2925, 2864,
1705, 1594,
1585, 1456, 1390, 1379, 1260, 1134, 1003, 908, 803, 764, 699, 609. HRMS
[M+NH4]+ calculated for C15H26NO2: 252.1964, measured: 252.1963.
Example 3 - Preparation of 3-fluorobiphenyl-2-carboxylic acid
HO2C
F
This compound is prepared from 2,6-difluorobenzoic acid (474 mg, 3 mmol)
and PhLi (4.55 mL, 6.6 mmol, 1.45 M in solution in di-n-butyl ether) according
to
the general procedure. The reaction mixture is stirred at -30 C during 2h.
The
compound is recovered and purified by column chromatography on silica gel
(cyclohexane: ethyl acetate 95: 5 to 90: 10) affording 3 - fluorobiphenyl-2-
carboxylic acid (185 mg, 0.856 mmol, 29%) as a yellow solid (mp 122.5 - 125
C).
'H NMR (200 MHz, CDC13) 6 7.53-7.40 (m, 6H), 7.22-7.09 (m, 2H). 13C NMR (50
MHz, CDC13) 8: 171.1, 159.8 (d, J= 252.6 Hz), 142.8 (d, J = 2.4 Hz), 139.0 (d,
J
= 2.3 Hz), 131.7 (d, J = 9.1 Hz), 128.5 (2*C), 128.2 (2*C), 128.1, 125.7 (d, J
= 3.2 Hz), 120.3 (d, J = 15.7 Hz), 114.7 (d, J = 21.6 Hz). IR (ATR, cm'):
2860,
2654, 1690, 1612, 1567, 1460, 1401, 1293, 1267, 1238, 1127, 1097, 897, 803,
771,
702, 549. HRMS [M]+ calculated for C13H9FO2: 216.0587, measured: 216.0587.
Example 4 - Preparation of 3-fluoro-4-methoxy-biphenyl-2-carboxylic acid
CA 02789373 2012-08-08
21
çczH
F
XXX
n-BuLi (7.9 mL, 11 mmol, 1.39 M in solution in hexane) is added at -78 C
dropwise to a 1 -bromo-4-methoxybenzene solution (2.057g, 1.40 mL, 11 mmol) in
anhydrous THF (20 mL). The reaction mixture is stirred at this temperature for
1 h,
then warmed up to -50 C and 2,6 - difluorobenzoic acid (791 mg, 5 mmol) in
solution in anhydrous THF is then added. The reaction mixture is warmed up to -
30 C and is stirred at this temperature during 2 h. The solution is hydrolyzed
at room
temperature with water (25 mL) and the two phases are separated. The aqueous
phase is washed with ethyl acetate (3x40 mL). The aqueous phase is then
acidified to
a pH of 1 and extracted with ethyl acetate (3x40 mL). The combined organic
phases
are dried over MgSO4 and concentrated under vacuum. The residue is purified by
chromatography on silica gel (cyclohexane: ethyl acetate 95: 5 to 8: 2). 3-
fluoro-4-
methoxybiphenyl-2-carboxylic acid is isolated (803 mg, 3.26 mmol, 65 %) as a
colorless oil. 'H NMR (200 MHz, CDC13) &. 7.50-7.30 (m, 3H), 7.20-7.06 (m,
2H),
6.97-6.90 (m, 2H), 3.84 (s, 3H). 13C NMR (50 MHz, CDC13) & 171.1, 159.8 (d,
J= 252.1 Hz), 159.6, 142.4 (d, J = 2.5 Hz), 131.6 (d, J = 9.2 Hz), 131.4 (d, J
= 2.4 Hz), 129.4 (2*C), 125.7 (d, J = 3.1 Hz), 120.3 (d, J = 15.7 Hz), 114.2
(d, J
= 21.5 Hz), 114.0 (2*C), 55.2. IR (ATR, cm1): 1703, 1698, 1610, 1514, 1462,
1455,
1288, 1236, 1178, 1094, 1029, 896, 806, 781, 692, 587. HRMS [M + H]+
calculated
for C 14H12FO3: 247.0770, measured: 247.0780.
Example 5 - Preparation of 2,6-bis-(diethylamino) benzoic acid
CO2H CO2H
Et2N NEt2
F 1 L F LiNEt2 _ I
CA 02789373 2012-08-08
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2,6-difluorobenzoic acid (474 mg; 3 mmol) in solution in anhydrous THF (10
mL) is added dropwise at -30 C to a lithium diethylamide solution (15 mmol,
prepared according to the general procedure in 30 mL of THF). The reaction
mixture
is stirred at -30 C during 1 h and then 3 h at 0 C. The reaction mixture is
hydrolyzed at room temperature with distilled water (20 mL) and the two phases
are
separated. The aqueous phase (AQ-1) is extracted with ethyl acetate (3 *20 mL)
and
the combined organic phases (ORGA 1) are dried over MgSO4. The ORGA 1 phase
contains predominantly to the carboxylate derived from the 2,6-
bis(diethylamino)benzoic acid., 10 mL of a 1N aqueous NaOH solution is added
in
order to purify it and the reaction mixture is concentrated under reduced
pressure.
After acidification at pH = 7 (with a solution of HC1 10 %) and extraction
with
AcOEt, pure 2,6-bis(diethylamino)benzoic acid is isolated (180 mg; 0.69 mmol)
as a
white solid. The aqueous phase AQ-1 is then acidified with an HC1 solution (10
%)
to pH = 7 and extracted with dichloromethane (3*20 mL). The combined organic
phases (ORGA2) are dried over MgSO4. The ORGA2 phase contains pure 2,6-
bis(diethylamino)benzoic acid (240 mg, 0.92 mmol). (overall yield: 420 mg, 53
%).
According to the same procedure, but using 2,6-dimethoxybenzoic acid (546
mg; 3 mmol) as the starting material, 2,6-bis(diethylamino)benzoic acid is
isolated
with a 53 % yield (420 mg). mp= 112-114 C. 'H NMR (CDC13; 200 MHz) O. 7.38
(t;
J = 8.0 Hz, 1 H), 6.90 (d; J = 8.0 Hz; 2H ), 3.21 (q; J = 7.2 Hz; 8H), 1.11
(t; J =
7.2 Hz; 12H). NMR 13C (CDC13; 100MHz): 167.1; 150.7; 131.3; 119.6; 115.6;
48.7;
11.9. IR (ATR, cm'): 3430; 2671; 2612; 2072; 1582; 1459; 1368; 1262. HRMS m/z
calculated for C15H25N202 ([M]+): 265.1871 found 265.1909.
Example 6 - Preparation of 2-(N-methyl-N-phenyl)-6-fluorobenzoic acid
CO2H CO2H
F NMePh
F I F LiNMePh` I
2,6-difluorobenzoic acid (474 mg; 3 mmol) in solution in anhydrous THF (10
mL) is added dropwise at room temperature to a lithium (N-methyl-N-
phenyl)amide
solution (15 mmol, prepared according to the general procedure in 30 mL of
THF).
CA 02789373 2012-08-08
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The solution is stirred at room temperature during 1 h then overnight at 60
C. The
reaction mixture is hydrolyzed at room temperature with distilled water (20
mL) and
the two phases are separated. The aqueous phase (AQ-1) is extracted with ethyl
acetate (3*20 mL) then acidified with an HC1 solution (10 %) to pH = 7 and
extracted with dichloromethane (3*20 mL). The combined organic phases (ORGA2)
are dried over MgSO4. The ORGA2 phase contains pure 2-(N-methyl-N-phenyl)-6-
fluorobenzoic acid (190 mg, 0.92 mmol). Alter acidification at pH = 1 (with
HC1
%), the residual aqueous phase is extracted with dichloromethane. The
resulting
organic phase (ORGA3) is dried over MgSO4. It contains protonated 2-fluoro-6-
(N-
10 methyl-N-phenyl)benzoic acid. 10 mL of a 1N aqueous NaOH solution are added
in
order to purify it and the reaction mixture is concentrated under reduced
pressure.
After acidification at pH = 7 (with HCI 10 %) and extraction with AcOEt, pure
2-(N-
methyl-N-phenyl)-6-fluorobenzoic acid is isolated as a dark beige solid (340
mg).
(overall yield: 530 mg, 72 %). mp = 120-122 C. 'H NMR (CDC13; 200 MHz): 7.46
(d; JH,H =8 Hz; JH,F = 6 Hz; I H), 7.24 (dd; J = 8.8 Hz; J = 7.2 Hz; 2H); 7.06
(dd; JH,H
= 8.8 Hz; JH,F = 9.6 Hz; I H), 6.98 (d; J = 8 Hz; I H), 6.94 (t; J = 7.2 Hz; I
H); ); 6.82
(d; J = 8.8 Hz; 2H); 3.25 (s; 3H). NMR '3C (CDCI3; 100MHz): 166.0; 160.5(J =
260
Hz); 149.0; 148.3; 133.6 (d, J = 10 Hz); 129.5; 123.7; 122.8; 121.4; 117.5;
114.1 (d,
J = 22 Hz); 41.4. NMR 19F (CDCl3, 376MHz) = -111Ø IR (ATR, cm'): 3063; 1705;
1613;1495;1350,1161;1209;995;825;756,694;608.
Example 7 - Preparation of 2,6-di-s-butylbenzoic acid
CO2H CO2H
F F s-BuLi s-Bu s-Bu
s-butyllithium (1.25 M in cyclohexane, 12 mL, 15 mmol) is added at 0 C to
2,6-difluorobenzoic acid (474 mg, 3 mmol) in solution in anhydrous THF (20
mL).
After 4 h of stirring at 0 C, the reaction mixture is hydrolyzed with
distilled water
(20 mL) and the aqueous phase is extracted with ethyl acetate (3*20 mL). The
combined organic phases are dried over MgSO4, filtered and concentrated under
reduced pressure. After recrystallization (cyclohexane/ethyl acetate), 2,6-di-
s-
CA 02789373 2012-08-08
24
butylbenzoic acid is isolated as a white solid (650 mg, 56 %). mp = 125-126
C. 'H
NMR (CDC13; 200 MHz): 7.35 (t; J = 7.8 Hz; 1H), 7.25 (d; J = 7.8 Hz; 2H), 2.72
(m;
1H), 1.68 (m; 2H), 1.26 (d; J = 7.0 Hz; 3H), 0.85 (t; J = 7.4 Hz; 3H). '3C NMR
(CDC13; 100 MHz): 176.5; 143.5; 133.0; 129.0; 122.5; 39.4; 31.5; 22.5; 12Ø
IR
(ATR, cm-'): 2954; 2925; 2863; 1704; 1594; 1584; 1456; 1390; 1379; 1260; 1234;
1134.
Example 8 - Preparation of 2-n-butyl-6-fluorobenzoic acid
CO2H CO 2H
F L F n-BuLi F L n-Bu
n-butyllithium (1.55 M in cyclohexane, 7.1 mL, 11 mmol) is added at 0 C to
2,6-difluorobenzoic acid (790 mg, 5 mmol) in solution in anhydrous THF (30
mL).
After stirring 2 h at 0 C, the reaction mixture is hydrolyzed with distilled
water (30
mL). The aqueous phase is extracted with ethyl acetate (3*30 mL), acidified to
pH =
1 with the addition of HCI (10 %) then extracted with ethyl acetate. The
combined
organic phases are dried over MgSO4, filtered and concentrated under reduced
pressure. After recrystallization (cyclohexane / ethyl acetate), 2-fluoro-6-n-
butylbenzoic acid is isolated as a pale yellow solid (560 mg, 57 %). 'H NMR
(CDC13;
200 MHz): 7.34 (dd; JH,H = 8.2 Hz; JH,F = 5.6 Hz; I H), 7.04 (d; J = 8.2 Hz; I
H), 6.96
(dd; JH,H = 8.2 Hz; JH,F = 9.6 Hz;1 H), 2.81 (t; J = 7.6 Hz; 2H), 1.68 (m;
2H), 1.39 (m;
2H), 0.91 (t; J = 7.6 Hz; 3H). 13C NMR (CDC13; 100 MHz): 172.1, 160.0 (d; J =
250
Hz), 144.3; 132.0 (d; J = 10 Hz); 131.2; 125.5 (d; J = 14 Hz); 120.0 (d; J =
21 Hz);
113.6; 33.6; 22.5; 13.8. IR (ATR, cm-'): 2960; 2873; 2662; 1704; 1615; 1576;
1466;
1405; 1293; 1125; 805; 774.8.
