U.S. patent application number 10/972575 was filed with the patent office on 2005-05-26 for intermediates for the production of a benzofuran or benzothiophene type derivative nitrated in the 5 position, and use thereof.
Invention is credited to Karrer, Philippe, Mettling, Armand, Schlama, Thierry.
Application Number | 20050113596 10/972575 |
Document ID | / |
Family ID | 9551278 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113596 |
Kind Code |
A1 |
Schlama, Thierry ; et
al. |
May 26, 2005 |
Intermediates for the production of a benzofuran or benzothiophene
type derivative nitrated in the 5 position, and use thereof
Abstract
The invention concerns novel nitroaromatic compounds of general
formula (I') wherein: R, R'1, R2, Z and n are as defined in claim
38. The invention also concerns a method for preparing
nitroaromatic compounds nitrated in position 4. The invention
further concerns the use of said compounds for preparing
heterocyclic benzofuran or benzothiophene derivatives nitrated in
position 5. The invention concerns particularly the preparation of
2-alkyl-5-nitrobezofuran
Inventors: |
Schlama, Thierry; (Dardilly,
FR) ; Mettling, Armand; (Mulhouse, FR) ;
Karrer, Philippe; (Zillisheim, FR) |
Correspondence
Address: |
Rhodia Inc.
259 Prospect Plains Road, CN 7500
CRANBURY
NJ
08512
US
|
Family ID: |
9551278 |
Appl. No.: |
10/972575 |
Filed: |
October 25, 2004 |
Current U.S.
Class: |
560/17 ;
560/20 |
Current CPC
Class: |
C07C 205/37 20130101;
C07C 69/712 20130101; C07C 205/37 20130101; C07C 67/31 20130101;
C07D 307/79 20130101; C07C 201/12 20130101; C07C 67/31 20130101;
C07D 333/54 20130101; C07C 201/12 20130101 |
Class at
Publication: |
560/017 ;
560/020 |
International
Class: |
C07C 323/22; C07C
025/53 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 21, 1999 |
FR |
99/13250 |
Claims
1. A process for preparing nitroaromatic compounds with formula
(I): 10in which: R.sub.1 represents a hydrogen atom, a linear or
branched alkyl group containing 1 to 12 carbon atoms, a phenyl
group that may be substituted by an alkyl group containing 1 to 4
carbon atoms, or a halogenophenyl group; R.sub.2 represents a
hydrogen atom, a hydrocarbon group containing 1 to 12 carbon atoms,
which may be a linear or branched alkyl group, a cycloalkyl group,
a phenyl group or a phenylalkyl group; Z represents an oxygen or
sulphur atom; R represents a hydrogen atom or a substituent; n is a
number equal to 0, 1, 2 or 3, preferably 0; when n is greater than
1, two groups R and the successive 2 atoms of the benzene ring can
together form a saturated, unsaturated or aromatic cycle containing
5 to 7 carbon atoms; characterized in that it consists of carrying
out selective nitration in the 4 position, using a source of
NO.sub.2.sup.+ and in the presence of sulphuric acid, of an
aromatic compound with formula (II): 11in which formula (II), R,
R.sub.1, R.sub.2, Z and n have the meanings given above.
2. A process according to claim 1, characterized in that the
starting substrate has formula (II), in which R represents a
hydrogen atom or one of the following groups: a hydroxyl group; a
linear or branched alkyl group containing 1 to 6 carbon atoms,
preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl; an alkoxy group
containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; an
ester group containing 1 to 10 carbon atoms, preferably 1 to 4
carbon atoms; an alkylamide group containing 1 to 6 carbon atoms,
preferably 1 to 4 carbon atoms; a carboxamide group; a halogen
atom; a trifluoromethyl group.
3. A process according to claim 1, characterized in that the
starting substrate has formula (II) in which R represents a
hydrogen atom, a methyl or ethyl group, or a methoxy or ethoxy
group.
4. A process according to claim 1, characterized in that the
starting substrate has formula (II) in which R.sub.1 represents an
alkyl group containing 1 to 4 carbon atoms.
5. A process according to claim 1, characterized in that the
starting substrate has formula (II) in which R.sub.2 represents an
alkyl group containing 1 to 4 carbon atoms.
6. A process according to claim 1, characterized in that the
starting substrate has formula (II) in which Z is an oxygen
atom.
7. A process according to claim 1, characterized in that nitration
of the compound with formula (II) is carried out by reacting it
with a source of NO.sub.2.sup.+ in the presence or absence of an
organic solvent, preferably an aliphatic halogenated hydrocarbon,
more preferably dichloromethane.
8. A process according to claim 7, characterized in that the
nitrating reagent is any source of NO.sub.2.sup.+, preferably
nitrogen dioxide NO.sub.2, nitrous anhydride N.sub.2O.sub.3,
dinitrogen tetroxide N.sub.2O.sub.4, nitric oxide NO associated
with an oxidising agent such as nitric acid, nitrogen dioxide or
oxygen; nitrous acid, nitrosyl sulphate or a nitrous salt,
preferably an alkali metal salt, still more preferably, sodium or
an alkyl nitrite.
9. A process according to claim 7, characterized in that the
quantity of nitrating reagent employed is a nitrating mixture.
10. A process according to claim 7, characterized in that the
quantity of nitric acid, expressed as the mole ratio of the
aromatic O- or S-alkylated compound/nitric acid is in the range 0.9
to 1.1, preferably in the range 0.95 to 1.05.
11. A process according to claim 7, characterized in that the
quantity of sulphuric acid, expressed as the mole ratio of the
aromatic O- or S-alkylated compound/sulphuric acid is in the range
0.9 to 1.1, preferably in the range 0.95 to 1.05.
12. A process according to claim 7, characterized in that the
nitration reaction temperature is in the range -10.degree. C. to
20.degree. C., preferably in the range -5.degree. C. to 10.degree.
C.
13. A process for preparing a compound with formula (II) as defined
in claim 1, characterized in that it is obtained by reacting: a
compound of the 2-hydroxy- or 2-thiobenzaldehyde-type with formula
(III): 12in which formula (III), R, Z and n have the meanings given
above in any one of claims 1 to 3; and a carboxylic acid or a
derivative with formula (IV): 13in which formula (IV): Y represents
a leaving group, preferably a halogen atom or a sulphonic ester
group with formula --OSO.sub.2- where is a hydrocarbon group;
R.sub.1, R.sub.2 have the meanings given above in any one of claims
1, 4 and 5.
14 A process according to claim 13, characterized in that the
compound with formula (III) is salicylic anhydride and the
carboxylic acid or derivative with formula (IV) is methyl or ethyl
2-bromohexanoate.
15 A process according to claim 13, characterized in that mole
ratio between the compound with formula (III) and the compound with
formula (IV) is between 1 and 1.2.
16 A process according to claim 13, characterized in that an
aromatic compound with formula (III) is reacted with a carboxylic
acid or a derivative with formula (IV), the reaction being carried
out in the presence of a base, preferably in an organic
solvent.
17 A process according to claim 16, characterized in that the base
can be a mineral base, preferably an alkali metal or alkaline-earth
metal salt, preferably an alkali or alkaline-earth metal hydroxide
which may be sodium, potassium or calcium hydroxide; or an alkali
metal carbonate or bicarbonate, preferably sodium carbonate; or an
organic base, preferably a quaternary ammonium hydroxide or a
tertiary amine.
18 A process according to claim 17, characterized in that the base
employed is sodium or potassium carbonate.
19 A process according to claim 16, characterized in that the
compound with formula (III) in its salt form and the compound with
formula (IV) are reacted in an organic solvent preferably selected
from aromatic hydrocarbons that may or may not be halogenated,
aliphatic, cycloaliphatic or aromatic ether-oxides, aliphatic or
aromatic nitrites; linear or cyclic carboxamides, preferably
N,N-dimethylacetamide or dimethylformamide.
20 A process according to claim 18, characterized in that iodide
ions are added, preferably alkali metal iodides, more preferably
potassium iodide.
21 A process according to any one of claims 13 to 20, characterized
in that the reaction between the compound with formula (III) and
the compound with formula (IV) is carried out at a temperature in
the range 0.degree. C. to 100.degree. C., preferably in the range
25.degree. C. to 50.degree. C.
22 A process according to claim 13, characterized in that an
aromatic compound with formula (III) is reacted with a carboxylic
acid or a derivative thereof, in an aqueous medium, in the presence
of a base and a phase transfer catalyst.
23 A process according to claim 22, characterized in that the phase
transfer catalyst is a tris(ether-amine), preferably
tris(3,3-dioxaheptyl)amine.
24 A process according to claim 22, characterized in that the phase
transfer catalyst is an onium salt wherein the onium has one of the
following formulae: 14in which formulae: Z represents N, P or As; Y
represents S, O, Se or C; X.sub.1, X.sub.2, X.sub.3 and X.sub.4,
which may be identical or different, represent: a linear or
branched alkyl group containing 1 to 16 carbon atoms, optionally
substituted by one or more phenyl, hydroxyl, halogen, nitro, alkoxy
or alkoxycarbonyl groups, the alkoxy groups containing 1 to 4
carbon atoms; a linear or branched alkenyl group containing 2 to 12
carbon atoms; an aryl group containing 6 to 10 carbon atoms,
optionally substituted by one or more alkyl groups containing 1 to
4 carbon atoms, an alkoxy group, an alkoxycarbonyl group, the
alkoxy group containing 1 to 4 carbon atoms, or a halogen; two of
said groups X.sub.1 to X.sub.4 can together form a linear or
branched alkylene, alkenylene or alkadienylene group containing 3
to 6 carbon atoms.
25. A process according to claim 24, characterized in that the
anion of said onium salts is selected from the following ions:
F.sup.-, ClO.sub.4.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.-,
SnCl.sub.6.sup.-, SbCl.sub.6.sup.-, B(Ph).sub.4.sup.-,
PO.sub.4.sup.3-, HPO.sub.4.sup.2-, H.sub.2PO.sub.4.sup.-,
CH.sub.3SO.sub.3.sup.-, Ph--SO.sub.3.sup.-, HSO.sub.4.sup.-,
NO.sub.3.sup.-, SO.sub.4.sup.2-, Cl.sup.-, Br.sup.-, I.sup.-,
OH.sup.-, Ph representing a phenyl group; the anion for said onium
salts preferably being selected from Br.sup.-, Cl.sup.- and
OH.sup.- ions.
26. A process according to claim 22, characterized in that the
phase transfer catalyst is selected from: tributylbenzylammonium or
phosphonium chloride or bromide; tetramethylammonium or phosphonium
chloride or bromide; tetraethylammonium or phosphonium chloride or
bromide, tetrabutylammonium or phosphonium chloride or bromide, and
preferably represents tributylbenzylammonium chloride or
bromide.
27. A process according to claim 22, characterized in that the base
is selected from potassium carbonate, sodium carbonate and ammonia,
preferably potassium carbonate.
28. A process according to claim 22, characterized in that the mole
ratio between said catalyst and the compound with formula (III) is
in the range 0.01 to 0.50, preferably in the range 0.05 to 0.2.
29. A process according to claim 22, characterized in that the
reaction is carried out in an aqueous medium.
30. A process according to claim 22, characterized in that the
reaction temperature is between ambient temperature and 80.degree.
C., preferably between 50.degree. C. and 65.degree. C.
31. A process for preparing a heterocyclic compound with general
formula (V): 15in which formula (V), R, R.sub.1, Z and n have the
meanings given above in any one of claims 1 to 4; characterized in
that the compound with formula (I) or (I') is optionally saponified
when R.sub.2 is an ester function, followed by cyclisation.
32. A process according to claim 31, characterized in that the
compound with formula (I) or (I') is cyclised in the presence of
sodium acetate and in an acetic anhydride medium.
33. A process according to claim 31, characterized in that the
compound with formula (I) or (I') is cyclised in the presence of
sodium or potassium carbonate and in an acetic anhydride
medium.
34. A process according to claim 31, characterized in that it is
obtained: by preparing the compound with formula (II) by reacting a
compound with formula (III) with a carboxylic acid or derivative
thereof with formula (IV) in the presence of a base and optionally,
a phase transfer catalyst; by carrying out selective nitration of
the compound with formula (II) in the 4 position using the process
described in any one of claims 1 to 12; if necessary, by
saponifying the compound obtained with formula (I) or (I') in the
case when R.sub.2 is an ester function; cyclising the product
obtained.
35. A process according to claim 31, characterized in that it is
obtained: by preparing the compound with formula (II) by reacting a
compound with formula (III) with a carboxylic acid or derivative
thereof with formula (IV) in the presence of a base and optionally,
a phase transfer catalyst; if necessary, by saponifying the
compound obtained with formula (II) in the case when R.sub.2 is an
ester function; by carrying out selective nitration of the compound
with formula (II) in which R.sub.2 is a hydrogen atom, using the
process described in any one of claims 1 to 12; cyclising the
product obtained.
36. A process according to claim 35 or claim 36, characterized in
that cyclisation is carried out using the process defined in claim
32 or claim 33.
37. A process according to any one of claims 31 to 36,
characterized in that the compound with formula (V) is
2-n-butyl-5-nitrobenzofuran.
38. Novel nitroaromatic compounds with general formula: 16in which:
R'.sub.1 represents a linear or branched alkyl group containing 1
to 12 carbon atoms, a phenyl group that may be substituted by an
alkyl group containing 1 to 4 carbon atoms, or a halogenophenyl
group; R.sub.2 represents a hydrogen atom, a hydrocarbon group
containing 1 to 12 carbon atoms, which may be a linear or branched
alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl
group; Z represents an oxygen or sulphur atom; R represents a
hydrogen atom or a substituent; n is a number equal to 0, 1, 2 or
3, preferably 0; when n is greater than 1, two groups R and the
successive 2 atoms of the benzene ring can together form a
saturated, unsaturated or aromatic cycle containing 5 to 7 carbon
atoms;
39. Novel nitroaromatic compounds according to claim 38,
characterized in that R represents a hydrogen atom or one of the
following groups: a hydroxyl group; a linear or branched alkyl
group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon
atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl; an alkoxy group containing 1 to 6 carbon
atoms, preferably 1 to 4 carbon atoms; an ester group containing 1
to 10 carbon atoms, preferably 1 to 4 carbon atoms; an alkylamide
group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon
atoms; a carboxamide group; a halogen atom; a trifluoromethyl
group.
40. Novel nitroaromatic compounds according to claim 38,
characterized in that R represents a hydrogen atom, a methyl or
ethyl group, or a methoxy or ethoxy group.
41. Novel nitroaromatic compounds according to claim 38,
characterized in that R'.sub.1 represents an alkyl group containing
1 to 4 carbon atoms.
42. Novel nitroaromatic compounds according to claim 38,
characterized in that R.sub.2 represents an alkyl group containing
1 to 4 carbon atoms.
Description
[0001] The present invention relates to novel nitroaromatic
compounds and to a process for their preparation.
[0002] The invention also relates to the use of these compounds in
preparing heterocyclic benzofuran or benzothiophene type
derivatives nitrated in the 5-position.
[0003] More particularly, the invention relates to the preparation
of a 2-alkyl-5-nitrobenzofuran.
[0004] Benzofuran or benzothiophene type structures are encountered
in many molecules used in the pharmaceutical field. In particular,
European patent EP-A-0 471 609 describes a process for preparing
n-butyl-2-nitro-5-benzofuran, which consists of reacting
2-hydroxy-5-nitro-benzyltriphenylphosphonium bromide with pentanoyl
chloride in the presence of pyridine:
2-hydroxy-5-nitro-benzyltriphenylph- osphonium bromide is obtained
from 2-hydroxy-5-nitro-benzyl bromide and triphenylphosphine.
[0005] A completely different synthesis route involving different
intermediates has now been discovered.
[0006] The present invention provides novel nitroaromatic compounds
with general formula: 1
[0007] in which:
[0008] R'.sub.1 represents a linear or branched alkyl group
containing 1 to 12 carbon atoms, a phenyl group that may be
substituted by an alkyl group containing 1 to 4 carbon atoms, or a
halogenophenyl group;
[0009] R.sub.2 represents a hydrogen atom, a hydrocarbon group
containing 1 to 12 carbon atoms, which may be a linear or branched
alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl
group;
[0010] Z represents an oxygen or sulphur atom;
[0011] R represents a hydrogen atom or a substituent;
[0012] n is a number equal to 0.1, 2 or 3, preferably 0;
[0013] when n is greater than 1, two groups R and the successive 2
atoms of the benzene ring can together form a saturated,
unsaturated or aromatic cycle containing 5 to 7 carbon atoms;
[0014] In formula (I'), the benzene ring can carry a
substituent.
[0015] The scope of the invention does not exclude the presence on
the benzene ring of any type of substituent, provided that it does
not react under the conditions of the invention.
[0016] More particular examples of group R that can be mentioned
include:
[0017] a hydroxyl group;
[0018] a linear or branched alkyl group containing 1 to 6 carbon
atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;
[0019] an alkoxy group containing 1 to 6 carbon atoms, preferably 1
to 4 carbon atoms;
[0020] an ester group containing 1 to 10 carbon atoms, preferably 1
to 4 carbon atoms;
[0021] an alkylamide group containing 1 to 6 carbon atoms,
preferably 1 to 4 carbon atoms;
[0022] a carboxamide group;
[0023] a halogen atom;
[0024] a trifluoromethyl group.
[0025] Preferred compounds of the invention have formula (I') in
which R represents a hydrogen atom, a methyl or ethyl group, or a
methoxy or ethoxy group.
[0026] When n is greater than 1, two groups R and the successive 2
atoms of the benzene ring can together form a saturated,
unsaturated or aromatic cycle containing 5 to 7 carbon atoms,
preferably 6 carbon atoms. Advantageously, two groups R form a
benzene ring.
[0027] Group R'.sub.1 is advantageously an alkyl group containing 1
to 4 carbon atoms.
[0028] The invention does not exclude the fact that R.sub.2
represents a further group such as cycloalkyl, phenyl or arylalkyl,
but since group R.sub.2 is eliminated, it is important from an
economic viewpoint that it should be as simple as possible, for
example a lower alkyl group, i.e., containing 1 to 4 carbon atoms.
R.sub.2 can also represent a hydrogen atom, which corresponds to
the presence of a carboxylic group.
[0029] In formula (I'), Z preferably represents an oxygen atom.
[0030] In a further aspect, the present invention provides a
process for preparing nitroaromatic compounds with formula (I):
2
[0031] in which:
[0032] R.sub.1 represents a hydrogen atom, a linear or branched
alkyl group containing 1 to 12 carbon atoms, a phenyl group that
may be substituted by an alkyl group containing 1 to 4 carbon
atoms, or a halogenophenyl group;
[0033] R.sub.2 represents a hydrogen atom, a hydrocarbon group
containing 1 to 12 carbon atoms, which may be a linear or branched
alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl
group;
[0034] Z represents an oxygen or sulphur atom;
[0035] R represents a hydrogen atom or a substituent;
[0036] n is a number equal to 0.1, 2 or 3, preferably 0;
[0037] when n is greater than 1, two groups R and the successive 2
atoms of the benzene ring can together form a saturated,
unsaturated or aromatic cycle containing 5 to 7 carbon atoms;
[0038] characterized in that it consists of carrying out selective
nitration in the 4 position, using a source of NO.sub.2.sup.+ and
in the presence of sulphuric acid, of an aromatic compound with
formula (II): 3
[0039] in which formula (II), R, R.sub.1, R.sub.2, Z and n have the
meanings given above.
[0040] The invention also encompasses nitration of a compound with
formula (II) in its acid form or in its ester form, i.e., a
compound with formula (II) in which R.sub.2 is either a hydrogen
atom or a hydrocarbon group.
[0041] In a further aspect, the invention provides a process for
preparing a compound with formula (II), consisting of reacting:
[0042] a compound of the 2-hydroxy- or 2-thiobenzaldehyde type with
formula (III): 4
[0043] in which formula (m), R, Z and n have the meanings given
above;
[0044] and a carboxylic acid or a derivative with formula (IV)
comprising a leaving group: 5
[0045] in which formula (IV):
[0046] Y represents a leaving group, preferably a halogen atom or a
sulphonic ester group with formula --OSO.sub.2- where is a
hydrocarbon group;
[0047] R.sub.1, R.sub.2 have the meanings given above.
[0048] In the formula for the sulphonic ester group, is a
hydrocarbon group of any nature. However, given that Y is a leaving
group, it is important from an economic viewpoint that should be
simple in nature, and more particularly represents a linear or
branched alkyl group containing 1 to 4 carbon atoms, preferably a
methyl or ethyl group; however, it can also represent a phenyl or
tolyl group or a trifluoromethyl group, for example. Preferably,
group Y is a triflate group, corresponding to a group representing
a trifluoromethyl group.
[0049] Preferred leaving groups that can be selected are halogen
atoms, namely bromine, chlorine or iodine, preferably a bromine or
chlorine atom.
[0050] The invention also encompasses the use of a compound with
formula (I) for the preparation of a heterocyclic compound with
general formula (V): 6
[0051] in which formula (V), R, R.sub.1, Z and n have the meanings
given above, optionally by saponification when R.sub.2 is an ester
function, followed by cyclising.
[0052] In accordance with the process of the invention, novel
intermediates with formula (I') are prepared.
[0053] They are obtained by a selective nitration reaction in the 4
position of compounds with formula (II) in which R.sub.1 is a
linear or branched alkyl group containing 1 to 12 carbon atoms, a
phenyl group that may be substituted by an alkyl group containing 1
to 4 carbon atoms, or a halogenophenyl group.
[0054] It has been discovered that it is only possible to carry out
selective nitration in a position para to the O or S atom if the
starting substrate is an O- or S-alkylated phenolic or thiophenolic
substrate.
[0055] It has been discovered that nitration is not selective if
the starting substrate is a phenolic substrate containing free OH
or SH groups.
[0056] It has also been discovered that nitration is only carried
out under good conditions if the NO.sub.2.sup.+ source is combined
with sulphuric acid.
[0057] The selective nitration process of the invention is
applicable both to preparing novel compounds with formula (I') in
which R'.sub.1 represents a linear or branched alkyl group
containing 1 to 12 carbon atoms; a phenyl group that may be
substituted by an alkyl group containing 1 to 4 carbon atoms or a
halogenophenyl group, and to compounds with formula (I) in which
R.sub.1 has the same meaning as R'.sub.1 but also includes
representing a hydrogen atom.
[0058] Compounds with formula (I) or (I') can be obtained by
nitration of an O- or S-alkylated compound with formula (II), by
reacting the latter with a source of NO.sub.2.sup.+: preferably,
the reaction may or may not be carried out in an organic
solvent.
[0059] To this end, said compound is reacted with a source of
NO.sub.2.sup.+.
[0060] It is possible to start with nitrogen dioxide NO.sub.2,
nitrous anhydride N.sub.2O.sub.3, dinitrogen tetroxide
N.sub.2O.sub.4, or nitric oxide NO associated with an oxidising
agent such as nitric acid, nitrogen dioxide or oxygen. When the
reactant is gaseous under the reaction conditions, it is bubbled
into the medium.
[0061] It is also possible to use nitrous acid, a nitrose or
nitrosyl sulphate or a nitrous salt, preferably an alkali metal
salt, still more preferably sodium associated with an oxidising
agent, preferably nitric acid.
[0062] It is also possible to use alkyl nitrites associated with an
oxidising agent, more particularly those with formula (VII):
R.sub.a--ONO (VII)
[0063] in which formula (VII), R.sub.a represents a linear or
branched alkyl group containing 1 to 12 carbon atoms, preferably 1
to 4 carbon atoms.
[0064] The quantity of NO.sub.2.sup.+ source is at least equal to
the stoichiometric quantity of the O- or S-alkylated aromatic
compound. The ratio between the number of moles of NO.sub.2.sup.+
source and the number of moles of aromatic O- or S-alkylated
compound is advantageously in the range 1.0 to 1.2.
[0065] Preferably, a concentrated nitric acid solution is used with
a preferred concentration in the range 70% to 99%.
[0066] As mentioned above, the NO.sub.2.sup.+ source is associated
with sulphuric acid.
[0067] In a variation, the process of the invention consists of
using a nitrating mixture (mixture of nitric acid and sulphuric
acid comprising 50% to 98% by weight of nitric acid).
[0068] The quantity of nitric acid, expressed as the mole ratio of
the O- or S-alkylated aromatic compound/nitric acid, is generally
in the range 0.9 to 1.1, preferably in the range 0.95 to 1.05.
[0069] The quantity of sulphuric acid, expressed as the mole ratio
of the O- or S-alkylated aromatic compound/sulphuric acid, is
generally in the range 0.9 to 1.1, preferably in the range 0.95 to
1.05.
[0070] The concentration of sulphuric acid is advantageously in the
range 50% to 98%.
[0071] To this end, nitric acid or a precursor of nitric acid is
used, such as dinitrogen tetroxide.
[0072] The nitration reaction can optionally be carried out in an
organic solvent that is inert under the reaction conditions.
[0073] More particular examples of organic solvents that can be
cited are aliphatic halogenated hydrocarbons, more particularly
perchlorinated hydrocarbons such as tetrachloromethane,
hexachloroethane; partially chlorinated hydrocarbons such as
dichloromethane, and 1,2-dichloromethane.
[0074] Dichloromethane is the preferred solvent.
[0075] Regarding the concentration of the O- or S-alkylated
aromatic compound in the reaction medium, it is preferably in the
range 0.2 to 3 mole/I, more preferably in the range 0.3 to 1.5
mole/l.
[0076] This is generally introduced in the liquid form.
[0077] The reaction is advantageously carried out at a temperature
in the range -10.degree. C. to 20.degree. C., preferably in the
range -5.degree. C. to 10.degree. C., and in an inert gas
atmosphere.
[0078] The process of the invention is generally carried out at
atmospheric pressure.
[0079] In a preferred variation of the process of the invention,
the nitration step is carried out in a controlled inert gas
atmosphere. A rare gas atmosphere can be established, preferably
argon, but it is cheaper to use nitrogen.
[0080] A number of implementations can be envisaged.
[0081] In a first variation, the sulphuric acid solution is charged
first, followed by the O- or S-alkylated aromatic compound and the
nitric acid at the same time.
[0082] In a further variation, the sulphuric acid and nitric acid
solution is introduced then the O- or S-alkylated aromatic compound
is added, preferably in portions, or it is poured in
continuously.
[0083] In a still further variation, the O- or S-alkylated aromatic
compound is introduced into a base stock on the one hand and the
sulphuric and nitric acid on the other hand.
[0084] The reaction advantageously lasts 3 to 10 hours.
[0085] At the end of the reaction, the desired product with formula
(I) is obtained.
[0086] The product is recovered using conventional techniques
employed in the field.
[0087] In particular, water hydrolysis can be carried out,
preferably using ice employed in an amount of 100% to 150% by
weight of the compound with formula (I) or (I'), for example.
[0088] A solid is obtained that is separated using conventional
solid/liquid separation techniques, preferably by filtering.
[0089] The desired product is then produced.
[0090] In accordance with the process of the invention, the
starting compound is a compound with formula (II) which can in
particular can be obtained using an O- or S-alkylation reaction of
a compound of the 2-hydroxy or 2-thiobenzaldehyde type with formula
(III) with a carboxylic acid or a derivative with formula (IV).
[0091] One implementation consists of reacting an aromatic compound
with formula (III) with a carboxylic acid or a derivative with
formula (IV): the reaction is carried out in the presence of a
base, preferably in an organic solvent.
[0092] A further variation of the process of the invention consists
of carrying out the O- or S-alkylation reaction in an aqueous
medium in the presence of a base and a phase transfer catalyst.
[0093] Of the compounds with formula (III), salicylic aldehyde is
preferred.
[0094] Regarding the carboxylic acid or derivative with formula
(IV), esters of .alpha.-halogenocarboxylic acids are preferably
used, more preferably methyl or ethyl 2-bromohexanoate.
[0095] The mole ratio between the compound with formula (III) and
the compound with formula (IV) is advantageously between 1 and
1.2.
[0096] In accordance with the process of the invention, the
2-hydroxy or 2-thiobenzaldehyde type compound with formula (III) is
reacted in its salt form with the carboxylic acid or derivative
with formula (IV), in an organic solvent.
[0097] A salt form of a 2-hydroxy or 2-thiobenzaldehyde type
compound that has been extemporaneously prepared can be used, but
it is also possible to prepare it in situ by reacting the compound
of the 2-hydroxy or 2-thiobenzaldehyde type compound and the
base.
[0098] Thus a base, which can be mineral or organic, is used in the
process of the invention.
[0099] Particularly suitable bases for use in carrying out the
process of the invention are mineral bases such as alkali metal or
alkaline-earth metal salts, preferably an alkali or alkaline-earth
metal hydroxide, which may be sodium, potassium or calcium
hydroxide; or an alkali metal carbonate or bicarbonate, preferably
sodium carbonate.
[0100] It is also possible to use an organic base such as a
quaternary ammonium hydroxide or an amine.
[0101] Preferred examples of quaternary ammonium hydroxides that
can be used are tetraalkylammonium or trialkylbenzylammonium
hydroxides in which the alkyl groups, which may be identical or
different, represent a linear or branched alkyl chain containing 1
to 12 carbon atoms, preferably 1 to 6 carbon atoms.
[0102] Preferably, tetramethylammonium hydroxide,
tetraethylammonium hydroxide or tetrabutylammonium hydroxide is
used.
[0103] It is also possible to use trialkylbenzylammonium
hydroxides, in particular trimethylbenzylammonium hydroxide.
[0104] Examples of amines that can be mentioned include tertiary
amines.
[0105] Suitable bases that can be cited are tertiary amines, more
particularly those with general formula (VIII):
N--(R.sub.3).sub.3 (VIII)
[0106] in which:
[0107] groups R.sub.3, which may be identical or different,
represent hydrocarbon residues containing 1 to 20 carbon atoms,
such as alkyl, cycloalkyl, aryl or heterocyclic groups;
[0108] 2 groups R.sub.3 together with the nitrogen atom form a
heterocycle containing 4 to 6 atoms.
[0109] More particularly:
[0110] symbols R.sub.3 represent an alkyl group containing 1 to 10
carbon atoms, preferably 1 to 4 carbon atoms, or a cyclopentyl or
cyclohexyl group or pyridinyl group;
[0111] 2 groups R.sub.3 together form a piperidine or pyrrolidine
cycle with the nitrogen atom.
[0112] Examples of such amines that can be cited are triethylamine,
tri-n-propylamine, tri-n-butylamine, methyldibutylamine,
methyldicyclohexylamine, ethyldiisopropylamine,
N,N-diethylcyclohexylamin- e, dimethylamino-4-pyridine,
N-methylpiperidine, N-ethylpiperidine, N-n-butylpiperidine,
1,2-dimethylpiperidine, N-methylpyrrolidine, and
1,2-dimethylpyrrolidine.
[0113] For reasons of economy, sodium or potassium carbonate are
preferred.
[0114] While the base is used in its solid form, it is also
possible to use the base in solution. The concentration of the
starting base solution is not critical. The alkali metal hydroxide
solution is employed in a concentration that is generally in the
range 10% to 50% by weight.
[0115] The quantity of base introduced into the reaction medium
takes into account the quantity necessary to change the hydroxyl or
thiol function of the 2-hydroxy or 2-thiobenzaldehyde type compound
into the salt form.
[0116] The hydroxyl or thiol group of the starting substrate with
formula (III) can be transformed into its salt form in an initial
step. Thus, the compound with formula (III) can be transformed into
its salt form either by introducing the base then causing it to
react at a temperature that is advantageously in the range
0.degree. C. to 100.degree. C., preferably in the range 25.degree.
C. to 50.degree. C., or by introducing the base at the same time as
the compound with formula (IV).
[0117] Generally, the quantity of base, expressed with respect to
the 2-hydroxy or 2-thiobenzaldehyde type compound, is in the range
90% to 120% of the stoichiometric quantity.
[0118] In accordance with the invention, the O- or S-alkylation
reaction is advantageously carried out in the liquid phase
comprising the compound with formula (III) and the compound with
formula (IV), in the presence of a base.
[0119] One of the starting reactants can act as the reaction
solvent, but it is also possible to use an organic solvent.
[0120] An organic solvent is selected that is less activated than
the starting substrate and which preferably dissolves it.
[0121] Examples of solvents that are suitable for use in the
present invention that can be cited are aromatic hydrocarbons,
which may or may not be halogenated, and aliphatic, cycloaliphatic
or aromatic ether-oxides.
[0122] Examples of aliphatic hydrocarbons that can be cited are
aromatic hydrocarbons, more particularly aromatic hydrocarbons such
as benzene, toluene, xylenes, cumene, and petroleum cuts
constituted by a mixture of alkylbenzenes, in particular Solvesso
type cuts.
[0123] Regarding aliphatic or aromatic halogenated hydrocarbons,
particular mention can be made of dichloromethane,
1,2-dichloroethane and mono- or dichlorobenzene.
[0124] The organic solvent can also be an aliphatic, cycloaliphatic
or aromatic ether-oxide, more particularly dipropyl oxide,
diisopropyl oxide, dibutyl oxide, methyltertiobutylether, ethylene
glycol dimethylether (or glyme), diethylene glycol dimethyl ether
(diglyme); phenyl oxide; dioxane, and tetrahydrofuran (THF).
[0125] Examples of more polar aprotic organic solvents that can
also be used in the process of the invention that can be cited are
aliphatic or aromatic nitriles such as acetonitrile, propionitrile,
benzonitrile; linear or cyclic carboxamides such as
N,N-dimethylacetamide (DMAC), dimethylformamide (DMF),
diethylformamide or 1-methyl-2-pyrrolidinone (NMP).
[0126] Preferred solvents are DMAC or DMF.
[0127] It is also possible to use a mixture of solvents.
[0128] Regarding the concentration of the 2-hydroxy or
2-thiobenzaldehyde type compound in the reaction medium, it is
preferably in the range 2% to 50% by weight.
[0129] In a variation of the process of the invention, iodide ions
are added to accelerate the reaction. Alkali metal iodides can in
particular be used, preferably potassium iodide or
tetraalkylammonium iodides, preferably tetrabutylammonium
iodide.
[0130] The quantity of iodide used, expressed as the ratio between
the number of moles of iodine salt and the number of moles of
compound with formula (III), can be in the range 0.05 to 0.2.
[0131] The temperature for reacting the aromatic compound with
formula (II) with a carboxylic acid or derivative with formula (IV)
is advantageously in the range 0.degree. C. to 100.degree. C.,
preferably in the range 25.degree. C. to 50.degree. C.
[0132] The reaction generally takes place at atmospheric
pressure.
[0133] In a preferred variation of the process of the invention,
the process of the invention is carried out in a controlled
atmosphere of inert gases. A rare gas atmosphere can be
established, preferably with argon, but it is cheaper to use
nitrogen.
[0134] From a practical viewpoint, the process is simple to carry
out.
[0135] One implementation of the invention consists of charging all
of the reactants, the base, the organic solvent and optionally the
iodide ions.
[0136] The medium is then heated to the selected reaction
temperature.
[0137] As mentioned above, salt formation can be carried out in a
previous step and the compound with formula (III), the base and the
organic solvent can be introduced, the medium is heated to the
selected temperature then the compound with formula (IV) is added
along with the optional iodide ions, then heated.
[0138] The desired product with formula (II) is obtained.
[0139] The product obtained is recovered conventionally.
[0140] As an example, the salts formed during the reaction can be
eliminated by adding water and extracting the product in the
organic phase, in a suitable solvent, for example isopropyl
ether.
[0141] The organic solvent can be eliminated conventionally by
evaporation.
[0142] In a variation of the process of the invention, the
2-hydroxy- or 2-thiobenzaldehyde type compound with formula (III)
is reacted with a carboxylic acid or derivative with formula (IV)
in an aqueous medium in the presence of a base and a phase transfer
catalyst.
[0143] The expression "phase transfer catalyst" means a catalyst
that can pass the anion from the aqueous phase to the organic
phase.
[0144] Known phase transfer catalysts can be used in the process of
the invention, in particular those described by Jerry MARCH in
"Advanced Organic Chemistry", third edition, John Wiley & Sons,
1985, p. 320 ff.
[0145] A first category of phase transfer catalysts that is
suitable for use in the invention includes those of the
tris(ether-amine) type which have been described in the literature,
in particular in French patent FR-A-2 455 570.
[0146] They have the following formula:
N-[-A-O--(--B--O--).sub.n--R.sub.b].sub.3 (VIII)
[0147] In which formula, R.sub.b represents an alkyl group
containing 1 to 24 carbon atoms, a cyclohexyl group, a phenyl
group, an alkylphenyl group the alkyl portion of which contains 1
to 12 carbon atoms, A and B, which may be identical or different,
represent a linear alkanediyl group containing 2 or 3 carbon atoms,
said atoms possibly being substituted by a methyl or ethyl
group.
[0148] A specific example of catalysts with formula (VIII) that can
in particular be mentioned is tris(3,3-dioxaheptyl)amine
(TDA-1).
[0149] Catalysts that are preferably employed in the process of the
invention are onium salts, more particular quaternary ammonium
and/or phosphonium salts.
[0150] Onium salts that can be used in the process of the invention
are those the onium ions of which derive in particular from
nitrogen, phosphorus, arsenic, sulphur, selenium, oxygen, carbon or
iodine and co-ordinated with hydrocarbon residues. Onium ions
deriving from nitrogen, phosphorus or arsenic will be
four-co-ordinate; onium ions deriving from sulphur, selenium,
oxygen or carbon will be three-coordinated; while onium ions
deriving from iodine will be two-coordinated.
[0151] The hydrocarbon residues co-ordinated to these different
elements are alkyl, alkenyl, aryl, cycloalkyl, optionally
substituted aralkyl groups, and two co-ordinated hydrocarbon
residues can together form a single divalent group.
[0152] The nature of the anions bonded to these organic cations is
not important. Any "hard" or "borderline" base will be suitable as
the anion.
[0153] The terms "hard" or "borderline" base means any anion
satisfying the conventional definition given by R. PEARSON in the
Journal of Chem. Ed. 45, pages 581-587 (1968).
[0154] Particularly suitable onium ions that can be used in the
process of the invention are those with the following general
formulae: 7
[0155] in which formulae:
[0156] Z represents N, P or As;
[0157] Y represents S, O, Se or C;
[0158] X.sub.1, X.sub.2, X.sub.3 and X.sub.4, which may be
identical or different, represent:
[0159] a linear or branched alkyl group containing 1 to 16 carbon
atoms, optionally substituted by one or more phenyl, hydroxyl,
halogen, nitro, alkoxy or alkoxycarbonyl groups, the alkoxy groups
containing 1 to 4 carbon atoms;
[0160] a linear or branched alkenyl group containing 2 to 12 carbon
atoms;
[0161] an aryl group containing 6 to 10 carbon atoms, optionally
substituted by one or more alkyl groups containing 1 to 4 carbon
atoms, an alkoxy group, or an alkoxycarbonyl group, the alkoxy
group containing 1 to 4 carbon atoms, or a halogen;
[0162] two of said groups X.sub.1 to X.sub.4 can together form a
linear or branched alkylene, alkenylene or alkadienylene group
containing 3 to 6 carbon atoms.
[0163] The following ions included in "hard" or "borderline" bases
that can constitute the anion in said onium salts can be cited:
F.sup.-, ClO.sub.4.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.-,
SnCl.sub.6.sup.-, SbCl.sub.6.sup.-, B(Ph).sub.4.sup.-,
PO.sub.4.sup.3-, HPO.sub.4.sup.2-, H.sub.2PO.sub.4.sup.-,
CH.sub.3SO.sub.3.sup.-, Ph-SO.sub.3.sup.-, HSO.sub.4.sup.-,
NO.sub.3.sup.-, SO.sub.4.sup.2-, Cl.sup.-, Br.sup.-, I.sup.-,
OH.sup.-, Ph representing a phenyl group, and any other anion
satisfying PEARSON's definition of a "hard" or "borderline"
base.
[0164] For ease of implementation, said anions can be selected from
PO.sub.4.sup.3-, HPO.sub.4.sup.2-, H.sub.3PO.sub.4.sup.-,
CH.sub.3SO.sub.3.sup.-, Ph--SO.sub.3.sup.-, NO.sub.3.sup.-,
SO.sub.4.sup.2-, PF.sub.6.sup.-, Cl.sup.-, Br.sup.-, F.sup.-,
OH.sup.-, Ph having the meaning given above. Advantageously,
Br.sup.- and Cl.sup.- anions are selected.
[0165] The following cations can be cited as examples of onium ions
with formula (IX):
[0166] tributylmethylammonium;
[0167] tetraethylammonium;
[0168] tetrabutylammonium;
[0169] dodecyltrimethylammonium;
[0170] methyltrioctylammonium;
[0171] heptyltributylammonium;
[0172] tetrahexylammonium;
[0173] tetraheptylammonium;
[0174] tetraoctylammonium;
[0175] benzyltrimethylammonium;
[0176] benzyldimethylpropylammonium;
[0177] benzyldimethyloctylammonium;
[0178] benzyltributylammonium;
[0179] benzyltriethylammonium;
[0180] phenyltrimethylammonium;
[0181] benzyldimethyltetradecylammonium;
[0182] benzyldimethylhexadecylammonium;
[0183] tetrabutylphosphonium;
[0184] trimethylpentylphosphonium;
[0185] trimethylphenylphosphonium;
[0186] diethyldimethylphosphonium;
[0187] dicyclohexydimethylphosphonium;
[0188] dimethyldiphenylphosphonium;
[0189] cyclohexyltrimethylphosphonium;
[0190] methyltribenzylphosphonium;
[0191] methyltri(4-methylphenyl)phosphonium;
[0192] ethyltri(n-propyl)phosphonium;
[0193] triethylpentylphosphonium;
[0194] hexadecyltributylphosphonium;
[0195] ethyltriphenylphosphonium;
[0196] n-butyltri(n-propyl)phosphonium;
[0197] tetraphenylphosphonium;
[0198] teiphenyl(4-meethylphenyl)phosphonium;
[0199] tetrakis(hydroxymethyl)phosphonium;
[0200] tetraphenylarsonium.
[0201] Examples of onium ions with formula (IX') that can be cited
are the following cations:
[0202] triethylsulphonium;
[0203] triphenylsulphonium.
[0204] Preferred onium ions that can be used in the present process
are quaternary ammonium ions and quaternary phosphonium ions.
[0205] Ammonium ions are particularly suitable, the ammonium ions
including four alkyl groups containing 1 to 5 carbon atoms or a
benzyl group.
[0206] Regarding the choice of anion, Br.sup.-, Cl.sup.- or
OH.sup.- are preferred.
[0207] The most suitable catalysts for use in the present invention
are tributylbenzyl ammonium or phosphonium chloride or bromide,
tetramethyl ammonium or phosphonium chloride or bromide, tetraethyl
ammonium phosphonium chloride or bromide, and tetrabutyl ammonium
or phosphonium chloride or bromide.
[0208] Benzyltributylammonium chloride or bromide is particularly
preferred, the chlorinated derivative being more particularly
preferred.
[0209] The onium salt can be introduced during the process of the
invention in the solid state or in the form of a solution in one of
its solvents, usually water.
[0210] The process of the invention is advantageously carried out
in the absence of solvent.
[0211] The process of the invention is carried out in the presence
of a water-soluble base.
[0212] Advantageously, potassium or sodium carbonate is used, or
ammonia.
[0213] In a preferred implementation, potassium carbonate is
used.
[0214] The quantity of base employed, expressed as the ratio
between the number of moles of compound with formula (III) an the
number of moles of base, is preferably between 1 and 5, more
preferably about 1.5.
[0215] In accordance with the process of the invention, the O- or
S-alkylation reaction of the compound with formula (III) is carried
out in the presence of a phase transfer catalyst, the different
reactants generally being used in the proportions defined
above.
[0216] The mole ratio between the number of moles of compound with
formula (III) and the number of moles of compound with formula (IV)
is preferably in the range 1 to 1.2.
[0217] Regarding the quantity of catalyst used, this is
advantageously such that the mole ratio between said catalyst and
the compound with formula (III) is in the range 0.01 to 0.50,
preferably in the range 0.05 to 0.2. The upper limit is not
critical and can be substantially exceeded without disadvantage as
the catalyst can optionally be recycled at the end of the
reaction.
[0218] As mentioned above, the reaction is carried out in an
aqueous medium, advantageously in the absence of any organic
solvent.
[0219] In a preferred implementation of the invention, the
concentration of the compound with formula (III) is as high as
possible.
[0220] The quantity of water present in the reaction medium
generally represents 30% to 100% of the total weight of the
reactants used.
[0221] The reaction is advantageously carried out following the
"one pot" principle, and the order in which the reactants and
reactive agents are introduced is not critical.
[0222] The temperature at which the process of the invention is
carried out is generally in the range from ambient temperature to
80.degree. C. Preferably, the temperature is in the range
50.degree. C. to 65.degree. C.
[0223] The reaction pressure is not critical and is generally
atmospheric pressure.
[0224] In order to reach the temperatures indicated above,
autogenous pressure conditions are usually applied.
[0225] The reaction period depends on the reaction temperature and
on the desired degree of transformation. When the temperature is in
the preferred zone, the reaction period can vary widely, for
example, from 6 to 10 hours.
[0226] At the end of the reaction, the aromatic O- or S-alkylated
compound with formula (II) is contained in or constitutes the
organic phase, which can be separated from the aqueous phase, in
particular by decanting.
[0227] The compound obtained can be isolated from the organic phase
using conventional techniques such as distillation or extraction
using a suitable solvent.
[0228] In accordance with the invention, the compound with formula
(I) or (I') is an intermediate in the production of the compound
with formula (V).
[0229] In a subsequent step, if necessary, the ester function can
be saponified to the carboxylic function then the product obtained
is cyclised. In a further variation, it is possible to carry out
saponification of the compound with formula (II) if necessary,
prior to the nitration operation.
[0230] To this end, the compound with formula (I) or (I') is
reacted with a base in a hydro-organic medium.
[0231] A preferred base is sodium hydroxide or potassium hydroxide,
used in the form of flakes or concentrated solutions, for example
40% for sodium hydroxide.
[0232] The quantity of base employed, expressed as the ratio
between the number of moles of compound with formula (I) or (I')
and the number of moles of base, is preferably between 1 and 5,
more preferably between 1 and 2.
[0233] The base is dissolved in an aqueous or hydroorganic
medium.
[0234] Preferably, a polar organic solvent is used.
[0235] More particular examples of suitable organic solvents that
can be cited are aliphatic alcohols such as ethanol, propanol,
butanol, pentanol, ethylene glycol; cycloaliphatic alcohols, in
particular cyclohexanol, and arylaliphatic alcohols, more
particularly benzyl alcohol. It is also possible to envisage the
monomethyl, monoethyl, monopropyl, monobutyl ethers of ethylene
glycol sold under the trade name Cellosolves.RTM..
[0236] The concentration of compound with formula (I) or (I') in
the reaction medium (water+organic solvents) advantageously varies
between 5% and 50%, preferably in the range 5% to 20% by
weight.
[0237] The volume ratio between the organic solvent and water can,
for example, be between 0.1 and 0.9, preferably in the range 0.1 to
0.2.
[0238] The choice of organic solvent and the water/organic solvent
ratio is determined so that the solution obtained is
homogeneous.
[0239] The saponification reaction is carried out at a temperature
in the range from ambient temperature to the reflux temperature of
the reaction mixture, preferably at a temperature close to
50.degree. C.
[0240] The term "ambient temperature" generally means a temperature
in the range 15.degree. C. to 25.degree. C.
[0241] In one practical implementation of the invention, the
compound with formula (I) or (I') is introduced into the aqueous or
hydro-organic medium then the base is added, and the reaction
mixture is heated to the selected temperature.
[0242] At the end of the reaction, if necessary, the excess base is
neutralised with an acidic solution, preferably a solution of a
mineral acid or a mineral salt such as hydrochloric acid or
ammonium chloride.
[0243] The product obtained precipitates out then it is separated
using conventional solid/liquid separation techniques, preferably
by filtering.
[0244] The product obtained can be cyclised by applying prior art
techniques, for example in acetic anhydride and in the presence of
sodium acetate (Brady, W. T.; Gu, Y-Q., J. Heterocyl. Chem. 1988,
25, 969-971).
[0245] The temperature of the cyclisation reaction is
advantageously between ambient temperature and the reflux
temperature of the reaction solvent.
[0246] A benzofuran or benzothiophene type derivative that is
nitrated in the 4 position is obtained with formula (V): 8
[0247] in which formula (V), R, R.sub.1, Z and n have the meanings
given above;
[0248] by optional saponification of the compound with formula (I)
or (I') when R.sub.2 is an ester function, then cyclising.
[0249] In a further implementation, the compound with formula (I)
or (I') is cyclised in a medium comprising a carboxylic acid
anhydride and the presence of a base selected from metallic or
ammonium carbonates and/or bicarbonates.
[0250] Suitable bases that can be mentioned in particular are
alkali or alkaline-earth metal carbonates and bicarbonates. Caesium
carbonate can be used but preferably, sodium carbonate or potassium
carbonate is used.
[0251] In accordance with the process of the invention, the
aromatic compound, preferably with formula (I) or (I'), is cyclised
in a carboxylic acid anhydride.
[0252] More particularly, this latter has the following formula:
9
[0253] in which formula (X):
[0254] R.sub.a and R.sub.b, which may be identical or different,
represent a monovalent hydrocarbon group that may or may not be
substituted, which can be a linear or branched, saturated or
unsaturated acyclic aliphatic group; or a monocyclic saturated,
unsaturated or aromatic carbocyclic group;
[0255] R.sub.a and R.sub.b can together form a divalent linear or
branched, saturated or unsaturated aliphatic group containing at
least 2 carbon atoms.
[0256] Groups R.sub.a and R.sub.b are preferably selected such that
the anhydride is liquid under the reaction conditions.
[0257] The anhydride used may or may not be cyclic.
[0258] More precisely, a cyclic anhydride containing 5 to 10 carbon
atoms in the cycle can be used that may or may not contain a double
bond; one of the atoms can be replaced by an oxygen atom.
[0259] Preferably, the cyclic anhydrides are saturated or contain a
double bond and 5 or 6 atoms in the cycle.
[0260] The cycle can comprise one or more substituents. More
particular examples of substituents that can be cited are linear or
branched alkyl groups containing 1 to 12 carbon atoms, preferably 1
to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, or halogen atoms or a
trihalogenomethyl group.
[0261] More particularly, when using a non cyclic anhydride with
formula (X), groups R.sub.a and R.sub.b, which may be identical or
different, represent:
[0262] a linear or branched acyclic aliphatic group preferably
containing 1 to 24, more preferably 1 to 12 carbon atoms, which may
be saturated or comprise one or more unsaturated bonds in its
chain, generally 1 to 3 unsaturated bonds, which may be simple
double bonds: the hydrocarbon chain may be interrupted by one of
the following groups: --O--; --CO--; and/or carry one or more
substituents, in particular: --X; --CX.sub.3; a saturated,
unsaturated or aromatic carbocyclic group containing 3 to 8 carbon
atoms, preferably 6 carbon atoms, optionally carrying one or more
halogen atoms, preferably chlorine or bromine.
[0263] Of the groups defined above, R.sub.a and R.sub.b preferably
represent:
[0264] a linear or branched alkyl group containing 1 to 12 carbon
atoms, optionally carrying one or more halogen atoms;
[0265] a cyclohexyl or phenyl group, optionally carrying one or
more halogen atoms, or a trihalogenomethyl group.
[0266] Examples of anhydride that can be cited are:
[0267] acetic anhydride;
[0268] propanoic anhydride;
[0269] isobutyric anhydride;
[0270] trichloroacetic anhydride;
[0271] trifluoroacetic anhydride;
[0272] benzoic anhydride;
[0273] monochloroacetyl anhydride;
[0274] dichloroacetyl anhydride;
[0275] pivalic anhydride.
[0276] Acetic anhydride is preferred from the above list of
anhydrides.
[0277] The invention does not exclude producing the carboxylic
anhydride in the medium, from a carboxylic acid.
[0278] As mentioned above, in a preferred variation of the process
of the invention, an organic solvent is used.
[0279] A number of criteria govern the choice of organic
solvent.
[0280] A first criterion for the organic solvent is that it should
be stable in the reaction medium.
[0281] A second criterion is that the solvent should have a high
boiling point, preferably 50.degree. C. or more.
[0282] Examples of solvents that are suitable for use in the
present invention that can be cited are aromatic hydrocarbons,
which may or may not be halogenated, and aliphatic, cycloaliphatic
or aromatic ether-oxides. Examples of such solvents have been given
above.
[0283] Examples of more polar aprotic organic solvents that can
also be used in the process of the invention that can be cited are
linear or cyclic carboxamides such as N,N-dimethylacetamide (DMAC),
N,N-diethylacetamide, dimethylformamide (DMF), diethylformamide or
1-methyl-2-pyrrolidinone (NMP); dimethysulphoxide (DMSO);
hexamethylphosphotriamide (HMPT); tetramethylurea; nitro compounds
such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane
or mixtures thereof, nitrobenzene; aliphatic or aromatic nitriles
such as acetonitrile, propionitrile, butanenitrile;
isobutanenitrile, benzonitrile, benzyl cyanide; tetramethylene
sulphone (sulpholane).
[0284] It is also possible to use a mixture of organic
solvents.
[0285] According to the process of the invention, the starting
substrate is cyclised in the presence of a base and a carboxylic
acid anhydride.
[0286] More precisely, the quantity of base, expressed as the ratio
between the number of moles of base and the number of moles of
starting substrate, preferably with formula (I) or (I'), is in the
range 0.05 to 1.0 and is preferably in the range 0.1 to 0.2.
[0287] The quantity of carboxylic acid anhydride employed is such
that the mole ratio of carboxylic acid anhydride/compound with
formula (I) or (I') is preferably in the range 2 to 10.
[0288] In the preferred variation of the process of the invention,
which consists of using an organic solvent, the quantity of
carboxylic acid anhydride employed is such that the mole ratio of
carboxylic acid anhydride/compound with formula (I) or (I') is
preferably in the range 1 to 3, more preferably in the range 1 to
2.
[0289] Regarding the quantity of organic solvent employed, it is
determined as a function of the nature of the organic solvent
selected.
[0290] It is determined such that the concentration of substrate in
the organic solvent is preferably in the range 1 to 10 mole/litre,
more preferably in the range 2 to 3 mole/litre.
[0291] The starting substrate cyclising reaction takes place at a
temperature that is advantageously in the range 50.degree. C. to
160.degree. C., preferably in the range 100.degree. C. to
140.degree. C.
[0292] The cyclisation reaction is generally carried out at
atmospheric pressure but preferably, it is carried out in a
controlled inert gas atmosphere. A rare gas atmosphere can be
established, preferably with argon, but it is cheaper to use
nitrogen.
[0293] From a practical viewpoint, the reaction is simple to carry
out.
[0294] The order in which the reactants are used is not critical. A
preferred variation consists of charging the organic solvent, if
present, the substrate, the carboxylic anhydride and then the base
and heating to the desired temperature.
[0295] At the end of the reaction, the cyclised product is
obtained, preferably with formula (V) and which can be recovered
conventionally.
[0296] More particularly, the invention concerns the preparation of
2-n-butyl-5-nitrobenzofuran.
[0297] The following examples illustrate the invention without in
any way limiting its scope.
EXAMPLES
Example 1
Preparation of 2-(2-formyl-4-nitro-phenoxy)-hexanoic Acid
[0298] 2-(2-formyl-4-nitro-phenoxy)-hexanoic acid can be prepared
as follows:
[0299] 29.5 g of methyl 2-(2-formyl-4-nitro-phenoxy)-hexanoate and
148 ml of water were charged in succession into a 250 ml four-neck
reactor provided with a Teflon half moon paddle stirrer, a
thermometer, a 50 ml dropping funnel, a cooling coil and a nitrogen
inlet.
[0300] 8.4 g of an aqueous 50% sodium hydroxide solution was added
over 20 minutes.
[0301] After stirring for 15 minutes at a temperature of close to
25.degree. C., the reaction medium was heated for 2 hours to about
50.degree. C.
[0302] The clear red medium obtained was partially evaporated (50
ml) under reduced pressure (20 mm Hg) to eliminate the methanol
formed then rediluted with 50 ml of water.
[0303] The pH of the reaction medium was brought to about 1.8 by
slowly adding 10.8 g of concentrated hydrochloric acid, keeping the
temperature to close to 45.degree. C. by stirring.
[0304] After stirring for one hour, the temperature of the medium
was raised to close to 55.degree. C. for 20 minutes then left at
ambient temperature for 12 hours.
[0305] The solid product was separated by filtering through a
n.degree. 3 glass frit and washed with twice 50 ml of water and
oven dried for 12 hours at a temperature of close to 55.degree.
C.
[0306] 26.8 g of 2-(2-formyl-4-nitro-phenoxy)-hexanoic acid was
obtained in the form of a pale yellow solid melting at
110-111.degree. C. and titrating at 97.5% by potentiometric
assay.
[0307] It had the following NMR spectrum:
[0308] .sup.1H NMR (DMSO-d6): .delta. 0.91 (t, 3H, CH.sub.3); 1.38
(m, 2H, CH.sub.2--CH.sub.3); 1.51 (m, 2H,
CH.sub.2--CH.sub.2--CH.sub.3); 2.02 (m, 2H, CH.sub.2--CH); 5.24 (t,
1H, CH); 7.34 (d, J=9 Hz, 1H, ArH); 8.44 (d, J=2 Hz, 1H, ArH); 8.47
(dd, J=9 Hz, J=2 Hz, 1H, ArH); 10.42 (s, 1H, CHO); 13.45 (broad
peak, 1H, COOH).
Example 2
Preparation of 2-(2-formyl-4-phenoxy)-hexanoic Acid
[0309] 2-(2-formyl-4-phenoxy)-hexanoic acid can be prepared as
follows:
[0310] 29.5 g of methyl 2-(2-formyl-phenoxy)-hexanoate and 148 ml
of water were charged in succession into a 250 ml four-neck reactor
provided with a Teflon half moon paddle stirrer, a thermometer, a
50 ml dropping funnel, a cooling coil and a nitrogen inlet.
[0311] 10.4 g of an aqueous 50% sodium hydroxide solution was added
over 20 minutes.
[0312] After stirring for 15 minutes at a temperature of close to
25.degree. C., the reaction medium was heated for 2 hours to about
50.degree. C.
[0313] The clear medium obtained was partially evaporated (50 ml)
under reduced pressure (20 mm Hg) to eliminate the methanol formed,
then re-diluted with 50 ml of water.
[0314] The pH of the reaction medium was brought to about 1.8 by
slowly adding 10.8 g of concentrated hydrochloric acid, keeping the
temperature to close to 45.degree. C. by stirring.
[0315] After stirring for one hour, the temperature of the medium
was raised to close to 55.degree. C. for 20 minutes then left at
ambient temperature for 12 hours.
[0316] The solid product was separated by filtering through a
n.degree. 3 glass frit and washed with twice 50 ml of water then
oven dried for 12 hours at a temperature of close to 55.degree.
C.
[0317] 27.4 g of 2-(2-formyl-phenoxy)-hexanoic acid was obtained in
the form of a pale yellow solid titrating at 98% by potentiometric
assay.
Example 3
Preparation of Methyl 2-(2-formyl-4-nitro-phenoxy)-hexanoate
[0318] Methyl 2-(2-formyl-4-nitro-phenoxy)-hexanoate can be
prepared as follows:
[0319] 123 g of 96% concentrated sulphuric acid was charged into a
250 ml four-neck reactor provided with a Teflon half moon paddle
stirrer, a thermometer, a 50 ml dropping funnel, a cooling coil and
a nitrogen inlet.
[0320] The reaction medium was cooled to a temperature of close to
5.degree. C. then 30 g (0.12 mole) of methyl
2-(2-formylphenoxy)-hexanoat- e was added at the same
temperature.
[0321] After stirring for 15 minutes, 15.9 g (0.126 mole) of
nitrating mixture (50/50) was added over 2 hours, keeping the
reaction medium close to 5.degree. C., then 76.9 g of ice was added
over 30 minutes, leading to an H.sub.2SO.sub.4 titre of 60%.
[0322] The reaction mixture was filtered through a n.degree. 3 frit
after stirring for 10 minutes.
[0323] The crude product obtained was dissolved in 100 ml of
dichloromethane and washed with twice 50 ml of water.
[0324] The decanted organic phase was concentrated in a rotary
evaporator at 20.degree. C. to 70.degree. C. in 20 mm of mercury
(duration: 2 hours).
[0325] 32.7 g of a beige yellow solid product was obtained, giving
a yield of methyl 2-(2-formyl-4-nitro-phenoxy)-hexanoate of 92.4%,
titrating at 96.7% by gas chromatography.
[0326] It had the following NMR spectrum:
[0327] .sup.1H NMR (DMSO-d6): .delta. 0.91 (t, 3H, CH.sub.3); 1.38
(m, 2H, CH.sub.2--CH.sub.3); 1.51 (m, 2H,
CH.sub.2--CH.sub.2--CH.sub.3); 2.02 (m, 2H, CH.sub.2--CH); 5.24 (t,
1H, CH); 7.34 (d, J=9 Hz, 1H, ArH); 8.44 (d, J=2 Hz, 1H, ArH); 8.47
(dd, J=9 Hz, J=2 Hz, 1H, ArH); 10.42 (s, 1H, CHO); 13.45 (broad
peak, 1H, COOH).
Example 4
Preparation of 2-(2-formyl-4-nitro-phenoxy)-hexanoic Acid
[0328] 2-(2-formyl-4-nitro-phenoxy)-hexanoic acid can be prepared
as follows:
[0329] 123 g of 96% concentrated sulphuric acid was charged into a
250 ml four-neck reactor provided with a Teflon half moon paddle
stirrer, a thermometer, a 50 ml dropping funnel, a cooling coil and
a nitrogen inlet.
[0330] The reaction medium was cooled to a temperature of close to
5.degree. C. then 28.4 g (0.12 mole) of
2-(2-formylphenoxy)-hexanoic acid was added at the same
temperature.
[0331] After stirring for 15 minutes, 15.9 g (0.126 mole) of
nitrating mixture (50/50) was added over 2 hours, keeping the
reaction medium close to 5.degree. C., then 76.9 g of ice was added
over 30 minutes, leading to an H.sub.2SO.sub.4 titre of 60%.
[0332] The reaction mixture was filtered through a n.degree. 3
frit.
[0333] The solid obtained was dissolved in 100 ml of
dichloromethane and washed with twice 50 ml of water.
[0334] The decanted organic phase was concentrated in a rotary
evaporator at 20.degree. C. to 70.degree. C. in 20 mm of mercury
(duration: 2 hours).
[0335] 32.1 g of a beige yellow solid product was obtained, giving
a yield of methyl 2-(2-formyl-4-nitro-phenoxy)-hexanoate of 95%,
titrating at 97.0% by gas chromatography.
[0336] It had the following NMR spectrum:
[0337] .sup.1H NMR (DMSO-d6): .delta. 0.91 (t, 3H, CH.sub.3); 1.38
(m, 2H, CH.sub.2--CH.sub.3); 1.51 (m, 2H,
CH.sub.2--CH.sub.2--CH.sub.3); 2.02 (m, 2H, CH.sub.2--CH); 5.24 (t,
1H, CH); 7.34 (d, J=9 Hz, 1H, ArH); 8.44 (d, J=2 Hz, 1H, ArH); 8.47
(dd, J=9 Hz, J=2 Hz, 1H, ArH); 10.42 (s, 1H, CHO); 13.45 (broad
peak, 1H, COOH).
Example 5
Preparation of Methyl 2-(2-formylphenoxy)-hexanoate
[0338] Methyl 2-(2-formylphenoxy)-hexanoate can be prepared as
follows:
[0339] 87.1 g (0.714 mole) of salicylic aldehyde, 158.2 g (0.756
mole) of methyl 2-bromohexanoate, 103.5 g (0.75 mole) of potassium
carbonate and 5.9 g (0.0355 mole) of potassium iodide were charged
in succession into a 1 litre four-neck flask provided with a half
moon paddle stirrer, a thermometer, a cooling coil and a 500 ml
dropping funnel.
[0340] 400 g of dimethylformamide was added and the mixture was
heated with stirring at a temperature of close to 80.degree. C. for
4 hours.
[0341] After cooling to a temperature of close to 25.degree. C.,
the reaction mixture was filtered through a n.degree. 3 glass frit
and washed with 50 g of dimethylformamide.
[0342] The filtrate was concentrated by evaporation under reduced
pressure (25-40 mbars) then diluted with 100 ml of water and
successively extracted with a 100 ml batch of dichloromethane then
50 ml of dichloromethane.
[0343] The combined organic phases were washed with 50 ml of water
and concentrated to dryness by evaporation under reduced
pressure.
[0344] 176.1 g of a clear yellow liquid was obtained, corresponding
to a yield of 98.6% of methyl 2-[2-(formylphenoxy)]-hexanoate,
titrating at 99.6% pure using gas chromatography.
Example 6
Preparation of Methyl 2-(2-formylphenoxy)-hexanoate
[0345] Methyl 2-(2-formylphenoxy)-hexanoate can be prepared as
follows:
[0346] 130.6 g (1.071 mole) of salicylic aldehyde, 237.3 g (1.134
mole) of methyl 2-bromohexanoate and 155.2 g (1.125 mole) of
potassium carbonate were charged in succession into a 2 litre
four-neck flask provided with a half moon paddle stirrer, a
thermometer, a cooling coil and a 1000 ml dropping funnel.
[0347] 600 g of dimethylformamide was added and the mixture was
heated with stirring to a temperature of close to 80.degree. C. for
4 hours.
[0348] After cooling to a temperature of close to 25.degree. C.,
the reaction mixture was filtered through a n.degree. 3 glass frit
and washed with 75 g of dimethylformamide.
[0349] The filtrate was concentrated by evaporation under reduced
pressure (25-40 mbars) then diluted with 150 ml of water and
successively extracted with a 150 ml batch of dichloromethane then
75 ml of dichloromethane.
[0350] The combined organic phases were washed with 75 ml of water
and concentrated to dryness by evaporation under reduced
pressure.
[0351] 265 g of a clear yellow liquid was obtained, corresponding
to a yield of 98.9% of methyl 2-[2-(formylphenoxy)]-hexanoate,
titrating at 99.6% pure using gas chromatography.
* * * * *