U.S. patent application number 12/750381 was filed with the patent office on 2010-08-26 for process for preparing nitrooxyalkyl substituted esters of carboxylic acids, intermediates useful in said process and preparation thereof.
This patent application is currently assigned to NICOX S.A.. Invention is credited to Francesca BENEDINI, Piero DEL SOLDATO, Giancarlo SANTUS.
Application Number | 20100217028 12/750381 |
Document ID | / |
Family ID | 31972201 |
Filed Date | 2010-08-26 |
United States Patent
Application |
20100217028 |
Kind Code |
A1 |
DEL SOLDATO; Piero ; et
al. |
August 26, 2010 |
PROCESS FOR PREPARING NITROOXYALKYL SUBSTITUTED ESTERS OF
CARBOXYLIC ACIDS, INTERMEDIATES USEFUL IN SAID PROCESS AND
PREPARATION THEREOF
Abstract
The present invention refers to a process for preparing a
compound of general formula (A), as reported in the description,
wherein R is a radical of a drug and R1-R12 are hydrogen or alkyl
groups, m, n, o, q, r and s are each independently an integer from
0 to 6, and p is 0 or 1, and X is O, S, SO, SO2, NR13 or PR13 or an
aryl, heteroaryl group, said process comprising reacting a compound
of formula (B) R--COOZ (B) wherein R is as defined above and Z is
hydrogen or a cation selected from: Li+, Na+, K+, Ca++, Mg++,
tetralkylammonium, tetralkylphosphonium, with a compound of formula
(C), as reported in the description, wherein R1-R12 and m, n, o, p,
q, r, s are as defined above and Y is a suitable leaving group.
Inventors: |
DEL SOLDATO; Piero; (Monza,
IT) ; SANTUS; Giancarlo; (Milano, IT) ;
BENEDINI; Francesca; (Milano, IT) |
Correspondence
Address: |
ARENT FOX LLP
1050 CONNECTICUT AVENUE, N.W., SUITE 400
WASHINGTON
DC
20036
US
|
Assignee: |
NICOX S.A.
Valbonne
FR
|
Family ID: |
31972201 |
Appl. No.: |
12/750381 |
Filed: |
March 30, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10522986 |
Sep 13, 2006 |
7723382 |
|
|
PCT/EP03/08700 |
Aug 6, 2003 |
|
|
|
12750381 |
|
|
|
|
Current U.S.
Class: |
560/22 ; 560/23;
562/66 |
Current CPC
Class: |
C07C 69/734 20130101;
C07C 271/28 20130101; C07C 201/02 20130101; C07C 303/28 20130101;
C07C 309/73 20130101; C07C 203/04 20130101; C07C 271/28 20130101;
C07C 269/06 20130101; C07C 303/28 20130101; C07C 67/10 20130101;
C07C 201/02 20130101; C07C 203/04 20130101; C07C 269/06
20130101 |
Class at
Publication: |
560/22 ; 560/23;
562/66 |
International
Class: |
C07C 205/04 20060101
C07C205/04; C07C 309/30 20060101 C07C309/30 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 29, 2002 |
IT |
MI2002A001861 |
Claims
1. A process for preparing a compound of general formula (C)
##STR00016## wherein R.sub.1-R.sub.12 are the same or different and
independently are hydrogen, straight or branched C.sub.1-C.sub.6
alkyl, optionally substituted with aryl; m, n, o, q, r and s are
each independently an integer from 0 to 6, and p is 0 or 1, and X
is O, S, SO, SO.sub.2, NR.sub.13 or PR.sub.13, in which R.sub.13 is
hydrogen, C.sub.1-C.sub.6 alkyl, or X is selected from the group
consisting of: saturated or unsaturated C.sub.5-C.sub.7
cycloalkylene, optionally substituted with one or more straight or
branched C.sub.1-C.sub.3 alkyl groups; arylene, optionally
substituted with one or more halogen atoms, straight or branched
alkyl groups containing from 1 to 4 carbon atoms, or a straight or
branched C.sub.1-C.sub.3 perfluoroalkyl; a 5 or 6 member saturated,
unsaturated, or aromatic heterocyclic ring selected from
##STR00017## ##STR00018## Y is selected from a Br, Cl, I;
--BF.sub.4, --SbF.sub.6, FSO.sub.3--, R.sub.ASO.sub.3--, in which
RA is a straight or branched C.sub.1-C.sub.6 alkyl, optionally
substituted with one or more halogen atoms, or a C.sub.1-C.sub.6
alkylaryl; R.sub.BCOO--, wherein R.sub.B is straight or branched
C.sub.1-C.sub.6 alkyl, aryl, optionally substituted with one or
more halogen atoms or NO.sub.2 groups, C.sub.4-C.sub.10 heteroaryl
and containing one or more heteroatoms, which are the same or
different, selected from nitrogen, oxygen sulfur or phosphorus;
aryloxy optionally substituted with one or more halogen atoms or
NO.sub.2 groups, or heteroaryloxy; comprising reacting a compound
of the following formula (E), ##STR00019## wherein
R.sub.1-R.sub.12, m, n, o, p, q, r, s, X, Y are as defined above
with a nitrating agent.
2. A process for preparing a compound of formula (C) according to
claim 1 wherein the nitrating agent is selected from alkaline metal
nitrates, quaternary ammonium nitrates, quaternary phosphonium
nitrates, AgNO.sub.3, Zn(NO.sub.3).sub.26H.sub.2O.
3. A process for preparing a compound of formula (C) according to
claim 1 wherein the compound (E) and the nitrating agent are at
molar ratio of 20:2.
4. A process for preparing a compound of formula (C) according to
claim 1 wherein the reaction is performed at a temperature ranging
from 0.degree. C. to 100.degree. C.
5. A process for preparing a compound of formula (C) ##STR00020##
wherein R.sub.1-R.sub.12, m, n, o, p, q, r, s, X, are as defined in
claim 1, and is selected from --BF.sub.4, --SbF.sub.6, FSO.sub.3--,
R.sub.ASO.sub.3--, in which R.sub.A is a straight or branched
C.sub.1-C.sub.6 alkyl, optionally substituted with one or more
halogen atoms, or a C.sub.1-C.sub.6 alkylaryl; R.sub.BCOO--,
wherein R.sub.B is straight or branched C.sub.1-C.sub.6 alkyl,
aryl, optionally substituted with one or more halogen atoms or
NO.sub.2 groups, C.sub.4-C.sub.10 heteroaryl and containing one or
more heteroatoms, which are the same or different, selected from
nitrogen, oxygen sulfur or phosphorus; aryloxy optionally
substituted with one or more halogen atoms or NO.sub.2 groups, or
heteroaryloxy; comprising reacting a compound of the following
formula (F), ##STR00021## wherein R.sub.1-R.sub.12, m, n, o, p, q,
r, s, X, are as defined above, W is OH or halogen, with a compound
selected from alkanoylsulfonylchloride and trifluoromethansulfonic
anhydride when W is OH or with AgSbF.sub.6, AgBF.sub.4,
CF.sub.3SO.sub.3Ag, AgSO.sub.3CH.sub.3,
CH.sub.3C.sub.6H.sub.4SO.sub.3Ag when W is halogen.
6. A process for preparing a compound of formula (C) according to
claim 5 wherein the compound (F) and the nitrating agent are at
molar ratio of 2:0.5.
7. A process for preparing a compound of formula (C) according to
claim 5 wherein the reaction is performed at a temperature ranging
from 0.degree. C. to 100.degree. C.
Description
[0001] The present invention relates to a process for preparing
nitrooxyalkyl substituted esters of carboxylic acids, to
intermediates useful in said process and to their preparation.
[0002] Many carboxylic acid nitrooxyalkyl esters are
pharmacologically active products. For example, 1,4-dihydropyridine
derivatives having nitrooxy moieties at the C-3 and/or C-5 ester
position have shown to be active calcium-channel blockers similar
to nifedipine and nicardipine (J. Chem. Soc. Perkin Trans I, 525
(1993)). In literature, several methods for synthesizing
nitrooxyalkyl esters are reported. In this way, the nitrooxy moiety
may be for example introduced by nucleophilic substitution of a
leaving group already present on the alkyl chain of alkyl ester
precursor. In particular, 2-(6-methoxy-2-naphtyl)-propionic acid
4-nitrooxybutyl ester has been synthesized reacting 4-chlorobutyl
2-(6-methoxy-2-naphtyl)-propionate with silver nitrate (WO
95/09831), whereas 2-(benzoylphenyl)propionic acid 4-nitrooxybutyl
ester (ketoprofen nitrooxybutyl ester) has been prepared reacting
the 2-(3-benzoylphenyl)propionic acid sodium salt with
1,4-dibromobutane to give the corresponding bromobutyl ester, which
was then treated with silver nitrate to yield the desired nitrooxy
derivative. Both processes have the disadvantage that during the
introduction of nitrooxy group, impurities of difficult removal are
often obtained, such as silver salts (AgCl, AgBr) and silver metal,
this being prejudicial to the use of the end-products in
therapeutic field, in which an improved purity is always
requested.
[0003] A further known process for preparing the above mentioned
nitrooxyalkyl esters is the insertion of nitrooxyalkyl group by
reacting the carboxylic acid or a derivative thereof (halide) with
a nitrooxyalkyl alcohol or with a nitrooxyalkyl bromide. For
example, 2-(S)-(6-methoxy-2-naphtyl)-propionic acid 4-nitrooxybutyl
ester is prepared treating the corresponding acid chloride with
4-nitrooxybutan-1-ol in methylene chloride and in presence of
potassium carbonate (WO 01/10814). This method has also the
disadvantage that several by-products are formed, being in fact
very difficult to obtain nitrooxyalkyl alcohols and the acyl halide
in a pure form; moreover, for example 4-nitrooxybutan-1-ol is
stable only in solution and it cannot be isolated as a pure
substance.
[0004] It was thus an object of the present invention to provide a
new process for preparing carboxylic acid nitrooxyalkyl esters not
having the above mentioned disadvantages and wherein impurities and
by-products are present in an essentially negligible amount.
[0005] The present invention relates to a process for preparing a
compound of general formula (A)
##STR00001##
wherein R.sub.1-R.sub.12 are the same or different and
independently are hydrogen, straight or branched C.sub.1-C.sub.6
alkyl, optionally substituted with aryl; m, n, o, q, r and s are
each independently an integer from 0 to 6, and p is 0 or 1, and X
is O, S, SO, SO.sub.2, NR.sub.13 or PRn, in which R.sub.13 is
hydrogen, C.sub.1-C.sub.6 alkyl, or X is selected from the group
consisting of:
[0006] saturated or unsaturated C.sub.5-C.sub.7 cycloalkylene,
optionally substituted with one or more straight or branched
C.sub.1-C.sub.3 alkyl groups;
[0007] arylene, optionally substituted with one or more halogen
atoms, straight or branched alkyl groups containing from 1 to 4
carbon atoms, or a straight or branched C.sub.1-C.sub.3
perfluoroalkyl;
[0008] a 5 or 6 member saturated, unsaturated, or aromatic
heterocyclic ring selected from
##STR00002## ##STR00003##
wherein the bonds, when they have an undefined position, are
intended to be in any possible position in the ring; R is selected
from:
##STR00004##
wherein M is a carbon or nitrogen atom; R.sup.C is selected from:
H, OH, NH.sub.2, R.sup.ECONH--, R.sup.ECOO--, an heterocyclic
residue with 5 or 6 atoms that may be aromatic, saturated or
unsaturated, containing one or more heteroatoms selected from
oxygen, nitrogen or sulfur, and phenylamino (PhNH--), in which the
aromatic ring may be substituted with one or more substituents
selected from the group consisting of halogen, preferably chlorine
or fluorine, straight or branched C.sub.1-C.sub.4-alkyl, for
example methyl, straight or if possible branched perfluoroalkyl,
for example trifluoromethyl;
[0009] R.sup.E is selected from the group consisting of straight or
branched C.sub.1-C.sub.5-alkyl, phenyl substituted with OCOR.sup.F,
wherein R.sup.F is selected from the group consisting of methyl,
ethyl or straight or branched C.sub.2-C.sub.6-alkyl or phenyl;
R.sup.D is selected from: H, OH, halogen, --NH.sub.2, straight or
branched C.sub.1-C.sub.6-alkoxy, perfluoroalkyl having from 1 to 4
carbon atoms, for example --CF.sub.2, mono o
di-(C.sub.1-C.sub.6)alkylamino; with the proviso that R.sup.C and
R.sup.D can not be both H;
##STR00005## ##STR00006##
wherein R.sup.F1 and R.sup.F2 are halogens selected from chlorine,
fluorine or bromine, R.sup.G is hydrogen, straight or branched
C.sub.1-C.sub.6-alkyl, preferably methyl;
##STR00007## ##STR00008## ##STR00009##
wherein the bond at 6 position in formula (XXVIII) may be .alpha.
or .beta.;
##STR00010##
wherein R' in formula (XXXII) is H or RICO)--, in which R is
selected from the radicals represented by formulae (I)-(XXXI); in
all the formulae (I-XXXII) listed above, the wavy line represents
always the position wherein --COO-- group is bound; said process
comprising reacting a compound of formula (B)
R--COOZ (B)
wherein R is as above defined and Z is hydrogen or a cation
selected from Li+, Na+, K+, Ca++, Mg++, trialkylammonium
tetralkylammonium, tetralkylphosphonium, with a compound of the
following formula (C)
##STR00011##
wherein R.sub.1-R.sub.12 and m, n, o, p, q, r, s are as defined
above and Y is selected from
[0010] an halogen atom such as Br, Cl, I;
[0011] --BF.sub.4, --SbF.sub.6, FSO.sub.3--, R.sub.ASO.sub.3--, in
which R.sub.A is a straight or branched C.sub.1-C.sub.6 alkyl,
optionally substituted with one or more halogen atoms, or a
C.sub.1-C.sub.6 alkylaryl;
[0012] R.sub.BCOO.sup.-, wherein R.sub.B is straight or branched
C.sub.1-C.sub.6 alkyl, aryl, optionally substituted with one or
more halogen atoms or NO.sub.2 groups, C.sub.4-C.sub.10 heteroaryl
and containing one or more heteroatoms, which are the same or
different, selected from nitrogen, oxygen sulfur or phosphorus;
[0013] aryloxy optionally substituted with one or more halogen
atoms or NO.sub.2 groups, or heteroaryloxy.
[0014] In particular when in formula (A) the R residue is as
defined by formula (I), wherein M is a carbon atom,
R.sup.C=R.sup.ECOO-- in 2 position, in which R.sup.E is CH.sub.3
and R.sup.D=H, the compound is known as acetylsalicylic acid;
when in formula (A) the R residue is represented by formula (I),
wherein M is a carbon atom, R.sup.C=NH.sub.2 in 5 position,
R.sup.D=OH in 2 position, the compound is known as mesalamine; when
in formula (A) the R residue is represented by formula (I), in
which M is a carbon atom, R.sup.D=PhNH-- in 2 position, wherein Ph-
is the 3-trifluoromethylbenzene radical, R.sup.D=H, the compound is
known as flufenamic acid; when in formula (A) the R residue is
represented by formula (I), in which M is a carbon atom,
R.sup.C=PhNH-- in 2 position, wherein Ph is the
2,6-dichloro-3-methyl-benzene moiety, and R.sup.D=H, the compound
is known as meclofenamic acid; when in formula (A) the R residue is
represented by formula (I), in which M is a carbon atom,
R.sup.C=PhNH-- in 2 position, wherein Ph e the 2,3-dimethylbenzene
radical, and R.sup.D=H, the compound is known as mefenamic acid;
when in formula (A) the R residue is defined by formula (I), in
which M is a carbon atom, R.sup.C=PhNH-- in 2 position, wherein Ph
is a 2-methyl-3-chlorobenzene group, and R.sup.D=H, the compound is
known as tolfenamic acid; when in formula (A) the R residue is
represented by formula (I), in which M is a nitrogen atom,
R.sup.C=PhNH-- in 2 position, wherein Ph is the
2-trifluoromethylbenzene radical, and R.sup.D=H, the compound is
known as niflumic acid; when in formula (A) the R residue is
represented by formula (I), in which M is a nitrogen atom,
R.sup.C=PhNH-- in 2 position, wherein Ph is the
2-methyl-3-trifluoromethylbenzene radical, and R.sup.D=H, the
compound is known as flunixin; when in formula (A) the R residue is
represented by formula (II), in which e=0 and R.sup.E is a methyl
group, the compound is known as acetylsalicylsalicylic acid; when
in formula (A) the R residue is defined by formula (III), the
compound is known as Ketorolac; when in formula (A) the R residue
is represented by formula (IV), the compound is known as etodolac;
when in formula (A) the R residue is represented by formula (V),
the compound is known as pirazolac; when in formula (A) the R
residue is defined by formula (VI), the compound is known as
tolmetin; when in formula (A) the R residue is defined by formula
(VII), the compound is known as bromfenac; when in formula (A) the
R residue is represented by formula (VIII), the compound is known
as fenbufen; when in formula (A) the R residue is represented by
formula (IX), the compound is known as e mofezolac; when in formula
(A) the R residue is represented by formula (X), wherein R.sup.F1
and R.sup.F2 are Cl and R.sup.G is hydrogen, the compound is known
as diclofenac; when in formula (A) the R residue is defined by
formula (X), wherein R.sup.F2 is chlorine, R.sup.F1 is fluorine and
R.sup.G is a methyl group, the compound is known as COX-189; when
in formula (A) the R residue is represented by formula (XI), the
compound is known as pemedolac; when in formula (A) the R residue
is defined by formula (XII), the compound is known as sulindac;
when in formula (A) the R residue is defined by formula (XIII), the
compound is known as indomethacin; when in formula (A) the R
residue is represented by formula (XIV), the compound is known as
suprofen; when in formula (A) the R residue is represented by
formula (XV), the compound is known as ketoprofen; when in formula
(A) the R residue is represented by formula (XVI), the compound is
known as tiaprofenic acid; when in formula (A) the R residue is
defined by formula (XVII), the compound is known as fenoprofen;
when in formula (A) the R residue is defined by formula (XVIII),
the compound is known as indoprofen; when in formula (A) the R
residue is represented by formula (XIX), the compound is known as
carprofen; when in formula (A) the R residue is defined by formula
(XXI), the compound is known as loxoprofen; when in formula (A) the
R residue is represented by formula (XXII), the compound is known
as ibuprofen; when in formula (A) the R residue is defined by
formula (XXIII), the compound is known as pranoprefen; when in
formula (A) the R residue is defined by formula (XXIV), the
compound is known as bermoprofen; when in formula (A) the R residue
is represented by formula (XXV), the compound is known as CS-670;
when in formula (A) the R residue is defined by formula (XXVI), the
compound is known as zaltoprofen; when in formula (A) the R residue
is represented by formula (XXVII), the compound is known as
flurbiprofen; when in formula (A) the R residue is represented by
formula (XXVIII), in which bond to the hydroxy group at 6 position
is .beta. standing, the compound is known as ursodeoxycholic acid;
when in formula (A) the R residue is represented by formula
[0015] (XXVIII), wherein bond to the hydroxy group at 6 position is
.alpha. standing, the compound is known as chenodeoxycholic
acid;
when in formula (A) the R residue is represented by formulae (XXIX)
and (XXX), the compounds belong to the nifedipine class; when in
formula (A) the R residue is defined by formula (XXXI), the
compound is known as apovincaminic acid; when in formula (A) the R
residue is represented by formula (XXXII), wherein R' is hydrogen,
the compound is known as ferulic acid;
[0016] It has been surprisingly found that when in the compound of
formula (B) R is the radical of formula (XXXII) wherein R' is H
(ferulic acid) the reaction is highly selective towards the
formation of the ester of formula (A), in spite of the fact that
the presence of two nucleophilic groups in the ferulic acid (the
carboxylic group and the fenolic group) could give a substantial
formation of the nitroxyalkylether.
[0017] Preferably the present invention relates to a process for
preparing a compound of formula (A) as above defined wherein:
the substituents R.sub.1-R.sub.12 are the same or different and
independently are hydrogen or straight or branched C.sub.1-C.sub.3
alkyl, m, n, o, p, q, r and s are as defined above,
X is O, S or
##STR00012##
[0019] Most preferably the present invention relates to a process
for preparing a compound of formula (A) as above defined wherein
R.sub.1-R.sub.4 and R.sub.7-R.sub.10 are hydrogens, m, n, q, r, are
1, and s are 0, p is 0 or 1, and X is O or S.
[0020] Preferred compounds of formula (C) as above defined are
those wherein Y is selected from the group consisting of
--BF.sub.4, --SbF.sub.6, FSO.sub.3--, CF.sub.3SO.sub.3--,
C.sub.2F.sub.6SO.sub.3--, C.sub.3F.sub.7SO.sub.3--,
C.sub.4F.sub.9SO.sub.3--, p-CH.sub.3C.sub.6H.sub.4SO.sub.3--.
[0021] The reaction is carried out in an organic solvent, generally
an aprotic, dipolar solvent such as acetone, tetrahyrofurane,
dimethylformamide, N-methylpyrrolidone, sulfolane,
acetonitrile.
[0022] Alternatively the above reported reaction is carried out in
a biphasic system comprising an organic solvent selected from
toluene, chlorobenzene, nitrobenzene, tert-butyl-methylether and a
water solution wherein the organic solution contains (C) and the
water solution contain an alkaline metal salt of (B), in presence
of a phase transfer catalyst such as onium salts, for example
tetralkylammonium and tetraalkylphosphonium salts.
[0023] The compounds of formula (B) and (C) are reacted at a
(B)/(C) molar ratio of 2-0.5, preferably of 1.5-0.7 and at a
temperature ranging from 0.degree. C. to 100.degree. C., preferably
from 15.degree. C. to 80.degree. C.
[0024] The carboxylic acid salt may be prepared separately or may
be generated "in situ", for example performing the reaction between
(B) and (C) in the presence of a stoichiometric amount of a
tertiary amine, or employing an amount in excess of said amine.
[0025] Another object of the present invention is the preparation
of compounds of formula (C), by nitrating compounds of formula (D)
reported here below, with a nitrating agent such as sulfonitric
mixture and the like:
##STR00013##
wherein M is OH, and Y, X, m, n, o, p, q, r, s and
R.sub.1-R.sub.12, have the meanings mentioned above.
[0026] Further object of the present invention is the preparation
of compounds of formula (C), characterized in that a compound of
the following formula (E) is reacted with nitrating agents selected
for example from alkaline metal nitrates, quaternary ammonium
nitrates, quaternary phosphonium salts and AgNO.sub.3,
Zn(NO.sub.3).sub.26H.sub.2O:
##STR00014##
wherein: Y, X, m, n, o, p, q, s and R.sub.1-R.sub.12, have the
meanings mentioned above,
[0027] Another object of the present invention is the preparation
of compounds of formula (C), characterized in that a compound of
formula (F)
##STR00015##
wherein W is OH or halogen is reacted with a compound selected from
alkanoylsulfonylchloride, trifluoromethansulfonic acid anhydride
when W is OH or AgSbF.sub.6, AgBF.sub.4, AgClO.sub.4,
CF.sub.3SO.sub.3Ag, AgSO.sub.3CH.sub.3,
CH.sub.3C.sub.6H.sub.4SO.sub.3Ag when W is halogen.
[0028] Nitration of compound (D) was performed in an organic
solvent, generally in a solvent selected from acetone,
tetrahydrofurane, dimethylformamide, N-methylpyrrolidone,
sulfolane, acetonitrile, methylene chloride etc., with nitrating
agents selected from transition metal salts or, when M is OH, with
nitrating systems based on nitric acid, such as the sulfonitric
mixture.
[0029] The (D)/nitrating agent molar ratio is of from 2 to 0.5, in
particular of 1.5 to 0.5.
[0030] Nitration was performed at a temperature ranging from
0.degree. C. to 100.degree. C., preferably from 15.degree. C. to
80.degree. C.
[0031] The reaction product (C) may be isolated or its solution can
be employed as such for the reaction with substrate (B) to give
W.
[0032] Nitration of compound (E) was carried out in an organic
solvent, generally in a solvent selected from acetone,
tetrahydrofurane, dimethylformamide, N-methylpyrrolidone,
sulfolane, acetonitrile, methylene chloride etc., with nucleophilic
nitrating agents such as alkaline metal nitrates, onium salt
nitrates, for example tetraalkylammonium, tetraalkyl-phosphonium or
trialkylammonium nitrate and so on.
[0033] Nitration was performed at a temperature of from 0.degree.
C. to 100.degree. C., in particular of 15.degree. C. to 80.degree.
C.
[0034] The molar ratio between (E) and the nitrating agent is of
from 20 to 2, preferably of 8 to 1.
[0035] The reaction product (C) may be isolated or its solution can
be employed such as in the reaction with substrate (B) to give
(A).
[0036] The reaction for obtaining compound (C) from (F) was carried
out in an organic solvent, generally selected from the group
consisting of acetone, tetrahydrofurane, dimethylformamide,
N-methylpyrrolidone, sulfolane, acetonitrile, methylene chloride
and the like, with a reactive compound selected from transition
metal salts of Y or, when W is OH, the reaction was performed with
an acid chloride such as methanesulfonyl chloride etc., or with a
suitable anhydride such as trifluoro-methanesulfonic anhydride.
[0037] The reaction was performed at a temperature ranging from
-20.degree. C. to 100.degree. C., in particular from -20.degree. to
60.degree. C.
[0038] The molar ratio between (F) and the reagent is of from 2 to
0.5, preferably of 1.5 to 0.5.
[0039] The reaction product (C) may be isolated or its solution can
be employed as such in the reaction with substrate (B) to give
(A).
[0040] The following examples are to further illustrate the
invention without limiting it.
EXAMPLES
Preparation of 4-nitrooxybutyl bromide according to Chem. Pharm.
Bull., 1993, 41, 1040
[0041] Nitric acid (90%, 0.8 mol) was dropped under stirring in
sulfuric acid maintained at 0.degree. C. (0.8 mol) and the mixture
was then stirred at 0.degree. C. for 80 minutes. In the solution
thus obtained and maintained at 0.degree. C., under stirring
4-bromobutanol was dropped (0.4 mol) and the mixture was stirred at
the same temperature for additional 210 minutes. The solution was
then poured in a water-ice mixture and extracted twice with diethyl
ether. The ether extracts were combined together and washed with a
sodium bicarbonate saturated solution. The solvent was evaporated
off under vacuum to give a yellow oil (yield: 84.8%).
Example 1
Preparation of 4-nitrooxybutyl p-toluenesulfonate
[0042] To a solution of 4-bromobutanol (5.0 g, 33 mmol) in pyridine
(50 ml) kept at 0.degree. C., under stirring and under nitrogen
atmosphere tosyl chloride (6.8 g, 36 mmol) was added. The resulting
solution was kept under stirring for further 20 minutes and then
stored overnight at -18.degree. C. The reaction mixture was poured
in a water/ice mixture (about 400 ml) and extracted with ethyl
ether (500 ml). The organic phase was washed with 6N hydrochloric
acid (500 ml) and dried on sodium sulfate. After evaporation of the
solvent under vacuum, an oily residue was obtained (7 g). To a
solution of the oily residue (7 g) in acetonitrile (50 ml) and
maintained under stirring at room temperature, silver nitrate (7.8
g, 46 mmol) was added. After nearly 15 minutes, the formation of a
yellow, insoluble product was observed. The heterogeneous mixture
was kept under stirring overnight. The insoluble was removed by
filtration and the solution was poured in water (200 ml) and
extracted with ethyl ether (2.times.250 ml). The combined organic
extracts were dried over sodium sulfate. Evaporation of the solvent
under vacuum afforded an oily residue (5 g).
[0043] Chromatography of the residue on silica gel (100 g), by
hexane/ethyl ether mixture as eluent, gave the title product (3 g),
m.p. 38-40.degree. C., purity higher than 98%, determined by
HPLC.
[0044] FTIR (solid KBr, cm -1): 2966, 1626, 1355, 1281, 1177, 1097,
959, 876, 815, 663, 553.
[0045] 300 MHz 1H NMR (CDCl.sub.3) delta 1.77 (m, 4H); 2.35 (s,
3H); 4.06 (m, 2H); 4.38 (m, 2H); 7.36 (2H); 7.7 (2H).
Example 2A
[0046] Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic
acid 4-nitrooxybutyl ester
[0047] A mixture obtained pouring ferulic acid (1.94 g, 10 mmol),
4-nitrooxybutyl bromide (1.98 g, 10 mmol) and triethylamine (1.21
g, 12 mmol) in dimethylformamide (10 ml), was stirred for 3 days at
25.degree. C. After evaporation in vacuo of DMF, an oil was
obtained (2.3 g) that, according to NMR and HPLC analysis, mainly
consists of unreacted ferulic acid and its 4-nitrooxybutyl ester.
The ester was separated from acid by flash chromatography with a
65% yield.
Example 2B
Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid
4-nitrooxybutyl ester
[0048] (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic acid (670 mg,
3.46 mmol) and 4-(nitrooxy)butyl 4-p-toluensulfonate (1.00 g, 3.46
mmol) were dissolved in 40 ml of DMF and the solution poured in a
three-necked flask kept under argon and under magnetic stirrer.
Subsequently, triethylamine (0.52 ml, 3.81 mmol) was added and the
mixture was allowed to react at room temperature. The course of the
reaction was followed by TLC (EtOAc as the eluent) and by LC/MS ESI
using a RP-C18 4.6.times.100 mm column. After 72 hours the reaction
conversion was ca. 40%. Additional 0.1 equivalents of tosylate were
then added to the solution (100 mg, 0.346 mmol) and the mixture was
reacted for other 24 hours. After this period the solution was
poured in water and extracted with Et.sub.2O (3.times.75 ml). The
combined organic phases were washed with a saturated solution of
NaHCO.sub.3 and water, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure.
[0049] The residue was chromatographed over silica gel (using ethyl
acetate/petroleum ether 9:1 as the eluent) to provide the desired
ester product in 70% yield.
[0050] The IR and LC-MS ESI- spectra of the peak product were
identical to those of an authentic sample.
Analyses
[0051] TLC: (Ethyl acetate) Rf=0.60
[0052] HPLC purity: 72%
[0053] MS (ESI neg): 310 (M-H)
[0054] IR (film) cm.sup.-1: 3450 (br OH), 2964, 1707 (C.dbd.O),
1631(ONO.sub.2), 1599, 1514, 1448, 1280 (ONO.sub.2)
Example 3A
Synthesis of 5-t-butoxycarbonylamino-2-hydroxybenzoic acid
4-(nitrooxy)butyl ester
[0055] The process of Example 2A was repeated, replacing however
ferulic acid by 5-t-butoxycarbonylaminosalicilic acid. The title
compound was obtained with a yield of 50%.
Example 3B
Synthesis of 5-t-butoxycarbonylamino-2-hydroxybenzoic acid
4-(nitrooxy)butyl ester
[0056] To a mixture comprising DMF (200 ml),
5-t-butoxycarbonylaminosalicylic acid (4.37 g, 17.3 mmol) and
4-nitrooxybutyl p-toluenesulfonate (5 g, 17.3 mmol), at room
temperature and under stirring triethylamine was added (2.6 ml; 19
mmol). The reaction mixture was maintained 3 days under stirring at
room temperature. It was then poured in water and extracted with
ethyl ether. The combined organic phases were washed with a sodium
carbonate solution and then with water. After drying on sodium
sulfate, the evaporation of the solvent yields a raw product that
purified by silica gel chromatography gives the title compounds
with a yield of 65%.
Example 4
Synthesis of potassium
(E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate
[0057] Potassium hydroxide (580 mg, 10.3 mmol) was dissolved in
methanol (10 ml) and put in a three-necked flask. Stirring was set
on. Subsequently, (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic
acid (2.00 g, 10.3 mmol) in methanol (20 mL) was added to this
solution through a funnel. After the addition was ended, the
solution was allowed to react at room temperature for 3 h. Methanol
was then evaporated off and then yellow solid residue was washed
with Et.sub.2O and dried under reduced pressure.
[0058] The product was obtained as a yellowish solid (2.40 g,
quantitative yield).
Analyses
[0059] IR (KBr) cm.sup.-1: 3388, 1643, 1561 (C.dbd.O), 1524, 1404,
1263, 1204, 1152, 1121.
Example 5A
Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid
4-(nitrooxy)butyl ester
[0060] Potassium (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoate
(1.00 g, 4.3 mmol) was dissolved in 40 ml of DMF and poured in a
three-necked flask kept under argon and magnetic stirring. The
mixture was cooled at 0-5.degree. C. through an ice bath and
4-(nitrooxy)butyl 4-p-toluensulfonate (1.25 g, 4.3 mmol) in DMF (10
ml) was added through a funnel. After the addition, the resulting
mixture was stirred under argon, while the temperature was allowed
to rise to r.t. (25.degree. C.). The reaction course was followed
by TLC and LC/MS ESI-. After 6 hours the conversion was complete.
The solution was then poured in water and extracted with Et.sub.2O
(3.times.75 ml). The combined organic phases were washed with a
saturated solution of NaHCO.sub.3 and water, dried over
Na.sub.2SO.sub.4 and the volatiles removed under reduced pressure
to provide a residue. The residue was washed with petroleum ether
and dried under reduced pressure to provide the desire ester in 95%
yield.
Analyses
[0061] HPLC purity: 95% MS (ESI neg): 310 (M-H)
[0062] IR (film) cm.sup.-1: 3450 (br OH), 2964, 1707 (C.dbd.O),
1631(ONO.sub.2), 1599, 1514, 1448, 1280 (ONO.sub.2).
[0063] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.72-1.93 (4H, m,
CH.sub.2--CH.sub.2), 3.92 (3H, s, OCH.sub.3), 4.22-4.26 (2H, m,
CH.sub.2--COO), 4.50-4.54 (2H, m, CH.sub.2--OCN.sub.2), 5.95 (1H,
br s, OH), 6.28 (1H, d, J=15.9 Hz, CH.dbd.), 7.03-7.10 (2H, m,
aromatic H), 7.36 (1H, d, J=7.8 Hz, aromatic H), 7.61 (1H, d,
J=15.9 Hz, CH.dbd.).
Example 5B
Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid
4-(nitrooxy)butyl ester
[0064] Ferulic acid (97 g, 0.50 mol) was dissolved in methanol (750
ml) and mixed with a solution of potassium hydroxide (33 g, 0.050
mol) in methanol (250 ml) to give a clear solution at 27.degree. C.
The potassium salt of ferulic acid was precipitated by addition of
toluene (1250 ml).
[0065] The suspension was cooled to 20.degree. C., filtered, and
washed with toluene (250 ml) and pentane (2.times.250 ml). The wet
cake was dissolved in DMF (750 ml), and potassium iodide (25 g) and
crude 4-Bromo-1-butylnitrate (165 g, 0.83 mol) were added. The
reaction mixture was stirred for 16 hours at 20-22.degree. C. The
reaction was added with water (750 ml) and the resulting mixture
was extracted with t-Butyl-methylether (800 ml+500 ml). The
combined extracts were washed with water (750 ml), with 25% sodium
chloride aqueous solution (250 ml), dried over sodium sulphate (250
g), filtered, and evaporated at 50.degree. C. (external bath water
temperature) under vacuum to give a light brown oil (220 g).
Cyclohexane (500 ml) was added, and the mixture was heated to
50.degree. C. to give a two phases system, a colorless upper phase
and a dark lower phase. The stirred mixture was cooled to room
temperature for 15 hours to give a dark solid cake and a white
suspension of fluffy material. The solid was crushed and the
suspension was filtered. The cake was washed with cyclohexane
(2.times.50 ml) and dried at 45.degree. C. to provide the desired
ester (128.8 g) with 92% purity.
[0066] Analytically pure product was obtained by crystallization
from toluene.
* * * * *