U.S. patent application number 11/214392 was filed with the patent office on 2005-12-29 for 5-nitrobenzofurans.
Invention is credited to Magerlein, Wolfgang.
Application Number | 20050288519 11/214392 |
Document ID | / |
Family ID | 31197072 |
Filed Date | 2005-12-29 |
United States Patent
Application |
20050288519 |
Kind Code |
A1 |
Magerlein, Wolfgang |
December 29, 2005 |
5-Nitrobenzofurans
Abstract
The present invention relates to 5-nitrobenzofurans, to a
process for preparing 5-nitrobenzofurans, and to
5-nitro-2,3-dihydrobenzofuran-3-ols, to a process for the
preparation thereof and to intermediates.
Inventors: |
Magerlein, Wolfgang;
(Leverkusen, DE) |
Correspondence
Address: |
LANXESS CORPORATION
111 RIDC PARK WEST DRIVE
PITTSBURGH
PA
15275-1112
US
|
Family ID: |
31197072 |
Appl. No.: |
11/214392 |
Filed: |
August 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11214392 |
Aug 29, 2005 |
|
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10642947 |
Aug 18, 2003 |
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Current U.S.
Class: |
549/462 |
Current CPC
Class: |
C07C 69/92 20130101;
A61P 9/06 20180101; C07D 307/83 20130101; C07D 307/79 20130101 |
Class at
Publication: |
549/462 |
International
Class: |
C07D 307/87 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 19, 2002 |
DE |
10237819.3 |
Claims
1. At least one compound of the formula (I), 10wherein R.sup.1 is
hydrogen or C.sub.1-C.sub.12-alkyl, and R.sup.2 are in each case
independently of one another: fluorine, chlorine, bromine, iodine,
C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy, hydroxyl,
NR.sup.3R.sup.4 or CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are
each, independently of one another, hydrogen or
C.sub.1-C.sub.12-alkyl, or NR.sup.3R.sup.4 as a whole is a cyclic
amino radical having 4 to 12 carbon atoms,
COO--(C.sub.1-C.sub.12-alkyl), --COO(C.sub.4-C.sub.24-aryl)- ,
--COO(C.sub.5-C.sub.25-arylalkyl), CO(C.sub.1-C.sub.12-alkyl),
CO(C.sub.4-C.sub.24-aryl) or C.sub.1-C.sub.12-fluoroalkyl and n is
zero, one, two or three, or in the case where n is two or three it
is possible for two adjacent R.sup.2 substituents to be part of a
fused ring system which in turn may optionally be substituted by
the radicals mentioned above for R.sup.2, with the proviso of
2-(n-butyl)-5-nitrobenzofuran being excluded.
2. (canceled)
3. (canceled)
4. At least one compound of the formula (III), 11wherein R.sup.2
and n have the meaning specified under formula (I) in claim 1, and
R.sup.1 is n-butyl.
5. 2-(n-Butyl)-5-nitro-3(2H)-benzofuranone.
6. At least one compound of the formula (V), 12wherein R.sup.2 and
n have the meaning specified under formula (I) in claim 1, R.sup.1
is n-butyl and R.sup.7 is C.sub.1-C.sub.12-alkyl,
C.sub.5-C.sub.25-arylalkyl, C.sub.4-C.sub.24-aryl or
C.sub.1-C.sub.12-fluoroalkyl.
7. 3-Acetoxy-2-(n-butyl)-benzofuran.
8. At least one compound of the formula (VII), 13wherein R.sup.2
and n have the meaning specified under formula (I) in claim 1,
R.sup.1 is n-butyl and R.sup.9 and R.sup.10 are independently of
one another C.sub.1-C.sub.12-alkyl, C.sub.5-C.sub.25-arylalkyl or
C.sub.4-C.sub.24-aryl, and furthermore not more than one R.sup.9 or
R.sup.10 radical is hydrogen.
9. At least one compound selected from the group consisting of
methyl 2-(1-methoxycarbonylpentoxy)benzoate, ethyl
2-(1-methoxycarbonylpentoxy)b- enzoate, ethyl
2-(1-ethoxycarbonylpentoxy)benzoate, methyl
2-(1-ethoxycarbonylpentoxy)benzoate,
2-(1-methoxycarbonylpentoxy)benzoic acid,
2-(1-ethoxycarbonylpentoxy)benzoic acid, ethyl
2-(1-carboxypentoxy)benzoate and methyl
2-(1-carboxypentoxy)benzoate.
10. A process for preparing at least one compound of the formula
(I), 14wherein R.sup.1 is hydrogen or C.sub.1-C.sub.12-alkyl, and
R.sup.2 are in each case independently: fluorine, chlorine,
bromine, iodine, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy,
hydroxyl, NR.sup.3R.sup.4 or CONR.sup.3R.sup.4, where R.sup.3 and
R.sup.4 are each, independently of one another, hydrogen or
C.sub.1-C.sub.12-alkyl, or NR.sup.3R.sup.4 as a whole is a cyclic
amino radical having 4 to 12 carbon atoms,
COO--(C.sub.1-C.sub.12-alkyl), --COO(C.sub.4-C.sub.24-aryl)- ,
--COO(C.sub.5-C.sub.25-arylalkyl), CO(C.sub.1-C.sub.12-alkyl),
CO(C.sub.4-C.sub.24-aryl) or C.sub.1-C.sub.12-fluoroalkyl and n is
zero, one, two or three, or in the case where n is two or three it
is possible for two adjacent R.sup.2 substituents to be part of a
fused ring system which in turn may optionally be substituted by
the radicals mentioned above for R.sup.2, wherein the process
comprises converting by dehydration at least one compound of the
formula (II) 15in which R.sup.1, R.sup.2 and n have the meaning
under formula (I), into compounds of the formula (I).
11. Process according to claim 10, characterized in that
2-(n-butyl)-5-nitrobenzofuran is prepared.
12. Process according to claim 10, characterized in that protic
acids or hydroxides are employed for the dehydration.
13-20. (canceled)
21. A process for preparing at least one compound of the formula
(II), 16wherein R.sup.1 is hydrogen or C.sub.1-C.sub.12-alkyl, and
R.sup.2 are in each case independently of one another: fluorine,
chlorine, bromine, iodine, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, hydroxyl, NR.sup.3R.sup.4 or
CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are each,
independently of one another, hydrogen or C.sub.1-C.sub.12-alkyl,
or NR.sup.3R.sup.4 as a whole is a cyclic amino radical having 4 to
12 carbon atoms, COO--(C.sub.1-C.sub.12-alkyl),
--COO(C.sub.4-C.sub.24-aryl)- , --COO(C.sub.5-C.sub.25-arylalkyl),
CO(C.sub.1-C.sub.12alkyl), CO(C.sub.4-C.sub.24-aryl) or
C.sub.1-C.sub.12-fluoroalkyl and n is zero, one, two or three, or
in the case where n is two or three it is possible for two adjacent
R.sup.2 substituents to be part of a fused ring system which in
turn may optionally be substituted by the radicals mentioned above
for R.sup.2, with the proviso of 2-(n-butyl)-5-nitrobenzofuran
being excluded; wherein the process comprises reducing compounds of
the formula (III) 17wherein R.sup.1 is hydrogen or
C.sub.1-C.sub.12-alkyl, and R.sup.2 are in each case independently:
fluorine, chlorine, bromine, iodine, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, hydroxyl, NR.sup.3R.sup.4 or
CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are each,
independently of one another, hydrogen or C.sub.1-C.sub.12-alkyl,
or NR.sup.3R.sup.4 as a whole is a cyclic amino radical having 4 to
12 carbon atoms, COO--(C.sub.1-C.sub.12-alkyl),
--COO(C.sub.4-C.sub.24-aryl) --COO(C.sub.5-C.sub.25-arylalkyl),
CO(C.sub.1-C.sub.12-alkyl), CO(C.sub.4-C.sub.24-aryl) or
C.sub.1-C.sub.12-fluoroalkyl and n is zero, one, two or three, or
in the case where n is two or three it is possible for two adjacent
R.sup.2 substituents to be part of a fused ring system which in
turn may optionally be substituted by the radicals mentioned above
for R.sup.2.
22. A process for preparing at least one compound of the formula
(III), 18wherein R.sup.1 is n-butyl and R.sup.2 are in each case
independently of one another: fluorine, chlorine, bromine, iodine,
C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy, hydroxyl,
NR.sup.3R.sup.4 or CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are
each, independently of one another, hydrogen or
C.sub.1-C.sub.12-alkyl, or NR.sup.3R.sup.4 as a whole is a cyclic
amino radical having 4 to 12 carbon atoms,
COO--(C.sub.1-C.sub.12-alkyl), --COO(C.sub.4-C.sub.24-aryl)- ,
--COO(C.sub.5-C.sub.25-arylalkyl), CO(C.sub.1-C.sub.12-alkyl),
CO(C.sub.4-C.sub.24-aryl) or C.sub.1-C.sub.12-fluoroalkyl wherein
the process comprises nitrating compounds of the formula (IV)
19wherein R.sup.1, R.sup.2 and n have the meanings specified under
formula (I). R.sup.1 is hydrogen or C.sub.1-C.sub.12-alkyl, and
R.sup.2 are in each case independently of one another: fluorine,
chlorine, bromine, iodine, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, hydroxyl, NR.sup.3R.sup.4 or
CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are each,
independently of one another, hydrogen or C.sub.1-C.sub.12-alkyl,
or NR.sup.3R.sup.4 as a whole is a cyclic amino radical having 4 to
12 carbon atoms, COO--(C.sub.1-C.sub.12-alkyl),
--COO(C.sub.4-C.sub.24-aryl)- , --COO(C.sub.5-C.sub.25-arylalkyl),
CO(C.sub.1-C.sub.12-alkyl), CO(C.sub.4-C.sub.24-aryl) or
C.sub.1-C.sub.12-fluoroalkyl.
23. A process for producing medicaments and physiologically active
substances comprising providing the compounds of claim 1.
24. A process for producing medicaments and physiologically active
substances comprising providing therefor the compounds of claim
10.
25. A process for treating cardiac arrhythmias comprising
administering medicaments and physiologically active substances as
recited in claim 23.
26. The process according to claim 25, characterized in that the
physiologically active substance is dronedarone.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to 5-nitrobenzofurans, to a
process for preparing 5-nitrobenzofurans, as well as to
5-nitro-2,3-dihydrobenzof- uran-3-ols, to a process for the
preparation thereof and to their intermediates.
[0003] 2. Brief Description of the Invention
[0004] Benzofurans have acquired industrial importance in
particular as intermediates for preparing medicaments. The
benzofuran structure is found for example in anti-arrhythmic active
ingredients such as, for example, amiodarone and bufuralol.
[0005] 2-(n-butyl)-5-nitrobenzofuran is used as intermediate in the
preparation of dronedarone
(N-[2-(n-butyl)-3-[4-[3-(dibutylamino)propoxy]-
benzoyl]-5-benzofuranyl]methanesulfonamide), which likewise has
anti-arrhythmic activity.
[0006] EP-A 0 471 609 describes a process for preparing
2-(n-butyl)-5-nitrobenzofuran which starts from
2-hydroxy-5-nitrobenzyl bromide. This involves reaction with
triphenylphosphane initially to prepare
2-hydroxy-5-nitrobenzyltriphenylphosphonium bromide, which is
acylated with pentanoyl chloride in the presence of an amine base
and subsequently cyclized to 2-(n-butyl)-5-nitrobenzofuran. The
disadvantages of this process are the costly precursor
2-hydroxy-5-nitrobenzyl bromide, the low yield and the large
amounts of waste, in particular of triphenylphosphane oxide.
[0007] WO-A 01/28974 and WO-A 01/29019 disclose processes for
preparing 5-nitrobenzofurans, starting from salicylaldehyde, and
proceeding in a four-stage synthesis via
2-(2-formyl-4-nitrophenoxy) carboxylic acids as intermediates. The
disadvantages of this process are the cost of salicylaldehyde, and
the fact that the oxidation-sensitive aldehyde functionality is
present in all intermediates.
[0008] In a further process disclosed in EP-A 1 116 719,
5-nitro-2(3H)-benzofuranone is reacted in the presence of pentanoic
acid and pentanoic anhydride to give
3-(1-hydroxypentylidene)-5-nitro-2(3H)-be- nzofuranone which reacts
under acidic conditions to give 2-(n-butyl)-5-nitrobenzofuran. The
disadvantage of this process is that 5-nitro-2(3H)-benzofuranone is
used as precursor, which makes industrial application
uneconomic.
[0009] There was thus a continuing need to develop an efficient and
widely applicable process for preparing 5-nitrobenzofuranones which
both starts from low-cost, easily obtainable precursors and can
easily be implemented industrially.
SUMMARY OF THE INVENTION
[0010] A process for preparing compounds of the formula (I) has now
been found 1
[0011] in which
[0012] R.sup.1 is hydrogen or C.sub.1-C.sub.12-alkyl, and
[0013] R.sup.2 are in each case independently of one another:
fluorine, chlorine, bromine, iodine, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, hydroxyl, NR.sup.3R.sup.4 or
CONR.sup.3R.sup.4, where R.sup.3and R.sup.4 are each, independently
of one another, hydrogen or C.sub.1-C.sub.12-alkyl, or
NR.sup.3R.sup.4 as a whole is a cyclic amino radical having 4 to 12
carbon atoms, COO--(C.sub.1-C.sub.12-alkyl),
--COO(C.sub.4-C.sub.24-aryl), --COO(C.sub.5-C.sub.25-arylalkyl),
CO(C.sub.1-C.sub.12-alkyl), CO(C.sub.4-C.sub.24-aryl) or
C.sub.1-C.sub.12-fluoroalkyl and
[0014] n is zero, one, two or three, or in the case where n is two
or three it is possible for two adjacent R.sup.2 substituents to be
part of a fused ring system which in turn may optionally be
substituted by the radicals mentioned above for R.sup.2,
[0015] which is characterized in that
[0016] compounds of the formula (II) 2
[0017] in which
[0018] R.sup.1, R.sup.2 and n have the meaning under formula
(I),
[0019] are converted by dehydration into compounds of the formula
(I).
[0020] For the purposes of the invention it is possible for all the
radical definitions, parameters and explanations which are general
or specified in preferred ranges and are given above and detailed
below to be combined with one another in any way, that is to say
also between the respective ranges and preferred ranges.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Alkyl or alkoxy is in each case independently a
straight-chain, cyclic, branched or unbranched alkyl or alkoxy
radical. The same applies to the nonaromatic part of an arylalkyl
radical.
[0022] C.sub.1-C.sub.4-Alkyl is, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl,
C.sub.1-C.sub.8-alkyl is additionally, for example, n-pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl,
1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylpropyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,
1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,
1-ethyl-2-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl and
n-octyl, and C.sub.1-C.sub.12-alkyl is furthermore, for example,
adamantyl, the isomeric menthyls, n-nonyl, n-decyl and
n-dodecyl.
[0023] C.sub.1-C.sub.4-Alkoxy is, for example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy,
C.sub.1-C.sub.8-alkoxy is additionally n-pentoxy, 1-methylbutoxy,
2-methylbutoxy, 3-methylbutoxy, neopentoxy, 1-ethylpropoxy,
cyclohexoxy, cyclopentoxy, n-hexoxy and n-octoxy, and
C.sub.1-C.sub.12-alkoxy is furthermore, for example, adamantoxy,
the isomeric menthoxy radicals, n-decoxy and n-dodecoxy.
[0024] Fluoroalkyl is in each case independently a straight-chain,
cyclic, branched or unbranched alkyl radical which is substituted
once, more than once or completely by fluorine atoms.
[0025] C.sub.1-C.sub.12-Fluoroalkyl is, for example,
trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
nonafluorobutyl, heptafluoroisopropyl, perfluorooctyl and
perfluorododecyl.
[0026] Aryl is in each case independently a heteroaromatic radical
having 4 to 24 carbon atoms in the framework, in which zero, one,
two or three carbon atoms in the framework of each ring, but at
least one carbon atom in the framework of the whole molecule, can
be replaced by hetero atoms selected from the group of nitrogen,
sulphur or oxygen, but is preferably a carbocyclic aromatic radical
having 6 to 24 carbon atoms in the framework.
[0027] Examples of carbocyclic aromatic radicals having 6 to 24
carbon atoms in the framework are phenyl, naphthyl, phenanthrenyl,
anthracenyl or fluorenyl, and heteroaromatic radicals having 4 to
24 carbon atoms in the framework in which zero, one, two or three
carbon atoms in the framework of each ring, but at least one carbon
atom in the framework of the whole molecule, can be replaced by
heteroatoms selected from the group of nitrogen, sulphur or oxygen
are, for example, pyridinyl, oxazolyl, benzofuranyl, dibenzofuranyl
or quinolinyl.
[0028] The carbocyclic aromatic radical or heteroaromatic radical
may additionally be substituted by up to five identical or
different substituents per ring, which are selected from the group
of chlorine, fluorine, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, di(C.sub.1-C.sub.8-alkyl)amino,
COO(C.sub.1-C.sub.8-alkyl), CON(C.sub.1-C.sub.8-alkyl).sub.2,
COO(C.sub.1-C.sub.8-arylalkyl), COO(C.sub.4-C.sub.14-aryl),
CO(C.sub.1-C.sub.8-alkyl), C.sub.5-C.sub.15-arylalkyl or
tri(C.sub.1-C.sub.6-alkyl)siloxy.
[0029] C.sub.4-C.sub.24-Aryl is, for example, and preferably,
phenyl, o-, p-, m-tolyl, o-, p-, m-anisyl, o-, p-, m-fluorophenyl,
o-, p-, m-chlorophenyl, o-, p-, m-trifluoromethylphenyl, o-, p-,
m-nitrophenyl and 2-, 3- and 4-pyridyl.
[0030] Arylalkyl is in each case independently a straight-chain,
cyclic, branched or unbranched alkyl radical as defined above which
can be substituted once, more than once or completely by aryl
radicals as defined above.
[0031] C.sub.5-C.sub.15-Arylalkyl is, for example and preferably,
benzyl or (R)- or (S)-1-henylethyl.
[0032] The preferred substitution pattern for compounds of the
formulae (I) and (II) is defined below:
[0033] R.sup.1 is preferably hydrogen or C.sub.1-C.sub.4-alkyl and
particularly preferably n-butyl.
[0034] R.sup.2 is preferably in each case independently: fluorine,
chlorine, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, hydroxyl,
COO--(C.sub.1-C.sub.4-alkyl), trifluoromethyl, NR.sup.3R.sup.4 or
CONR.sup.3R.sup.4, where R.sup.3 and R.sup.4 are each independently
of one another hydrogen or C.sub.1-C.sub.4-alkyl, or
NR.sup.3R.sup.4 as a whole is pyrrolidinyl or piperidinyl.
[0035] n is preferably zero or one, and more preferably zero.
[0036] The very particularly preferred compound of the formula (I)
is 2-(n-butyl)-5-nitrobenzofuran.
[0037] Apart from 2-(n-butyl)-5-nitrobenzofuran, the compounds of
the formula (I) are likewise included by the invention and
represent starting materials for the development of new active
ingredients for the treatment of cardiac arrhythmias.
[0038] The compounds of the formula (II) are also furthermore
included by the invention. The very particularly preferred compound
of the formula (II) is
2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol. Moreover, in the
case of the compounds of the formula (II) where R.sup.1 is not
hydrogen, the (2R,3R); (2S,3S); (2S,3R) and (2R,3S) isomers each in
pure form, and any mixtures of the isomers, are encompassed by the
invention.
[0039] Particularly suitable dehydrating reagents, which may be
employed in catalytic amounts where appropriate, for the purposes
of the invention are: protic acids such as H.sub.2SO.sub.4 or
H.sub.3PO.sub.4 or bisulphates such as KHSO.sub.4, hydroxides such
as NaOH and KOH, P.sub.2O.sub.5, I.sub.2, and salts of zinc and
copper such as, in particular, CuSO.sub.4 and ZnCl.sub.2. Protic
acids are particularly preferred for the process of the invention.
H.sub.2SO.sub.4 is very particularly preferred for the process of
the invention.
[0040] The dehydration can be carried out in an organic solvent.
Organic solvents preferably used are polar, protic and aprotic
solvents. Polar solvents mean those having a dielectric constant at
25.degree. C. of 5 or more. Organic solvents particularly preferred
for the process of the invention are aliphatic
C.sub.1-C.sub.6-alcohols. Ethanol is very particularly preferred
for the process of the invention.
[0041] The dehydration can be carried out for example at
temperatures from -20 to 150.degree. C., preferably at 20 to
150.degree. C., particularly preferably at 50 to 100.degree. C. and
very particularly preferably at 70 to 78.degree. C.
[0042] The reaction may take for example from 0.5 to 20 hours,
preferably 0.5 to 8 hours and particularly preferably from 4 to 5
hours.
[0043] The pressure during the reaction is not critical and can be,
for example, 0.5 to 100 bar, preferably 0.8 to 10 bar. Ambient
pressure is particularly preferred.
[0044] The compounds of the formula (II) can be obtained in a
particularly advantageous manner by reducing compounds of the
formula (III) 3
[0045] in which
[0046] R.sup.1, R.sup.2 and n have the meanings specified under
formula (I), including the preferred ranges.
[0047] Compounds of the formula (III) encompassed by the invention
are those in which R.sup.2 and n have the meanings specified under
formula (I), including the preferred ranges, and R.sup.1 is
n-butyl. A particularly preferred compound of the formula (III) is
2-(n-butyl)-5-nitro-3(2H)-benzofuranone.
[0048] The compounds of the formula (III) can be reduced for
example by transfer hydrogenation or by means of aluminium-hydrogen
or boron-hydrogen compounds. The reduction is preferably effected
by aluminium-hydrogen or boron-hydrogen compounds, particularly
preferably by compounds of the formula (RI)
Met[EH.sub.qR.sup.5.sub.(4-q)].sub.p (RI)
[0049] in which
[0050] Met is a monovalent or divalent metal such as, preferably,
zinc, lithium, sodium or potassium, and
[0051] E is aluminium or boron and
[0052] R.sup.5 is C.sub.1-C.sub.8-alkyl, and
[0053] q is 1, 2, 3 or 4, preferably 4 or 1 and
[0054] p is the valency of Met,
[0055] r by compounds of the formula (RII)
BH.sub.rR.sup.5.sub.(3-r) (RII)
[0056] in which
[0057] R.sup.5 has the meaning specified under formula (RI),
and
[0058] r is one, two or three.
[0059] Very particularly preferred compounds of the formulae (RI)
and (RII) are LiBH.sub.4, NaBH.sub.4, Zn(BH.sub.4).sub.2,
LiAlH.sub.4, Li[BHEthyl.sub.3] and Li[AlH(sec-butyl).sub.3], with
NaBH.sub.4 being even further preferred.
[0060] The amount of the aluminium-hydrogen or boron-hydrogen
compounds is preferably chosen so that the molar ratio of hydrogen
in the aluminium-hydrogen or boron-hydrogen compounds and the
substrate is from 0.5 to 10, preferably 0.95 to 5 and particularly
preferably 1.0 to 1.2. Larger ratios are possible but
uneconomic.
[0061] Depending on the reagent employed, it is possible to employ
polar solvents as solvents. The use of alkali metal boranates in
aliphatic C.sub.1-C.sub.6-alcohols or ethers such as, in
particular, 1,4-dioxane is preferred for the process of the
invention. The reduction is very particularly preferably carried
out with sodium borohydride in ethanol.
[0062] The reaction can be carried out for example at temperatures
from -78 to 100.degree. C., preferably 0 to 100.degree. C. and
particularly preferably 60 to 78.degree. C.
[0063] The compounds of the formula (III) can be obtained in a
particularly advantageous manner by nitration of compounds of the
formula (IV) 4
[0064] in which R.sup.1, R.sup.2 and n have the meanings specified
under formula (I), including the preferred ranges.
[0065] The reagents advantageously employed for the nitration are
those able to generate nitrile cations (NO.sub.2.sup.+). Nitric
acid is preferred for example, preferably with a content of from 60
to 100% by weight based on HNO.sub.3. The use of nitric acid, where
appropriate as a mixture with sulphuric acid with a content of from
50 to 160% by weight based on H.sub.2SO.sub.4 and/or phosphoric
acid with a content of from 70 to 160% by weight based on
H.sub.3PO.sub.4, is likewise preferred. The use of nitrogen oxides
such as NO.sub.2, N.sub.2O.sub.3, N.sub.2O.sub.4, N.sub.2O.sub.5 or
of NO is additionally preferred, where appropriate in the presence
of an oxidizing agent. Preference is likewise given to nitration
with nitrous acid HNO.sub.2 or a salt of nitrous acid such as, in
particular, NaNO.sub.2, preferably in the presence of an oxidizing
agent, or with ionic nitrite compounds such as, for example,
NO.sub.2.sup.+BF.sub.4.sup.-. Alkyl nitrites of the general formula
R.sup.6--ONO, where R.sup.6 is C.sub.1-C.sub.12-alkyl, are further
preferably to be employed for the nitration.
[0066] The amount of nitration reagent employed is advantageously
chosen so that the molar ratio of theoretically nitrating agent to
compound of the formula (IV) is from 0.9 to 2, preferably 1.0 to
1.5 and particularly preferably 1.0 to 1.2.
[0067] A mixture of nitric acid with a content of from 60 to 100%
by weight based on HNO.sub.3 and sulphuric acid with a content of
from 90 to 100% by weight based on H.sub.2SO.sub.4 is particularly
preferably employed for the nitration.
[0068] Likewise particularly preferred for the nitration is nitric
acid with a content of from 95 to 100% by weight.
[0069] In a preferred embodiment, the molar ratio of compound of
the formula (IV) and nitric acid is between 0.9 and 1, particularly
preferably between 0.95 and 1.05.
[0070] The nitration can be carried out for example with or without
organic solvent, the organic solvent necessarily being inert under
reaction conditions. Representatives of such organic solvents which
may be particularly mentioned are halogenated aliphatic
hydrocarbons such as, in particular, chlorinated aliphatic
hydrocarbons such as, for example, dichloromethane,
1,2-dichloroethane, tetrachloromethane and hexachloroethane.
Dichloromethane is preferred for the nitration of compounds of the
formula (IV).
[0071] However, the nitration is preferably carried out without
organic solvent. The amount concentration of the compound of the
formula (IV) in the reaction medium can be, for example, from 0.2
to 3 mol/l, and from 0.3 to 1.6 mol/l is preferred.
[0072] The nitration can be carried out for example in a
temperature range from -10 to 50.degree. C., preferably between -10
and 20.degree. C., particularly preferably between -5 to 10.degree.
C.
[0073] The process of the invention can be carried out under an
inert gas atmosphere at atmospheric pressure, with the procedure
possibly being for example as follows: for example it is possible
to introduce the sulphuric acid first and then to meter in the
compound of the formula (IV) and the nitric acid or a mixture of
nitric acid and sulfuric acid. A further possibility is also for
the nitric acid and the sulphuric acid to be introduced first and
then the compound of the formula (IV) to be added, preferably in
portions.
[0074] The reaction may take, depending on the amount employed, for
example and preferably from 0.1 to 10 hours.
[0075] The product can be isolated by using the techniques which
are customary in nitration reactions and are known to the skilled
person. It is preferred for the process of the invention to
transfer the reaction mixture to ice or ice-water and then filter
or extract.
[0076] The compounds of the formula (IV) can be obtained in a
preferred manner by hydrolysing compounds of the formula (V) 5
[0077] in which
[0078] R.sup.1, R.sup.2 and n have the meaning specified under
formula (I), including the preferred ranges, and
[0079] R.sup.7 is C.sub.1-C.sub.12-alkyl,
C.sub.5-C.sub.25-arylalkyl, C.sub.4-C.sub.24-aryl or
C.sub.1-C.sub.12-fluoroalkyl,
[0080] R.sup.7 is preferably C.sub.1-C.sub.4-alkyl and particularly
preferably methyl.
[0081] The hydrolysis can in this case be carried out with acids,
bases, metal ions, enzymes or nucleophiles, where appropriate in
catalytic amounts, and where appropriate in the presence of an
organic solvent.
[0082] Preferably employed are bases such as, for example, aqueous
amines such as, in particular, aqueous ammonia, hydroxides or
carbonates such as, in particular, NaOH and KOH or acids such as,
for example, aqueous hydrochloric acid, sulphuric acid, phosphoric
acid, bisulphates, carboxylic acids such as, for example, formic
acid or acetic acid, and sulphonic acids such as, for example,
methanesulphonic acid or para-toluenesulfonic acid in various
concentrations.
[0083] Acids are particularly preferably employed, very
particularly preferably hydrochloric acid, sulphuric acid, or
phosphoric acid, with 6N hydrochloric acid being even further
preferred.
[0084] The acid is in this case preferably employed in amounts such
that the molar ratio of compounds of the formula (V) to acid is
from 1:1 to 1:100, preferably 1:1.1 to 1:10 and particularly
preferably 1:5 to 1:6.
[0085] It is possible in a preferred embodiment to employ an
organic solvent to improve the solubility of the compounds of the
formula (V). Vigorous stirring and the use of ultrasound or of
phase-transfer catalysts is also possible in addition. Preferred
organic solvents are aliphatic C.sub.1-C.sub.6-alcohols or cyclic
ethers. Ethanol is particularly preferably employed.
[0086] The reaction can be carried out at temperatures from 25 to
200.degree. C., preferably at 60 to 100.degree. C., particularly
preferably at 70 to 78.degree. C.
[0087] The reaction may last for example from 0.5 to 24 hours, and
1 to 6 hours are preferred.
[0088] The compounds of the formula (V) encompassed by the
invention are those in which R.sup.2 and n have the meanings
specified under formula (I), including the referred ranges, R.sup.7
has the abovementioned meaning, including the preferred ranges
thereof, and R.sup.2 is n-butyl. A particularly preferred compound
of the formula (V) is 3-acetoxy-2-(n-butyl)benzofuran.
[0089] The compounds of the formula (V) can be obtained in a
particularly advantageous manner by cyclizing decarboxylation of
compounds of the formula (VI) 6
[0090] in which R.sup.1, R.sup.2 and n have the meanings specified
under formula (I), including the preferred ranges,
[0091] in the presence of at least one compound of the formula
(RIII)
R.sup.7COR.sup.8 (RIII)
[0092] in which
[0093] R.sup.7 has the meaning specified under formula (V),
including the preferred ranges, and
[0094] R.sup.8 is --O.sub.2CR.sup.7, hydroxyl or OM, where M is an
alkaline earth metal or alkali metal.
[0095] The reaction is preferably carried out in the presence of a
mixture of compounds of the formula (RIII), employing in each case
an anhydride, preferably a homoanhydride (R.sup.7CO).sub.2O, an
alkali metal salt and a free acid. The R.sup.7 radicals in the said
compounds are preferably identical in each case. It is particularly
preferred to employ mixtures of sodium acetate, acetic acid and
acetic anhydride. The ratio of the amount of substances in this
case is preferably (0.8 to 1.5):(2 to 4):(3 to 8), particularly
preferably about 1:3:5.
[0096] The reaction temperature can be for example from 20 to
150.degree. C., preferably 60 to 150.degree. C. and particularly
preferably 120 to 140.degree. C.
[0097] The compounds of the formula (VI) can be obtained in a
preferred manner by hydrolysing compounds of the formula (VII)
7
[0098] in which
[0099] R.sup.1, R.sup.2 and n have the meanings specified under
formula (I), including the preferred ranges, and
[0100] R.sup.9 and R.sup.10 are each independently of one another
C.sub.1-C.sub.12-alkyl, C.sub.5-C.sub.25-arylalkyl or
C.sub.4-C.sub.24-aryl, and not more than one R.sup.9 or R.sup.10
radical can be hydrogen.
[0101] R.sup.9 and R.sup.10 are preferably each independently of
one another C.sub.1-C.sub.4-alkyl, particularly preferably each
independently of one another methyl or ethyl and very particularly
preferably each identically methyl or ethyl.
[0102] The hydrolysis can in this case be carried out with acids,
bases, metal ions, enzymes or nucleophiles, where appropriate in
catalytic amounts, and where appropriate in the presence of an
organic solvent.
[0103] Bases such as, for example, aqueous amines such as, in
particular, aqueous ammonia, hydroxides such as, in particular,
LiOH, NaOH, KOH and Ca(OH).sub.2, carbonates such as
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or CaCO.sub.3 or aqueous acids
such as, for example, hydrochloric acid, sulphuric acid, phosphoric
acid, bisulphates, carboxylic acids such as, for example, formic
acid or acetic acid, and sulphonic acids such as, for example,
methanesulphonic acid or para-toluenesulfonic acid are preferably
employed.
[0104] In a preferred embodiment, the hydrolysis is carried out in
the presence of bases, with the use of LiOH, NaOH, KOH or
Ca(OH).sub.2 being preferred. It is particularly preferred to use
sodium hydroxide solution with a content of from 5 to 25% by
weight. It is furthermore possible in a preferred embodiment to
employ an organic solvent to improve the solubility of the
compounds of the formula (VII).
[0105] For efficient hydrolysis of the ester groups, the base is
preferably employed in amounts such that the molar ratio of base to
compounds of the formula (VII) is from 1.5:1 to 20:1, preferably
2:1 to 7:1 and particularly preferably 3:1 to 5:1.
[0106] An organic solvent can be employed to improve the solubility
of the substrate. Vigorous stirring and the use of ultrasound or of
phase-transfer catalysts is additionally possible. The organic
solvents preferably used for the process of the invention are
aliphatic C.sub.1-C.sub.6-alcohols or cyclic ethers. Methanol or
ethanol is particularly preferably employed.
[0107] The reaction can be carried out at temperatures from 20 to
200.degree. C., preferably at 40 to 75.degree. C. and particularly
preferably at 40 to 60.degree. C.
[0108] Compounds of the formula (VII) encompassed by the invention
are those in which R.sup.2 and n have the meanings specified under
formula (I), including the preferred ranges, R.sup.9 and R.sup.10
then have the abovementioned meaning, including the preferred
ranges thereof, and R.sup.1 is n-butyl. Compounds of the formula
(VII) which may be mentioned are:
[0109] methyl 2-(1-methoxycarbonylpentoxy)benzoate, ethyl
2-(1-methoxycarbonylpentoxy)benzoate, ethyl
2-(1-ethoxycarbonylpentoxy)be- nzoate and methyl
2-(1-ethoxycarbonylpentoxy)benzoate,
2-(1-methoxycarbonylpentoxy)benzoic acid,
2-(1-ethoxycarbonylpentoxy)benz- oic acid, ethyl
2-(1-carboxypentoxy) benzoate and methyl
2-(1-carboxypentoxy)benzoate, and methyl
2-(1-methoxycarbonylhexoxy)benzo- ate, ethyl
2-(1-methoxycarbonylhexoxy)benzoate, ethyl
2-(1-ethoxycarbonylhexoxy)benzoate and methyl
2-(1-ethoxycarbonylhexoxy) benzoate,
2-(1-methoxycarbonylhexoxy)benzoic acid,
2-(1-ethoxycarbonylhexoxy)benzoic acid, ethyl
2-(1-carboxyhexoxy)benzoate and methyl
2-(1-carboxyhexoxy)benzoate.
[0110] The compounds of the formula (VII) can be obtained in a
preferred manner by reacting compounds of the formula (VIII) 8
[0111] in which
[0112] R.sup.2 and n have the meanings specified under formula (I),
including the preferred ranges, and
[0113] R.sup.10 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.5-C.sub.25-arylalkyl or C.sub.4-C.sub.24-aryl, with compounds
of the formula (IX) 9
[0114] in which
[0115] R.sup.1 has the meanings specified under formula (I),
including the preferred ranges,
[0116] R.sup.9 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.5-C.sub.25-arylalkyl or C.sub.4-C.sub.24-aryl, and
[0117] X is chlorine, bromine, iodine or R.sup.11SO.sub.3-- where
R.sup.11 is C.sub.1-C.sub.12-alkyl, C.sub.4-C.sub.24-aryl,
C.sub.5-C.sub.25-arylal- kyl or C.sub.1-C.sub.12-fluoroalkyl.
[0118] R.sup.11 at is preferably C.sub.1-C.sub.4-alkyl or
C.sub.4-C.sub.24-aryl, particularly preferably methyl, ethyl,
phenyl, o-, m- or p-tolyl or trifluoromethyl.
[0119] X is preferably chlorine or bromine, particularly preferably
bromine.
[0120] The compounds of the formula (VIII) which are preferably
employed are methyl o-hydroxybenzoate and ethyl
o-hydroxybenzoate.
[0121] The compounds of the formula (IX) which are preferably
employed are the methyl or ethyl 2-bromo carboxylates such as, in
particular, methyl or ethyl 2-bromohexanoate.
[0122] The reaction of compounds of the formula (VIII) with
compounds of the formula (IX) to give compounds of the formula
(VII) is preferably carried out in the presence of base. A possible
alternative to this is for the compound of the formula (VIII) first
to be converted into the corresponding phenolate and be employed as
such in the reaction.
[0123] The reaction can be carried out in an organic solvent.
Reaction in water in the presence of a phase-transfer catalyst is
also furthermore possible. Polar protic or aprotic solvents are
preferably employed for the process of the invention, such as, for
example, ketones such as acetone, amides such as
N,N-dimethylformamide or N,N-dimethylacetamide, lactams such as
1,-methyl-2-pyrrolidinone, ethers such as tetrahydrofuran or
dioxane, nitrites such as acetonitrile or benzonitrile or alcohols
such as methanol or ethanol. Even further preferred for the process
of the invention are acetone or acetonitrile.
[0124] The reaction can, where appropriate, be carried out under an
inert gas atmosphere, for example an argon atmosphere.
[0125] The bases employed are those which are able at least partly
to deprotonate the compounds of the formula (VIII) on the phenol
function.
[0126] Inorganic bases or organic bases for example can be
employed. Organic bases which can preferably be used are tertiary
amines such as triethylamine or alkali metal alcoholates such as
sodium methoxide or ethoxide, an inorganic base is for example
alkali metal or alkaline earth metal hydroxides, carbonates or
bicarbonates. Preferred bases are alkali metal carbonates,
especially potassium carbonate or sodium carbonate.
[0127] The ratio of the amounts of the compounds of the formula
(IX) employed and of the compounds of the formula (VIII) is
advantageously chosen so that it is between 1.0 and 1.2.
[0128] The ratio of amounts between the base employed and the
compound of the formula (VIII) employed is advantageously chosen
between 1.0 and 1.5, with a ratio between 1.1 and 1.3 being
preferred.
[0129] The reaction can be carried out for example at temperatures
from 0 to 150.degree. C., with preferred reaction temperatures
being from 50 to 100.degree. C., particularly preferably 70 to
80.degree. C.
[0130] The compounds of the general formula (VI) may, where
appropriate, also be prepared directly, without isolating the
compounds of the formula (VII), by reacting compounds of the
formula (VIII) with compounds of the formula (IX) in a one-pot
process with hydrolysis of the ester functions taking place
simultaneously.
[0131] An alternative possibility is also to prepare compounds of
the formula (VI) by reacting those compounds of the formula (VIII)
with those compounds of the formula (IX) in which R.sup.9 and
R.sup.10 are each hydrogen. The amount of base is advantageously
increased appropriately in this reaction.
[0132] The invention encompasses, besides a process for preparing
compounds of the formula (I) from compounds of the formula (II),
also processes for preparing compounds of the formula (I) from
compounds of the formula (III), (IV), (V), (VI), (VII), (VIII) and
(IX), each of which proceed via the described intermediates. The
invention further encompasses processes for preparing compounds of
the formula (II) from compounds of the formula (III) and, in each
case, from the compounds (IV), (V), (VI), (VII), (VIII) and (IX),
each of which proceed via the described intermediates.
[0133] The invention further encompasses processes for preparing
compounds of the formula (III) from compounds of the formula (IV)
and, in each case, from the compounds (V), (VI), (VII), (VIII) and
(IX), each of which proceed via the described intermediates.
[0134] The compounds of the formulae (I), (II) and (III) prepared
according to the invention are particularly suitable for producing
medicaments and physiologically active substances and for use in a
process for producing medicaments and physiologically active
substances.
[0135] Preferred medicaments and physiologically active substances
in this connection are those employed for treating cardiac
arrhythmias. A particularly preferred physiologically active
substance is dronedarone.
[0136] The invention is distinguished through the fact that
5-nitrobenzofurans, 5-nitro-2,3-dihydrobenzofuran-3-ols and
5-nitro-3(2H)-benzofuranones can be obtained by a highly efficient
and economic route, and synthetic processes for a wide spectrum of
potential development candidates are disclosed.
[0137] The invention is further described by the following
illustrative but non-limiting examples.
EXAMPLES
Example 1
Synthesis of methyl 2-(1-methoxycarbonylpentoxy)benzoate
[0138] 15.2 g of methyl salicylate and 18.0 g of potassium
carbonate were introduced into 125 ml of acetonitrile in a 250 ml
flask under an argon atmosphere and, at room temperature, 20.9 g of
methyl 2-bromohexanoate were added. The colourless suspension was
heated under reflux with stirring for 16 hours, and the progress of
the reaction was checked by thin-layer chromatography. After
cooling to room temperature, the suspension was filtered and the
residue was washed with acetone. Concentration of the filtrate in
vacuo resulted in 27.8 g (99% of theory) of methyl
2-(1-methoxycarbonylpentoxy)benzoate as yellow oil.
Example 2
Synthesis of 2-(1-carboxypentoxy)benzoic acid
[0139] 13.0 g of methyl 2-(1-methoxycarbonylpentoxy)benzoate were
dissolved in methanol in a 250 ml flask, and a solution of 9.1 g of
sodium hydroxide in 40 ml of water was added. The reaction mixture
was stirred at 40.degree. C. for one hour, during which a
precipitate formed. This was dissolved after cooling to room
temperature by adding further methanol and sodium hydroxide
solution. The reaction mixture was washed with dichloromethane, and
the aqueous phase was subsequently adjusted to pH 0 with
concentrated hydrochloric acid while cooling in ice. A colourless
solid precipitated during this and was filtered off and dried. 10.1
g (87% of theory) of 2-(1-carboxypentoxy)benzoic acid were obtained
in this way.
Example 3
Synthesis of 3-acetoxy-2-(n-butyl)benzofuran
[0140] 5.0 g of 2-(1-carboxypentoxy)benzoic acid and 1.6 g of
sodium acetate were introduced into a 25 ml flask, and 3.4 ml of
glacial acetic acid and 9.4 ml of acetic anhydride were added. The
colourless suspension was heated to reflux for 4 hours. Cooling,
transferring the reaction mixture into ice-water, extracting with
dichloromethane, drying the combined organic phases over sodium
sulphate and removing the solvent resulted in a yellow oil in
which, according to GC, the precursor and the product were present
in an approximate ratio (percentage areas) of 50:50.
[0141] This oil was again mixed with 1.6 g of sodium acetate, 3.4
ml of glacial acetic acid and 9.4 ml of acetic anhydride and once
more heated to reflux for 4 hours. Cooling and the same working up
as described above resulted in 4.3 g (92% of theory) of
3-acetoxy-2-(n-butyl)benzofuran as pale yellow oil.
Example 4
Synthesis of 2-(n-butyl)-3(2H)-benzofuranone
[0142] 4.6 g of 3-acetoxy-2-(n-butyl)benzofuran were dissolved in
20 ml of ethanol in a 100 ml flask, and 20 ml 6N hydrochloric acid
were added. The mixture was heated to reflux for 4 hours. After
cooling to room temperature, the pH was adjusted to 4 to 6 with
sodium hydroxide, and the ethanol was distilled off. This was
followed by extraction with dichloromethane. Drying of the combined
organic phases over sodium sulphate and removal of the solvent
resulted in 2.8 g (76% of theory) of
2-(n-butyl)-3(2H)-benzofuranone as yellow oil.
Example 5
Synthesis of 2-(n-butyl)-5-nitro-3(2H)-benzofuranone
[0143] 2.9 ml of concentrated sulphuric acid were introduced into a
50 ml flask and cooled to 5.degree. C. Then 1.0 g of
2-(n-butyl)-3(2H)-benzofur- anone was slowly added, during which
the reaction mixture assumed a brownish colour. It was stirred for
15 minutes. Subsequently, 0.7 g of nitration acid was slowly added
dropwise in such a way that the temperature did not rise much above
5.degree. C. The reaction mixture was then poured onto ice, stirred
and extracted with dichloromethane. The dichloromethane extracts
were washed with water, dried over sodium sulphate and evaporated
to dryness in vacuo. The material (1.0 g) obtained in this way had,
according to GC, a content of about 70% (percentage areas) of
2-(n-butyl)-5-nitro-3(2H)-benzofuranone. Further purification is
possible by column chromatography (eluent: hexane:ethyl
acetate=10:1).
[0144] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.=8.49 (d, J=2.4
Hz, 1 H, Ar--H), 8.45 (dd, J.sub.1=9.0 Hz, J.sub.2=2.4 Hz, 1 H,
Ar--H), 7.17 (d, J=9.0 Hz, 1 H, Aryl-H), 4.69 (dd, J.sub.1=8.0 Hz,
J.sub.2=4.4 Hz, 1 H, O.dbd.C--CH), 2.0-1.9 (2.times.m, 2 H,
CH--CH.sub.2), 1.40 (m, 2 H, CH.sub.2), 1.33 (m, 2 H, CH.sub.2),
0.85 (t, J=7.2 Hz, 3 H, CH.sub.3).
Example 6
Synthesis of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol
[0145] 700 mg of 2-(n-butyl)-5-nitro-3(2H)-benzofuranone were
introduced into 10 ml of ethanol in a 50 ml flask and cooled to
0.degree. C. A solution of 130 mg of NaBH.sub.4 in 5 ml of ethanol
was added dropwise thereto, an intense red coloration immediately
appearing. The mixture was allowed to reach room temperature and
was then briefly heated to reflux. After cooling to room
temperature, the reaction mixture was taken up in water and
dichloromethane, the organic phase was separated off, and the
aqueous phase was extracted once more with dichloromethane. Drying
of the combined organic phases over sodium sulphate, removal of the
solvent in vacuo and column chromatography (eluent: hexane:ethyl
acetate=5:1) resulted in 400 mg (57% of theory) of
2-(n-butyl)-5-nitro-2,3-dihydrobenz- ofuran-3-ol.
Example 7
Synthesis of 2-(n-butyl)-5-nitrobenzofuran
[0146] 300 mg of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol
were introduced into ethanol in a 50 ml flask, and 1 ml of
concentrated sulphuric acid was added. The mixture was then heated
to reflux for 4 hours. After cooling, 10 ml of water were added,
the ethanol was distilled off, and the mixture was extracted with
dichloromethane. Washing of the organic phase with sodium
bicarbonate solution, drying over sodium sulphate and removal of
the solvent in vacuo resulted in 220 mg (80% of theory) of
2-(n-butyl)-5-nitrobenzofuran as yellow oil.
[0147] Although the invention has been described in detail in the
foregoing for the purpose of illustration, it is to be understood
that such detail is solely for that purpose and that variations can
be made therein by those skilled in the art without departing from
the spirit and scope of the invention except as it may be limited
by the claims.{private}
* * * * *