U.S. patent application number 10/311319 was filed with the patent office on 2004-01-08 for process for the preparation of nitroalkenes.
This patent application is currently assigned to ZAMBON GROUP S.P.A. Invention is credited to Belli, Aldo, Paiocchi, Maurizio, Ponzini, Francesco, Villa, Marco.
Application Number | 20040006248 10/311319 |
Document ID | / |
Family ID | 8175386 |
Filed Date | 2004-01-08 |
United States Patent
Application |
20040006248 |
Kind Code |
A1 |
Paiocchi, Maurizio ; et
al. |
January 8, 2004 |
Process for the preparation of nitroalkenes
Abstract
A process for the nitration of conjugated alkenes of formula (I)
wherein R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the meanings
reported in the description, which allows to obtain the
corresponding .beta.-nitro-alkenes, characterised in that the
nitrating agent is a mixture of an inorganic nitrite and iodine in
the presence of an oxidising agent is described. 1
Inventors: |
Paiocchi, Maurizio; (Milan,
IT) ; Belli, Aldo; (Cornate D'Adda, IT) ;
Ponzini, Francesco; (Milan, IT) ; Villa, Marco;
(Padova, IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
ZAMBON GROUP S.P.A
VICENZA
IT
|
Family ID: |
8175386 |
Appl. No.: |
10/311319 |
Filed: |
December 30, 2002 |
PCT Filed: |
June 19, 2001 |
PCT NO: |
PCT/EP01/06902 |
Current U.S.
Class: |
568/959 |
Current CPC
Class: |
C07C 201/08 20130101;
C07D 311/58 20130101; C07C 205/05 20130101; C07C 201/08 20130101;
C07C 2602/28 20170501 |
Class at
Publication: |
568/959 |
International
Class: |
C07C 027/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 28, 2000 |
EP |
00830453.7 |
Claims
1) A process for the nitration of conjugated alkenes of formula
7wherein R is a hydrogen atom, an optionally substituted phenyl, a
linear or branched C.sub.1-C.sub.4 alkyl; R.sub.1 is a hydrogen
atom or a linear or branched C.sub.1-C.sub.4 alkyl, optionally
substituted by an OH or C.sub.1-C.sub.4 alkoxy group; R.sub.2,
R.sub.3 and R.sub.4, the same or different, are selected among
hydrogen and halogen atoms, linear or branched C.sub.1-C.sub.4
alkyl or alkoxy groups, carboxylic groups, aminocarbonyl groups,
alkyloxycarbonyl, alkylcarbonyl, mono- or di-alkylaminocarbonyl,
alkylcarbonylamino and alkylcarbonyloxy groups having from 1 to 4
carbon atoms in the alkyl moiety; or two of R.sub.2, R.sub.3 and
R.sub.4, in ortho between them, form a methylendioxy group; or
R.sub.1 together with R.sub.2 forms a cyclic system with 5-7 terms
condensed with the aromatic ring and optionally containing an
oxygen atom; or R.sub.1 together with R forms a cyclic system with
5-7 terms; which allows to obtain .beta.-nitro-alkenes of formula
8wherein R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the already
reported meanings; characterised in that the nitrating agent is a
mixture of an inorganic nitrite and iodine in the presence of an
oxidising agent:
2) A process according to claim 1 wherein the iodine is in an
amount from 0.1 to 0.8 moles per mole of the compound of formula
I.
3) A process according to claim 1 wherein the inorganic nitrite is
selected among silver nitrite, sodium nitrite and potassium
nitrite.
4) A process according to claim 3 wherein the inorganic nitrite is
sodium nitrite.
5) A process according to claim 1 herein the inorganic nitrite is m
an amount from 2 to 4 moles per mole of the compound of formula
I.
6) A process according to claim 1 wherein the oxidant agent is
selected among peracids, oxygen peroxide and inorganic
nitrites.
7) A process according to claim 6 wherein the oxidant agent is a
mixture of peracetic acid, oxygen peroxide and water.
8) A process according to claim 1 wherein the iodine is formed in
situ from alkaline iodides.
9) A process according to claim 1 wherein the temperature is from
40.degree. C. to 50.degree. C.
10) A process according to claim 1 for the nitration of styrenes,
optionally substituted on the aromatic ring by from 1 to 3 methoxy
groups or by a methylenedioxy group.
11) A process according to claim 1 for the nitration of
dihydronaphthalenes, optionally substituted by methoxy, methyl,
ethyl, fluoro, chloro, bromo, iodo, carboxy, methoxycarbonyl groups
or by a methylenedioxy group.
12) A process according to claim 11 for the nitration of
dihydronaphthalenes of formula 9wherein R.sub.3A and R.sub.4A, the
same or different, are hydrogen atoms, methoxy, methyl, ethyl,
fluoro, chloro, bromo, iodo, carboxy, methoxycarbonyl groups or,
together, form a methylenedioxy group; R is a hydrogen atom, an
optionally substituted phenyl, a linear or branched C.sub.1-C.sub.4
alkyl.
13) A process according to claim 1 for the nitration of
benzopyranes optionally substituted by methoxy, methyl, ethyl,
fluoro, chloro, bromo, iodo, carboxy, methoxycarbonyl,
aminocarbonyl or methylaminocarbonyl groups.
14) A process according to claim 13 for the nitration of the
benzopyranes of formula 10wherein R.sub.3B and R.sub.4B, the same
or different, are hydrogen atoms, methoxy, methyl, ethyl, fluoro,
chloro, bromo, iodo, carboxy, methoxycarbonyl, aminocarbonyl or
methylaminocarbonyl groups; R is a hydrogen atom, an optionally
substituted phenyl, a linear or branched C.sub.1-C.sub.4 alkyl.
15) A process according to claim 13 for the nitration of the
compound 8-fluoro-2H-chromene-5-carboxylic acid amide.
Description
[0001] The present invention relates to a process for the
preparation of nitroalkenes and, more particularly, it relates to a
process for the preparation of conjugated .beta.-nitroalkenes by
reaction of a conjugated alkene with a nitrite in the presence of
iodine and of an oxidising agent. Conjugated .beta.-nitroalkenes
are widely used synthetic intermediates because they can be easily
converted into a variety of different compounds. For example, we
can cite .beta.-nitrostyrene, useful intermediate for the
preparation of several phenylethylamines and fungicides (Chemical
Abstracts, vol. 118, no. 38576 k), 2-nitro-dihydronaphthalenes, key
intermediates for the synthesis of 2-amino-trahydronaphthalenes
(Debasis Ghosh et al., Synthesis, 1996, pages 195-197) and
8-fluoro-3-nitro-2H-chromene-5 carboxylic acid amide, an
intermediate for the preparation of
(R)-3-dicyclobutylamino-8-fluoro-c- hroman-5carboxylic acid amide,
a compound useful in the treatment of disorders of the central
nervous system (WO 98/46586-Astra Aktiebolag).
[0002] The nitration of alkenes with nitrites and iodine is known
in the literature [Hassner et al, J. Org. Chem., 1969, 34(9), pages
2628-2632].
[0003] The method foresees the use of a mixture of silver nitrite
and iodine as nitrating agent.
[0004] After the paper of Hassner et al., some papers were
published with the attempt of improving the nitration
conditions.
[0005] Wing-Wah Sy et al [Tetr. Lett., 1985, 26(9), pages
1193-1196] describe the nitration of substituted alkenes with
silver nitrite and iodine, the only difference from Hassner et al
being the use of a higher molar amount of silver nitrite, which is
then equimolar with respect to the iodine.
[0006] Jew et al. [Chemistry Letters, 1986, pages 1747-1748]
replace silver nitrite with sodium nitrite and use 2 moles of
iodine and 4 moles of nitrite per mole of styrene, respectively. In
the already cited paper published by Debasis Ghosh et al. potassium
nitrite is used in the presence of a phase transfer catalyst and by
treating with ultrasounds in order to increase the solubility of
the nitrite ion. Different amounts of iodine were evaluated to
optimise the yield and the reported general method foresees the use
of 2.6 moles of nitrite and 2.75 moles of iodine per mole of
alkene, respectively.
[0007] Then it is evident that the methods for the nitration of
alkenes described in the literature show the relevant drawback of
using high amounts of iodine which remarkably decrease the reaction
productivity because of the high molecular weight of iodine, make
the subsequent treatment with bisulphites, for transforming all the
iodine in excess into iodides at the end of the reaction,
particularly cumbersome and suffer from the problem of the removal
of iodides from the waste waters.
[0008] We have now found that the amount of iodine to be used for
the nitration of conjugated alkenes can be significantly decreased
by adding an oxidazing agent to the reaction mixture containing the
alkene, the nitrite and iodine.
[0009] Therefore, object of the present invention is a process for
the nitration of conjugated alkenes of formula 2
[0010] wherein
[0011] R is a hydrogen atom, an optionally substituted phenyl, a
linear or branched C.sub.1-C.sub.4 alkyl; R.sub.1 is a hydrogen
atom or a linear or branched C.sub.1-C.sub.4 alkyl, optionally
substituted by an OH or C.sub.1-C.sub.4 alkoxy group; R.sub.2,
R.sub.3 and R.sub.4, the same or different, are selected among
hydrogen and halogen atoms, linear or branched C.sub.1-C.sub.4
alkyl or alkoxy groups, carboxylic groups, aminocarbonyl groups,
alkyloxycarbonyl, alkylcarbonyl, mono- or di-alkylaminocarbonyl
alkylcarbonylamino and alkylcarbonyloxy groups having from 1 to 4
carbon atoms in the alkyl moiety; or two of R.sub.2, R.sub.3 and
R.sub.4, in ortho between them, form a methylendioxy group; or
R.sub.1 together with R.sub.2 forms a cyclic system with 5-7 terms
condensed with the aromatic ring and optionally containing an
oxygen atom; or R.sub.1 together with R forms a cyclic system with
5-7 terms;
[0012] which allows to obtain .beta.-nitroalkenes of formula 3
[0013] wherein R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the
already reported meanings;
[0014] characterised in that the nitrating agent is a mixture of an
inorganic nitrite and iodine in the presence of an oxidising
agent.
[0015] The nitration process object of the present invention allows
to obtain .beta.-nitroalkenes under mild conditions with good
yields.
[0016] In the present context, unless otherwise specified, linear
or branched C.sub.1-C.sub.4 alkyl means an alkyl selected among
methyl, ethyl, n-propyl, isopropyl n-butyl sec-butyl isobutyl and
t-butyl; linear or branched C.sub.1-C.sub.4 alkoxy means a group
selected among methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
sec-butoxy, isobutoxy and t-butoxy; halogen means fluorine,
chlorine, bromine and iodine.
[0017] Substituted phenyl means a phenyl substituted by one or more
substituents selected among the meanings of R.sub.2, R.sub.3 and
R.sub.4.
[0018] It is evident to the man skilled in the art that the
substituents on the aromatic ring should be compatible with the
used reaction conditions.
[0019] The compounds of formula I used in the nitration process
object of the present invention are known.
[0020] Preferred examples of the compounds of formula I are
styrenes optionally substituted on the aromatic ring by from 1 to 3
methoxy groups or by a methylenedioxy group, dihydronaphthalenes
optionally substituted by methoxy, methyl, ethyl, fluoro, chloro,
bromo, iodo, carboxy, methoxycarbonyl groups or by a methylenedioxy
group or benzopyranes optionally substituted by methoxy, methyl,
ethyl, fluoro, chloro, bromo, iodo, carboxy, methoxycarbonyl,
aminocarbonyl or methylaminocarbonyl groups.
[0021] Particularly preferred are the nitration of the compounds of
formula 4
[0022] wherein
[0023] R.sub.3A and R.sub.4A, the same or different, are hydrogen
atoms, methoxy, methyl, ethyl, fluoro, chloro, bromo, iodo,
carboxy, methoxycarbonyl groups or, together, form a methylenedioxy
group; R has the already reported meanings;
[0024] and the nitration of the compounds of formula 5
[0025] wherein
[0026] R.sub.3B and R.sub.4B, the same or different, are hydrogen
atoms, methoxy, methyl, ethyl, fluoro, chloro, bromo, iodo,
carboxy, methoxycarbonyl, aminocarbonyl or methylaminocarbonyl
groups; R has the already reported meanings;
[0027] to obtain the corresponding nitroderivatives of formula
6
[0028] and of formula
[0029] wherein R, R.sub.3A, R.sub.3B, R.sub.4A and R.sub.4B have
the already reported meanings.
[0030] Examples of inorganic nitrites which can be used in the
process object of the present invention are silver nitrite, sodium
nitrite and potassium nitrite.
[0031] Preferably sodium nitrite is used.
[0032] The amount of nitrite is in excess with respect to the
compound of formula I, generally not lower Man 2 moles per mole of
compound to be nitrated.
[0033] Preferably an amount of nitrite from 2 and 4 moles per mole
of compound of formula I is used.
[0034] The most characterizing feature of the present process is
represented by the amount of iodine which is used.
[0035] In fact, the presence, of an oxidising agent allows to
significantly decrease the amount of iodine up to an amount
generally equal or lower than 1 mole per mole of compound of
formula I, preferably from 0.1 and 0.8 moles per mole of substrate
to be nitrated.
[0036] As already underlined, the remarkable decrease of the amount
of iodine necessary to carry out the nitration gives to the process
object of the present invention the advantages related to the
increased productivity and to the higher simplicity of the work-up
of the reaction mixture. This is mainly in the final treatment to
remove the iodine, still present, which is generally carried out
with bisulphites, but which can be also avoided in the process
object of the present invention.
[0037] The advantages of the process object of the present
invention are particularly evident by comparing the nitration
reported in example 2 and the nitration carried out according to
the prior art on the same subsume, as reported in the already cited
WO 98/46586 (see in particular the example on page 12).
[0038] In fact by working according to the method object of the
present invention the nitroderivatives is obtained with a
practically triplicate yield.
[0039] Generally, the oxidation agent is slowly added, usually in
34 hours, to the reaction mixture containing the nitrite, iodine
and the compound of formula I.
[0040] A hypothesis on the role of the oxidant is that of oxidising
the iodides formed in the reaction mixture according to the
following scheme
AlkH+NaNO.sub.2+l.sub.2.fwdarw.AlkNO.sub.2+Hl+Nal
[0041] wherein AlkH represents the compound of formula I,
[0042] so forming an amount of iodine which is sufficient to go on
with the nitration reaction.
[0043] A further stage is represented by the fact that, by using an
oxidising agent, the iodine can also be prepared in situ by
oxidation of iodides. Iodides which can be used for such purposes
are generally alkali metal iodides, preferably potassium
iodide.
[0044] Specific examples of oxidising agents which can be used in
the process object of the present invention are peracids such as
peracetic acid and m-chloroperbenzoic acid, oxygen peroxide and
inorganic nitrites, optionally in admixture each other.
[0045] It is evident that when an inorganic nitrite is used as
oxidant agent, the same inorganic nitrite which is present in the
nitrating mixture will be preferably used.
[0046] The oxidising agent must be used in an acid environment,
preferably at a pH lower than 5.
[0047] Then, depending on the selected oxidant, it could be
necessary also the addition of an acidifying agent to bring the pH
up to the desired value.
[0048] Then, when peracids such as peracetic acid which is not
sufficiently acid are used, it will be suitable to use the oxidant
in solution with an acid solvent, preferably acetic acid. In a
similar way, when oxygen peroxide or an inorganic nitrate are used
as oxidising agent, acetic acid will be preferably used.
[0049] The use of a mixture of peracetic acid, oxygen peroxide,
acetic acid and water, already available on the market
(Oxistrong.RTM.-Ausimont) is particularly advantageous.
[0050] It is evident that the amount of oxidant will be in relation
to the used amount of iodine, preferably in slight excess. When the
iodides are used to form iodine directly in the reaction medium, a
higher amount of oxidant will be needed to allow the initial
oxidation of the iodides The process object of the present
invention is carried out in the presence of a suitable organic
solvent which is selected in relation to the solubility of the
compound of formula I but which is not a critical parameter for the
achievement of the process.
[0051] Examples of suitable solvents are esters such as ethyl
acetate, isopropyl acetate and isobutyl acetate, aromatic
hydrocarbons such as toluene and xylene, chlorinated hydrocarbons
such as methylene chloride and 1,2-dichloropropane and ethers such
as tert-butyl methyl ether.
[0052] When the reaction mixture contains water, the addition of a
phase transfer catalyst can be. useful.
[0053] Also the temperature is not a critical parameter. Preferably
temperatures from 20.degree. C. to 70.degree. C. are used. A still
more preferred temperature range is from 40.degree. C. to
50.degree. C.
[0054] A preferred embodiment of the process object of the present
invention is the following.
[0055] Iodine and then, slowly, a solution of the oxidising agent
are added to a mixture of the alkene of formula I and of sodium
nitrite in a suitable organic solvent. At the end of the addition
and at the completion of the reaction, an aqueous solution of
sodium metabisulphite is optionally added up to decoloration of the
iodine and the compound of formula II is separated according to
usual techniques.
[0056] In order to better illustrate the present invention the
following examples are now given.
EXAMPLE 1
[0057] Preparation of 2-nitro-3.4 dihydronaphthalene
[0058] Into a three-necks flask equipped with a reflux condenser
and a mechanic stirrer, at room temperature and under inert gas,
1,2-dihydronaphthalene (3.9 g; 30 mmoles), sodium nitrite (6.2 g;
90 mmoles) and isopropyl acetate (40 ml) were charged. The mixture
was kept under stirring and heated at 50.degree. C. Iodine (3.8 g;
15 mmoles) and then, through a rubber separator, a solution of
peracetic acid in acetic acid (8.5 ml--solution 39% w/w) were added
in 4 hours. At the end of the addition, the mixture was kept under
stirring for further 30 minutes, cooled to 20.degree. C., then a
freshly prepared 10% sodium metabisulphite solution was slowly (15
minutes). added up to decoloration of iodine (about 30 mil). The
phases were separated and the aqueous phase was washed with
isopropyl acetate (2.times.10 ml). The collected organic phases
were washed with a saturated sodium chloride aqueous solution (10
ml). After separation of the phases, the organic phase was dried on
sodium sulphate, filtered and the solvent was removed under reduced
pressure obtaining crude 2-nitro-3,4-dihydronaphthalene (4.7 g; 73%
yield) as a brown oil.
M.sup.+=175
EXAMPLE 2
[0059] Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic
acid amide
[0060] Into a reactor, equipped with a reflux condenser and under
inert gas, 8-fluoro-2H-chromene-5-carboxylic acid amide (4.94 g;
25.6 mmoles), sodium nitrite (4.4 g; 64 mmoles) and isopropyl
acetate (40 ml) were charged. The mixture was kept under mechanic
stirring and heated at 50.degree. C. In one portion iodine (1.9 g;
7.5 mmoles) and then, in 3 hours, Oxistrong 15.RTM. (6 ml) were
added. At the end of the addition the reaction mixture was kept
under stirring for 1 hour and cooled to 20.degree. C. After
addition of water (30 ml), the mixture was further cooled at
5.degree. C. for 1 hour. The solid was filtered and washed with
isopropyl acetate (3.times.10 ml), pre-cooled at 0.degree. C., and
with water (2.times.10 ml). After drying in oven under vacuum at
50.degree. C. overnight, 8-fluoro-3-nitro-2H-chromene-5-carboxylic
acid amide (4.7 g; HPLC titre 90%; 70% yield) was obtained. The
mother liquors of the reaction were treated with a 15% solution of
sodium metabisulphite (20 ml) up to decoloration. The phases were
separated the organic phase was dried and the organic solvent was
removed under reduced pressure, obtaining a solid (0.8 g)
containing 49% of 8-fluro-3-nitro-2H-chromene-5- -carboxylic acid
amide. Overall yield: 76.4%
EXAMPLE 3
[0061] Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic
acid amide
[0062] Into a reactor, equipped with a mechanic stirrer and a
reflux condenser, 8-fluoro-2H-chromene-5 carboxylic acid amide (3.1
g; 15 mmoles), sodium nitrite (3.1 g; 45 mmoles) and toluene, (30
ml) were charged at room temperature and under inert gas. The
mixture was heated under stirring at 50.degree. C., then iodine
(1.9 g, 7.5 mmoles) and, slowly in 4 hours, Oxistrong 15.RTM. (3.7
ml) were added. At the end of the addition the reaction mixture was
kept under siring for a further hour, then cooled to 0.degree. C. A
20% solution of sodium metabisulphite (about 15 ml) was added and
the mixture was kept under stirring for 1 hour. After filtration
the solid was washed with water (2.times.10 ml) and with toluene
(10 ml) and dried in oven under vacuum at 50.degree. C. overnight
obtain 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (3.4 g;
titre 78%; 74% yield).
EXAMPLE 4
[0063] Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic
acid methyl ester
[0064] Into a reactor, equipped with mechanic stirrer and reflux
condenser, 8-fluoro-2H-chromene-5-carboxylic acid methyl ester (6.6
g; 30 mmoles), sodium nitrite (6.2 g; 90 mmoles) and ethyl acetate
(60 ml) were added at room temperature and under inert gas. The
mixture was heated under stirring at 50.degree. C., then iodine
(2:6 g; 10 mmoles) and, slowly in 4 hours, Oxistrong 15.RTM. (7.4
ml) were added. At the end of the addition the reaction mixture was
kept under stirring for a further hour, then cooled at 0.degree. C.
A 20% solution of sodium metabisulphite (about 25 ml) was added and
the mixture was kept under stirring for 1 hour. After filtration
the solid was washed with water (2.times.10 ml). The mother liquors
were separated and, the previously filtered solid was added to the
organic phase. The solvent was removed under reduced pressure and
the semisolid residue was taken up with methanol (about 10 ml) and
kept under stirring at 0.degree. C. for 1 hour. After filtration
and wash of the panel with methanol pre-cooled at 0.degree. C. (3
ml), the resultant solid was dried in oven under vacuum at
40.degree. C. overnight obtaining
8-fluoro-3-nitro-2H-chromene-5-carboxylic acid methyl ester (4.6 g;
titre 92%; 55% yield). The mother liquors were evaporated to
dryness obtaining an oil (2.7 g) containing 55% of
8-fluoro-3-nitro-2H-chromene-5-carboxylic acid methyl ester.
Overall yield 75%.
EXAMPLE 5
[0065] Preparation of 8-fluoro-3-nitro-2-chromene-5-carboxylic acid
amide
[0066] Into a reactor, equipped with a mechanic stirrer and a
reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (2
g; 10 mmoles), sodium nitrite (1.4 g; :20 mmoles), potassium iodide
(0.33 g; 2 mmoles) and ethyl acetate (20 ml) were charged at room
temperature and under inert gas. The mixture was heated at
40.degree. C., then Oxistrong 15.RTM. (4 ml) was added in 4 hours.
At the end of the addition the reaction mixture was kept under
stirring for 1.5 hours, then cooled at 20.degree. C. and diluted
with ethyl acetate up to complete dissolution (about 150 ml). After
washing with a 20% sodium metabisulphite solution, the phases were
separated. The organic phase was washed with a saturated sodium
chloride solution, dried and the solvent was removed under reduced
pressure, obtaining 8-fluoro-3-nitro-2-chromene-5-carboxylic acid
amide (1.8 g; titre 88%; 66% yield).
EXAMPLE 6
[0067] Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic
acid amide
[0068] Into a reactor, equipped with a mechanic stirrer and a
reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (120
g; 0.609 moles), sodium nitrite (96.6 g; 1.4 moles), iodine (31.2
g; 0.123 moles) and ethyl acetate (720 ml) were charged at room
temperature and under inert gas. The mix was heated under stirring
at 40.degree. C., then Oxistrong 156 (173.4 g) was added in 4
hours. At the end of the addition the reaction mixture was kept
under stirring for 1 hour, then cooled at 20.degree. C. Water (480
ml) was added and the mixture was kept under stirring for 1 hour.
After filtration and wash of the panel with isopropyl acetate
pre-cooled at 0.degree. C. (2.times.120 ml) and then with water
(150 ml), the solid was dried in oven under vacuum at 50.degree. C.
overnight obtaining 8-fluoro-3-nitro-chromene-5-carboxylic acid
amide (112.7 g; titre 91%; 70% yield).
* * * * *