US20040006248A1 - Process for the preparation of nitroalkenes - Google Patents
Process for the preparation of nitroalkenes Download PDFInfo
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- US20040006248A1 US20040006248A1 US10/311,319 US31131902A US2004006248A1 US 20040006248 A1 US20040006248 A1 US 20040006248A1 US 31131902 A US31131902 A US 31131902A US 2004006248 A1 US2004006248 A1 US 2004006248A1
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- 0 */C(=C/[1*])C1=CC=CC=C1.[2*]C.[3*]C.[4*]C Chemical compound */C(=C/[1*])C1=CC=CC=C1.[2*]C.[3*]C.[4*]C 0.000 description 11
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Definitions
- 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 ⁇ -nitroalkenes by reaction of a conjugated alkene with a nitrite in the presence of iodine and of an oxidising agent.
- Conjugated ⁇ -nitroalkenes are widely used synthetic intermediates because they can be easily converted into a variety of different compounds. For example, we can cite ⁇ -nitrostyrene, useful intermediate for the preparation of several phenylethylamines and fungicides (Chemical Abstracts, vol. 118, no.
- 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.
- Jew et al. replace silver nitrite with sodium nitrite and use 2 moles of iodine and 4 moles of nitrite per mole of styrene, respectively.
- 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.
- object of the present invention is a process for the nitration of conjugated alkenes of formula
- R is a hydrogen atom, an optionally substituted phenyl, a linear or branched C 1 -C 4 alkyl
- R 1 is a hydrogen atom or a linear or branched C 1 -C 4 alkyl, optionally substituted by an OH or C 1 -C 4 alkoxy group
- R 2 , R 3 and R 4 are selected among hydrogen and halogen atoms, linear or branched C 1 -C 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 2 , R 3 and R 4 , in ortho between them, form a methylendioxy group; or R 1 together with R 2 forms a cyclic system with 5-7 terms conden
- the nitrating agent is a mixture of an inorganic nitrite and iodine in the presence of an oxidising agent.
- the nitration process object of the present invention allows to obtain ⁇ -nitroalkenes under mild conditions with good yields.
- linear or branched C 1 -C 4 alkyl means an alkyl selected among methyl, ethyl, n-propyl, isopropyl n-butyl sec-butyl isobutyl and t-butyl;
- linear or branched C 1 -C 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.
- Substituted phenyl means a phenyl substituted by one or more substituents selected among the meanings of R 2 , R 3 and R 4 .
- 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.
- R 3A and R 4A 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;
- R 3B and R 4B are hydrogen atoms, methoxy, methyl, ethyl, fluoro, chloro, bromo, iodo, carboxy, methoxycarbonyl, aminocarbonyl or methylaminocarbonyl groups; R has the already reported meanings;
- R, R 3A , R 3B , R 4A and R 4B have the already reported meanings.
- Examples of inorganic nitrites which can be used in the process object of the present invention are silver nitrite, sodium nitrite and potassium nitrite.
- 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.
- nitrite from 2 and 4 moles per mole of compound of formula I is used.
- the most characterizing feature of the present process is represented by the amount of iodine which is used.
- 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.
- the oxidation agent is slowly added, usually in 34 hours, to the reaction mixture containing the nitrite, iodine and the compound of formula I.
- AlkH represents the compound of formula I
- 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.
- 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.
- the oxidising agent must be used in an acid environment, preferably at a pH lower than 5.
- the amount of oxidant will be in relation to the used amount of iodine, preferably in slight excess.
- 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.
- 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
- ethers such as tert-butyl methyl ether.
- reaction mixture contains water
- addition of a phase transfer catalyst can be. useful.
- the temperature is not a critical parameter. Preferably temperatures from 20° C. to 70° C. are used. A still more preferred temperature range is from 40° C. to 50° C.
- a preferred embodiment of the process object of the present invention is the following.
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Abstract
A process for the nitration of conjugated alkenes of formula (I) wherein R, R1, R2, R3 and R4 have the meanings reported in the description, which allows to obtain the corresponding β-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.
Description
- 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 β-nitroalkenes by reaction of a conjugated alkene with a nitrite in the presence of iodine and of an oxidising agent. Conjugated β-nitroalkenes are widely used synthetic intermediates because they can be easily converted into a variety of different compounds. For example, we can cite β-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-chroman-5carboxylic acid amide, a compound useful in the treatment of disorders of the central nervous system (WO 98/46586-Astra Aktiebolag).
- 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].
- The method foresees the use of a mixture of silver nitrite and iodine as nitrating agent.
- After the paper of Hassner et al., some papers were published with the attempt of improving the nitration conditions.
- 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.
- 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.
- 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.
- 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.
-
- wherein
- R is a hydrogen atom, an optionally substituted phenyl, a linear or branched C1-C4 alkyl; R1 is a hydrogen atom or a linear or branched C1-C4 alkyl, optionally substituted by an OH or C1-C4 alkoxy group; R2, R3 and R4, the same or different, are selected among hydrogen and halogen atoms, linear or branched C1-C4 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 R2, R3 and R4, in ortho between them, form a methylendioxy group; or R1 together with R2 forms a cyclic system with 5-7 terms condensed with the aromatic ring and optionally containing an oxygen atom; or R1 together with R forms a cyclic system with 5-7 terms;
-
- wherein R, R1, R2, R3 and R4 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.
- The nitration process object of the present invention allows to obtain β-nitroalkenes under mild conditions with good yields.
- In the present context, unless otherwise specified, linear or branched C1-C4 alkyl means an alkyl selected among methyl, ethyl, n-propyl, isopropyl n-butyl sec-butyl isobutyl and t-butyl; linear or branched C1-C4 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.
- Substituted phenyl means a phenyl substituted by one or more substituents selected among the meanings of R2, R3 and R4.
- 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.
- The compounds of formula I used in the nitration process object of the present invention are known.
- 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.
-
- wherein
- R3A and R4A, 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;
-
- wherein
- R3B and R4B, 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;
-
- and of formula
- wherein R, R3A, R3B, R4A and R4B have the already reported meanings.
- Examples of inorganic nitrites which can be used in the process object of the present invention are silver nitrite, sodium nitrite and potassium nitrite.
- Preferably sodium nitrite is used.
- 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.
- Preferably an amount of nitrite from 2 and 4 moles per mole of compound of formula I is used.
- The most characterizing feature of the present process is represented by the amount of iodine which is used.
- 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.
- 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.
- 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).
- In fact by working according to the method object of the present invention the nitroderivatives is obtained with a practically triplicate yield.
- 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.
- 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+NaNO2+l2→AlkNO2+Hl+Nal
- wherein AlkH represents the compound of formula I,
- so forming an amount of iodine which is sufficient to go on with the nitration reaction.
- 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.
- 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.
- 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.
- The oxidising agent must be used in an acid environment, preferably at a pH lower than 5.
- 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.
- 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.
- The use of a mixture of peracetic acid, oxygen peroxide, acetic acid and water, already available on the market (Oxistrong®-Ausimont) is particularly advantageous.
- 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.
- 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.
- When the reaction mixture contains water, the addition of a phase transfer catalyst can be. useful.
- Also the temperature is not a critical parameter. Preferably temperatures from 20° C. to 70° C. are used. A still more preferred temperature range is from 40° C. to 50° C.
- A preferred embodiment of the process object of the present invention is the following.
- 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.
- In order to better illustrate the present invention the following examples are now given.
- Preparation of 2-nitro-3.4 dihydronaphthalene
- 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° 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° 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 (2×10 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 +=175
- Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide
- 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° C. In one portion iodine (1.9 g; 7.5 mmoles) and then, in 3 hours, Oxistrong 15® (6 ml) were added. At the end of the addition the reaction mixture was kept under stirring for 1 hour and cooled to 20° C. After addition of water (30 ml), the mixture was further cooled at 5° C. for 1 hour. The solid was filtered and washed with isopropyl acetate (3×10 ml), pre-cooled at 0° C., and with water (2×10 ml). After drying in oven under vacuum at 50° 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%
- Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide
- 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° C., then iodine (1.9 g, 7.5 mmoles) and, slowly in 4 hours, Oxistrong 15® (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° 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 (2×10 ml) and with toluene (10 ml) and dried in oven under vacuum at 50° C. overnight obtain 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (3.4 g; titre 78%; 74% yield).
- Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid methyl ester
- 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° C., then iodine (2:6 g; 10 mmoles) and, slowly in 4 hours, Oxistrong 15® (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° 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 (2×10 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° C. for 1 hour. After filtration and wash of the panel with methanol pre-cooled at 0° C. (3 ml), the resultant solid was dried in oven under vacuum at 40° 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%.
- Preparation of 8-fluoro-3-nitro-2-chromene-5-carboxylic acid amide
- 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° C., then Oxistrong 15® (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° 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).
- Preparation of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide
- 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° 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° 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° C. (2×120 ml) and then with water (150 ml), the solid was dried in oven under vacuum at 50° C. overnight obtaining 8-fluoro-3-nitro-chromene-5-carboxylic acid amide (112.7 g; titre 91%; 70% yield).
Claims (15)
1) A process for the nitration of conjugated alkenes of formula
wherein
R is a hydrogen atom, an optionally substituted phenyl, a linear or branched C1-C4 alkyl; R1 is a hydrogen atom or a linear or branched C1-C4 alkyl, optionally substituted by an OH or C1-C4 alkoxy group; R2, R3 and R4, the same or different, are selected among hydrogen and halogen atoms, linear or branched C1-C4 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 R2, R3 and R4, in ortho between them, form a methylendioxy group; or R1 together with R2 forms a cyclic system with 5-7 terms condensed with the aromatic ring and optionally containing an oxygen atom; or R1 together with R forms a cyclic system with 5-7 terms;
which allows to obtain β-nitro-alkenes of formula
wherein R, R1, R2, R3 and R4 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° C. to 50° 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
wherein
R3A and R4A, 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 C1-C4 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
wherein
R3B and R4B, 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 C1-C4 alkyl.
15) A process according to claim 13 for the nitration of the compound 8-fluoro-2H-chromene-5-carboxylic acid amide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US11/247,600 US7265251B2 (en) | 2000-06-28 | 2005-10-12 | Process for the preparation of nitroalkenes |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP00830453 | 2000-06-28 | ||
EP00830453.7 | 2000-06-28 | ||
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AT (1) | ATE289986T1 (en) |
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Cited By (12)
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US20100331268A1 (en) * | 2004-04-28 | 2010-12-30 | The Uab Research Foundation | Nitrated Lipids and Methods of Making and Using Thereof |
US8563609B2 (en) | 2010-05-13 | 2013-10-22 | Nitromega Corp. | Nitro fatty acids - neuroprotection and/or inhibition of cognitive decline |
US9585855B2 (en) | 2008-06-19 | 2017-03-07 | The University Of Utah Research Foundation | Use of nitrated lipids for treatment of side effects of toxic medical therapies |
US9663444B2 (en) | 2009-10-02 | 2017-05-30 | Complexa, Inc. | Heteroatom containing substituted fatty acids |
US9700534B2 (en) | 2007-08-01 | 2017-07-11 | University of Pittsburgh—of the Commonwealth System of Higher Education | Nitrated-fatty acids modulation of type II diabetes |
US9750725B2 (en) | 2009-07-31 | 2017-09-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fatty acids as anti-inflammatory agents |
US9790167B2 (en) | 2008-05-01 | 2017-10-17 | Complexa, Inc. | Vinyl substituted fatty acids |
US10010532B2 (en) | 2011-08-19 | 2018-07-03 | The University Of Utah Research Foundation | Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system |
US10369125B2 (en) | 2008-06-19 | 2019-08-06 | The University Of Utah Research Foundation | Method of treating renal system damage |
US10537541B2 (en) | 2015-10-02 | 2020-01-21 | Complexa Inc. | Treatment of focal segmental glomerular sclerosis (FSGS) using therapeutically effective oral doses of 10-nitro-9(E)-octadec-9-enoic acid |
US11608342B2 (en) | 2015-07-07 | 2023-03-21 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
US12006319B2 (en) | 2018-05-25 | 2024-06-11 | Cardurion Pharmaceuticals, Inc. | Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one |
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BR112012009107B1 (en) | 2009-10-20 | 2019-08-27 | Angus Chemical | process for synthesizing at least one nitroalkane and apparatus for synthesizing at least one nitroalkane |
FR2985999B1 (en) | 2012-01-23 | 2014-01-31 | Arkema France | PROCESS FOR THE PRODUCTION OF 2-OCTYL ACRYLATE BY TRANSESTERIFICATION |
CN105152935A (en) * | 2015-09-06 | 2015-12-16 | 安徽理工大学 | Method for preparing beta-nitrostyrolene compound |
CN106995372B (en) * | 2017-05-17 | 2018-12-18 | 沅江华龙催化科技有限公司 | A method of (E)-beta-nitrostyrene derivative is catalyzed and synthesized based on tetaraary porphyrin iron |
CN106995373B (en) * | 2017-05-17 | 2019-01-11 | 沅江华龙催化科技有限公司 | Using ammonium iodide as nitro source one-pot synthesis α, β-unsaturation nitroolefin derivative method |
CN107032939B (en) * | 2017-05-17 | 2020-09-11 | 沅江华龙催化科技有限公司 | Synthetic method of alpha, beta-unsaturated nitroolefin derivative |
CN107098811B (en) * | 2017-05-17 | 2019-03-26 | 沅江华龙催化科技有限公司 | (E)-beta-nitrostyrene synthetic method |
CN109970701B (en) * | 2019-04-02 | 2021-05-04 | 常州大学 | By using I2O5/NaNO2Process for nitrating electron-rich aromatic compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9701438D0 (en) * | 1997-04-17 | 1997-04-17 | Astra Ab | A new process |
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2001
- 2001-06-19 CA CA2412232A patent/CA2412232C/en not_active Expired - Lifetime
- 2001-06-19 AT AT01956483T patent/ATE289986T1/en active
- 2001-06-19 US US10/311,319 patent/US20040006248A1/en not_active Abandoned
- 2001-06-19 PT PT01956483T patent/PT1294658E/en unknown
- 2001-06-19 DK DK01956483T patent/DK1294658T3/en active
- 2001-06-19 ES ES01956483T patent/ES2239155T3/en not_active Expired - Lifetime
- 2001-06-19 EP EP01956483A patent/EP1294658B1/en not_active Expired - Lifetime
- 2001-06-19 WO PCT/EP2001/006902 patent/WO2002000575A1/en active IP Right Grant
- 2001-06-19 JP JP2002505326A patent/JP4705307B2/en not_active Expired - Fee Related
- 2001-06-19 CN CNB018116868A patent/CN1232480C/en not_active Expired - Fee Related
- 2001-06-19 DE DE60109163T patent/DE60109163T2/en not_active Expired - Lifetime
- 2001-06-19 AU AU2001278456A patent/AU2001278456A1/en not_active Abandoned
-
2005
- 2005-10-12 US US11/247,600 patent/US7265251B2/en not_active Expired - Fee Related
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US10869850B2 (en) | 2007-08-01 | 2020-12-22 | University of Pittsburgh—of the Commonwealth System of Higher Education | Nitrated-fatty acids modulation of type II diabetes |
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US10258589B2 (en) | 2007-08-01 | 2019-04-16 | University of Pittsburgh—of the Commonwealth System of Higher Education | Nitrated-fatty acids modulation of type II diabetes |
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US10369125B2 (en) | 2008-06-19 | 2019-08-06 | The University Of Utah Research Foundation | Method of treating renal system damage |
US10568857B2 (en) | 2008-06-19 | 2020-02-25 | The University Of Utah Research Foundation | Method of treating renal system damage |
US10835518B2 (en) | 2009-07-31 | 2020-11-17 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fatty acids as anti-inflammatory agents |
US10213417B2 (en) | 2009-07-31 | 2019-02-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fatty acids as anti-inflammatory agents |
US9750725B2 (en) | 2009-07-31 | 2017-09-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fatty acids as anti-inflammatory agents |
US11723897B2 (en) | 2009-07-31 | 2023-08-15 | University of Pittsburgh—of the Commonwealth System of Higher Education | Fatty acids as anti-inflammatory agents |
US9663444B2 (en) | 2009-10-02 | 2017-05-30 | Complexa, Inc. | Heteroatom containing substituted fatty acids |
US8563609B2 (en) | 2010-05-13 | 2013-10-22 | Nitromega Corp. | Nitro fatty acids - neuroprotection and/or inhibition of cognitive decline |
US10709690B2 (en) | 2011-08-19 | 2020-07-14 | The University Of Utah Research Foundation | Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system |
US10010532B2 (en) | 2011-08-19 | 2018-07-03 | The University Of Utah Research Foundation | Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system |
US11608342B2 (en) | 2015-07-07 | 2023-03-21 | H. Lundbeck A/S | PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases |
US10537541B2 (en) | 2015-10-02 | 2020-01-21 | Complexa Inc. | Treatment of focal segmental glomerular sclerosis (FSGS) using therapeutically effective oral doses of 10-nitro-9(E)-octadec-9-enoic acid |
US12006319B2 (en) | 2018-05-25 | 2024-06-11 | Cardurion Pharmaceuticals, Inc. | Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one |
Also Published As
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DE60109163D1 (en) | 2005-04-07 |
JP4705307B2 (en) | 2011-06-22 |
PT1294658E (en) | 2005-07-29 |
CA2412232C (en) | 2010-03-30 |
DK1294658T3 (en) | 2005-06-27 |
WO2002000575A1 (en) | 2002-01-03 |
ES2239155T3 (en) | 2005-09-16 |
ATE289986T1 (en) | 2005-03-15 |
CN1438977A (en) | 2003-08-27 |
CA2412232A1 (en) | 2002-01-03 |
CN1232480C (en) | 2005-12-21 |
US7265251B2 (en) | 2007-09-04 |
DE60109163T2 (en) | 2006-04-13 |
US20060063953A1 (en) | 2006-03-23 |
JP2004501878A (en) | 2004-01-22 |
AU2001278456A1 (en) | 2002-01-08 |
EP1294658A1 (en) | 2003-03-26 |
EP1294658B1 (en) | 2005-03-02 |
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