Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrate esters or chalcogen analogues thereof
Reexamination Certificate
2002-01-09
2004-02-24
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrate esters or chalcogen analogues thereof
C548S577000
Reexamination Certificate
active
06696591
ABSTRACT:
The present invention relates to a process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivatives.
It is known in the prior art that the (nitroxymethyl)phenyl esters of the salicylic acid derivatives can be prepared by various synthesis processes. In the patent application WO 97/16405 the reaction of the acyl chloride of the acetylsalicylic acid with (nitroxymethyl)phenol is described. The (nitroxymethyl)phenol is prepared by a synthesis which comprises the following steps:
reaction of the phenol with HBr in organic solvent to obtain (bromomethyl)phenol, and
reaction of the (bromomethyl)phenol in organic solvent with AgNO
3
with formation of (nitroxymethyl)phenol
The process based on the reaction between (nitroxymethyl)phenol and the acyl chloride of the acetylsalicylic acid shows the following drawbacks:
the (bromomethyl)phenol obtained in the first synthesis step is a chemically unstable and irritating compound;
the nitrating agent used in the reaction with (bromomethyl)phenol is a very expensive reactant;
the (nitroxymethyl)phenol is an unstable compound, which can easily decompose in an uncontrollable way; and it must be purified before the reaction with the acetylsalicylic acid chloride, furtherly increasing the production costs and requiring supplementary units in the production plant.
In conclusion the synthesis of above derivatives, by using the intermediate (nitroxymethyl)phenol, is difficult and expensive to be carried out on an industrial scale.
In PCT Patent EP 00/00353 in the name of the Applicant a synthesis process of nitroxy derivatives of formula (I) (see hereunder) is described, by submitting to nitration with AgNO
3
(hydroxymethyl)phenyl esters of the acetylsalicylic acid, obtained by reacting the acid chloride with hydroxybenzaldehyde and reducing the aldehydic group to primary alcohol. Also this process, as the above mentioned uses silver nitrate as nitrating agent and therefore it is not much advantageous from an industrial point of view. Besides the process global yields are not high.
By using the teaching of the prior art, it is possible to obtain the salicylic acid nitroxyderivatives of formula (I) (see below) by reacting a (hydroxymethyl)phenyl ester of the acetylsalicylic acid with nitrating reactants based on nitric acid. However under the reaction conditions of the prior art the nitric acid produces undesired reactions, such as for example the nitration of aromatic substrata (ref. “Nitration: Methods and Mechanism”, 1984 VCH ed., p. 269) and the oxidation of primary alcohols to aldehydes (ref. “Industrial and Laboratory Nitration” 1976 ACS publ., p. 156).
Therefore also said processes of the prior art are unable to solve the problem of the preparation on industrial scale of the nitroxyderivatives of the salicylic acid as above defined.
The need was felt to prepare nitroxy derivatives of (hydroxymethyl)phenyl esters of the acetylsalicylic acid by a process cheaper than those of the prior art both for the nitrating agent used and for the yields, and substantially without the drawbacks of the prior art.
An object of the present invention is a process for obtaining (nitroxymethyl)phenyl esters of the salicylic acid derivatives, compounds having the following formula (I):
wherein:
R
1
is the OCOR
3
group; wherein R
3
is methyl, ethyl or linear or branched C
3
-C
5
alkyl, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, containing hetero-atoms independently selected between O and N;
R
2
is hydrogen, halogen, linear or branched when possible C
1
-C
4
alkyl, linear or branched when possible C
1
-C
4
alkoxyl; linear or branched when possible C
1
-C
4
perfluoroalkyl, for example trifluoromethyl; mono- or di-(C
1
-C
4
)alkylamino;
preferably in (I) R
1
is acetoxy and is in ortho position with respect to the carboxylic group, R
2
is hydrogen; the oxygen of the ester group is bound to the aromatic ring substituted with the (nitroxy)methylene group in ortho, meta or para position with respect to the (nitroxy)methylene group; preferably the position is the meta one;
said process comprising the following steps:
a) reaction of a halide of a salicylic acid derivative of formula (I-A):
wherein Hal═Cl, Br, and K and R
1
and R
2
have the above indicated meaning, with hydroxybenzylalcohol in the presence of a base, in an organic solvent, or in a mixture of water with a miscible or immiscible organic solvent with water, to give the compound (I-B) having the following formula:
wherein R
1
and R
2
are as above defined;
b) nitration of the compound (I-B) in anhydrous conditions, in an inert organic solvent, by a mixture formed by steaming nitric acid with an inorganic acid different from nitric acid or with an organic acid, or with the anhydride of one or two organic acids, to give the nitroxyderivative of formula (I).
c) recovery of the final product by adding water to the organic phase, separating the phases, drying and evaporating the organic phase.
In step a) the base can be an inorganic base, such as for example hydroxides, oxides, carbonates and bicarbonates of alkaline metals (sodium, potassium, lithium); or an organic base, for example a tertiary amine, for example aliphatic, cycloaliphatic, heterocyclic, heterocyclic aromatic, such as triethylamina, diisopropyl-ethylamine, N-methylmorpholine, diazaabicyclooctane, etc.
The organic solvent used in step a) can be an organic solvent miscible with water such as C
1
-C
4
aliphatic alcohols, for example methanol, ethanol, isopropanol, n-butanol; or an organic solvent immiscible with water for example aromatic hydrocarbons such as toluene and xylene, chlorinated organic solvents such as methylene chloride, chlorobenzene, other solvents which can be used are aliphatic esters for example of C
1
-C
4
acids with C
1
-C
5
alcohols such as for example ethyl acetate and butyl acetate, etc.: aliphatic and cycloatiphatic ketones, such as C
3
-C
12
for example acetone, methylketone, cyclohexanone, etc.
In step a) the reaction is carried out at a temperature in the range −20° C., and +50° C., preferably 0° C.-20° C., by using, with respect to the hydroxybenzylalcohol moles under reaction, an amount by moles of acid halide (I-A) in a ratio between 1 and 2, preferably between 1.2 and 1.5, and an amount by moles of base between 0.1 and 2, preferably between and 2.
The compound I-B) is recovered from the reaction mixture by addition of water and optionally, when the reaction takes place in an aqueous solvent or in a mixture of water with an hydrosoluble organic solvent, by addition of an organic solvent immiscible with water, such as ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried, evaporated and the product is recovered. If necessary, the compound can be purified by crystallization from solvents such as for example n-hexane, n-heptane, ligroin, toluene, methanol, isopropanol, diisopropylether, etc or their mixtures. Generally the yields are higher than 80%.
In step b) the nitration reaction is carried out at a temperature in the range −20° C. and +40° C., preferably from 0° C. to 20° C.; the used amount by moles of nitric acid is in a ratio between 1 and 6, preferably 1 and 3, with respect to the moles of the hydroxyester (I-B); the amount by moles of organic or inorganic acid different from nitric acid, or of anhydride as above defined, is in a ratio comprised between 0.5 and 6, preferably between 1 and 3 with respect to the moles of the compound (I-B).
The inorganic acid different from nitric acid is for example sulphuric acid; the organic acid is for example methansulphonic acid, trifluoromethansulphonic acid, trifluoroacetic acid, trichloroacetic acid, acetic acid; the organic acid anhydride is for example acetic anhydride, trifluoromethansulphonic anhydride, trifluoroacetic anhydride, trichloroacetic anhydride, etc., or mixed anhydrides such as for example trifluoroacetic-trifluoromethansulphonic anhydride, etc.
The inert organic solvent used in step b) is a solvent which has boiling point lowe
Benedini Francesca
Castaldi Graziano
Oldani Erminio
Razzetti Gabriele
Arent Fox Kintner Plotkin & Kahn
Nicox S.A.
Rotman Alan L.
Saeed Kamal
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