Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-23
2002-01-29
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S430000, C549S445000
Reexamination Certificate
active
06342613
ABSTRACT:
FIELD OF THE INVENTION
The present invention regards the field of synthesis of benzodioxols, with particular in the perfumery industry and in the sector of insecticides.
PRIOR ART
Various biologically active natural substances, such as flavones and alkaloids contain the methylene dioxy-1,2-benzene (also known as benzo[1,3]dioxol) group. For example, derivatives of benzo[1,3]dioxol are used in the treatment of liver disorders (Chem. Abstracts, 1990, 452534).
The most widespread applications of these derivatives are, however, those in the field of perfumery, flavouring, and insecticides. Compounds having insecticidal action containing the benzo[1,3]dioxol group have been described in various publications (e.g., Bull. Soc. Chim. France, 1964,1892-1895). 5-(2-propenyl)-benzo[1,3]dioxol (safrole) is a constituent of many essential oils among which oil of sassafras, of which it constitutes approximately 75%. (Oswald et al., Biochim. Biophys. Acta 230, 237 (1971).).
5-(1-propenyl)-benzo[1,3]dioxcl (isosafrole), is an essence used in perfumery and as a deodorant for soaps; isosafrole is in turn used in the synthesis of piperonal (heliotropin, benzo[1,3]dioxol-5-carboxyaldehyde), another essence used industrially for producing perfumes and aromas.
Likewise, also 5-hydroxymethyl-benzo[1,3]dioxol (piperonyl alcohol) and its derivatives are of considerable industrial interest in the sectors cited above. The present invention meets the need of identifying effective methods for the synthesis of piperonyl alcohol and its derivatives.
The prior art describes a number of processes having this purpose. The most widely used method consists in reacting an aldehyde of formula
with Grignard reagents, (alkylmagnesium bromides), to obtain benzodioxol derivatives substituted in position 5 with an a-hydroxyalkyl group (see, for example, U.S. Pat. No. 3946040). The same compounds may be obtained starting from 5-keto-substituted derivatives of benzo[1,3]dioxol (DE-A-2210374).
The above processes of synthesis, albeit useful from the analytical standpoint, present significant limitations as regards their industrial applicability. These reactions, in fact, call for the availability of products already containing the benzodioxol cycle: such products are far from being readily available and are very costly. In addition, Grignard reactions are carried out with reagents and anhydrous solvents that are highly unstable and difficult to handle (e.g., magnesium, ethyl ether, tetrahydrofuran), so entailing the adoption of costly safety precautions for the production plants.
Selective acylation, as a means for introducing substituents on the benzodioxol cycle, has so far proved difficult to apply industrially in view of the low yields and the difficulty of purification of the acylated product; for example, in WOA-9639133 the acylated benzodioxol was difficult to purify and involved repeated treatments of decolourization. Other authors have obtained selective acylation of benzodioxols using costly solutions, such as passing the product over a bed of zeolite catalysts (J. Chem. Soc. Chem. Commun., 1994, 717). In view of the limitations pointed out, the need is felt for an effective process for the production of 5-hydroxyalkylbenzodioxols. In particular, a process is sought which is industrially applicable on a wide scale and which may be carried out with reactions that are easy to apply and with a low environmental impact. Finally, the need is felt for a synthetic process that uses as reagents products which are readily available and of low cost.
SUMMARY
The present invention regards a three-step process for the synthesis of 5-(&agr;-hydroxyalkyl)benzo[1,3]dioxols. The process comprises: (i) the reaction of pyrocatechin (1,2-dihydroxybenzene) with a dihalo or di-alkoxyalkane, with the formation of a benzo[1,3]dioxol derivative; (ii) 5-selective catalytic acylation of the benzo[1,3]dioxol derivative, with formation of a 5-alkanoylbenzo[1,3]dioxol and its subsequent (iii) reduction to 5-(&agr;-hydroxyalkyl)benzo[1,3]dioxol. Also described are new benzodioxols obtainable using the above-mentioned process. The process of the invention is industrially simple and has low environmental impact; it allows to obtain in high yields derivatives of considerable interest, in particular for the perfumery industry, and in the sector of insecticides.
DETAILED DESCRIPTION OF THE INVENTION
The subject of the present invention is a new process for the synthesis of 5-(&agr;-hydroxyalkyl)benzo[1,3]dioxols. The process comprises the following steps:
a) reacting 1,2-dihydroxybenzene (pyrocatechin) (I) in a dipolar aprotic solvent, at a temperature comprised between 70° C. and 190° C., with a compound of formula (II), where R
1
is chosen from H, and a C
1
-C
3
linear or branched alkyl, and X is chosen from chlorine, fluorine, bromine, iodine, and a C
1
-C
5
linear or branched alkoxy, obtaining the product of formula (Ill), where R
1
has the meanings described above.
b) Reacting the compound (III) with an aliphatic anhydride of formula (IV) or with an aliphatic acid of formula (V), where R
2
is a C
1
-C
19
linear or branched alkyl, in the presence of an acylation catalyst, obtaining a compound of formula (VI), where R
1
and R
2
have the aforesaid meanings.
c) Reducing of the compound (VI), obtaining the 5-(&agr;-hydroxyalkyl)benzo[1,3]dioxol of formula (VII)
Reaction a) is carried out in dipolar aprotic solvents. Preferred solvents of this type are N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulphoxide. The temperature of the reaction is that of reflux of the reaction mixture, and is generally between 70° C. and 190° C. In the case where N,N-dimethylformamide is used as reaction solvent, this temperature is generally between 110° C. and 150° C., or more preferably between 110° C. and 130° C. Reaction a) may be carried out in the presence of an iodine salt. In this case, the salt is preferably chosen from among Lil, Nal, KI, Cal
2
.
The choice of the reagent of formula (II) to be used in reaction a)/depends upon the nature of the final product (VII) that is to be synthesized: if the aim is to obtain benzo[1,3]dioxols not substituted in position 2, reagents of formula (II) will be chosen in which R
1
=H . Examples of such products are methylene chloride and dimethoxymethane. If the aim is to obtain benzo[1,3]dioxols alkyl-substituted in position 2, the reagent of formula (II) will be chosen in which R
1
is the same as the alkyl radical that it is intended to introduce on the benzodioxol ring. Appropriate R
1
radicals are methyl, ethyl, n-propyl, and isopropyl.
As has been seen above, the reagent of formula (II) contains two X=halogen groups or else two X=C
1
-C
5
alkoxy groups, either linear or branched. If derivatives of formula (II) are used, where X=halogen, reaction a) is carried out in the presence of an inorganic base, preferably chosen from among NaOH, KOH, Na
2
CO
3
, and K
2
CO
3
. The inorganic bases of a solid nature (e.g., carbonates) are preferably added to the reaction mixture in a finely ground form.
In the case where derivatives of formula (II) are used, where X=C
1
-C
5
linear or branched alkoxy, reaction a) is carried out in the presence of a transesterification catalyst, preferably chosen from among CH
3
ONa, C
2
H
5
ONa, (C
4
H
9
)
2
SnO, and Ti (OC
4
H
9
)
4
.
Various ways of mixing the aforesaid reagents are possible.
In a preferred embodiment, reaction a) is carried out as follows: Compound (II) is mixed with the dipolar aprotic solvent and with the inorganic base (or transesterification catalyst). To the resulting mixture, heated up to the reflux temperature, pyrocatechin is then added. This addition is preferably made by dripping a liquid mixture obtained by mixing pyrocatechin, derivative (II) and dipolar aprotic solvent.
The mixture thus obtained is heated up to reflux for a period of betw
Borzatta Valerio
Brancaleoni Dario
Abelman ,Frayne & Schwab
Endura S.p.A.
Higel Floyd D.
Shameem Golam M. M.
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