WO2005105774A1

WO2005105774A1 - Process for the preparation of 3-(3,4-methylenedioxyphenyl)-2-methylpropanal

Info

Publication number: WO2005105774A1
Application number: PCT/EP2005/051953
Authority: WO
Inventors: Valerio Borzatta; Elisa Capparella; Elisa Poluzzi
Original assignee: Endura S.P.A.
Priority date: 2004-04-30
Filing date: 2005-04-29
Publication date: 2005-11-10
Also published as: ITMI20040873A1; CN1950355B; CN1950355A

Abstract

Process for the preparation of 3-(3,4-methylenedioxyphenyl)-2-methylpropanal (I) comprising the following steps: a) reacting 5-propanoyl-1,3- benzodioxol (III) with the Vilsmeier reagent at temperatures ranging between 0° and 40°C and subsequently treating of the reaction mixture with a base in aprotic apolar solvent to obtain the unsaturated chloroaldehyde of formula (IV); b) reacting the unsaturated chloroaldehyde of formula (IV), obtained in the previous step, with hydrogen in the presence of a supported heterogeneous catalyst containing a metal chosen amongst Pd, Pt, Rh, Ru in the presence of an organic base or of a mixture of an organic and inorganic base.

Description

PROCESS FOR THE PREPARATION OF 3-(3,4-METHYLENEDlOXYPHENYL)- 2- ETHY PROPANAL

FIELD OF THE INVENTION .

The present invention relates to a process for the preparation of 3-(3,4- methylenedioxyphenyl)-2~methylpropanal.

STATE OF THE ART

The 3-(3,4-methylenedioxyphenyl)-2-methylpropanal of formula (I)

(I) commercially known as Helional^® is a product used in fragrances, as a base for perfumes, because it gives persistence to perfumes. Various synthetic schemes for the related preparation are known.

The most commonly used synthesis envisages the aldolic condensation of 5- carboxyaldehyde-1,3-benzodioxol (heliotropin) with propionaldehyde to obtain the unsaturated aldehyde (A) that is reduced to the compound of formula (I) by catalytic hydrogenation according to the following synthetic scheme: This method, carried out on variously substituted aromatic aldehydes and different

from the aforesaid aldehydes, is described in GB 798,001, DE 3,105,446 and FR 1,496,304; however, when it is utilized in the preparation of the compound of formula (I), it leads to a series of disadvantages, such as for example the fact that yields higher than 50-55% cannot be obtained during the aldolic condensation, because of the self-condensation of the propionaldehyde and/or the reaction of the latter with the intermediate (A); the need for the use of a chemoselective catalyst under basic conditions to avoid the simultaneous reduction of the aldehydic group to alcohol during the reduction of the alkenylic bond, the need to separate by distillation the abovementioned by-products thus formed during the reduction reaction.

Another synthetic method that may be employed for the synthesis of the compound of formula (I) envisages the Heck reaction carried out on 5-bromo-1,3- benzodioxol with unsaturated alcoholic derivatives and subsequent transposition,

as reported in the following synthetic scheme.

This synthetic scheme is reported in EP 119067, US 4,070,374 and in the Journal of Organic Chemistry 41.(7), 1976. ,.

An alternative to this synthetic scheme, reported in Bull. Soc. Chem. Fr.1961,

1194-8 and in EP 43526, envisages the reaction of 1,3- benzodioxol with methacrolein diacetate and the subsequent hydrolysis of the intermediate formed to unsaturated aldehyde that is reduced to obtain the compound of formula (I), according to the following synthetic scheme:

Both the abovementioned methods, which envisage the use of catalysts that are expensive or difficult to handle such as palladium complexes in the first case, and Lewis acids such as titanium tetrachloride and boron trifluoride etherate in the second case, and of reagents such as 5-bromo-1 , 3-benzodioxol in the first case, and of methacrolein diacetate in the second case, reagents that are equally expensive, do not allow the production, in an industrial preparation process, of a compound such as that of formula (I).

The synthetic scheme reported below herein and described in US 4,435,585 envisages the reaction of 5-propanoyl-1 , 3-benzodioxol with an alcohol to obtain the corresponding ketal, subsequent carbonylation, hydrolysis and reduction reaction of the unsaturated aldehyde, according to the following synthetic scheme.

Finally, JP 1012Q674 describes the reaction of isosafrole with the Vilsmejer reagent and subsequent reduction of the unsaturated aldehyde of formula (A) to obtain the corresponding product of formula (I), according to the scheme reported here below:

The disadvantage of this process consists of the use of isosafrole, which is a component obtained by transposition from the natural safrole, obtained in turn by extraction from plants, with the limitations typical of the use of natural products. There was, therefore, the need to have a process that would be easily practicable from an industrial point of view and that would allow the obtainment of the compound of formula (I) with high yields.

In US 4,182,730 and in Organic Preparations and Procedures Int. "t4_(1-2), 9-20, 1982, a process is described for the preparation of α-aikyldihydrocinnamaldehydes from the corresponding alkylphenones or β-tetrahydronaphthalene carboxaldehydes from α-tetralones with a process that comprises the following steps: a) reaction of the abovementioned ketones with the Vilsmeier reagent formed in situ by the reaction of N,N-dimethylformamide with POCI₃ and obtainment of the corresponding unsaturated β-chloro-α-β aldehyde; b) hydrogenation with palladium on carbon in the presence of bases and obtainment of the abovementioned alkyldihydrocinnamaldehydes or tetrahydronaphthalene carboxaldehydes.

Step (a) is generally carried out at temperatures higher than 50°C, preferably between 70° and 85°C. The base used in step (b) is generally chosen amongst hydroxides of alkaline or alkaline-earth metals, carbonates of alkaline or alkaline-earth metals and amines. This process has never been employed on substrates constituted by aryl-alkyl- ketones condensed with heterocyclic rings. SUMMARY OF THE INVENTION

The Applicant has now astonishingly found that it is possible to prepare the compound of formula (I) with high yields, in the order of 90-95%, with a process that is inexpensive and easily practicable from an industrial point of view. Such process, in particular, comprises the following steps: a) reacting of 5-propanoyl-1 ,3- benzodioxol (III)

with the Vilsmeier reagent (II)

(ID at temperatures ranging between 0° and 40°C and subsequently treating the reaction mixture with a base in aprotic apolar solvent to obtain the unsaturated chloroaldehyde of formula (IV),

(IV)

b) reacting of the unsaturated chloroaldehyde of formula (IV), obtained in the previous step, with hydrogen in the presence of a supported heterogeneous catalyst containing a metal selected from Pt, Pd, Rh, Ru and in the presence of an organic base or in the presence of a mixture of an organic and inorganic base. The Applicant has in fact astonishingly found that step (a) must be carried out at temperatures not higher than 40^DC, otherwise the compound of formula (V) is obtained A further advantage of the process object of the present invention consists of the

(V) use, as the reagent, of the ketone of formula (III), easily obtainable from 1,3- benzodioxoJ, in turn a commercial product, by Friedel-Crafts acylation, as for example described in US 6,342,613.

Further object of the invention is the intermediate of formula (IV).

DESCRIPTION OF THE FIGURES Figure 1 represents the GC-MS spectrum of the intermediate of formula (IV).

Figure 2 represents the GC-MS spectrum of the by-product of formula (V).

In both the abovementioned figures, the first spectrum refers to the fragmentation obtained by electron impact (e.L), whereas the second relates to the fragmentation obtained by chemical ionization (c.i.). DETAILED DESCRIPTION OF THE INVENTION

According to an especially preferred procedure for the execution of the process of the invention, the Vilsmeier reagent is prepared in situ in step (a), by making N,N- dimethylformamide react with a halide of an inorganic acid preferably selected from PCI₅, PCl₃, POC.3, SOCl₂, COCI₂, even more preferably POCI₃. The temperature of the reaction between the ketone (III) and the Vilsmeier reagent of step (a) preferably ranges between 20° and 40°C, even more preferably between 30° and 35°C. The base used in step (a) is a base preferably chosen between a hydroxide of an alkaline or alkaline-earth metal, a salt of a strong alkaline or alkaline-earth base, with a weak organic or inorganic acid.

It is preferably chosen amongst sodium carbonate, sodium acetate, sodium hydroxide, calcium hydroxide, calcium carbonate, more preferably sodium hydroxide.

The aprotic apolar solvent used during the treatment with bases at the end of step (a) is preferably selected from the classes consisting of the aliphatic, aromatic, cycloaliphatϊc hydrocarbons, halogenated aliphatic hydrocarbons. Even more preferably, it is. selected from toluene, hexane, cyclohexane, methylene chloride.

According to an especially preferred solution, it is toluene.

In step (b), preferably Pd/C is used as the hydrogenation catalyst.

In the same step, preferably a tertiary amine, even more preferably the triethylamine, is used as the organic base. The inorganic base is preferably a salt of a strong alkaline or alkaline-earth base with a weak inorganic acid, even more preferably sodium carbonate.

According to an especially preferred solution, in the process object of the present invention, a mixture of sodium carbonate and triethylamine is used, because in this way the chemoselectivity is increased (see comparative examples). Preferably a mixture with organic base / inorganic base in molar ratio ranging between 5 and 25 is used, more preferably between 10 and 20, and even more preferably between 12 and 16, and in which the unsaturated chloroaldehyde (IV) / base total moles molar relationship ranges between 0.4 and 0.8, more preferably between 0.5 and 0.7. The reaction temperature of step (b) preferably ranges between 40° and 110°C, preferably between 90° and 95°C. Step (b) is preferably carried out in the presence of water. According to an especially preferred solution, the intermediate obtained in step (a) in which the aprotic apolar solvent has been partially removed is directly utilized in step (b) in its raw state without undergoing purification treatments. Some examples of preparation according to the process object of the present invention are reported for illustrative but not limitative purposes. EXAMPLE 1 - Preparation of the intermediate of formula (IV) Into a 2 L reactor fitted with dropping funnel, condenser, thermometer, 200.5 g (2.75 moles) of DMF are loaded; it is cooled to 15°C and 230 g (1.5 moles) of POCI₃ are dripped during 2 hours. The temperature is brought to 20°C and it is left under stirring for 30 minutes. It is then heated to 35°C, and 143.3 g (0.5 moles) of the ketone of formula (III) dissolved in DMF are dripped. It is left stirring at 35°C for 6 hours. The temperature is cooled to 10°C, 350 g of toluene are added and 950 g of NaOH 3M are dripped during 5 hours (making sure that the temperature never exceeds 20°C).

^* At the end of the dripping the temperature is brought to 25°C and it is left under stirring for 2 hours. The phases then separate. The aqueous phase is extracted with 100 ml of toluene and the solvent is partially evaporated at reduced pressure (40°C/8 mbar). A raw product that weighs 233.0 g and contains 46.73% w/w of the intermediate (IV) and 0.27% w/w of the product of formula (III) is obtained. Yield 97%, conversion 99.3%. EXAMPLE 2 - Preparation of the intermediate (IV). With operating conditions analogous to those described in the previous example, the intermediate (IV) that is crystallized by a methanol/water: 1/1 v/v mixture is prepared. After filtration and drying under vacuum at 25°C/8 mbar the product of formula (IV) is obtained with .p. = 60°- 61 °C (with softening). The isolated product is analysed by GC-MS and ¹H and ¹³C NMR.

The GC-MS spectrum is reported in Figure 1.

*H NMR (400 MHz; CDCI₃): δ, ppm: 2.05 (s, 3H); 6.04 (s, 2H); 6.81 (d, 1H, J=8.0Hz); 6.89 (dd, 1H, Jι=8.0Hz, J₂=1.5Hz); 6.94 (d, 1 H, J=1.5Hz).

¹ CNMR (100MHz, CDCI₃): δ, ppm: 13.40 (CH₃); 101.79 (O-CH₂), 107.77, 109.83, 125.23 (aromatic CH),

136.07, 154.06 (vinylic C); 129.42, 147.90, 149.55, (aromatic C), 190.16 (CHO)

EXAMPLE 3 - Preparation of the compound of formula (I) Into an autoclave are introduced: 233.0 g of the reaction raw product from the previous step containing 46.73% of unsaturated chloroaldehyde (IV), 5.2 g (0.0485 moles) of Na₂CO₃, 36.4g of water, 73.5 g (0.728 moles) of triethylamine and 2.18 g of 50% wet 5% Pd/C.

The hydrogenation at PH₂ 6 bar at 95°C for 12 hours is carried out maintaining the reaction mixture under stirring.

At the end of the reaction, the catalyst is filtered, washed with 50 ml of water which is added to the filtrate. The phases separate. The catalyst is washed with 50 ml of toluene, with which the aqueous phase is extracted. The solvent is evaporated at reduced pressure (40°C/ 8 mbar) A raw product is obtained that weighs 105.3 g and contains the compound of formula (I) in an amount corresponding to 84.57% by weight.

Yield 95.6%.

EXAMPLE 1 A - Vilsmeier reaction carried out at 70°C.

Into a 250 ml reactor fitted with dropping funnel, thermometer and condenser, 40 g (0.55 moles) of DMF are loaded. Maintaining the temperature at 20°-25°C, 46 g

(0.3 moles) of POCI₃ are dripped. The reaction mixture is left under stirring for about 30 minutes maintaining the temperature at 20°C, then the reaction mixture is heated to 70°C.

28.7 g (0.1 moles) of the ketone (III) dissolved in DMF are dripped in 30 minutes. The reaction mixture is then left at 70°C for 5 hours under stirring.

67 g (0.55 moles) of NaOH at 32% are dripped (making sure that the temperature remains at 70°C). A solid precipitates, which is filtered, washed with toluene and subsequently extracted in toluene after treatment with an aqueous solution of NaOH 32%. By evaporation of the solvent an oil is obtained, which is analysed by GC-MS and ¹H and ¹³C NMR and which has the structure of formula (V) as previously reported. ¹HNMR (300 MHz; CDCI₃): δ, ppm: 2.03 (s, 3H); 2.33 (s, 6H); 4.04 (s, 1H); 5.95 (dd, 1H, J=1.5Hz), 5.97 (dd,

1H, J=1.5Hz), 6.80, 6.994 (2s, 2H).

¹³CNMR (75MHz, CDCI₃): δ, ppm; 12.82 (CH ); 40.92 (CH₃); 72.32 (CH); 101.10 (O-CH₂); 100.05, 106.01 (aromatic CH); 127.43, 135.91 (vinylic C), 134.78, 138.9 (aromatic C); 146.01,

147.36 (aromatic C).

The MS spectrum is reported in Figure 2.

EXAMPLE 4 - Preparation of the product of formula (I)

Into an autoclave are introduced 71.8 g of a reaction raw product constituted by 46.97% by weight of unsaturated aldehyde (IV) equivalent to 0.15 moles and the remainder by toluene, 11.25 g of water, 22.77 g (0.225 moles) of triethylamine and

0.67 g of 50% wet 5% Pd/C.

It is hydrogenated at PH₂= 6 bar at T = 95°C for 15 hours.

The catalyst is filtered, washed with water that is reunited with the filtrate. The phases separate, the catalyst is washed with 50 ml of toluene, with which the aqueous phase is extracted. The solvent is evaporated at reduced pressure under the same operational conditions described in example 3.

A raw product is obtained, which weighs 30.75 g and contains the compound of (I) equivalent to 84.2% by weight and the piperonylidene propanal [product of formula (A)] in an amount equivalent to 6% by weight.

Reaction yields: 89.9%.

EXAMPLE 2A - Preparation of the product of formula (I)

Into an autoclave are introduced 71.8 g of a reaction raw product constituted by

46.97% by weight of unsaturated aldehyde equivalent to 0.15 moles, 11.25 g of water, 23.85 g (0.225 moles) of sodium carbonate and 0.67g of 50% wet 5% Pd/C.

A slurry is obtained that is difficult to stir and does not allow the reaction to continue.

Claims

1. Process for the preparation of 3-(3,4-methyIenedioxyphenyI)-2-methylpropanal of formula (I) comprising the following steps:

a) reacting 5-propanoyl-1 ,3- benzodioxol (III)

with the Vilsmeier reagent (II)

(II) at temperatures ranging between 0° and 40°C and subsequently treating the reaction mixture with a base in aprotic apolar solvent to obtain the unsaturated chloroaldehyde of formula (IV);

(IV) b) reacting the unsaturated chloroaldehyde of formula (IV) obtained in the previous step with hydrogen in the presence of a supported heterogeneous catalyst containing a metal selected from Pd, Pt, Rh, Ru and in the presence of an organic base or of a mixture of an organic and inorganic base.

2. Process according to claim 1, characterised in that the Vilsmeier reagent is prepared in situ in step (a), by making N,N-dimethylformamide react with an inorganic acid halide.

3. Process according to claim 2, characterised in that said inorganic acid halide is selected from: POCI₃, SOCI₂, COCI₂ PCI₅, PCI₃.

4. Process according to claim 3, characterised in that said inorganic acid halide is POCia.

5. Process according to any of claims 1-4 characterised in that the reaction between the ketone (III) and the Vilsmeier reagent (II) is carried out at a temperature between 20° and 40°C.

6. Process according to claim 5, characterised in that said temperature ranges between 30° and 35°C.

7. Process according to any of claims 1-6, characterised in that the base utilized in step (a) is a base selected from a hydroxide of an alkaline or alkaline-earth metal, a salt of a strong alkaline or alkaline-earth base, with a weak organic or inorganic acid.

8. Process according to claim 7, characterised in that said base is selected from sodium carbonate, calcium carbonate, sodium acetate, sodium hydroxide, calcium hydroxide.

9. Process according to claim 8 characterised in that said base is sodium hydroxide.

10. Process according to any of claims 1-9, characterised in that the aprotic apolar solvent used during the treatment with bases at the end of step (a) is selected from the classes consisting of the aliphatic, aromatic, cycloaliphatic hydrocarbons, halogenated hydrocarbons.

11. Process according to claim 10, characterised in that said solvent is selected from toluene, hexane, cyclohexane, methylene chloride.

12. Process according to claim 11, characterised in that the said solvent is toluene.

13. Process according to any of claims 1-12, characterised in that said heterogeneous catalyst utilized in step (b) is Pd/C

14. Process according to any of claims 1-13, characterised in that in step (b) an organic base consisting of a tertiary amine is employed.

15. Process according to any of claims 1-14, characterised in that the inorganic base consists of a salt of a strong alkaline or earth alkaline base with a weak acid.

16. Process according to claim 14, characterised in that the tertiary amine is triethylamine.

17. Process according to claim 15, characterised in that said salt is sodium carbonate.

18. Process according to any of claims 16 and 17, characterised in that a mixture of sodium carbonate and triethylamine is used.

19. Process according to claim 18, characterised in that the organic base / inorganic base molar ratios ranges between 5 and 25 and the unsaturated chloroaldehyde (IV) / base total moles molar ratio ranges between 0.4 and 0.8.

20. Process according to claim 19, in which said organic base / inorganic base molar ratio ranges between 10 and 20 and said unsaturated chloroaldehyde (IV) / base total moles molar ratio ranges between 0.5 and 0.7.

21. Process according to claim 20 characterised in that said organic base / inorganic base molar ratio ranges between 12 and 16.

22. Process according to any of claims 1-21, characterised in that step (b) is carried out at a temperature ranging between 40° and 110°C.

23. Process according to claim 22, characterised in that step (b) is carried out at a temperature between 90° and 95°C.

24. Process according to any of claims 1-23, characterised in that step (b) is carried out in the presence of water.

25. Process according to any of claims 1-24, characterised in that the intermediate (IV) obtained in step (a) from which the aprotic apolar solvent has been partially removed is utilized in step (b) without undergoing purification treatments.

26. Unsaturated chloroaldehyde of formula (IV)

(IV)