Field of Invention:

The present invention describes a process for the preparation of β ionylideneacetaldehyde having the following structure:

β -ionylideneacetaldehyde Figure 1
β -ionylideneacetaldehyde is a key intermediate in the synthesis of several active pharmaceutical ingredients such as isotretinoin, tretinoin, vitamin-A, carotenoids, etc.

Background of the Invention:

Methods reported earlier for the preparation of P-ionylideneacetaldehyde involve oxidation of β -ionylidene ethanol using heavy metal based oxidants such as manganese oxide, chromium salts and ruthenium complexes.

In 1955 Robesen et al, prepared p-ionylideneacetaldehyde by oxidizing β -ionylidene ethanol using manganese oxide (J. Am. Chem. Soc, 1955, 75,4111-4117):

The reaction involves treating the solution of P-ionylidene ethanol in petroleum ether with about 15 equivalents of manganese dioxide for 24 hours. In 1994, Wada et al reported the same reaction using alcohol as the solvent (Chem Pharm Bull., 1994, 42, 757-759). In 2005, Salman et al described the preparation of P-ionylideneacetaldehyde by refluxing a solution of P-ionylidene ethanol in hexane with manganese oxide at about 60°C for 3 hours (Org. Process Res. Dev., 2005, 9, 302-305). Similar reaction is also described in US patent application US 2005/0027143 Al. The U.S.Pat. 5508456 described the same reaction with dichloromethane as solvent to prepare tritium labelled β -ionylideneacetaldehyde. Thus in the past fifty years, oxidation using manganese dioxide was the preferred method for the preparation of P-ionylideneacetaldehyde.

Another method based on heavy metal oxidation using chromium (VI) reagent is also reported. Guziee and Luzzio have used 4.5 equivalents of 4-(dimethylamino)-pyridinium chloro-chromate to oxidize P-ionylidene ethanol to obtain β -ionylideneacetaldehyde in about 26% yield (J.Org.Chem., 1982, 47, 1787-1789). McLean et al have reported a ruthenium based reagent, tetrapropylammonium perruthenate (TPAP) to prepare C-labeled β -ionylideneacetaldehyde (Tetrahedron, 2011, 67, 8404-8410).
The heavy metal based oxidations are highly polluting and cause environmental hazards. Further, these reagents are to be used in stoichiometric ratios and many times in more than stoichiometric ratios.

Summary of the Invention:

The preparation of β -ionylideneacetaldehyde through the oxidation of β -ionylidene ethanol still needs a satisfactory practical solution. To develop a process which is environmentally friendly, several non-metallic oxidation methods such as Swern oxidation, Dess-Martin periodinane, Corey-Kim oxidation, Pfitzner-Moffatt oxidation and NaN02/Ac20 were probed. But none of them were found to be satisfactory.

Since the stable free-radical TEMPO (2, 2, 6, 6-tetramethylpiperidinyloxy) based oxidations are catalytic in nature, the present inventors explored TEMPO-hypochlorite system. Such an application is reported in EP0734392B1 for converting bisnoralcohol to bisnoraldehyde, an intermediate in the synthesis of progesterone. However, the TEMPO-hypochlorite system for the oxidation of P-ionylidene ethanol did not give the required β -ionylidene acetaldehyde. Hypochlorite itself reacted with P-ionylidene ethanol giving rise to a number of products. The role of hypochlorite is to oxidize TEMPO to oxoammonium ion which is the true oxidizing agent. Hence other oxidants to replace hypochlorite were explored. When ferric chloride was used with TEMPO in toluene, significant conversion of P-ionylidene ethanol to P-ionylidene acetaldehyde was observed.

Although for maximum yields ferric chloride is required in stoichimetric ratio (1 eq), the requirement of TEMPO is catalytic (0.3 eq). Only ferric chloride, without presence of TEMPO, is unable to oxidize β -ionylidene ethanol. This suggested that the TEMPO is the main oxidant in the reaction and ferric chloride only regenerates the reduced TEMPO (Scheme-1).
Wang et al have reported aerobic oxidation of benzylic alcohol to benzaldehyde using TEMPO-FeCl3 -NaNO2 in triflurotoluene as solvent (Chem. Commun., 2005, 5322-5324). In this system, ferrous ions are oxidized by nitrite to regenerate ferric ions and in turn nitrite is regenerated by aerial oxygen. Here all the reagents are catalytic and oxidation is through the oxygen present in the air. Hence sodium nitrite was added to the TEMPO-Ferric chloride system. On addition of catalytic amount (0.3 eq) of sodium nitrite to TEMPO-Ferric chloride system, complete conversion of β -ionylidene ethanol was observed resulting in β -ionylidene-acetaldehyde in quantitative yields. In the new system, the requirement of ferric chloride was also found to be catalytic (0.15 eq). With nitrite requirement also being catalytic, actual oxidation is by the oxygen from the atmospheric air. The complete reaction can be shown as in Scheme-2:

Further, there is no need to use expensive triflurotoluene as solvent as used by Wang et al and the reaction can be conducted in toluene. Interestingly, according to Wang et al, the catalytic system of TEMPO-ferric-nitrite was ineffective in the absence of any one component of the catalyst. However, in the present study, TEMPO-ferric system itself was effective and sodium nitrite only helped in reducing the quantity of ferric chloride required for the reaction.

Thus, the present invention discloses a novel process for the preparation of β -ionylideneacetaldehyde by oxidation of P-ionylidene ethanol using TEMPO-FeCl3-NaNO2 under aerobic conditions. The process is environmentally friendly and uses only catalytic amounts of reagents unlike the prior art processes based on stoichiometric quantities of heavy metal based oxidants.

Detailed Description Of The Invention:

The required starting material, β -ionylidene ethanol can be prepared by the methods described in the literature (Org. Process Res. Dev., 2005, 9, 302-305; U.S.Pat. 5508456). It is dissolved in a suitable solvent. Triflurotoluene used in prior art (Chem. Comm., 2005, 5322) is highly flammable, toxic and expensive. Hence, other solvents were tried. Toluene and chlorobenzene both gave very good results. Solvents such as methyl tert-butyl ether, tetrahydrofuran and dimethylformamide made the reaction sluggish. TEMPO reaction is highly exothermic. Hence, the solution is to be cooled to 10 (± 5)° C. The catalyst consisting of TEMPO (0.3 eq), FeCl3 (0.15 eq), and NaN02 (0.3 eq) is added while stirring. The resulting suspension is stirred at ambient temperature and pressure. Monitoring by TLC showed that most conversion takes place in about 10 hours (90-95%). However, complete conversion is observed in about 20 hours. After the reaction, the reaction mixture is filtered to remove insoluble salts. The filtrate is washed with water containing sodium thiosulphate (0.5 eq) to remove any possible residual oxidants. The organic layer is dried over Na2S04 and concentrated under vacuum to obtain P-ionylideneacetaldehyde in high yields and purity (98% yield, 98.5% HPLC).

The embodiments of the present invention are illustrated in the following examples, which are not intended in any way to limit the scope of the invention. One skilled in the art can easily modify the details to suit the inputs and desired outcomes without affecting the present invention.

Examples:
Chemical purity was determined by HPLC using Lichrospher 100 RP-18 125x4.0mm, 5fi (HP/HIB/388) column with detector set at 342.0 nm with mobile phase as H20:ACN:TFA (15:85:0.01%)

Example 1:
To a solution of p-ionylidene ethanol (5.0g, 22.6 mmol) in toluene (20ml) at 10°C, TEMPO (1.06g, 6.78 mmol, 0.3eq), FeCl3.6H20 (0.91g, 3.39 mmol, 0.15eq), and NaN02 (0.46g , 6.78 mmol, 0.3eq) are added. The resulting mixture is stirred at room temperature and ambient pressure for about 20h. After the reaction is completed, the mixture is filtered. The filtrate is washed with water containing sodium thiosulphate (1.78g, 0.5eq) and dried over Na2S04 and concentrated under vacuum to obtain (3-ionylideneacetaldehyde in high yields and purity (4.85g, 98% yield, 98.9% HPLC).

Example 2:
To a solution of β -ionylidene ethanol (5.0g, 22.6 mmol) in monochloro benzene (20ml) at 10°C TEMPO (1.06g, 6.78 mmol, 0.3eq), FeCl3.6H20 (0.91g, 3.39 mmol, 0.15eq) and NaN02 (0.46g , 6.78 mmol, 0.3eq) are added. The resulting mixture is stirred at room temperature and ambient pressure for about 20h. After the reaction is completed, the mixture is filtered. The filtrate is washed with water containing sodium thiosulphate (1.78g, 0.5eq) and dried over Na2S04 and concentrated under vacuum to obtain P-ionylideneacetaldehyde in high yields and purity (4.86g, 98.2% yield, 98.99% HPLC).

Example 3:
To a solution of β -ionylidene ethanol (5.0g, 22.6 mmol) in monochloro benzene (20ml) at 10°C TEMPO (1.06g, 6.78 mmol, 0.3eq), and FeCl3.6H20 (6.10g, 22.6 mmol, l.0eq) are added. The resulting mixture is stirred at room temperature and ambient pressure for about 20h. After completion of reaction, the reaction mixture is worked up as in example 1 to obtain P-ionylideneacetaldehyde (4.45g, 90% yield, 98% HPLC).

Example 4 (M11O2 method for reference):
To a solution of β-ionylidene ethanol (5.0g, 22.6 mmol) in hexane (28 ml) and THF (6 ml), MnO2 (18.7g, 215 mmol, 9.5 eq) was added. The resulting mixture was refluxed at 60°C for three hours and filtered. The filter cake was washed with hexane (15 ml). The combined organic layer was concentrated to dryness to obtain p-ionylideneacetaldehyde. (4.78g, 96.5% yield, 95-99% HPLC)

We claim:

1. A process for the preparation of P-ionylideneacetaldehyde by reacting p-ionylidene ethanol with 2, 2, 6, 6-tetramethylpiperidine-l-oxyl (TEMPO) - and ferric chloride in a suitable solvent.

2. The process according to claim-1, with optional addition of sodium nitrite, in the range of 0.05 to 0.9 mol equivalent, and the reaction carried out in the presence of air or oxygen.

3. The process according to claim-1, wherein the suitable solvent is toluene or chlorobenzene.