Title of Invention	PROCESS FOR THE SYNTHESIS OF 5-BENZYL-3-FURFURYL ALCOHOL
Abstract	This invention discloses a process for the synthesis of 5-benzyl-3-furfuryl alcohol comprising the following steps: a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl) acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite (NaOCl) at a temperature between -10 °C and 80°C to give 3-benzyl-5- hydroxymethyl-5-carboxymethyl isoxazoline; b) reduction reaction with sodium borohydride (NaBH4) or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2) of 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline; c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline at a temperature between 15°C and 100°C and hydrogen pressure between 0.5 and 40 bar and consequent rearrangement to give 5-benzyl-3- furfuryl alcohol.

Title of Invention

PROCESS FOR THE SYNTHESIS OF 5-BENZYL-3-FURFURYL ALCOHOL

Abstract

This invention discloses a process for the synthesis of 5-benzyl-3-furfuryl alcohol comprising the following steps: a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl) acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite (NaOCl) at a temperature between -10 °C and 80°C to give 3-benzyl-5- hydroxymethyl-5-carboxymethyl isoxazoline; b) reduction reaction with sodium borohydride (NaBH4) or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2) of 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline; c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline at a temperature between 15°C and 100°C and hydrogen pressure between 0.5 and 40 bar and consequent rearrangement to give 5-benzyl-3- furfuryl alcohol.

Full Text	PROCESS FOR THE SYNTHESIS OF 5-BENZYL-3-FURFURYL ALCOHOL FIELD OF THE INVENTION The present invention concerns a synthesis process of 5-benzyl-3-furfuryl alcohol. PRIOR ART Synthesis processes of 5-benzyl-3-furfuryl alcohol are well known to the art, an intermediate through the synthesis of the pyrethroid type of insecticide known by its commercial name of Resmethrin and described, for instance, in GB 1,168,797. For instance the patent US 3,466,304 claims the synthesis of 5-benzyl-3-furfuryl alcohol through condensation of Claisen of benzylcyanide and dialkylsuccinate, consequent hydrolysis, esterification, protection of the ketone group, formyiation, cyclization to 5-benzyl-3- furfuryl ester and subsequent reduction to alcohol with lithium aluminium hydride. The process is particularly laborious, it requires anhydrous solvents and uses Lithium aluminium hydride the handling of which requires numerous precautions. The patent EP 187 345 claims a procedure for the synthesis of substituted furanes by substituted isoxazolidine obtained from isobutylene diacetate and the appropriate aldoxime. The process envisages, therefore, the use of isobutylene diacetates, obtained from dichloroisobutylenes, or of dihydroxy isobutylenes which are difficult to prepare and find (DE 3,243,543 and DE 3,415,336). The patent SU 1768601 claims the synthesis of 5-benzyl-3-furfuryl alcohol through reduction of the corresponding ester with Lithium aluminium hydride. The furane ester is obtained through the condensation of 2-benzylfurane with an alkyl ester of propiolic acid at 200- 250°C in autoclave. The conditions described by way of example are demanding or as such to be hardly exploited in industrial-scale plants. The need was therefore felt to realize new ways of synthesis with reactions characterized by high yields, easily to be scaled up to industrial size, with intermediates of high degree of purity, by using reagents commercially available. SUMMARY A new synthesis process of 5-benzyl-3-furfuryl alcohol has now been found which is able to overcome the drawbacks typical of the processes known to the art The Applicant has unexpectedly and surprisingly found a new synthesis process of 5-benzyl-3-furfuryl alcohol comprising: a. Condensation of the alky) a-(hydroxymethyl) acrylate, obtained through a Witting-Homer type reaction of a alkyl phosphonate with formaldehyde, with phenyl acetaldehyde oxime in the presence of an aqueous solution of sodium hypochlorite to give 3-benzyl-5-hydroxymethyl-5-carboxyalkyl isoxazoline. b. Reduction of the 3-benzyl-5-hydroxymethyl-5-carboxyalkyl isoxazoline with sodium borohydride or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline. c. Hydrogenation and consequent rearrangement of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline to give 3-benzyl-5-furfuryl alcohol. The process under discussion is characterized by few steps of easy industrial applicability and high yield, starting with reagents easily found on the market, of reasonable cost and safer to handle compared to the raw materials pointed out in the known art among which, in particular, the difficult to find and expensive dichloro or dihydroxy isobutylene, (Organic Syntheses Vol.75, pages 89-97 (1997)). DESCRIPTION OF THE FIGURE Figure 1: scheme of the synthesis of 5-benzyl-2-hydroxymethyl furane alcohol. DETAILED DESCRIPTION OF THE INVENTION It is an object of the present invention a synthesis process of 5-benzyl-3-furfuryl alcohol comprising the following steps: a) condensation reaction of the alkyl (C1-C4) alpha-(hydroxymethyl) acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite (NaOCI) to give 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline; b) reduction reaction with sodium borohydride (NaBI-U) or sodium dihydro-bis- (2- methoxyethoxy) aluminium hydride (NaAIH2OCH2CH2OCH3) of 3-benzyl-5- hydroxymethyl-5-carboxymethyl isoxazoline to give 3-benzyt-5,5-bte (hydroxymethyl) isoxazoline; c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline and consequent rearrangement to give 5-benzyl-3-furfuryl alcohol. According to the synthesis process of the present invention, the condensation reaction of step a) is preferably carried out in aromatic or aliphatic halogenated solvents. The aliphatic halogenated solvents and particularly the chlorinated ones of 1 to 2 carbon atoms are the most preferred. Methylene chloride is particularly preferred. The technique is carried out at a temperature of between -10°C and 80°C; the range between -10°C and 50°C is preferred; temperature between -10°C and 30°C is particularly preferred. The condensation reaction at step a) is carried out in the presence of an aqueous solution of sodium hypochlorite with an active chlorine titre of between 5 and 10% p/p. A titre of between 8 and 10% p/p is preferred. A titre of 10% p/p is particularly preferred. The reduction reaction at step b) with sodium borohydride is carried out in a C1-C4 aliphatic alcohol or mixtures thereof, methyl alcohol is particularly preferred; when sodium dihydro bis- (2-methoxyethoxy) aluminium hydride is used, the reaction is carried out in aliphatic or aromatic solvents selected from the group consisting of benzene, toluene, xylene, cyclohexane, methylcyclohexane or mixtures thereof. Toluene is particularly preferred. ' The temperature of the reduction reaction at step b) is between -15°C and 30°C; the range from -10°C to 25°C is preferred. The reduction reaction is preferably carried out with sodium borohydride granules (10-40 mesh) in methanol or sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride in toluene, for the latter case a 70% p/p solution, in toluene, of sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (Synhydrid®) is particularly preferred. The hydrogenation reaction at step c) is carried out at a hydrogen pressure of between 0.5 and 40 bar, a range between 1 and 20 bar is preferred; the range between 1 and 10 bar is particularly preferred. The temperature of hydrogenation is between 15°C and 100°C; the range between 20oC and 60oC is preferred. The catalysts used in the hydrogenation reaction are those commonly used for catalytic hydrogenation, as such or supported on the appropriate inert matrix. Typical examples of catalysts are RtO2. PtO, Ni Raney, Pt on carbon, Pd on carbon, Pd on BaSO4, Pd on AI2O3, Pt on AI2O3, Ru on carbon. Pd on carbon, RO2 and Ni Raney are preferred. Ni Raney is particularly preferred. The hydrogenation reaction at step c) is carried out in a C1-C4 alcoholic solvent or mixtures thereof, or in hydroalcoholic mixtures of said C1-C4 alcohols, the quantity of water of said mixtures ranging from 7 to 50% v/v of the solution. Methanol is preferred as the alcohol. A methanol/water mixture is preferred with a quantity of water from 10 to 30% v/v. A methanol/water mixture containing from 15% to 20% v/v of water is particularly preferred. The hydrogenation reaction of step c) is carried out in the presence of a weak organic or inorganic protic acid such as for example acetic, propionic, butyric, boric acid. Acetic acid and boric acid are particularly preferred. Upon termination of the hydrogenation reaction at step c) the residue is treated with aqueous solutions of strong inorganic acids as described in EP 187 345. A 10% (p/v) solution of HCI is preferred. An additional advantage of the synthesis process, object of the present invention, is the use of basic reagents such as lower alkyls, from 1 to four carbon atoms, alpha- (hydroxymethyl) acrylates, preferably methyl, ethyl or propyl alpha- (hydroxymethyl) acrylates, more preferably ethyl alpha- (hydroxymethyl) acrylate and phenylacetaldehyde oxime easily available on the market or obtainable according to the description by Villieras J. et Rambaud M. in Organic Syntheses 66, pages 220-224 (1988), in Synthesis, pages 300-301, (4) (1983), through the synthesis of ethyl alpha- (hydroxymethyl) acrylate, or as described in J. March Advanced Organic Chemistry through the synthesis of phenylacetaldehyde oxime. The stages characterizing the process, object of the present invention, comprise easily realizable reactions with high yields and with standard reagents such as sodium hypochlorite, sodium borohydride, hydrogen and catalysts. In particular, the use of a reducing reagent such as sodium borohydride or sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2 known as VTTRIDE, much less dangerous reagents than other reductants described in literature such as UAIH4, but however able to achieve excellent yields; The whole combined with the use of basic reagents of low cost and easily available, such as ethyl alpha- (hydroxymethyl) acrylate and phenylacetaldehyde oxime. According to the tests carried out by the Applicant, the process object of the present invention allows the attainment of 5-benzyl-3-furfuryl alcohol by means of a series of easy-to-do intermediate reactions characterized by yields ranging from over 70% and over 90%, with solvents and reagents commercially available, in mild and easily controllable reaction conditions, starting with basic reagents such as ethyl alpha- (hydroxymethyl) acrylate and phenylacetaldehyde oxime commercially available or which can be synthesized through reactions well known to the art, characterized by high yields, such as those described in the examples reported below. The reaction products and intermediates were characterized by means of HPLC, TLC, GC and NMR analysis techniques: 1H and 13C. Some illustrative, but non-limiting examples of the present invention are described below. Example 1: Synthesis of ethvl a-(hvdroxvmethyl) acrviate In a 11 capacity reactor are added 96 g (3.2 mol) of p-formaldehyde, 8 ml of orthophosphoric acid (H3PO4) 1N and 220 ml of H2O. It is heated to 90°C for 1h 30 min. At the end, the solution is clear. It is cooled to room temperature and, under strong stirring, are added in order 60.86 g (0.27 mol) of triethylphosphonacetate, 41.04 g (0.44 mol) of potassium carbonate in 40.56 ml of water. First 10 ml in 10 min, then the rest in 40 min, maintaining the temperature under 35°C. Once the addition is completed, the solution is allowed to stir at 40oC for 5 min, then It is quickly cooled to room temperature while in sequence are added 200 ml of ethyl ether and 150 ml of brine (supersaturated solution of sodium chloride). The two phases are separated: the aqueous phase is retroextracted three times, each time with a volume of 150 ml, with ethyl ether, the organic phases are collected, and washed twice, each time with a volume of 150 ml, with brine and are dried with sodium sulphate. After evaporation of the solvent, 41.55 g of raw ethyl a (hydroxymethyl) acrylate are obtained, which, distilled (70-72oC/ 1mmHg). leads to 30.89 g of a colourless liquid product. Example 2: Synthesis of phenvlacetaldehvde oxime In a 11 flask equipped with a mechanical stirrer, two dropping funnels and a thermometer, are added: 33.35 g (0.48 mol) of hydroxylamine hydrochloride dissolved in 69 ml of a 1:2 ethanol/water mixture. Under stirring for 1 h, are simultaneously added dropwise, maintaining the temperature between 10-15°C: 48.0g (0.4 mol) of phenylacetaldehyde dissolved in 56 ml of ethanol, 25.44 g (0.24 mol) of sodium carbonate dissolved in 93 ml of water. The formation of a white precipitate is noted 5 min. after starting the addition. Once the addition is completed the temperature is increased up to room temperature and the solution is allowed to react for 15h. The precipitate obtained is filtered, washing several times with water. It is vacuum dried for 48h at room temperature. 49.63 g of phenylacetaldehyde oxime are obtained as a white crystalline solid with a melting point of 84-86°C. 2.05 g of product are recovered from the mother liquors. Example 3: Synthesis of 3-benzyl-5-hvdroxvmethvl-5-carboxvethvt isoxazoline In a 11 flask, equipped with a mechanical stirrer, thermometer and two dropping funnels, are added: 39.0 g (0.3 mol) of ethyl alpha (hydroxymethyl) acrylate in 115ml of methylene chloride. The solution is cooled to -5°C and in 4h are simultaneously added dropwise: 42.0 g (0.3 mol) of raw phenylacetaldehyde oxime, obtained from Example 2, dissolved in 350 ml of methylene chloride, 343 ml of a sodium hypochlorite solution with an active chlorine titre of 10% (titrated before use) equivalent to 0.48 mol of NaOCI. The reaction is slightly exothermic: a temperature rise of about 5°C is noted; then the dropwise adition is interrupted until the temperature falls to -5°C. The reaction can be checked by gas- chromatography (GC). Once the addition of hypochlorite and oxine is completed, the solution is alowed to stir at room temperature for 2 hr. The two phases that formed are separated: the aqueous phase is retroextracted five times, each time with a volume of 150 ml, of methylene chloride. The organic phases are collected and are washed, first with 200 ml of water, and then twice, each time with a volume of 200 ml, with brine. The organic phase is dried with sodium sulphate. After evaporation of the solvent are obtained 71.55 g of raw 3-benzyl-5- hydroxymethyl-5-carboxyethyl isoxazoline (95.5% pure, by uncalibrated GC analysis), used as such in the subsequent step. Example 4: Synthesis of 3-benzvl. 5.5-bis (hvdroxvmethvn isoxazoline with NaBH4 In a 11 flask, equipped with thermometer and mechanical stirrer, in a nitrogen atmosphere are added: 71.55 g (0.272 mol) of raw 3-benzyl-5-hydroxymethyl-5- carboxyethyl isoxazoline deriving from Example 3 and 553 ml of methanol. The solution is cooled to -10°C and in the time period of 1h are added: 10.29 g (0.272 mol) of NaBH4 granules (10-40 mesh). Once the addition is completed the temperature is increased up to room temperature and the solution is allowed to stir for 1h 30'. Then are added 250 ml of a saturated ammonium chloride solution maintaining the temperature at approx. 20°C. The solvent is evaporated under vacuum (24 mbar at 25°C). The residue is taken up with 150 ml of methylene chloride and the residue formed after evaporation is dissolved in a minimum quantity of water. The two phases obtained are separated and the aqueous one is retroextracted three times, each time with a volume of 100 ml, with methylene chloride. The organic phases are collected and dried with sodium sulphate. It is filtered and, after evaporation of the solvent, 59.85 g of a raw orange oil product are obtained. The raw product is crystallized in 150 ml of ethyl acetate and 140ml of hexane. 39.91 g of 3-benzy!-5,5-bis (hydroxymethyl) isoxazoline as a pale yellow solid are obtained. Another 4.16 g of product are recovered from the mother liquors. Example 4-b: Synthesis of 3-benzvl. 5.5-bis (hvdroxvmethyl) isoxazoline with sodium_____dihvdro-bis-_____(2-methoxvethoxv)_____aluminium_____hvdride (NaAIH?(OCH2CH2OCH3)2) Following the same procedure described in example 4, 71.55g (0.272 mol) of raw 3-benzyl-5-hydroxymethyl-5-carboxyl isoxazoline (95.5% titre) dissolved in 550 ml of methanol are made to react at -10"C with 80g (0.272 mol) of 70% (p/p) toluene solution of sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride. The reaction is carried out according to the description in example 4. obtaining 43.3g of product Example 5: Synthesis of 5-benzyl-2-hvdroxvmethvl furane In a 1000 ml autoclave are added: 50.5 g (0.225 mol) of 3-benzyl,5-bis (hydroxymethyi) isoxazoline deriving from Example 4 or from example 4-b, 3.0 g (0.05 mol) of orthoboric acid (H3BO3), a hydroalcoholic solution of methanol/water in a ratio of 550ml/110 ml and'5.0 g of Ni raney. The mixture is pressurized at 4 bar of hydrogen and left at this pressure for 8 hours, The mixture is filtered and evaporated under vacuum (25°C/24 mbar). The residue is treated with dichloromethane and 10% HCI. The organic phase is separated, washed with water and with a brine solution and is afterwards dried on sodium sulphate. It is filtered and the organic phase evaporated under vacuum obtaining an oil that is purified through distillation (125-128oC/ 0.4 mbar). 35.0 g of 5-benzyl- 2-hydroxymethyl furane are obtained (yield 83%). We Claim: 1. A process for the synthesis of 5-benzyl-3-furfuryl alcohol comprising the following steps: a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl) acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite Naclo at a temperature between -10 °C and 80°C to give 3- benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline; b) reduction reaction with sodium borohydride (NaBH4) or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2) of 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline; c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline at a temperature between 15°C and 100°C and hydrogen pressure between 0.5 and 40 bar and consequent rearrangement to give 5- benzyl-3-furfuryl alcohol. 2. The process as claimed in claim 1 wherein in the condensation reaction at step a) the alkyl alpha- (hydroxymethyl) acrylate is selected from the group consisting of methyl, ethyl or propyl alpha- (hydroxymethyl) acrylates. 3. The process as claimed in claim 2 wherein the alkyl alpha- (hydroxymethyl) acrylate is ethyl alpha- (hydroxymethyl) acrylate. 4. The process as claimed in claim 1 wherein the condensation reaction at step a) is carried out in aromatic or aliphatic halogenated solvents, such as herein described. 5. The process as claimed in claim 4 wherein the aliphatic halogenated solvents are 1 to 2 carbon atom aliphatic chlorinated solvents, such as herein described. 6. The process as claimed in claim 5 wherein the solvent is methylene chloride. 7. The process as claimed in claim 1 wherein the condensation reaction at step a) is carried out at a temperature of between -10°C and 50°C. 8. The process as claimed in claim 7 wherein the reaction is carried out at a temperature of between -10°C and 30°C. 9. The process as claimed in claim 1 wherein the condensation reaction at step a) is carried out in the presence of an aqueous solution of sodium hypochlorite with an active chlorine titre of between 5 and 10% p/p. 10. The process as claimed in claim 9 wherein the aqueous solution of sodium hypochlorite has an active chlorine titre of between 8 and 10% p/p. 11. The process as claimed in claim 10 wherein the aqueous solution of sodium hypochlorite has an active chlorine titre of 10% p/p. 12. The process as claimed in claim 1 wherein the reduction reaction at step b) is carried out in a CrC4 aliphatic alcohol or their mixtures, or in aliphatic or aromatic solvents selected from the group consisting of benzene, toluene, xylene, cyclohexane, methylcyclohexane or mixtures thereof. 13. The process as claimed in claim 12 wherein the alcohol is methyl alcohol. 14. The process as claimed in claim 12 wherein the aromatic solvent is toluene. 15. The process as claimed in claim 1 wherein the reduction reaction at step b) is carried out at a temperature of between -10°C and 25°C. 16. The process as claimed in claim 1 wherein the reduction reaction at step b) is carried out with sodium borohydride granules (10-40 mesh) in methanol or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride in toluene. 17. The process as claimed in claim 16 wherein the reduction reaction at step b) is carried out in a 70% p/p solution in toluene of sodium dihydro-bis- (2- methoxyethoxy) aluminium hydride. 18. The process as claimed in claim 1 wherein the hydrogenation reaction at step c) is carried out at a hydrogen pressure is between 1 and 20 bar. 19. The process as claimed in claim 18 wherein the hydrogen pressure is between 1 and 10 bar. 20. The process as claimed in claim 1 wherein the temperature of hydrogenation at step c) is between 20°C and 60°C. 21. The process as claimed in claim 1 wherein the catalysts used in the hydrogenation reaction at step c) are selected from the group consisting of PtO2, PtO, Ni Raney, Pt on carbon, Pd on carbon, Pd on BaSO4, Pd on AI2O3, Pt on AI2O3, Ru on carbon. 22. The process as claimed in claim 21 wherein the catalyst is selected from the group consisting of Pd on carbon, PtO2 and Ni Raney. 23. The process as claimed in claim 22 wherein the catalyst is Ni Raney. 24. The process as claimed in claim 1 wherein the hydrogenation reaction at step c) is carried out in a C1-C4 alcoholic solvent or mixtures thereof, or in hydroalcoholic mixtures of said C1-C4 alcohols, the quantity of water of said mixtures ranging from 7 to 50% v/v of the solution. 25. The process as claimed in claim 24 wherein the alcoholic solvent is methanol. 26. The process as claimed in claim 24 wherein the solvent is a methanol/water mixture with a quantity of water from 10 to 30% v/v. 27. The process as claimed in claim 26 wherein the methanol/water mixture has a water content of 15% to 20% v/v. 28. The process as claimed in claim 1 wherein the hydrogenation reaction of step c) is carried out in the presence of a weak organic or inorganic protic acid. 29. The process as claimed in claim 28 wherein the acid is selected from the group consisting of acetic acid, propionic, butyric, boric acid. 30. The process as claimed in claim 29 wherein the acid is selected out of acetic acid or boric acid. 31. The process as claimed in claim 1 optionally comprising the treatment of the residue obtained at the end of the hydrogenation reaction at step c) with aqueous solutions of strong inorganic acids. 32. The process as claimed in claim 31 wherein the aqueous solution is a 10% (p/v) solution of HCI. This invention discloses a process for the synthesis of 5-benzyl-3-furfuryl alcohol comprising the following steps: a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl) acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite (NaOCl) at a temperature between -10 °C and 80°C to give 3-benzyl-5- hydroxymethyl-5-carboxymethyl isoxazoline; b) reduction reaction with sodium borohydride (NaBH4) or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2) of 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline; c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline at a temperature between 15°C and 100°C and hydrogen pressure between 0.5 and 40 bar and consequent rearrangement to give 5-benzyl-3- furfuryl alcohol.

Full Text

PROCESS FOR THE SYNTHESIS OF 5-BENZYL-3-FURFURYL ALCOHOL
FIELD OF THE INVENTION
The present invention concerns a synthesis process of 5-benzyl-3-furfuryl alcohol.
PRIOR ART
Synthesis processes of 5-benzyl-3-furfuryl alcohol are well known to the art, an
intermediate through the synthesis of the pyrethroid type of insecticide known by
its commercial name of Resmethrin and described, for instance, in GB 1,168,797.
For instance the patent US 3,466,304 claims the synthesis of 5-benzyl-3-furfuryl
alcohol through condensation of Claisen of benzylcyanide and dialkylsuccinate,
consequent hydrolysis, esterification, protection of the ketone group, formyiation,
cyclization to 5-benzyl-3- furfuryl ester and subsequent reduction to alcohol with
lithium aluminium hydride.
The process is particularly laborious, it requires anhydrous solvents and uses
Lithium aluminium hydride the handling of which requires numerous precautions.
The patent EP 187 345 claims a procedure for the synthesis of substituted furanes
by substituted isoxazolidine obtained from isobutylene diacetate and the
appropriate aldoxime. The process envisages, therefore, the use of isobutylene
diacetates, obtained from dichloroisobutylenes, or of dihydroxy isobutylenes which
are difficult to prepare and find (DE 3,243,543 and DE 3,415,336).
The patent SU 1768601 claims the synthesis of 5-benzyl-3-furfuryl alcohol through
reduction of the corresponding ester with Lithium aluminium hydride. The furane
ester is obtained through the condensation of 2-benzylfurane with an alkyl ester of
propiolic acid at 200- 250°C in autoclave.
The conditions described by way of example are demanding or as such to be
hardly exploited in industrial-scale plants.
The need was therefore felt to realize new ways of synthesis with reactions
characterized by high yields, easily to be scaled up to industrial size, with
intermediates of high degree of purity, by using reagents commercially available.
SUMMARY
A new synthesis process of 5-benzyl-3-furfuryl alcohol has now been found which
is able to overcome the drawbacks typical of the processes known to the art
The Applicant has unexpectedly and surprisingly found a new synthesis process of
5-benzyl-3-furfuryl alcohol comprising:
a. Condensation of the alky) a-(hydroxymethyl) acrylate, obtained through a
Witting-Homer type reaction of a alkyl phosphonate with formaldehyde, with
phenyl acetaldehyde oxime in the presence of an aqueous solution of sodium
hypochlorite to give 3-benzyl-5-hydroxymethyl-5-carboxyalkyl isoxazoline.
b. Reduction of the 3-benzyl-5-hydroxymethyl-5-carboxyalkyl isoxazoline with
sodium borohydride or with sodium dihydro-bis- (2-methoxyethoxy) aluminium
hydride to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline.
c. Hydrogenation and consequent rearrangement of 3-benzyl-5,5-bis
(hydroxymethyl) isoxazoline to give 3-benzyl-5-furfuryl alcohol.
The process under discussion is characterized by few steps of easy industrial
applicability and high yield, starting with reagents easily found on the market, of
reasonable cost and safer to handle compared to the raw materials pointed out in
the known art among which, in particular, the difficult to find and expensive
dichloro or dihydroxy isobutylene, (Organic Syntheses Vol.75, pages 89-97
(1997)).
DESCRIPTION OF THE FIGURE
Figure 1: scheme of the synthesis of 5-benzyl-2-hydroxymethyl furane alcohol.
DETAILED DESCRIPTION OF THE INVENTION
It is an object of the present invention a synthesis process of 5-benzyl-3-furfuryl
alcohol comprising the following steps:
a) condensation reaction of the alkyl (C1-C4) alpha-(hydroxymethyl) acrylate with
phenylacetaldehyde oxime in the presence of sodium hypochlorite (NaOCI) to give
3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline;
b) reduction reaction with sodium borohydride (NaBI-U) or sodium dihydro-bis- (2-
methoxyethoxy) aluminium hydride (NaAIH2OCH2CH2OCH3) of 3-benzyl-5-
hydroxymethyl-5-carboxymethyl isoxazoline to give 3-benzyt-5,5-bte
(hydroxymethyl) isoxazoline;
c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline
and consequent rearrangement to give 5-benzyl-3-furfuryl alcohol.
According to the synthesis process of the present invention, the condensation
reaction of step a) is preferably carried out in aromatic or aliphatic halogenated
solvents.
The aliphatic halogenated solvents and particularly the chlorinated ones of 1 to 2
carbon atoms are the most preferred. Methylene chloride is particularly preferred.
The technique is carried out at a temperature of between -10°C and 80°C; the
range between -10°C and 50°C is preferred; temperature between -10°C and 30°C
is particularly preferred.
The condensation reaction at step a) is carried out in the presence of an aqueous
solution of sodium hypochlorite with an active chlorine titre of between 5 and 10%
p/p. A titre of between 8 and 10% p/p is preferred. A titre of 10% p/p is particularly
preferred.
The reduction reaction at step b) with sodium borohydride is carried out in a C1-C4
aliphatic alcohol or mixtures thereof, methyl alcohol is particularly preferred;
when sodium dihydro bis- (2-methoxyethoxy) aluminium hydride is used, the
reaction is carried out in aliphatic or aromatic solvents selected from the group
consisting of benzene, toluene, xylene, cyclohexane, methylcyclohexane or
mixtures thereof. Toluene is particularly preferred. '
The temperature of the reduction reaction at step b) is between -15°C and 30°C;
the range from -10°C to 25°C is preferred.
The reduction reaction is preferably carried out with sodium borohydride granules
(10-40 mesh) in methanol or sodium dihydro-bis- (2-methoxyethoxy) aluminium
hydride in toluene, for the latter case a 70% p/p solution, in toluene, of sodium
dihydro-bis- (2-methoxyethoxy) aluminium hydride (Synhydrid®) is particularly
preferred.
The hydrogenation reaction at step c) is carried out at a hydrogen pressure of
between 0.5 and 40 bar, a range between 1 and 20 bar is preferred; the range
between 1 and 10 bar is particularly preferred.
The temperature of hydrogenation is between 15°C and 100°C; the range between
20oC and 60oC is preferred.
The catalysts used in the hydrogenation reaction are those commonly used for
catalytic hydrogenation, as such or supported on the appropriate inert matrix.
Typical examples of catalysts are RtO2. PtO, Ni Raney, Pt on carbon, Pd on
carbon, Pd on BaSO4, Pd on AI2O3, Pt on AI2O3, Ru on carbon.
Pd on carbon, RO2 and Ni Raney are preferred. Ni Raney is particularly preferred.
The hydrogenation reaction at step c) is carried out in a C1-C4 alcoholic solvent or
mixtures thereof, or in hydroalcoholic mixtures of said C1-C4 alcohols, the quantity
of water of said mixtures ranging from 7 to 50% v/v of the solution.
Methanol is preferred as the alcohol.
A methanol/water mixture is preferred with a quantity of water from 10 to 30% v/v.
A methanol/water mixture containing from 15% to 20% v/v of water is particularly
preferred.
The hydrogenation reaction of step c) is carried out in the presence of a weak
organic or inorganic protic acid such as for example acetic, propionic, butyric, boric
acid.
Acetic acid and boric acid are particularly preferred.
Upon termination of the hydrogenation reaction at step c) the residue is treated
with aqueous solutions of strong inorganic acids as described in EP 187 345.
A 10% (p/v) solution of HCI is preferred.
An additional advantage of the synthesis process, object of the present invention,
is the use of basic reagents such as lower alkyls, from 1 to four carbon atoms,
alpha- (hydroxymethyl) acrylates, preferably methyl, ethyl or propyl alpha-
(hydroxymethyl) acrylates, more preferably ethyl alpha- (hydroxymethyl) acrylate
and phenylacetaldehyde oxime easily available on the market or obtainable
according to the description by Villieras J. et Rambaud M. in Organic Syntheses
66, pages 220-224 (1988), in Synthesis, pages 300-301, (4) (1983), through the
synthesis of ethyl alpha- (hydroxymethyl) acrylate, or as described in J. March
Advanced Organic Chemistry through the synthesis of phenylacetaldehyde oxime.
The stages characterizing the process, object of the present invention, comprise
easily realizable reactions with high yields and with standard reagents such as
sodium hypochlorite, sodium borohydride, hydrogen and catalysts. In particular,
the use of a reducing reagent such as sodium borohydride or sodium dihydro-bis-
(2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2 known as
VTTRIDE, much less dangerous reagents than other reductants described in
literature such as UAIH4, but however able to achieve excellent yields; The whole
combined with the use of basic reagents of low cost and easily available, such as
ethyl alpha- (hydroxymethyl) acrylate and phenylacetaldehyde oxime.
According to the tests carried out by the Applicant, the process object of the
present invention allows the attainment of 5-benzyl-3-furfuryl alcohol by means of
a series of easy-to-do intermediate reactions characterized by yields ranging from
over 70% and over 90%, with solvents and reagents commercially available, in
mild and easily controllable reaction conditions, starting with basic reagents such
as ethyl alpha- (hydroxymethyl) acrylate and phenylacetaldehyde oxime
commercially available or which can be synthesized through reactions well known
to the art, characterized by high yields, such as those described in the examples
reported below.
The reaction products and intermediates were characterized by means of HPLC,
TLC, GC and NMR analysis techniques: 1H and 13C.
Some illustrative, but non-limiting examples of the present invention are described
below.
Example 1: Synthesis of ethvl a-(hvdroxvmethyl) acrviate
In a 11 capacity reactor are added 96 g (3.2 mol) of p-formaldehyde, 8 ml of
orthophosphoric acid (H3PO4) 1N and 220 ml of H2O. It is heated to 90°C for 1h 30
min. At the end, the solution is clear. It is cooled to room temperature and, under
strong stirring, are added in order 60.86 g (0.27 mol) of triethylphosphonacetate,
41.04 g (0.44 mol) of potassium carbonate in 40.56 ml of water. First 10 ml in 10
min, then the rest in 40 min, maintaining the temperature under 35°C.
Once the addition is completed, the solution is allowed to stir at 40oC for 5 min,
then It is quickly cooled to room temperature while in sequence are added 200 ml
of ethyl ether and 150 ml of brine (supersaturated solution of sodium chloride).
The two phases are separated: the aqueous phase is retroextracted three times,
each time with a volume of 150 ml, with ethyl ether, the organic phases are
collected, and washed twice, each time with a volume of 150 ml, with brine and
are dried with sodium sulphate.
After evaporation of the solvent, 41.55 g of raw ethyl a (hydroxymethyl) acrylate
are obtained, which, distilled (70-72oC/ 1mmHg). leads to 30.89 g of a colourless
liquid product.
Example 2: Synthesis of phenvlacetaldehvde oxime
In a 11 flask equipped with a mechanical stirrer, two dropping funnels and a
thermometer, are added: 33.35 g (0.48 mol) of hydroxylamine hydrochloride
dissolved in 69 ml of a 1:2 ethanol/water mixture. Under stirring for 1 h, are
simultaneously added dropwise, maintaining the temperature between 10-15°C:
48.0g (0.4 mol) of phenylacetaldehyde dissolved in 56 ml of ethanol, 25.44 g (0.24
mol) of sodium carbonate dissolved in 93 ml of water. The formation of a white
precipitate is noted 5 min. after starting the addition.
Once the addition is completed the temperature is increased up to room
temperature and the solution is allowed to react for 15h. The precipitate obtained
is filtered, washing several times with water. It is vacuum dried for 48h at room
temperature.
49.63 g of phenylacetaldehyde oxime are obtained as a white crystalline solid with
a melting point of 84-86°C. 2.05 g of product are recovered from the mother
liquors.
Example 3: Synthesis of 3-benzyl-5-hvdroxvmethvl-5-carboxvethvt isoxazoline
In a 11 flask, equipped with a mechanical stirrer, thermometer and two dropping
funnels, are added: 39.0 g (0.3 mol) of ethyl alpha (hydroxymethyl) acrylate in
115ml of methylene chloride. The solution is cooled to -5°C and in 4h are
simultaneously added dropwise: 42.0 g (0.3 mol) of raw phenylacetaldehyde
oxime, obtained from Example 2, dissolved in 350 ml of methylene chloride, 343
ml of a sodium hypochlorite solution with an active chlorine titre of 10% (titrated
before use) equivalent to 0.48 mol of NaOCI. The reaction is slightly exothermic: a
temperature rise of about 5°C is noted; then the dropwise adition is interrupted
until the temperature falls to -5°C. The reaction can be checked by gas-
chromatography (GC). Once the addition of hypochlorite and oxine is completed,
the solution is alowed to stir at room temperature for 2 hr. The two phases that
formed are separated: the aqueous phase is retroextracted five times, each time
with a volume of 150 ml, of methylene chloride. The organic phases are collected
and are washed, first with 200 ml of water, and then twice, each time with a
volume of 200 ml, with brine. The organic phase is dried with sodium sulphate.
After evaporation of the solvent are obtained 71.55 g of raw 3-benzyl-5-
hydroxymethyl-5-carboxyethyl isoxazoline (95.5% pure, by uncalibrated GC
analysis), used as such in the subsequent step.
Example 4: Synthesis of 3-benzvl. 5.5-bis (hvdroxvmethvn isoxazoline with NaBH4
In a 11 flask, equipped with thermometer and mechanical stirrer, in a nitrogen
atmosphere are added: 71.55 g (0.272 mol) of raw 3-benzyl-5-hydroxymethyl-5-
carboxyethyl isoxazoline deriving from Example 3 and 553 ml of methanol. The
solution is cooled to -10°C and in the time period of 1h are added: 10.29 g (0.272
mol) of NaBH4 granules (10-40 mesh). Once the addition is completed the
temperature is increased up to room temperature and the solution is allowed to stir
for 1h 30'. Then are added 250 ml of a saturated ammonium chloride solution
maintaining the temperature at approx. 20°C. The solvent is evaporated under
vacuum (24 mbar at 25°C). The residue is taken up with 150 ml of methylene
chloride and the residue formed after evaporation is dissolved in a minimum
quantity of water. The two phases obtained are separated and the aqueous one is
retroextracted three times, each time with a volume of 100 ml, with methylene
chloride. The organic phases are collected and dried with sodium sulphate. It is
filtered and, after evaporation of the solvent, 59.85 g of a raw orange oil product
are obtained. The raw product is crystallized in 150 ml of ethyl acetate and 140ml
of hexane. 39.91 g of 3-benzy!-5,5-bis (hydroxymethyl) isoxazoline as a pale
yellow solid are obtained. Another 4.16 g of product are recovered from the mother
liquors.
Example 4-b: Synthesis of 3-benzvl. 5.5-bis (hvdroxvmethyl) isoxazoline with
sodium_____dihvdro-bis-_____(2-methoxvethoxv)_____aluminium_____hvdride
(NaAIH?(OCH2CH2OCH3)2)
Following the same procedure described in example 4, 71.55g (0.272 mol) of raw
3-benzyl-5-hydroxymethyl-5-carboxyl isoxazoline (95.5% titre) dissolved in 550 ml
of methanol are made to react at -10"C with 80g (0.272 mol) of 70% (p/p) toluene
solution of sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride. The
reaction is carried out according to the description in example 4. obtaining 43.3g of
product
Example 5: Synthesis of 5-benzyl-2-hvdroxvmethvl furane
In a 1000 ml autoclave are added: 50.5 g (0.225 mol) of 3-benzyl,5-bis
(hydroxymethyi) isoxazoline deriving from Example 4 or from example 4-b, 3.0 g
(0.05 mol) of orthoboric acid (H3BO3), a hydroalcoholic solution of methanol/water
in a ratio of 550ml/110 ml and'5.0 g of Ni raney. The mixture is pressurized at 4
bar of hydrogen and left at this pressure for 8 hours,
The mixture is filtered and evaporated under vacuum (25°C/24 mbar). The residue
is treated with dichloromethane and 10% HCI. The organic phase is separated,
washed with water and with a brine solution and is afterwards dried on sodium
sulphate. It is filtered and the organic phase evaporated under vacuum obtaining
an oil that is purified through distillation (125-128oC/ 0.4 mbar). 35.0 g of 5-benzyl-
2-hydroxymethyl furane are obtained (yield 83%).
We Claim:
1. A process for the synthesis of 5-benzyl-3-furfuryl alcohol comprising the
following steps:
a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl)
acrylate with phenylacetaldehyde oxime in the presence of sodium
hypochlorite Naclo at a temperature between -10 °C and 80°C to give 3-
benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline;
b) reduction reaction with sodium borohydride (NaBH4) or with sodium
dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2)
of 3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature
between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl)
isoxazoline;
c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl)
isoxazoline at a temperature between 15°C and 100°C and hydrogen
pressure between 0.5 and 40 bar and consequent rearrangement to give 5-
benzyl-3-furfuryl alcohol.
2. The process as claimed in claim 1 wherein in the condensation reaction at
step a) the alkyl alpha- (hydroxymethyl) acrylate is selected from the group
consisting of methyl, ethyl or propyl alpha- (hydroxymethyl) acrylates.
3. The process as claimed in claim 2 wherein the alkyl alpha- (hydroxymethyl)
acrylate is ethyl alpha- (hydroxymethyl) acrylate.
4. The process as claimed in claim 1 wherein the condensation reaction at
step a) is carried out in aromatic or aliphatic halogenated solvents, such as
herein described.
5. The process as claimed in claim 4 wherein the aliphatic halogenated
solvents are 1 to 2 carbon atom aliphatic chlorinated solvents, such as herein
described.
6. The process as claimed in claim 5 wherein the solvent is methylene
chloride.
7. The process as claimed in claim 1 wherein the condensation reaction at
step a) is carried out at a temperature of between -10°C and 50°C.
8. The process as claimed in claim 7 wherein the reaction is carried out at a
temperature of between -10°C and 30°C.
9. The process as claimed in claim 1 wherein the condensation reaction at
step a) is carried out in the presence of an aqueous solution of sodium
hypochlorite with an active chlorine titre of between 5 and 10% p/p.
10. The process as claimed in claim 9 wherein the aqueous solution of
sodium hypochlorite has an active chlorine titre of between 8 and 10% p/p.
11. The process as claimed in claim 10 wherein the aqueous solution of
sodium hypochlorite has an active chlorine titre of 10% p/p.
12. The process as claimed in claim 1 wherein the reduction reaction at step
b) is carried out in a CrC4 aliphatic alcohol or their mixtures, or in aliphatic or
aromatic solvents selected from the group consisting of benzene, toluene,
xylene, cyclohexane, methylcyclohexane or mixtures thereof.
13. The process as claimed in claim 12 wherein the alcohol is methyl alcohol.
14. The process as claimed in claim 12 wherein the aromatic solvent is
toluene.
15. The process as claimed in claim 1 wherein the reduction reaction at step
b) is carried out at a temperature of between -10°C and 25°C.
16. The process as claimed in claim 1 wherein the reduction reaction at step
b) is carried out with sodium borohydride granules (10-40 mesh) in methanol
or with sodium dihydro-bis- (2-methoxyethoxy) aluminium hydride in toluene.
17. The process as claimed in claim 16 wherein the reduction reaction at step
b) is carried out in a 70% p/p solution in toluene of sodium dihydro-bis- (2-
methoxyethoxy) aluminium hydride.
18. The process as claimed in claim 1 wherein the hydrogenation reaction at
step c) is carried out at a hydrogen pressure is between 1 and 20 bar.
19. The process as claimed in claim 18 wherein the hydrogen pressure is
between 1 and 10 bar.
20. The process as claimed in claim 1 wherein the temperature of
hydrogenation at step c) is between 20°C and 60°C.
21. The process as claimed in claim 1 wherein the catalysts used in the
hydrogenation reaction at step c) are selected from the group consisting of
PtO2, PtO, Ni Raney, Pt on carbon, Pd on carbon, Pd on BaSO4, Pd on AI2O3,
Pt on AI2O3, Ru on carbon.
22. The process as claimed in claim 21 wherein the catalyst is selected from
the group consisting of Pd on carbon, PtO2 and Ni Raney.
23. The process as claimed in claim 22 wherein the catalyst is Ni Raney.
24. The process as claimed in claim 1 wherein the hydrogenation reaction at
step c) is carried out in a C1-C4 alcoholic solvent or mixtures thereof, or in
hydroalcoholic mixtures of said C1-C4 alcohols, the quantity of water of said
mixtures ranging from 7 to 50% v/v of the solution.
25. The process as claimed in claim 24 wherein the alcoholic solvent is
methanol.
26. The process as claimed in claim 24 wherein the solvent is a
methanol/water mixture with a quantity of water from 10 to 30% v/v.
27. The process as claimed in claim 26 wherein the methanol/water mixture
has a water content of 15% to 20% v/v.
28. The process as claimed in claim 1 wherein the hydrogenation reaction of
step c) is carried out in the presence of a weak organic or inorganic protic
acid.
29. The process as claimed in claim 28 wherein the acid is selected from the
group consisting of acetic acid, propionic, butyric, boric acid.
30. The process as claimed in claim 29 wherein the acid is selected out of
acetic acid or boric acid.
31. The process as claimed in claim 1 optionally comprising the treatment of
the residue obtained at the end of the hydrogenation reaction at step c) with
aqueous solutions of strong inorganic acids.
32. The process as claimed in claim 31 wherein the aqueous solution is a
10% (p/v) solution of HCI.
This invention discloses a process for the synthesis of 5-benzyl-3-furfuryl alcohol
comprising the following steps:
a) condensation reaction of the C1-C4 alkyl alpha- (hydroxymethyl)
acrylate with phenylacetaldehyde oxime in the presence of sodium hypochlorite
(NaOCl) at a temperature between -10 °C and 80°C to give 3-benzyl-5-
hydroxymethyl-5-carboxymethyl isoxazoline;
b) reduction reaction with sodium borohydride (NaBH4) or with sodium
dihydro-bis- (2-methoxyethoxy) aluminium hydride (NaAIH2(OCH2CH2OCH3)2) of
3-benzyl-5-hydroxymethyl-5-carboxymethyl isoxazoline at a temperature
between -15°C and 30°C to give 3-benzyl-5,5-bis (hydroxymethyl) isoxazoline;
c) catalytic hydrogenation reaction of 3-benzyl-5,5-bis (hydroxymethyl)
isoxazoline at a temperature between 15°C and 100°C and hydrogen pressure
between 0.5 and 40 bar and consequent rearrangement to give 5-benzyl-3-
furfuryl alcohol.

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Patent Number

225276

Indian Patent Application Number

01397/KOLNP/2003

PG Journal Number

45/2008

Publication Date

07-Nov-2008

Grant Date

05-Nov-2008

Date of Filing

31-Oct-2003

Name of Patentee

ENDURA S.P.A.

Applicant Address

VIALLE PIETRAMELLARA 5, I-40121 BOLOGNA

Inventors:

#	Inventor's Name	Inventor's Address
1	BORZATTA VALERIO	VIA BELLETTINI, 20, I-40127 BOLOGNA
2	BRANCALEONI DARIO	VIA GAGARIN, 40, I-40044 SASSO MARCONI
3	ROSINI GOFFREDO	VIA A FRANK, 11, I-40135 BOLOGNA
4	D' ADAMO LUCILLA	CORSO EUROPA, 31, I-66054 VASTO

PCT International Classification Number

C07D 307/42

PCT International Application Number

PCT/EP02/04576

PCT International Filing date

2002-04-25

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2001A000914	2001-05-04	Italy