METHOD FOR PRODUCING ESTERS OF HOMOVANILLIC ACID

Abstract

The present invention primarily relates to a method for producing a compound of formula (I) and/or a physiologically acceptable salt thereof from vanillylmandelic acid and/or a physiologically acceptable salt thereof. The present invention further relates to the simultaneous use of one or more iodide salt(s) or hydrate(s) thereof, one or more reducing agent(s), one or more inorganic and/or organic acid(s) other than phosphonic acid, and methanol and/or a physiologically acceptable salt thereof or an alcohol of formula (II) as defined herein and/or a physiologically acceptable salt thereof for converting vanillylmandelic acid and/or a physiologically acceptable salt thereof into a compound of formula (I) and/or a physiologically acceptable salt thereof or into a compound of formula (III) as defined herein and/or a physiologically acceptable salt thereof.

Claims

1-15. (canceled)

16. A method for producing a compound of formula (I) or a physiologically acceptable salt thereof comprising: ##STR00021## (a) simultaneously reacting vanillylmandelic acid and/or a physiologically acceptable salt thereof with: one or more iodide salts or hydrates thereof, one or more reducing agents, one or more inorganic and/or organic acids other than phosphonic acid, and methanol and/or a physiologically acceptable salt thereof or an alcohol of formula (II) and/or a physiologically acceptable salt thereof: ##STR00022## and (b) provided that methyl-2-(4-hydroxy-3-methoxy-phenyl)acetate of formula (III) and/or a physiologically acceptable salt thereof is obtained in (a), ##STR00023## subjecting the compound of formula (III) and/or physiologically acceptable salt thereof and an alcohol of formula (II) and/or a physiologically acceptable salt thereof to a transesterification reaction to obtain a compound of formula (I) and/or a physiologically acceptable salt thereof, or provided that a compound of formula (I) and/or a physiologically acceptable salt thereof is obtained in (a), optionally subjecting the compound of formula (I) and/or salt thereof obtained in (a) and an alcohol of formula (II) that is different from the alcohol of formula (II) of (a) and/or a physiologically acceptable salt thereof to a transesterification reaction, wherein in the compound of formula (I) and in the alcohol of formula (II), respectively, (i) R.sup.1 and R.sup.2 independently represent hydrogen or an alkyl residue with 1-2 carbon atoms, and R.sup.3 and R.sup.4 independently represent a residue selected from hydrogen, linear or branched alkyl with 1-5 carbon atoms, phenyl, alkylphenyl, phenylalkyl, linear or branched alkenyl with 2-4 carbon atoms, alkenylphenyl, and phenylalkenyl, or (ii) R.sup.1 and R.sup.3 form a cyclohexyl ring together with carbon atoms that link them, the cyclohexyl ring optionally carrying a residue R.sup.5, wherein R.sup.5 represents an alkyl residue with 1-2 carbon atoms, and R.sup.2 represents hydrogen or an alkyl residue with 1-2 carbon atoms, and R.sup.4 represents a residue selected from hydrogen, linear or branched alkyl with 1-5 carbon atoms, phenyl, alkylphenyl, phenylalkyl, linear or branched alkenyl with 2-4 carbon atoms, alkenylphenyl, and phenylalkenyl.

17. The method of claim 16, wherein a total amount of 0.1-1 equivalents of the one or more iodide salts or hydrates thereof is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

18. The method of claim 16, wherein a total amount of 0.5-2 equivalents of the one or more reducing agents is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

19. The method of claim 16, wherein a total amount of 0.1-2 equivalents of the one or more inorganic and/or organic acids is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

20. The method of claim 16, wherein a total amount of 2-20 equivalents of the methanol and/or salt thereof or alcohol of formula (II) and/or salt thereof is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

21. The method of claim 16, wherein the one or more iodide salts or hydrates thereof are selected from magnesium iodide, magnesium iodide hydrate, potassium iodide, potassium iodide hydrate, ammonium iodide, ammonium iodide hydrate, sodium iodide, sodium iodide hydrate, lithium iodide, and lithium iodide hydrate.

22. The method of claim 16, wherein the one or more inorganic and/or organic acids are selected from sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid.

23. The method of claim 16, wherein the alcohol of formula (II) is selected from ethanol, 2-phenylethanol, (E)-3-phenylprop-2-en-1-ol, hexan-3-ol, 3-methylbut-2-en-1-ol, (E)-hex-2-en-1-ol, (Z)-hex-3-en-1-ol, propan-2-ol, butan-2-ol, 2-methylpropan-1-ol, 2-methylbutan-2-ol, 3-methylbutan-1-ol, 2-methylbutan-1-ol, hexan-2-ol, heptan-1-ol, heptan-2-ol, 2-isopropyl-5-methyl-cyclohexanol, propan-1-ol, butan-1-ol, pentan-1-ol, hexan-1-ol, 3-phenylpropan-1-ol, and 4-phenylbutan-1-ol.

24. The method of claim 16, wherein the compound of formula (I) and/or a physiologically acceptable salt thereof is incorporated into a pharmaceutical preparation, a preparation used in nutrition, oral hygiene, or consumed for pleasure.

25. A method for converting vanillylmandelic acid and/or a physiologically acceptable salt thereof into a compound of formula (I) and/or a physiologically acceptable salt thereof or into methyl-2-(4-hydroxy-3-methoxy-phenyl)acetate of formula (III) and/or a physiologically acceptable salt thereof comprising: ##STR00024## simultaneously combining: one or more iodide salts or hydrates thereof, one or more reducing agents, one or more inorganic and/or organic acids other than phosphonic acid, and methanol and/or a physiologically acceptable salt thereof or an alcohol of formula (II) and/or a physiologically acceptable salt thereof. ##STR00025## wherein in the compound of formula (I) and in the alcohol of formula (II), respectively, (i) R.sup.1 and R.sup.2 independently represent hydrogen or an alkyl residue with 1-2 carbon atoms, and R.sup.3 and R.sup.4 independently represent a residue selected from hydrogen, linear or branched alkyl with 1-5 carbon atoms, phenyl, alkylphenyl, phenylalkyl, linear or branched alkenyl with 2-4 carbon atoms, alkenylphenyl, and phenylalkenyl, or (ii) R.sup.1 and R.sup.3 form a cyclohexyl ring together with carbon atoms that link them, the cyclohexyl ring optionally carrying a residue R.sup.5, wherein R.sup.5 represents an alkyl residue with 1-2 carbon atoms, and R.sup.2 represents hydrogen or an alkyl residue with 1-2 carbon atoms, and R.sup.4 represents a residue selected from hydrogen, linear or branched alkyl with 1-5 carbon atoms, phenyl, alkylphenyl, phenylalkyl, linear or branched alkenyl with 2-4 carbon atoms, alkenylphenyl, and phenylalkenyl.

26. The method of claim 25, wherein a total amount of 0.1-1 equivalents of the one or more iodide salts or hydrates thereof is used based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

27. The method of claim 25, wherein a total amount of 0.5-2 equivalents of the one or more reducing agents is used based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

28. The method of claim 25, wherein a total amount of 0.1-2 equivalents of the one or more inorganic and/or organic acids is used based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

29. The method of claim 25, wherein a total amount of 2-20 equivalents of the methanol and/or salt thereof or alcohol of formula (II) and/or salt thereof is used based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

30. The method of claim 25, wherein the one or more iodide salts or hydrates thereof are selected from magnesium iodide, magnesium iodide hydrate, potassium iodide, potassium iodide hydrate, ammonium iodide, ammonium iodide hydrate, sodium iodide, sodium iodide hydrate, lithium iodide, and lithium iodide hydrate, the one or more inorganic and/or organic acid(s) is/are selected from the group consisting of sulfuric acid, preferably concentrated sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid monohydrate, and hydrochloric acid, preferably wherein the inorganic and/or organic acid is methanesulfonic acid, the alcohol of formula (II) is selected from ethanol, 2-phenylethanol, (E)-3-phenylprop-2-en-1-ol, hexan-3-ol, 3-methylbut-2-en-1-ol, (E)-hex-2-en-1-ol, (Z)-hex-3-en-1-ol, propan-2-ol, butan-2-ol, 2-methylpropan-1-ol, 2-methylbutan-2-ol, 3-methylbutan-1-ol, 2-methylbutan-1-ol, hexan-2-ol, heptan-1-ol, heptan-2-ol, 2-isopropyl-5-methyl-cyclohexanol, propan-1-ol, butan-1-ol, pentan-1-ol, hexan ol, 3-phenylpropan-1-ol, and 4-phenylbutan-1-ol.

31. The method of claim 16, wherein the one or more reducing agents is phosphoric acid.

32. The method of claim 16, wherein a total amount of 0.35-0.85 equivalents of the one or more iodide salts or hydrates thereof is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

33. The method of claim 16, wherein a total amount of 0 0.9-1.2 equivalents of the one or more reducing agents is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof, and wherein the one or more reducing agents comprise phosphonic acid.

34. The method of claim 16, wherein a total amount of 0.3-1.5 equivalents of the one or more inorganic and/or organic acids is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

35. The method of claim 16, wherein a total amount of 4-12 equivalents of the methanol and/or salt thereof or alcohol of formula (II) and/or salt thereof is reacted in (a) based on 1 equivalent of the vanillylmandelic acid and/or salt thereof.

Description

EXAMPLES

Example 1: Method According to the Invention for Producing ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17)

[0113] ##STR00010##

[0114] Step (a): To a solution of vanillylmandelic acid (600 g, 3.03 mol) in ethanol (642 g, 13.96 mol) was given sodium iodide (364 g, 2.43 mol), phosphonic acid (248 g, 3.02 mol), and methanesulfonic acid (36.4 g, 0.38 mol) at room temperature. The resulting reaction mixture was then heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 1600 g water and 336 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Next, under reduced pressure a water/ethanol mixture was distilled off and the remaining residue was extracted with 800 g MtBE (methyl-tert-butyl ether) and 400 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and the product was purified by distillation. Ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17) was isolated as liquid in 85% yield and 97% purity.

[0115] Analytical data of the ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17) obtained:

[0116] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.85 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.76 (dd, J=8.1, 2.0, 1H), 5.62 (s, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.87 (s, 3H), 3.53 (s, 2H), 1.25 (t, J=7.1 Hz, 3H).

[0117] .sup.13C-NMR (100 MHz, CDCl.sub.3): δ=171.9, 146.5, 144.7, 125.9, 122.1, 114.4, 111.7, 60.8, 55.9, 41.0, 14.2.

[0118] GCMS: m/z (%)=210 [M.sup.+] (30), 137 (100), 122 (11), 107 (2), 94 (8), 77 (2), 66 (3), 51 (3), 39 (3), 29 (8).

Example 2: Method According to the Invention for Producing 3-phenylpropyl 2-(4-hydroxy-3-methoxy-phenyl)acetate (22) via Transesterification of ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17)

[0119] ##STR00011##

[0120] Step (a) of the method is carried out as described in Example 1.

[0121] Step (b): To 308 g (1.44 mol) of ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17) were added 235 g (1.73 mol) of 3-phenyl-propan-1-ol and 5.8 g (0.06 mol) of methanesulfonic acid. The reaction mixture was first stirred for 30 minutes under reflux at 200 mbar. Next, the reaction mixture was then stirred under reflux at 150 mbar for 12 hours while ethanol was continuously distilled off. After the addition of 4.3 g (0.04 mol) soda at room temperature, excess 3-phenyl-propan-1-ol as well as remaining amounts of ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17) were distilled off at 1 mbar and 135-175° C. Finally, using a thin film evaporator, 3-phenylpropyl 2-(4-hydroxy-3-methoxy-phenyl)acetate (22) was obtained in 85% yield and 98% purity.

[0122] Analytical data of the 3-phenylpropyl 2-(4-hydroxy-3-methoxy-phenyl)acetate (22) obtained:

[0123] .sup.1H-NMR (600 MHz, CDCl.sub.3): δ=7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.14-7.10 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.78 (dd, J=8.1, 2.0 Hz, 1H), 5.57 (s, 1H), 4.10 (t, J=6.5 Hz, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 2.64 (dd, J=8.5, 6.8 Hz, 2H), 1.98-1.90 (m, 2H).

[0124] .sup.13C-NMR (151 MHz, CDCl.sub.3): δ=171.91, 146.46, 144.75, 141.09, 128.42, 128.37, 126.00, 125.88, 122.13, 114.36, 111.68, 64.10, 55.90, 41.08, 32.06, 30.16.

[0125] GC-MS: m/z (%)=300 [M+] (28), 182 (62), 137 (100), 122 (16), 118 (20), 91 (34), 77 (6), 65 (6), 51 (4), 28 (4).

Example 3: Method According to the Invention for Producing the Compound of Formula (III) (methyl-2-(4-hydroxy-3-methoxy-phenyl)acetate)

[0126] ##STR00012##

[0127] Step (a): To a solution of vanillylmandelic acid (500 mg, 2.5 mmol) in methanol (1.6 g, 50.5 mmol), sodium iodide (300 mg, 2.0 mmol), phosphonic acid (200 mg, 2.5 mmol) and methanesulfonic acid (400 mg, 3.8 mmol) were added at room temperature. The resulting reaction mixture was then heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 10 g water and 2 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, methanol was distilled off under reduced pressure and the remaining residue was extracted with 20 g MtBE and 20 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and the compound of formula (III) was isolated by silica gel column chromatography (n-hexane/EtOAc, 4:1) in 86% yield and 99% purity.

[0128] Analytical data of the compound of formula (III) obtained:

[0129] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 6.76 (ddq, J=8.0, 2.0, 0.5 Hz, 1H), 5.63-5.59 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 3.55 (t, J=0.6 Hz, 2H).

[0130] .sup.13C-NMR (151 MHz, CDCl.sub.3): δ=172.4, 146.5, 144.8, 125.7, 122.4, 114.4, 111.73, 55.9, 52.0, 40.8.

Example 4: Method According to the Invention for Producing (2-iso-propyl-5-methyl-cyclohexyl)-2-(4-hydroxy-3-methoxy-phenyl)acetate (16) via Transesterification of the Compound of Formula (III)

[0131] ##STR00013##

[0132] Step (a) of the method is carried out as described in Example 3.

[0133] Step (b): To 5 g (25.5 mmol) of compound of formula (III) 4.5 g (28.5 mmol) of 2-isopropyl-5-methyl-cyclohexanol and 0.2 g (2.4 mmol) of methanesulfonic acid were added. The reaction mixture was first stirred for 30 minutes under reflux at 200 mbar. Subsequently, the reaction mixture was stirred under reflux at 150 mbar for 12 hours while methanol was continuously distilled off. After the addition of soda at room temperature, excess 2-isopropyl-5-methyl-cyclohexanol as well as remaining amounts of compound of formula (III) were distilled off at 1 mbar and 170-185° C. Finally, silica gel column chromatography (n-hexane/EtOAc, 5:1) of the residue was performed to obtain (2-iso-propyl-5-methyl-cyclohexyl)-2-(4-hydroxy-3-methoxy-phenyl)acetate (16) in 36% yield and 99% purity.

[0134] Analytical data of the (2-iso-propyl-5-methyl-cyclohexyl)-2-(4-hydroxy-3-methoxy-phenyl)acetate (16) obtained:

[0135] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.85 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.76 (dd, J=8.1, 2.0 Hz, 1H), 5.53 (s, 1H), 4.66 (td, J=10.9, 4.4 Hz, 1H), 3.88 (s, 3H), 3.51 (s, 2H), 1.97 (dtd, J=12.0, 3.8, 1.9 Hz, 1H), 1.75 (heptd, j=7.0, 2.7 Hz, 1H), 1.71-1.60 (m, 2H), 1.53-1.40 (m, 1H), 1.36 (ddt, J=12.4, 10.8, 3.2 Hz, 1H), 1.09-1.00 (m, 1H), 0.98-0.92 (m, 1H), 0.89 (d, J=6.5 Hz, 3H), 0.84 (d, J=7.1 Hz, 3H), 0.81 (s, 1H), 0.69 (d, J=7.0 Hz, 3H).

[0136] .sup.13C-NMR (100 MHz, CDCl.sub.3): δ=171.5, 146.4, 144.6, 126.2, 122.1, 114.3, 111.6, 74.6, 55.9, 47.1, 41.5, 40.8, 34.2, 31.4, 26.2, 23.4, 22.1, 20.7, 16.3.

Example 5: Method According to the Invention for Producing 2-phenylethyl-2-(4-hydroxy methoxy-phenyl)acetate (1) Via Transesterification of the Compound of Formula (III)

[0137] ##STR00014##

[0138] Step (a) of the method is carried out as described in Example 3.

[0139] Step (b): To 5 g (25.5 mmol) of compound of formula (III) 3.5 g (28.5 mmol) of 2-phenyl-ethanol and 0.2 g (2.4 mmol) of methanesulfonic acid were added. The reaction mixture was first stirred for 30 minutes under reflux at 200 mbar. Subsequently, the reaction mixture was stirred under reflux at 150 mbar for 12 hours while methanol was continuously distilled off. After the addition of soda at room temperature, excess 2-phenyl-ethanol as well as remaining amounts of compound of formula (III) were distilled off at 1 mbar and 135-175° C. Finally, silica gel column chromatography (n-hexane/EtOAc, 5:1) of the residue was performed to obtain 2-phenylethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (1) in 82% yield and 99% purity.

[0140] Analytical data of the 2-phenylethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (1) obtained:

[0141] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.29-7.24 (m, 2H), 7.24-7.19 (m, 1H), 7.16-7.42 (m, 2H), 6.85 (d, J=7.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 6.72 (dd, J=8.0, 1.9 Hz, 1H), 5.57 (s, 1H), 4.30 (t, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.51 (s, 2H), 2.91 (t, J=6.9 Hz, 2H).

[0142] .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=171.8, 146.4, 144.7, 137.7, 128.9, 128.9, 128.4, 128.4, 126.5, 125.7, 122.2, 114.3, 111.7, 65.3, 55.9, 41.1, 35.0

Example 6: Method According to the Invention for Producing hexyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (21)

[0143] ##STR00015##

[0144] Step (a): To a solution of vanillylmandelic acid (500 mg, 2.5 mmol) in n-hexanol (5.2 g, 50.5 mmol), sodium iodide (300 mg, 2.0 mmol), phosphonic acid (200 mg, 2.5 mmol), and methanesulfonic acid (400 mg, 3.8 mmol) were added at room temperature. The resulting reaction mixture was then heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 10 g water and 2 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, n-hexanol was distilled off under reduced pressure and the remaining residue was extracted with 20 g MtBE and 20 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and hexyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (21) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 43% yield and 99% purity.

[0145] Analytical data of the hexyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (21) obtained:

[0146] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.85 (dd, J=8.1, 0.3 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.76 (ddq, J=8.1, 2.0, 0.5 Hz, 1H), 5.58 (s, 1H), 4.08 (t, J=6.7 Hz, 2H), 3.86 (s, 3H), 3.53 (s, 2H), 165-1.56 (m, 2H), 1.36-1.2 (m, 6H), 0.87 (t, J=7.0 Hz, 3H).

[0147] .sup.13C-NMR (100 MHz, CDCl.sub.3): δ=172.0, 146.5, 144.7, 126.0, 122.1, 114.3, 111.7, 65.0, 55.9, 41.1, 31.4, 28.6, 25.5, 22.5, 14.0.

Example 7: Method According to the Invention for Producing butyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (19)

[0148] ##STR00016##

[0149] Step (a): To a solution of vanillylmandelic acid (500 mg, 2.5 mmol) in n-butanol (3.8 g, 50.5 mmol), sodium iodide (300 mg, 2.0 mmol), phosphonic acid (200 mg, 2.5 mmol), and methanesulfonic acid (400 mg, 3.8 mmol) were added at room temperature. The resulting reaction mixture was then heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 10 g water and 2 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, n-butanol was distilled off under reduced pressure and the remaining residue was extracted with 20 g MtBE and 20 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and butyl-2-(4-hydroxy methoxy-phenyl)acetate (19) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 56% yield and 99% purity.

[0150] Analytical data of the butyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (19) obtained:

[0151] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.85 (d, J=8.1 Hz, 1H), 6.81 (dd, J=2.0, 0.5 Hz, 1H), 6.76 (ddt, J=8.1, 1.9, 0.6 Hz, 1H), 5.60 (s, 1H), 4.09 (t, J=6.7 Hz, 2H), 3.87 (d, J=0.3 Hz, 3H), 3.53 (t, J=0.5 Hz, 2H), 1.67-1.55 (m, 2H), 1.42-1.29 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).

[0152] .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=172.0, 146.5, 144.7, 126.0, 122.1, 114.3, 111.7, 64.7, 55.9, 41.1, 30.6, 19.1, 13.7.

Example 8: Method According to the Invention for Producing 2-methylbutyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (12)

[0153] ##STR00017##

[0154] Step (a): To a solution of vanillylmandelic acid (500 mg, 2.5 mmol) in 2-methylbutan-1-ol (3.0 g, 34.0 mmol), sodium iodide (300 mg, 2.0 mmol), phosphonic acid (200 mg, 2.5 mmol), and methanesulfonic acid (400 mg, 3.8 mmol) were added at room temperature. The resulting reaction mixture was then heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 10 g water and 2 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, 2-methylbutan-1-ol was distilled off under reduced pressure and the remaining residue was extracted with 20 g MtBE and 20 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and 2-methylbutyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (12) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 49% yield and 99% purity.

[0155] Analytical data of the 2-methylbutyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (12) obtained:

[0156] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.86 (d, J=8.1 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 5.55 (s, 1H), 3.97 (dd, J=10.7, 6.0 Hz, 1H), 3.90 (dd, J=10.8, 6.7 Hz, 1H), 3.88 (s, 3H), 3.54 (s, 2H), 1.69 (dddd, J=12.4, 7.8, 6.8, 5.8 Hz, 1H), 1.38 (dtd, J=13.1, 7.5, 5.6 Hz, 1H), 1.23-1.08 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.5 Hz, 3H).

[0157] .sup.13C-NMR (100 MHz, CDCl.sub.3): δ=172.0, 146.4, 144.7, 126.0, 122.1, 114.3, 111.7, 69.4, 55.9, 41.1, 34.1, 26.0, 16.3, 11.2.

Example 9: Method According to the Invention for Producing ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17)

[0158] ##STR00018##

[0159] Step (a): Sodium iodide (500 mg, 12.6 mmol), phosphonic acid (4.2 g, 50.5 mmol), and 4-methylbenzenesulfonic acid (9.6 g, 50.5 mmol) were added at room temperature to a solution of vanillylmandelic acid (5 g, 25.2 mmol) in ethanol (23 g, 514.7 mmol). The resulting reaction mixture was heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 160 g water and 30 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, a water/ethanol mixture was distilled off under reduced pressure and the remaining residue was extracted with 100 g MtBE and 40 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and the ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 91% yield and 98% purity.

Example 10: Method According to the Invention for Producing ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17)

[0160] ##STR00019##

[0161] Step (a): Magnesium iodide (2.1 g, 7.6 mmol), phosphonic acid (4.2 g, 50.5 mmol), and 4-sulfuric acid (4.9 g, 50.5 mmol) were added at room temperature to a solution of vanillylmandelic acid (5 g, 25.2 mmol) in ethanol (23 g, 514.7 mmol). The resulting reaction mixture was heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 160 g water and 30 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, a water/ethanol mixture was distilled off under reduced pressure and the remaining residue was extracted with 100 g MtBE and 40 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and the ethyl-2-(4-hydroxy methoxy-phenyl)acetate (17) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 79% yield and 99% purity.

Example 11: Method According to the Invention for Producing ethyl-2-(4-hydroxy-3-methoxy-phenyl)acetate (17)

[0162] ##STR00020##

[0163] Step (a): Potassium iodide (2.1 g, 7.6 mmol), phosphonic acid (4.2 g, 50.5 mmol), and 4-methanesulfonic acid (4.8 g, 50.5 mmol) were added at room temperature to a solution of vanillylmandelic acid (5 g, 25.2 mmol) in ethanol (23 g, 514.7 mmol). The resulting reaction mixture was heated for 4 hours at 80° C. while stirring. After cooling to room temperature, 160 g water and 30 g solid Na.sub.2SO.sub.3 were added to the mixture and stirred for an additional 10 minutes. Subsequently, a water/ethanol mixture was distilled off under reduced pressure and the remaining residue was extracted with 100 g MtBE and 40 g saturated NaCl solution. The organic phase was finally concentrated under reduced pressure and the ethyl-2-(4-hydroxy methoxy-phenyl)acetate (17) was isolated by silica gel column chromatography (n-hexane/EtOAc, 3:1) in 82% yield and 97% purity.