Process for preparing substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds

Abstract

A process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds which has advantages over conventional processes with respect to higher conversions and yields, flexibility, a shorter overall route, environmentally acceptable conditions, influence of stereoselectivity such as diastereoselectivity in a targeted manner and at least partial suppression of the formation of undesired side-products and/or undesired stereoisomers, in particular undesired diastereomers.

Claims

1. A method of preparing a compound according to formula (I) ##STR00030## wherein R.sup.1, R.sup.2, and R.sup.3 are each independently selected from H or C.sub.1-4 aliphatic residues, or a physiologically acceptable acid addition salt thereof, said method comprising the steps of: hydrogenating a compound according to formula (C—I) ##STR00031## wherein R.sup.3 is defined above, to a compound a according to formula (C-II) ##STR00032## wherein R.sup.3 is defined as above, substituting at least one hydrogen atom of the primary amine group of the compound according to formula (C-II) with a C.sub.1-4 aliphatic residue to form the compound according to formula (I), and optionally converting the compound according to formula (I) into a physiologically acceptable acid addition salt thereof.

2. The method according to claim 1, wherein said compound is in the form of an isolated stereoisomer.

3. The method according to claim 2, wherein said compound is in the form of an isolated enantiomer or diastereomer.

4. The method according to claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

5. The method according to claim 4, wherein said compound is in the form of a racemic mixture of stereoisomers.

6. The method according to claim 1, wherein the hydrogenation is effected by a homogeneous or heterogeneous catalyst in the presence of hydrogen.

7. The method according to claim 6, wherein the homogenous catalyst is a transition metal complex.

8. The method according to claim 7, wherein the transition metal complex includes rhodium, iridium or ruthenium, or rhodium with diphosphine ligands, wherein the diphosphine ligands.

9. The method according to claim 7, wherein the homogeneous catalyst is rhodium (−)-DIPAMP [(R,R)-(+1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodium (+)-DIPAMP [(S, S)-(+)-1,2-Bis[(2-methoxyphenyl(phenyl)phosphino]ethane], rhodium R-Solphos [R-(+)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine ]or rhodium S-Solphos [S-(−)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine].

10. The method according to claim 6, wherein the heterogeneous catalyst is one or more transition metals, wherein the one or more transition metals is in the same or different oxidation states or in two or more different oxidation states.

11. The method according to claim 10, wherein the heterogeneous catalyst is Raney nickel, palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon or rhodium on carbon.

12. The method according to claim 1, wherein the compound according to formula (C-II) is optionally converted into a physiologically acceptable acid addition salt.

13. The method according to claim 1, wherein the compound according to formula C-I is prepared according to the following steps: desiylating a compound according to formula (C-0-I) ##STR00033## wherein R.sup.3 is H or a C.sub.1-4 aliphatic residue, and R.sup.a, R.sup.b, R.sup.c is C.sub.1-8 aliphatic residue or aryl, to a compound according to formula (C-0-II) ##STR00034## and dehydrating the compound according to formula (C-0-II) to the compound according to formula (I).

14. The method according to claim 13, wherein the compound according to formula (C-0-I) and (C-0-II) are produced into the compound according to formula (I) without any isolation steps.

15. The method according to claim 13, wherein the desilylating is acid catalyzed, acid promoted or performed in the presence of a fluoride source or optionally in the presence of a base when R.sup.a, R.sup.b, R.sup.c is each methyl.

16. The method according to claim 13, wherein the desilylating is acid catalyzed in the presence of a catalytically effective or at least stoichiometric amount of an acid selected from formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, phosphoric acid, or combinations thereof.

17. The method according to claim 13, wherein the dehydrating is acid catalyzed or acid promoted in the presence of a catalytically effective or at least stoichiometric amount of an acid selected from formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, phorphorous pentoxide, thionyl chloride, phosphoryl chloride, or combinations thereof.

18. The method according to claim 13, wherein any one of the compounds according to formula (C-I), (C-II), (C-0I), (C-0-II), or (I), wherein R.sup.3 is not hydrogen, undergoes deprotecting to produce a compound according to formula (Ib) ##STR00035##

19. The method according to claim 18, wherein the compound according to formula (C-I), (C-II), or (I) undergoes deprotecting.

20. The method according to claim 13, wherein the compound according to formula (C-I) is produced according to the following steps: reacting a compound according to formula (C-0-III) ##STR00036## wherein R.sup.3 is a H or a C.sub.1-4 aliphatic residue with a compound having a formula SiR.sup.aR.sup.bR.sup.c(CN), wherein R.sup.a, R.sup.b, R.sup.care each independently selected from C.sub.1-8aliphatic residues or aryl, to produce a compound, according to formula (C-0-I).

21. The method according to claim 20, wherein the compound according to formula SiR.sup.aR.sup.bR.sup.c(CN) is trimethylsilylcyanide, triethylsilylcyanide, tri-n-propylsilylcyanide or triisopropylsilylcyanide.

22. The method according to claim 1, wherein R.sup.1 and R.sup.2 of formula (I) are each selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; R.sup.3 of formula (I) is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

23. The method according to claim 1, wherein R.sup.1 and R.sup.2 of formula (I) are each selected from H or methyl; and R.sup.3 of formula (I) is selected from H or methyl.

Description

EXAMPLES

(1) In the following, the present invention is illustrated by a number of examples for each of the alternatives A to C of the process of the invention. The examples are only illustrative do not limit the scope of the invention.

(2) Abbreviations Used In The Examples

(3) AlBN: azo-bis-isobutyronitrile

(4) AlCl.sub.3: aluminium chloride

(5) Eq.: equivalents

(6) CC: column chromatography on silica gel

(7) DCC: N,N′-dicyclohexyl carbodiimide

(8) THF: tetrahydrofuran

(9) TEA: triethylamine

(10) h: hour(s)

(11) HPLC: high performance liquid chromatography

(12) HBr: hydrobromic acid

(13) HCl: hydrochloric acid

(14) MgSO.sub.4: magnesium sulfate

(15) NH.sub.4HSO.sub.4: ammonium hydrogen sulfate

(16) NaOH: sodium hydroxide

(17) NaCl: sodium chloride

(18) NaHCO.sub.3: sodium hydrogen carbonate

(19) Na.sub.2CO.sub.3: sodium carbonate

(20) KOtBu: potassium tert-butylate

(21) LAH: lithium aluminium hydride

(22) HOBT (1-HBT): 1-hydroxybenzotriazol

(23) RT: room temperature

(24) TMSCN: trimethylsilylcyanide

(25) TBAB: tetra-n-butylammoniumbromide

(26) GC-MS: gas chromatographic/mass spectrometric analysis

(27) “M” and “N” are concentrations in mol/l. “%” is wt.-% unless indicated otherwise. The yields of any compounds obtained in any steps of the process of the invention have not been optimized. Any temperatures were not corrected.

(28) All compounds not explicitly described were either commercially available (e.g. from Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood etc.) (syntheses of these compounds may e.g. be researched in the “Symyx® Available Chemicals Database” of the company MDL, San Ramon, US) or the syntheses of these compounds has been already described by technical literature sources (experimental procedures may e.g. by researched in the “Reaxys®” database of the company Elsevier, Amsterdam, NL) or these compounds may be synthesized according to conventional procedures known to a person skilled in the art.

(29) Silica gel 60 (0.010-0.063 mm; company: Merck, Darmstadt, Germany) was used as stationary phase for CC (column chromatography). Mixing ratios of any solvent or eluent mixtures are indicated in volume/volume. The analytical characterization of all compounds was performed by means of .sup.1H-NMR spectroscopy and mass spectrometric analyses.

(30) A process according to alternative A for the preparation of different stereoisomers of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol is depicted in the following Scheme A:

(31) ##STR00026## ##STR00027##

Step a1a: Compound A2 (N,N-2-trimethyl-3-oxopentanamide)

(32) 32.1 ml (0.35 mol) phosphoryl trichloride (POCl.sub.3) were dissolved in 100 mL of toluene. 32.6 ml (0.3 mol) N,N-dimethylpropionamide (A1) (dissolved in 50 mL toluene) were added to the resulting solution under stirring under an inert gas atmosphere. The reaction mixture was heated to 80° C. for 6 h, allowed to cool to RT and stirred for another 12 h at RT. After evaporation of toluene under reduced pressure, the resulting mixture was stirred for 2 h. 100 mL toluene were then added, the resulting mixture was cooled to below 0° C. and icy water (100 mL) was added. Then, 24 g of solid NaOH, dissolved in water, were added to the mixture. After 1 h of stirring, 47.7 g Na.sub.2CO.sub.3 as solid were added and the resulting mixture was stirred for 16 h at RT. The organic layer was separated, dried over MgSO.sub.4 and distilled (0.8 bar, 78-82° C.). 10.8 g (46%) of A2 was obtained in form of a colorless solid.

Step a2a: Compounds A3a and A3b ((2RS,3SR)-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

(33) To 699 mg (29 mmol) of magnesium 20 mL of dry THF were added. A solution of 3.64 mL of 3-bromoanisole in 10 mL of dry THF was slowly added dropwise. After addition, the remaining suspension was refluxed for 2 h and then cooled to 0° C. 7.1 g (29 mmol) of anhydrous cerium (III) chloride were dissolved in 65 mL of dry THF and added to the reaction mixture which was then stirred for 90 minutes at 0° C. 3 g (19 mmol) of A2 (dissolved in 10 mL dry THF) were slowly added dropwise. After 1 h the reaction mixture was hydrolyzed by an aqueous saturated solution of NaHCO.sub.3 at 10-15° C. The organic layer was separated and the aqueous layer was extracted with diethyl ether three times. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:4)) yielded 3.29 g (65%) of A3a and A3b in form of a yellowish oil.

Step a1b: Compound A5 (3-(3-methoxyphenyl)-N,N,2-trimethyl-3-oxopropanamide)

(34) To 2,2,6,6-tetramethylpiperidine (17.5 g, 125 mmol) in 50 ml dry THF were added dropwise 72 ml (115 mmol) of a n-butyllithium solution in n-hexane (1.6 M) at −30° C. After 30 minutes of stirring, 5.0 g (50 mmol) N,N-dimethylpropionamide (A1) (dissolved in 50 mL dry THF) were added and the mixture was cooled to −70° C. and stirred for 1 h at this temperature. 22.5 g (125 mmol) ethyl-3-methoxybenzoate (dissolved in 30 mL dry THF) were slowly added dropwise and the resulting mixture was stirred for another 2 h at −70° C. After the mixture had been allowed to warm to RT, it was hydrolyzed by employing a diluted aqueous solution of HCl (36 mL). The mixture was then washed with diethyl ether several times. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/ethyl acetate (1:4)) yielded 6.5 g (55%) of A5 in form of a colorless oil.

Step a2b: Compounds A3c and A3d ((2RS,3RS)-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

(35) 2.4 g (6.4 mmol) anhydrous cerium (III) chloride were dissolved in 22 mL of dry THF. 2.13 mL (6.4 mmol) of a solution of ethyl magnesium bromide in diethyl ether (3 M) were added to the resulting solution at 0° C. and the mixture was stirred for 90 minutes at this temperature.

(36) 1 g (4.3 mmol) of A2 (dissolved in 5 mL dry THF) were slowly added dropwise. After 1 h of stirring the reaction mixture was hydrolyzed by employing an aqueous saturated solution of NaHCO.sub.3 at 10-15° C. The organic layer was separated and the aqueous layer was extracted with diethyl ether three times. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 740 mg (66%) of A3c and A3d in form of a yellowish oil.

Step a3a: Compound A6 (Z,E-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

(37) 3.25 g (12 mmol) A3a and A3b were dissolved in 35 mL of an aqueous solution of HBr (47%) and stirred for 20 h. The reaction mixture was then cooled to 0° C. 50 mL of ethyl acetate and 50 mL of water were added and the resulting mixture was alkalized with solid NaHCO.sub.3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 1.61 g (54%) of A6 in form of a colorless oil.

Step a3b: Compound A6 (Z,E-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

(38) 3.25 g (12 mmol) A3c and A3d were dissolved in 35 mL of an aqueous solution of HBr (47%) and stirred for 20 h. The reaction mixture was then cooled to 0° C. 50 mL of ethyl acetate and 50 mL of water were added and the resulting mixture was alkalized with solid NaHCO.sub.3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate several times. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 2.68 g (90%) of A6 in form of a colorless oil.

Step a4: Compound A7 (Z,E-3-(3-met-oxyphenyl)-N,N,2-trimethylpent-2-enamide)

(39) 700 mg (2.8 mmol) A6 were dissolved in 20 mL of dry THF. 318 mg (2.8 mmol) KOtBu were added to the resulting solution. The resulting mixture was refluxed for 3 h. After cooling to RT 50 mL of ethyl acetate and 50 mL of water were added. The layers of the resulting solution were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 430 mg (61%) of A7 in form of a colorless oil.

Step a5: Compounds A8a and A8b ((2RS,3RS)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

(40) 400 mg (1.6 mmol) A7 were placed in a hydrogenation apparatus and dissolved in 10 mL of methanol. 1 drop of concentrated HCl and a small amount of mg Pd/C (10% Pd) covering the tip of a spatula as catalyst were added under inert gas atmosphere. The resulting mixture was hydrogenated at room temperature under a H.sub.2-pressure of 1 bar for 6 h (91 mL H.sub.2 were used). The solids were filtered off and washed with methanol. The methanol portion and the filtrate were combined. After evaporation of the organic solvents, the residue was suspended in a mixture of water and diethyl ether (30 mL each). A diluted aqueous solution of NaOH was added to the mixture until alkalization. The layers of the resulting solution were separated and the aqueous layer was washed three times with diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 160 mg (45%) of A8a and A8b in form of a colorless oil. As a side product, A8c and A8d could be obtained in a yield of 25% (80 mg) in form of a colorless oil.

Step e0: Compounds A8a and A8b ((2RS,3RS)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

(41) 200 mg (0.8 mmol) of a mixture of A8c and A8d were dissolved in 4 mL of dry THF. 90 mg (0.8 mmol) KOtBu were added to the resulting solution. The resulting mixture was refluxed for 3 h. After cooling to RT 50 mL of ethyl acetate and 50 mL of water were added. The layers of the resulting solution were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo yielding a mixture of A8a/A8b and the starting material A8c/A8d (GC-MS: 1:4) in form of a yellowish oil.

Step a6: Compounds A9a and A9b ((2RS,3RS)3-(3-hydroxyphenyl)-N,N,2-trimethylpentanamide)

(42) To 202 mg D,L-methionine (1.4 mmol) and 2 mL methane sulfonic acid were added 170 mg (0.68 mmol) of A8a and A8b. The reaction mixture was stirred for 6 h. Water and ethyl acetate (20 mL each) were added. After neutralization with solid NaHCO.sub.3 the layers were separated from each other. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. 160 mg (99%) of A9a and A9b were obtained in form of a colorless oil.

Step a7: Compounds 1a and 1b ((2R,S,3RS)-3-(1-(dimethylamino)-2-methylpentan-3-yl)-phenol)

(43) To 1.6 mL (0.35 mmol) of LAH-THF solution (2.3 M) were added 120 mg (0.90 mmol) of AlCl.sub.3. The resulting mixture was stirred for 45 minutes at RT. 170 mg (0.72 mmol) of A9a and A9b (dissolved in 5 ml of dry THF) were added to the mixture at RT. The resulting mixture was then refluxed for 1 h. Then the reaction mixture was hydrolyzed by addition of 20 mL of an aqueous solution of NaHCO.sub.3 (10%). 20 mL of diethyl ether were added and the layers were separated from each other and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. 1a and 1b were obtained in form of a colorless oil. The hydrochloride salts of 1a and 1b were obtained by addition of trimethylsilylchloride (76 μl) to a solution of 1a and 1b in acetone (yield: 100 mg (54%) in form of a colorless solid).

Step a8: Compound A8c and A8d ((2RS,3SR)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

(44) 1 g (4 mmol) A6 were placed in a hydrogenation apparatus and dissolved in 10 mL of methanol. 1 drop of concentrated HCl and 250 mg Pd/C (10% Pd) as catalyst were added under inert gas atmosphere. The resulting mixture was hydrogenated at room temperature under a H.sub.2-pressure of 1 bar for 6 h (118 mL H.sub.2 were used). The solids were filtered out and washed with methanol. The methanol portion and the filtrate were combined. After evaporation of the organic solvents, the residue was suspended in a mixture of water and diethyl ether (30 mL each). Diluted aqueous solution of NaOH was added to the mixture until alkalization. The layers of the resulting solution were separated and the aqueous layer was washed three times with diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 1 g (99%) of A8c and A8D as a yellowish oil.

Step a10: Compound A9c and A9d ((2RS,3SR)-3-(3-hydroxyphenyl)-N,N,2-trimethylpentanamide)

(45) To 170 mg D,L-methionine (1.4 mmol) and 2 mL methane sulfonic acid were added 200 mg (0.80 mmol) of A8c and A8d. The reaction mixture was stirred for 6 h. Water and ethyl acetate (20 mL each) were added. After neutralization with solid NaHCO.sub.3 the layers were separated from each other. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. 170 mg (90%) of A9c and A9d were obtained in form of a colorless oil.

Step a11: Compound 1c and 1d ((2RS,3SR)-3-(1-(dimethylamino)-2-methylpentan-3-yl) phenol)

(46) To 1.56 mL (0.32 mmol) of LAH-THF solution (2.3 M) were added 113 mg (0.85 mmol) of AlCl.sub.3. The resulting mixture was stirred for 45 minutes at RT. 160 mg (0.68 mmol) of A9c and A9d (dissolved in 5 ml of dry THF) were added to the mixture at RT. The resulting mixture was then refluxed for 1 h. Then the reaction mixture was hydrolyzed by addition of 20 mL of an aqueous solution of NaHCO.sub.3 (10%). 20 mL of diethyl ether were added and the layers were separated from each other and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. 1c and 1d were obtained in form of a colorless oil. The hydrochloride salts of 1c and 1d were obtained by addition of trimethylsilylchloride (76 μl) to a solution of 1c and 1d in diethyl ether (yield: 100 mg (54%) in form of a colorless solid).

(47) A process according to alternative B for the preparation of 3-(3-methoxyphenyl)-2-methyl-pentyl-dimethylamine is depicted in the following Scheme B:

(48) ##STR00028##

Step b1: Compound B2 (3-(3-methoxyphenyl)-2-methylpentanal)

(49) Alternative a)

(50) To 1.46 g (0.06 mol) of magnesium were added 50 mL of dry THF. 5 drops of 3-bromoanisole were added to this mixture and the resulting suspension was refluxed until the reaction started. Then, a solution of 7.63 mL of 3-bromoanisole (0.06 mol) in 15 mL of dry THF was slowly added dropwise, thereby maintaining a constant reflux of the reaction mixture. After addition and refluxing of the reaction mixture for another hour, the mixture was cooled to −70° C. At this temperature 11.4 g (0.06 mol) copper(I) iodide (CuI) and 30 mL of dry THF were added. The mixture was then allowed to warm to around −65 to −60° C. At this temperature, commercially available 2-methyl-2-pentenal, dissolved in 15 mL of dry THF were added slowly to the reaction mixture. After stirring for 1 h at −65-−60° C., the reaction mixture was allowed to warm to 0° C. The reaction mixture was hydrolyzed by addition of 50 mL of a saturated aqueous solution of NH.sub.4HSO.sub.4. The mixture was then extracted three times with 100 mL of diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated and the remaining residue was dried in vacuo. CC (eluent: diisopropyl ether/n-hexane (1:30)) yielded 2.3 g (29%) of B2 as a colorless oil.

(51) Alternative b)

(52) 10.2 ml 3-bromoanisole (82 mmol) were dissolved in 30 mL of a mixture of dry diethyl ether/toluene (1:1) and cooled to −70° C. A solution of n-butyl lithium in n-hexane (55 mL, 1.6 M) was then added to the mixture and the reaction mixture was stirred for 4 h at this temperature. 3.6 g (80 mmol) of copper(I) cyanide (CuCN) were then added and the mixture was stirred another 30 minutes at −70° C. 4.6 mL (40 mmol) of pre-cooled 2-methy-2-pentenal and 5.9 mL of a BF.sub.3-diethyl ether-solution (47 mmol) in 30 mL of a mixture of dry diethyl ether/toluene (1:1) were slowly added dropwise at this temperature. The reaction mixture was the allowed to warm to RT and stirred or 16 h. 25 mL of a saturated aqueous solution of

(53) NH.sub.4OH were then added and the mixture was extracted with diethyl ether three times. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated and the remaining residue was dried in vacuo. 8 g (99%) of a colorless oil were obtained which—according to GC-MS analysis—contained 24% of B2.

Step b2: Compound 2 (3-(3-ethoxyphenyl)-2-methyl-pentyl-dimethylamine)

(54) To 4.8 mL of a methanolic solution of dimethylamine (9.6 mmol, 2M) were added 5 ml of methanol, 0.40 g (4.8 mmol) of dimethylamine hydrochloride and 0.18 g Na(CN)BH.sub.3 (4.8 mmol). Then, 1 g (4.8 mmol) B2, dissolved in 15 ml methanol, were added dropwise and the resulting mixture was stirred for 20 h at RT. The reaction mixture was poured into 15 mL of a cooled aqueous solution of HCl (16%) and extracted with dichloromethane. The layers were separated from each other and the aqueous layer was alkalized with solid KOH, saturated with NaCl and then extracted with dichloromethane. The dichloromethane layer was separated and dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. 0.21 g (19%) of 2 in form of a colorless oil were obtained.

(55) In Scheme C a process according to alternative C for the preparation of 3-(2-(aminomethyl)cyclohexyl)phenol is depicted and described below.

(56) ##STR00029##

Step c0: Compound C1 (3-(3-methoxyphenyl)pentan-2-one)

(57) To 2 mL (13 mmol) of commercially available 1-(3-methoxyphenyl)propan-2-one (e.g. from Lancaster)) were added 6.5 mL of an aqueous solution of NaOH (50%), a small amount of TBAB covering the tip of a spatula and 1.1 mL (14.1 mmol) of ethyl iodide. The resulting mixture was stirred for 12 h. After addition of 30 mL distilled water and 30 mL of toluene, the mixture was stirred for another hour. The layers were separated and the organic layer was washed with a saturated aqueous solution of NaCl. The layers were separated and the organic layer was dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. 2.2 g (86%) of C1 were obtained in form of a yellow oil.

Step c1: Compound C2 (3-(3-methoxyphenyl)-2-methyl-2-(trimethylsilyloxy)pentanenitrile)

(58) To a small amount covering the tip of a spatula of ZnI.sub.2 were added 4.4 g (23 mmol) of C1 and 3.4 mL (25 mmol) TMSCN. The resulting mixture was stirred for 60 minutes. After addition of 40 mL of dry n-hexane, the mixture was refluxed for 15 minutes. After addition of a small amount of charcoal covering the tip of a spatula, the resulting mixture was refluxed for another 15 minutes. The reaction mixture was then filtered. The solvents of the filtrate were then evaporated under reduced pressure. 6.5 g (97%) of C1 were obtained in form of a grey oil.

Step c2: Compound C3 (2-hydroxy-3-(3-methoxyphenyl)-2-methylpentanenitrile)

(59) To 120 mg (0.41 mmol) C2 were added 1.5 mL of dry methanol and the resulting mixture was cooled to 0° C. 300 μl of an aqueous solution of HCl (5 M) were added at this temperature and the mixture was stirred for 3 h at RT. The organic solvents were evaporated under reduced pressure and a mixture of water and diethyl ether was added to the remaining residue. NaHCO.sub.3 was added until the aqueous layer had been alkalized. The layers were separated and the aqueous layer was extracted several times with diethyl ether. The combined organic layers were dried over MgSO.sub.4. The organic solvent was evaporated under reduced pressure and the remaining residue was dried in vacuo. 89 mg (99%) of C3 were obtained in form of a colorless oil.

Step c3: Compounds C4 (Z,E-3-(3-methoxyphenyl)-2-methylpent-2-enenitrile)

(60) To 3.72 g (17 mmol) C3 were added 80 mL of toluene, 40 mL of pyridine and 81 mL of phosphoryl chloride (POCl.sub.3), dissolved in 16 mL pyridine. The resulting mixture was refluxed for 1 h. After cooling, the reaction mixture was poured into ice water. Ethyl acetate was then added and the layers were separated from each other. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with distilled water, with a diluted aqueous solution of NaOH and were then dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether (10:1)) yielded 1.71 g (50%) of Z-regioisomer of C4 well as 850 mg (25%) of the E-regioisomer of C4, each as a yellowish oil.

Step c4: Compound C5 (Z,E-3-(3-hydroxyphenyl)-2-methylpent-2-enenitrile)

(61) To 0.13 g D,L-methionine and 1.6 mL methane sulfonic acid were added 120 mg (0.6 mmol) of C4. The reaction mixture was stirred for 16 h. Water and ethyl acetate were added. After neutralization with solid NaHCO.sub.3 the layers were separated from each other. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO.sub.4. The organic solvents were evaporated under reduced pressure and the remaining residue was dried in vacuo. CC (eluent: ethyl acetate/n-hexane (1:5)) yielded 90 g (80%) of C5 (mixture of Z,E-regioisomers) in form of a yellow oil.

Step c5: Compound 3 (3-(1-amino-2-methylpentan-3-yl)phenol)

(62) 70 mg (3.5 mmol) C5 were dissolved in 5 mL of dry methanol and placed in a hydrogenation apparatus. A small amount of a commercially available Raney-Nickel (Ra—Ni) suspension (in water) covering the tip of a spatula was added to the mixture. The resulting mixture was hydrogenated at room temperature under a H.sub.2-pressure of 2 bar for 12 h (use of H.sub.2: 128 ml). The solids were filtered off and the solvents of filtrate were evaporated under reduced pressure and the remaining residue was dried in vacuo. 70 mg (98%) of compound 3 were obtained in form of a brownish oil.

(63) The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.