2-amino-2-methyl-1-phenylpropan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 74.5 g. (0.4 mole) of 1-naphthyl acetic acid, 111.0 g. (0.45 mole) of EEDQ and 66.0 g. (0.4 mole) of α-(1-amino-1-methylethyl)benzenemethanol in 1 l. tetrahydrofuran is stirred and heated for 2 hours at 65° C. and then allowed to stand for 20 hours at room temperature. THF is evaporated in vacuo, and the residue is taken up with ice and 10% aqueous H2SO4 solution to pH 2. The resulting amide is extracted twice with 750 ml. ethyl acetate. The combined organic extracts are washed with 500 ml. dilute NaHCO3, dried (Na2SO4) and evaporated to dryness in vacuo. The oil is dissolved in 1 l. hot isopropyl ether and on standing at 25° C. gives 101.0 g. (77% yield) of N-(2-hydroxy-1,1-dimethyl-2-phenylethyl)-1-naphthaleneacetamide as an off-white crystalline solid of analytical purity, m.p. 106°-107° C. THF is evaporated in vacuo The resulting amide is extracted twice with 750 ml The combined organic extracts are washed with 500 ml dilute NaHCO3, dried (Na2SO4) evaporated to dryness in vacuo The oil is dissolved in 1 l on standing at 25° C. gives 101.0 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 8.3 g. (0.05 mole) of α-(1-amino-1-methylethyl)benzenemethanol, 9.8 g. (0.05 mole) of 3,4-dimethoxyphenylacetic acid and 13.6 g. (0.055 mole) of EEDQ (Aldrich Chem. Co.) in 300 ml. of tetrahydrofuran-ethanol is refluxed for 45 minutes and then allowed to stand for 20 hours at 25° C. The solution is evaporated in vacuo. The residue is taken up with 250 ml. of ethyl acetate, washed with dilute HCl, followed by washing with aqueous NaHCO3. Subsequently, the extract is washed with aqueous NaCl, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from ether gives 14.0 g. (82% yield) of pure 2-(3,4-dimethoxyphenyl)-N-(β-hydroxy-α,α-dimethylphenethyl)acetamide, m.p. 123°-124° C. The solution is evaporated in vacuo of ethyl acetate, washed with dilute HCl by washing with aqueous NaHCO3 Subsequently, the extract is washed with aqueous NaCl dried (Na2SO4) evaporated to dryness in vacuo Crystallization of the residue from ether gives 14.0 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 8.3 g. (0.05 mole) of α-(1-amino-1-methylethyl)benzenemethanol, 9.8 g. (0.05 mole) of 3,4-dimethoxyphenylacetic acid and 13.6 g. (0.055 mole) of EEDQ (Aldrich Chem. Co.) in 300 ml. of tetrahydrofuran-ethanol is refluxed for 45 minutes and then allowed to stand for 20 hours at 25° C. The solution is evaporated in vacuo. The residue is taken up with 250 ml. of ethyl acetate, washed with dilute HCl, followed by washing with aqueous NaHCO3. Subsequently, the extract is washed with aqueous NaCl, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from ether gives 14.0 g. (82% yield) of pure 2-(3,4-dimethoxyphenyl)-N-(β-hydroxy-α,α-dimethylphenethyl)acetamide, m.p. 123°-124° C. The solution is evaporated in vacuo of ethyl acetate, washed with dilute HCl by washing with aqueous NaHCO3 Subsequently, the extract is washed with aqueous NaCl dried (Na2SO4) evaporated to dryness in vacuo Crystallization of the residue from ether gives 14.0 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6.6 g. (0.03 mole) of α-(1-amino-1-methylethyl)benzenemethanol and 4.8 g. (0.03 mole) of phenylacetaldehyde in 75 ml. benzene is refluxed for 1 hour while 0.7 ml. of water separates in a Dean-Stark trap. The infrared absorption spectrum showed absence of the C=O function and the presence of a C=N function at 1650 cm-1. The solvent is removed in vacuo. The residue of the imino derivative was taken up with 60 ml. of methanol and 1.6 g. of KBH4 is added with stirring at 20°-25° C. After 20 hours, the solution is evaporated in vacuo. The residue is taken up with cold water, and the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration. Recrystallization from methanol gives pure α-{1-methyl-1-[(2-phenylethyl)amino]-ethyl}benzenemethanol as white crystals, m.p. 105°-106° C. The infrared absorption spectrum The solvent is removed in vacuo of KBH4 is added the solution is evaporated in vacuo the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration Recrystallization from methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6.6 g. (0.03 mole) of α-(1-amino-1-methylethyl)benzenemethanol and 4.8 g. (0.03 mole) of phenylacetaldehyde in 75 ml. benzene is refluxed for 1 hour while 0.7 ml. of water separates in a Dean-Stark trap. The infrared absorption spectrum showed absence of the C=O function and the presence of a C=N function at 1650 cm-1. The solvent is removed in vacuo. The residue of the imino derivative was taken up with 60 ml. of methanol and 1.6 g. of KBH4 is added with stirring at 20°-25° C. After 20 hours, the solution is evaporated in vacuo. The residue is taken up with cold water, and the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration. Recrystallization from methanol gives pure α-{1-methyl-1-[(2-phenylethyl)amino]-ethyl}benzenemethanol as white crystals, m.p. 105°-106° C. The infrared absorption spectrum The solvent is removed in vacuo of KBH4 is added the solution is evaporated in vacuo the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration Recrystallization from methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 37% Hydrochloric acid (1 mL) was added to a stirred solution of 2-methyl-2-nitro-1-phenylpropan-1-ol (26c, 0.12 g, 0.6 mmol in EtOH (10 mL) and water (5 mL). Zinc powder (0.241 g, 3.6 mmol) was slowly added in small portions, the mixture was stirred for 4 hours at +70° C. The mixture was filtered to remove solid zinc residues and concentrated to ⅓ volume by evaporation, diluted with water (50 mL) and washed with ether (125 mL). The acidic waterphase was made basic using KOH (aq) solution, the formed slurry was extracted with ether (3×150 mL). The organic phase was dried (MgSO4) filtered and evaporated. The crude product was further purified by HPLC. Yield 60 mg (60%). The mixture was filtered to remove solid zinc residues concentrated by evaporation diluted with water (50 mL) washed with ether (125 mL) the formed slurry was extracted with ether (3×150 mL) The organic phase was dried (MgSO4) filtered evaporated The crude product was further purified by HPLC

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: There are many possible methods for hydrogenating the hydroxyl group at benzyl position of APPD. For example, U.S. Pat. No. 3,084,099 issued to Hays et al. describes a method of preparing 1-benzyl-iso-propyl amine from 1phenyl-2-methyl-2-amino-propanol by hydrogenation in 57% hydriodic acid with red phosphorous. However, the strongly acidic condition of this system may induce iodination of other hydroxyl groups. In fact, the hydrogenation of APPD in the above conditions produced 1-phenyl-2-amino-3-iodopropane instead of phenylalaninol, as disclosed in Japanese Patent 3910914. Other approaches were made by two independent groups, Boerner et al. prepared D-phenylalaninol from L(+)-APPD by 4 steps with a total yield of 31% (Pharmazie 45, 531 (1990)). On the other hand, the hydrogenation of L(+)-APPD in the presence of sulfuric acid was found to give D-phenylalaninol (D-PAO)in 73-85% yield (Hashizume, Japanese Patent 63255254). It is obvious that the latter is quite cost-effective. However, in this process, it is necessary to use excess amounts of base to neutralize the reaction mixture for the recovery of D-PAO because an excess amount of sulfuric acid is used. When the pH of the reaction mixture is adjusted to above 11, large amounts of salts are produced and some of them, including small amount of D-PAO, are precipitated. This phenomenon makes the work-up process very complicated. Furthermore, it makes it impossible to derivatize phenylalaninol into desired forms such as N-terminal blocked phenylalaninols without isolation of phenylalaninol.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: There are many possible methods for hydrogenating the hydroxyl group at benzyl position of APPD. For example, U.S. Pat. No. 3,084,099 issued to Hays et al. describes a method of preparing 1-benzyl-iso-propyl amine from 1phenyl-2-methyl-2-amino-propanol by hydrogenation in 57% hydriodic acid with red phosphorous. However, the strongly acidic condition of this system may induce iodination of other hydroxyl groups. In fact, the hydrogenation of APPD in the above conditions produced 1-phenyl-2-amino-3-iodopropane instead of phenylalaninol, as disclosed in Japanese Patent 3910914. Other approaches were made by two independent groups, Boerner et al. prepared D-phenylalaninol from L(+)-APPD by 4 steps with a total yield of 31% (Pharmazie 45, 531 (1990)). On the other hand, the hydrogenation of L(+)-APPD in the presence of sulfuric acid was found to give D-phenylalaninol (D-PAO)in 73-85% yield (Hashizume, Japanese Patent 63255254). It is obvious that the latter is quite cost-effective. However, in this process, it is necessary to use excess amounts of base to neutralize the reaction mixture for the recovery of D-PAO because an excess amount of sulfuric acid is used. When the pH of the reaction mixture is adjusted to above 11, large amounts of salts are produced and some of them, including small amount of D-PAO, are precipitated. This phenomenon makes the work-up process very complicated. Furthermore, it makes it impossible to derivatize phenylalaninol into desired forms such as N-terminal blocked phenylalaninols without isolation of phenylalaninol.