(2R)-2-amino-4-methylpentan-1-ol

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

Procedure: This compound was prepared from the compound of Example 15 and (R)-2-amino-4-methyl-1-pentanol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=554.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phthalic anhydride (10.30 g, 69.55 mmol) and D-Leucinol (8.15 g, 69.55 mmol) were mixed in THF (100 mL), the reaction mixture was heated at 85° C. and refluxed for 18 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with 1 N HCl, water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 8.1 g of (R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (47%). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.54 (m, 2H); 1.99 (m, 1H); 3.86 (m, 1H); 4.04 (m, 1H); 4.47 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H). refluxed for 18 hours After cooling to room temperature the solution was extracted with EtOAC the extracts were washed with 1 N HCl, water, aq. NaHCO3, water and brine dried over MgSO4 filtered evaporated

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

Procedure: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (R)-(−)-leucinol instead of 2-aminoethyl isopropylether, to the title compound (130 mg, 49%) which was obtained as a white solid. MS: m/e=408.4 [M−H]−.

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

Procedure: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (R)-(−)-leucinol instead of 2-aminoethyl isopropylether, to the title compound (130 mg, 49%) which was obtained as a white solid. MS: m/e=408.4 [M−H]−.

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

Procedure: (1R)-1-(Hydroxymethyl)-3-methylbutylamine was made from (D)-leucine methyl ester according to B1b. The 2-hydroxyethylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(N-isobutyl-N-(2-methyl-5-nitrophenyl)amino)-4-isobutyl-1,3-thiazoline HCl salt.

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

Procedure: (1R)-1-(Hydroxymethyl)-3-methylbutylamine was made from (D)-leucine methyl ester according to B1b. The 2-hydroxyethylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(N-isobutyl-N-(2-methyl-5-nitrophenyl)amino)-4-isobutyl-1,3-thiazoline HCl salt.

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

Procedure: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

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

Procedure: The following compound was synthesized by the method of Scheme 5 using 2-naphthylacetic acid as J-COOH, D-leucinol as NH2—CH(R5)—CH(R4)—OH, D-leucine methyl ester as NH2—CH(R5)—COOCH3, and Boc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group was attached to the amino group of D-2-Nal by reaction of the compound of Example 35 with Ac-OSu in DMF. It was tested as described above with the results shown. The mass was analyzed as 635.9 (M+H).

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

Procedure: To a solution of D-(−)-leucinol (2.0 g, 17.1 mmol) in THF (30 mL) was slowly added 1,3-propanesultone (1.94 g, 16.3 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH (240 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (2.55 g, (65%). 1H NMR (D2O, 500 MHz) δ ppm 3.74 (d, 1H, J=12.7 Hz), 3.56 (d, 1H, J=12.7 Hz), 3.20 (m, 1H), 3.10 (t, 2H, J=7.3 Hz), 2.87 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.49 (m, 2H), 1.31 (m, 1H), 0.80 (d, 3H, J=6.3 Hz), 0.76 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 58.74, 58.01, 48.19, 43.56, 35.98, 24.34, 22.54, 21.63, 20.90. [α]D=−16.3° (c=0.0019 in water), ES-MS 238 (M−1). at reflux for 2 hours The solid was collected by filtration washed with acetone (2×20 mL) The solid was dissolved in 50% water/EtOH (240 mL) Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution The suspension was stirred for 15 minutes before the resin was removed by filtration The filtrate was evaporated under reduced pressure filtered dried in the vacuum oven (50° C.)

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

Procedure: The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2R)-2-amino-4-methyl-1-pentanol (CAN 53448-09-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H)+.

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

Procedure: The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2R)-2-amino-4-methyl-1-pentanol (CAN 53448-09-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H)+.

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

Procedure: Step AK (1): (R)-2-amino-4-methylpentan-1-ol (1.0 g, 8.53 mmol) was dissolved in ethyl trifluoroacetate (2.5 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine. The organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give (R)-2,2,2-trifluoro-N-(1-hydroxy-4-methylpentan-2-yl)acetamide (1.48 g, 81%) as a colorless oil. LC-MS (M+H)+=214.81. extracted with EtOAc The combined organic phases were washed with water and brine The organic phases were dried over Na2SO4 filtered concentrated in vacuum The residue was purified by silica gel chromatography