(2R)-2-amino-3-methylbutan-1-ol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine are added followed by 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol. The reaction mixture is heated to 100° C. until there is no further reaction, then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained in the form of a solid. Analytical HPLC (method A): RT=2.75 min no further reaction cooled evaporated down The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath filtered dried 8.3 g (III-2) are obtained in the form of a solid

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.2 g of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin (II) are in 36 ml dioxane placed, and then first 18 ml diisopropylethylamine, then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C., until there is no further reaction and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min no further reaction cooled evaporated down The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath filtered dried 8.3 g (III-1) are obtained as a solid

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

Procedure: By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-3-methyl-1-butanol. Then, the product was recrystallized with acetone and hexane to give a desired compound. By the same procedure as described in the example 1, synthesis Then, the product was recrystallized with acetone and hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.2 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C. until there is no further reaction and after cooling it is evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min no further reaction after cooling it is evaporated down The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath filtered dried 8.3 g (III-2) are obtained as a solid

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

Procedure: (1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.

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

Procedure: (1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.

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

Procedure: A solution of 882 mg (5.0 mmol) of 2,4-Dichloro-5-ethyl-pyrimidine and 0.75 ml (5.5 mmol) triethylamine in 5 ml of acetonitrile is mixed with 672 mg (6.5 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 90:10). 742 mg of the product is obtained that still contains considerable amounts of (R)-2-Amino-3-methyl-butan-1-ol. The material is used without further purifications. is finally concentrated by evaporation The remaining residue is purified by chromatography (DCM/EtOH 90:10)

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

Procedure: A solution of 882 mg (5.0 mmol) of 2,4-Dichloro-5-ethyl-pyrimidine and 0.75 ml (5.5 mmol) triethylamine in 5 ml of acetonitrile is mixed with 672 mg (6.5 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 90:10). 742 mg of the product is obtained that still contains considerable amounts of (R)-2-Amino-3-methyl-butan-1-ol. The material is used without further purifications. is finally concentrated by evaporation The remaining residue is purified by chromatography (DCM/EtOH 90:10)

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

Procedure: A solution of 10.05 g (36.6 mmol) of 2,4-Dichloro-5-iodo-pyrimidine and 5.6 ml (40.0 mmol) triethylamine in 30 ml of acetonitrile is mixed with 4.85 g (47.0 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally diluted with water. The batch is filtered and the solid is washed with small amounts of acetonitrile and water. The solid is dried. 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained. The batch is filtered the solid is washed with small amounts of acetonitrile and water The solid is dried 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained

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

Procedure: A solution of 10.05 g (36.6 mmol) of 2,4-Dichloro-5-iodo-pyrimidine and 5.6 ml (40.0 mmol) triethylamine in 30 ml of acetonitrile is mixed with 4.85 g (47.0 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally diluted with water. The batch is filtered and the solid is washed with small amounts of acetonitrile and water. The solid is dried. 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained. The batch is filtered the solid is washed with small amounts of acetonitrile and water The solid is dried 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained

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

Procedure: The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-3-methyl-1-butanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl α-{6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer A) and t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B), were obtained as oils. were obtained as oils

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

Procedure: The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-3-methyl-1-butanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl α-{6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer A) and t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B), were obtained as oils. were obtained as oils