methyl (2R)-2-aminopropanoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: D-alanine methyl ester (1.5 g, 10.75 mmol) is taken up in 50 mL methanol and is cooled to 0° C. To this is added hexanal (1.3 mL, 10.75 mmol) followed by sodium acetate (2.62 g, 32 mmol). After stirring for 15 minutes at 0° C. sodium cyanoborohydride (440 mg, 7 mmol) is added and the mixture is stirred for further 16 hours at room temperature. The methanol is evaporated and the resulting residue is taken up in ether and is transferred to a separatory funnel, washed with water (2×), dried over sodium sulfate, and is evaporated to give 1.81 g of N-hexyl-D-alanine methyl ester as a colorless oil. is added The methanol is evaporated is transferred to a separatory funnel washed with water (2×) dried over sodium sulfate is evaporated

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

Procedure: D-Alanine methyl ester (4 g, 28.66 mmol) is taken up in methanol (100 mL). To this is added sodium acetate (5.88 g, 71.65 mmol) and benzaldehyde (2.9 mL, 28.66 mmol). The mixture is stirred for 15 minutes and then a solution of sodium cyanoborohydride (1.08 g, 17.2 mmol) in methanol (5 mL) is added dropwise to the mixture. After stirring for 2 hours methanol is evaporated under reduced pressure and the product is extracted into ether and washed with water (2×). The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate) to give 3.3 g of N-benzyl D-alanine methyl ester as an oil. is evaporated under reduced pressure the product is extracted into ether washed with water (2×) The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate)

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

Procedure: 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, was coupled with 0.40 g of D-Alanine methyl ester analogously to Example A-54 a) and 0.200 g of off-white, solid product were obtained: MS-(+)-icon, M+1=308.8 amu. a) and 0.200 g of off-white, solid product were obtained

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

Procedure: 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, was coupled with 0.40 g of D-Alanine methyl ester analogously to Example A-54 a) and 0.200 g of off-white, solid product were obtained: MS-(+)-icon, M+1=308.8 amu. a) and 0.200 g of off-white, solid product were obtained

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

Procedure: 7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester analogously to Example A-1 a). 0.246 g of off-white solid were obtained: MS-(+)-ion, M+1=415.0 amu.

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

Procedure: 7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester analogously to Example A-1 a). 0.246 g of off-white solid were obtained: MS-(+)-ion, M+1=415.0 amu.

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

Procedure: To a solution of D-Alanine methylester (1.33 g, 12.9 mmol) in acetonitrile (15 mL was added 1,3-propane sultone (1.42 g, 11.7 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with acetonitrile (2×15 mL). The solid was dissolved in water (30 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 and dried in vacuo, affording the title compound (1.52 g, 42%). 1H NMR (D2O, 500 MHz) δ ppm 4.07 (m, 1H), 3.72 (s, 3H), 3.14 (m, 2H), 2.89 (t, 2H, J=7.3 Hz), 2.03 (m, 2H), 1.46 (dd, 3H, J=1.95 Hz, 7.3 Hz). 13C (DMSO, 125 MHz) δ ppm 170.74, 55.62, 53.82, 47.96, 44.76, 21.53, 14.03. [α]D=+1.4° (c=0.0088 in water), ES-MS 224 (M−1). at reflux for 2 hours The solid material was filtered washed with acetonitrile (2×15 mL) The solid was dissolved in water (30 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 dried in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ 1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s, 3H); 4.15-4.27 (m,1H); 4.50-4.60 (m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82 (--CHCH3 ; 24.33(--CH2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522MH+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98; H 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C. Heating is chromatographed on silica gel using variable gradient hexane/ethyl acetate Purified product (6.7 g) is recovered The material is crystallized from hexanes-ether

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s,3H); 4.15-4.27(m,1H); 4.50-4.60(m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82(--CHCH3 ; 24.33(--C H2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522(MH)+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98;H, 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C. Heating is chromatographed on silica gel using variable gradient hexane/ethyl acetate Purified product (6.7 g) is recovered The material is crystallized from hexanes-ether

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s,3H); 4.15-4.27(m,1H); 4.50-4.60(m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82(--CHCH3 ; 24.33(--C H2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522(MH)+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98;H, 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C. Heating is chromatographed on silica gel using variable gradient hexane/ethyl acetate Purified product (6.7 g) is recovered The material is crystallized from hexanes-ether

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

Procedure: 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, was coupled with 0.40 g of D-Alanine methyl ester analogously to Example A-54 a) and 0.200 g of off-white, solid product were obtained: MS-(+)-icon, M+1=308.8 amu. a) and 0.200 g of off-white, solid product were obtained

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

Procedure: 7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester analogously to Example A-1 a). 0.246 g of off-white solid were obtained: MS-(+)-ion, M+1=415.0 amu.