Yield:174636-32-9 79.9%

Reaction Conditions:

Stage #1: oxycinchophenwith triethylamine;1,1'-carbonyldiimidazole in acetonitrile at 20 - 50; for 2 - 5 h;
Stage #2: (R)-1-phenylpropylamine in acetonitrile at 25 - 75;Product distribution / selectivity;

Steps:

1; 2; 3; 4; 5; 6; 7

Example 1; To a 1000 mL 3-neckθd round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (60.0 g, 0.226 mol, 1.00 eq), MeCN (240 mL, 4 vol) and triethylamine (41.0 mL, 0.294 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1 , 1'-carbonyldiimidazole (40.3 g, 0.249 mol, 1.10 eq) was charged in one portion. The mixture was heated to 25 ⁰C, and held at the same temperature for 5 h. Then S-1-phenylpropylamine (33.6 g, 0.249 mol, 1.10 eq) was charged in one portion at 25 ⁰C. The mixture was heated to 75 ⁰C, held at 75⁰C for 5 h, cooled to room temperature, and stirred at room temperature overnight. At room temperature, glacial acetic acid (180 mL, 3.0 vol) was added in one portion, causing the solution temperature to rise to -38⁰C. The mixture was cooled slowly from 38 ⁰C to 0⁰C over ca. 4.5 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 120 mL, 2 x 2 vol) and de-ionized water once (120 mL, 2 vol) and dried under vacuum at 70 ⁰C overnight to afford 73.4 g of (-)-(S)-N-(α- ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide as a light yellow to off- white solid, in 84.8% yield.; Example 2; To a 1000 mL 3-necked round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (60.0 g, 0.226 mol, 1.00 eq), ACN (240 mL, 4 vol) and triethylamine (41.0 mL, 0.294 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1 , 1'-carbonyldiimidazole (40.3 g, 0.249 mol, 1.10 eq) was charged in one portion. The mixture was heated to 50⁰C, and held at the same temperature for 5 h. Then S-1-phenylpropylamine (33.6 g, 0.249 mol, 1.10 eq) was charged in one portion at 50 ⁰C. The mixture was held at 50 ⁰C for 5 h, cooled to room temperature, and stirred at room temperature EPO overnight. At room temperature, glacial acetic acid (180 mL, 3.0 vol) was added in one portion, causing the solution temperature to rise to -39 ⁰C. The mixture was cooled slowly from 39 ⁰C to 0 ⁰C over ca. 2 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 120 mL, 2 x 2 vol) and de-ionized water once (120 mL, 2 vol) and dried under vacuum at 70 ⁰C overnight to afford 71.2 g of (-)-(S)-N-(α-ethylbenzyl)-3- hydroxy-2-phenylquinoline-4-carboxamide as a light yellow to off-white solid, in 82.3% yield.; Example 3; To a 1000 mL 3-necked round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (60.Og, 0.226 mol, 1.00 eq), ACN (240 mL, 4 vol) and triethylamine (41.0 mL, 0.294 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1 , 1'-carbonyldiimidazole (40.3 g, 0.249 mol, 1.10 eq) was charged in one portion. The mixture was heated to 37 ⁰C, and held at the same temperature for 5 h. Then S-1-phenylpropylamine (33.6 g, 0.249 mol, 1.10 eq) was charged at in one portion 37 ⁰C. The mixture was heated to 63 ⁰C, and held at 63 ⁰C for 5 h, cooled to room temperature, and stirred at room temperature overnight. At room temperature, glacial acetic acid (180 mL, 3.0 vol) was added in one portion, causing the solution temperature to rise to -39⁰C. The mixture was cooled slowly from 39 ⁰C to 0 ⁰C over ca. 5 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 120 mL, 2 x 2 vol) and de-ionized water once (120 mL, 2 vol) and dried under vacuum at 70 ⁰C overnight to afford 70.3 g of (-)-(S)-N-(α- ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide as a light yellow to off- white solid, in 81.2% yield.; Example 4; To a 1000 mL 3-necked round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (60.0 g, 0.226 mol, 1.00 eq), ACN (240 mL, 4 vol) and triethylamine (41.0 mL, 0.294 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1, 1'-carbonyldiimidazole (40.3 g, EPO 0.249 mol, 1.10 eq) was cnarged in one portion. The mixture was heated to 25 ⁰C, and held at the same temperature for 5 h. Then S-1-phenylpropylamine (33.6 g, 0.249 mol, 1.10 eq) was charged in one portion at 25 ⁰C. The mixture was heated to 50 ⁰C₁ held at 50 ⁰C for 5 h, cooled to room temperature, and stirred at room temperature overnight. At room temperature, glacial acetic acid (180 ml_, 3.0 vol) was added in one portion, causing the solution temperature to rise to -39 ⁰C. The mixture was cooled slowly from 39 ⁰C to 0 ⁰C over ca. 5.5 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 120 ml_, 2 x 2 vol) and de-ionized water once (120 mL, 2 vol) and dried under vacuum at 70 ⁰C overnight to afford 76.4 g of (-)-(S)-N-(α- ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide as a light yellow to off- white solid, in 88.3% yield.; Example 5; To a 1000 mL 3-necked round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (60.0 g, 0.226 mol, 1.00 eq), ACN (240 mL, 4 vol) and triethylamine (41.0 mL, 0.294 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1 , 1'-carbonyldiimidazole (40.3 g, 0.249 mol, 1.10 eq) was charged in one portion. The mixture was heated to 50 ⁰C, and held at the same temperature for 5 h. Then S-1-phenylpropylamine (33.6 g, 0.249 mol, 1.10 eq) was charged in one portion at 50 ⁰C. The mixture was heated to 75 ⁰C, held at 75 ⁰C for 5 h, cooled to room temperature, and stirred at room temperature overnight. At room temperature, glacial acetic acid (180 mL, 3.0 vol) was added in one portion, causing the solution temperature to rise to -38 ⁰C. The mixture was cooled slowly from 38 ⁰C to 0 ⁰C over ca. 5 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 120 mL, 2 x 2 vol) and de-ionized water once (120 mL, 2 vol) and dried under vacuum at 70 ⁰C overnight to afford 69.1 g of (-)-(S)-N-(α- ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide as a light yellow to off- white solid, in 79.9% yield.; Example 6; To a reaction vessel under nitrogen atmosphere were charged 3-hydroxy-2- phenyl-4-quinolinecarboxylic acid (60.0 kg, 1 equivalent) and acetonitrile (2400L, 4 EPO volumes). Triethylamine (29.8 kg, 1.3 equivalents) was added at ambient temperature. The reaction mixture was stirred for -20 min at 20-35 ⁰C to a cloudy brown solution. 1, 1'-carbonyldiimidazole (GDI) (40.3 kg, 1.1 equivalents) was charged in one portion. The reaction mixture was then heated to 40-50 ⁰C and held at 40-50 ⁰C for 2-4 hours. Reaction was monitored by HPLC analysis of In- Process-Monitoring (IPM) samples. IPM sample was quenched with HPLC grade methanol immediately. When IPM results indicate the ratio of methyl 3-hydroxy-2- phenyl-4-quinolinecarboxylate and 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid was ≥98:1 , the first reaction was complete. S-1-phenylpropylamine (33.6 kg, 1.1 equivalents) was added in one portion at 40-50 ⁰C. The reaction was heated to 70- 75 ⁰C under nitrogen and held for 2-3 hours at 70-75 ⁰C. The reaction was deemed complete when IPM results indicate the ratio of (-)-(S)-N-(α-ethylbenzyl)-3-hydroxy- 2-phenylquinoline-4-carboxamide to methyl 3-hydroxy-2-phenyl-4- quinolinecarboxylate was greater than 99.5:1. The reaction mixture was cooled to 20-25 ⁰C and filtered through in-line filter. Glacial acetic acid (1800L, 3 volumes) was added to the above reaction mixture, while keeping the process temperature at 40-55⁰C. The reaction mixture was stirred for ~1 hour at 35-45 ⁰C and then cooled slowly to approx. 0 ⁰C at ~ 1 ⁰C per minute. The resulting slurry was stirred for 2 hrs at approx. 0⁰C. The crude product was isolated by filtration in centrifuge. The wet cake was washed with cold acetonitrile (approx. 0 ⁰C, 120L, 2 volumes) twice and deionized water (120L, 2 volumes). The crude product was dried in vacuum oven at 60-70 ⁰C under vacuum. Yield: 69.2 kg, 80.1%; and 73.9 kg, 85.5%; Example 7; To a 1000 mL 3-necked round bottom flask equipped with air-driven mechanical stirrer, thermometer, reflux condenser, addition funnel and nitrogen inlet/outlet, were added 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid (32.0 g, 0.121 mol, 1.00 eq), ACN (128mL, 4 vol) and triethylamine (21.8 mL, 0.156 mol, 1.30 eq) at room temperature with stirring. The mixture was stirred at room temperature until a solution was observed. Then 1 , 1 '-carbonyldiimidazole (21.5 g, 0.133 mol, 1.10 eq) was charged in one portion. The mixture was heated to 50 ⁰C, and held at the same temperature for 2 h. Then S-1-phenylpropylamine (17.9 g, 0.133 mol, 1.10 eq) was charged in one portion at 50 ⁰C. The mixture was heated to 75 ⁰C, held at 75 ⁰C for 4 h, cooled to room temperature, and stirred at room temperature overnight. The reaction mixture was filtered through 1 micron paper in a Buchner funnel. The filtrate was heated to 30 ⁰C. Glacial acetic acid (prefiltered through 1 micron paper, 96 mL, 3.0 vol) was added in one portion, causing the EPO solution temperature to rise to -47⁰C. The mixture was cooled slowly from 47 ⁰C to 0 ⁰C over ca. 3 h and the suspension was filtered through a filter paper under vacuum. The cake was washed with cold acetonitrile twice (2 x 64 mL, 2 x 2 vol) and de-ionized water once (64 mL, 2 vol) and dried under vacuum at 60 ⁰C overnight to afford 37 g of (-)-(S)-N-(oc-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4- carboxamide as a light yellow to off-white solid, in 82.3% yield, m.p. 122-125 ⁰C . 1 H-NMR (400 MHz, DMSO-d6): 9.81 (s, 1H), 9.15 (d, 1 H), 7.96-8.02(m, 3 H), 7.44- 7.63(m, 8 H), 7.36-7.42(m, 2 H), 7.26-7.32 (m, 1 H), 5.01-5.08 (q, 1 H), 1.72-1.84 (m, 3H), 0.93-0.98(t, 3H).

References:

WO2007/16609,2007,A2 Location in patent:Page/Page column 20-24