3-(p-Tolyl)acrylic acid → 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one 4-methyl-cinnamate

HRID 1670803Notes

Reaction equation

HRID 1670803 reaction equation
[NH2:1][C:2]([CH3:37])([CH3:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][CH2:21][C@@H:22]([C:24]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28](=[O:35])[NH:29]4)[OH:23])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[CH3:38][C:39]1[CH:49]=[CH:48][C:42]([CH:43]=[CH:44][C:45]([OH:47])=[O:46])=[CH:41][CH:40]=1>O1CCCC1.O>[CH3:38][C:39]1[CH:49]=[CH:48][C:42]([CH:43]=[CH:44][C:45]([OH:47])=[O:46])=[CH:41][CH:40]=1.[NH2:1][C:2]([CH3:37])([CH3:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][CH2:21][C@@H:22]([C:24]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28](=[O:35])[NH:29]4)[OH:23])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1

Participants

5

Reactant 2

HCID 158353-(p-Tolyl)acrylic acidHCID 111693655-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one

Product 1

HCID 667958465-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one 4-methyl-cinnamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy) -phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (17.77 g) was dissolved in a mixture of tetrahydrofuran (89 mL) and water (89 mL). 4-methyl-cinnamic acid (6.02 g, predominantly trans) was weighed out and about one-quarter was added to the free base solution followed by seed crystals, obtained by the procedure of part e. The mixture was stirred and the remaining acid was added in portions over the following 1.5 h. The slurry was stirred for a further 4 h and then the slurry was filtered. The cake was washed with aqueous tetrahydrofuran (1:1 THF:water, 36 mL) and then with tetrahydrofuran (2×18 mL) to afford the title compound which was dried overnight under vacuum at 40-50° C. (yield: 16.916 g). 1H NMR (400 MHz, CD3OD; TMS as reference at δ (ppm) 0) δ (ppm): 1.39 (6H) s; 2.32 (3H) s; 2.79 (2H) t J=7.2 Hz; 2.92-3.03 (4H) m; 3.87 (2H) s; 5.25 (1H) d of d J=3.9 and 8.8 Hz; 6.44 (1H) d J=15.9 Hz; 6.63 (1H) d J=9.8 Hz; 6.86-6.93 (4H) m; 6.96 (1H) d J=8.3 Hz; 6.99-7.05 (4H) m; 7.15 (2H) d J=7.8 Hz; 7.19 (1H) d J=8.3 Hz; 7.36 (1H) d J=15.9 Hz; 7.38 (2H) d J=7.6 Hz; 8.34 (1H) d J=9.8 Hz. The crystalline product was characterized by XRPD and DSC.

Workup

  1. additionwas added to the free base solution
  2. customobtained by the procedure of part e
  3. additionthe remaining acid was added in portions over the following 1.5 h
  4. stirringThe slurry was stirred for a further 4 h
  5. filtrationthe slurry was filtered
  6. washThe cake was washed with aqueous tetrahydrofuran (1:1 THF:water, 36 mL)

Sources & evidence

ORD record
ord-d8bc421d069649deaf490e5667d7d152
Source dataset
uspto-grants-2011_08
Patent number
US07994165B2

Reaction notes

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