Hydrochloric Acid → ((1S)-5-{3-[[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl](propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

HRID 2235956Notes

Reaction equation

HRID 2235956 reaction equation
C([O:3][C:4](=[O:31])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:23]3[C:28]([CH3:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[Li+].[OH-].Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.C1(C)C=CC=CC=1>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:25]2[N:24]=[C:23]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:31])[CH2:7][CH2:8]4)[C:28]([CH3:29])=[CH:27][N:26]=2)=[CH:36][CH:35]=1)[CH3:33]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 2734352Boronic acid, (4-ethylphenyl)-HCID 59300511ethyl((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate

Product 1

HCID 59300510((1S)-5-{3-[[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl](propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetic acidYield 21.4%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

To a mixture of toluene (2.8 mL) and 1,4dioxane (0.56 mL) were added ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(propyl)amino]propoxy}-2,3-dihydro-1-H-inden-1-yl)acetate (Example 409, 50 mg, 0.11 mmol), 4-ethylphenyl boronic acid (67.3 mg, 0.45 mmol), and PdCl2(dppf).CH2Cl2 (8.2 mg, 0.01 mmol). A flow of argon was passed through the reaction mixture for 30 min, then Na2CO3 (0.56 mL, 1.12 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was partly purified by preparative HPLC. The resulting crude ester was dissolved in a mixture of THF (2 mL), water (2 mL), and EtOH (1.0 mL), and then LiOH (24.2 mg, 1.01 mmol) was added. The reaction mixture was vigorously stirred for 18 h, acidified to pH ˜5 using HCl (1N aqueous solution), and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (11.5 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.27 (t, 3H), 1.69 (q, 2H), 1.76-1.81 (m, 1H), 2.13-2.16 (m, 2H) 2.30 (s, 3H), 2.40-2.51 (m, 2H), 2.68-2.85 (m, 5H), 3.47-3.55 (m, 3H), 3.80 (t, 2H), 3.98 (t, 2H), 6.66 (d, 1H), 6.71 (s, 1H), 7.07 (d, 1H), 7.267 (d, 2H), 8.05 (s, 1H), 8.22 (d, 2H); LC-MS: RT=3.38 min, (M+H)+ 488.4.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. concentrationconcentrated under reduced pressure
  3. customThe residue was partly purified by preparative HPLC
  4. dissolutionThe resulting crude ester was dissolved in a mixture of THF (2 mL), water (2 mL), and EtOH (1.0 mL)
  5. stirringThe reaction mixture was vigorously stirred for 18 h
  6. extractionthe aqueous phase was extracted with CH2Cl2
  7. dry with materialThe combined organic phases were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-4967f7c8faff49829a81fbb4ec25a910
Source dataset
uspto-grants-2010_05
Patent number
US07714004B2

Reaction notes

Loading…