Toluene → [(1S)-5-({1-[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl]-4-piperidinyl}methyl)-2,3-dihydro-1H-inden-1-yl]acetic acid

HRID 2235965Notes

Reaction equation

HRID 2235965 reaction equation
C(OC(=O)C[C@H]1C2C(=CC(O[CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([CH3:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=4)[CH2:18][CH2:17]3)=CC=2)CC1)C.[CH2:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH3:32].C(Cl)Cl.[C:45]([O-:48])([O-])=[O:46].[Na+].[Na+].[Li+].[OH-].[C:53]1([CH3:59])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>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>[CH2:31]([C:33]1[CH:38]=[CH:37][C:36]([C:24]2[N:23]=[C:22]([N:19]3[CH2:18][CH2:17][CH:16]([CH2:59][C:53]4[CH:58]=[C:57]5[C:56](=[CH:55][CH:54]=4)[C@H:17]([CH2:18][C:45]([OH:48])=[O:46])[CH2:16][CH2:21]5)[CH2:21][CH2:20]3)[C:27]([CH3:28])=[CH:26][N:25]=2)=[CH:35][CH:34]=1)[CH3:32]

Participants

9

Reactant 6

HCID 1140TolueneHCID 3939Lithium HydroxideHCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 2734352Boronic acid, (4-ethylphenyl)-HCID 59300488ethyl ((1S)-5-{[1-(2-chloro-5-methyl-4-pyrimidinyl)-4-piperidinyl]oxy}-2,3-dihydro-1H-inden-1-yl)acetate

Product 1

HCID 67018876[(1S)-5-({1-[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl]-4-piperidinyl}methyl)-2,3-dihydro-1H-inden-1-yl]acetic acidYield 43%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
75 °C

Procedure

To a mixture of toluene (5.8 mL) and 1,4-dioxane (1.16 mL) were added ethyl ((1S)-5-{[1-(2-chloro-5-methyl-4-pyrimidinyl)-4-piperidinyl]oxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 459, 100 mg, 0.23 mmol), 4-ethylphenyl boronic acid (139.5 mg, 0.93 mmol), and PdCl2(dppf).CH2Cl2 (17 mg, 0.02 mmol). A flow of argon was passed through the mixture for 30 min, then Na2CO3 (1.16 mL, 2.33 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 4 h. The reaction mixture was cooled to rt and filtered through a plug of silica gel. Then the desired fractions were concentrated under reduced pressure. The crude ester was dissolved in a mixture of THF (3 mL), water (3 mL), and EtOH (1.5 mL) was added LiOH (55.8 mg, 2.33 mmol). The reaction mixture was vigorously stirred for 24 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC and the fractions containing the desired product were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, treated with to Dowex 66® resin, filtered, and then concentrated under reduced pressure to give the product (50 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.73-1.78 (m, 1H), 1.90-1.96 (m, 2H), 2.18-2.22 (m, 2H), 2.40 (s, 3H), 2.35-2.44 (m, 2H), 2.69-2.91 (m, 4H), 3.46-3.49 (m, 1H), 3.67-3.72 (m, 2H), 4.00-4.06 (m, 2H), 4.70-4.72 (m, 1H), 6.81 (d, 1H), 6.90 (d, 1H), 7.16 (s, 1H), 7.34 (d, 2H), 8.29 (s, 1H), 8.35 (d,2H); LC-MS: MS: RT=2.66 min, (M+H)+ 472.4.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. filtrationfiltered through a plug of silica gel
  3. concentrationThen the desired fractions were concentrated under reduced pressure
  4. dissolutionThe crude ester was dissolved in a mixture of THF (3 mL), water (3 mL), and EtOH (1.5 mL)
  5. stirringThe reaction mixture was vigorously stirred for 24 h
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by preparative HPLC
  8. additionthe fractions containing the desired product
  9. concentrationwere concentrated under reduced pressure
  10. dissolutionThe residue was dissolved in CH2Cl2
  11. additiontreated with to Dowex 66® resin
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-225388bb5eb04afb9d5d975cb1b26a55
Source dataset
uspto-grants-2010_05
Patent number
US07714004B2

Reaction notes

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