Potassium Phosphate, Tribasic → 5-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic Acid

HRID 533276Notes

Reaction equation

HRID 533276 reaction equation
[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([CH3:17])=[N:3]1.Br[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:20]=1[C:43]([O:45]CC)=[O:44].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]1[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=1)[C:20]([C:43]([OH:45])=[O:44])=[C:19]2[C:5]1[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27953111,3,5-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 67316184ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate

Product 1

HCID 673170265-fluoro-1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic Acid

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43.2 mg), ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 134B as an intermediate) (43 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (15.01 mg) and K3PO4 (58.2 mg) in toluene (2.1 ml) was heated in a microwave reactor (CEM Discover) at 110° C. for 2 hours. The reaction was directly loaded into a silica cartridge, and eluted with 0%-25% ethyl acetate in dichloromethane. The collected desired ester was hydrolized with NaOH in tetrahydrofuran-methanol-H2O at 50° C. overnight to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.15 (d, J=8.90 Hz, 1H), 7.86 (d, J=7.36 Hz, 1H), 7.71 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.56 (m, 3H), 7.32-7.41 (m, 1H), 7.05-7.16 (m, 1H), 6.92 (dd, J=9.36, 2.61 Hz, 1H), 6.86 (d, J=7.36 Hz, 1H), 4.69-5.00 (m, 2H), 4.17 (t, J=5.83 Hz, 2H), 3.72 (s, 3H), 2.27-2.43 (m, 2H), 1.99 (s, 3H), 1.90 (s, 3H).

Workup

  1. customThe synthesis of this compound
  2. washeluted with 0%-25% ethyl acetate in dichloromethane
  3. customThe collected desired ester

Sources & evidence

ORD record
ord-5f27b8c9e5ab4244aa12bd1e3279ab26
Source dataset
uspto-grants-2014_10
Patent number
US08853209B2

Reaction notes

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