Triethylamine → Ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate

HRID 1909598Notes

Reaction equation

HRID 1909598 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.FC1C(F)=C(C(O)=O)C2OC(C)(C)CC=2C=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][CH:34]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][CH:38]=2)=[O:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[CH:12]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 111923Propylphosphonic anhydrideHCID 46941402Ethyl 3-(4-aminophenyl)-2-methylpropanoateHCID 585663065,6-difluoro-2,2-dimethyl-3H-benzofuran-7-carboxylic acidHCID 585664155-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid

Product 1

HCID 67405616Ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (803) (Compound was prepared in a similar manner as that described for the synthesis of (735) (101.3 mg, 0.482 mmol) was dissolved in dichloromethane (4 mL) and ethyl 3-(4-aminophenyl)-2-methylpropanoate (646) (100 mg, 0.482 mmol), triethyl amine (0.4 mL, 2.89 mmol), and 1-propanephosphonic acid cyclic anhydride (0.34 mL, 0.58 mmol, 50% in ethyl acetate) were added and stirred overnight at room temperature. The reaction was purified in vacuo and purified by flash column chromatography on silica gel with hexanes and EtOAc to give ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 4 h. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid (97). 1H NMR (400 MHz, CDCl3) δ 9.53 (br, 1H), 7.66 (dd, J=9.9, 2.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.02 (dd, J=9.9, 2.6 Hz, 1H), 3.13-3.00 (m, 3H), 2.72 (m, 2H), 1.60 (s, 6H), 1.19 (d, J=8.0 Hz, 3H).

Workup

  1. customThe reaction was purified in vacuo
  2. custompurified by flash column chromatography on silica gel with hexanes and EtOAc

Sources & evidence

ORD record
ord-9bd95b15f63a46a3bf99f833b15b5b2b
Source dataset
uspto-grants-2013_12
Patent number
US08598374B2

Reaction notes

Loading…