Dichloromethane → 2-(5-Chloro-2-cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester

HRID 1047922Notes

Reaction equation

HRID 1047922 reaction equation
COCC=CC1C(C)=CC=[CH:23][C:7]=1[C:8]([NH:10][C:11]1([C:20]([OH:22])=[O:21])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:9].CN(C(ON1N=NC2C=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.[F:45][P-](F)(F)(F)(F)F.C([O:54][C:55]([C:57]1(N)[CH2:65]C2C(=CC=C(F)C=2)[CH2:58]1)=O)C.CCN([CH:74]([CH3:76])C)C(C)C.[CH2:77]([Cl:79])Cl>CC(O)C.C(Cl)Cl>[CH2:74]([O:22][C:20]([C:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:23]=[C:77]([Cl:79])[CH:58]=[C:57]([CH3:65])[C:55]=2[O:54][CH:37]2[CH2:42][CH2:41][CH2:40]2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:45])[CH:17]=2)[CH2:12]1)=[O:21])[CH3:76]

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59314154Ethyl 2-amino-5-fluoro-2,3-dihydro-1H-indene-2-carboxylateHCID 685908492-[2-(3-Methoxy-propenyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid

Product 1

HCID 593141472-(5-Chloro-2-cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 21966342Isopropanol methylene chlorideSolvent

Procedure

A 40 mL reaction vial is charged with 2-cyclobutoxyl-3-methyl-5-chloro-benzoic acid (221, 0.40 g, 1.62 mmol) and dry DCM (5 mL). A stirring bar is added. Stirring is initiated. After dissolution is complete, the HBTU (630 mg, 1.66 mmol) is added. After 5 min, the 2-amino-5-fluoro-indane-2-carboxylic acid ethyl ester. (19, 371 mg, 1.66 mmol is added followed by DIPEA (0.74 mL, 4.16 mmol). The reaction is allowed to stir for 5 days. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 1 g of light yellow oil. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 24 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 4 column volumes followed by a linear gradient to 70% EtOAc in heptanes over 10 column volumes. 17 mL fractions are collected. Fractions 22 through 28 are combined and evaporated in vacuo by pumping to a constant weight to give white solid (0.65 g, 88%).

Workup

  1. customA 40 mL reaction
  2. additionA stirring bar is added
  3. dissolutionAfter dissolution
  4. addition(19, 371 mg, 1.66 mmol is added
  5. stirringto stir for 5 days
  6. customconsumption of the starting amine
  7. customThe contents of the reaction flask are transferred to a separatory funnel
  8. additiondiluted with EtOAc (50 mL)
  9. washThis is washed consecutively with dilute aqueous HCl (3%, 20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL)
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. customevaporated in vacuo

Sources & evidence

ORD record
ord-68bf4be24dbe40cc89146d4612962b48
Source dataset
uspto-grants-2013_10
Patent number
US08569535B2

Reaction notes

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