Ethanol → 2-Tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid

HRID 514128Notes

Reaction equation

HRID 514128 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])[C:3]=1[CH3:30].[CH3:31][N:32]([CH2:34][C:35]#[CH:36])[CH3:33].C1COCC1.CCO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[C:26]([O:25][CH:19]([C:4]1[C:3]([CH3:30])=[C:2]([C:36]#[C:35][CH2:34][N:32]([CH3:33])[CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]

Participants

8

Reactant 4

HCID 702EthanolHCID 8028Tetrahydrofuran2×HCID 81643N,N-DimethylpropargylamineHCID 67126305Ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate

Product 1

HCID 671261652-Tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetic acidYield 17.9%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 178418476HCID 178418476, compoundCatalyst2×HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (40 mg, 81.7 μmol), N,N-dimethylpropargylamine (26 μL, 0.245 mmol), PdCl2(PPh3)2 (5.7 mg, 16.3 μmol), CuI (3.1 mg, 16.3 μmol) and THF (1.00 mL) was heated to 70° C. for 18 h in a sealed vessel. Conversion was incomplete, so the vessel was charged with more PdCl2(PPh3)2 (5.7 mg, 16.3 μmol) and CuI (3.1 mg, 16.3 μmol) and heated to 100° C. for an additional 26 h. The reaction was cooled to 23° C. THF (1.0 mL), EtOH (absolute, 500 μL), and H2O (500 μL) were added followed by LiOH monohydrate (100 mg, 2.37 mmol). The reaction was heated to 100° C. for 4 h. After cooling to 23° C., the crude reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt) (6.8 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, broad, 1H), 10.26 (s, broad, 1H), 8.30 (d, J=8.6 Hz, 1H), 7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 5.03 (s, 1H), 4.56 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H), 0.90 (s, 9H). 19F NMR (377 MHz, DMSO-d6) δ−74.1 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31ClNO3: 464.2; Found: 464.0.

Workup

  1. temperatureThe reaction was cooled to 23° C
  2. temperatureThe reaction was heated to 100° C. for 4 h
  3. temperatureAfter cooling to 23° C.
  4. customthe crude reaction
  5. filtrationwas filtered through a 0.45 micron
  6. filtrationfilter
  7. customdirectly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-f1f1d8bd138241cb95a56f9fa9869462
Source dataset
uspto-grants-2015_08
Patent number
US09102614B2

Reaction notes

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