1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 7-(4-Cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide

HRID 79076Notes

Reaction equation

HRID 79076 reaction equation
[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:19]4[S:18][N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:20]([OH:22])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CC1(C)[O:38][C@@H:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[OH:38][C@H:37]([CH2:36][OH:35])[CH2:39][O:40][NH:41][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]=[N:17][S:18][C:19]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:22]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11298047(R)-O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamineHCID 673534187-((4-Cyclopropyl-2-fluorophenyl)amino)benzo[d]isothiazole-6-carboxylic acid

Product 1

HCID 446032687-(4-Cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amideYield 59%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (155 mg, 0.47 mmol) and diisopropylethylamine (0.10 mL, 0.61 mmol) in DMF (5 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (97 mg, 0.66 mmol), EDCI (117 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken in MeOH (10 mL) and a 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour before being diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes) to afford the title compound as a yellow solid (115 mg, 59%). LCMS (method A): RT=9.02 min, [M+H]+=418. 1H NMR (DMSO-d6, 400 MHz) 9.98 (1 H, s), 8.97 (1 H, s), 7.72 (1 H, s), 7.61 (1 H, d, J=8.35 Hz), 7.09-6.90 (3 H, m), 3.95 (1 H, dd, J=9.94, 3.81 Hz), 3.79 (2 H, d, J=16.92 Hz), 3.40 (2 H, d, J=5.46 Hz), 2.03-1.94 (1 H, m), 1.03-0.97 (2 H, m), 0.77-0.71 (2 H, m).

Workup

  1. washwashed with water
  2. dry with materiala saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. additiona 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added
  6. stirringThe reaction mixture was stirred at room temperature for 1 hour
  7. additionbefore being diluted with ethyl acetate
  8. washwashed with a saturated aqueous solution of sodium hydrogen carbonate
  9. dry with materialbrine, dried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customwas subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes)

Sources & evidence

ORD record
ord-5c1cb5f698b041eaab1951d42d1949a7
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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