Hydrochloric Acid → HCID 68617266, compound

HRID 1893655Notes

Reaction equation

HRID 1893655 reaction equation
C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:37])[NH:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:30][CH:29]1[CH:31]=[CH2:32])=O)(C)(C)C.Cl.Cl.O1CCOCC1.[C:46]([O:50][C:51]([NH:53][CH:54]([CH:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1)[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33]([C:28]1([NH:27][C:26]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)[CH2:12][N:8]2[C:55](=[O:56])[CH:54]([NH:53][C:51]([O:50][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:52])[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)=[O:37])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:34]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 35593192-(((Tert-butoxy)carbonyl)amino)-2-cyclohexylacetic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 204431481,4-Dioxane hydrochlorideHCID 68615943HCID 68615943, compound2×

Product 1

HCID 68617266HCID 68617266, compoundYield 156.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 2-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Example 27; 0.50 g, 0.98 mmol) in THF (3 mL) was treated with 4M HCl in dioxanes (1.2 mL, 4.9 mmol) at rt. After 4 h, additional 2-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.58 mmol) and 4M HCl/dioxane solution (5 mL) were added. After an additional 4 h, the solvent was removed in vacuo and the resulting foamy white solid was taken up in DMF (3 mL) and treated with tert-Butoxycarbonylamino-cyclohexyl-acetic acid (0.55 g, 2.1 mmol), HATU (1.0 g, 2.7 mmol) and DIPEA (0.78 mL, 4.5 mmol) at rt and allowed to age overnight. The reaction mixture was diluted in EtOAc and washed consecutively with saturated NaHCO3, brine and then dried over anhydrous Na2SO4. After concentration in vacuo, the residue was purified via column chromatography on SiO2 (0-75% EtOAc/hex) to produce 1.0 g (89% over two steps) of 1-{[1-(2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester as an off-white solid. LCMS found 651.1 [M+H]+.

Workup

  1. waitAfter an additional 4 h
  2. customthe solvent was removed in vacuo
  3. customallowed to age overnight
  4. washwashed consecutively with saturated NaHCO3, brine
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationAfter concentration in vacuo
  7. customthe residue was purified via column chromatography on SiO2 (0-75% EtOAc/hex)

Sources & evidence

ORD record
ord-ea88d4f024374fa9838ece3bb2210e5c
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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