Methyl chloroformate → 2-(4,4-Difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indole-1-carboxylic acid methyl ester

HRID 19845

Reaction equation

HRID 19845 reaction equation
[F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][O:41][C:42](Cl)=[O:43]>O1CCCC1.[Cl-].[Na+].O>[CH3:40][O:41][C:42]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]1)=[O:9])=[O:43]

Participants

6

Reactant 3

HCID 6586Methyl chloroformateHCID 2733832Lithium HexamethyldisilazideHCID 11603838(4,4-Difluoropiperidin-1-yl)[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]methanone2×

Product 1

HCID 167394112-(4,4-Difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indole-1-carboxylic acid methyl esterYield 15.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), lithium bis-(trimethylsilyl)amide (1M solution in tetrahydrofuran, 271 ul, 1.1 eq.) and methylchloroformate (26 mg, 1.1 eq.) in tetrahydrofuran (2 mL) was stirred at room temperature for 48 h, then poured into brine, extracted with dichloromethane, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 98:2 to 97:3 gradient of dichloromethane/methanol, to yield 18 mg (15%) of the desired product as yellow oil. MS (m/e): 464.2 (MH+, 100%).

Workup

  1. extractionextracted with dichloromethane
  2. dry with materialdried over sodium sulfate
  3. filtrationfiltered
  4. customevaporated to dryness
  5. custompurified on silica gel
  6. washeluting with a 98:2 to 97:3 gradient of dichloromethane/methanol

Sources & evidence

ORD record
ord-0b28f7277bb243879e98cc1ec3c71219
Source dataset
uspto-grants-2010_06
Patent number
US07745479B2

Linked notes

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