Acetyl chloride → HCID 66587956, compound

HRID 1408115Notes

Reaction equation

HRID 1408115 reaction equation
[CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7][CH2:6]1.Cl[CH2:61]Cl.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>ClCCl>[C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH2:18][C:19]2[N:20]=[C:21]([C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:29][C:28]=3[C:39]3[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=4)[CH:42]=[CH:41][N:40]=3)=[O:59])[CH:22]=[CH:23][CH:24]=2)[CH3:1])[CH2:10][CH2:9]1)(=[O:13])[CH3:61]

Participants

6

Reactant 4

HCID 6367Acetyl chlorideHCID 81531DiisopropylethylamineHCID 21863450Trifluoroacetic acid methylene chlorideHCID 66586745HCID 66586745, compound

Product 1

HCID 66587956HCID 66587956, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)-methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 50-mL round-bottom flask, was placed a solution of this amine (110 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL), and N,N-diisopropylethylamine (30 mg, 0.23 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of acetyl chloride (14.4 mg, 0.18 mmol, 1.20 equiv) in dichloromethane (1 mL) with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 90.3 mg (44%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.77 (s, 1H), 9.56 (t, J=5.7 Hz, 1H), 9.06 (d, J=5.1 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.28 (s, 1H), 8.15-8.09 (m, 2H), 7.90-7.79 (m, 2H), 7.72-7.56 (m, 5H), 7.34 (s, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.20 (s, 2H), 3.56 (s, 4H), 3.34 (s, 4H), 3.18-2.95 (m, 7H), 2.56-2.49 (m, 4H), 1.96 (s, 3H), 1.74 (s, 4H), 1.60 (d, J=4.2 Hz, 2H). MS (ES, m/z): 757 [M+H]+.

Workup

  1. customby partitioning between ethyl acetate and aqueous sodium bicarbonate solution
  2. customInto a 50-mL round-bottom flask, was placed
  3. stirringThe resulting solution was stirred for 3 h at room temperature
  4. concentrationThe resulting mixture was concentrated under vacuum
  5. customThe crude product (200 mg) was purified by reverse phase HPLC
  6. washeluting with a water/CH3CN gradient
  7. additioncontaining 0.05% TFA
  8. customThe product was obtained as 90.3 mg (44%) of as a yellow solid

Sources & evidence

ORD record
ord-b8b5f71086c143d5b21a0fec75cf53fa
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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