Diisopropylethylamine → N-{2-[4-(2-diethylamino-ethyl)-piperazine-1-carbonyl]-6-fluoro-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-2-dimethylamino-acetamide

HRID 2234638Notes

Reaction equation

HRID 2234638 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:40][CH2:39]1)=[O:37].Cl.[CH3:52][N:53]([CH2:55][C:56](Cl)=[O:57])[CH3:54].CCN(C(C)C)C(C)C>ClCCl>[CH2:49]([N:46]([CH2:47][CH3:48])[CH2:45][CH2:44][N:41]1[CH2:40][CH2:39][N:38]([C:36]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:6]=[C:7]([F:8])[C:2]=2[NH:1][C:56](=[O:57])[CH2:55][N:53]([CH3:54])[CH3:52])=[O:37])[CH2:43][CH2:42]1)[CH3:50]

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 139949912-(Dimethylamino)acetyl chloride hydrochloride2×HCID 57731559{2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone

Product 1

HCID 59700178N-{2-[4-(2-diethylamino-ethyl)-piperazine-1-carbonyl]-6-fluoro-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-2-dimethylamino-acetamideYield 7.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

30 mg (0.04 mmol) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone was combined with 9.0 mg (0.06 mmol) of dimethylaminoacetylchloride hydrochloride and 32 mg (0.11 mmol, 3.31 mmol/gram loading) of PS-DIEA resin (Argonaut Technologies, Inc.) in 1.0 mL dichloromethane. The reaction was shaken gently at room temperature for 48 hours. 22 mg (0.14 mmol) of dimethylaminoacetylchloride hydrochloride and 26 mg (0.09 mmol) more PS-DIEA resin (Argonaut Technologies, Inc.) was added and the reaction was continued to shake at room temperature for 24 more hours. The resin was filtered off and rinsed well with methanol and dichloromethane. The filtrate was concentrated down. The dried residue was dissolved in 0.5 mL methanol and 0.5 mL acetone. 150 μL of a 50% w/v potassium hydroxide (aqueous) solution was added and the reaction was stirred at room temperature for 1 hour. The reaction was neutralized by adding a few drops of acetic acid and concentrated. The residue was dissolved in dimethyl sulfoxide, filtered through a 0.45 μm syringe filter, and purified by reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 1.9 mg (0.003 mmol, 7% yield) of N-{2-[4-(2-diethylamino-ethyl)-piperazine-1-carbonyl]-6-fluoro-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-2-dimethylamino-acetamide as a fluffy white powder. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, 1H), 8.28 (d, 1H), 7.70 (s, 1H), 7.67 (dd, 1H), 7.60 (dd, 1H), 7.46 (s, br., 1H), 7.32 (t, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 3.87 (s, 3H), 3.77 (s, br., 2H), 3.56 (d, 2H), 3.19 (s, 2H), 3.13 (s, br., 2H), 2.71 (t, 2H), 2.64 (t, 2H), 2.59 (d, 2H), 2.41 (s, 6H), 1.26 (t, 6H); MS: m/z 630.2 (M+H+).

Workup

  1. customto shake at room temperature for 24 more hours
  2. filtrationThe resin was filtered off
  3. washrinsed well with methanol and dichloromethane
  4. concentrationThe filtrate was concentrated down
  5. dissolutionThe dried residue was dissolved in 0.5 mL methanol
  6. addition150 μL of a 50% w/v potassium hydroxide (aqueous) solution was added
  7. stirringthe reaction was stirred at room temperature for 1 hour
  8. additionby adding a few drops of acetic acid
  9. concentrationconcentrated
  10. dissolutionThe residue was dissolved in dimethyl sulfoxide
  11. filtrationfiltered through a 0.45 μm syringe
  12. filtrationfilter
  13. custompurified by reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid)

Sources & evidence

ORD record
ord-ca2d6660d1934243a8a5992eb021b8c1
Source dataset
uspto-grants-2010_05
Patent number
US07709645B2

Reaction notes

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