Hydrochloric Acid → HCID 67347241, compound

HRID 705523Notes

Reaction equation

HRID 705523 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:40])[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].Cl>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:27]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:40])[CH2:28][CH2:29]4)(=[O:37])=[O:38])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 752601-(4-Fluorophenyl)piperazineHCID 58379254HCID 58379254, compound

Product 1

HCID 67347241HCID 67347241, compoundYield 67%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

1-(4-Fluorophenyl)piperazine (185 mg, 1.0 mmol) and pyridine (1 mL) were dissolved in dichloromethane (60 mL) under argon. The solution was chilled in ice-water bath and XW2-004 1-(4-methoxy-4-oxobutanoyl)indoline-5-sulfonyl chloride (333 mg, 1.0 mmol) was added. The reaction solution was then warmed to room temperature and stirred for 3 hours. After the reaction, water [(50 mL with 37% HCl (1 L)] was added to the solution. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. Removal of dichloromethane afforded light green solid product which was then triturated with methanol (10 mL). The white solid product was filtered off to give methyl 4-(5-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)indolin-1-yl)-4-oxobutanoate, the methyl ester of XW2-011B, (320 mg, yield 67%); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.62 (dd, 1H, J=8.3, 2.0 Hz), 7.58 (d, 1H, J=2.0 Hz), 6.95 (t, J=9.0 Hz, 2H), 6.84 (m, 2H), 4.21 (t, J=8.6 Hz, 2H), 3.72 (s, 3H), 3.30 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.77 (s, 4H). The white solid obtained from the above reaction (289 mg, 0.63 mmol) was mixed with methanol (10 mL) and lithium hydroxide (1 mL of a 1.0 M aq. solution) in a 20 mL microwave reaction tube. The tube was capped and irradiated in the microwave reactor (Biotage Initiator I) at 90° C. for 10 minutes. The reaction solution was concentrated under vacuum and the residue was diluted with 20 mL of water treated with NaOH solution (1.0 M) till pH>10. The aqueous solution was extracted with ethyl acetate (2×10 mL). Then the aqueous layer was acidified to pH˜4, extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulted solid was washed with dichloromethane to afford XW2-011B (180 mg, 69%) as a light orange solid product. Mp=213-215° C.; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=8.3 Hz, 1H), 7.58-7.65 (m, 2H), 6.95 (t, J=9.0 Hz, 2H), 6.82 (dd, J=4.5, 4.5 Hz, 2H), 4.20 (t, J=8.6 Hz, 2H), 3.31 (t, J=8.6 Hz, 2H), 3.15 (s, 8H), 2.80 (s, 4H); HPLC 98% (Rt=3.30, 90% methanol in acetonitrile); HRMS (ESI-ve) m/z calculated for C22H23FN3O5S (M−H)−460.13479. found 460.13475.

Workup

  1. additionwas added to the solution
  2. customThe organic layer was separated
  3. washwashed with water, brine
  4. dry with materialdried over magnesium sulfate
  5. customRemoval of dichloromethane afforded light green solid product which
  6. customwas then triturated with methanol (10 mL)
  7. filtrationThe white solid product was filtered off

Sources & evidence

ORD record
ord-22306178ea384120a7f848d323d1eff0
Source dataset
uspto-grants-2015_11
Patent number
US09174969B2

Reaction notes

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