Sulfuryl chloride → HCID 49781875, compound

HRID 578576Notes

Reaction equation

HRID 578576 reaction equation
C(OC(NCC[N:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:12][C:13]1[N:14]([CH3:18])C=NC=1)=O)(C)(C)C.[C:31](O)([C:33](F)(F)F)=O.[CH2:38](Cl)Cl.[CH3:41][N:42]1[CH:46]=[C:45]([S:47](Cl)(=[O:49])=[O:48])[N:44]=[CH:43]1.CCN([CH:57]([CH3:59])[CH3:58])C(C)C.S(Cl)(Cl)(=O)=O>CC#N>[CH2:18]([N:14]([CH2:13][CH2:12][NH:11][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)[S:47]([C:45]1[N:44]=[CH:43][N:42]([CH3:41])[CH:46]=1)(=[O:49])=[O:48])[C:33]1[CH:31]=[CH:58][CH:57]=[CH:59][CH:38]=1

Participants

7

Reactant 5

HCID 24648Sulfuryl chlorideHCID 81531Diisopropylethylamine2×HCID 27368871-methyl-1H-imidazole-4-sulfonyl chlorideHCID 16086188HCID 16086188, compoundHCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 49781875HCID 49781875, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Previously reported 1-tert-butoxycarbonylamino-{2-[biphenyl-4-yl-(3-methyl-3H-imidazol-4-ylmethyl)-amino]}-ethane (compound 9a in reference 31b) (30 mg, 0.0739 mmol) was deprotected by stirring in a 1:1 mixture of TFA-CH2Cl2 (1 mL) for 30 minutes. After removal of all solvent in vacuo, the residue (23 mg, 0.0739 mmol) was sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride, but with 5 equiv of DIPEA. Generally, the appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. After the usual work-up, the residue was purified by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to afford 1-methyl-1H-imidazole-4-sulfonic acid benzyl-[2-(biphenyl-4-ylamino)-ethyl]-amide as a colorless film (30 mg, 91%) Next, the secondary aniline of 1-methyl-1H-imidazole-4-sulfonic acid benzyl-[2-(biphenyl-4-ylamino)-ethyl]-amide (30 mg, 0.067 mmol, 1 equiv) was alkylated with the HCl salt of 5-chloromethyl-1-methyl-1H-imidazole. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. After the usual work-up, the crude material was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to give 11 as a glassy film (24 mg, 65%): δH (500 MHz, CDCl3) 3.16 (m, 2H, (Bn)NCH2CH2N), 3.33 (m, 2H, (Bn)NCH2CH2N), 3.44 (s, 3H, CH3 (Im)), 3.75 (s, 3H, CH3 (Im)), 4.27 (s, 2H, CH2Ph), 4.38 (s, 2H, CH2Im), 6.56 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.79 (s, 1H, CH (Im)), 7.34-7.51 (m, 15H, 10 CH (Ph), 3 CH (Im), 2 CH (Ar)); δC (125 MHz, CDCl3) δ1.9, 34.2, 44.9, 45.4, 50.0, 54.5, 113.5, 124.6, 126.4, 126.5, 128.1, 128.3 (2), 128.9, 129.0, 129.2, 129.4, 130.5, 136.8, 138.8, 139.3, 139.9, 141.1, 147.2; HRMS (ES+) calcd for [C30H32N6O2S+H] 541.2380. found 541.2386; HPLC (I) tR=13.01 min (100%), (II) tR=20.24 min (100%).

Workup

  1. customAfter removal of all solvent in vacuo
  2. customwas evaporated
  3. dissolutionThe residue was re-dissolved in CH2Cl2
  4. washwashed with 5% NaHCO3, water, brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customAfter the usual work-up, the residue was purified by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1)

Sources & evidence

ORD record
ord-4f3914af38d84118a437a4387f993816
Source dataset
uspto-grants-2015_05
Patent number
US09040563B2

Reaction notes

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