Phosgene → HCID 118098784, compound

HRID 708917Notes

Reaction equation

HRID 708917 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:51]2([C:54]#[N:55])[CH2:53][CH2:52]2)=[C:6]([CH2:8][N:9]([CH3:50])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:56](Cl)(Cl)=[O:57]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:50])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[C:51]4([C:54]#[N:55])[CH2:52][CH2:53]4)[NH:1][C:56](=[O:57])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[C:15]([CH3:23])=[CH:14][C:13]3=[CH:18][CH:17]=4)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:42])([CH3:39])([CH3:40])[CH3:41]

Participants

5

Reactant 2

HCID 6371PhosgeneHCID 118098782HCID 118098782, compound

Product 1

HCID 118098784HCID 118098784, compoundYield 73.5%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 36I (0.371 g, 0.495 mmol) in acetonitrile (5 mL) and dichloromethane (5 mL) was cooled to 0° C. To this solution, was added phosgene (20% in toluene, 0.257 mL, 0.520 mmol). The mixture was stirred at 0° C. for 15 min, then bubbled with Ar for 25 min to remove excess phosgene and HCl. The resulting solution was added dropwise over 5 h via a syringe pump into a solution of TEA (0.690 mL, 4.95 mmol) in dichloromethane (200 mL). The solution was stirred for an additional 30 min and then concentrated. The crude product was purified by flash chromatography (1-15% MeOH/dichloromethane) to give di-Boc protected intermediate (0.326 g, 85%) as a diastereomeric mixture. The diastereomers were separated by a prep chiral HPLC (CHIRALCEL® OD 10 um 4.6×250 mm) to yield 36J (0.141 g, 0.182 mmol, 73.5% yield) as a yellowish solid. MS (ESI) m/z: 775.3 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 8.05 (1H, d, J=5.81 Hz), 7.68 (1H, dd, J=7.83, 1.77 Hz), 7.61 (1H, d, J=9.09 Hz), 7.52 (1H, d, J=5.81 Hz), 7.46 (1H, d, J=8.08 Hz), 7.27 (1H, dd, J=9.22, 2.15 Hz), 7.18-7.24 (2H, m), 6.88 (1H, d, J=2.02 Hz), 6.71 (1H, dd, J=8.08, 2.27 Hz), 6.11 (1H, d, J=2.02 Hz), 5.73 (1H, s), 5.67 (1H, d, J=16.93 Hz), 4.65 (1H, t, J=10.99 Hz), 4.14 (1H, d, J=16.93 Hz), 3.96 (1H, dd, J=10.86, 4.29 Hz), 3.40 (3H, s), 2.31 (3H, s), 1.27 (25H, s).

Workup

  1. custombubbled with Ar for 25 min
  2. customto remove excess phosgene and HCl
  3. stirringThe solution was stirred for an additional 30 min
  4. concentrationconcentrated
  5. customThe crude product was purified by flash chromatography (1-15% MeOH/dichloromethane)
  6. customto give di-Boc protected intermediate (0.326 g, 85%) as a diastereomeric mixture
  7. customThe diastereomers were separated by a prep chiral HPLC (CHIRALCEL® OD 10 um 4.6×250 mm)

Sources & evidence

ORD record
ord-b224db8ac1e7460e959a87c8103d1c6e
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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