Triethylamine → 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl) thiazol-2-yl)cyclopropanecarboxamide

HRID 530002Notes

Reaction equation

HRID 530002 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(C(Cl)=O)=O.[NH2:22][C:23]1[S:24][C:25]([C@H:28]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:22][C:23]4[S:24][C:25]([C@H:28]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 143496081-(1,3-Dioxaindan-5-yl)cyclopropane-1-carboxylic acidHCID 58048512(R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide

Product 1

HCID 597571121-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl) thiazol-2-yl)cyclopropanecarboxamideYield 69%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-10 °C

Procedure

To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (618 mg, 3.0 mmol) in anhydrous CH2C2 (6 mL) was slowly added (COCl)2 (0.3 mL, 3.4 mmol) at −10° C. followed by DMF (3 drops). The reaction mixture was stirred at −10° C. for 0.5 h. The excess (COCl)2 was removed under vacuum. The acid chloride (10.5 mmol) was then dissolved in anhydrous CH2Cl2 (3 mL) and was slowly added to a solution of (R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (648 mg, 1.8 mmol) and Et3N (1.8 mL, 6 mmol) in anhydrous CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with CH2Cl2 and washed with 1N HCl, NaHCO3 and brine. The organic layer was separated from the aqueous layer and dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40-60% EtOAc/Hexane) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)cyclopropanecarboxamide as a colorless solid (680 mg, 69%). 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.60 (dd, J=8.7, 5.9 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.3, 2.6 Hz, 1H), 7.05 (td, J=8.2, 2.6 Hz, 1H), 6.90 (td, J=8.3, 1.7 Hz, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.18 (d, J=4.3 Hz, 1H), 6.04 (s, 2H), 3.90 (d, J=4.3 Hz, 1H), 1.73 (td, J=5.4, 2.0 Hz, 2H), 1.28 (t, J=7.1 Hz, 2H), 1.29 (s, 9H). HPLC ret. time 3.65 min, 10-99% CH3CN, 5 min run; ESI-MS 550.5 m/z (MH+).

Workup

  1. customat −10° C.
  2. customThe excess (COCl)2 was removed under vacuum
  3. stirringThe reaction mixture was stirred at room temperature for 1 h
  4. washwashed with 1N HCl, NaHCO3 and brine
  5. customThe organic layer was separated from the aqueous layer
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customThe crude product was purified by column chromatography (40-60% EtOAc/Hexane)

Sources & evidence

ORD record
ord-8c3f4ee221024dcfa0bcdad4a6001b10
Source dataset
uspto-grants-2016_05
Patent number
US09351962B2

Reaction notes

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