1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → HCID 71711978, compound

HRID 528602Notes

Reaction equation

HRID 528602 reaction equation
COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.Br[C:30]1[C:31]([O:40][CH3:41])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:41][O:40][C:31]1[C:30]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([NH:8][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]2=3)=[CH:35][CH:34]=[C:33]([C:36]([F:39])([F:37])[F:38])[N:32]=1

Participants

7

Reactant 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 72210962HCID 72210962, compoundHCID 89761436N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide2×

Product 1

HCID 71711978HCID 71711978, compoundYield 18%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

To a 10-20 ml microwave vial charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M) (0.05 g, 0.120 mmol), 3-bromo-2-methoxy-6-(trifluoromethyl)pyridine (Anichem) (0.046 g, 0.180 mmol), sodium t-butoxide (0.029 ml, 0.240 mmol), xantphos (0.014 g, 0.024 mmol), and Pd2(dba)3 (10.97 mg, 0.012 mmol) was added toluene (1.198 ml). The mixture was purged with argon and the vessel was sealed and irradiated at 130° C. for 30 mins. LC-MS indicated complete conversion to desired product (PMB protected, m/z=593). To the mixture was added TFA (200 μl) and the resulting mixture stirred at room temperature for 2 hrs. The mixture was filtered through celite and the filtrate dried under reduced pressure. The crude material was purified with a 25 g HP spherical silica column (15 μm, Interchim) ramping EtOAc in heptane (0-50%, then isocratic at 50%, 10% DCM isocratic throughout) providing product as a film which was lyophilized yielding an off-white solid. The material was further purified with preparative RP-HPLC ramping ACN in H2O (10-90%, 0.1% TFA) affording 4-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (10 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.67-3.72 (m, 2 H) 3.92 (s, 3 H) 4.29-4.33 (m, 2 H) 6.44 (d, J=8.51 Hz, 1 H) 6.79 (d, J=4.60 Hz, 1 H) 7.13 (dd, J=8.51, 2.15 Hz, 1 H) 7.16 (d, J=2.05 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.56 (d, J=7.92 Hz, 1 H) 7.90-7.97 (m, 1 H). m/z (ESI) 473.2 (M+H)+.

Workup

  1. customThe mixture was purged with argon
  2. customthe vessel was sealed
  3. customirradiated at 130° C. for 30 mins
  4. additionTo the mixture was added TFA (200 μl)
  5. filtrationThe mixture was filtered through celite
  6. customthe filtrate dried under reduced pressure
  7. customThe crude material was purified with a 25 g HP spherical silica column (15 μm, Interchim)
  8. customisocratic at 50%, 10% DCM isocratic throughout) providing product as a film which
  9. customwas lyophilized yielding an off-white solid
  10. customThe material was further purified with preparative RP-HPLC ramping ACN in H2O (10-90%, 0.1% TFA)

Sources & evidence

ORD record
ord-1b17ce71c3374067840bfaa4c6bb9285
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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