Triethylamine → N-((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

HRID 2170403Notes

Reaction equation

HRID 2170403 reaction equation
[NH2:1][C@H:2]([C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:16][CH:15]=[C:14]([Cl:34])[N:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1.C(N(CC)CC)C.[F:42][C:43]1([F:60])[C:47]2[N:48]([CH2:55][C:56](O)=[O:57])[N:49]=[C:50]([C:51](F)([F:53])[F:52])[C:46]=2[C@H:45]2[CH2:59][C@@H:44]12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:34][C:14]1[N:13]=[C:12]([C@@H:2]([NH:1][C:56](=[O:57])[CH2:55][N:48]2[C:47]3[C:43]([F:42])([F:60])[C@@H:44]4[CH2:59][C@@H:45]4[C:46]=3[C:50]([CH:51]([F:53])[F:52])=[N:49]2)[CH2:3][C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:16][CH:15]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 90281213(S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamideHCID 90281286(3bS,4aR)-5,5-Difluoro-3b,4,4a,5-tetrahydro-3-(trifluoromethyl)-1H-cyclopropa(3,4)cyclopenta(1,2-c)pyrazole-1-acetic acid

Product 1

HCID 90281321N-((S)-1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

To a solution of crude (S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (60A, 400 mg, 0.76 mmol) in DMA (6 mL) was added triethylamine (0.32 mL, 2.28 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J, 0.61 mmol), then HATU (173.4 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then additional HATU (86.7 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for an additional 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound (60B). MS (m/z) 790.05 [M+H]+.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for an additional 15 minutes
  2. concentrationUpon completion, the reaction mixture was concentrated in vacuo
  3. custompurified by silica gel column chromatography
  4. washeluting with 0-100% EtOAc in hexanes

Sources & evidence

ORD record
ord-ae0fb14d069c40ddbadf8a07b9b8abce
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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