Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate → tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({2-fluoro-4-[(2R)-1-hydroxypropan-2-yl]-5-methoxyphenyl})methyl]amino}-7-fluoroisoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamate

HRID 708891Notes

Reaction equation

HRID 708891 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C@@H:8]([CH3:11])[CH2:9][OH:10])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1B(O)O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:23][CH:22]=[C:21]2F.O.[C:45]([OH:49])(=O)[CH:46]=O.Cl.[CH:51]1([S:54]([C:57]2[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][C:58]=2[CH2:64][NH:65][CH3:66])(=[O:56])=[O:55])[CH2:53][CH2:52]1.[F:67][P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.CN(C=O)C.CCOC(C)=O>[NH2:61][C:60]1[CH:62]=[CH:63][C:57]([S:54]([CH:51]2[CH2:53][CH2:52]2)(=[O:55])=[O:56])=[C:58]([CH2:64][N:65]([CH3:66])[C:45]([CH:46]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[F:67])[C:24]([N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[N:23][CH:22]=[CH:21]3)[C:3]2[CH:4]=[C:5]([O:12][CH3:13])[C:6]([C@@H:8]([CH3:11])[CH2:9][OH:10])=[CH:7][C:2]=2[F:1])=[O:49])[CH:59]=1

Participants

9

Reactant 5

HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 15620607Glyoxylic acid, monohydrateHCID 1177499146-Amino-1-(di-tert-butoxycarbonylamino)-4-fluoroisoquinolineHCID 123951308(R)-(2-Fluoro-4-(1-hydroxypropan-2-yl)-5-methoxyphenyl)boronic acidHCID 1317338614-(Cyclopropylsulfonyl)-3-((methylamino)methyl)aniline hydrochloride

Product 1

HCID 118101244tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({2-fluoro-4-[(2R)-1-hydroxypropan-2-yl]-5-methoxyphenyl})methyl]amino}-7-fluoroisoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamateYield 56.2%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

25C (0.075 g, 0.329 mmol), Intermediate 4 (0.124 g, 0.329 mmol) and glyoxylic acid monohydrate (0.033 g, 0.362 mmol) were dissolved in acetonitrile (1 mL)/DMF (1.000 mL) and heated at 80° C. for 3 h. A solution of Intermediate 8 (0.103 g, 0.329 mmol)) and TEA (0.138 mL, 0.987 mmol) in DMF (1.000 mL) was added followed by BOP (0.160 g, 0.362 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 15 min using a 12 g silica gel cartridge) to yield 25D (155 mg, 0.185 mmol, 56.1% yield) as a yellow solid. MS (ESI) m/z: 840.4 (M+H)+.

Workup

  1. washwashed with water and brine
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. customThe crude product was purified by flash chromatography (loading in chloroform
  5. wait0% to 100% ethyl acetate in hexane over 15 min using

Sources & evidence

ORD record
ord-6676f26e5d844287ae47e647f4193128
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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