Trifluoroacetic acid → Dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate

HRID 511255Notes

Reaction equation

HRID 511255 reaction equation
[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][P:8](=[O:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])([O-])=O.Cl[C:22]1[N:27]=[C:26]([NH:28][CH2:29][C:30]2[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]([C:42]([F:45])([F:44])[F:43])=[CH:24][N:23]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>CO.[Pd]>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[C:30]([CH2:29][NH:28][C:26]2[C:25]([C:42]([F:45])([F:43])[F:44])=[CH:24][N:23]=[C:22]([NH:1][C:4]3[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=3)[CH2:7][P:8](=[O:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])[N:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 15205360Dipropan-2-yl(3-nitrobenzyl)phosphonateHCID 57584561N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide

Product 1

HCID 86654005Dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetateYield 34%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

A mixture of triisopropyl phosphite (500 mg, 2.31 mmol) and 1-bromomethyl-3-nitrobenzene (506 mg, 2.43 mmol) was heated at 100° C. under nitrogen for 3 h. The crude dipropan-2-yl (3-nitrobenzyl)phosphonate thus formed was dissolved in MeOH (5 mL) and hydrogenated in the presence of 5% Pd/C (49 mg) for 2 h. The mixture was filtered and concentrated in vacuo and the dipropan-2-yl (3-aminobenzyl)phosphonate residue heated in a microwave reactor at 105° C. under nitrogen for 40 minutes with N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.051 mmol), TFA (12 uL, 0.15 mmol) and 0.5 mL TFE. The mixture was evaporated to dryness and purified by preparative HPLC to afford 11 mg of dipropan-2-yl [3-({4-[({2-[methyl (methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 35, yield: 34%). 1H NMR (400 MHz, CD3OD) δ=1.19 (d, J=6.1 Hz, 6 H), 1.28 (d, J=6.1 Hz, 6 H), 3.06-3.12 (m, 4 H), 3.12-3.19 (m, 4 H), 4.51-4.63 (m, 2 H), 4.96 (s, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.21-7.28 (m, 1 H), 7.29-7.33 (m, 1 H), 7.35-7.43 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 8.21 (s, 1 H), 8.45 (dd, J=4.8, 1.8 Hz, 1 H). MS (ES+): m/z 631.27 (100) [MH+]; HPLC: tR=1.03 min (UPLC, purity).

Workup

  1. filtrationThe mixture was filtered
  2. concentrationconcentrated in vacuo
  3. customThe mixture was evaporated to dryness
  4. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-390e675c9542433f8eda277c583f1b30
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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