Pseudoephedrine → n1-[(1r,2s)-2-Hydroxy-1-methyl-2-phenylethyl]-n1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide

HRID 432374Notes

Reaction equation

HRID 432374 reaction equation
[CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[NH2:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH2:47][C:48](OCC)=[O:49])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=4[Cl:45])(=[O:37])=[O:36])=[C:30]([F:46])[CH:29]=3)[C:20]=12>COCCOC>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@H:2]([N:11]([CH3:12])[C:48](=[O:49])[CH2:47][N:25]1[C:21]2=[N:22][CH:23]=[N:24][C:19]([NH2:18])=[C:20]2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=3[Cl:45])(=[O:37])=[O:36])=[C:30]([F:46])[CH:29]=2)=[N:26]1)[CH3:1]

Participants

5

Reactant 3

HCID 7028PseudoephedrineHCID 22346920Ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetateHCID 178418339Butyllithium

Product 1

HCID 69779418n1-[(1r,2s)-2-Hydroxy-1-methyl-2-phenylethyl]-n1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]acetamideYield 20.3%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
50 °C

Procedure

A solution of (+)-pseudoephedrine (0.037 g, 0.224 mmol) in ethylene glycol dimethyl ether (0.75 mL) was treated with a solution of n-butyllithium (2.5 M in hexanes, 0.060 mL, 0.150 mmol). After 20 min, this solution was transferred via cannula into a solution of ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.040 g, 0.074 mmol) in N,N-dimethylfornamide (0.75 mL). The resulting solution was stirred at 50° C. for 15 h. It was then cooled to ambient temperature and partitioned between methanol/dichloromethane (1:9, 50 mL), and water (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 11.88-12.65 min) afforded N1-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.010 g, 0.015 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersi1HS C18, 250×4.6 mm column) Rt 9.63 min; MS: (MH)+ 658.

Workup

  1. temperatureIt was then cooled to ambient temperature
  2. custompartitioned between methanol/dichloromethane (1:9, 50 mL), and water (15 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customPurification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min

Sources & evidence

ORD record
ord-57433a48d8b243a88c332ed73ae5f32b
Source dataset
uspto-grants-2003_12
Patent number
US06660744B1

Reaction notes

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