Lithium Hydroxide → (R)-2-{5-Chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide

HRID 1986312Notes

Reaction equation

HRID 1986312 reaction equation
[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C(OC([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[C@H:31]([CH3:39])[CH2:30]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>O1CCOCC1.ClCCl>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:38][CH2:37][CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][NH:29][CH2:30][C@H:31]4[CH3:39])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]

Participants

9

Reactant 6

HCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 81531DiisopropylethylamineHCID 68858197(R)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl esterHCID 866253822-(2,5-Dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide

Product 1

HCID 68856124(R)-2-{5-Chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamideYield 46.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide (0.30 g, 0.89 mmol), (R)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.57 g, 2.2 mmol) and diisopropylethylamine (0.29 g, 2.2 mmol) in 1,4-dioxane (5 mL) is heated at 90° C. under a nitrogen atmosphere for 14 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-8%, the intermediate is obtained as a solid. The solid is suspended in dichloromethane (3 mL), followed by the successive addition of triethylsilane (0.50 mL) and TFA (3 mL). The resultant yellow solution is stirred for 7 hours. After concentration a wet solid is obtained. The solid is treated with 2 N LiOH, with sonication, until pH reaches 12. The mixture is filtered, the solid is dried before it is subject to chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-20%, to give the title compound as a yellow solid (190 mg, 46% yield). ES+(m/z) 459 (35Cl) and 461 (37Cl) [M+H].

Workup

  1. concentrationAfter concentration and subsequent chromatography on silica gel
  2. washeluting with 2 M NH3/MeOH in dichloromethane 0-8%
  3. customthe intermediate is obtained as a solid
  4. concentrationAfter concentration a wet solid
  5. customis obtained
  6. filtrationThe mixture is filtered
  7. customthe solid is dried before it
  8. washeluting with 2 M NH3/MeOH in dichloromethane 0-20%

Sources & evidence

ORD record
ord-262dbbb1cc374d6db764a17da58a714d
Source dataset
uspto-grants-2009_06
Patent number
US07547691B2

Reaction notes

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