Water → tert-butyl methyl[2-({[3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-thienyl]carbonyl}amino)ethyl]carbamate

HRID 570509Notes

Reaction equation

HRID 570509 reaction equation
[NH2:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C[Al](C)C.C[O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27]1[C:28]2[CH:35]=[CH:34][NH:33][C:29]=2[N:30]=[CH:31][N:32]=1)=O.O>C1(C)C=CC=CC=1.CO>[CH3:12][N:4]([CH2:3][CH2:2][NH:1][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27]1[C:28]2[CH:35]=[CH:34][NH:33][C:29]=2[N:30]=[CH:31][N:32]=1)=[O:18])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]

Participants

7

Reactant 4

HCID 962WaterHCID 2756424N-Boc-N-methylethylenediamineHCID 16682925TrimethylaluminumHCID 669578463-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester

Product 1

HCID 66958001tert-butyl methyl[2-({[3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-thienyl]carbonyl}amino)ethyl]carbamate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
105 °C

Procedure

To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (158 μl; 154 mg; 0.88 mmol) in anhydrous toluene (3 mL) placed in a sealed tube under nitrogen was added a solution of trimethylaluminum (354 μl; 2 M; 0.71 mmol) in toluene. The colorless solution was stirred at 25° C. for 1 h, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (55 mg; 0.18 mmol) was added and the resulting yellow suspension was heated to 105° C. overnight. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting gray suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using hexane and ethyl acetate as eluents to afford crude tert-butyl methyl[2-({[3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-thienyl]carbonyl}amino)ethyl]carbamate as a white solid. The solid was suspended in methanol (1 mL) in a 5 mL flask with magnetic stir bar. To the white suspension was added hydrochloric acid (0.21 mL, 2.0N in diethyl ether, 0.42 mmol). The resulting solution was stirred at 25° C. overnight and the resulting precipitate was collected by filtration. The precipitate was purified using preparative HPLC to afford 3-(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid (2-methylamino-ethyl)-amide (1 mg, 2%) as a brown solid. 1H NMR (MeOH-d4) 8.55 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 7.66 (d, J=5.2 Hz, 1H), 7.29 (d, J=3.7 Hz, 1H), 6.61 (d, J=3.3 Hz, 1H), 3.73-3.67 (m, 2H), 3.34-3.28 (m, 2H), 2.75 (s, 3H); MS (m/z) 317 [M+H]+.

Workup

  1. additionwas added
  2. additionwas added
  3. custompurified by chromatography on a SP1 Biotage system

Sources & evidence

ORD record
ord-bc5dbf95b5e54967962b09fca564edeb
Source dataset
uspto-grants-2015_05
Patent number
US09023847B2

Reaction notes

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