1-Methylpiperazine → (3-Amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (4-methyl-piperazin-1yl)-amide

HRID 656648Notes

Reaction equation

HRID 656648 reaction equation
[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.O[N:26]1C2C=CC=CC=2N=[N:27]1.[CH:35]([N:38]([CH2:42][CH3:43])[CH:39](C)C)(C)[CH3:36].Cl.CN(C)CCCN=C=NCC.CN1CCNCC1>CN(C=O)C.C1COCC1>[CH3:39][N:38]1[CH2:42][CH2:43][N:26]([NH:27][C:15](=[O:17])[CH2:14][O:13][C:7]2[N:6]=[C:5]3[S:4][C:3]([C:18](=[O:23])[NH:19][CH:20]4[CH2:22][CH2:21]4)=[C:2]([NH2:1])[C:10]3=[C:9]([CH3:11])[C:8]=2[Cl:12])[CH2:36][CH2:35]1

Participants

8

Reactant 5

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 68436813(3-Amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid

Product 1

HCID 86629767(3-Amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (4-methyl-piperazin-1yl)-amideYield 33%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.200 g, 0.562 mmol) in a 1:1 mixture of THF:DMF (1.5 ml each) are added 1-hydroxybenzotriazole hydrate (0.099 g, 0.731 mmol), N,N-diisopropylethylamine (0.109 g, 0.843 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.162 g, 0.843 mmol), and N-methylpiperazine (0.169 g, 1.69 mmol). The resulting solution is stirred at room temperature for 24 hours, then at 50° C. for 24 hours. The reaction is cooled to room temperature and quenched by the addition of water. The mixture is partitioned between water and EtOAc (40 ml each), and the layers are shaken and separated. The aqueous layer is acidified to pH 3 with 1 N HCl and then extracted with EtOAc (40 ml). The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (100% EtOAc) to give the title compound as a yellow solid (0.080 g, 33%). Mass (m/z): 438.2 (M++1), 436.2 (M+−1).

Workup

  1. waitat 50° C. for 24 hours
  2. temperatureThe reaction is cooled to room temperature
  3. customquenched by the addition of water
  4. customThe mixture is partitioned between water and EtOAc (40 ml each)
  5. stirringthe layers are shaken
  6. customseparated
  7. extractionextracted with EtOAc (40 ml)
  8. dry with materialThe combined organic layers are dried (anhydrous magnesium sulfate)
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-ddd98f7e421640fcbcd324c555d52e4c
Source dataset
uspto-grants-2011_12
Patent number
US08071776B2

Reaction notes

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