Hydrochloric Acid → N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamide

HRID 1969631Notes

Reaction equation

HRID 1969631 reaction equation
S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([CH2:23][C:24]4([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C(OC([NH:37][C:38]1([CH2:42][C:43](O)=[O:44])CCC1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C(CC(O)=O)#N.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.O>[C:20]1([CH2:23][C:24]2([CH2:28][NH:29][C:43](=[O:44])[CH2:42][C:38]#[N:37])[CH2:25][CH2:26][CH2:27]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 9740Cyanoacetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 10751878(1-Aminocyclobut-1-yl)acetic acid, N-BOC protectedHCID 58557629(1-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)-cyclobutyl)methanamine

Product 1

HCID 136009630N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamideYield 17%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of (1-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)-cyclobutyl)methanamine (0.225 g, 0.548 mmol) (prepared using A from Example #1, Step D, 2-(1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid [prepared as described WO9921824A1], EDC•HCl, B with TEA, E with 4.0 M HCl in 1,4-dioxane) in DMF (10 mL) was added cyanoacetic acid (0.070 g, 0.822 mmol), HOBt (0.101 g, 0.658 mmol), EDC•HCl (0.126 g, 0.658 mmol) and DIEA (0.190 mL, 1.096 mmol) to give a brown solution. The mixture was stirred at ambient temperature for about 18 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd in vacuo. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give N-((1-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclobutyl)methyl)-2-cyanoacetamide as an off-white solid (0.030 g, 17%): LC/MS (Table 1, Method a) Rt=1.48 min; MS m/z: 324 (M+H)+.

Workup

  1. customto give a brown solution
  2. extractionthe mixture was extracted with EtOAc (3×25 mL)
  3. dry with materialThe combined organic layers were dried over anhydrous MgSO4
  4. filtrationfiltered
  5. customThe crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM

Sources & evidence

ORD record
ord-518aecc66ce448b5baabaad60c21f9d8
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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