Formic Acid → (S)-7-Cyano-4-((3-hydroxypyridin-2-yl)methyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester

HRID 449850Notes

Reaction equation

HRID 449850 reaction equation
[CH:1]([O:4][C:5](=[O:32])[NH:6][C@@H:7]1[CH2:31][C:10]2[N:11]([CH2:20][C:21]3[C:26]([O:27]CC=C)=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O1CCOCC1.C(N(CC)CC)C.C(O)=O>CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]([O:4][C:5](=[O:32])[NH:6][C@@H:7]1[CH2:31][C:10]2[N:11]([CH2:20][C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 284Formic AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 66933414[(S)-4-(3-Allyloxy-pyridin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester

Product 1

HCID 66932978(S)-7-Cyano-4-((3-hydroxypyridin-2-yl)methyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl esterYield 86.5%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

[(S)-4-(3-Allyloxy-pyridin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (40 g, 87.3 mmol) and 1,4-dioxane (400 mL) are combined and the mixture degassed by bubbling in nitrogen for one hour. Then triethylamine (24.4 mL, 174.7 mmol) and formic acid (6.60 mL, 174.7) are added and the mixture heated under nitrogen at 80° C. Tetrakis(triphenylphosphine)palladium (1.02 g, 0.87 mmol) is added while maintaining the nitrogen atmosphere. The reaction is heated at 80° C. for 3 h and then cooled to room temperature. The reaction is filtered through a pad of diatomaceous earth. The filtrate is evaporated and the crude material dried under vacuum to afford a brown solid. The solid is dissolved in NMP (100 mL) and then added to water (1.2 L). A pale cream solid is collected by filtration and dried overnight under vacuum to afford 41 g of crude material. The material is purified by recrystallization from acetonitrile and then dried under vacuum to constant weight to afford the title compound (29.5 g, 86%). LC-ES/MS m/z: 391.1 [M+H]+.

Workup

  1. customthe mixture degassed
  2. customby bubbling in nitrogen for one hour
  3. temperaturewhile maintaining the nitrogen atmosphere
  4. temperatureThe reaction is heated at 80° C. for 3 h
  5. temperaturecooled to room temperature
  6. filtrationThe reaction is filtered through a pad of diatomaceous earth
  7. customThe filtrate is evaporated
  8. dry with materialthe crude material dried under vacuum
  9. customto afford a brown solid
  10. filtrationA pale cream solid is collected by filtration
  11. customdried overnight under vacuum
  12. customto afford 41 g of crude material
  13. customThe material is purified by recrystallization from acetonitrile
  14. customdried under vacuum to constant weight

Sources & evidence

ORD record
ord-79c973916949401fb638340f00c0a702
Source dataset
uspto-grants-2013_07
Patent number
US08486943B2

Reaction notes

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