Ammonia → 3-[3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-3-pyridyl]propyloxy]pyrrolidine

HRID 2216376Notes

Reaction equation

HRID 2216376 reaction equation
[CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:30]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]#[CH:38])[CH2:31]1)C1C=CC=CC=1.C(N(CC)CC)C.N>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.[Cu]I.C(OCC)(=O)C.O.CN(C)C=O.CO>[CH2:1]([C:8]1[C:13]([CH2:38][CH2:37][CH2:36][O:35][CH:32]2[CH2:33][CH2:34][NH:30][CH2:31]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

11

Reactant 4

HCID 222AmmoniaHCID 8471TriethylamineHCID 113843072-Benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridineHCID 219422551-Benzyl-3-(2-propynyloxy)pyrrolidine

Product 1

HCID 587007473-[3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-3-pyridyl]propyloxy]pyrrolidineYield 62.5%

Reagents, catalysts & solvents 6

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of 742 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1), 389 mg of 1-benzyl-3-(2-propynyloxy)pyrrolidine (Production Example 16), 62.7 mg of tetrakis(triphenylphosphine)palladium (0), 51.7 mg of copper (I) iodide, 757 μl of triethylamine, 4 ml of methanol and 4 ml of N,N-dimethylformamide was stirred under nitrogen atmosphere at 75° C. for 2 hours. After standing to cool, water, ethyl acetate and aqueous ammonia were added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered through NH-silica gel and the solvent was removed. After 10 ml of methanol, 1 ml of acetic acid and 50 mg of 10% palladium carbon were added to the residue and hydrogen substitution was performed, the mixture was stirred at room temperature overnight. After the reaction mixture was nitrogen-purged, it was filtered through Celite. The solvent was removed, and then the residue was purified by silica gel column chromatography with ethyl acetate/methanol/aqueous ammonia (100/5/2), to give 465 mg of the title compound.

Workup

  1. temperatureto cool
  2. customThe organic layer was separated
  3. washwashed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered through NH-silica gel
  6. customthe solvent was removed
  7. additionAfter 10 ml of methanol, 1 ml of acetic acid and 50 mg of 10% palladium carbon were added to the residue and hydrogen substitution
  8. stirringthe mixture was stirred at room temperature overnight
  9. custompurged
  10. filtrationit was filtered through Celite
  11. customThe solvent was removed
  12. customthe residue was purified by silica gel column chromatography with ethyl acetate/methanol/aqueous ammonia (100/5/2)

Sources & evidence

ORD record
ord-b13bc79ac65445dcb2644ae8e9a00b4f
Source dataset
uspto-grants-2006_09
Patent number
US07112593B2

Reaction notes

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