1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → (+)-6-(2-Fluoromethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one

HRID 2278558Notes

Reaction equation

HRID 2278558 reaction equation
[Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>N1C=CC=CC=1.CN(C)C=O.O>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[CH3:33])=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1

Participants

8

Reactant 4

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 5360545SodiumHCID 6994335(2S)-2-methyl-2,3-dihydro-1H-indoleHCID 136378673[4-(2-Fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid

Product 1

HCID 136098498(+)-6-(2-Fluoromethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
20 °C

Procedure

In a three-necked flask under argon, 0.5 g of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid previously obtained (example 30b, step 3b) is placed in 7 ml of pyridine and 7 ml of dimethylformamide, and then N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added at ambient temperature, followed by 0.25 g of (S)-2-methylindoline (CAS 22160-09-4). The reaction medium is stirred at ambient temperature (20° C.) for 72 hours. 25 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 25 ml of water, washing is carried out with twice approximately 15 ml of 1M hydrochloric acid solution, washing is carried out with 25 ml of water, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and ethanol (95/5, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from 1 ml of dichloromethane and 10 ml of diisopropyl ether, filtered, and dried at ambient temperature (20° C.). (+)-6-(2-Fluoromethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated (0.315 g).

Workup

  1. extractionextraction
  2. washwashing
  3. washwashing
  4. washwashing
  5. washwashing
  6. customdrying
  7. filtrationis carried out over MgSO4, filtration
  8. filtrationfilter
  9. concentrationthe resulting product is concentrated under vacuum
  10. customThe compound obtained
  11. customis chromatographed on silica gel (40-63 μm), elution
  12. additionbeing carried out with a mixture of dichloromethane and ethanol (95/5
  13. additionThe fractions containing the expected compound
  14. customevaporated
  15. customThe compound obtained
  16. customis triturated from 1 ml of dichloromethane and 10 ml of diisopropyl ether
  17. filtrationfiltered
  18. customdried at ambient temperature (20° C.)

Sources & evidence

ORD record
ord-1be8390f7d814c8fa34e3fcf0a5d77f1
Source dataset
uspto-grants-2015_09
Patent number
US09133168B2

Reaction notes

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