Acetic Acid → methyl[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride

HRID 1866503Notes

Reaction equation

HRID 1866503 reaction equation
O=[C:2]([CH3:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:43]CCl>>[ClH:43].[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C@H:2]([NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[CH3:15])[CH:5]=1

Participants

6

Reactant 5

HCID 176Acetic AcidHCID 6344DichloromethaneHCID 6431891-Phenethylamine, (+)-HCID 5049666Sodium triacetoxyborohydrideHCID 21035403Methyl [3-(2-oxopropyl)phenyl]acetate

Product 1

HCID 46938908methyl[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride

Procedure

A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 27) (8.5 g, 41.2 mmol), (R)-α-methyl benzylamine (4.8 ml, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with dichloromethane (100 ml). The combined organic extracts were dried (magnesium sulfate) and reduced in vacuo. Purification by flash column chromatography eluting with dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume) gave a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil (8.71 g). Treatment with hydrogen chloride (40 ml of a 1M solution in methanol, 40 mmol) followed by three successive crystallisations (diisopropylether/methanol) gave the title compound as a white crystalline solid (5.68 g). 1H NMR (400 MHz, CD3OD): δ=7.52-7.48 (5H, m), 7.28-7.25 (1H, m), 7.18-7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1H, q), 3.62 (2H, s), 3.30 (3H, s), 3.30-3.25 (1H, m), 3.26-3.15 (1H, m), 2.66-2.60 (1H, m), 1.68 (3H, d), 1.18, (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 312, [M+Na]+ 334.

Workup

  1. customThe reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200 ml)
  2. customThe organic phase was separated
  3. extractionthe aqueous phase extracted with dichloromethane (100 ml)
  4. dry with materialThe combined organic extracts were dried (magnesium sulfate)
  5. customPurification by flash column chromatography
  6. washeluting with dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume)
  7. customgave
  8. customTreatment with hydrogen chloride (40 ml of a 1M solution in methanol, 40 mmol) followed by three successive crystallisations (diisopropylether/methanol)

Sources & evidence

ORD record
ord-2f64a41b55b244dbb7ee1cf20afe935c
Source dataset
uspto-grants-2009_12
Patent number
US07629358B2

Reaction notes

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