Ethylamine → HCID 67279226, compound

HRID 1943294Notes

Reaction equation

HRID 1943294 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:24])[CH3:23].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:22]([NH:24][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19])[CH3:23]

Participants

7

Reactant 5

HCID 6341EthylamineHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 111923Propylphosphonic anhydrideHCID 574858713-(3-Chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 67279226HCID 67279226, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜30 mL, ˜34.5 mmol) was added 2.0M ethylamine in THF (34.5 mL, 69 mmol) and T3P (50% solution in EtOAc, 33 ml, 51.8 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75M Biotage™ column, eluting with a gradient of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (4.0 g, 35% yield). Rf=0.40 (15% MeOH/CH2Cl2+0.2% NH4OH), LRMS m/z Calcd for C18H25ClN2O2, 336.9, found, 337.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.54 (dd, J=8.3, 2.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 6.52-6.35 (br m, 1H), 3.86 (s, 2H), 3.29-3.22 (m, 2H), 2.81-2.60 (m, 7H), 2.48 (d, J=8.3 Hz, 2H), 1.83 (br s, 4H), 1.11 (dt, J=7.3, 2.9 Hz, 3H); 13C-NMR (CDCl3) δ 176.7, 147.0, 134.2, 133.3, 131.4, 126.5, 123.8, 73.8, 73.9, 56.1, 54.1, 41.2, 35.0, 33.0, 23.6, 14.9.

Workup

  1. customThe resulting reaction mixture
  2. customthe layers were separated
  3. extractionThe aqueous layer was subjected to EtOAc extraction (2×500 ml) again
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. customevaporated
  6. customThe residue was purified by flash column chromatography
  7. washeluting with a gradient of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH
  8. additionThe product containing fractions
  9. customwere collected
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-e89d8fa8d0a04cffa1d41c1a40d084a4
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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