Methylamine → 3-(3-Chloro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid methylamide

HRID 1943278Notes

Reaction equation

HRID 1943278 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.[CH3:22][NH2:23].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][NH:23][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]

Participants

6

Reactant 4

HCID 6329MethylamineHCID 14798Sodium HydroxideHCID 111923Propylphosphonic anhydrideHCID 574858713-(3-Chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 566481263-(3-Chloro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid methylamideYield 48.2%

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 (˜666 mL, ˜121.5 mmol) was added 2.0 M methylamine (95 mL, 190 mmol, in THF) and T3P (50 wt % solution in EtOAc, 96.6 mL, 152 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 75 L Biotage™ column, eluting with gradients 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 (18.9 g, 48% yield). Rf=0.35 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C17H23ClN2 O2, 322.2, found, 323.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47-7.45 (m, 2H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 5.94 (brs, 1H), 5.67 (brs, 1H), 3.75 (s, 3H), 2.85 (d, J=4.9 Hz, 3H), 2.86-2.73 (m, 3H), 2.62-2.56 (m, 4H), 2.54-2.47 (m, 2H), 1.84-1.76 (m 4H); 100 MHz 13C NMR (CDCl3) δ 177.6, 146.0, 135.5, 134.0, 130.8, 126.3, 123.6, 74.3, 56.8, 54.3, 41.1, 33.3, 26.9, 23.7.

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 gradients 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-a36ae72fbf0b4cfc946bf1d2621892a7
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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