Isobutylamine → 3-(5-Chloro-2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amide

HRID 1943267Notes

Reaction equation

HRID 1943267 reaction equation
Br[C:2]1[C:13]([F:14])=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([Cl:15])[CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[O:28]=[C:29]1[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C1COCC1.CCOC(C)=O>[CH2:36]([NH:40][C:33]([CH:31]1[CH2:30][C:29]([C:2]2[CH:3]=[C:4]([Cl:15])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:12][C:13]=2[F:14])([OH:28])[CH2:32]1)=[O:35])[CH:37]([CH3:39])[CH3:38]

Participants

9

Reactant 6

HCID 6558IsobutylamineHCID 111923Propylphosphonic anhydrideHCID 49133583-Oxocyclobutane-1-carboxylic acidHCID 18522661Acetone cardiceHCID 672787301-(4-Bromo-2-chloro-5-fluorobenzyl)pyrrolidineHCID 178418339Butyllithium

Product 1

HCID 672787093-(5-Chloro-2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amideYield 15.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To Intermediate 11, 1-(4-Bromo-2-chloro-5-fluorobenzyl)pyrrolidine (4.0 g, 13.7 mmol) in THF (34 mL) at −78° C. (acetone/dry ice bath) was added a solution of nBuLi (5.5 mL, 13.7 mmol, 2.5 M THF). After 15 min, a precooled (−78° C.) solution of 3-oxocyclobutanecarboxylic acid (0.78 g, 6.8 mmol, in 5 mL of THF) was added via cannula. The reaction was allowed to slowly warm to rt overnight. After approximately 16 h, isobutylamine (1.4 mL, 13.7 mmol) was added, followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 6.6 mL, 10.2 mmol). After 1 hr the reaction was diluted with EtOAc and then quenched with 1N NaOH. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 120 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound (400 mg, 15% yield) as a yellow foam: Rf=0.23 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28Cl FN2O2, 382.9, found, 383, 385 (M+H) APCI; 1H NMR (300 MHz, CDCl3): δ 7.37 (d, J=7.0 Hz, 1H), 7.20 (d, J=11.6 Hz, 1H), 6.25-6.22 (bm, 2H), 3.68 (s, 2H), 3.09-2.84 (m, 5H), 2.57 (apt bs, 4H), 2.46-2.43 (m, 2H), 1.79-1.70 (m, 5H); 0.88 (d, J=6.6 Hz, 6H); 100 MHz 13C NMR (CDCl3) δ 177.5, 159.5 (d, JC-F=247.2), 138.3, 132.1, 128.2, 117.9 (d, JC-F=24.7 Hz), 73.2, 56.5, 54.3, 47.4, 40.1, 34.6, 28.7, 23.8, 20.3.

Workup

  1. waitAfter approximately 16 h
  2. customquenched with 1N NaOH
  3. customThe layers were separated
  4. extractionthe aqueous layer was back extracted with EtOAc
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customPurification of this material
  9. washeluting with 5% MeOH/CH2Cl2 with 0.1% NH4OH
  10. additionThe product containing fractions
  11. customwere collected
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-9e98de7e00884d4294c9f9bf0a8379f9
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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