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

HRID 1694404노트

반응식

HRID 1694404 반응식
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]

참가 물질

9

반응물 6

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

생성물 1

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

시약·촉매·용매 2

HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

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 C20H28ClFN2O2, 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.

후처리

  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

출처 및 근거

ORD 기록
ord-82e0678a079c4aaebee847107ae9e801
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08158673B2

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