Acetic Acid → 2-(R)-(3-(S)-((4-(3,3-Difluoro-3-(2-pyridyl)propyl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid

HRID 1386804노트

반응식

HRID 1386804 반응식
[F:1][C:2]([F:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CC(O)=O.COC1C=CC(C[O:29][C:30](=[O:50])[C@H:31]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[C@@H:38]([CH:48]=O)[CH2:37]2)[CH2:32][CH:33]2[CH2:35][CH2:34]2)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:17][C:2]([F:1])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:48][C@@H:38]2[C@@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:40][N:36]([C@H:31]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:30]([OH:50])=[O:29])[CH2:37]2)[CH2:7][CH2:6]1

참가 물질

7

반응물 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 186197434-(3,3-Difluoro-3-(2-pyridyl)propyl)piperidineHCID 539781992-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid (4-methoxy)benzyl ester

생성물 1

HCID 206723582-(R)-(3-(S)-((4-(3,3-Difluoro-3-(2-pyridyl)propyl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid수율 89.4%

시약·촉매·용매 2

HCID 111,2-Dichloroethane용매HCID 8857Ethyl Acetate용매

실험 절차

A solution of 4-(3,3-difluoro-3-(2-pyridyl)propyl) piperidine (20 mg. 0.083 mmol, from EXAMPLE 202, Step E) and AcOH (0.0050 mL, 5.2 mg, 0.087 mmol) in 1,2-dichloroethane (1.1 mL) was transferred to a vial containing 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid (4-methoxy)benzyl ester (30 mg, 0.076 mmol, from EXAMPLE 21, Step E). Molecular sieve pellets (100 mg, 3 Å) were added and the mixture was stirred for 10 min. at RT before the addition of sodium triacetoxyborohydride (19 mg, 0.090 mmol). After 3 h, the mixture was diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (20 mL) followed by saturated aq. NaCl (20 mL). The aq. layers were extracted with EtOAc (40 mL) and the combined organic layers were dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 50:50 v/v CH2Cl2/EtOAc, to give 36 mg of the title compound. Further purification by preparative HPLC on a 20×250 mm Chiralcel OD column, eluting with 98:2 v/v hexanes/i-PrOH, gave 23 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 8.60 (d, J=5, 1H), 7.94 (td, J=8, 2, 1H), 7.66 (d, J=8, 1H), 7.48 (dd, J=8, 5, 1H), 7.35 (d, J=8, 2H), 7.25 (td, J=8, 6, 1H), 7.01-6.95 (m, 2H), 6.92-6.87 (m, 2H), 5.13 (s, 2H), 3.77 (s, 3H), 3.33 (dd, J=9, 6, 1H), 3.10 (q, J=9, 2H), 2.84-2.74 (m, 2H), 2.66-2.59 (m, 2H), 2.52 (dd, J=9,7, 1H), 2.36-2.21 (m, 5H), 1.81 (bt, J=12, 1H), 1.73 (bt, J=12, 1H), 1.71-1.51 (m, 4H), 1.30-1.24 (m, 2H), 1.21-0.99 (m, 3H), 0.72-0.64 (m, 1H), 0.45-0.55 (m, 2H), 0.07-0.00 (m, 2H); ESI-MS 650 (M+H); HPLC A: 3.33 min.

후처리

  1. additionMolecular sieve pellets (100 mg, 3 Å) were added
  2. washwashed with saturated aq. NaHCO3 (20 mL)
  3. extractionThe aq. layers were extracted with EtOAc (40 mL)
  4. dry with materialthe combined organic layers were dried (Na2SO4)
  5. customdecanted
  6. customevaporated
  7. customThe crude product was purified by flash column chromatography on silica gel
  8. washeluting with 50:50 v/v CH2Cl2/EtOAc

출처 및 근거

ORD 기록
ord-f1a66117b1f143ac9811d508d619f4e5
출처 데이터셋
uspto-grants-2001_07
특허 번호
US06265434B1

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