1-N-Boc-4-Piperidinecarboxylic acid methyl ester → 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester

HRID 1170228노트

반응식

HRID 1170228 반응식
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:13][O:14][C:15]([C:17]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)=[O:16]

참가 물질

4

반응물 3

HCID 3928701-N-Boc-4-Piperidinecarboxylic acid methyl esterHCID 162270134-Chloro-7-fluoroquinazolineHCID 23714775LiHMDS tetrahydrofuran2회

생성물 1

HCID 595517614-(7-Fluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester

실험 절차

A mixture of 4-chloro-7-fluoro-quinazoline (2.87 g, 15.4 mmol) (WO 9609294 A1) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (4.15 g, 17.1 mmol), as prepared in Example 1b, was placed in a −78° C. bath for 5 min under argon before adding a 1.08 M LiHMDS/THF solution (17.8 mL, 19.2 mmol) rapidly by syringe along the sides of the flask (to allow cooling and dispersion of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was manually swirled in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 2.5 h stirring at rt, the dark brown homogeneous solution was quenched with 1.0 M NaH2PO4 (38 mL) and extracted with DCM (1×150 mL and 1×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure, and subject to high vacuum at 90° C. with toluene chasers (3×10 mL) to provide the crude title compound as an opaque thick yellow oil that was used in the next step without further purification (6.83 g). 1H—NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.11 (dd, 1H), 7.70 (dd, 1H), 7.36 (ddd, 1H), 3.74-3.64 (m, 2H), 3.62-3.51 (m, 2H), 3.61 (s, 3H), 2.47-2.38 (br m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 389.2, found 390.1 (MH)+.

후처리

  1. customas prepared in Example 1b
  2. customwas placed in a −78° C.
  3. customfor 5 min
  4. temperatureto allow cooling
  5. custombefore removing the cold bath
  6. stirringAfter 2.5 h stirring at rt
  7. customthe dark brown homogeneous solution was quenched with 1.0 M NaH2PO4 (38 mL)
  8. extractionextracted with DCM (1×150 mL and 1×25 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated under reduced pressure
  11. customsubject to high vacuum at 90° C. with toluene chasers (3×10 mL)

출처 및 근거

ORD 기록
ord-c820c82974544b56a526df069f0ab223
출처 데이터셋
uspto-grants-2010_11
특허 번호
US07825244B2

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