Triethylamine → (R)-tert-Butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

HRID 75397

반응식

HRID 75397 반응식
C(N(CC)CC)C.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:22]1[C:23]2[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(OCC)(=O)C>CCCCO>[CH3:31][C@H:30]1[C:23]2[C:22]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)=[N:27][CH:26]=[N:25][C:24]=2[CH2:28][CH2:29]1

참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 59670769(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

생성물 1

HCID 59682823(R)-tert-Butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate수율 74.1%

시약·촉매·용매 1

HCID 2631-Butanol용매

실험 절차

Neat POCl3 (463.9 mL, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux under stirring for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as an oil. Triethylamine (93.0 mL, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) were added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours), after which it was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and was concentrated. The resulting oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a powder. LC/MS (APCI+) m/z 319.1 [M+H]+.

후처리

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux under nitrogen
  3. concentrationafter which it was concentrated on a rotavap
  4. dissolutionThe resulting oil was dissolved in DCM
  5. washwashed with H2O
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationwas concentrated
  9. customThe resulting oil was purified on silica gel eluting first with 2:1 hexanes
  10. washethyl acetate until product eluting cleanly

출처 및 근거

ORD 기록
ord-eef4148b314b4f92993a5beff55976d9
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08835434B2

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