Bromotrimethylsilane → Tenofovir

HRID 1716372

반응식

HRID 1716372 반응식
[OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].CC(C)([O-])C.[Mg+2].CC(C)([O-])C.CC(C)[O-].[Mg+2].CC(C)[O-].C1(C)C=CC(S(O[CH2:45][P:46](=[O:53])([O:50]CC)[O:47]CC)(=O)=O)=CC=1.Br[Si](C)(C)C>CN(C=O)C>[P:46]([CH2:45][O:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13])([OH:53])([OH:50])=[O:47]

참가 물질

7

반응물 5

HCID 76113BromotrimethylsilaneHCID 4452119-(2-Hydroxypropyl)adenine, (R)-HCID 4193599Diethyl P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]phosphonateHCID 10197750Magnesium dipropan-2-olateHCID 12040442Magnesium 2-methylpropan-2-olate

생성물 1

HCID 464205Tenofovir수율 63.5%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
65 °C

실험 절차

(R)-9-[2-(hydroxy)propyl]adenine (HPA) (20.0 g, 0.104 mol) was suspended in DMF (44.5 ml) and heated to 65° C. Magnesium t-butoxide (14.2 g, 0.083 mol), or alternatively magnesium isopropoxide, was added to the mixture over one hour followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.205 mol) over two hours while the temperature was kept at 78° C. The mixture was stirred at 75° C. for 4 hours. After cooling to below 50° C., bromotrimethylsilane (73.9 g, 0.478 mol) was added and the mixture heated to 77° C. for 3 hours. When complete, the reaction was heated to 80° C. and volatiles were removed via atmospheric distillation. The residue was dissolved into water (120 ml) at 50° C. and then extracted with ethyl acetate (101 ml). The pH of the aqueous phase was adjusted to pH 1.1 with sodium hydroxide, seeded with authentic (R)-PMPA, and the pH of the aqueous layer was readjusted to pH 2.1 with sodium hydroxide. The resulting slurry was stirred at room temperature overnight. The slurry was cooled to 4° C. for three hours. The solid was isolated by filtration, washed with water (60 ml), and dried in vacuo at 50° C. to yield 18.9 g (63.5%) of crude (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) as an off-white solid.

후처리

  1. customwas kept at 78° C
  2. temperatureAfter cooling to below 50° C.
  3. temperaturethe mixture heated to 77° C. for 3 hours
  4. temperatureWhen complete, the reaction was heated to 80° C.
  5. customvolatiles were removed via atmospheric distillation
  6. dissolutionThe residue was dissolved into water (120 ml) at 50° C.
  7. extractionextracted with ethyl acetate (101 ml)
  8. stirringThe resulting slurry was stirred at room temperature overnight
  9. temperatureThe slurry was cooled to 4° C. for three hours
  10. customThe solid was isolated by filtration
  11. washwashed with water (60 ml)
  12. customdried in vacuo at 50° C.

출처 및 근거

ORD 기록
ord-44a8448e4cd146d5b2ab80c040935c1b
출처 데이터셋
uspto-grants-2010_09
특허 번호
US07803788B2

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