Phosphoric Acid → (R)-benzyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3 a-amino-5 a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate

HRID 338633

반응식

HRID 338633 반응식
FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.P(=O)(O)(O)O.[K].CC1(C)C(C)(C)OB([C:53]2[CH2:58][CH2:57][C@@H:56]([C:59]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[O:60])[CH2:55][CH:54]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:53]2[CH2:58][CH2:57][C@@H:56]([C:59]([O:61][CH2:62][C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)=[O:60])[CH2:55][CH:54]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1

참가 물질

9

반응물 5

HCID 1004Phosphoric AcidHCID 5462222PotassiumHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 71698571(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonateHCID 86692346(R)-benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate

생성물 1

HCID 86692345(R)-benzyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3 a-amino-5 a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate수율 67.1%

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 312751,4-Dioxane용매

반응 조건

온도
75 °C

실험 절차

To a vial containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.65 g, 1.165 mmol) was added phosphoric acid, potassium salt (0.742 g, 3.50 mmol), (R)-benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.8 g, 2.338 mmol) (enantiomer 1 prepared above), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-phos) (0.072 g, 0.175 mmol) and palladium(II) acetate (0.026 g, 0.117 mmol). The mixture was diluted with 1,4-dioxane (10 mL) and water (1 mL), flushed with nitrogen, then the vial was sealed and heated to 75° C. After 6 h of heating, the mixture was cooled to rt, diluted with water (20 mL) and brine (20 mL), and was extracted with dichloromethane (5×40 mL). The organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-60% ethyl acetate in hexanes gradient and a 40 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give (R)-benzyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.488 g, 0.782 mmol, 67.1% yield) as an off-white solid. LCMS: m/e 624.65 (M+H)+, 2.18 min (method 1). 1H NMR (500 MHz, chloroform-d) δ=7.40-7.30 (m, 5H), 5.35 (br. s., 1H), 5.18 (dd, J=6.2, 1.8 Hz, 1H), 5.14 (s, 2H), 4.73 (d, J=2.0 Hz, 1H), 4.60 (s, 1H), 2.65-2.50 (m, 2H), 2.38-2.30 (m, 2H), 2.25-1.94 (m, 5H), 1.70 (s, 3H), 1.07 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 1.80-0.83 (m, 23H).

후처리

  1. customflushed with nitrogen
  2. customthe vial was sealed
  3. temperatureAfter 6 h of heating
  4. temperaturethe mixture was cooled to rt
  5. additiondiluted with water (20 mL) and brine (20 mL)
  6. extractionwas extracted with dichloromethane (5×40 mL)
  7. dry with materialThe organic layers were dried with sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by flash chromatography
  11. additionThe fractions containing the expected product
  12. concentrationwere concentrated under reduced pressure

출처 및 근거

ORD 기록
ord-821f68e87b5e47ef9fcd3846cb1155d1
출처 데이터셋
uspto-grants-2014_11
특허 번호
US08889854B2

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