Water → (11beta,16alpha,17beta)-17-Cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one

HRID 638818Notes

Reaction equation

HRID 638818 reaction equation
C([Sn]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(CCCC)CCCC)CCC.Br[C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][C@@H:40]([CH3:50])[C@@H:41]3[C:45]([CH:47]3[CH2:49][CH2:48]3)=[O:46])[C@H:37]3[C:28]2=[C:29]2[C:34]([CH2:35][CH2:36]3)=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:47]1([C:45]([C@H:41]2[C@H:40]([CH3:50])[CH2:39][C@H:38]3[C@H:37]4[C:28]([C@@H:27]([C:24]5[CH:25]=[CH:26][C:21]([C:18]6[CH:19]=[CH:14][N:15]=[N:16][CH:17]=6)=[CH:22][CH:23]=5)[CH2:44][C@:42]23[CH3:43])=[C:29]2[C:34](=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)[CH2:35][CH2:36]4)=[O:46])[CH2:49][CH2:48]1

Participants

6

Reactant 3

HCID 962WaterHCID 27632603-(Tributylstannanyl)pyridazineHCID 68576237(11beta,16alpha,17beta)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one

Product 1

HCID 68576684(11beta,16alpha,17beta)-17-Cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-oneYield 80%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).

Workup

  1. temperaturecooled to room temperature
  2. extractionthe mixture was extracted three times with dichloromethane
  3. customThe combined organic layers were dried through a phase
  4. customseparate
  5. filtrationfilter
  6. customevaporated to dryness
  7. customPurification by LCMS

Sources & evidence

ORD record
ord-a66c99d57e8e4ae89e0ecc13198d2d00
Source dataset
uspto-grants-2010_04
Patent number
US07691836B2

Reaction notes

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