Potassium Hydroxide → 8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

HRID 27914Notes

Reaction equation

HRID 27914 reaction equation
[OH-].[K+].Cl.[F:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]3[CH2:21][CH2:22][NH:23][CH2:24][CH:8]3[C:7]=2[CH:6]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[O:36][CH:35](O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO>[F:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:9]3[CH2:21][CH2:22][N:23]([CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:24][CH:8]3[C:7]=2[CH:6]=1

Participants

6

Reactant 4

HCID 14797Potassium Hydroxide2×HCID 5003444Sodium cyanoborohydrideHCID 118300545-(p-Fluorophenyl)-2-hydroxytetrahydrofuranHCID 130143858-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride

Product 1

HCID 126660468-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleYield 56%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent4×

Procedure

To a solution of 53 mg. (0.95 mmole) of potassium hydroxide in 50 ml. of methanol under a nitrogen atmosphere was added 613 ml. (1.90 mmole) of levorotatory 8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride, [α]D =(-)40.9 (methanol) and the mixture stirred until solution was complete. To the solution was added 346 mg. (1.90 mmole) of levorotatory 5-(p-fluorophenyl)2-hydroxytetrahydrofuran (from Example 19, Part B), dissolved in a small volume of methanol and the resulting solution stirred for 15 minutes at room temperature. The solution was cooled to 5° C. and 120 mg. (1.90 mmole) of sodium cyanoborohydride in a small amount of methanol was added over 20 minutes. The reaction mixture was stirred at room temperature for 45 minutes, then 250 mg. of potassium hydroxide was added and stirred until dissolved. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. After reextraction of the aqueous phase, the combined organic extracts were dried (MgSO4) and evaporated in vacuo to provide 1.014 g. of oil. This was chromatographed on 30 g. of silica gel as described above to obtain 653 mg. of the desired product as an oil. The oil was converted to the hydrochloride salt, as above, 400 mg., M.P. 252°-257° C. (dec.), [α]D23 =(-)33.7° (methanol) which was found to be 99% pure β-enantiomer by HPLC. Reworking the mother liquors afforded 80 mg. of a second crop, M.P. 254°-258° C. (dec.). Total yield 56%.

Workup

  1. additionTo the solution was added 346 mg
  2. temperatureThe solution was cooled to 5° C.
  3. stirringThe reaction mixture was stirred at room temperature for 45 minutes
  4. stirringstirred
  5. dissolutionuntil dissolved
  6. customThe solvent was evaporated in vacuo
  7. customthe residue partitioned between ethyl acetate and water
  8. dry with materialAfter reextraction of the aqueous phase, the combined organic extracts were dried (MgSO4)
  9. customevaporated in vacuo
  10. customto provide 1.014 g
  11. customThis was chromatographed on 30 g
  12. customto obtain 653 mg

Sources & evidence

ORD record
ord-69095fb507214587b31a9f69c74b8389
Source dataset
uspto-grants-1980_09
Patent number
US04224329

Reaction notes

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