Hydrochloric Acid → HCID 13207815, compound

HRID 1649362Notes

Reaction equation

HRID 1649362 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[Mg].[Mg].CI.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](Cl)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC.C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 798IndoleHCID 6328Methyl iodideHCID 5462224MagnesiumHCID 20479781Phenylmethyl 4-(2-chloro-2-oxoethyl)-1-piperidinecarboxylateHCID 86584867HCID 86584867, compound

Product 1

HCID 13207815HCID 13207815, compoundYield 55.8%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
0 °C

Procedure

17.6 g of indole in solution in 100 ml of ether were added to a magnesium methyl iodide solution prepared from 6.5 g magnesium and 38.6 g methyl iodide in 150 ml ethyl ether. Heating under reflux took place for 2 hours and the solution was cooled to 0° C. before adding, drop by drop while stirring, a solution of 36.3 g of 1-benzyloxycarbonyl-4-piperidyl-acetyl chloride (U.S. Pat. No. 4,064,255) in 300 ml toluene. The solution was stirred for 2 hours at 10° C. and then hydrolyzed with 170 ml of 2 N hydrochloric acid. 25.8 g of 2-(1-benzyloxycarbonyl-4-piperidyl)-1-(3-indolyl)- ethanone melting at 122° C. were obtained and then converted into a tosylated derivative by the action of 15.7 g of tosyl chloride in the presence of 27.8 g potassium carbonate in 400 ml of acetone. 34.5 g of 2-(1-benzyloxycarbonyl- 4-piperidyl)-1-(1-p-toluenesulfonyloxy-3-indolyl)-ethanone were obtained and put into suspension in 600 ml ethyl ether. This suspension was added, little by little, to a magnesium methyl iodide solution prepared from 3.1 g of magnesium and 18.5 g of methyl iodide in 200 ml of ethyl ether. The mixture was stirred over night at the ambient temperature and hydrolyzed at about 5° C. with 650 ml of a 20% by weight aqueous solution of ammonium acetate. 35.5 g of 1-(1-benzyloxycarbonyl-4-piperidyl)-2-(1-tosyl-3-indolyl)-2-propanol were obtained. The piperidine protective group was then eliminated by the action of cyclohexene in the presence of aluminum chloride and 10% palladized carbon; the reagents were added at or near 0° C. in an inert atmosphere. The process was completed by heating under reflux for 4 hours. After filtration, concentration under vacuum and purification by silica gel chromatography (eluant: toluene-ethanol-diethylamine=5-5-1), 10 g of 1-(4-piperidyl)-2-(1-p-toluenesulfonyloxy-3-indolyl)-2-propanol were obtained which were used as such for the preparation of 3-[2-(4-piperidyl)-1-methyl-ethyl]-indole.

Workup

  1. temperatureHeating
  2. temperatureunder reflux
  3. customfor 2 hours
  4. additionbefore adding
  5. stirringThe solution was stirred for 2 hours at 10° C.

Sources & evidence

ORD record
ord-5051abd3b5574b86bf65500a55227e85
Source dataset
uspto-grants-1983_11
Patent number
US04416888

Reaction notes

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