Author Topic: 4 Acetoxy DET  (Read 1042 times)

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Vibrating_Lights

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4 Acetoxy DET
« on: February 05, 2003, 09:37:00 PM »
I modified this from the stnyh on rhodiums site fir the production of psilocybin. My question is after the The H2 parr reduction is the Ho compound the acetoxy or the hydroxy or is it the same thing??  I ask because to get the acetoxy part there in the thikal 4acetoxydet synthesis acetic anhydirde is utalized on the hydroxy compound.  Will that be needed here.
Experimental:

4-Benzyloxyindol-3-yl-N,N-diethylglyoxylamide (3)

A solution of 4-benzyloxyindole (17.5 g, 0.078 mol) (Biosynth) in anhyd Et20 (500 mL) was mechanically stirred in a 1 L, 3 necked flask and cooled in an ice-salt bath to an internal temperature of 0°C. Oxalyl chloride (20.3 g, 0.16 moles) was added dropwise at a rate that maintained an internal temperature between 0-5°C. Stirring was continued for 3 h at a temperature between 5-10°C with a gentle argon sparge to remove evolved HCl. The argon sparge was replaced by a gas inlet tube and a dry ice/acetone condenser. Anhyd dimethylamine was then bubbled into the reaction with cooling and vigorous stirring until a pH (determined by moist pH paper) between 9 and 11 was achieved. At this time, the orange color of the initial solution had been mostly discharged, and the reaction had the appearance of a slightly off-white slurry with a few flecks of yellow unreacted starting material. CH2Cl2 (20 mL) was added to assist solubilization of the unreacted material and the reaction was stirred for an additional 6 h to yield finally an offwhite slurry. Et2O (150 mL) was added, and the mixture was cooled to 10°C. The white solids were collected by suction filtration on filter paper in a Buchner funnel and then were suspended in distilled H20 (250 mL) and stirred for 1 h to remove diethylamine hydrochloride. The slurry was filtered, and the collected solids were washed on the filter with distilled H2O (3 x 75 mL) and hexane (75 mL) and dried overnight in a vacuum oven. The dried product weighed 18.3 g. The organic filtrates and washes were combined and the solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL) and the organic solution was washed with distilled H2O (2 x 50 mL) and brine (2 x 50 mL). After drying (MgS04) the volume was reduced by rotary evaporation. The concentrated residual solution was subjected to flash chromatography over silica gel, first eluting with CH2Cl2 to recover unreacted indole (1.3 g, 7.4%), followed by elution with 10% MeOH in CH2CI2 to recover 3.3 g of 3. The latter was combined with the initial product to provide a total weight of 21.6 g (85.9%). The crude product was recrystallized from MeOH/EtOAc to give 19.5 g (77%) of 3 with mp 152-155 °C (Lit .4 mp 146-150 °C).

4-Benzyloxy-N,N-diethyltryptamine (4)

A slurry of LiAlH4 (8.90 g, 0.234 mol) in anhyd THF (100 mL) was prepared in a 2 L, 3-neck flask, previously dried with a heat gun under an argon purge. The flask was fitted with a reflux condenser, mechanical stirrer, and addition funnel. Anhyd dioxane (200 mL) was added, and the mixture was heated to 60°C on an oil bath. 4-benzyloxyindol-3yl-N,N-dimethylglyoxylamide (3) (14.5 g, 0.045 moles) was dissolved in a mixture of dioxane (250 mL) and THF (150 mL) and, with rapid stirring, this solution was added dropwise over 1 h. The oil bath temperature was held at 70°C for 4 h, followed by vigorous reflux overnight (16 h) at an oil bath temperature of 95 °C. Thin layer chromatographic analysis (9:1 CH2Cl2/MeOH silica plates) showed nearly complete reduction. The reaction was heated at reflux for an additional 4 h and then cooled to 20 °C. A solution of distilled H20 (27 mL) in THF (100 mL) was added dropwise, resulting in a gray flocculent precipitate. Et2O (250 mL) was added to assist breakup of the complex and improve filtration. This slurry was stirred for 1 h and the mixture was then filtered with a Buchner funnel. The filter cake was washed on the filter with warm Et2O (2 x 250 mL) and was broken up, transferred back into the reaction flask and vigorously stirred with additional hot Et2O (500 mL). This slurry was filtered, and the cake was washed on the filter with Et2O (150 mL) and hexane (2 x 150 mL). All of the organic filtrates were combined and dried (MgS04). After the drying agent was removed by filtration, the filtrate was concentrated under vacuum at 40°C and dried under high vacuum at 0.01 mm Hg, leading to crystallization of the residue as a white waxy solid. Recrystallization from EtOAc yielded 12.57 g, (94.8%) of 4 with mp 124126 °C (lit .4 mp 125-126 °C).

4-Hydroxy-N,N-diethyltryptamine (ethylacin, 5)

A solution of 4 (4.0 g, 0.0135 moles) in 95% EtOH (250 mL) was added to 1.5 g Pd/C (10% w/w) in a 500 mL Parr low pressure hydrogenation bottle. The mixture was shaken under 60 psig of Hz pressure for 2 h. The catalyst was removed by vacuum filtration through Celite and was washed on the filter with EtOH (3 x 50 mL). The filtrate was concentrated by rotary evaporation. The clear residual oil was placed under high vacuum and induced to crystallize by seeding. The white crystalline powder (2.68 g, 97.0%) was used in the next step without further purification.




Barium

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The smoothest way to the 4-acetoxy compounds,
« Reply #1 on: February 06, 2003, 01:20:00 AM »
The smoothest way to the 4-acetoxy compounds, following your route, is to perform the removal of the 4-benzyloxy group in the presence of acetic anhydride. This will allow the phenol to be protected as soon as it´s formed. Believe me, you want to protect it very quick.


Vibrating_Lights

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4-Hydroxy-N,N-diethyltryptamine
« Reply #2 on: February 06, 2003, 04:20:00 AM »
How do i incorporate the Acetic Anhydride in to the debenzylation step. 



Barium

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Perform the hydrogenolysis of the benzyloxy...
« Reply #3 on: February 06, 2003, 04:33:00 AM »
Perform the hydrogenolysis of the benzyloxy group in an inert solvent (don´t use alcohols here) in the presence of a slight excess acetic anhydride.


Vibrating_Lights

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A solution of 4-benzyol-NN-diethyltryptamine...
« Reply #4 on: February 06, 2003, 08:44:00 AM »
A solution of 4-benzyol-NN-diethyltryptamine (4.0 g, 0.0135 moles) THF (250 mL) was added to 1.5 g Pd/C (10% w/w) in a 500 mL Parr low pressure hydrogenation bottle Along with (.0135moles)Acetic anydride . The mixture was shaken under 60 psig of H2 pressure for 2 h. The catalyst was removed by vacuum filtration through Celite and was washed on the filter with EtOH (3 x 50 mL). The filtrate was concentrated by rotary evaporation. The clear residual oil was placed under high vacuum and induced to crystallize by seeding. 

Would 20psi suffice for this perhaps a slightly longer rxn time.  


Lilienthal

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The O-debenzylation should proceed at room...
« Reply #5 on: February 06, 2003, 12:37:00 PM »
The O-debenzylation should proceed at room pressure (with really good shaking) in a few hours.

civicSyStem

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that sounds about right. good luck VL.
« Reply #6 on: February 10, 2003, 09:06:00 PM »
that sounds about right.  good luck VL.