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All 8 posts Subject: Synthesis of Olivetol Please login to post Down

demorol
(Hive Bee)
04-16-03 13:33
No 427257
      Synthesis of Olivetol
(Rated as: excellent)

This one is for you, Rhodium. I have decided to post it after reading one of your requests for its synthesis in Russian Hyperlab.

Synthesis of Olivetol

Step 1: 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate

Into a 2-liter 3-necked flask fitted with a reflux condenser topped with a nitrogen gas inlet tube attached to a constant pressure mercury gauge, mechanical stirrer, dropping funnel and thermometer were placed 230mL of anhydrous methanol (reagent grade) and 32.4g (0.6 mole) of sodium methoxide. A slow current of nitrogen was introduced and the mixture was stirred until a complete dissolution of sodium methoxide. 110g (0.68 mole) of diethyl malonate was added, the solution was stirred for additional 10 min and 75g (0.48 mole) of pure 3-nonene-2-one was added portionwise at a rate such that the reaction temperature was kept below the boiling point (ca. 50-60°C). Stirring and refluxing were continued for 3 h. The reaction mixture was allowed to cool to room temperature, neutralized with conc. HCl (~50mL) and allowed to stand overnight. The solvent was removed under reduced pressure and the residue was partitioned between 200mL of 1 N HCl and 800mL of ethyl acetate. The aqueous layer was separated and the organic phase was washed with   two 300mL portions of water and the product was then extracted from the ethyl acetate with a saturated solutioin of sodium bicarbonate until a small portion on acidification no longer gave a turbid solution (= five 200mL portions). The sodium bicarbonate solution was cautiously acidified and extracted with three 300mL portions of ether. The ether solution was dried over sodium sulfate and distilled under reduced pressure. The semi-solid residue was dried at 50°C under high vacuum for 5 h to yield 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate as a white solid, mp 83-85°C.
Step 2: Methyl 3-bromo-2-hydroxy-4-oxo-6-n-pentyl-cyclohex-2-ene-1-carboxylate

Into a 2-liter 4-necked flask fitted with a reflux condenser, mechanical stirrer, dropping funnel and thermometer were placed 60g (0.25 mole) of a compound from a previous step, 200mL of acetic acid and 200mL of water. The mixture was stirred vigorously until a fine suspension was obtained, cooled and maintained at 5-10°C while 44.4g (0.28 mole) of bromine, dissolved in 70mL of acetic acid, was added dropwise over a period of 2 h. The reaction mixture was stirred at room temperature for 1 h and then diluted with 500mL of water and allowed to stand at 5-10°C overnight. The solids were filtered, washed with cold water until the washings gave a negative test for bromine (ca. 3 Ч 75mL) and dried in a vacuum oven at 50°C for 4 h to give the title compound, mp 100-102°C.

Step 3: Olivetol (5-pentylresorcinol)

Into a 500mL 3-necked flask fitted with a reflux condenser, mechanical stirred and thermometer were placed 60g (0.182 mole) of a compound from step 1 and 90g (0.75 mole) of anhydrous pyridine HCl. The semi-solid mixture was heated in an oil bath at 90°C for 4 h (internal temp. 82-84°C) and then at 200°C for 2 h. The reaction mixture was cooled to room temperature and partitioned between 550mL of ether and 100mL of 1.2 N HCl. The aqueous layer was separated and the ether phase washed with 50mL of 1.2 N HCl and then with 75mL of water. The organic phase was then washed with two 75mL portions of 10% sodium hydrosulfite (dithionite) followed by two 75mL portions of saturated NaHCO₃ and then with 75mL of water, dried over anhydrous Na₂SO₄ and the solvent evaporated under reduced pressure. The dark oil (34.6g) was distilled at 125-130°C/0.05 mmHg to yield olivetol.

Reference: Patent US3919322

I'm dreaming of the white crystals.

cattleprodder
(Hive Bee)
04-16-03 21:09
No 427369
      Yes.

With olivetol in hand, 2,6-dimethoxy-4-(n)-pentylamphetamine is just over the horizon.

foxy2
(Distinctive Doe)
04-17-03 02:50
No 427468
User Picture       And DELTA-9-TETRAHYDROCANNABINOL is just under

And DELTA-9-TETRAHYDROCANNABINOL is just under the horizon.

Rhodium
(Chief Bee)
04-18-03 03:10
No 427723
      THC better than PEA in this case

2,6-dimethoxy-4-pentylamphetamine is not likely to be a good compound, either it is a very long-winded so/so thing, or it is simply a completely boring antagonist.

With Olivetol in hand, don't waste it - go directly to THC.

Megatherium
(Hive Bee)
04-18-03 10:41
No 427786
      There is something in "Organic ...

There is something in "Organic chemistry", Morrison and Boyd, 6th ed. (this isn't such a good book) p 915 about the citral + olivetol reaction.

They say:"When the terpene citral is allowed to react in the presence of dilute acid with olivetol, there is a mixture of products containing delta-3,4-trans-THC, the racemic form of one of the physiologically active components of hashish."

Hmm, (at first glance) that synthesis doesn't seem to be examplified in:
https://www.rhodium.ws/chemistry/psychedelicchemistry/chapter2.html

Rhodium
(Chief Bee)
04-18-03 20:45
No 427892
User Picture       But the citral/olivetol reaction must be ...

But the citral/olivetol reaction must be mentioned in one of the other THC synthesis articles on my site, right?

SpicyBrown
(Hive Bee)
04-18-03 22:06
No 427912
      ... Was just looking at this yesterday.

... Was just looking at this yesterday. See
https://www.rhodium.ws/chemistry/thc/ and more specifically, https://www.rhodium.ws/chemistry/thc/page6.html
Also, it actually is in https://www.rhodium.ws/chemistry/psychedelicchemistry/chapter2.html just search the page w/your broswer for "citral"..

-SpicyBrown

demorol
(Hive Bee)
04-19-03 12:53
No 428050
      Another one!
(Rated as: excellent)

Step 1: 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester

9.6g (0.2 mole) of sodium hydride (50% oil suspension) is added portionwise in a nitrogen atmosphere, with stirring and ice cooling (internal temperature 10°C) to the mixture of 34.8g (0.2 mole) of 3-oxoglutaric acid dimethyl ester and 30.8g (0.2 mole) of 2-octynoic acid methyl ester in 500mL of anhydrous benzene. The ice bath is removed and the yellowish stirred for a further 15 min at room temp before the second portion of 11.2g of sodium hydride is added without cooling. The reaction mixture is refluxed for 1 h and the resulting yellow suspension poured (after cooling) on 600g of ice. The aqueous phase is separated and extracted with 500mL of ether. The extract is combined with the organic phase and the whole extracted twice with 200mL of 0.2 N NaOH. The alkaline solution is combined with the aqueous phase, the whole filtered through purified diatomaceous earth and acidifiedwith conc. HCl. After cooling, the colourless emulsion is extracted with 500mL of ether, the extract dried over MgSO₄ and concentrated by evaporation. After drying in vacuo, 47.3g of crude product is obtained as yellow crystallizing oil. This is then dissolved in 50mL of IPA and 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester precipitates immediately in the form of large needles. After standing for ~14 h in a refrigerator, the crystals are filtered off with suction, washed with small amount of cold IPA and dried. Yield: 33.82g of the title product as yellowish crystals; mp 59-60°C.

Step 2: 2,4-dihydroxy-6-phenyl-isophthalic acid

83.4g (0.282 mole) of the product from previous step is refluxed in 810mL of 0.67 N NaOH for 2 h under nitrogen. The reaction mixture is cooled, 500mL of ether is added, and the whole carefully acididfied with 50mL of conc. HCl (CO₂ evolution!). The mixture is shaken in separatory funnel, the ether layer separated and the aqueous layer subsequently extracted with 200mL of ether. The ether extracts are dried over MgSO₄ and concentrated in vacuo. Yield: 65.2g of crude 2,4-dihydroxy-6-phenyl-isophthalic acid as an oil.

Step 3: Olivetol

The crude product from Step 2 is stirred with 200mL of sulfuric acid (volume ratio of conc. H₂SO₄ to water is 5:1) until a clear solution is formed. This is allowed to stand at room temp for 1 h. The solution is then poured into a 3-necked flask in which 500g of ice has been placed, and the formed suspension is stirred fro 14 h in a nitrogen atmosphere. The suspension obtained after cooling is extracted twice with 500mL of ether. The combined extracts are extracted four times with 200mL of 2 N NaOH, the basic extracts combined, cooled with ice and acidified with 160mL of conc. HCl. The reaction product in the form of oil is taken up in 500mL of ether, the solution is washed with water, dried over MgSO₄, and concentrated in vacuo to obtain 49.5g of crude product as reddish oil. Purification is effected y distillation in high vacuum. The olivetol distilling over at 126-130°C/0.002-0.001 mmHg is obtained firstly as a pale yellow viscous oil, which fully crystallizes on standing, mp 48-50°C. Yield: 45.2g (89.3%).

Reference: Patent US4249027

I'm dreaming of the white crystals.

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	All 8 posts		Subject: Synthesis of Olivetol		Please login to post		Down


		demorol (Hive Bee) 04-16-03 13:33 No 427257				Synthesis of Olivetol (Rated as: excellent)
						This one is for you, Rhodium. I have decided to post it after reading one of your requests for its synthesis in Russian Hyperlab. Synthesis of Olivetol Step 1: 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate Into a 2-liter 3-necked flask fitted with a reflux condenser topped with a nitrogen gas inlet tube attached to a constant pressure mercury gauge, mechanical stirrer, dropping funnel and thermometer were placed 230mL of anhydrous methanol (reagent grade) and 32.4g (0.6 mole) of sodium methoxide. A slow current of nitrogen was introduced and the mixture was stirred until a complete dissolution of sodium methoxide. 110g (0.68 mole) of diethyl malonate was added, the solution was stirred for additional 10 min and 75g (0.48 mole) of pure 3-nonene-2-one was added portionwise at a rate such that the reaction temperature was kept below the boiling point (ca. 50-60°C). Stirring and refluxing were continued for 3 h. The reaction mixture was allowed to cool to room temperature, neutralized with conc. HCl (~50mL) and allowed to stand overnight. The solvent was removed under reduced pressure and the residue was partitioned between 200mL of 1 N HCl and 800mL of ethyl acetate. The aqueous layer was separated and the organic phase was washed with two 300mL portions of water and the product was then extracted from the ethyl acetate with a saturated solutioin of sodium bicarbonate until a small portion on acidification no longer gave a turbid solution (= five 200mL portions). The sodium bicarbonate solution was cautiously acidified and extracted with three 300mL portions of ether. The ether solution was dried over sodium sulfate and distilled under reduced pressure. The semi-solid residue was dried at 50°C under high vacuum for 5 h to yield 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate as a white solid, mp 83-85°C. Step 2: Methyl 3-bromo-2-hydroxy-4-oxo-6-n-pentyl-cyclohex-2-ene-1-carboxylate Into a 2-liter 4-necked flask fitted with a reflux condenser, mechanical stirrer, dropping funnel and thermometer were placed 60g (0.25 mole) of a compound from a previous step, 200mL of acetic acid and 200mL of water. The mixture was stirred vigorously until a fine suspension was obtained, cooled and maintained at 5-10°C while 44.4g (0.28 mole) of bromine, dissolved in 70mL of acetic acid, was added dropwise over a period of 2 h. The reaction mixture was stirred at room temperature for 1 h and then diluted with 500mL of water and allowed to stand at 5-10°C overnight. The solids were filtered, washed with cold water until the washings gave a negative test for bromine (ca. 3 Ч 75mL) and dried in a vacuum oven at 50°C for 4 h to give the title compound, mp 100-102°C. Step 3: Olivetol (5-pentylresorcinol) Into a 500mL 3-necked flask fitted with a reflux condenser, mechanical stirred and thermometer were placed 60g (0.182 mole) of a compound from step 1 and 90g (0.75 mole) of anhydrous pyridine HCl. The semi-solid mixture was heated in an oil bath at 90°C for 4 h (internal temp. 82-84°C) and then at 200°C for 2 h. The reaction mixture was cooled to room temperature and partitioned between 550mL of ether and 100mL of 1.2 N HCl. The aqueous layer was separated and the ether phase washed with 50mL of 1.2 N HCl and then with 75mL of water. The organic phase was then washed with two 75mL portions of 10% sodium hydrosulfite (dithionite) followed by two 75mL portions of saturated NaHCO₃ and then with 75mL of water, dried over anhydrous Na₂SO₄ and the solvent evaporated under reduced pressure. The dark oil (34.6g) was distilled at 125-130°C/0.05 mmHg to yield olivetol. Reference: Patent US3919322 I'm dreaming of the white crystals.



		cattleprodder (Hive Bee) 04-16-03 21:09 No 427369				Yes.
						With olivetol in hand, 2,6-dimethoxy-4-(n)-pentylamphetamine is just over the horizon.



		foxy2 (Distinctive Doe) 04-17-03 02:50 No 427468				And DELTA-9-TETRAHYDROCANNABINOL is just under
						And DELTA-9-TETRAHYDROCANNABINOL is just under the horizon.



		Rhodium (Chief Bee) 04-18-03 03:10 No 427723				THC better than PEA in this case
						2,6-dimethoxy-4-pentylamphetamine is not likely to be a good compound, either it is a very long-winded so/so thing, or it is simply a completely boring antagonist. With Olivetol in hand, don't waste it - go directly to THC.



		Megatherium (Hive Bee) 04-18-03 10:41 No 427786				There is something in "Organic ...
						There is something in "Organic chemistry", Morrison and Boyd, 6th ed. (this isn't such a good book) p 915 about the citral + olivetol reaction. They say:"When the terpene citral is allowed to react in the presence of dilute acid with olivetol, there is a mixture of products containing delta-3,4-trans-THC, the racemic form of one of the physiologically active components of hashish." Hmm, (at first glance) that synthesis doesn't seem to be examplified in: https://www.rhodium.ws/chemistry/psychedelicchemistry/chapter2.html



		Rhodium (Chief Bee) 04-18-03 20:45 No 427892				But the citral/olivetol reaction must be ...
						But the citral/olivetol reaction must be mentioned in one of the other THC synthesis articles on my site, right?



		SpicyBrown (Hive Bee) 04-18-03 22:06 No 427912				... Was just looking at this yesterday.
						... Was just looking at this yesterday. See https://www.rhodium.ws/chemistry/thc/ and more specifically, https://www.rhodium.ws/chemistry/thc/page6.html Also, it actually is in https://www.rhodium.ws/chemistry/psychedelicchemistry/chapter2.html just search the page w/your broswer for "citral".. -SpicyBrown



		demorol (Hive Bee) 04-19-03 12:53 No 428050				Another one! (Rated as: excellent)
						Step 1: 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester 9.6g (0.2 mole) of sodium hydride (50% oil suspension) is added portionwise in a nitrogen atmosphere, with stirring and ice cooling (internal temperature 10°C) to the mixture of 34.8g (0.2 mole) of 3-oxoglutaric acid dimethyl ester and 30.8g (0.2 mole) of 2-octynoic acid methyl ester in 500mL of anhydrous benzene. The ice bath is removed and the yellowish stirred for a further 15 min at room temp before the second portion of 11.2g of sodium hydride is added without cooling. The reaction mixture is refluxed for 1 h and the resulting yellow suspension poured (after cooling) on 600g of ice. The aqueous phase is separated and extracted with 500mL of ether. The extract is combined with the organic phase and the whole extracted twice with 200mL of 0.2 N NaOH. The alkaline solution is combined with the aqueous phase, the whole filtered through purified diatomaceous earth and acidifiedwith conc. HCl. After cooling, the colourless emulsion is extracted with 500mL of ether, the extract dried over MgSO₄ and concentrated by evaporation. After drying in vacuo, 47.3g of crude product is obtained as yellow crystallizing oil. This is then dissolved in 50mL of IPA and 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester precipitates immediately in the form of large needles. After standing for ~14 h in a refrigerator, the crystals are filtered off with suction, washed with small amount of cold IPA and dried. Yield: 33.82g of the title product as yellowish crystals; mp 59-60°C. Step 2: 2,4-dihydroxy-6-phenyl-isophthalic acid 83.4g (0.282 mole) of the product from previous step is refluxed in 810mL of 0.67 N NaOH for 2 h under nitrogen. The reaction mixture is cooled, 500mL of ether is added, and the whole carefully acididfied with 50mL of conc. HCl (CO₂ evolution!). The mixture is shaken in separatory funnel, the ether layer separated and the aqueous layer subsequently extracted with 200mL of ether. The ether extracts are dried over MgSO₄ and concentrated in vacuo. Yield: 65.2g of crude 2,4-dihydroxy-6-phenyl-isophthalic acid as an oil. Step 3: Olivetol The crude product from Step 2 is stirred with 200mL of sulfuric acid (volume ratio of conc. H₂SO₄ to water is 5:1) until a clear solution is formed. This is allowed to stand at room temp for 1 h. The solution is then poured into a 3-necked flask in which 500g of ice has been placed, and the formed suspension is stirred fro 14 h in a nitrogen atmosphere. The suspension obtained after cooling is extracted twice with 500mL of ether. The combined extracts are extracted four times with 200mL of 2 N NaOH, the basic extracts combined, cooled with ice and acidified with 160mL of conc. HCl. The reaction product in the form of oil is taken up in 500mL of ether, the solution is washed with water, dried over MgSO₄, and concentrated in vacuo to obtain 49.5g of crude product as reddish oil. Purification is effected y distillation in high vacuum. The olivetol distilling over at 126-130°C/0.002-0.001 mmHg is obtained firstly as a pale yellow viscous oil, which fully crystallizes on standing, mp 48-50°C. Yield: 45.2g (89.3%). Reference: Patent US4249027 I'm dreaming of the white crystals.

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