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Syntheses of THC and Analogs

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L-(-)-delta-1(6)-THC

Method I
This method gives about 50% yield for THC and about 90% for the 1',1'- dimethylpentyl analog. Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or trans p-methadien (2,8)-ol-1 (the racemic compound can be used but yield will be one-half), 0.8g p-toluenesulfonic acid in 250 ml benzene; reflux two hours (or use 0.004 Moles trifluoracetic acid and reflux five hours). Cool, add ether, wash with NaHCO3 and dry, evaporate in vacuum to get about 9 g of mixture (can chromatograph on 350 g silica gel benzene elutes the THC; benzene:ether 98:2 elutes an inactive product; then benzene:ether 1:1 elutes unreacted olivetol; evaporate in vacuum to recover olivetol).

Method 2
Dissolve the olivetol or analog and p-menthadienol or p-methatriene (1,5,8) in 8 ml liquid SO2 in a bomb and fuse 70 hours at room temperature. Proceed as above to get about 20% yield. L (-)-delta-1(6)- THC. Convert (-) alpha- pinene to (-) verbenol. Add 1M(-) verbenol (racemic verbenol will give one-half yield), 1M olivetol or analog with methylene chloride as solvent. Add BF3 etherate and let stand at room temperature one-half hour to get approximately 35% yield after evaporating in vacuum or purifying as above to recover unreacted olivetol. Solvent and catalyst used in Method 1 above will probably also work. Either cis or trans verbenol can be used. The JCS paper adds 1 g BF3-etherate to a solution of 1 g olivetol and 1.1 g verbenol in 200 ml methylene chloride and let stand two hours at room temperature. JACS 94,6164(1972) recommends two hours at -10øC, then one-half hour at room temperature and the use of cis rather than trans verbenol (the latter gradually decomposes at room temperature). The reaction is also carried out under nitrogen, using twice as much verbenol as olivetol, 0.85 ml BF3 etherate and 85 ml methylene chloride/g verbenol (both freshly distilled over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972) for the use of citral and Arzneim. Forsch. 22,1995(1972) for use of p-TSA. In the synthesis of THC with verbenol, the cis isomer is preferable to the trans since the latter decomposes at room temperature. Pinene or cawone give active THC's.

Method 3
L(-)-delta-1 and delta-1(6) THC. 1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog, 0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and evaporate in vacuum (or can separate the unreacted olivetol as above) to get about 30% yield THC. Olivetol can also be separated as described below. For synthesis of 2-epoxycarene (delta-4 carene oxide) from delta-4 carene (preparation given later) see p-methadieneol preparation (Method 2). 3-carene oxide gives 20% yield of delta-1(6) THC.

Methods for Racemic THC

Delta-3 THC
1M pulegone, 1M olivetol or analog, 0.3 M POCl3, reflux four hours in 1 L benzene and evaporate in vacuum or pour into excess saturated NaHCO3 and extract with dilute NaOH to recover unreacted olivetol. Dry, and evaporate in vacuum the benzene layer to get the THC.

Delta-1(6) THC from Cannabidiol
Reflux 1g cannabidiol, 60 mg p-toluenesulfonic acid (or 0.003 M trifluoroacetic acid) in 50 ml benzene for 1 1/2 hours. Evaporate in vacuum to get about 0.7 g THC. Alternatively, add 1.8g cannabidiol to 100 ml 0.005N HCl and reflux four hours. Proceed as above to get about 0.5 g THC.

Nitrogen Analogs of Delta-3 THC
5.4 g olivetol or 0.03M analog, 5.8 g 4-carbethoxy-N-benzyl-3- piperidone hydrochloride or 0.03M analog give an old and clumsy synthesis, and Heterocyclic Compounds, Klingenberg (Ed.), part 3, chaps. IX-XII (1962) gives information on related compounds) in 10 ml concentrated sulfuric acid. The concentrated sulfuric acid should be added dropwise, with cooling. Add 3 ml POCl3 and stir at room temperature for 24 hours. Neutralize with NaHCO3 to precipitate 2.3g (I). Filter; wash precipitate with NaHCO3 and recrystallize from acetonitrile. Dissolve 4.3 g (I) in 30 ml anisole and add 0.1 M methyl MgI in 50 ml anisole. Stir 12 hours and evaporate in vacuum or acidify with sulfuric acid, neutralize with NaHCO3 and filter; wash to get 2.4 g N-benzyl analog of THC. Recover unreacted olivetol as usual.

The 5-aza analogs given in the JOC ref. seem to be active but they use the pyrone intermediate from certain routes of THC synthesis for a precursor.

Delta-1(6) THC

This synthetic route allows one to proceed from the alkylresorcinol dimethyl ether without using a compound of the verbenol or cyclohexanone type.

Synthesis of olivetol aldehyde
To a stirred solution of phenyllithium (1.6g bromobenzene and 0.16g Li) in 50 ml ether, add 0.01M olivetol dimethyl ether (or analog -- see elsewhere here for preparation) in 5 ml ether and reflux 4 hours. Add 5 ml N-methylformanilide, reflux 1 hour and wash with 2x50 ml dilute sulfuric acid, 50 ml water, 25 ml saturated NaCl and dry, evaporate in vacuum the ether (can dissolve in benzene and filter through 100g of alumina) to get 60% yield of the dimethylolivetol aldehyde (I) (recrystallize from ether-pentane). Can recover unreacted starting material by refluxing the vacuum distillate 3 hours with excess 10% HCl, removing the organic layer and extracting the aqueous layer with ether: wash and dry, evaporate in vacuum the combined ether layers. In a 200 ml 3 neck round bottom flask with a stirrer, a reflux condenser, a dropping funnel and a nitrogen inlet tube, introduce a rapid stream of nitrogen and in the stream issuing from the central neck, cut 1.5g of lithium into ca. 70 pieces and drop into the flask containing about 25 ml dry ether. Place the fittings in position, slow the nitrogen stream and add 1/2 of the solution of 9.2g n-butyl-chloride in 25 ml dry ether. Start the stirring and add the rest of the n-butyl-chloride at a rate giving a gentle reflux. Continue stirring and reflux 2 hours and add 15 ml olivetol dimethyl ether in 25 ml dry ether. Reflux 2 hours and add dropwise a solution of 15 ml N-methylformanilide in 25 ml dry ether with stirring at a rate sufficient to produce refluxing. Continue stirring 1 hour, treat with 3% sulfuric acid and then pour into excess of this acid. Remove upper layer and extract aqueous layer twice with ether. Wash combined ether layers with dilute aqueous NaHCO3 and water and dry, evaporate in vacuum the ether (can distill 148-52/0.3) to get 78% (I). JACS 65,361(1943). A mixture of 6.5g (I) (or analog), 20 ml pyridine, 1 ml piperidine and 9g malonic acid is warmed on a steam bath 1 hour. Add another 1 g malonic acid and heat another 1/2 hour. Reflux 1/2 hour and pour into excess iced 10% HCl, stirring occasionally over 2 hours. Filter and dry to get 6 g 2,6-dimethoxy-4-n-amycinnamic acid (II) (recrystallize from ethanol). 10g (II), 40 ml 80% isoprene and 40 ml dry xylene or toluene is heated in an autoclave at 185øC for 15 hours. Cool, dilute with 160 ml petroleum ether and shake with 100 ml saturated aq. Na2CO3. Let stand and separate the middle layer. Wash the middle layer with a mixture of petroleum ether and dilute aq. Na2CO3 and again separate the middle layer and treat with 75 ml 10% HCl and 75 ml ether. Shake, separate the aqueous layer and wash the ether 3 times with water. Dry and evaporate in vacuum the ether and dissolve the residue in petroleum ether. The solid which ppts. after about 10 minutes is unchanged (II). Filter and let stand in refrigerator overnight and dry and evaporate in vacuum to precipitate about 7 g of the 1-methyl-5 (2,6- dimethoxy-4-n-amylphenyl)-1-cyclohexene-4-COOH (III) (recrystallize from petroleum ether). 1g (III) in 5 ml dry ether is added to 10 ml 3M MeMgI (from 0.21 g Mg and 1.2g methyl iodide) in ether, heated to 130øC to evaporate the solvent and the oil kept at a bath temperature of 165ø C for 1/2 hour. Cool in dry ice-acetone bath and cautiously add ammonium chloride-ice water mix to decompose the excess Grignard reagent. Acidify with dilute HCl and extract with ether. Wash with NaCl, dilute K2CO3, NaCl and dry, evaporate in vacuum to get the dimethyl derivative (IV). Reflux (IV) in 25 ml benzene with 100 mg p-toluenesulfonic acid for 1 hour with a Dean-Stark trap and dry, evaporate in vacuum (or wash with NaHCO3, NaCl first) to get the THC or analog. Hydrolysis of benzopyrones (for synthesis see elsewhere here) will produce compounds of type (III) which will work in this synthesis. The hydrolysis proceeds as follows (JCS 926(1927)): Add 10g of the benzopyrone to 20g 30% NaOH, cool and shake 1 hour with 19 ml methylsulfate. Extract the oil with ether and dry, evaporate in vacuum to get the ester. Acidify the aqueous solution and filter, wash, dissolve ppt. in sodium carbonate and acidify, filter to get the free acid. Both the acid and the ester will work in this synthesis.

Delta-3 THC Analogs
11.6g 5-(1,2-dimethy))-heptyl resorcinol or equimolar amount of olivetol or other analog, 9.2g 2-carbethoxy-5-methyl cyclohexanone (4-carbethoxy- 1-methyl-3-cyclohexanone), 5 g POCl3, 70 ml dry benzene (protect from moisture with CaCl2 tube). Boil 5 minutes (HCl evolution) and let stand at room temperature 20 hours. Pour into 10% NaHCO3, separate the benzene layer and wash with 3x50 ml 10% NaHCO3. Dry and evaporate in vacuum the benzene and recrystallize from 50 ml ethyl acetate to get 6.6 g of the pyrone (I). 4.5g (I), 150 ml benzene; add dropwise to a solution prepared from 7.8 g Mg, 18 ml methyl iodide, and 90 ml ether. Reflux 20 hours and add 45 ml saturated NH4Cl. Separate the organic layer and extract the aqueous phase with benzene. Combine the organic layer and benzene and dry, evaporate in vacuum to get the THC analog.

Delta-3 THC analogs from Resorcinol
22g resorcinol,36 g 4-carbethoxy-1-methyl-3-cyclohexanone, 20g polyphosphoric acid; heat to 105øC and when the exothermic reaction which occurs subsides, heat at 140øC for one-half hour. Pour onto ice- water; filter; wash with water and recrystallize-ethanol to get 34g of the pyrone (I). 6.4g (I), 8 ml caproyl-Cl or analog (for preparation see above reference, page 84); heat on oil bath (can use mineral oil) at 120øC until the exothermic reaction subsides (HCl evolution). Cool and pour into ethanol. Filter to get 8g precipitate (II). 3.2g (II), 4.4g dry AlCl3; heat on oil bath at 170øC for one hour. Cool and add HCl; filter and dissolve precipitate in 7 ml 2N NaOH. Filter and acidify with HCl to precipitate 1.4 g (III) (recrystallize-ethanol). Test this for activity. Use benzoyl-Cl or benzoic anhydride to esterify the OH group (this may not be necessary), methyl MgBr or methyl MgI to methylate the keto group, and sulfuric acid to dehydrate and hydrogenate as described elsewhere here to get the THC analog. Since the resulting THC analog has the side chain at the 6' position, it may not be active. This paper also gives a synthesis for THC analogs with the side chain in the 4' position, but again their activity in man is unknown. Verbenol, etc., should work in this synthesis, thus obviating the need for the methylation step.

Delta-1(6) THC
1 M olivetol or analog, 1 M citral in 10% BF3 etherate in benzene about eight hours at 5-10øC. Extract unreacted olivetol with dilute NaOH and evaporate in vacuum the ether to get about 20% yield of the trans THC, and 20% of the cis THC which can be converted to the active trans isomer by reacting with BBr3 in methylene chloride at -20øC for 1 1/2 hours. Alternatively, the reaction can be carried out in 1 % BF3 etherate in methylene chloride to get 20% Delta-1 THC.

Delta-3 THC Analogs
7.6g 5-n-heptyl resorcinol or equimolar amount analog, 6.6g (0.037M) 4- carbethoxy-1-methyl-3-cyclohexanone or analog, 5.8g POCl3 in 60 ml benzene. Reflux 5 hours, cool and pour into NaHCO3 to get about 6 g THC analog and 1 g more by concentrating the mother liquor, or proceed as described elsewhere here to recover unreacted resorcinol. 3-carbethoxy- 1-methyl-2 or 4-cyclohexanone, 2-carbethoxy-cyclohexanone, etc. will probably also give active THC analogs.

Delta-3 THC Analogs
1.75 g 2-Br-4-methyl-benzoic acid, 1.5 g olivetol or analog, 10 ml 1N Na OH and heat to boiling; add 0.5ml CuSO4. Filter; wash with ethanol and recrystallize from ethanol to get (I). 10g (I) in 150 ml benzene; add to methyl-MgI prepared from 47.5 g methyl iodide, 8 g Mg, 120 ml ether. Reflux fifteen hours, cool and pour on ice. Add saturated NH4Cl and separate the ether. Wash two times with water and dry and evaporate in vacuum the ether to get the THC.

Precursors For THC Synthesis

(-)Verbenol

Racemic alpha-pinene will yield racemic verbenol which will give one- half the yield of (-)verbenol.

27 g (-)alpha-pinene in 500 ml dry benzene; heat and keep temperature at 60-65øC throughout. Add with stirring over 20 minutes 84 g dry (dry over P2O5) lead tetra-acetate. Stir one-half hour; cool and filter and add filtrate to water. Filter and evaporate in vacuum the benzene layer (can distill 96-7/9) to get 21.2 g cis-2-acetoxy-pin-3-ene(I). 5 g (I) in 25 ml glacial acetic acid; keep at 20øC for one-half hour and add water and extract with ether. Wash the extract with aqueous Na2CO3 and evaporate in vacuum the ether (can distill 97-8/9) to get 4.3 g trans verbenyl acetate (II). Hydrolyze (II) with NaOH to give the (-) cis and trans verbenol.

Compounds I-III may be able to give active THC analogs if used in place of olivetol for synthesis.

45 g 1-(3,5-dimethoxyphenyl)-1-hexanone(I) or analog (for preparation see the following methods) in 400 ml ether and 0.3 M methyl-MgI in 150 ml ether react to give 49 g 2-(3,5-dimethoxyphenyl)-2-heptanol(II). Heat 49 g (II) with 1 ml 20% sulfuric acid to 105-125øC/30mm for 1 1/2 hours to get 34 g of the 2-heptene compound (III). 33 g (III) in 100 ml ethanol, 6 g Raney- Ni,1500 PSI hydrogen,150øC to get 26 g of the 2- heptane (IV). 26 g (IV), 118 ml 57% hydrogen iodide; add 156 ml acetic anhydride and heat at 155o C for two hours to get 22 g of the resorcinol.


Olivetol

Reduce 3,5-dimethoxybenzoic acid with lithium aluminum hydride to 3,5- dimethoxybenzyl alcohol (I). to 10.5 g (I) in 100 ml methylene chloride at 0ø C add 15 g PBr3; warm to room temperature and stir for one hour. Add a little ice water and then more methylene chloride. Separate and then dry, evaporate in vacuum the methylene chloride. Add petroleum ether to precipitate about 11.5 g of the benzyl bromide (II). To 9.25 g (II), 15 g CuI, 800 ml ether at 0ø C, add butyl (or other alkyl)-Li (16% in hexane), and stir for four hours at 0ø C. Add saturated NH4Cl and extract with ether. Dry and evaporate in vacuum the ether (can distill 100/0.001) to get about 4.5 g olivetol dimethyl ether (III) or analog. Distill water from a mixture of 90 ml pyridine, 100 ml concentrated HCl until temperature is 21 0øC. Cool to 140øC and add 4.4 g (III); reflux two hours under N2. Cool and pour into water. Extract with ether and wash with NaHCO3. Make pH 7 and dry, evaporate in vacuum to get 3.8 g olivetol which can be chromatographed on 200 g silica gel (elute with CHCl3) or distill (130/0.001) to purify.


Olivetol

Dissolve 100 g malonic acid in 360 g dry pyridine and heat 48-52øC for forty hours with 100 g n-hexaldehyde (n-capronaldehyde) or homolog. Cool in ice bath and with good stirring add dropwise 150 ml ice cold concentrated sulfuric acid (keep temperature below 5øC). After addition add water to dissolve the precipitate and extract with ether two times. Dry, evaporate in vacuum the ether and distill (70/0.7 or 102/5) to get about 98 g 2-octenoic acid (I). 95 g (I) in 300 ml ether; cool to -5øC and slowly add a solution of an excess of diazomethane in ether dried over KOH and let react for about one hour. Let stand twelve hours, evaporate in vacuum and distill (91/17) to get about 94 g clear methyl- 2-octenoate (II). To 16.3 g Na in 210 ml ethanol add 93 g ethyl- acetoacetate (ethyl-3-oxo-butanoate), heat to boil and add dropwise 92 g (II) over 20 minutes. Stir and reflux five hours and cool to precipitate.Filter, wash with ethanol and dissolve precipitate in 800 ml water. Cool to 0ø C and slowly add 80 ml ice cold concentrated HCl to precipitate. Filter, wash with water and ligroin to get about 108 g 6- carbethoxy-4,5-dihydro-olivetol (III) (recrystallize from petroleum ether). To 104 g (III) in 260 ml glacial acetic acid at room temperature with good stirring, add dropwise over one hour 69 ml Bromine. Heat four to five hours at 60o C, cool and add 300 ml water and let stand twelve hours. Oil separates which will precipitate on agitation and rubbing. Filter, wash with water until colorless (recrystallize from ligroin, recrystallize from glacial acetic acid and precipitate with water) to get about 86 g 6-carbethoxy-2,4-dibromo- olivetol (IV). 0.035 g Palladium-Carbon catalyst in 25 ml hydrogenation bottle. Saturate with H2 (pressure - 2.8 Kg/cm2) and add 0.33g (IV) in 5 ml glacial acetic acid, which takes up 39.5 cm3 H2 at atmospheric pressure over 1 1/2 hours at 60-70øC. Filter and acidify at 0øC with ice cold 6N HCl. Extract with ether and dry, evaporate in vacuum. Recrystallize the oil from ligroin and then from glacial acetic acid by adding water to get about 0.2 g 6-carbethoxyolivetol (V). (IV) can also be hydrogenated at room temperature and atmospheric pressure over 1/2g Palladium-Carbon catalyst by dissolving 70 g in 500 ml 1 N NaOH. Heat 35 g (V) with 45 g NaOH in 170 ml water for two hours or until no more CO2 is evolved. Cool, acidify with 6N HCl and boil 3 minutes. Extract the oil with ether and dry, evaporate in vacuum the ether (can distill on Vigreux column 123/0.01, oil bath 160o C) and let oil stand in refrigerator until crystalline to get about 21 g olivetol.

Olivetol

Prepare 3,5-dimethoxybenzoic acid as described elsewhere here, and to a solution of 18.2 g in 250 ml dry tetrahydrofuran under N2, add 1 g 85% LiH, stir for fourteen hours and then reflux for one-half hour. Add a solution of about 1.3 M butyllithium in ether with stirring and ice cooling until the reaction mixture gives a positive Gilman test. Then add 500 ml ice water, extract with ether and dry, evaporate in vacuum the organic phase to get a yellow oil which is dissolved in an equal amount of absolute ethanol; left in refrigerator twelve hours to precipitate. Filter and evaporate in vacuum the ethanol to one-half volume to give more precipitate for a total of 18 g 1-(3,5-dimethoxyphenyl)-1 pentanone (I). 5.64 g (I) in 200 ml methanol; 0.66 g 20% Pd(OH)2 on carbon and hydrogenate at room temperature and atmospheric pressure over two to three hours (or use other reducing method as described here).Filter and evaporate in vacuum to get olivetol dimethyl ether (II). 4.88 g (II), 40 ml HI (density 1.7, decolorized with red phosphorous) and stir three hours at 115-125øC under N. Dry, evaporate in vacuum or pour into 100 ml ice water and extract with methylene chloride; wash methylene chloride with water and dry, evaporate in vacuum (can distill 160-170/3-4) to get 3.5 g olivetol.
 
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