22972-51-6

Synthetic route

C16H22O2S → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
With piperidine In dimethyl sulfoxide at 170℃; for 4h;	75%

(1S,2S,5R)-2-hydroxy-N,N,2-trimethyl-5-(prop-1-en-2-yl)cyclohexanamineoxide (1415961-21-5) → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
at 180℃; under 1 Torr; Cope Elimination; Pyrolysis;	74%
With dihydrogen peroxide In ethanol; water at 150 - 162℃; Reflux; Schlenk technique; Glovebox; Inert atmosphere;	38.2 g

(1S,2S,4R)-2-phenylseleninyl-p-menth-8-en-1-ol (74756-11-9) → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
In chloroform for 0.5h; Heating;	53%
In chloroform at 62℃; for 6h; Inert atmosphere;	512 g

(1S,2R,4R)-limonene-1,2-epoxide (6909-30-4) → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
Stage #1: (1S,2R,4R)-limonene-1,2-epoxide With sodium tetrahydroborate; diphenyl diselenide for 2h; Heating; Stage #2: With dihydrogen peroxide for 7h; Heating; Further stages.;	31.6%
Multi-step reaction with 2 steps 1.1: H2O / 18 h / 150 °C 2.1: H2O2 / H2O / 18 h / 20 °C 2.2: 150 - 180 °C View Scheme
Multi-step reaction with 3 steps 1: H2O / 150 °C / sealed vessel 2: 30percent H2O2 / H2O 3: pyrolysis View Scheme

D-limonene (5989-27-5) → (1R,4R)-p-mentha-2,8-dien-1-ol (52154-82-2) + (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
With oxygen; rose bengal In methanol at 0℃; for 8.5h; UV-irradiation;	A 5.3% B 13.4%
With air Erwaermen des Reaktionsprodukts mit wss. Natriumsulfit-Loesung;
(i) O2, MeOH, (irradiation), (ii) LiAlH4, Et2O; Multistep reaction;
(i) O2, rose bengal, MeOH, (irradiation), (ii) LiAlH4, Et2O; Multistep reaction;
With air Erwaermen des Reaktionsprodukts mit wss. Natriumsulfit-Loesung;

D-limonene (5989-27-5) → (4R,6R)-carveol (99-48-9, 1197-06-4, 1197-07-5, 2102-58-1, 2102-59-2, 5157-78-8, 5503-11-7, 7632-16-8, 18383-51-2) + (-)-trans-carveol (18383-51-2) + (1R,4R)-p-mentha-2,8-dien-1-ol (52154-82-2) + (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6) + p-Menthadiene-<1(7),8>-trans-ol-(2) (2102-62-7) + p-Menthadiene<1(7),8>-cis-ol-(2) (10374-04-6)

Conditions	Yield
With 1,4-diaza-bicyclo[2.2.2]octane; air; zinc 5,10,15,20-tetraphenylporphyrin; triphenylphosphine In benzene for 3h; Irradiation; multistep reaction: photosensitized oxygenation of olefines;
With sodium tetrahydroborate; tetraphenylporphyrine; oxygen Product distribution; 1.) acetonitrile, irradiation, 2.) methanol; other sensitizers;	A 5 % Chromat. B 7 % Chromat. C 9 % Chromat. D 40 % Chromat. E 16 % Chromat. F 23 % Chromat.
With oxygen; fullerene-C60 In toluene at 0 - 10℃; for 4h; Product distribution; Irradiation; other sensitizer in other solvent;

limonene. (138-86-3) → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
With oxygen Irradiation;

D-limonene (5989-27-5) → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
With oxygen Irradiation;
Multi-step reaction with 4 steps 1: 3-chloro-benzenecarboperoxoic acid / chloroform / 1.5 h / -5 - 20 °C 2: water / 18 h / 20 °C / Reflux 3: dihydrogen peroxide / water; acetonitrile / 2 h / 20 °C / Cooling with ice 4: 180 °C / 1 Torr / Pyrolysis View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 0 - 5 °C 2.1: sodium tetrahydroborate / ethanol / 1 h / 8 °C / Inert atmosphere 2.2: 4 h / 8 - 80 °C / Inert atmosphere 3.1: dihydrogen peroxide / ethanol; tetrahydrofuran / 6 h / 6 - 20 °C / Inert atmosphere 4.1: chloroform / 6 h / 62 °C / Inert atmosphere View Scheme

(+)-trans-N.N-Dimethylamino-2-p-menthen-8-ol-1-N-oxyd → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
at 140℃;

(1S,2S,4R)-4-Isopropenyl-1-methyl-2-nitroso-cyclohexanol → (1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6)

Conditions	Yield
pyrolysis; Yield given;

Upstream product

• 138-86-3 limonene. 
• 1686-14-2 α-pinene epoxide 
• 5989-27-5 D-limonene 
• 4942-88-5 (+)-1-Hydroxy-neo-dihydrocarveyl-acetat 
• 1195-92-2 (4R)-limonene 1,2-epoxide 
• 1415961-21-5 (1S,2S,5R)-2-hydroxy-N,N,2-trimethyl-5-(prop-1-en-2-yl)cyclohexanamineoxide 
• 5989-54-8 (-)-(S)-limonene 
• 521925-06-4 (1S,4R)-2-chloro-4-(1-methylvinyl)-1-methylcyclohexanol 
• 106-25-2 Nerol 
• 106-24-1 Geraniol 
• 1195-92-2 Limonene oxide 
• 74756-09-5 1α-hydroxy-2β-phenylseleno-trans-p-menth-8-ene 
• 34837-55-3 Phenylselenyl bromide 

Downstream Products

• 14132-18-4 6,6,9-Trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol 
• 16849-50-6 tetrahydrocannabinol 
• 536697-79-7 abn-cannabidiol 
• 3556-78-3 cannabidiol 
• 43009-38-7 (6aS,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol 
• 6909-05-3 iso-Δ⁸-tetrahydrocannabinol 
• 111319-95-0 (5R)-2-methyl-5-(1-methylethenyl)-1,3-cyclohexadiene 
• 3901-95-9 cis p-menthanol 
• 35482-50-9 O 1821 
• 22972-64-1 1-Hydroxy-3,6,6,9-tetramethyl-Δ⁸-6a,10a-trans-tetrahydro-6H-dibenzopyran 
• 120467-18-7 p-hydroxybibenzyl/o-cannabidiol monomethyl ether hybrid 
• 120467-12-1 (6aR,10aR)-6,6,9-trimethyl-3-phenethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol 
• 120467-11-0 (6aR,10aR)-6,6,9-trimethyl-3-phenethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol 
• 1972-05-0 Cannabidiol monomethyl ether 

Relevant academic research and scientific papers

Highly efficient catalysts in directed oxygen-transfer processes: Synthesis, structures of novel manganese-containing heteropolyanions, and applications in regioselective epoxidation of dienes with hydrogen peroxide

A series of novel manganese(II)-substituted polyoxometalates, [(M(II)(H2O)3)2(WO2)2(BiW9O33)2] 10-(1), [(Mn(II)(H2O))3(SbW9O33)2]12- (2), and [(Mn(II)(H2O)3)2(Mn(II)(H2O)2)2(TeW9O33)2]8- (3), were synthesized and characterized by X-ray structure analyses. The use of these oxidatively and solvolytically stable heteropolyanions as homogeneous catalysts for the epoxidation of dienes was investigated by gas chromatography/mass spectrometry, IR spectroscopy, UV-visible studies, and cyclic voltammetric measurements. The catalytic performance is exemplified by the model substrate (R)-(+)-limonene, at ambient temperatures in a biphasic system, with excellent regioselectivities, >99%, and very high turnovers even with only a small molar excess of hydrogen peroxide.

Stereoselective Synthesis of Nonpsychotic Natural Cannabidiol and Its Unnatural/Terpenyl/Tail-Modified Analogues

Here, we report a three-step concise and stereoselective synthesis route to one of the most important phytocannabinoids, namely, (-)-cannabidiol (-CBD), from inexpensive and readily available starting material R-(+)-limonene. The synthesis involved the diastereoselective bifunctionalization of limonene, followed by effective elimination leading to the generation of key chiral p-mentha-2,8-dien-1-ol. The chiral p-mentha-2,8-dien-1-ol on coupling with olivetol under silver catalysis provided regiospecific (-)-CBD, contrary to reported ones which gave a mixture. The newly developed approach was further extended to its structural analogues cannabidiorcin and other tail/terpenyl-modified analogues. Moreover, its opposite isomer (+)-cannabidiol was also successfully synthesized from S-(-)-limonene.

Preparation method of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol

The invention relates to a preparation method of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, and belongs to the technical field of organic solvents. The preparation method comprises the following steps: reacting limonene with a halogenating reagent to obtain an intermediate shown in a formula (1), then reacting the intermediate shown in the formula (1) with a tertiary amine compound to obtain an intermediate shown in a formula (2), and finally carrying out a pyrolysis elimination reaction on the intermediate shown in the formula (2) to obtain (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol. The preparation method has the advantages of mild conditions, no need of an oxidation process of hydrogen peroxide with high preparation condition requirements and high safety risk, no need of an expensive catalyst, high yield, high product purity, simple steps, and suitableness for industrial production.

CANNABINOID DERIVATIVES, PRECURSORS AND USES

The present disclosure relates to new cannabinoid derivatives and precursors and processes for their preparation. The disclosure also relates to pharmaceutical and analytical uses of the new cannabinoid derivatives.

Preparation method of (1S, 4R)-1-methyl-4-(1-methyl vinyl)-2-cyclohexene-1-alcohol

The invention discloses a preparation method of (1S, 4R)-1-methyl-4-(1-methyl vinyl)-2-cyclohexene-1-alcohol, which comprises the following steps: by using D-limonene as a raw material, carrying out double bond addition and hydroxyl protection to obtain an intermediate compound; and carrying out elimination reaction and continuing deprotection to finally prepare the product. The method has the advantages of two-step continuous reaction, short process route and few byproducts, the obtained product has high chiral selectivity, and the yield is up to 70% or above and is greatly improved comparedwith the existing process.

A trans - menthyl - 2, 8 - diene -1 - alcohol synthesis process

The invention belongs to the trans - menthyl - 2, 8 - diene - 1 - ol preparation technology field, in particular to a trans - menthyl - 2, 8 - diene - 1 - ol synthesis process. The synthesizing process comprises the following steps: (1) in order to limonene as raw materials, in order to lipase catalytic oxidation to obtain the 1, 2 - epoxy limonene; (2) the 1, 2 - epoxy limonene in the presence of sodium borohydride and diphenyl [...] open-loop formed limonene selenide; (3) the limonene selenide in under the action of the oxidizing agent forms the selenium oxide then undergo elimination reaction trans - menthyl - 2, 8 - diene - 1 - ol. The invention through the material and a prepared selective lipase catalyzed the situation that the 1, 2 - epoxy limonene, the need for complex purification process can increase the purity of the reaction intermediate, thereby improving the final product trans - menthyl - 2, 8 - diene - 1 - ol of chiral purity.

Activated vs. pyrolytic carbon as support matrix for chemical functionalization: Efficient heterogeneous non-heme Mn(II) catalysts for alkene oxidation with H2O2

Two types of heterogeneous catalytic materials, MnII-L3imid@Cox and MnII-L3imid@PCox, have been synthesized and compared by covalent grafting of a catalytically active [MnII-L3imid] complex on the surface of an oxidized activated carbon (Cox) and an oxidized pyrolytic carbon from recycled-tire char (PCox). Both hybrids are non-porous bearing graphitic layers intermixed with disordered sp2/sp3 carbon units. Raman spectra show that (ID/IG)activatedcarbon > (ID/IG)pyrolyticcarbon revealing that oxidized activated carbon(Cox) is less graphitized than oxidized pyrolytic carbon (PCox). The MnII-L3imid@Cox and MnII-L3imid@PCox catalysts were evaluated for alkene oxidation with H2O2 in the presence of CH3COONH4. Both showed high selectivity towards epoxides and comparing the achieved yields and TONs, they appear equivalent. However, MnII-L3imid@PCox catalyst is kinetically faster than the MnII-L3imid@Cox (accomplishing the catalytic runs in 1.5 h vs. 5 h). Thus, despite the similarity in TONs MnII-L3imid@PCox achieved extremely higher TOFs vs. MnII-L3imid@Cox. Intriguingly, in terms of recyclability, MnII-L3imid@Cox could be reused for a 2th run showing a ～20% loss of its catalytic activity, while MnII-L3imid@PCox practically no recyclable. This phenomenon is discussed in a mechanistic context; interlinking oxidative destruction of the Mn-complex with high TOFs for MnII-L3imid@PCox, while the low-TOFs of MnII-L3imid@Cox are preventive for the oxidative destruction of the Mn-complex.

Oligomer-cannabinoid conjugates

The invention relates to (among other things) oligomer-cannabinoid conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over previously administered un-conjugated cannabinoid compounds.

Continuous flow photooxygenation of monoterpenes

Photooxygenation of monoterpenes was conducted in two continuous flow reactors. The first, suitable for lab-scale research, had a maximum yield of 99.9%, and the second, focused on industrial applications, showed a daily output that was 270.0-fold higher than that in batch systems. The use of sunlight instead of an LED lamp gave 68.28% conversion.

Improved accessibility to the desoxy analogues of Δ9- tetrahydrocannabinol and cannabidiol

Desoxy analogues of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been reported to provide a novel mode of analgesia whilst avoiding the psychotropic side effects associated with most cannabinoid drugs. A detailed and improved synthesis of desoxy THC, desoxy CBD and didesoxy CBD is reported here. The key improvements include a concentration-dependent boron trifluoride mediated electrophilic aromatic substitution which was used to synthesize both THC and CBD analogues. The synthetic route is general and could be applied to the development of a library of modified desoxy THC and desoxy CBD analogues.