Process for the creation of cannabinoids

Abstract

Δ 9 A process for the preparation of substantially pure and diverse known and novel cannabinoids 1 and 2, including tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), and other naturally occurring tetracyclic and tricyclic cannabinoids, and other synthetic tetracyclic and tricyclic analogs, via intermediates 3, 6, 4, and 5 using a cascade sequence of allylic rearrangement, cyclization, and, for tricyclic cannabinoids, further highly stereoselective and regioselective cyclization. These synthesized cannabinoids can be readily obtained at higher purity levels than cannabinoids isolated or synthesized via known methods. Cannabinoid 2 is a Δ 9 -Undesirable Δ, including tetrahydrocannabinol (7) and tetrahydrocannabivarin (9) 8 These compounds are obtained with very low levels of isomeric cannabinoids such as -tetrahydrocannabinol. Known and novel analogs with variations in aromatic ring substituents are readily synthesized by novel methodologies, but would be very difficult to make from either cannabis or components of cannabis oil.

Description

[Technical field]

[0001] The present invention provides, but is not limited to, Δ 9 - The present invention relates to methods for the synthesis of high purity known and novel cannabinoids, including tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), and other naturally occurring cannabinoids, as well as other synthetic analogues. The field of the present invention further extends to novel cannabinoids, which may be used as active compounds, alone or mixed in combination with known cannabinoids and / or other agents in formulations for the treatment of pain, multiple sclerosis-related spasticity, nausea, anorexia, epilepsy, Alzheimer's disease and neurodegenerative diseases, brain injury / concussion / traumatic brain injury, stroke, cancer, inflammation and immunoinflammatory related diseases, glaucoma, dry eye, eye diseases / injuries including but not limited to corneal injury or disease and retinal degeneration or disease, immunoinflammatory disorders, lung injury or disease, liver injury or disease, kidney injury or disease, pancreatitis and pancreatic disorders, cardiovascular injury or disease, and organ transplantation, reduction of post-operative inflammation, antioxidants and indications, among other diseases. [Background technology]

[0002] Cannabis ("marijuana") is a rather notorious plant, used specifically for the species Cannabis sativa. Its use as a recreational drug, widespread around the world, continues to be the subject of high interest and legal review in many countries of the world. The use of this plant and its extracts as an ethnomedicinal drug has been of great interest for millennia, even mentioned in Herodotus (The Histories, Book IV, page 295, Penguin Books, Ltd., Middlesex (1972). The plant and its extracts have been and are used medicinally for pain, including cancer pain, pain, neuropathic pain, spasmodic analgesics, to combat the side effects of cancer chemotherapy, including nausea, in the treatment of glaucoma, epilepsy, as a hypnotic, anxiolytic, inflammatory and immunoinflammatory regulator, and as an appetite stimulant for AIDS patients, among other users.

[0003] There are over 60 constituent compounds that have been isolated and characterized from Cannabis sativa oil (see, for example, S.A. Ahmed, S.A. Ross, D. Slade, M.M. Radwan, F. Zulfiqar and M.A. El Sohly, “Cannabinoid Ester Constituents from High-Potency Cannabis sativa”, Journal of Natural Products, 2008, volume 71, pages 536-542, and references therein). In addition, a significant number of these natural products and analogs have been prepared by total synthesis from aromatic and monoterpene precursor compounds. Such total synthesis has been reported (e.g., RK Razdan, “The Total Synthesis of Cannabinoids” in “The Total Synthesis of Natural Products”, Editor J. ApSimon, 1996, volume 4, pages 185-262, New York, NY: Wiley and Sons; JW Futman and JAH Lainton, “Recent Developments in the Medicinal Chemistry of Cannabinoids”, Current Medicinal Chemistry, 1996, volume 3, pages 101-116; N. Itagaki, T. Sugahara and Y. Iwabuchi, “Expedient Synthesis of Potent Cannabinoid Receptor Agonist(-)-CP55,940”, Organic Letters, 2005, volume 7, pages 4181-4183; J. A Teske and A. Deiters, “A Cyclotrimerization Route to Cannabinoids”, Organic Letters,2008,volume 10,pages 2195-2198, S.Tchilibon and R.Mechoulam,“Synthesis of a Primary Metabolite of Cannabidiol”,Organic Letters,2000,volume 2,pages 3301-3303、Y.Song,S.Hwang,P.Gong,D.Kim and S.Kim*,“Stereoselective Total Synthesis of(-)-Perrottetinene and Assignment of Its Absolute Configuration”,Organic Letters,2008,volume 10,pages 269-271、Y.Kobayashi,A.Takeuchi and Y.-G.Wang,“Synthesis of Cannabidiols via Alkenylation of Cyclohexenyl Monoacetate”,Organic Letters,2006,volume 8,pages 2699-2702、B.M.Trost and K.Dogra,“Synthesis of(-)-Δ. 9 -trans-Tetrahydrocannabinol:Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction”,Organic Letters,2007,volume 9,pages 861-863、L.-J.Cheng,J.-H.Xie,Y.Chen,L.-X.Wang and Q.-L.Zhou,“Enantioselective Total Synthesis of(-)-Δ 8 -THC and(-)-Δ 9 -THC via Catalytic Asymmetric Hydrogenation and S NAr Cyclization”Organic Letters,2013,volume 15,pages 764-767、P.R.Nandaluru and G.J.Bodwell,“Multicomponent Synthesis of 6H-Dibenzo[b,d]pyran-6-ones and a Total Synthesis of Cannabinol”,Organic Letters,2012,volume 14,pages 310-313、S.Ben-Shabat,L.O.Hanus,G.Katzavian and R.Gallily,“New Cannabidiol Derivatives:Synthesis,Binding to Cannabinoid Receptor,and Evaluation of Their Antiinflammatory Activity”,Journal of Medicinal Chemistry,2006,volume 49,pages 1113-1117、A.Mahadevan,C.Siegel,B.R.Martin,M.E.Abood,I.Beletskaya and R.K.Razdan,“Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors”,Journal of Medicinal Chemistry,2000,volume 43,pages 3778-3785、S.P.Nikas,S.O.Alapafuja,I.Papanastasiou,C.A.Paronis,V.G.Shukla,D.P.Papahatjis,A.L.Bowman,A.Halikhedkar,X.Han and A.Makriyannis, “Novel 1',1'-Chain Substituted Hexahydrocannabinols:9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol(AM2389)a Highly Potent Cannabinoid Receptor 1(CB1)Agonist”, Journal of Medicinal Chemistry, 2010, volume 53, pages 6996-7010). .

[0004] In the last two decades, cannabinoids have been undergoing a renaissance in diverse biomedical uses. The pharmacology of cannabinoids has been shown to be linked to many receptors and mechanisms, including cannabinoid receptors, GPCR receptors, serotonin receptors, and several voltage-gated channels (Ca 2+ , Na + , and various types of K +These include the regulation of ion-transporting membrane proteins such as ligand-gated ion channels (i.e., GABA, glycine and TRPV), toll-like receptors, opioid receptors, NMDA or excitatory amino acid receptors, catecholamine receptors, enzymes that regulate endocannabinoids, and transient potential receptor class (TRP) channels (L. De Petrocellis, M. Nabissi, G. Santoni and A. Ligresti, “Actions and Regulation of Ionotropic Cannabinoid Receptors”, Advances in Pharmacology, 2017, volume 80, pages 249-289; P. Morales and PH Reggio, “An Update on Non-CB1, Non-CB2 Cannabinoid Related G-Protein-Coupled Receptors”, Cannabis Cannabinoid Research, 2017, volume 2, pages 265-273). It would therefore be useful to have a novel agent(s) comprising one or more cannabinoids for the treatment of afflictions known to be treatable by affecting or using these physiological mechanisms.

[0005] In most studies with cannabinoids, their actions are believed to involve direct or indirect receptor-mediated effects in many indications through two G protein-coupled receptors with 44% sequence homology in humans, named CB1 and CB2. The CB1 subtype is the most widely expressed G protein-coupled receptor in the brain, in areas controlling movement, emotion, cognition, sensory responses, pain perception, thermoregulation, as well as cardiovascular, gastrointestinal, and respiratory physiology.

[0006] It is localized in the central (CNS) and peripheral nervous system, including the olfactory bulb, cortical areas, parts of the basal ganglia, thalamus, hypothalamus, cerebellar cortex, brain stem, and spinal cord.

[0007] CB1 receptors also occur in the pituitary gland, thyroid gland, some fat, muscle, and liver cells, and in cells in the lungs and kidneys. CB2 subtypes are expressed in immune cells, hematopoietic cells, osteoclasts, and osteoblasts, where they mediate immune system responses, control inflammation, and regulate inflammatory and neuropathic pain as well as bone remodeling.

[0008] Therefore, it would be useful to have a novel agent(s) comprising one or more cannabinoids for the treatment of afflictions known to be treatable by affecting these physiological pathways to prevent, treat, or cure one or more inflammation mediated diseases or conditions from the group consisting of the central or peripheral nervous system, the cardiovascular-renal system, the skin, the gastrointestinal system, the pulmonary-respiratory system, the endocrine system, the joints, the musculoskeletal system, the blood or lymphatic system, the genitourinary system, the eye, and the ear, or for the prevention, treatment, or cure of one or more of anorexia, arthritis, cancer, pain, glaucoma, migraine, persistent muscle spasms, and stroke in an individual or animal in need of treatment.

[0009] The pharmacology of CB1 and CB2 receptor modulators is reviewed, for example, by Vemuri and Makriyannis (VK Vemuri and A. Makriyannis, “Medicinal Chemistry of Cannabinoids”, Clinical Pharmacology & Therapeutics, 2015, volume 97, pages 553-558). Δ 9 -Tetrahydrocannabinol (7) and its primary metabolite 11-hydroxy-Δ 9The psychoactive effects of -tetrahydrocannabinol (8) are mediated by its partial agonism of the CNS CB1 receptor (J. van Amsterdam, T. Brunt and W. van den Brink, “The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects”, Journal of Psychopharmacology, 2015, volume 29, pages 254-263; RG Pertwee, “The diverse CB1and CB2receptor pharmacology of three plant cannabinoids:Δ 9 -tetrahydrocannabinol,cannabidiol and Δ 9-tetrahydrocannabivarin”, British Journal of Pharmacology, 2008, volume 153, pages 199-215). It is useful as an analgesic, antiemetic, and to treat anorexia in AIDS patients. Other CB1 receptor modulators include tetrahydrocannabivarin (9) (weak antagonist) and cannabinol (10) (weak agonist), both of which are moderate CB2 agonists. The non-psychoactive drugs (-)-cannabidiol (11) and cannabidivarin (12) both do not significantly interact with either receptor subclass, and their mode of action is largely unclear (J. Fernandez-Ruiz, O. Sagredo, MR Pazos, C. Garcia, R. Pertwee, R. Mechoulam, J. Martinez-Orgado, “Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?", British Journal of Clinical Pharmacology, 2013, volume 75, pages 323-333, S. Rosenthaler, B. Pohn, C. Kolmanz, CN Huu, C. Krewenka, A. Huber, B. Kranner, W.-D. Rausch and R. Moldzio, "Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures”,Neurotoxicology and Teratology,2014,volume 46,pages 49-56).Δ 9-Tetrahydrocannabinol (7) and cannabidiol (11) combinations (Sativex, Nabiximols) have been used to treat multiple sclerosis-associated spasms and as a potent painkiller in patients with advanced cancer. More recently, purified cannabidiol (11) was granted orphan drug status for treating epilepsy. CB1 receptor antagonists are appetite suppressants, enhance cognition, and control addictive behaviors. Selective CB2 agonists may provide superior painkillers and immunomodulators without the undesirable psychoactive effects associated with CNS CB1 agonism. Δ 9 -Tetrahydrocannabinol (7) (Dronabinol) has been shown to be clinically effective as monotherapy or in combination with ondansetron (Zofran, a 5-HT3 antagonist) and in combination with prochlorperazine (a dopamine D2 receptor antagonist) to treat chemotherapy-induced nausea and vomiting in cancer patients (MB May and AE Glode, “Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics”, Cancer Management and Research, 2016, volume 8, pages 49-55). [ka]

[0010] Cannabinoids used as therapeutic agents are currently obtained from fractionation of cannabis or cannabis oil, or from total synthesis, usually from aromatic and terpene starting materials. There are more than 60 different natural products in cannabis and its oil, so such fractionation requires expensive chromatographic purification to provide any individual component in substantially pure form, making many components difficult to produce and store reproducibly. In the context of this patent application, substantially pure means at least 99% chemically (structurally, diastereomeric, and enantiomeric) pure, and further free from contamination by any pesticides, including herbicides, fungicides, and insecticides, or any pathogens that may be associated with the cannabinoids isolated from the plant-derived cannabis oil.

[0011] 9 -tetrahydrocannabinol (7) is isolated from other cannabis compounds, particularly its isomer Δ 8-tetrahydrocannabinol is inefficient and expensive to separate. Furthermore, because many of the cannabinoids in cannabis oil have different effects as full, partial, opposing, or neutral agonists or antagonists at either or both of the CB1 and CB2 receptors, it is particularly important that the individually isolated natural products are free of significant levels (less than parts per million) of any other cannabinoid natural products that have undesirable biological effects, and are efficiently reproducible to specification. To further complicate matters, many cannabinoid natural products are obtained as oils, generally cannot be crystallized, are prone to air oxidative degradation, and their isolation requires the use of chromatography and / or derivatization, which are rather expensive and difficult to avoid (see, for example, B. Trawick and M H Owens, “Process for the Preparation of (-)-delta 9-Tetrahydrocannabinol”, WO 2009 / 099868 A1; E. Arslantas and U. Weigl, “Method for Obtaining Pure Tetrahydrocannabinol”, U.S. Patent No. 7,923,558 B2; J E Field, J. Oudenes, Bl Gorin, R. Orprecio, FE Silva e Souza, N J Ramjit and E.-L. Moore, “Separation of Tetrahydrocannabinols”, U.S. Patent No. 7,321,047 B2; P. Bhatarah, K J Batchelor, D. McHattie and See A. K. Greenwood, "Delta 9 Tetrahydrocannabinol Derivatives", WO 2008 / 099183 A1; D. C. Burdick, S. J. Collier, F. Jos, B. Biolatto, B. J. Paul, H. Meckler, M. A. Helle and A. J. Habershaw, "Process for Production of Delta-9-Tetrahydrocannabinol", U.S. Patent No. 7,674,922 B2).Second, many routes to prepare cannabinoids use expensive reagents that are uneconomical for large-scale use or rely on condensation reactions of monoterpene starting materials with derivatives of alkyl-resorcinols, such as 5-n-pentyl-resorcinol (olivetol), under acidic reaction conditions that often give rise to by-products derived from carbenium ion rearrangement reactions and / or side reactions, e.g., Δ from olivetol and monoterpenes via Brønsted or Lewis acid catalyzed condensation reactions. 9 -The production of tetrahydrocannabinol (7) involves, among other impurities, its isomer Δ 8 -tetrahydrocannabinol. Such impurities also complicate and increase the cost of obtaining a substantially pure cannabinoid active pharmaceutical ingredient (see, for example, RK Razdan, "The Total Synthesis of Cannabinoids" in "The Total Synthesis of Natural Products", Editor J. ApSimon, 1996, volume 4, pages 185-262, New York, NY: Wiley and Sons; C. Steup and T. Herkenroth, "Process for Preparing Synthetic Cannabinoids", U.S. Patent Application No. 2010 / 0298579 A1; RJ Kupper, "Cannabinoid Active Pharmaceutical Ingredient for Improved Dosage Forms", WO2006 / 133941A2; J. Erler, and S. Heitner, "Method for the Preparation of Dronabinol”, U.S. Patent No. 8,324,408B2, AL Gutman, M. Ettinger, I. Fedotev, R. Khanolkar, GANisnevich, B. Pertsikov, I. Rukhman and B. Tishin, “Methods for Purifying trans-(-)-Δ 9 -Tetrahydrocannabinol and trans-(+)-Δ9 (See U.S. Pat. No. 9,278,083 B2, “Tetrahydrocannabinol”). The present invention is directed to overcoming these problems and providing an efficient / reproducible manufacturing route for known cannabinoids, providing a flexible synthesis of novel cannabinoids that can be used as active compounds, alone or in admixture with known and / or other drugs, in formulations for the treatment of pain, multiple sclerosis associated spasticity, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, immune inflammatory mediated disorders, among other pathologies. Summary of the Invention

[0012] Among the benefits and improvements disclosed herein, other objects and advantages of the disclosed embodiments will become apparent from the following. Although cannabinoid compounds, intermediate compounds, and processes for the preparation of cannabinoids and cannabimimetic compounds and their intermediates are disclosed, it should be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Moreover, each of the examples shown in connection with various embodiments of the invention is intended to be illustrative and not limiting.

[0013] Throughout the specification and claims, the following terms are to have the meanings expressly associated therewith, unless the context clearly dictates otherwise: The phrases "in some embodiments" and "in some embodiments" as used herein do not necessarily refer to the same embodiment or embodiments, although they may.

[0014] As used herein, the phrases "in another embodiment" and "in some other embodiments" do not necessarily refer to different embodiments, although they may. As such, various embodiments, as described below, can be readily combined without departing from the scope and spirit of the present invention.

[0015] Additionally, as used herein, the term "or" is an inclusive "or" operator and is equivalent to the term "and / or" unless the context clearly dictates otherwise. The term "based on" is not exclusive and may be based on additional factors not listed unless the context clearly dictates otherwise. Additionally, throughout this specification, the meanings of "a," "an," and "the" include plural references. The meaning of "in" includes "in" and "on."

[0016] Additionally, the terms "substantial," "substantially," "similar," "similarly," "similarly," "approximately," and any combination thereof mean that the difference between the compared properties or characteristics is less than 25% of the respective value / magnitude by which the compared properties or characteristics are measured and / or determined.

[0017] As used herein, the term "substituted benzyl" refers to a benzyl ring having one, two, or three independently variable C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl groups at any position on the aromatic ring, or one or two independently variable C1-C4 alkyl at the benzyl methylene.

[0018] As used herein, the term "optionally substituted aryl" means a phenyl ring optionally bearing one, two, or three independently variable C1-C4 alkyl, C1-C4 alkyloxy, fluoro, or chloro groups.

[0019] Unless otherwise defined herein, the term "substituted" means optionally substituted at any position with a varying C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl group.

[0020] The present invention provides the synthesis of a variety of known and novel cannabinoids 1 and 2 from novel precursors 3 or 6 or mixtures of 3 and 6, either as racemates or as the specific enantiomers shown below, or as Δ 9 -Tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids, and for tricyclic cannabinoids, aryl rearrangements, aromatization, and undesirable Δ 8 - Δ with almost no isomers 9 - a process for the preparation, via novel intermediate 4, of the enantiomers of 1 or 2, including other known and novel synthetic tetracyclic and tricyclic analogues from simple and inexpensive starting materials using a cascade sequence of further cyclizations in a highly stereo- and regioselective manner to generate cannabinoid 2. [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and RB is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s (s is 4, 5, or 6) and Rα and Rβ are preferably both methyl.

[0021] The present invention also relates to a related process for the preparation of novel intermediates of formula 3 from the reaction of monoterpene starting material 13 with 1,3-dioxanedione 14, either as a racemate or as a mixture of the two enantiomers in unequal ratios, or as the specific enantiomer or enantiomers of 3 shown below: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and Rγ is H, C1-C6 alkyl and Rδ is an optionally substituted aryl; s is 4, 5, or 6.

[0022] The present invention also relates to a related process for the preparation of novel intermediates of formula 6 from the reaction of monoterpene starting material 15 with 1,3-dioxanedione 14, either as a racemate or as a mixture of the two enantiomers in unequal ratios, or as the specific enantiomer or enantiomer of 6 shown below: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and Rγ is H, C1-C6 alkyl and Rδ is an optionally substituted aryl; s is 4, 5, or 6.

[0023] The synthesis method is suitable for large-scale use and manufacturing purposes. Examples of known cannabinoids that can be used in the synthesis route include cannabidiol (11), cannabidivarin (12), Δ 9 -Tetrahydrocannabinol (7), a compound related to tetrahydrocannabivarin (9), and nabilone (16). [ka]

[0024] The present synthetic method is also suitable for the synthesis of other known and novel cannabinoids, which compounds are also part of the present invention. The following cannabinoids 1 are novel analogues of cannabidiol (11), and cannabidivarin (12), which are also accessible by the synthetic routes described herein and are part of the present invention. These cannabinoids 1 have the following formula: [ka] During the ceremony, R 1 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2)p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0025] The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9 - in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration, or by other known methods of clinical administration.

[0026] The following cannabinoids 1 are novel analogues of cannabidiol (11), cannabidivarin (12), which are also available by the synthetic route described herein and are part of the present invention. These cannabinoids 1 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0027] The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9 -tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9 - in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration, or by other known methods of clinical administration.

[0028] The following cannabinoids 1 are novel analogues of cannabidiol (11), cannabidivarin (12), which are also available by the synthetic route described herein and are part of the present invention. These cannabinoids 1 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; RC is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other cannabinoids, including, but not limited to, ΔΨ ... 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9 - in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, topical, rectal, or parenteral drug administration, or by other known methods of clinical administration.

[0029] The following dioxinone derivatives 3 are intermediates for the synthesis of cannabinoids, are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 3 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R3 is a hydroxy protecting group, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0030] The following dioxinone resorcylic acid derivatives 4 are novel intermediates for the synthesis of cannabinoids, which are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 4 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR For C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0031] The following cannabinoid 2 is Δ 9 - Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), which are also available by the synthetic route described herein and are part of the present invention. These cannabinoids 2 have the following formula: [ka] During the ceremony, R 1 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R Ais H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R Fis C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0032] The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other agents, including but not limited to, Δ 9 -tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above formula 2 may be used alone or in combination with, but not limited to, Δ 9 - in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug, subcutaneous administration, or by other known methods of clinical administration.

[0033] The following cannabinoid 2 is Δ 9 - Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), which are also available by the synthetic route described herein and are part of the present invention. These cannabinoids 2 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9 -tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above formula 2 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug, transdermal administration, or by other known methods of clinical administration.

[0034] The following cannabinoid 2 is Δ 9 - Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), which are also available by the synthetic route described herein and are part of the present invention. These cannabinoids 2 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A CONHR D ,CONR D R E and R Bis H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0035] The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other agents, including but not limited to, Δ 9 -tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above formula 2 may be used alone or in combination with, but not limited to, Δ 9 - in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain pharma- ceutical acceptable diluents and excipients in addition to the active cannabinoid(s) and / or other agents in the combination therapy. The pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration, or by other known methods of clinical administration.

[0036] The following resorcylic acid cannabinoids 5 are intermediates for the synthesis of cannabinoids and are also available by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 5 have the formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) n -C3-C6 cycloalkyl, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0037] The following dioxinone derivatives 6 are novel intermediates for the synthesis of cannabinol, which are also accessible by the synthetic route described herein and are part of the present invention. These dioxinone derivatives 6 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) n -C3-C6 cycloalkyl, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The present invention provides a variety of known and novel cannabinoids 1 and 2, either as racemates or as the specific enantiomers shown below, or as Δ 9 -Tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids, and for tricyclic cannabinoids, aryl rearrangements, aromatization, and undesirable Δ 8 - Δ with almost no isomers 9 - as enantiomers of 1 or 2, including other known and novel synthetic tetracyclic and tricyclic analogues from simple and inexpensive starting materials using a cascade sequence of highly stereoselective and regioselective further cyclizations to produce cannabinoid 2. The invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates and polymorphs, as appropriate. [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The process is R 1 and / or R 2 [R 2 (CH2) m (1) reacting a first novel intermediate of formula 3, in which any hydroxyl group in one or more of the intermediates is —OH, with an acylating reagent R B COY and R B Any hydroxyl group (1) in B (2) COY, (3) a palladium catalyst 19 with optional additional ligand 20, (4) successive treatment with silica or an equivalent solid reagent or a second mild base 21, followed by a Brønsted or Lewis acid 22, or a mild base alone such as cesium acetate, and optional deprotection to provide a second novel intermediate 4, which is then hydrolyzed with optional decarboxylation of 4 or by transesterification or by amide formation with optional deprotection to provide 1, During the ceremony, Y is a halogen, preferably chlorine, or R B COY is an alternative reactive electrophilic acylating reagent, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s (s is 4, 5, or 6) and Rα and Rβ are preferably both methyl; The first mild base 17 is an amine or a heterocyclic amine such as pyridine; The mild Lewis acid 18 is preferably magnesium chloride; The palladium catalyst 19 is derived from a palladium(II) pre-catalyst or a palladium(0) catalyst itself, with optional additional ligands 20 including, but not limited to, one or more phosphines or diphosphines or their equivalents, preferably the palladium catalyst 19 and ligands 20 specifically include, but are not limited to, phosphine complexes of palladium(0) such as tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba))3] in the presence of a triarylphosphine or triheteroarylphosphine, particularly tri-2-furylphosphine; The second mild base 21 is cesium acetate or cesium carbonate or potassium carbonate, The Bronsted or Lewis acid 22, when used, is acetic acid or hydrogen chloride; the optional hydroxyl protecting group(s) is a silyl protecting group; The optional hydroxyl protecting group(s) is preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, or tri-iso-propylsilyl protecting group.

[0039] Protective groups are well known to those of skill in the art and are described in textbooks such as Greene and Wut (PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York). Amide formation can be carried out by activation of a carboxylic acid, e.g., by formation of an N-hydroxysuccinimide ester and coupling with the corresponding amine, see, e.g., Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid-carrier protein conjugate by matrix-assisted laser desorption / ionization mass spectrometry and antibody formation”, Organic Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include, but are not limited to, dicyclohexylcarbodiimide (DCC), di-iso-propylcarbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631). [ka]

[0040] The present invention provides a variety of known and novel cannabinoids 1 and 2, either as racemates or as the specific enantiomers shown below, or as Δ 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and related processes for the preparation of other naturally occurring tetracyclic and tricyclic cannabinoids and other known and novel synthetic tetracyclic and tricyclic analogues from simple and inexpensive starting materials using a cascade sequence of allylic rearrangements, aromatization, and, for tricyclic cannabinoids, further cyclization. The invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates, and polymorphs, as appropriate. [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The process is R 1 and / or R 2 [R 2 (CH2) m (1) reacting a first novel intermediate of formula 6, in which any hydroxyl group in BCOY and R B Any hydroxyl group(s) in B (2) COY, (3) a palladium catalyst 19 with optional additional ligand 20, (4) successive treatment with silica or an equivalent solid reagent or a second mild base 21, followed by a Brønsted or Lewis acid 22, or a mild base alone such as cesium acetate, and optional deprotection to provide a second novel intermediate 4, which is then hydrolyzed with optional decarboxylation of 4 or by transesterification or by amide formation with optional deprotection to provide 1, During the ceremony, Y is a halogen, preferably chlorine, or R B COY is an alternatively reactive electrophilic acylating reagent, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s (s is 4, 5, or 6) and Rα and Rβ are preferably both methyl; The first mild base 17 is an amine or a heterocyclic amine such as pyridine; The mild Lewis acid 18 is preferably magnesium chloride; The palladium catalyst 19 is derived from a palladium(II) pre-catalyst or a palladium(0) catalyst itself, with optional additional ligands 20 including, but not limited to, one or more phosphines or diphosphines or their equivalents, preferably the palladium catalyst 19 and ligands 20 specifically include, but are not limited to, phosphine complexes of palladium(0) such as tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba))3] in the presence of a triarylphosphine or triheteroarylphosphine, particularly tri-2-furylphosphine; The second mild base 21 is cesium acetate or cesium carbonate or potassium carbonate, The Bronsted or Lewis acid 22, when used, is acetic acid or hydrogen chloride; During the ceremony, the optional hydroxyl protecting group(s) is a silyl protecting group; The optional hydroxyl protecting group(s) is preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, or tri-iso-propylsilyl protecting group. [ka]

[0041] Protective groups are well known to those of skill in the art and are described in textbooks such as Greene and Wut (PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0042] Of particular note in the present invention is that the method of attaching the terpene unit to intermediate 4 ensures that the position of the alkene unit in the cyclohexane ring unit is regiospecifically formed as shown in structure 4 as a result of the π-allyl-palladium mediated step, and other isomers are not formed to any significant extent (for a discussion of the mechanism, see R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642, and references therein).

[0043] Amide formation can be carried out by activation of a carboxylic acid, e.g., by formation of an N-hydroxysuccinimide ester and coupling with the corresponding amine, see, e.g., Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid-carrier protein conjugate by matrix-assisted laser desorption / ionization mass spectrometry and antibody formation”, Journal of Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include, but are not limited to, dicyclohexylcarbodiimide (DCC), di-iso-propylcarbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0044] The present invention also provides various known and novel cannabinoids 1 and 2, either as racemates or as the specific enantiomers shown below, or as Δ 9- related processes for the preparation of tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetra- and tricyclic cannabinoids and other known and novel synthetic tetra- and tricyclic analogues, including as 1 or 2 enantiomers, from a mixture of novel intermediates 3 and 6 from simple and inexpensive starting materials using a cascade sequence of allylic rearrangement, aromatization, and, for tricyclic cannabinoids, further cyclization to produce resorcylic acid derivative 4.

[0045] It should be noted that some of the intermediates in these syntheses can exist as keto- and enol tautomers. The depiction of a structure as a keto form also includes the corresponding enol form, including mixtures of both keto and enol forms. Furthermore, the depiction of a structure as an enol form also includes the corresponding keto form, including mixtures of both keto and enol forms. By way of illustration, intermediates 3 and 6 exist as mixtures of both keto and enol forms, but for simplicity, the structures are depicted as keto forms. Furthermore, it should be noted that while the structures are depicted as specific stereoisomers and enantiomers, the present invention also includes enantiomeric compounds, racemates, and mixtures of two enantiomers in unequal ratios. Furthermore, the present invention also encompasses structurally feasible diastereomers. The present invention includes the synthesis of target cannabinoids as oil or crystalline derivatives, including solvates, hydrates, and polymorphs, as appropriate.

[0046] The present invention also relates to related processes for the preparation of various known and novel cannabinoids of formula 2, either as a racemate or as a mixture of the two enantiomers in unequal ratios, or as the specific enantiomer shown below, or as the two enantiomers: [ka] During the ceremony, R 1is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2)r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6; The process is R 1 , R 2 [In the formula, R 2 (CH2) m -OH] and / or any hydroxyl group(s) in R B (1) treating a first novel intermediate or cannabinoid 1 of formula 4, in which the formula is protected, with a Lewis acid 23, and then treating the resulting novel intermediate 5 by hydrolysis, with optional decarboxylation, or by transesterification, or by amide formation, with optional deprotection as necessary, to provide 2, [ka] During the ceremony, Rα and Rβ are both preferably methyl; Lewis acid 23 is a derivative of a metal or metalloid, such as, but not limited to, boron (III), aluminum (III), zinc (II), tin (IV), titanium (IV), zirconium (IV), scandium (III), lanthanide (III), or bismuth (III), or an inorganic solid, such as a zeolite or equivalent, or is replaced by a Bronsted acid, such as methanesulfonic acid, 4-toluenesulfonic acid, or hydrogen chloride, or any combination of such Lewis acids and Bronsted acids, Lewis acids and inorganic solids, Bronsted acids and inorganic solids, or Lewis acids, Bronsted acids and inorganic solids.

[0047] Lewis acid 23 may alternatively be a derivative of boron(III), such as boron trifluoride or boron trifluoride etherate, Lewis acid 23 is alternatively a derivative of aluminum(III), such as aluminum chloride, ethylaluminum dichloride, or diethylaluminum chloride; Lewis acid 23 is alternatively a derivative of zinc(II), such as zinc chloride or zinc bromide, Lewis acid 23 is alternatively tin(IV) such as stannic chloride; Lewis acid 23 is alternatively a derivative of titanium(IV) such as titanium tetrachloride or iso-propoxytitanium trichloride, The Lewis acid 23 may alternatively be a derivative of zirconium(IV), such as zirconium tetrachloride, Lewis acid 23 is alternatively a derivative of scandium(III), such as scandium tris-trifluoromethanesulfonate or scandium tris-(di-(trifluoromethanesulfonyl)amide or scandium tris-(tri-(trifluoromethanesulfonyl)methide), Lewis acid 23 is alternatively a derivative of a lanthanide(III), such as ytterbium tris-trifluoromethanesulfonate or ytterbium tris-(di-(trifluoromethanesulfonyl)amide or ytterbium tris-(tri-(trifluoromethanesulfonyl)methide), Lewis acid 23 is alternatively a derivative of bismuth(III), such as bismuth tris-trifluoromethanesulfonate or bismuth tris-(di-(trifluoromethanesulfonyl)amide or bismuth tris-(tri-(trifluoromethanesulfonyl)methide), During the ceremony, the hydroxyl protecting group(s) is a silyl protecting group; The hydroxyl protecting group(s) are preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, or tri-iso-propylsilyl protecting groups.

[0048] Protective groups are well known to those of skill in the art and are described in textbooks such as Greene and Wut (PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0049] Amide formation can be carried out by activation of a carboxylic acid, e.g., by formation of an N-hydroxysuccinimide ester and coupling with the corresponding amine, see, e.g., Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid-carrier protein conjugate by matrix-assisted laser desorption / ionization mass spectrometry and antibody formation”, Journal of Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include, but are not limited to, dicyclohexylcarbodiimide (DCC), di-iso-propylcarbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0050] The Lewis acid 23 mediated cyclization reaction of cannabinoid 4 to cannabinoid 5 is known for related compounds lacking this key RαRβC ketal unit, such as in the example of cannabinoid 1, and the extension of this reaction to compounds bearing this ketal unit is part of this invention.Among others, Rhee, Childers, Gaoni, Adams, Glaser, Koch, Steup, Burdick, Kupper, and G.S utman (M.-H. Rhee, Z. Vogel, J. Barg, M. Bayewitch, R. Levy, L. Hanus, A. Breuer). and R.Mechoulam,“Cannabinol Derivatives:Binding to Cannabinoid Receptors and Inhibition of Adenylyl Cyclease”,Journal of Medicinal Chemistry,1997,volume 40,pages 3228-3233; Cannabinoids”,Journal of Organic Chemistry,1984,volume 49,pages 5276-5277;Y.Gaoni and R.Mechoulam”Isolation,Structure,and Partial Synthesis of an Active Constituent of Hashish”. 1646-1647、R.Adams,DCPease,CKCain and JHClark,“Structure of Cannabidiol.VI.Isomerization of Cannabidiol to Tetrahydrocannabinol,a Physiologically Active Product 2402-2405, R. Glaser, I. Adin, R. Machoulam and L. Hanus, “2-Methyl- and 4-Methyl-Δ”. 8-tetrahydrocannabinol:Correlation of Spatial Distinction with Cannabinoid Receptor Binding”,Heterocycles,1994,volume 39,pages 867-877; thereof.” Public Paper 2015 / 0336874Al, C. Steup and T. Herkenroth, “Process for preparing synthetic cannabinoids” National Paper No. 2010 / 298579A1 in DCBurdick, SJCollier,F.Jos,B.Biolatto,BJPaul,H.Meckler,MAHelle,AJHabershaw,“Process for production of delta-9-tetrahydrocannabinol” with a dose of 7,674,922B2 (2010) with RJKupper,“Cannabinoid active pharmaceutical ingredient for improved dosage forms”,WO2006 / 133941 A2;J.Erler and S.Heitner,“Method for the production of Dronabinol from Cannabidiol,using a molecular sieve“,WO2006 / 136273A1、ALGutman,M.Etinger,I.Fedotev,R.Khanolkar,GANisnevich,B.Pertsikov,I.Rukhman and B.Tishin,“Methods for purifying trans-(-)-Δ 9 -tetrahydrocannabinol and trans-(+)-Δ 9No. 9,278,083 B2). As a result, hydrolysis with optional decarboxylation and by amide formation via transesterification or, if necessary, by optional deprotection, can be used to obtain the undesired Δ 8 - Δ with very low levels of cannabinoids 9 -to provide the cannabinoid 2. The use of the RαRβC ketal unit to control the regioselectivity of the reaction is highly inventive, while the monoprotection of the cannabinoid as a methyl ether occurs in situ, Δ 9 A regiospecific synthesis of .ALPHA.-tetrahydrocannabinol (7) has been reported (WE Childers, Jr. and HW Pinnick, “A Novel Approach to the Synthesis of the Cannabinoids”, The Journal of Organic Chemistry, 1984, volume 49, pages 5276-5277).

[0051] The present invention also relates to related processes for the preparation of novel intermediates of formula 3, either as a racemate or as a mixture of the two enantiomers in unequal ratios, or as the specific enantiomer shown below, or as the enantiomer of 3, [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6; The process is R 1 and / or R 2 [R 2 (CH2) m -OH] with a mild acylating reagent 14 in an inert solvent at a temperature of 40-100° C. to produce intermediate 3 which retains the hydroxyl protecting groups in place; [ka] At that time, The inert solvent is a halogenated solvent or an aromatic hydrocarbon; The inert solvent is preferably an aromatic hydrocarbon such as toluene; The reaction temperature is preferably 40 to 60° C. Preferably, the temperature of the reaction is 50° C. and the solvent is toluene; At that time, the hydroxyl protecting group(s) is a silyl protecting group; The hydroxyl protecting group(s) are preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, or tri-iso-propylsilyl protecting groups.

[0052] Protective groups are well known to those of skill in the art and are described in textbooks such as Greene and Wut (PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0053] The present invention also relates to related processes for the preparation of novel intermediates of formula 6, either as a racemate or as a mixture of the two enantiomers in unequal ratios, or as the specific enantiomer shown below, or as the enantiomer of 6, [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6; The process is R 1 and / or R 2 [R 2 (CH2) m-OH] with mild acylating reagent 14 in an inert solvent at temperatures between 40-100° C. to generate novel intermediate 6, [ka] During the ceremony, The inert solvent is a halogenated solvent or an aromatic hydrocarbon; The inert solvent is preferably an aromatic hydrocarbon such as toluene; The reaction temperature is preferably 40 to 60° C. Preferably, the temperature of the reaction is 50° C. and the solvent is toluene; During the ceremony, the hydroxyl protecting group(s) is a silyl protecting group; The hydroxyl protecting group(s) are preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, or tri-iso-propylsilyl protecting groups.

[0054] Protective groups are well known to those of skill in the art and are described in textbooks such as Greene and Wut (PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0055] An example of the novel method is shown below in Scheme 1. Keto-ester dioxinones 24 are synthesized from keto-dioxinones 29 and imidazolides 30 or equivalent reagents such as, but not limited to, benzotriazole carbonate derivatives or 4-nitrophenyl carbonate, using methods similar to those published for other related keto-ester dioxinones (R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642, and references therein).

[0056] C-acylation of the keto-ester dioxinone 24 is carried out using hexanoyl chloride in the presence of a base such as pyridine in the presence of magnesium chloride to provide the corresponding adduct 25, which can be isolated and separated, but in a preferred embodiment is carried forward directly to the next step. Subsequent decarboxylation and allylic rearrangement, using methods similar to those published for other related diketo-dioxinones (R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642 and references therein), provides the corresponding β,δ-diketo-dioxinones 26, derivatives with a monoterpene unit attached at the α-carbon. Common catalysts for the conversion of intermediate 25 to diketo-dioxinone 26 include palladium(0) catalysts, which may already be in the palladium(0) oxidation state such as Pd(PPh3)4, or as palladium(II) in the presence of a phosphine or equivalent monodentate ligand or alternative bidentate or higher dentate ligands. Alternative metal catalysts may also be used in the conversion of 25 to 26, including but not limited to iron or molybdenum complexes, known by those skilled in the art to be used in metal-catalyzed reactions that proceed via a π-allylmetal intermediate. [ka]

[0057] Intermediate 26 can be isolated and separated, but in a preferred embodiment, it is carried forward directly to the next step without isolation. Reaction of diketo-dioxynone 26 with a second catalyst, such as silica gel or cesium carbonate, followed by hydrochloric acid, produces resorcylic acid derivative 27. Alternative catalysts for this cyclization reaction are shown in the Accounts of Chemical Research paper cited above. In the most preferred embodiment of this reaction, keto-ester 24 is converted to resorcylic acid 27 in a single pot via intermediates 25 and 26, without any separation or purification, except for product 27, which is a derivative of cannabidiol (11).

[0058] Cyclization of 27 using boron trifluoride etherate as reported in the synthesis of Hongoquercin B (TN Barrett and AGM Barrett, “Cascade Polyketide and Polyene Cyclizations: Biomimetic Total Synthesis of Hongoquercin B”, The Journal of the American Chemical Society, 2014, volume 136, pages 17013-17015), or cyclization with other Lewis or Brönsted acids or Lewis / Brönsted acid combinations well known to those skilled in the cannabinoid art, can be used to obtain Δ 1 -tetrahydrocannabinolic acid derivative 28.

[0059] Cleavage of the dioxinone ring of intermediate 28 by saponification or an equivalent process described in the Accounts of Chemical Research paper cited above affords Δ 1 -tetrahydrocannabinolic acid (31). Δ 1Decarboxylation of Δ-tetrahydrocannabinolic acid (31) gives tetrahydrocannabinol (7) (H. Perrotin-Brunel, W. Buijs, J. van Spronsen, M.J. Evan Roosmalen, C.J. Peters, R. Verpoorte and G.-J. Witkamp, ​​“Decarboxylation of Δ 9 (See "Cannabidiol-tetrahydrocannabinol: Kinetics and molecular modeling", Journal of Molecular Structure, 2011, volume 987, pages 67-73 and references therein). In a similar manner, saponification or an equivalent process of intermediate 27 and decarboxylation leads to cannabidiol (11). [ka]

[0060] Furthermore, the starting materials are pure, e.g., hexanoyl chloride is free of butanoyl chloride, so that the product cannabidiol with an n-pentyl side chain, e.g., Δ 9 It should be emphasized that n-tetrahydrocannabinol (7) is not contaminated by the corresponding cannabinoids bearing an n-propyl side chain, such as cannabidivarin (12) and tetrahydrocannabivarin (9). Furthermore, because the method used for the attachment of the aromatic core to the terpene unit is so mild and regiospecific, it is considerably easier to purify than those produced by conventional synthetic routes, which may contain impurities derived from the well-known monoterpene rearrangement as well as other contaminants.

[0061] It should be noted that the synthesis in Scheme 1 is carried out with equivalent starting materials. For example, the sequence is carried out starting with terpene 32 or an alternative terpene compound bearing a protected 2-hydroxy-propyl group. In these cases, intermediates bearing the protected 2-hydroxy-propyl group corresponding to 30, 25, 26, and 27 as well as those corresponding to 11 also maintain the same substituents. [ka]

[0062] It should be noted that the synthesis in Scheme 1 is carried out in the same manner as in Scheme 2, substituting butanoyl chloride for hexanoyl chloride. This step directly parallels that of the earlier scheme, and provides tetrahydrocannabivarin (9) and cannabidivarin (12) as well as the above Δ 1 -C-3 analogs of tetrahydrocannabinolic acid (31) are provided and rely on equivalent inventive steps.

[0063] Furthermore, the starting materials are pure, e.g., butanoyl chloride is free of hexanoyl chloride, so the product cannabidiol with an n-propyl side chain is cannabidiol (11) and Δ 9 It should be emphasized that the terpene units are not contaminated by the corresponding cannabinoids bearing n-pentyl side chains, such as -tetrahydrocannabinol (7). Moreover, because the method used for the attachment of the aromatic core to the terpene unit is so mild and regiospecific, they are considerably easier to purify than those produced by conventional synthetic routes, which may contain impurities from the well-known monoterpene rearrangement as well as other contaminants. In the present invention, the use of the Me2C ketal unit allows the cyclization reaction to produce the cannabinoid 36 to proceed in a Δ 9 -Provides only isomers and not the desired Δ 8 It should also be emphasized that the decarboxylation hydrolysis ensures that the -isomer is not produced to any significant extent. As a result, the decarboxylation hydrolysis produces a very low amount of the undesirable Δ8 - has isomer Δ 9 -isomer, tetrahydrocannabivarin (9). [ka]

[0064] The methods of Schemes 1 and 2 are also of use for the straightforward synthesis of a family of novel cannabinoids bearing previously unknown ring substituents from C-acylation of dioxinone 37 with carboxylic acyl chloride 38, decarboxyl allylic rearrangement, aromatization, and hydrolysis and decarboxylation. Examples of such novel cannabinoids include, but are not limited to, analogs 39 and 40 (R 1 = C2-C5 alkyl, cyclopropyl, phenyl 2 = n-pentyl) and (R 1 = CH3 and R 2 = cyclopropyl, cyclobutyl, cyclopentyl, phenyl) and the "reversed" analogues 39 and 40 (R 1 = n-pentyl, R 2 =CH3). The present invention includes the synthesis of target cannabinoids as oil or crystalline derivatives, optionally including solvates, hydrates, and polymorphs. [ka]

[0065] The above novel cannabinoids having the above defined formulas 39 and 40 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or in combination with other drugs. In some embodiments, the novel cannabinoids having the above formulas 39 and 40 may be used as active compounds alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma-ceutical acceptable disintegrants, petrolatum, dimethyl sulfoxide, mineral oil, or in an omega-3 oil-in-water nanoemulsion, or as a complex with a cyclodextrin, such as hydroxypropyl-beta-cyclodextrin. preservatives or alternative pharma- ceutically acceptable preservatives, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, and the like; anti-adherents such as magnesium stearate, stearic acid, talc, silica, lubricants, and glidants; pharma-ceutically acceptable fats or oils; coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma-ceutically acceptable coatings; flavors and fragrances, such as, but not limited to, cannabis and citrus fruit volatile terpenes, and other pharma-ceutically acceptable diluents and excipients. The pharmaceutical compositions may be administered to a patient by enteral administration, e.g., as pills, tablets, or capsules; by sublingual administration, e.g., as tablets, strips, drops, sprays, lozenges, effervescent tablets; by intranasal administration, e.g., as a spray, or as a micronized powder; by inhalation, e.g., as a spray or micronized powder; by rectal administration, e.g., as a suppository or solution; by parenteral drug administration, e.g., by intramuscular, subcutaneous, or intravenous injection of a solution, or by other known clinical administration methods.

[0066] In another embodiment of the invention, key intermediates for the decarboxylation, allylic rearrangement, and cyclization steps are prepared using the methods shown in Schemes 3 and 4. Terpene allylic alcohol building blocks such as 41 or 44 undergo reaction with dioxane dione 14 under mild heating to give the corresponding dioxane β-keto-esters 42 or 45, respectively. In a preferred embodiment, the reaction is carried out at a temperature between 50°C and 60°C between alcohol 41 or alcohol 44 and reagent 14 (Rα=Rβ=Rγ=methyl, Rδ=phenyl or Rα=Rβ=methyl, Rγ=H, Rδ=phenyl). However, alternative dioxane diones 14 can be used under conditions where the substituents Rα, Rβ, Rγ, and Rδ are selected such that the addition of the terpene alcohol occurs exclusively at the dione moiety. For example, the combined Rα and Rβ have Rγ and Rδ both as methyl (CH2) n (n=4, 5). [ka] [ka] Dioxane diones 14 are prepared by coupling Meldrum's acid derivatives 48 with carboxylic acids 47 and a suitable activating reagent such as (but not limited to) N,N'-dicyclohexylcarbodiimide (DCC) or equivalents (see DC Elliott, T.-K. Ma, A. Selmani, R. Cookson, PJ Parsons, and AGM Barrett "Sequential Ketene Generation from Dioxane-4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcylates", Organic Letters, 2016, volume 18, pages 1800-1803). [ka]

[0067] C-acylation of compounds 42 or 45 can be achieved by R B This is carried out with a suitable acylating reagent such as COX with X=Cl, Br, OSO2CF3. In a preferred embodiment, hexanoyl chloride is reacted with (X=Cl) and R in the presence of magnesium chloride and a base such as pyridine. B =(CH2)4CH3 to give diketo-dioxinone 43 and 46, respectively. Preferably, without further purification, the crude esters 43 and 46 are subjected to the above-mentioned decarboxylation and palladium-catalyzed allylic rearrangement as separate compounds or a mixture of these two regioisomers to give the corresponding β,δ-diketo-dioxinone 49 with a monoterpene specifically linked at the γ-carbon as shown in Scheme 5. Common catalysts for the conversion of intermediates 43 and 46 to diketo-dioxinone 49 include palladium(0) catalysts such as Pd2dba3 in the presence of phosphines or equivalent monodentate ligands such as P(2-furyl)3. Alternative catalysts can also be used by those skilled in the art as already discussed above.

[0068] Intermediate 49 is preferably directly converted to the next step intermediate without isolation and separation. Thus, reaction of diketo-dioxynone 49 with a second catalyst such as cesium acetate produces resorcylic acid derivative 50. Conversion of resorcylic acid derivative 50 to intermediates 51 and cannabinoids such as 52 and 53 is carried out by the methods already discussed above. [ka]

[0069] The syntheses in Schemes 3, 4, and 5 are carried out with appropriate starting materials and reagents to enable the synthesis of analogs and families of cannabinoids, including but not limited to, cannabinoids 5, 54, and 55, starting from monoterpene analogs 15 and / or 13 (or their enantiomers 56), condensation with reagent 14, C-acylation of intermediates 6 and / or 3 (or their enantiomers 57) to give esters 58 and / or 59 (or their enantiomers) and subsequent decarboxylative allylic rearrangement and cyclization.

[0070] For example, the synthetic sequences carried out in Schemes 3 and 4 starting with terpenes 41 and / or 44 can also be used to prepare, but are not limited to, alternative monoterpene analogs 15 and / or 56 (R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 wherein n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2). Additionally, C-acylation of ketodioxinones 42 and / or 45, or more generally 6 and / or 57, can be carried out with acylating agents to provide cannabinoids with different side chains on the aromatic ring. Examples include, but are not limited to, R B = n-propyl (cannabidivarin and tetrahydrocannabivarin families), R B = natural side chain with n-pentyl (cannabidiol and tetrahydrocannabinol families) or R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro groups, linear or branched C3-C10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or a non-natural side chain which is a C3-C6 cycloalkyl optionally substituted with a C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; [ka]

[0071] The synthetic methods in Schemes 1, 2, 3, 4, and 5 are suitable for large-scale use and manufacturing purposes, especially since the main cyclization reaction in the present invention does not give rise to undesired isomeric by-products. Examples of known cannabinoids that can be used in the synthetic pathway include cannabidiol (11), cannabidivarin (12), Δ 9 -Tetrahydrocannabinol (7), tetrahydrocannabivarin (9), and nabilone (16) are related compounds. The invention involves the synthesis of target cannabinoids as oil or crystalline derivatives, optionally including solvates, hydrates, and polymorphs. [ka]

[0072] The synthetic methods in schemes 1, 2, 3, 4, and 5 are suitable for the synthesis of novel cannabinoids, which are also part of the present invention. The following cannabinoids 1 are novel analogues of cannabidiol (11) and cannabidivarin (12), which are also accessible by the synthetic routes described herein and are also part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates, and polymorphs, as appropriate. These cannabinoids 1 have the formula: [ka] During the ceremony, R 1 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, linear or branched C3-C 10 Alkyl or double branched C4-C 10 alkyl, each optionally substituted with one or two hydroxy groups, or one or more fluoro groups, (CH) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted by C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0073] The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other agents, including but not limited to, for the treatment or prevention of pain, multiple sclerosis-related spasms, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, glaucoma and retinal degeneration, immune-inflammatory disorders, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, among other disease conditions. 9 -tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrins. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0074] The following cannabinoids 1 are novel analogs of cannabidiol (11) and cannabidivarin (12), which are also available by the synthetic routes described herein and are part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates, and polymorphs, as appropriate. These cannabinoids 1 have the formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR For C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0075] The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrins. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0076] The following cannabinoids 1 are novel analogs of cannabidiol (11) and cannabidivarin (12), which are also available by the synthetic routes described herein and are part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates, and polymorphs, as appropriate. These cannabinoids 1 have the formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The novel cannabinoids having the above defined formula 1 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9-Tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), nabilone (16), or other known cannabinoids, such as endocannabinoids, and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above specific formula 1 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrins. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0077] The following dioxinone derivatives 3 are novel intermediates for the synthesis of cannabinoids, which are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 3 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is a hydroxyl protecting group, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0078] The following novel dioxinone resorcylic acid derivatives 4 are intermediates for the synthesis of cannabinoids, are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 4 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0079] The following cannabinoid 2 is Δ 9- Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), also available by the synthetic routes described herein, are part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates and polymorphs, as appropriate. These cannabinoids 2 have the formula: [ka] During the ceremony, R 1 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR For C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0080] The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other agents, including but not limited to, for the treatment or prevention of pain, multiple sclerosis-related spasms, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, glaucoma and retinal degeneration, immune-inflammatory disorders, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, among other disease conditions. 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), nabilone (16), or endocannabinoids, and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above formula 2 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids, or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrins. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0081] The following cannabinoid 2 is Δ 9- Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), also available by the synthetic routes described herein, are part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates and polymorphs, as appropriate. These cannabinoids 2 have the formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is C2-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A is H, CO2H and its pharma- ceutically acceptable salts, CO2R C ,CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR For C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with one or two hydroxyl or hydroxymethyl groups, provided that a hydroxyl group cannot be present on the heterocyclic nitrogen bearing morpholine or on the carbon bearing the heterocyclic oxygen; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6; The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other agents, including but not limited to, for the treatment or prevention of pain, multiple sclerosis-related spasms, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, glaucoma and retinal degeneration, immune-inflammatory disorders, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, among other disease conditions. 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above defined formula 2 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids, or nabilone (16), and / or other agents are formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical acceptable diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 in oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrin. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0082] The following cannabinoid 2 is Δ 9- Novel analogues of tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), also available by the synthetic routes described herein, are part of the present invention. The present invention includes the synthesis of the target cannabinoids as oil or crystalline derivatives, including solvates, hydrates and polymorphs, as appropriate. These cannabinoids 2 have the formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R A CONHR D ,CONR D R E and R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R C is C1-C6 alkyl, (CH2) q -C3-C6 cycloalkyl, C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is 0, 1, 2, 3, 4, 5, or 6; R D is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that a hydroxyl group cannot be present on the carbon bearing the heterocyclic nitrogen or on the heterocyclic oxygen bearing the morpholine; R F is C1-C6 alkyl, (CH2) r -C3-C6 cycloalkyl, r is independently 0, 1, 2, 3, 4, 5, or 6.

[0083] The novel cannabinoids having the above defined formula 2 may be used alone or in combination with other cannabinoids, including, but not limited to, Δ 9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids, or nabilone (16), and / or other drugs, may be used as active compounds. In some embodiments, the novel cannabinoids having the above formula 2 may be used alone or in combination with, but not limited to, Δ 9- in combination with known cannabinoids such as tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), or nabilone (16) and / or other agents and formulated into pharmaceutical compositions in a form suitable for administration to a patient. Such formulations contain, in addition to the active cannabinoid(s) and / or other agents in the combination therapy, pharma- ceutical diluents and excipients, such as binders, such as lactose, starch, cellulose, sorbitol, polyethylene glycol, or polyvinyl alcohol, or other pharma- ceutical acceptable oligosaccharides or polymers, disintegrants, such as polyvinylpyrrolidone, carboxymethylcellulose, or other pharma- ceutical acceptable disintegrants, such as petrolatum, dimethyl sulfoxide, mineral oil, or omega-3 oil-in-water nanoemulsions, or hydroxypropyl-beta-cyclodextrins. The pharmaceutical composition may include a vehicle such as a complex with cyclodextrin, for example phosphate, a preservative or alternative pharma- ceutical acceptable preservative, including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, etc., an anti-adherent agent such as magnesium stearate, stearic acid, talc, silica, a lubricant, and a glidant, a coating such as pharma- ceutical acceptable fat or oil, cellulose ether hydroxypropyl methylcellulose, gelatin, or other pharma- ceutical acceptable coating, and other pharma- ceutical acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by enteral administration, for example as a pill, tablet, or capsule, by sublingual administration, for example as a tablet, strip, drop, spray, lozenge, effervescent tablet, by intranasal administration, for example as a spray, or as a micronized powder, by inhalation, for example as a spray or micronized powder, by rectal administration, for example as a suppository or solution, by parenteral drug administration, for example by intramuscular, subcutaneous, or intravenous infusion of a solution, or by other known clinical administration methods.

[0084] The following dioxinone resorcylic acid derivatives 5 are intermediates for the synthesis of cannabinoids and are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 5 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) n -C3-C6 cycloalkyl, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6.

[0085] The following dioxinone derivatives 6 are intermediates for the synthesis of cannabinoids and are also accessible by the synthetic routes described herein and are part of the present invention. These dioxinone derivatives 6 have the following formula: [ka] During the ceremony, R 1 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and R 2 is H, C1-C6 alkyl, (CH2) n -C3~C6 cycloalkyl, (CH2) m -OR 3 and n is independently 0, 1, or 2; m is independently 1 or 2; R 3 is H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, R B is H or C1-C2 alkyl, in each case optionally substituted by one or two hydroxyl groups or by one or more fluoro groups, linear or branched C3-C 10 Alkyl or double branched C4-C 10 Alkyl, (CH2) o -C3~C6 cycloalkyl, (CH2) p -OR F or C3-C6 cycloalkyl optionally substituted with C1-C8 alkyl; o is 0, 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, 5, or 6; R F is C1-C6 alkyl, (CH2) n -C3-C6 cycloalkyl, Rα and Rβ are independently C1-C6 alkyl or optionally substituted aryl, or Rα and Rβ are combined to form (CH2) s and s is 4, 5, or 6. EXAMPLES

[0086] Example 1: (1R,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (6,R 1 =R 2 =Rα=Rβ=CH3). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol, 1 equiv.) and 4-dimethylaminopyridine (6.0 g, 50 mmol, 1 equiv.) were added sequentially to a solution of 2-phenyl-1,3-dioxane-4,6-dione (9.6 g, 50 mmol, 1 equiv.) in anhydrous dichloromethane (0.5 L). After 5 min, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (9.4 g, 50 mmol, 1 equiv.) was added in one portion. The reaction mixture was stirred at room temperature for 17 h. After this period, water (0.5 L) was added and the organic fraction was separated. The organic phase was washed with 1 M HCl (2 x 0.5 L) and brine (0.5 L). The washed organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was immediately dissolved in anhydrous toluene (0.5 L) and (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (4) (3.9 g, 25 mmol, 0.5 equiv.) was added dropwise. The solution was heated to 55° C. and the temperature was maintained for 3 h. After the starting material was consumed, the solution was concentrated under reduced pressure. The crude reaction product was purified by flash column chromatography (EtOAc:pentane 2:20 to 4:20) to give the title compound as a colorless oil (4.3 g, 12 mmol, 48%). 1 H NMR(400MHz, CDCl3) δ principal isomer 5.46(dq,J=8.7,2.1Hz,1H),5.40-5.30(m,2H),4.78(q,J=1.6Hz,1H),4.74(dt,J=1.9,0.9Hz,1H),3.49(s, 2H),3.47(s,2H),2.37-2.26(m,1H),2.15-2.02(m,1H),2.02-1.90(m,1H),1.79-1.73(m,2H),1.71(t,J=1.0Hz,16H),1.70-1.66(m,1H); 13C NMR (101MHz, CDCl3) δ isomer mixture 195.7,166.2,163.8,160.6,145.5,140.2, 120.3,118.8,112.3,111.5,107.5,97.2,96.6,92.4,73.6,72.4,69.5,61. 8,49.6,46.9,46.6,44.2,39.6,39.5,29.8,26.3,26.2,25.1,23.3,19.8,1 4.2;IR(neat)2937,1720,1639,1375,1250,1201,1014,901;HRMS(ES-)m / z C 20 H 25 O6[MH] + Calculated 361.1651, measured 361.1651; R f 0.2 (EtOAc:pentane; 4:20) UV / vanillin.

[0087] Example 2: (1R,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxooctanoate. Pyridine (1.2 mL, 14 mmol, 2.0 equiv.) and MgCl2 (0.66 g, 6.9 mmol, 1.0 equiv.) were dissolved in (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (6,R 1 =R 2 To a solution of 1.0 eq. (Rα=Rβ=CH3) (2.5 g, 6.9 mmol, 1.0 equiv.) was added hexanoyl chloride (1.3 g, 10 mmol, 1.5 equiv.) dropwise and the mixture was stirred for 1 h.

[0088] The cooling bath was removed and the mixture was stirred for an additional 2 h. Saturated aqueous NH4Cl (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic extract was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc:pentane 2:20) to give the title compound as a colorless oil (2.9 g, 6.3 mmol, 91%). NMR(400MHz,CDCl3)δ5.60(dp,J=8.6,2.1Hz,1H),5.40-5.26(m,2H),4.84-4.73(m,2H),3.66(s,2 H),2.74-2.56(m,2H),2.42-2.32(m,2H),2.20-1.94(m,3H),1.40-1.21(m,7H),0.97-0.87(m,5H); 13 C NMR(100MHz,CDCl3)δ198.4,192.4,166.4,165.5,161.0,145.8,140.1,120.4,112.3,109.1,107.3,96.6,73.2,47.0,42.9,37.6,31.7,31.4 ,29.9,26.8,25.9,24.6,23.3,22.6,22.4,19.9,14.1;IR(neat)2933,1732,1702,1639,1390,1375,1271,1202,1068,899,755;HRMS(ES-)m / z C 26 H 35 O7[MH] + Calculated 459.2383, measured 459.2390; R f 0.4 (EtOAc:pentane; 2:20) UV / vanillin.

[0089] Example 3: 7-Hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (4,R 1 =R 2 =Rα=Rβ=CH3,R B =n-C5H 11 ). Tri(2-furyl)phosphine (46 mg, 0.2 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.05 equiv) were added sequentially to a solution of (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxooctanoate (0.46 g, 1 mmol, 1 equiv) in THF (10 mL) cooled to 0° C. The mixture was immediately warmed to room temperature.

[0090] After 3 h, 0.5 M CsOAc in iso-propanol (6 mL, 3 mmol, 3 equiv.) was added dropwise and the reaction mixture was stirred for an additional 72 h. The reaction was quenched with 10% aqueous citric acid (10 mL), the biphasic solution was separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The organic extracts were combined and washed with brine (30 mL). The washed organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane:pentane 1:1) to give the title compound as a white solid (128 mg, 0.32 mmol, 32%). 1 H NMR(400MHz,CDCl3)δ6.45(s,1H),6.41(s,1H),5.48(s,1H),4.57-4.51(m,1H),4.41(s, 1H),3.91-3.82(m,1H),2.99(t,J=7.7Hz,2H),2.42(td,J=11.4,10.9,3.8Hz,1H),2.24( t,J=13.0Hz,1H),2.11(ddd,J=15.5,5.1,2.6Hz,1H),1.86-1.76(m,4H),1.69-1.65(m,5 H),1.60(d,J=14.1Hz,6H),1.34(pd,J=6.8,3.9Hz,4H),0.88(tq,J=7.3,2.6,2.1Hz,3H); 13C NMR(101MHz,CDCl3)δ160.8,156.4,148.3,146.4,146.4,123.5,115.1,113.9,112.5,104.7,104.4,46.4,35.6,34.5,32.0, 30.6,30.4,28.2,26.3,24.9,23.8,22.7,14.2;IR(neat)3271,2926,1693,1604,1587,1418,1287,1129,1052;HRMS(ES-)m / z C 25 H 33 O4[MH] + Calculated 397.2379, measured 397.2386; R f 0.3 (Et2O:pentane; 2:20) UV / vanillin.

[0091] Example 4: Cannabidiol (11) A 6M aqueous NaOH solution (4 mL) was purged with nitrogen for 5 min in a sealable reaction vial. A nitrogen purged solution of 7-hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (80 mg, 0.20 mmol) in methanol (4 mL) was added to the aqueous solution. The reaction vial was sealed and the solution was heated to 120° C. for 5 h. The reaction solution was added to a vigorously stirring 10% aqueous citric acid solution (10 mL) and Et2O (10 mL). After 5 min, the layers were separated and the aqueous layer was extracted with Et2O (3×10 mL). The ether extract was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtO:pentane 1:2:20 to 2:20) to give cannabidiol (11) as a white solid (38 mg, 0.12 mmol, 60%). 1H NMR(400MHz,MeOD)δ6.07(s,2H),5.28(dq,J=2.3,1.3Hz,1H),4.49-4.39(m,2H),3.96-3.88( m,1H),2.90(td,J=10.2,5.5Hz,1H),2.41-2.33(m,2H),2.20(dd,J=12.5,6.4Hz,1H),1.99(d d,J=17.0,3.5Hz,1H),1.73(ddd,J=8.6,6.8,2.8Hz,2H),1.67(dt,J=2.5,1.1Hz,3H),1.63(t ,J=1.1Hz,3H),1.54(ddd,J=14.7,8.4,6.7Hz,2H),1.37-1.24(m,5H),0.89(t,J=7.0Hz,3H); 13 C NMR(101MHz,MeOD)δ157.5,150.3,142.7,134.3,127.3,116.0,110.5,108. 3,108.3,46.4,37.5,36.6,32.6,32.0,31.7,30.8,23.7,23.6,19.5,14.4;R f 0.3 (Et2O:pentane; 1:20) UVKMnO4.

[0092] Example 5:Δ 9 -Tetrahydrocannabinol (7) Cannabidiol (11) (40 mg, 0.12 mmol) in dichloromethane (1 mL) was cooled to -10 °C. An ice-cold solution of BF3·2Et2O in dichloromethane (1.2 mL, 0.12 mmol, 0.1 M) was added dropwise over 20 min. The reaction mixture was stirred at 20 °C for a further 40 min. It was diluted with diethyl ether (5 mL) and a saturated solution of NaHCO3 (5 mL) was added dropwise. The layers were separated and the aqueous fraction was extracted with diethyl ether (3 × 5 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure.

[0093] The crude product was purified by flash column chromatography (5% diethyl ether in pentane) to give trans-Δ9-tetrahydrocannabinol (7) tetrahydrocannabinol (31 mg, 0.99 mmol, 83%). 1H NMR(400MHz,CD3OD)δ 6.43(app.pent,J=1.7Hz,1H),6.16(d,J=1.7Hz,1H),6.07(d,J=1.7Hz,1H),3.15(d,J=11.0Hz,1H),2.44-2.37(m,2H),2.15(d,J= 13C NMR(100MHz,CD3OD)δ 157.2,155.8,143.3,133.5,126.2,110.4,109.7,108.4,77.9,47.5,36.6,35.2,32.7,32.3,32.1,28.0,2 6.3,23.6,23.6,19.4,14.4;IR(neat)3383,2952,2924,2855,1621,1577,1423,1233,1181,1049,1036,835 HRMS (ES+) m / z C21H31O2[MH]+ calculated 315.2319, found 315.2319; Rf 0.21 (Et2O:pentane; 1:20) UV / KMnO4.

[0094] Example 6: Bioassay of Synthetic Cannabidiol (11) The biological activity of the synthesized cannabidiol (11, CBD) described herein, as assessed using TRPV channel activity, was shown to be identical to the cannabidiol reference standard, thus further confirming the identity of the synthesized cannabidiol (11, CBD).TRPV channels, including TRPV1, have been shown to mediate the effects of cannabinoids (H. Turner, D. Chueh, T. Ortiz, AJ Stokes and ALSmall-Howard, Therapeutics in Parkinson's Disease: Promise and Paradox, Journal of Herbs, Spices & Medicinal Plants, 2017, volume 23, 2017, pages 231-248) and (B. Costa, G. Giagnoni, C. Franke, A. E. Trovato and M. Colleoni, Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation, British Journal of Pharmacology, 2004, volume 143, pages 247-250) and capsaicin has also been shown to be useful as a reference standard (I. Diaz-Franulic, J. Caceres-Molina, RV Sepulveda, F. Gonzalez-Nilo, R. Latorre, Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1. Molecular Pharmacology, 2016, volume 90, pages 300-308). HEK 293 cells, which contain the TRPV1 channel, have been used as a model system (P. Geppetti and M. Trevisani, Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function, British Journal of Pharmacology, 2004, volume 141, pages 1313-1320). [Brief description of the drawings]

[0095] [Figure 1] The results shown in Figures 1A-1D indicate that samples of cannabidiol (11, CBD) synthesized by the process described herein and the reference standard cannabidiol (obtained from Sigma Aldrich) have the same "biological fingerprint" and dose response in the TRPV1 channel as shown using the following previously reported analytical method (JS Horton, T. Shiraishi, N. Alfulaij, ALS Small-Howard, HC Turner, T. Kurokawa, Y. Mori and AJ Stokes, TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure, Channels (Austin), 2019, volume 13, pages 1-16).

[0096] cell culture HEK TRexTRPV1 were cultured in DMEM, 10% fetal bovine serum, 2 mM L-glutamine, 10 μg / ml blastocyticin (Calbiochem, San Diego CA), 400 mg / ml zeocin (InvivoGen, San Diego CA) followed by induction of indicated transgene expression using 1 μg / ml tetracycline for 16–24 h. Comparisons were made to non-transfected HEK cells or induced or non-induced HEK TRexTRPV1.

[0097] Calcium assay Cells were washed and incubated with 0.2 μM Fluo-4

[54] for 30 min at 37 °C in standard modified Ringer's solution containing (in mM): NaCl 145, KCl 2.8, CsCl 10, CaCl2 10, MgCl2 2, glucose 10, Hepes·NaOH 10, pH 7.4, 330 mOsm. Cells were transferred to 96-well plates at 50,000 cells / well and stimulated as indicated. Calcium signals were acquired using a Flexstation3 (Molecular Devices, Sunnydale, USA). The data are analyzed according to the method in I. Diaz-Franulic, J. Caceres-Molina, RV Sepulveda, F. Gonzalez-Nilo, R. Latorre, Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1, Molecular Pharmacology, 2016, volume 90, pages 300-8.

[0098] Dose response and comparison in HEK-TRPV1 cells between cannabidiol (11, CBD) synthesized according to the described method (identified in Figures 1A-1D as "CBD, synthetic") and CBD obtained from Sigma (CAS number 13956-29-1, identified in Figures 1A-1D as "CBD, Sigma") are shown in Figures 1A-1D. A saline reference standard is identified in Figures 1A-1D as "NS."

[0099] All samples were run under identical conditions: Fluo-4 loaded cells in 1 mM external calcium chloride, 0-20 sec baseline, 20 sec compound addition (uM = micromolar). The present invention includes the following preferred embodiments. (1) 1. A process for the preparation of substantially pure product compounds of formula 1 and formula 2, or as enantiomers of a compound of formula 1 or formula 2, or as racemic mixtures of enantiomers of a compound of formula 1 or formula 2, comprising: [ka] During the ceremony, R 1 , H, C 1 ~C 6 Alkyl, (CH 2 ) n -C 3 ~C 6 Cycloalkyl, (CH 2 ) m -OR 3 is selected from the group consisting of R 2 , H, C 1 ~C 6 Alkyl, (CH 2 ) n -C 3 ~C 6 Cycloalkyl, (CH 2 ) m -OR 3 is selected from the group consisting of Each n is independently an integer selected from 0 to 2; each m is independently 1 or 2; R 3 H, CH 3 , C.H. 2 CH 3 , and C.H. 2 CH 2 CH 3 or CH(CH 3 ) 2 is selected from the group consisting of R A H and CO 2 H and its pharma- ceutically acceptable salts, CO 2 R C ,CONHR D , and CONR D R E is selected from the group consisting of R B , H, C 1 ~C 2 Linear or branched C optionally substituted with alkyl, one or two hydroxyl groups, one or more fluoro groups 3 ~C 10 Alkyl or double branched C 4 ~C 10 Alkyl, (CH 2 )o -C 3 ~C 6 Cycloalkyl, (CH 2 ) p -OR F 、C 1 ~C 8 C optionally substituted with alkyl 3 ~C 6 cycloalkyl; o is an integer selected from 0 to 6; p is an integer selected from 1 to 6; R C is C 1 ~C 6 Alkyl, (CH 2 ) q -C 3 ~C 6 selected from cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is an integer selected from 0 to 6; R D is C 1 ~C 6 Alkyl, (CH 2 ) r -C 3 ~C 6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is C 1 ~C 6 Alkyl, (CH 2 ) r -C 3 ~C 6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl, or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R F is C 1 ~C 6 Alkyl, (CH 2 ) r -C 3 ~C 6 cycloalkyl; Each r is independently an integer selected from 0 to 6; The process comprises: providing a first intermediate selected from the group consisting of compounds of formula 3 or formula 6,

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Claims

1. 1. A process for the preparation of substantially pure product compounds of formula 1 and formula 2, or as enantiomers of a compound of formula 1 or formula 2, or as racemic mixtures of enantiomers of a compound of formula 1 or formula 2, comprising: 【Chemistry 1】 During the ceremony, R １ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer selected from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , and C.H. ２ CH ２ CH ３ or CH (CH ３ ) ２ is selected from the group consisting of R Ａ is H, and CO ２ H and pharma- ceutically acceptable salts thereof, CO ２ R Ｃ , C.O.N.R. Ｄ , and CONR Ｄ R Ｅ is selected from the group consisting of R Ｂ is H, C １ ~C ２ Linear or branched C optionally substituted with alkyl, one or two hydroxyl groups, one or more fluoro groups ３ ~C １０ Alkyl or double branched C ４ ~C １０ Alkyl, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , and C １ ~C ８ C optionally substituted with alkyl ３ ~C ６ cycloalkyl; o is an integer selected from 0 to 6; p is an integer selected from 1 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; q is an integer selected from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR Ｄ R Ｅ is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl, and (CH ２ ) ｒ -C ３ ~C ６ cycloalkyl; each r is independently an integer selected from 0 to 6; The process comprises: providing a first intermediate selected from the group consisting of compounds of formula 3 and formula 6, 【Chemistry 2】 In the formula, R １ and / or R ２ [R ２ (CH ２ ) ｍ any hydroxyl group in is —OH is protected; To provide and The first intermediate, (a) reacting an acylating reagent R 2 in the presence of a first base 17 with a Lewis acid 18 selected from the group consisting of magnesium chloride, lithium chloride, and zinc chloride; Ｂ１ COY, where R Ｂ１ is R in which any hydroxyl group(s) are protected Ｂ The acylating reagent R Ｂ１ COY and (b) a palladium catalyst 19, optionally with additional ligands 20; (c) sequential treatment with silica or a second base 21, followed by a Bronsted or Lewis acid 22, or base alone, and optional deprotection to provide a second intermediate 4; 【Chemistry 3】 treating said second intermediate 4 under hydrolysis conditions with optional decarboxylation; or treating said second intermediate 4 under transesterification or amide forming conditions with optional deprotection as appropriate to provide said compound of formula 1; or R １ , R ２ (R ２ (CH ２ ) ｍ —OH), or R Ｂ wherein one or more of the hydroxyl groups in is protected, treating said second intermediate 4 with a Lewis acid 23 to provide intermediate 5; 【Chemistry 4】 hydrolyzing intermediate 5, with optional decarboxylation, or by transesterification, or by amide formation with optional deprotection, to provide a compound of formula 2; During the ceremony, Y is a halogen or R Ｂ COY is an alternative reactive electrophilic acylating reagent; Rα and Rβ are independently １ ~C ６ alkyl and optionally substituted aryl, or Rα and Rβ taken in combination are selected from the group consisting of (CH ２ ) ｓ Forming During the ceremony, The process wherein s is an integer selected from 4 to 6.

2. Y is a halide; Rα and Rβ are both methyl; the first base 17 is an amine or a heterocyclic amine; 2. The process of claim 1, wherein the silyl protecting groups, if present, are independently selected from the group consisting of t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl, and tri-iso-propylsilyl protecting groups.

3. The palladium catalyst 19 is derived from a palladium(II) complex in the presence of a phosphine as ligand 20, the second base 21 is selected from the group consisting of cesium acetate, cesium carbonate, and potassium carbonate; 2. The process of claim 1, wherein the Bronsted or Lewis acid 22, if used, is acetic acid or hydrogen chloride.

4. 2. The process of claim 1, wherein the Lewis acid 23 is a metal or metalloid derivative, or an inorganic solid, or is replaced by a Bronsted acid, or any combination such as a Lewis acid and a Bronsted acid, a Lewis acid and an inorganic solid, a Bronsted acid and an inorganic solid, or a Lewis acid, a Bronsted acid and an inorganic solid, and the hydroxyl protecting group(s), if present, is a silyl protecting group.

5. Y is chloride; the first base 17 is pyridine; the first Lewis acid 18 is magnesium chloride; The palladium catalyst 19 is tris(dibenzylideneacetone)dipalladium(0) [Pd ２ (dba) ３ ], 2. The process of claim 1, wherein the second base 21 is cesium acetate.

6. Y is chloride; the first base 17 is pyridine; 3. The process of claim 2, wherein the first Lewis acid 18 is magnesium chloride.

7. The palladium catalyst 19 is tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in the presence of tri-2-furylphosphine as ligand 20; 4. The process of claim 3, wherein the second base 21 is cesium acetate.

8. The product compound is a compound of formula 1, 【Chemistry 5】 During the ceremony, R １ is C ２ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ H, CO ２ H and pharma- ceutically acceptable salts thereof, CO ２ R Ｃ , C.O.N.R. Ｄ , and C.O.R. Ｄ R Ｅ is selected from the group consisting of R Ｂ is H, C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ Cycloalkyl, C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

9. The product compound is a compound of formula 1, 【Chemistry 6】 During the ceremony, R １ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is C ２ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ H, CO ２ H and pharma- ceutically acceptable salts thereof, CO ２ R Ｃ , C.O.N.R. Ｄ , and C.O.R. Ｄ R Ｅ is selected from the group consisting of R Ｂ is H or C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl, and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

10. The product compound is a compound of formula 1, 【Chemistry 7】 During the ceremony, R １ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ CONHR Ｄ or CONR Ｄ R Ｅ and R Ｂ is H or C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl, and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ Cycloalkyl, C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ Cycloalkyl, C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

11. The product compound is a compound of formula 2, 【Chemistry 8】 During the ceremony, R １ is C ２ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ H, CO ２ H and pharma- ceutically acceptable salts thereof, CO ２ R Ｃ , C.O.N.R. Ｄ , and C.O.R. Ｄ R Ｅ is selected from the group consisting of R Ｂ is H, C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl, and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each optionally substituted with one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

12. The product compound is a compound of formula 2, 【Chemistry 9】 R １ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is C ２ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ H, CO ２ H and pharma- ceutically acceptable salts thereof, CO ２ R Ｃ , C.O.N.R. Ｄ , and C.O.R. Ｄ R Ｅ is selected from the group consisting of R Ｂ is H, C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl, and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ Cycloalkyl, C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each optionally substituted with one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

13. The product compound is a compound of formula 2, 【Chemistry 10】 During the ceremony, R １ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of R ２ is H, C １ ~C ６ Alkyl, (CH ２ ) ｎ -C ３ ~C ６ Cycloalkyl, and (CH ２ ) ｍ -OR ３ is selected from the group consisting of each n is independently an integer from 0 to 2; each m is independently 1 or 2; R ３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , and CH(CH ３ ) ２ is selected from the group consisting of R Ａ CONHR Ｄ or CONR Ｄ R Ｅ and R Ｂ is H, C １ ~C ２ Alkyl, linear or branched C ３ ~C １０ Alkyl, and double branched C ４ ~C １０ alkyl, in each case optionally substituted by one or two hydroxyl groups, or one or more fluoro groups, (CH ２ ) ｏ -C ３ ~C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ ~C ６ Optionally substituted by cycloalkyl or C １ ~C ８ is optionally substituted with alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; R Ｃ is C １ ~C ６ Alkyl, (CH ２ ) ｑ -C ３ ~C ６ Cycloalkyl, C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; q is an integer from 0 to 6; R Ｄ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ is selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; and R Ｅ is C １ ~C ６ Alkyl, (CH ２ ) ｒ -C ３ ~C ６ selected from the group consisting of cycloalkyl, allyl, benzyl, substituted benzyl, and 2-phenylethyl; N.R. Ｄ R Ｅ is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted by one or two hydroxyl or hydroxymethyl groups, with the proviso that said hydroxyl groups cannot be present on a carbon bearing a heterocyclic nitrogen or a heterocyclic oxygen with morpholine; R Ｆ is C １ ~C ６ Alkyl or (CH ２ ) ｒ -C ３ ~C ６ is cycloalkyl, 2. The process of claim 1, wherein each r is independently an integer from 0 to 6.

14. 2. The process of claim 1, wherein the product compound of formula 1 or 2 is selected from the group consisting of: 【Chemistry 11】

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