Novel cannabinoids and cannabinoid acids and derivatives thereof

Abstract

The present invention relates to novel cannabinoids 1 and 2 synthesized from simple starting materials using a cascade sequence of allylic rearrangement, aromatization, and further cyclization that is highly stereoselective and regioselective for tetracyclic cannabinoids. The synthesized cannabinoids can be obtained more easily at a higher purity level than cannabinoids isolated or synthesized by known methods. Cannabinoid 2 is obtained containing very low levels of unwanted isomer cannabinoids, such as Δ8-tetrahydrocannabinol. While they are easily synthesized by the new methodology, analogs with modifications of aromatic ring substituents would be much more difficult to produce from any of the components of cannabis oil. Novel compounds of formulas 3, 4, 5, and 6 are disclosed as intermediates for the synthesis of cannabinoids of formulas 1 and 2.

Description

Technology Field

[0001] The field of the present invention relates to the construction of an aromatic core from simple and inexpensive starting materials, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 The invention relates to methods for synthesizing known novel cannabinoids of high purity, including but not limited to ) and other naturally occurring cannabinoids and other synthetic analogs. The field of the invention further comprises novel cannabinoids that can be used alone as an active compound in a drug formulation or mixed in combination with known cannabinoids and / or other drugs 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, treatment of cancer, inflammation and immune inflammation-related diseases, glaucoma, dry eye, corneal injury or disease and retinal degeneration or disease, immune inflammatory disorders, lung injury or disease, liver injury or disease, kidney injury or disease, pancreatitis and pancreatic disorders, cardiovascular injury or disease, and reduction of organ transplants, particularly postoperative inflammation among other diseases, antioxidants, and reduction of indications. Background Technology

[0002] Cannabis ("marijuana") is a fairly notorious plant, and especially cannabis ( Cannabis sativaIt is a plant used for various purposes. Marijuana is used globally as a recreational drug and has been the subject of high interest and legal review in many countries around the world. There has been significant interest, even to the extent that the plant and its extracts have been used as folk medicine for thousands of years, citing Herodotus (Herodotus, The Histories, Book IV, page 295, Penguin Books, Ltd., Middlesex (1972)). The plant and its extracts have been used in medicine for their effects as hypnotics, anti-anxiety agents, and modulators of inflammation and immune inflammation for pain, including cancer pain, general pain, and neuropathic pain; as antispasmodics to combat side effects of cancer chemotherapy, including nausea; in the treatment of glaucoma and epilepsy; and as appetite stimulants, particularly for AIDS patients among other users.

[0003] There are over 60 constituent compounds isolated and characterized from hemp oil (e.g., SA Ahmed, SA Ross, D. Slade, MM Radwan, F. Zulfiqar and MA ElSohly "Cannabinoid Ester Constituents from High-Potency Cannabis sativa ", Journal of Natural Products (See , 2008, volume 71, pages 536-542 and its references). In addition, a significant number of the above-mentioned natural products and analogs have been prepared through total synthesis from aromatic and monoterpene precursor compounds. Such total synthesis is reported (e.g., see below: 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, N.Y.: Wiley and Sons; J.W. Huffman and J.A.H. 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 N Ar Cyclization" Organic Letters , 2013, volume 15, pages 764-767; P.R. Nandaluru and G.J. Bodwell, "Multicomponent Synthesis of 6 H -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, BR Martin, ME Abood, I. Beletskaya and RK Razdan, “Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors”, Journal of Medicinal Chemistry , 2000, volume 43, pages 3778-3785; SP Nikas, SO Alapafuja, I. Papanastasiou, CA Paronis, VG Shukla, DP Papahatjis, AL Bowman, A. Halikhedkar, (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist", Journal of Medicinal Chemistry , 2010, volume 53, pages 6996-7010).

[0004] Over the past 20 years, it has become clear that cannabinoids have entered a renaissance for various biomedical uses. The pharmacology of cannabinoids involves cannabinoid receptors, GPCR receptors, serotonin receptors, and various voltage-dependent channels (Ca 2+ , Na + , and various types of K +It has been shown to be associated with numerous receptors and mechanisms, including the regulation of (including channels), ligand-gated ion channels (i.e., GABA, glycine, and TRPV), Toll-like receptors, opioid receptors, NMDA or excitatory amino acid receptors, catecholamine receptors, enzymes regulating endocannabinoids, and ion transport membrane proteins, such as 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). Therefore, it would be helpful to have new drugs or drugs containing one or more cannabinoids to treat diseases known to affect or utilize the above physiological mechanisms.

[0005] Many studies on cannabinoids have considered that their actions pertain to numerous indications, including direct or indirect receptor-mediated effects by two G protein-coupled receptors called CB1 and CB2, which share 44% sequence homology in humans. The aforementioned CB1 subtype is the most widely expressed G protein-coupled receptor in the brain, controlling, for example, movement, emotional, cognitive, and sensory responses, pain perception, and thermoregulation, as well as cardiovascular, gastrointestinal, and respiratory physiology. It is localized to the central (CNS) and peripheral nervous systems, including the olfactory bulb, cortical regions, basal ganglia, thalamus, hypothalamus, cerebellar cortex, brainstem, and spinal cord. CB1 receptors also occur in cells of the pituitary gland and thyroid, as well as in some fat, muscle, and liver cells, and in the lungs and kidneys. The above-mentioned subtype of CB2 is expressed in immune and hematopoietic cells, osteoclasts, and osteoblasts, mediates the response of the immune system, regulates inflammation, and modulates bone remodeling as well as inflammation and neuropathic pain. Therefore, it would be helpful to have new agents or drugs for treating diseases known to be treatable by affecting physiological pathways containing one or more cannabinoids to prevent, treat, or cure one or more inflammation-mediated diseases or conditions from the group consisting of the central or peripheral nervous system, cardiovascular-renal system, skin, gastrointestinal system, pulmonary-respiratory system, endocrine system, joints, musculoskeletal system, blood or lymphatic system, genitourinary system, eyes, and ears in individuals or animals requiring treatment, or to prevent, treat, or cure one or more of anorexia, arthritis, cancer, pain, glaucoma, migraine, persistent muscle spasms, and seizures.

[0006] The pharmacology of CB1 and CB2 receptor modulators has been reviewed, for example, by Vemuri and Makriyannis (V.K. Vemuri and A. Makriyannis, "Medicinal Chemistry of Cannabinoids", Clinical Pharmacology & Therapeutics, 2015, volume 97, pages 553-558). Δ 9 -Tetrahydrocannabinol( 7 ) as well as its major metabolite, 11-hydroxy-Δ 9 -Tetrahydrocannabinol( 8 The psychotropic effects of ) are mediated by the partial action of CNS CB1 receptors (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 CB1 and CB2 receptor 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 for the treatment of anorexia in AIDS patients. Other CB1 receptor modulators are tetrahydrocannabivarin ( 9 )(antibody) and cannabinol ( 10 It contains )(weak agent) and both are weak CB2 agonists. Non-psychotropic (-)-cannabidiol ( 11 ) and cannabidivarin (12 Neither of them significantly interacts with one of the receptor subclasses, and their mode of action is less clear (J. Fern ndez-Ruiz, O. Sagredo, M. R. Pazos, C. Garc. a, R. Pertwee, R. Mechoulam, J. Mart. nez-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.P. hn, C. Kolmanz, C. N. 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 The combination of ) (Sativex, Nabiximols) is used to treat spasticity associated with multiple sclerosis and as a potent analgesic for patients with advanced cancer. More recently, purified cannabidiol ( 11It is also recognized as a rare drug for the treatment of epilepsy. CB1 receptor antagonists are appetite suppressants that improve cognitive abilities and control addictive behaviors. Selective CB2 agonists can provide excellent analgesics and immunomodulators that do not have the undesirable psychotropic effects associated with CNS CB1 action. Δ 9 -Tetrahydrocannabinol( 7 Dronabinol has been shown to be clinically effective in treating chemotherapy-induced nausea and vomiting in cancer patients as monotherapy or in combination with ondansetron (Zofran, a 5-HT3 antagonist) and prochlorperazine (a dopamine D2 receptor antagonist) (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).

[0007]

[0008]

[0009] Cannabinoids used as therapeutic agents are currently obtained from fractionation methods of cannabis or cannabis oil, or generally from complete synthesis from aromatic and terpene starting materials. Because cannabis and its oil contain over 60 natural products, such fractionation methods require extensive chromatographic purification to provide any individual component in a substantially pure manner, and regenerative production and storage are difficult due to the large number of components. In relation to the aforementioned patent application, "substantially pure" means chemically (constitutively, diastereomericly, and enantiomerically) pure by more than 99% and additionally not contaminated by any pesticides, including herbicides, fungicides, insecticides, or any pathogens that may be associated with cannabinoids isolated from plant-derived cannabis oil from plants. From other cannabis components, in particular Δ, an isomer thereof 8 -Δ from tetrahydrocannabinol 9 -Tetrahydrocannabinol( 7Purification of ) is inefficient and costly. In addition, because many cannabinoids in cannabis oil have different effects as complete, partial, inverse, or neutral agonists or antagonists of one or both of CB1 and CB2 receptors, it is particularly important that the established specifications are efficiently reproducible without the individually isolated natural products containing any other natural cannabinoid products with unwanted biological effects at a significant level (parts per million level). There is another complex problem in that many natural cannabinoid products are generally obtained as oils that are not crystallizable, are susceptible to oxidative degradation in air, and are difficult to separate extensively, expensively, and difficult to scale up for chromatography and / or derivatization (e.g., B. Trawick and MH Owens, "Process for the Preparation of (-)-delta 9-Tetrahydrocannabinol", WO 2009 / 099868 Al; E. Arslantas and U. Weigl, "Method for Obtaining Pure Tetrahydrocannabinol", US Patent 7,923,558 B2; J.E. Field, J. Oudenes, B. Gorin, R. Orprecio, FE. Silva e. Souza, NJ. Ramjit and E.-L. Moore, "Separation of Tetrahydrocannabinols", US Patent 7,321,047 B2; P. Bhatarah, K.J. Batchelor, D. McHattie and AK Greenwood, “Delta 9 Tetrahydrocannabinol Derivatives”, WO 2008 / 099183 Al; 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", US Patent 7,674,922 B2). Second, many synthetic routes for producing cannabinoids are uneconomical for large-scale use due to the use of expensive reagents or 5- under acidic reaction conditions. n It depends on the condensation reaction of monoterpene starting materials with derivatives of alkyl-resorcinols, such as pentyl-resorcinol (olivetol), reactions that frequently generate byproducts derived from carbenium ion rearrangement reactions, and / or side reactions. For example, Δ by Brønsted or Lewis acid-catalyzed condensation reactions from olivetol and monoterpenes 9 -Tetrahydrocannabinol( 7 The production of ) involves, among other impurities, particularly its isomer Δ 8 - It becomes complicated due to the co-formation of tetrahydrocannabinol. The aforementioned impurities also significantly increase the cost and complicate the process of obtaining substantially pure cannabinoid active pharmaceutical ingredients (e.g., see 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", US Patent Application 2010 / 0298579 Al; RJ Kupper, "Cannabinoid Active Pharmaceutical Ingredient for Improved Dosage Forms", WO 2006 / 133941 A2; J. Erler, and S. Heitner, “Methods for the Preparation of Dronabinol”, US Patent 8,324,408 B2; trans-(-)-Δ 9 -Tetrahydrocannabinol and trans-(+)-Δ 9 -Tetrahydrocannabinol", US Patent 9,278,083 B2). The present invention not only overcomes the above problems but also provides efficient / reproducible manufacturing routes for known cannabinoids, thereby providing flexible synthesis of novel cannabinoids that can be used alone as an active compound in a drug formulation or mixed in combination with known cannabinoids and / or other drugs to treat diseases related to immune inflammation, particularly pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, and other diseases.

[0010] Among the advantages and improvements disclosed herein, other purposes and advantages of the disclosed embodiments will become apparent from the following, wherein the same numbers indicate the same parts throughout the drawings. Detailed embodiments of cannabinoid compounds, intermediate compounds, and processes for manufacturing cannabinoid and cannabinoid mimic compounds and their intermediates are disclosed. However, it should be understood that the disclosed embodiments are merely examples of the invention which may be embodied in various forms. Furthermore, each example given in connection with various embodiments of the invention is intended to be illustrative and not limiting.

[0011] Throughout the specification and claims, the following terms have the expressly associated meanings as used herein unless the context clearly indicates otherwise. The phrases “in some embodiments” and “in some embodiments” as used herein do not necessarily refer to the same embodiment(s), but may refer to them. The phrases “in other embodiments” and “in some other embodiments” as used herein do not necessarily refer to different embodiments, but may refer to them. Accordingly, as described below, various embodiments can be easily combined without departing from the scope or spirit of the invention.

[0012] Additionally, as used herein, the term "or" is an inclusive "or" operator and corresponds to the term "and / or" unless otherwise specified in the context. The term "based on" is not exclusive and may be based on additional elements not described unless otherwise specified in the context. Furthermore, throughout the specification, "a," "an," and "the" include plural meanings. The meaning of "inside" includes "inside" and "on."

[0013] Additionally, “substantial,” “substantially,” “similar,” “similarly,” “likely,” “similarly,” “approximately,” “approximately,” and combinations thereof indicate that the difference between the features or characteristics being compared is less than 25% of the respective value / size at which the features or characteristics being compared are measured or defined.

[0014] As used herein, the term “substituted benzyl” means a benzyl ring having one, two, or three independently changed C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl groups at an aromatic ring position, or comprising one or two independently changed C1-C4 alkyl groups in benzyl methylene.

[0015] As used herein, the term “optionally substituted aryl” means a phenyl ring optionally comprising one, two, or three independently modified C1-C4 alkyl, C1-C4 alkyloxy, fluoro, or chloro groups.

[0016] Unless otherwise defined herein, the term “substituted” means optionally substituted with a C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl group at any position.

[0017] The present invention relates to a precursor 3 or 6 , or 3 and 6 intermediate from a mixture 4 Through, as a racemic modification, or as a specific enantiomer shown below, or 1 or 2 As a mirror image isomer of Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogs, from simple and inexpensive starting materials, allylic site rearrangement, aromatization, and tetracyclic cannabinoids 2 For this purpose, using a highly stereoselective and regioselective additional cyclization cascade sequence to remove unwanted Δ 8 -Δ where isomers are generally absent 9 - Cannabinoid 2 Various announced new cannabinoids that generate 1 and 2 This concerns a process for manufacturing.

[0018]

[0019]

[0020]

[0021] In the above chemical formula:

[0022] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0023] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0024] N is independently 0, 1, or 2;

[0025] m is independently 1 or 2 and;

[0026] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0027] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C, CONHR D , CONR D R E And;

[0028] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0029] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0030] p is 1, 2, 3, 4, 5 or 6 and;

[0031] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0032] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0033] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0034] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0035] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0036] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s (s is 4, 5 or 6) and Rα and Rβ are preferably both methyl.

[0037] The present invention also relates to monoterpene starting materials 13 1,3-dioxandion of 14 As a racemic modification from a reaction with, or as a mixture of unequal proportions of two enantiomers, or the specific enantiomers shown below or 3 As a mirror image isomer of the chemical formula 3 This relates to a related process for the manufacture of intermediates,

[0038]

[0039]

[0040] In the above chemical formula:

[0041] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0042] R 2 is H, C1 to C6 alkyl, (CH2) n-C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0043] n is independently 0, 1, or 2 and;

[0044] m is independently 1 or 2 and;

[0045] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0046] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0047] Rγ is H, C1 to C6 alkyl and Rδ is an optionally substituted aryl;

[0048] s is 4, 5, or 6.

[0049] The present invention also relates to monoterpene starting materials 15 1,3-dioxandion of 14 As a racemic modification from a reaction with, or as a mixture of unequal proportions of two enantiomers, or the specific enantiomers shown below or 6 As a mirror image isomer of the chemical formula 6 This relates to a related process for the manufacture of intermediates,

[0050]

[0051]

[0052] In the above chemical formula:

[0053] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0054] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2)m -OR 3 And;

[0055] n is independently 0, 1, or 2 and;

[0056] m is independently 1 or 2 and;

[0057] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0058] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0059] Rγ is H, C1 to C6 alkyl and Rδ is an optionally substituted aryl;

[0060] s is 4, 5, or 6.

[0061] The above synthesis methods are suitable for large-scale use and manufacturing purposes. Examples of available known cannabinoids using the above synthesis routes are cannabidiol ( 11 ), cannabidivarine ( 12 ), Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ) and Navilone( 16 These are compounds related to ).

[0062]

[0063]

[0064] The above synthesis methods are also suitable for the synthesis of novel cannabinoids, and said compounds are also part of the present invention. Cannabidiol ( 11 ) and cannabidivarin ( 12 The following cannabinoids, which are novel analogues of ) 1 The cannabinoid is also available by the synthetic routes described herein and is part of the invention. 1 has the following chemical formula:

[0065]

[0066] In the above chemical formula:

[0067] R 1 H, C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0068] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0069] n is independently 0, 1, or 2 and;

[0070] m is independently 1 or 2 and;

[0071] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0072] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0073] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0074] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0075] p is 1, 2, 3, 4, 5 or 6 and;

[0076] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0077] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0078] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0079] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0080] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0081] The above limited chemical formula 1 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, 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, particularly more than other diseases, Δ9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 1 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration or other known clinical administration methods.

[0082] Cannabidiol 11 ), cannabidivarine( 12 The following cannabinoids, which are also novel analogues of ) 1 The cannabinoid is also available by the synthetic routes described herein and is part of the invention. 1 has the following chemical formula:

[0083]

[0084] In the above chemical formula:

[0085] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR3 And;

[0086] R 2 is a C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0087] n is independently 0, 1, or 2 and;

[0088] m is independently 1 or 2 and;

[0089] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0090] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0091] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0092] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0093] p is 1, 2, 3, 4, 5 or 6 and;

[0094] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0095] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0096] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0097] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0098] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0099] The above limited chemical formula 1 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 1 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration or other known clinical administration methods.

[0100] Cannabidiol 11 ), cannabidivarine( 12 The following cannabinoids, which are novel analogues of ) 1 The cannabinoid is also available by the synthetic routes described herein and is part of the invention. 1 has the following chemical formula:

[0101]

[0102] In the above chemical formula:

[0103] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0104] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0105] n is independently 0, 1, or 2 and;

[0106] m is independently 1 or 2 and;

[0107] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0108] R A CONHR D , CONR D R E And;

[0109] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0110] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0111] p is 1, 2, 3, 4, 5 or 6 and;

[0112] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0113] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0114] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2)r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that the hydroxyl group cannot be on a carbon containing a heterocyclic nitrogen or a heterocyclic oxygen having morpholin;

[0115] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0116] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0117] The above limited chemical formula 1 The aforementioned novel cannabinoid having Δ is used as an active compound, either alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, nausea, epilepsy, Alzheimer's brain injury / concussion, cancer, glaucoma, eye injury or disease including dry eyes and retinal degeneration, immune inflammatory disorders, pain, side effects of chemotherapy, anxiety, lung injury or disease, liver injury or disease, kidney injury or disease, particularly more than other diseases. 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 1 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, topical, rectal, or parenteral drug administration or other known clinical administration methods.

[0118] The following deoxynon derivatives that are intermediates for the synthesis of cannabinoids 3 is also available by the synthetic routes described herein and is part of the present invention. The deoxynon derivative 3 has the following chemical formula:

[0119]

[0120] In the above chemical formula:

[0121] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0122] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0123] n is independently 0, 1, or 2 and;

[0124] m is independently 1 or 2 and;

[0125] R 3 is a hydroxyl protecting group, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0126] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0127] s is 4, 5, or 6.

[0128] The following deoxynon resorcylate derivatives, which are intermediates for the synthesis of cannabinoids 4 is also available by the synthetic routes described herein and is part of the invention. The deoxynon derivative 4 has the following chemical formula:

[0129]

[0130] In the above chemical formula:

[0131] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0132] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0133] n is independently 0, 1, or 2 and;

[0134] m is independently 1 or 2 and;

[0135] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0136] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o-C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0137] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0138] p is 1, 2, 3, 4, 5 or 6 and;

[0139] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0140] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0141] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0142] s is 4, 5, or 6.

[0143] Δ 9 -Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are novel analogues of ) 2 is also available by the synthetic routes described herein and is part of the invention. The cannabinoid 2 has the following chemical formula:

[0144]

[0145] In the above chemical formula:

[0146] R 1 H, C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0147] R 2 is H, C1 to C6 alkyl, (CH2) n-C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0148] n is independently 0, 1, or 2 and;

[0149] m is independently 1 or 2 and;

[0150] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0151] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0152] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0153] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0154] p is 1, 2, 3, 4, 5 or 6 and;

[0155] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0156] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0157] R D is a C1 to C6 alkyl, (CH2)r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0158] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0159] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0160] The above limited chemical formula 2 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, nausea, epilepsy, Alzheimer's disease and neurodegenerative diseases, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral transdermal drug administration or other known clinical administration methods.

[0161] Δ 9 -Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are novel analogues of ) 2 is also available by the synthetic routes described herein and is part of the invention. The cannabinoid 2 has the following chemical formula:

[0162]

[0163] In the above chemical formula:

[0164] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0165] R 2 is a C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0166] n is independently 0, 1, or 2 and;

[0167] m is independently 1 or 2 and;

[0168] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0169] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0170] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0171] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0172] p is 1, 2, 3, 4, 5 or 6 and;

[0173] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0174] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0175] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r-C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NRDRE is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0176] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0177] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0178] The above limited chemical formula 2 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone(16 It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral transdermal drug administration or other known clinical administration methods.

[0179] Δ 9 -Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are also novel analogues of ) 2 is also available by the synthetic routes described herein and is part of the invention. The cannabinoid 2 has the following chemical formula:

[0180]

[0181] In the above chemical formula:

[0182] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0183] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0184] n is independently 0, 1, or 2 and;

[0185] m is independently 1 or 2 and;

[0186] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0187] R A CONHRD , CONR D R E And;

[0188] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0189] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0190] p is 1, 2, 3, 4, 5 or 6 and;

[0191] R C is a C1 to C6 alkyl, (CH2) q -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0192] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0193] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0194] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0195] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0196] The above limited chemical formula 2 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, nausea, epilepsy, Alzheimer's disease and neurodegenerative diseases, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient in combination with ) and / or other drugs. The formulations contain pharmaceutically acceptable diluents and excipients in addition to the active cannabinoid or the cannabinoid and / or other drugs in the combination therapy. The aforementioned pharmaceutical compositions may be administered to a patient by enteral, sublingual, intranasal, inhalation, rectal, or parenteral drug administration or other known clinical administration methods.

[0197] The following deoxynon resorcylate derivatives, which are intermediates for the synthesis of cannabinoids 5 is also available by the synthetic routes described herein and is part of the invention. The deoxynon derivative 5 has the following chemical formula:

[0198]

[0199] In the above chemical formula:

[0200] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0201] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0202] n is independently 0, 1, or 2 and;

[0203] m is independently 1 or 2 and;

[0204] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0205] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0206] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0207] p is 1, 2, 3, 4, 5 or 6 and;

[0208] R F is a C1 to C6 alkyl, (CH2) n - It is a C3 to C6 cycloalkyl;

[0209] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0210] s is 4, 5, or 6.

[0211] The following deoxynon derivatives that are intermediates for the synthesis of cannabinoids 6 is also available by the synthetic routes described herein and is part of the present invention. The deoxynon derivative 6 has the following chemical formula:

[0212]

[0213] In the above chemical formula:

[0214] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0215] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR3 And;

[0216] n is independently 0, 1, or 2 and;

[0217] m is independently 1 or 2 and;

[0218] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0219] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0220] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0221] p is 1, 2, 3, 4, 5 or 6 and;

[0222] R F is a C1 to C6 alkyl, (CH2) n - It is a C3 to C6 cycloalkyl;

[0223] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0224] s is 4, 5, or 6. Specific details for implementing the invention

[0225] The present invention is a racemic modification, or a specific enantiomer shown below, or 1 or 2 As a mirror image isomer of Δ 9 -Tetrahydrocannabinol(7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogs, from simple and inexpensive starting materials, allylic site rearrangement, aromatization, and tetracyclic cannabinoids 2 For this purpose, using a highly stereoselective and regioselective additional cyclization cascade sequence to remove unwanted Δ 8 -Δ where isomers are generally absent 9 - Cannabinoid 2 Various announced new cannabinoids that generate 1 and 2 The present invention relates to a process for manufacturing [a specific compound]. The present invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph.

[0226]

[0227] In the above chemical formula:

[0228] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0229] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0230] n is independently 0, 1, or 2 and;

[0231] m is independently 1 or 2 and;

[0232] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0233] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0234] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0235] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0236] p is 1, 2, 3, 4, 5 or 6 and;

[0237] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0238] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0239] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0240] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0241] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0242] The above process is:

[0243] The following chemical formula 3 As a step of processing the first intermediate of, R 1 and / or R 2 [R 2 is (CH2) m Any hydroxyl group of [-OH] is (1) R B Any hydroxyl group or group in the first weak base 17 in the presence of and / or Lewis Mountain 18 Acylation reagent R protected in the presence of B COY, (2) Optional additional ligands 20 Palladium catalyst having 19 , and (3) silica or a substitute equivalent solid reagent or a second drug base 21 Later on, Bronstead or Lewis Mountain 22 , or a weak base alone, e.g., cesium acetate and sequentially protected by selective deprotection to form a second intermediate 4 Providing, and the above 4 by appropriately secondarily hydrolyzing by selective decarboxylation, by ester exchange, or by amide formation having selective deprotection 1 Includes a step of obtaining;

[0244] In the above chemical formula:

[0245] Y is a halogen, preferably chlorine, or R B COY is an alternative reactive electrophilic acylating agent;

[0246] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s (s is 4, 5, or 6) and Rα and Rβ are preferably both methyl;

[0247] The above first weak base 17 is an amine or heterocyclic amine, e.g., pyridine;

[0248] The above Lewis acid 18 It is preferably magnesium chloride;

[0249] The above palladium catalyst 19 is derived from a palladium (II) precatalyst or a palladium (O) catalyst itself, and the optional additional ligands 20 It comprises one or more phosphines or diphosphines or equivalents thereof, but is not limited thereto, and preferably the palladium catalyst 19 and the above ligands 20 Specifically, it is a phosphine complex of palladium (0) in the presence of triarylphosphine or triheteroarylphosphine, particularly tri-2-furylphosphine, e.g., tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0) [Pd2(dba)3], but is not limited thereto;

[0250] The above second drug base 21 is cesium acetate or cesium carbonate or potassium carbonate;

[0251] The aforementioned Bronstead or Lewis Mountain 22 is, when used, acetic acid or hydrogen chloride, and

[0252] Here:

[0253] Optional hydroxyl protectors or groups are cylindrical protectors;

[0254] The above optional hydroxyl protecting groups or groups are preferably independently t -butyldimethylsilyl, thihexyldimethylsilyl, t -butyldiphenylsilyl or tri- Iso - It is a propylsilyl protector.

[0255] Protective devices are generally known to those skilled in the art and are described in textbooks such as Greene and Wuts (PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0256] Amid formation is caused by the activation of carboxylic acids, for example N - This is carried out by the formation of hydroxysuccinimide esters and coupling with corresponding amines, see, for example, 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 are dicyclohexyl carbodiimide (DCC), di- Iso -Propyl carbodiimide (DIC), O -(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) are included, but not limited to (E. Valeur and M. Bradley, "Amide bond formation: beyond the myth of coupling reagents", Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0257]

[0258] The present invention also relates to a racemic modification, or to a specific enantiomer shown below, or 1 or 2 As a mirror image isomer of Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 Various known novel cannabinoids using a cascade sequence of allylic site rearrangement, aromatization, and further cyclization for tetracyclic cannabinoids from simple and inexpensive starting materials, including ) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogs. 1 and 2 The present invention relates to a related process for manufacturing [a specific substance]. The present invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph.

[0259]

[0260] In the above chemical formula:

[0261] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2)m -OR 3 And;

[0262] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0263] n is independently 0, 1, or 2 and;

[0264] m is independently 1 or 2 and;

[0265] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0266] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0267] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0268] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0269] p is 1, 2, 3, 4, 5 or 6 and;

[0270] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0271] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0272] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0273] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0274] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0275] The above process is:

[0276] The following chemical formula 6 As a step of processing the first intermediate of, R 1 and / or R 2 [R 2 is (CH2) m Any hydroxyl group of [-OH] is (1) R B Any hydroxyl group or group in the first weak base 17 in the presence of and / or Lewis Mountain 18 Acylation reagent R protected in the presence of B COY, (2) Optional additional ligands 20 Palladium catalyst having 19 , and (3) silica or a substitute equivalent solid reagent or a second drug base 21Later on, Bronstead or Lewis Mountain 22 , or a weak base alone, e.g., cesium acetate and sequentially protected by selective deprotection to form a second intermediate 4 Providing, and the above 4 by appropriately secondarily hydrolyzing by selective decarboxylation, by ester exchange, or by amide formation having selective deprotection 1 Includes a step of obtaining;

[0277] In the above chemical formula:

[0278] Y is a halogen, preferably chlorine, or R B COY is an alternative reactive electrophilic acylating agent;

[0279] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s (s is 4, 5, or 6) and Rα and Rβ are preferably both methyl;

[0280] The above first weak base 17 is an amine or heterocyclic amine, e.g., pyridine;

[0281] The above Lewis acid 18 It is preferably magnesium chloride;

[0282] The above palladium catalyst 19 is derived from a palladium (II) precatalyst or a palladium (O) catalyst itself, and the optional additional ligands 20 It comprises one or more phosphines or diphosphines or equivalents thereof, but is not limited thereto, and preferably the palladium catalyst 19 and the above ligands 20Specifically, it is a phosphine complex of palladium (0) in the presence of triarylphosphine or triheteroarylphosphine, particularly tri-2-furylphosphine, e.g., tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0) [Pd2(dba)3], but is not limited thereto;

[0283] The above second drug base 21 is cesium acetate or cesium carbonate or potassium carbonate;

[0284] The aforementioned Bronstead or Lewis Mountain 22 is, when used, acetic acid or hydrogen chloride, and

[0285] Here:

[0286] Optional hydroxyl protectors or groups are cylindrical protectors;

[0287] The above optional hydroxyl protecting groups or groups are preferably independently t -butyldimethylsilyl, thihexyldimethylsilyl, t -butyldiphenylsilyl or tri- Iso - It is a propylsilyl protector.

[0288]

[0289] Protective devices are generally known to those skilled in the art and are described in textbooks such as Greene and Wuts (PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0290] What is particularly interesting in the present invention is the above intermediate 4 According to the method of linking terpene units to an aromatic ring, the position of the alkene unit on the cyclohexene ring unit as a result of the π-allyl-palladium-mediated step is the structure 4As described in [reference], it is ensured that formation occurs site-specifically and that other isomers are not formed to any significant degree (for a discussion regarding the relevant mechanism, see below: R. Cookson, TN Barrett and AGM 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).

[0291] Amid formation is caused by the activation of carboxylic acids, for example N - This is carried out by the formation of hydroxysuccinimide esters and coupling with corresponding amines, see, for example, 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 are dicyclohexyl carbodiimide (DCC), di- Iso -Propyl carbodiimide (DIC), O -(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) are included, but not limited to (E. Valeur and M. Bradley, "Amide bond formation: beyond the myth of coupling reagents", Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0292] The present invention also relates to a racemic modification, or to a specific enantiomer shown below, or 1 or 2 As a mirror image isomer of Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol (11), cannabidivarin ( 12 Novel intermediates including ) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogs 3 and 6 Resorcylate derivatives formed from mixtures of simple and inexpensive starting materials using a cascade sequence of allylic site rearrangement, aromatization, and further cyclization for tetracyclic cannabinoids. 4 Various announced new cannabinoids that generate 1 and 2 This concerns the related process for manufacturing.

[0293] It should be noted that in the above synthesis, some intermediates may exist as keto- and enol tautomeric isomers. Describing the structure in the keto form also includes the corresponding enol form, which includes a mixture containing both the keto and enol forms. Additionally, describing the structure in the enol form also includes the corresponding keto form, which includes a mixture containing both the keto and enol forms. For example, the intermediate 3 and 6 For reasons of simplicity, its structure is depicted in the keto form, but exists as a mixture of both keto and enol forms. Additionally, it should be noted that while the structure is depicted as a specific stereoisomer and enantiomer, the present invention also includes enantiomer compounds, racemic compounds, and mixtures of unequal proportions of the two enantiomers. Furthermore, the present invention also includes structurally feasible diastereomers. The present invention comprises synthesizing the target cannabinoid as an oil or crystalline derivative, appropriately including solvates, hydrates, and polymorphs.

[0294] The present invention also relates to a racemic modification or as a mixture of unequal proportions of two enantiomers, or to a specific enantiomer as shown below or 2 As a mirror image isomer of, the following chemical formula 2 This relates to a related process for the manufacture of various cannabinoids.

[0295]

[0296] In the above chemical formula:

[0297] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0298] R 2 is H, C1 to C6 alkyl, (CH2) n-C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0299] n is independently 0, 1, or 2 and;

[0300] m is independently 1 or 2 and;

[0301] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0302] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0303] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, (CH2) p -OR F , optionally substituted with C3 to C6 cycloalkyl groups optionally substituted with C1 to C8 alkyl groups;

[0304] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0305] p is 1, 2, 3, 4, 5 or 6 and;

[0306] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0307] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0308] R Dis a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0309] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0310] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0311] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0312] s is 4, 5, or 6;

[0313] The above process is:

[0314] The following chemical formula 4 The first intermediate or cannabinoid of 1 As a step for processing, R 1 , R 2 [R 2 is (CH2) m -OH] and / or R B Any hydroxyl group or group of (1) Lewis acid 23 Protected by, and an intermediate generated as a result 5by appropriately secondarily treating by hydrolysis having selective decarboxylation, by ester exchange, or by amide formation having selective deprotection 2 Includes a step of obtaining;

[0315]

[0316] In the above step:

[0317] Rα and Rβ are both preferably methyl;

[0318] The aforementioned Lewis Mountain 23 A derivative of a metal or metalloid, e.g. 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, e.g., zeolite or equivalent, or a Brønsted acid, e.g. but not limited to methanesulfonic acid, 4-toluenesulfonic acid or hydrogen chloride, or said Lewis acid and Brønsted acid, Lewis acid and inorganic solid; replaced by a Brønsted acid and an inorganic solid or any combination of a Lewis acid, Brønsted acid and an inorganic solid;

[0319] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of boron(III), such as boron trifluoride or boron trifluoride etherate;

[0320] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of aluminum(III), such as aluminum chloride, ethylaluminum dichloride, or diethylaluminum chloride;

[0321] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of zinc(II), such as zinc chloride or zinc bromide;

[0322] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of tin(IV), e.g., tin chloride;

[0323] The aforementioned Lewis Mountain 23 Alternatively, derivatives of titanium(IV), such as titanium tetrachloride or titanium trichloride Iso - It is propoxytitanium;

[0324] The aforementioned Lewis Mountain 23 Alternatively, it is a derivative of zirconium(IV), e.g., zirconium tetrachloride;

[0325] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of scandium(III), such as scandium tris-trifluoromethanesulfonate or scandium tris-(di-(trifluoromethanesulfonyl)amide or scandium tris-(tri-(trifluoromethanesulfonyl)methide;

[0326] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of lanthanide(III), such as ytterbium tris-trifluoromethanesulfonate or ytterbium tris-(di-(trifluoromethanesulfonyl)amide or ytterbium tris-(tri-(trifluoromethanesulfonyl)methide;

[0327] The aforementioned Lewis Mountain 23 Alternatively, is a derivative of bismuth(III), such as bismuth tris-trifluoromethanesulfonate or bismuth tris-(di-(trifluoromethanesulfonyl)amide or bismuth tris-(tri-(trifluoromethanesulfonyl)methide;

[0328] Here:

[0329] The hydroxyl protector or groups are cylindrical protectors;

[0330] The above hydroxyl protectors or groups are preferably independently t -butyldimethylsilyl, thihexyldimethylsilyl, t -butyldiphenylsilyl or tri- Iso - It is a propylsilyl protector.

[0331] Protective devices are generally known to those skilled in the art and are described in textbooks such as Greene and Wuts (PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0332] Amid formation is caused by the activation of carboxylic acids, for example N - This is carried out by the formation of hydroxysuccinimide esters and coupling with corresponding amines, see, for example, 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 are dicyclohexyl carbodiimide (DCC), di- Iso -Propyl carbodiimide (DIC), O -(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) are included, but not limited to (E. Valeur and M. Bradley, "Amide bond formation: beyond the myth of coupling reagents", Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0333] cannabinoids 5 cannabinoids regarding 4 Mount Lewis 23 The mediated cyclization reaction is cannabinoid 1 Related compounds lacking the core RαRβC ketal unit are known, as in the example, and the extension of the above reaction to compounds having said unit is part of the present invention. Such indirect precedents include publications by Rhee, Childers, Gaoni, Adams, Glaser, Koch, Steup, Burdick, Kupper, and Gutman (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 Adenylylcyclase", Journal of Medicinal Chemistry , 1997, volume 40, pages 3228-3233; WE Childers, Jr., HW Pinnick, “A Novel Approach to the Synthesis of the 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", The Journal of the American Chemical Society , 1964, volume 86, pages 1646-1647; R. Adams, D.C. Pease, C.K. Cain and J.H. Clark, "Structure of Cannabidiol. VI. Isomerization of Cannabidiol to Tetrahydrocannabinol, a Physiologically Active Product. Conversion of Cannabidiol to Cannabinol", The Journal of the American Chemical Society , 1940, volume 62, pages 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; O. Koch, M.R. G tz, J. Looft and T. V ssing, "Mixtures of cannabinoid compounds, and production and use thereof", US Patent Application 2015 / 0336874 Al; C. Steup and T. Herkenroth, “Process for preparing synthetic cannabinoids”, US Patent Application 2010 / 298579 A1; DC Burdick, SJ Collier, F. Jos, B. Biolatto, BJ Paul, H. Meckler, MA Helle, AJ Habershaw, “Process for production of delta-9-tetrahydrocannabinol”, US Patent 7,674,922 B2 (2010); RJ Kupper, “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 / 136273 A1; A. L. Gutman, M. Etinger, I. Fedotev, R. Khanolkar, G. A. Nisnevich, B. Pertsikov, I. Rukhman and B. Tishin, “Methods for purifying trans -(-)-Δ 9 -tetrahydrocannabinol and trans -(+)-Δ 9 -tetrahydrocannabinol", US Patent 9,278,083 B2). Consequently, hydrolysis by selective decarboxylation or ester exchange, or by amide formation having selective deprotection, results in undesirable Δ where appropriate.8 - Δ having very low levels of cannabinoids 9 - Cannabinoid 2 It provides. The use of RαRβC ketal units to control the regioselectivity of the reaction is inventive, but the single protection of cannabidiol as a methyl ether generated in situ is Δ 9 -Tetrahydrocannabinol( 7 It has been reported that the synthesis of ) is site-specific (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).

[0334] The present invention also relates to a racemic modification or as a mixture of unequal proportions of two enantiomers, or to a specific enantiomer as shown below or 3 As a mirror image isomer of, the following chemical formula 3 This relates to a related process for the manufacture of intermediates,

[0335]

[0336] In the above chemical formula:

[0337] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0338] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0339] n is independently 0, 1, or 2 and;

[0340] m is independently 1 or 2 and;

[0341] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0342] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0343] s is 4, 5, or 6;

[0344] The above process is:

[0345] R 1 and / or R 2 [R 2 is (CH2) m [It is -OH] A chemical formula in which any hydroxyl group within it is protected 13 The intermediate of a weak acylating agent in an inert solvent 14 An intermediate appropriately retaining the hydroxyl protecting group by processing at a temperature of 40 to 100°C 3 It includes the step of generating.

[0346]

[0347] In the above chemical formula:

[0348] The above inert solvent is a halogenated solvent or an aromatic hydrocarbon;

[0349] The above inert solvent is preferably an aromatic hydrocarbon such as toluene;

[0350] The above reaction temperature is preferably 40 to 60°C;

[0351] Preferably, the reaction temperature is 50°C and the solvent is toluene.

[0352] In the above chemical formula:

[0353] The hydroxyl protector or groups are cylindrical protectors;

[0354] The above hydroxyl protectors or groups are preferably independently t -butyldimethylsilyl, thihexyldimethylsilyl, t-butyldiphenylsilyl or tri- Iso - It is a propylsilyl protector.

[0355] Protective devices are generally known to those skilled in the art and are described in textbooks such as Greene and Wuts (PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0356] The present invention also relates to a racemic modification or as a mixture of unequal proportions of two enantiomers, or to a specific enantiomer as shown below or 6 As a mirror image isomer of, the following chemical formula 6 This relates to a related process for the manufacture of intermediates,

[0357]

[0358] In the above chemical formula:

[0359] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0360] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0361] n is independently 0, 1, or 2 and;

[0362] m is independently 1 or 2 and;

[0363] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0364] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0365] s is 4, 5, or 6;

[0366] The above process is:

[0367] R 1 and / or R 2 [R 2 is (CH2) m [It is -OH] A chemical formula in which any hydroxyl group within it is protected 15 The intermediate of a weak acylating agent in an inert solvent 14 Intermediate by processing at a temperature of 40 to 100°C 6 It includes the step of generating.

[0368]

[0369] In the above chemical formula:

[0370] The above inert solvent is a halogenated solvent or an aromatic hydrocarbon;

[0371] The above inert solvent is preferably an aromatic hydrocarbon such as toluene;

[0372] The above reaction temperature is preferably 40 to 60°C;

[0373] Preferably, the reaction temperature is 50°C and the solvent is toluene.

[0374] In the above chemical formula:

[0375] The hydroxyl protector or groups are cylindrical protectors;

[0376] The above hydroxyl protectors or groups are preferably independently t -butyldimethylsilyl, thihexyldimethylsilyl, t -butyldiphenylsilyl or tri- Iso - It is a propylsilyl protector.

[0377] Protective devices are generally known to those skilled in the art and are described in textbooks such as Greene and Wuts (PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 2006, Fourth Edition, John Wiley, New York).

[0378] An example of the new method is below Reaction Equation 1 Keto-ester deoxynon is presented in 24 is keto-deoxynon 29 and imidazolid 30 Or they are synthesized from equivalent reagents, such as but not limited to benzotriazole carbonate derivatives or 4-nitrophenyl carbonate, using methods equivalent to those disclosed for other related keto-ether dioxinones (R. Cookson, TN Barrett and AGM 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).

[0379] Keto-ester deoxynon 24 of C - Corresponding adducts by carrying out acylation using hexanoyl chloride in the presence of a base such as pyridine in the presence of magnesium chloride 25It provides. This can be separated and purified, but in a preferred embodiment, it proceeds directly to the next step. Decarboxylation and allylic rearrangement after using a method equivalent to that disclosed for other related diketo-dioxinones (R. Cookson, TN Barrett and AGM 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) the corresponding β,δ-diketo-deoxynon having a monoterpene unit attached to the α-carbon 26 Provides. Intermediate 25 diketo-deoxynon 26 A typical catalyst for conversion comprises a palladium (0) catalyst, which may already exist as a palladium (II) pre-catalyst in the presence of a palladium (0) oxidation state, e.g., Pd(PPh3)4 or phosphine or an equivalent monodentate or alternative doubate or more ligand. It comprises, but is not limited to, complexes of iron or molybdenum known to those skilled in the art for use in metal-catalyzed reactions proceeding through π-allyl metal intermediates. 25 cast 26 An alternative metal catalyst can be used to convert it.

[0380]

[0381] intermediate 26 It can be separated and purified, but in a preferred embodiment, it proceeds directly to the next step. Diketo-deoxynon 26 A resorcylate derivative is produced by reacting it with a second catalyst, such as silica gel or cesium carbonate, and then reacting it with hydrochloric acid. 27This is generated. An alternative catalyst for the above aromatization reaction is presented in the paper "Accounts of Chemical Research" cited above. In the most preferred embodiment of the above reaction, keto-ester 24 is an intermediate 25 and 26 Through this, the product within a single container 27 in cannabidiol ( 11 Except for derivatives of ), resorcylate without any separation and purification 27 It is converted to.

[0382] In the synthesis of hongoquercin B reported (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) using boron trifluoride etherate or other Lewis acids or Bronsted acids or combinations of Lewis / Bronnsted acids generally known to those skilled in the art in the cannabinoid region 27 The cyclization of Δ 1 - Tetrahydrocannabinol derivatives 28 It provides

[0383] intermediate by saponification or an equivalent process described in the aforementioned paper "Accounts of Chemical Research" 28 Cleaving the deoxynon ring of Δ 1 -Tetrahydrocannabinol ( 31 Provides ). Δ 1 -Tetrahydrocannabinol ( 31 The decarboxylation of ) is tetrahydrocannabinol ( 7) (see H. Perrotin-Brunel, W. Buijs, J. van Spronsen, MJE van Roosmalen, CJ Peters, R. Verpoorte and G.-J. Witkamp, ​​"Decarboxylation of Δ 9 -tetrahydrocannabinol: Kinetics and molecular modeling", Journal of Molecular Structure, 2011, volume 987, pages 67-73 and references therein). In the same way, the intermediate 27 The saponification or equivalent process and decarboxylation of cannabidiol ( 11 Creates ).

[0384]

[0385] Because the starting material is pure, for example, hexanoyl chloride does not contain butanoyl chloride, and n - Cannabinoids that are products having a pentyl side chain, for example, Δ 9 -Tetrahydrocannabinol( 7 )silver n - Corresponding cannabinoids having a propyl side chain, e.g., cannabidivarin ( 12 ) and tetrahydrocannabivarin ( 9 It is necessary to further emphasize that it is not contaminated by ). In addition, because the method used to link the aromatic core to the terpene unit is very pure and position-specific, the product can be purified much more easily than those produced by conventional synthetic routes, which may contain impurities derived from generally known monoterpene rearrangements as well as other contaminants.

[0386] Reaction Equation 1 It should be noted that the synthesis of is carried out with equivalent starting materials. For example, the sequence is a terpene having a protected 2-hydroxy-propyl group. 32Or, proceed by starting with alternative terpene compounds. In the above case, 30 , 25 , 26 and 27 not only the protected 2-hydroxy-propyl group corresponding to 11 The intermediate having the corresponding group also possesses the same substituent.

[0387]

[0388] Reaction Equation 1 The synthesis of Reaction Equation 2 It should be noted that the process is carried out by replacing hexanoyl chloride with butanoyl chloride as in. The step is directly similar to that presented in the previous reaction scheme and tetrahydrocannabivarin ( 9 ) and cannabidivarin ( 12 ) and the above Δ 1 -Tetrahydrocannabinol ( 31 It provides a C-3 analogue of ) and depends on the inventive step of equivalence.

[0389] Because the starting material is pure, for example, butanoyl chloride does not contain hexanoyl chloride, and n - Cannabinoids, which are products having a propyl side chain, n - Corresponding cannabinoids having a pentyl side chain, such as cannabidiol ( 11 ) and Δ 9 -Tetrahydrocannabinol( 7 It is necessary to further emphasize that it is not contaminated by ). In addition, because the method used to link the aromatic core to the terpene unit is very pure and site-specific, the product can be purified much more easily than those produced by conventional synthetic routes, which may contain impurities derived from generally known monoterpene rearrangements as well as other contaminants. Furthermore, the present invention relates to the use of Me2C ketal units in cannabinoids 36 The cyclization reaction to produce Δ 9 - Provides only isomers and undesirable Δ 8- It is necessary to emphasize that it ensures that isomers are not formed to any significant degree. Consequently, hydrolysis via decarboxylation results in unwanted Δ 8 Δ having very low levels of isomers 9 - As an isomer, tetrahydrocannabivarin ( 9 It provides ).

[0390]

[0391]

[0392] Reaction Equation 1 and Reaction Equation 2 The method also involves carboxylic acid acyl chloride 38 deoxynon through 37 of C - It is useful for concisely synthesizing a family of cannabinoids having previously unknown cyclic substituents from acylation, decarboxylation, allylic rearrangement, aromatization, and hydrolysis and decarboxylation. Examples of the novel cannabinoids mentioned above are analogs 39 and 40 (R 1 = C2 to C5 alkyl, cyclopropyl, phenyl + R 2 = n-pentyl) and (R 1 = CH3+ R 2 = Cyclopropyl, Cyclobutyl, Cyclopentyl, Phenyl) as well as "reverse" analogs 39 and 40 (R 1 = n - Pentyl, R 2 = includes (CH3), but is not limited thereto. The present invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative including a solvate, hydrate, and polymorph.

[0393]

[0394] The above chemical formula 39 and 40The aforementioned novel cannabinoids having Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), Navilone( 16 It may be mixed in combination with ) and / or other drugs. In some embodiments, the above formula 39 and 40 The novel cannabinoids having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Antioxidants, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, flavorings and flavorings, such as but not limited to volatile terpenes of cannabis and citrus fruits, and other pharmaceutically acceptable diluents or excipients are included.The aforementioned pharmaceutical compositions may be administered to a patient by, for example, by enteral administration using a pill, tablet, or capsule; by, for example, by sublingual administration using a tablet, strip, drop, spray, lozenge, or effervescent tablet; by, for example, intranasal administration using a spray or finely powdered powder; by, for example, inhalation administration using a spray or finely powdered powder; by, for example, rectal administration using a suppository or solution; by, for example, parenteral drug administration by intramuscular, subcutaneous, or intravenous injection of a solution; or by other known methods of clinical administration.

[0395] In another embodiment of the present invention, the main intermediate for the decarboxylation, allylic rearrangement, and aromatication steps is Reaction Equation 3 and Reaction Equation 4 It is manufactured using the method shown in. Terpene allylic alcohol components, for example 41 or 44 Dioxanedione under weak heating 14 Reacting with the corresponding deoxynon β-keto-ester, 42 or 45 Each is obtained. In a preferred embodiment, the reaction is an alcohol 41 or alcohol 44 and reagent 14 (Rα = Rβ = Rγ = methyl, Rδ = phenyl or Rα = Rβ = methyl, Rγ = H, Rδ = phenyl) is carried out together at a temperature of 50ºC to 60ºC. However, if the substituents Rα, Rβ, Rγ, and Rδ are selected so that the addition of the terpene alcohol occurs exclusively in the dione moiety, the dioxanedione 14 It should be noted that [it] can be used. For example, Rα and Rβ can be used in combination, and Rγ and Rδ are both methyl (CH2) n (n = 4, 5) can be.

[0396]

[0397]

[0398] Dioxandion 14 is an acid derivative of Meldrum 48 carboxylic acid 47 and suitable activators, e.g. (but not limited to) N , N It is prepared by coupling with dicyclohexyl carbodiimide (DCC) or an equivalent (see below: 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 to 1803).

[0399]

[0400] compound 42 or 45 of C - Acylation is performed using a suitable acylating agent, e.g., R B It is implemented as COX (where X = Cl, Br, OSO2CF3, etc.). In a preferred embodiment, the hexanoyl chloride is (X = Cl) and R B = Diketo-deoxynon used in the presence of bases such as magnesium chloride and pyridine in (CH2)4CH3. 43 and 46 Each is obtained. Preferably, without further purification, crude ester 43 and 46 It specifically undergoes the aforementioned decarboxylation and allylic rearrangement through palladium catalysis as a separate compound or as a mixture of the two positional isomers. Reaction Equation 5 The corresponding β,δ-diketo-deoxynon with a monoterpene unit attached to the γ-carbon shown in 49 Obtains the intermediate 43 and46 diketo-deoxynon 49 Typical catalysts for conversion include palladium (0) catalysts, such as Pd2dba3, in the presence of phosphine or an equivalent monodentate ligand, such as P(2-furyl)3. Alternative catalysts may also be used by those skilled in the art as described above.

[0401] intermediate 49 It is preferably converted directly into the intermediate of the next step without separation and purification. Thus, diketo-deoxynon 49 The reaction of a second catalyst, for example, with cesium acetate, is a resorcylate derivative 50 Produces resorcylate derivatives 50 intermediate of 51 and cannabinoids, for example 52 and 53 The conversion to is carried out by the method described above.

[0402]

[0403] Reaction Equations 3 and 4 and 5 The synthesis of monoterpene analogs 15 and / or 13 (or its enantiomer 56 cannabinoids starting from ) 5 , 54 and 55 Synthesis of cannabinoids and analogs including, but not limited to, reagents 14 Condensation with, intermediate 6 and / or 3 (or its enantiomer 57 )of C -Esters via acylation 58 and / or 59 It should be noted that the generation of (or its enantiomer) and subsequent decarboxylation, allylic site rearrangement, and aromatization can be carried out with suitable starting materials and reagents.

[0404] for example, Reaction Equation 3 and 4 terpenes41 and / or 44 The synthetic sequence performed starting with is also a substitute monoterpene analog. 15 and / or 56 (R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 and; R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 and; n is independently 0, 1, or 2; m is independently 1 or 2; and R 3 It may be implemented as H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, but is not limited thereto. Additionally, keto deoxynon 42 and / or 45 , or more generally 6 and / or 57 of C - Acylation is carried out with an acylating agent to obtain cannabinoids having different side chains on an aromatic ring. An example is R B = n-propyl(cannabidivarin and tetrahydrocannabivarin family), R B = Natural side chains having n-pentyl (cannabidiol and tetrahydrocannabinol groups) or R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or comprises, but is not limited to, non-natural side chains optionally substituted with C3 to C6 cycloalkyls optionally substituted with C1 to C8 alkyls;

[0405] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0406] p is 1, 2, 3, 4, 5 or 6 and;

[0407] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0408] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0409] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0410] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0411] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0412]

[0413]

[0414]

[0415]

[0416] Reaction equations 1, 2, 3, 4 and 5The synthesis method of is suitable for large-scale and manufacturing purposes, particularly because the major cyclization reaction of the present invention does not produce unwanted isomer byproducts. Examples of available known cannabinoids using the above synthesis routes are cannabidiol ( 11 ), cannabidivarine ( 12 ), Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ) and Navilone( 16 These are compounds related to ). The present invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative including a solvate, hydrate, and polymorph.

[0417]

[0418]

[0419] Reaction equations 1, 2, 3, 4 and 5 The synthesis method of is suitable for the synthesis of novel cannabinoids, and said compounds are also part of the present invention. Cannabidiol ( 11 ) and cannabidivarin ( 12 The following cannabinoids, which are novel analogues of ) 1 ...is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 1 has the following chemical formula:

[0420]

[0421] In the above chemical formula:

[0422] R 1 H, C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0423] R 2is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0424] n is independently 0, 1, or 2 and;

[0425] m is independently 1 or 2 and;

[0426] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0427] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0428] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0429] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0430] p is 1, 2, 3, 4, 5 or 6 and;

[0431] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0432] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0433] RD is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0434] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0435] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0436] The aforementioned novel cannabinoids having the restricted formula 1 are used alone as active compounds to treat or prevent, in particular, pain, multiple sclerosis-related stiffness, 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, or known cannabinoids, such as but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), Navilone( 16 It may be mixed in combination with ) and / or other drugs. In some embodiments, the limited formula 1The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0437] Cannabidiol11 ), cannabidivarine( 12 The following cannabinoids, which are also novel analogues of ) 1 ...is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 1 has the following chemical formula:

[0438]

[0439] In the above chemical formula:

[0440] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0441] R 2 is a C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0442] n is independently 0, 1, or 2 and;

[0443] m is independently 1 or 2 and;

[0444] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0445] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0446] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0447] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0448] p is 1, 2, 3, 4, 5 or 6 and;

[0449] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0450] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0451] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0452] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0453] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0454] The above limited chemical formula 1 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 It may be used in combination with ) and / or other drugs. In some embodiments, the limited formula 1 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0455] Cannabidiol11 ), cannabidivarine( 12 The following cannabinoids, which are novel analogues of ) 1 ...is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 1 has the following chemical formula:

[0456]

[0457] In the above chemical formula:

[0458] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0459] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0460] n is independently 0, 1, or 2 and;

[0461] m is independently 1 or 2 and;

[0462] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0463] R A CONHR D , CONR D R E And;

[0464] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0465] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0466] p is 1, 2, 3, 4, 5 or 6 and;

[0467] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0468] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0469] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that the hydroxyl group cannot be on a carbon containing a heterocyclic nitrogen or a heterocyclic oxygen having morpholin;

[0470] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0471] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0472] The above limited chemical formula 1 The aforementioned novel cannabinoid having Δ is used as an active compound alone or with known cannabinoids, e.g., but not limited to Δ, to treat pain, multiple sclerosis-related stiffness, 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, particularly more than other diseases, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16 ) or it may be used in combination with endocannabinoids and / or other drugs. In some embodiments, the limited formula 1 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0473] The following deoxynon derivatives that are intermediates for the synthesis of cannabinoids 3 is also available by the synthetic routes described herein and is part of the present invention. The deoxynon derivative 3 has the following chemical formula:

[0474]

[0475] In the above chemical formula:

[0476] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0477] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0478] n is independently 0, 1, or 2 and;

[0479] m is independently 1 or 2 and;

[0480] R 3 is a hydroxyl protecting group, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0481] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0482] s is 4, 5, or 6.

[0483] The following deoxynon resorcylate derivatives, which are intermediates for the synthesis of cannabinoids 4 is also available by the synthetic routes described herein and is part of the invention. The deoxynon derivative 4 has the following chemical formula:

[0484]

[0485] In the above chemical formula:

[0486] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0487] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0488] n is independently 0, 1, or 2 and;

[0489] m is independently 1 or 2 and;

[0490] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0491] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0492] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0493] p is 1, 2, 3, 4, 5 or 6 and;

[0494] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0495] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0496] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0497] s is 4, 5, or 6.

[0498] Δ 9 -Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are novel analogues of ) 2 It is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 2 has the following chemical formula:

[0499]

[0500] In the above chemical formula:

[0501] R 1 H, C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0502] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0503] n is independently 0, 1, or 2 and;

[0504] m is independently 1 or 2 and;

[0505] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0506] R Ais H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0507] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0508] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0509] p is 1, 2, 3, 4, 5 or 6 and;

[0510] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0511] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0512] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R Eis azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0513] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0514] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0515] The above limited chemical formula 2 The aforementioned novel cannabinoids having Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), Navilone( 16 ) or may be mixed in combination with endocannabinoids and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoids having Δ are used alone, or known cannabinoids, such as, but not limited to, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), endocannabinoid or navilone ( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0516] Δ 9-Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are novel analogues of ) 2 It is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 2 has the following chemical formula:

[0517]

[0518] In the above chemical formula:

[0519] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0520] R 2 is a C2 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0521] n is independently 0, 1, or 2 and;

[0522] m is independently 1 or 2 and;

[0523] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0524] R A is H, CO2H and their pharmaceutically acceptable salts, CO2R C , CONHR D , CONR D R E And;

[0525] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0526] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0527] p is 1, 2, 3, 4, 5 or 6 and;

[0528] R C is a C1 to C6 alkyl, (CH2) q - It is a C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0529] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0530] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NRDRE is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0531] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0532] r is independently 0, 1, 2, 3, 4, 5, or 6;

[0533] The aforementioned novel cannabinoids having the restricted formula 2 are used alone as active compounds to treat or prevent, in particular, pain, multiple sclerosis-related rigidity, 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, or known cannabinoids, such as but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), Navilone( 16 It may be mixed in combination with ) and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoids having Δ are used alone, or known cannabinoids, such as, but not limited to, Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), endocannabinoid or navilone ( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0534] Δ 9-Tetrahydrocannabinol( 7 ) and tetrahydrocannabivarin ( 9 The following cannabinoids, which are also novel analogues of ) 2 It is also available by the synthetic routes described herein and is part of the invention. The invention comprises synthesizing a target cannabinoid as an oil or crystalline derivative, appropriately comprising a solvate, hydrate, and polymorph. said cannabinoid 2 has the following chemical formula:

[0535]

[0536] In the above chemical formula:

[0537] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0538] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0539] n is independently 0, 1, or 2 and;

[0540] m is independently 1 or 2 and;

[0541] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0542] R A CONHR D , CONR D R E And;

[0543] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0544] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0545] p is 1, 2, 3, 4, 5 or 6 and;

[0546] R C is a C1 to C6 alkyl, (CH2) q -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl;

[0547] q is 0, 1, 2, 3, 4, 5 or 6 and;

[0548] R D is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; R E is a C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, benzyl, substituted benzyl, or 2-phenylethyl; or NR D R E is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with one or two of the said hydroxyl groups or hydroxymethyl groups, except that there is no hydroxyl group on the carbon containing the heterocyclic nitrogen or heterocyclic oxygen having morpholin;

[0549] R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl;

[0550] r is independently 0, 1, 2, 3, 4, 5, or 6.

[0551] The aforementioned novel cannabinoids having the restricted formula 2 are used alone as active compounds to treat or prevent, in particular, pain, multiple sclerosis-related rigidity, 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, or known cannabinoids, such as but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ), endocannabinoids or navilone ( 16 It may be mixed in combination with ) and / or other drugs. In some embodiments, the limited formula 2 The novel cannabinoid having Δ alone or known cannabinoids, e.g., but not limited to Δ 9 -Tetrahydrocannabinol( 7 ), tetrahydrocannabivarin( 9 ), cannabidiol( 11 ), cannabidivarine( 12 ) or Navilone( 16It is formulated into a pharmaceutical composition suitable for administration to a patient by mixing with ) and / or other drugs. In addition to the active cannabinoid or cannabinoids and / or other drugs in the combination therapy, said formulations contain pharmaceutically acceptable diluents and excipients, which include binders, e.g., lactose, starch, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers; disintegrants, e.g., polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants; vehicles, e.g., in petroleum jelly, dimethyl sulfoxide, mineral oil or omega-3 oil-in-water nanoemulsions, or vehicles as complexes having cyclodextrin, e.g., hydroxypropyl-beta-cyclodextrin; preservatives including antioxidants, e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, attachment Inhibitors, lubricants and lubricants, such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable oils, coatings, such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients are included. The aforementioned pharmaceutical compositions may be administered to a patient by enteral administration, for example, using pills, tablets or capsules; sublingual administration, for example, using tablets, strips, drops, sprays, lozenges, or effervescent tablets; intranasal administration, for example, using sprays or finely powdered powders; inhalation administration, for example, using sprays or finely powdered powders; rectal administration, for example, using suppositories or solutions; parenteral drug administration, for example, by intramuscular, subcutaneous, or intravenous injection of solutions; or other known methods of clinical administration.

[0552] The following deoxynon resorcylate derivatives, which are intermediates for the synthesis of cannabinoids 5 is also available by the synthetic routes described herein and is part of the invention. The deoxynon derivative 5 has the following chemical formula:

[0553]

[0554] In the above chemical formula:

[0555] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0556] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0557] n is independently 0, 1, or 2 and;

[0558] m is independently 1 or 2 and;

[0559] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0560] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0561] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0562] p is 1, 2, 3, 4, 5 or 6 and;

[0563] R F is a C1 to C6 alkyl, (CH2) n - It is a C3 to C6 cycloalkyl;

[0564] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0565] s is 4, 5, or 6.

[0566] The following deoxynon derivatives that are intermediates for the synthesis of cannabinoids 6 is also available by the synthetic routes described herein and is part of the present invention. The deoxynon derivative 6 has the following chemical formula:

[0567]

[0568] In the above chemical formula:

[0569] R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0570] R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, (CH2) m -OR 3 And;

[0571] n is independently 0, 1, or 2 and;

[0572] m is independently 1 or 2 and;

[0573] R 3 is H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0574] R B is H or C1 to C2 alkyl, straight chain or side chain C3 to C10 Alkyl or double side chain C4 to C 10 It is alkyl, optionally substituted in each case with one or two hydroxyl groups, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with C3 to C6 cycloalkyl which is optionally substituted with C1 to C8 alkyl;

[0575] o is 0, 1, 2, 3, 4, 5 or 6 and;

[0576] p is 1, 2, 3, 4, 5 or 6 and;

[0577] R F is a C1 to C6 alkyl, (CH2) n - It is a C3 to C6 cycloalkyl;

[0578] Rα and Rβ are independently C1 to C6 alkyl or optionally substituted aryls, or Rα and Rβ are in combination (CH2) s And;

[0579] s is 4, 5, or 6.

[0580] Examples

[0581] Example 1: (1 R ,4 R )-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 = CH 3 ).

[0582] N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol, 1 equivalent) and 4-dimethylaminopyridine (6.0 g, 50 mmol, 1 equivalent) were sequentially added to a solution of 2-phenyl-1,3-dioxane-4,6-dione (9.6 g, 50 mmol, 1 equivalent) in anhydrous dichloromethane (0.5 L). After 5 minutes, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (9.4 g, 50 mmol, 1 equivalent) was added as a partial amount. The reaction mixture was stirred at room temperature for 17 hours. After the above period, water (0.5 L) was added and the organic fraction was separated. The organic phase was washed with 1M 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 then (1 R ,4 R )-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (4) 3.9 g, 25 mmol, 0.5 equivalents of (3.9 g, 25 mmol, 0.5 equivalents) were added dropwise. The solution was heated to 55°C and maintained for 3 hours. Once 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 obtain the title compound as a colorless oil (4.3 g, 12 mmol, 48%): 1 ¹H NMR (400 MHz, CDCl₃) δ major isomer 5.46 (dq, J = 8.7, 2.1 Hz, 1H), 5.40 - 5.30 (m, 2H), 4.78 (q, J = 1.6 Hz, 1H), 4.74 (dt, J= 1.9, 0.9 Hz, 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 = 1.0 Hz, 16H), 1.70 - 1.66 (m, 1H); 13 13C NMR (101 MHz, CDCl3)δ mixture of isomers 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, 14.2; IR (neat) 2937, 1720, 1639, 1375, 1250, 1201, 1014, 901; HRMS (ES-) m / z calculated for C 20 H 25 O6[MH] + 361.1651, found 361.1651; R f 0.2 (EtOAc : pentane; 4 : 20) UV / Vanillin.

[0583] Example 2: (1 R ,4 R )-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-oxo-octanoate.

[0584] Pyridine (1.2 mL, 14 mmol, 2.0 equivalents) and MgCl2 (0.66 g, 6.9 mmol, 1.0 equivalents) in anhydrous dichloromethane (50 mL) (1 R ,4 R )-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 = CH 3 )(2.5 g, 6.9 mmol, 1.0 equivalent) was added to the solution and cooled to 0°C. Hexanoyl chloride (1.3 g, 10 mmol, 1.5 equivalent) was added dropwise, and the mixture was stirred for 1 hour. The cooling bath was removed, and the mixture was stirred for an additional 2 hours. Saturated aqueous NH4Cl (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 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 obtain the title compound as a colorless oil (2.9 g, 6.3 mmol, 91%): NMR (400 MHz, CDCl3) δ 5.60 (dp, J = 8.6, 2.1 Hz, 1H), 5.40 - 5.26 (m, 2H), 4.84 - 4.73 (m, 2H), 3.66 (s, 2H), 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 (100 MHz, CDCl3) δ 198.4, 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 calculated for C 26 H 35 O7[MH] +459.2383, found 459.2390; R f 0.4 (EtOAc : pentane; 2 : 20) UV / Vanillin.

[0585] Example 3: 7-hydroxy-2,2-dimethyl-8-((1 R ,6 R )-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 = CH 3 , R B = nC 5 H 11 ).

[0586] Tri(2-furyl)phosphine (46 mg, 0.2 mmol, 0.2 equivalents) and tris(dibenzylideneacetone)dipalladium (0) (46 mg, 0.05 mmol, 0.05 equivalents) in THF (10 mL) (1 R ,4 R It was sequentially added to a solution of )-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-oxo-octanoate (0.46 g, 1 mmol, 1 equivalent) and cooled to 0°C. The mixture was immediately heated to room temperature. After 3 hours, Iso 0.5 M CsOAc was added dropwise to 6 mL of propanol (3 mmol, 3 equivalents), and the reaction mixture was stirred for an additional 72 hours. The reaction was stopped with 10% aqueous citric acid (10 mL), the two-phase solution was separated, and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The organic extracts were collected 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 obtain the title compound as a white solid (128 mg, 0.32 mmol, 32%): 1H NMR (400 MHz, CDCl3) δ 6.45 (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 = 7.7 Hz, 2H), 2.42 (td, J = 11.4, 10.9, 3.8 Hz, 1H), 2.24 (t, J = 13.0 Hz, 1H), 2.11 (ddd, J = 15.5, 5.1, 2.6 Hz, 1H), 1.86 - 1.76 (m, 4H), 1.69 - 1.65 (m, 5H), 1.60 (d, J = 14.1 Hz, 6H), 1.34 (pd, J = 6.8, 3.9 Hz, 4H), 0.88 (tq, J = 7.3, 2.6, 2.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.8, 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 calculated for C 25 H 33 O4[M-H] + 397.2379, found 397.2386; R f 0.3 (Et2O : pentane; 2 : 20) UV / Vanillin.

[0587] Example 4: Cannabidiol (11)

[0588] Aqueous 6M NaOH (4 mL) was purged with nitrogen for 5 minutes in a sealable reaction vial. 7-hydroxy-2,2-dimethyl-8-((1 R ,6 R A nitrogen-purged solution of )-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) was added to the aqueous solution. The reaction vial was sealed, and the solution was heated at 120°C for 5 hours. The reaction solution was added to 10% aqueous citric acid (10 mL) and Et2O (10 mL) while vigorously stirring. After 5 minutes, the layers were separated, and the aqueous layer was extracted with Et2O (3 x 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 (Et2O : pentane; 1 : 20 to 2 : 20) to obtain cannabidiol ( 11 ) was obtained as a white solid (38 mg, 0.12 mmol, 60%): 1 H NMR (400 MHz, MeOD) δ 6.07 (s, 2H), 5.28 (dq, J = 2.3, 1.3 Hz, 1H), 4.49 - 4.39 (m, 2H), 3.96 - 3.88 (m, 1H), 2.90 (td, J = 10.2, 5.5 Hz, 1H), 2.41 - 2.33 (m, 2H), 2.20 (dd, J = 12.5, 6.4 Hz, 1H), 1.99 (dd, J = 17.0, 3.5 Hz, 1H), 1.73 (ddd, J = 8.6, 6.8, 2.8 Hz, 2H), 1.67 (dt, J = 2.5, 1.1 Hz, 3H), 1.63 (t, J = 1.1 Hz, 3H), 1.54 (ddd, J= 14.7, 8.4, 6.7 Hz, 2H), 1.37 - 1.24 (m, 5H), 0.89 (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, 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) UV / KMnO4.

[0589] Example 5: Δ 9 - Tetrahydrocannabinol (7)

[0590] Cannabidiol in dichloromethane (1 mL) 11 )(40 mg, 0.12 mmol) was cooled to -10°C. The cooled solution of BF3·2Et2O in dichloromethane (1.2 mL, 0.12 mmol, 0.1 M) was added dropwise over 20 minutes. The reaction mixture was stirred at 20°C for an additional 40 minutes. 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 aggregated organic layer fraction was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (5% diethyl ether in pentane) to obtain trans-Δ 9 - Tetrahydrocannabinol (7) Tetrahydrocannabinol (31 mg, 0.99 mmol, 83%) was obtained: 1 H NMR (400 MHz, CD3OD) δ 6.43 (app. pent, J = 1.7 Hz, 1H), 6.16 (d, J = 1.7 Hz, 1H), 6.07 (d, J = 1.7 Hz, 1H), 3.15 (d, J= 11.0 Hz, 1H), 2.44 - 2.37 (m, 2H), 2.15 (d, J = 8.6 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.66 (dq, J = 2.4, 1.1 Hz, 3H), 1.60 - 1.24 (m, 6H), 1.37 (s, 3H), 1.05 (s, 3H), 0.90 (t, J = 7.0 Hz, 4H); 13 C NMR (100 MHz, 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, 26.3, 23.6, 23.6, 19.4, 14.4; IR (neat) 3383, 2952, 2924, 2855, 1621, 1577, 1423, 1233, 1181, 1049, 1036, 835

[0591] HRMS (ES+) m / z calculated for C 21 H 31 O2[MH] + 315.2319, found 315.2319; Rf 0.21 (Et2O:pentane; 1:20) UV / KMnO4.

[0592] Example 6: Bioassay of synthetic cannabidiol (11)

[0593] The synthesized cannabidiol described herein utilizing TRPV channel activity ( 11 As we evaluated and demonstrated that the biological activity of , CBD) is equivalent to that of the reference standard cannabidiol, synthesized cannabidiol ( 11 The identity of , CBD) was further confirmed. TRPV channels, including TRPV1, have been shown to mediate the effects of cannabinoids. (H. Turner, D. Chueh, T. Ortiz, A. J. Stokes and A. L. Small-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, AE 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) Capsaicin was also useful as a reference standard, and (I. D az-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 with TRPV1 channels were 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);

[0594] According to the results presented in FIGS. 1A to 1D, cannabidiol synthesized by the process described herein ( 11Samples of CBD and reference standard cannabidiol (supplied by Sigma Aldrich) have the same "biological fingerprint" and dose-response in TRPV channel 1 as shown using the analytical methods below and as previously described ( JS Horton , T. Shiraishi , N. Alfulaij , AL 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).

[0595] cell culture

[0596] HEK TRexTRPV1 was cultured in DMEM, 10% fetal bovine serum, 2 mM L-glutamine, 10 micrograms / ml blasticidin (Calbiochem, San Diego, California), and 400 mg / ml zeocin (InvivoGen, San Diego, California), and then expression of the indicated transplant gene was induced for 16–24 hours using 1 microgram / ml tetracycline. Untransfected HEK cells or HEKTRexTRPV1 were compared with or without induction.

[0597] Calcium test

[0598] Wash the cells and 37 in a standard modified Ringer solution with the following composition (in mM units) with 0.2 micromolar Fluo-4

[54] o Incubate at C for 30 minutes: NaCl 145, KCl 2.8, CsCl 10, CaCl210, MgCl22, Glucose 10, Hepes·NaOH 10, pH 7.4, 330 mOsm. Seed cells in 96-well plates at 50,000 cells per well and stimulate as directed. Acquire calcium signals using Flexstation 3 (Molecular Devices, Sunnydale, USA). Analyze data according to the methods presented below: I. D az-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.

[0599] Cannabidiol synthesized according to the described method (identified as "CBD, Synth" in FIG. 1A to 1D) ( 11 The dose response and comparison of HEK-TRPV1 cells between CBD and Sigma-supplied CBD (CAS No. 13956-29-1, identified as "CBD, Sigma" in Figures 1A to 1D) are illustrated in Figures 1A to 1D. A normal saline reference standard is identified as "NS" in Figures 1A to 1D.

[0600] All samples were tested under identical conditions: Fluo-4 loaded cells were placed in 1 mM external calcium chloride, and the compound was added at 20 seconds, based on a 0–20 second timeframe (uM = micromolar).

Claims

Claim 1 delete Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 As an intermediate compound of Formula 4 or Formula 5, In the above chemical formula: R 1 H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, and (CH2) m -OR 3 Selected from a group consisting of;R 2 is H, C1 to C6 alkyl, (CH2) n -C3 to C6 cycloalkyl, and (CH2) m -OR 3 Selected from a group consisting of; each n is independently an integer from 0 to 2; each m is independently 1 or 2; and R 3 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2; R B is H, C1 to C2 alkyl, straight chain or side chain C3 to C 10 Alkyl, and double side chains C4 to C 10 Selected from the group consisting of alkyls, optionally substituted with one or two hydroxyl groups in each case, or one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F , or optionally substituted with a C3 to C6 cycloalkyl optionally substituted with a C1 to C8 alkyl; o is an integer from 0 to 6; p is an integer from 0 to 6; and R F is a C1 to C6 alkyl, (CH2) r - It is a C3 to C6 cycloalkyl; each r is independently an integer from 0 to 6; each Rα and Rβ is independently a C1 to C6 alkyl or optionally a substituted aryl, or Rα and Rβ are in combination (CH2) s A compound in which s is an integer from 4 to 6. Claim 7 In paragraph 6, each Rα and Rβ is a compound that is methyl. Claim 8 In Paragraph 6, R 1 It is methyl, a compound. Claim 9 In Paragraph 6, R 2 is a methyl compound. Claim 10 In Paragraph 6, R 1 is methyl;R 2 is a methyl compound. Claim 11 In Paragraph 6, R 1 is methyl;R 2 is methyl; a compound in which Rα and Rβ are methyl, respectively. Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete

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