Cannabichromene and cannabichromenic acid analogs and methods for producing the same

Abstract

This invention relates to a method for preparing a variety of known and novel racemic cannabinoids 7 from a precursor 8 via a racemic intermediate 9. [Solution] Novel cannabinoids, cannabichromene (CBC,1), cannabichromeneic acid (CBCA,2), cannabichromemenin (CBCV,3), cannabichromemenic acid (CBCVA,4), and other chromene-based cannabinoids 7, exist as racemates, single enantiomers (S)-7 or (R)-7, or scalar mixtures of (S)-7 and (R)-7. These are all analogs of the racemates, single enantiomers, and scalar mixtures of cannabichromene (CBC,1), cannabichromeneic acid (CBCA,2), cannabichromemenin (CBCV,3), and cannabichromemenic acid (CBCVA,4).

Description

[Technical Field]

[0001] The present invention relates to a method for synthesizing cannabichromene (CBC, 1), cannabichromeneic acid (CBCA, 2), cannabiclomevalin (CBCV, 3), cannabiclomevalic acid (CBCVA, 4), and related cannabinoids and other synthetic analogs in high purity by constructing an aromatic skeleton from inexpensive and simple starting materials. The present invention also relates to the synthesis of cannabichromene (CBC, 1), cannabichromeneic acid (CBCA, 2), cannabiclomevalin (CBCV, 3), cannabiclomevalic acid (CBCVA, 4), and related chromene-based cannabinoids and cannabinoid carboxylic acids by direct separation of enantiomers by HPLC, or by the formation and separation of diastereoisomer cocrystals and reconversion to the separated cannabinoids, or by cannabichromeneic acid (CBCA, 2), cannabiclomevalic acid (CBCVA, 4), and other synthetic analogs. The present invention relates to a method for forming diastereoisomer cocrystals of related cannabinoid acids and chiral amines, and then, after alkali or base treatment, converting them through oxidation (including decarboxylation as necessary) to single enantiomers of cannabichromene (CBC, 1), cannabichromenic acid (CBCA, 2), cannabiclomevalin (CBCV, 3), cannabiclomevalic acid (CBCVA, 4), and related cannabinoids of both enantiomer series, as well as a non-racemic (scaremic) mixture of enantiomers. Furthermore, the present invention relates to novel cannabinoids, which can be used alone or in combination with known cannabinoids, terpenes, and other pharmaceuticals in pharmaceutical compositions to treat or prevent infections, pain, spasticity, nausea, loss of appetite associated with multiple sclerosis, epilepsy, Alzheimer's disease and neurodegenerative diseases, brain injury / concussion / traumatic brain injury, stroke, cancer, inflammation and immune-inflammatory diseases, postviral hyperinflammation, eye diseases / injuries (including but not limited to glaucoma, dry eye, corneal injury or disease, retinal degeneration or disease), immune-inflammatory diseases, lung diseases / injuries, liver diseases / injuries, kidney diseases / injuries, pancreatitis and pancreatic diseases, cardiovascular diseases / injuries, organ transplantation, and postoperative inflammation. They are also useful as antioxidants and skin disease treatments. [Background technology]

[0002] Cannabis sativa ("marijuana") is a widely known and used plant. The recreational use of marijuana or cannabis remains a subject of legal review in many countries around the world. There is great interest in the ethnopharmacological uses of this plant and its extracts, with a history spanning thousands of years, and it is even mentioned in Herodotus's "The Histories" (The Histories, Book IV, p.295, Penguin Books Ltd., Middlesex, 1972). Based on its analgesic, antispasmodic, and hypnotic effects, as well as its immuno-inflammatory modulating properties, this plant and its extracts have been used to alleviate nausea side effects associated with cancer chemotherapy, and to treat glaucoma, neuropathic pain, epilepsy, spasticity and pain associated with multiple sclerosis, pain in patients with advanced cancer, and AIDS-related anorexia and pain.

[0003] More than 60 constituent compounds have been isolated and structurally determined from Cannabis sativa oil (see, for example, SA Ahmed, SA Ross, D. Slade, MM Radwan, F. Zulfiqar and MA ElSohly, "High-potency cannabinoid ester components from Cannabis sativa," Journal of Natural Products, 2008, Vol. 71, pp. 536-542; MM Lewis, Y. Yang, E. Wasilewski, HC Clarke and LP Kotra, "Chemical profiling of medicinal cannabis extracts," ACS Omega, 2017, Vol. 2, pp. 6091-6103, and the references cited therein). Furthermore, a considerable number of these natural products and their analogues have been prepared by total synthesis using aromatic and monoterpene compounds as precursors. Reports on such total synthesis include: R.K. Razdan, "The Total Synthesis of Cannabinoids", The Total Synthesis of Natural Products, edited by J. ApSimon, 1996, Volume 4, pp.185 - 262, Wiley & Sons, New York; J.W. Huffman and J.A.H. Lainton, "Recent Developments in the Medicinal Chemistry of Cannabinoids", Current Medicinal Chemistry, 1996, Volume 3, pp.101 - 116; N. Itagaki, T. Sugahara and Y. Iwabuchi, "Stereoselective Total Synthesis of (-)-Perrottetinene and Assignment of Its Absolute Configuration", Organic Letters, 2005, Volume 7, pp.4181 - 4183; J.A. Teske and A. Deiters, "A Cyclotrimerization Route to Cannabinoids", Organic Letters, 2008, Volume 10, pp.2195 - 2198; S. Tchilibon and R. Mechoulam, "Synthesis of Cannabidiols via Alkenylation of Cyclohexenyl Monoacetate", Organic Letters, 2000, Volume 2, pp.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, pp.269 - 271; Y. Kobayashi, A. Takeuchi and Y.-G. Wang, "Synthesis of Cannabidiols via Alkenylation of Cyclohexenyl Monoacetate", Organic Letters, 2006, Vol. 8, pp. 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, Vol. 9, pp. 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, Vol. 15, pp. 764-767; P.R. Nandaluru and G.J. Bodwell, "Multicomponent Synthesis of 6H-Dibenzo[b,d]pyran-6-ones and a Total Synthesis of Cannabinol", Organic Letters, 2012, Vol. 14, pp. 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, Vol. 49, pp. 1113-1117; A. Mahadevan, C. Siegel, B.R. Martin, M.E. Abood, I. Beletskaya and R.K. Razdan, "Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors", Journal of Medicinal Chemistry, 2000, Vol. 43, pp. 3778-3785; S.P. Nikas, S.O. Alapafuja, I. Papanastasiou, C.A. Paronis, V.G. Shukla, D.P. Papahatjis, A.L. Bowman, A. Halikhedkar, X. Han and A. Makriyannis, "Novel 1’,1’-Chain Substituted Hexahydrocannabinols: 9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist", Journal of Medicinal Chemistry, 2010, Vol. 53, pp. 6996-7010; M.J. Kavarana and R.C. Peet, "Bioenzymatic Synthesis of THC-V, CBV and CBN and their use as Therapeutic Agents", US Publication 2017 / 0283837A1; R. Winnicki, M. Donsky, M. Sun and R. Peet, "Apparatus and Methods for Biosynthetic Production of Cannabinoids", U.S. Patent No. 9,879,292; P.D. Giorgi, V. Liautard, M. Pucheault and S. Antoniotti, "Biomimetic Cannabinoid Synthesis Revisited: Batch and Flow All-Catalytic Synthesis of (±)-ortho-Tetrahydrocannabinols and Analogues from Natural Feedstocks", European Journal of Organic Chemistry, 2018, pp.1307-1311; S. Morimoto, K. Komatsu, F. Taura and Y. Shoyama, "Enzymological Evidence for Cannabichromenic Acid Biosynthesis", Journal of Natural Products, 1997, Vol. 60, pp.854-857; H. Saimoto, K. Yoshida, T. Murakami, M. Morimoto, H. Sashiwa and Y. Shigemasa, "Effect of Calcium Reagents on Aldol Reactions of Phenolic Enolates with Aldehydes in Alcohol", Journal of Organic Chemistry, 1996, Vol. 61, pp.6768-6769; F. Pollastro, D. Caprioglio, P. Marotta, AS Moriello, L. De Petrocellis, O. Taglialatela-Scafati and G. Appendino. pp. 630-633; KP Bastola, A. Hazekamp and R. Verpoorte.

[0004] Over the past 20 years, cannabinoids have been re-evaluated for a variety of biomedical applications, and it is clear that they are experiencing a renaissance, so to speak. The pharmacological effects of cannabinoids have been shown to be associated with ion transport membrane proteins such as cannabinoid receptors, GPCR receptors, serotonin receptors, multiple voltage-gated channels (including Ca2+, Na+, and various K+ channels), ligand-gated ion channels (GABA, glycine, TRPV, etc.), Toll-like receptors, opioid receptors, NMDA or excitatory amino acid receptors, catecholamine receptors, enzymes that regulate endocannabinoids, and transient receptor potential (TRP) channels (L. De Petrocellis, M. Nabissi, G. Santoni and A. Ligresti, “Actions and Regulation of Ionotropic Cannabinoid Receptors”, Advances in Pharmacology, 2017, Vol. 80, pp. 249-289; P. Morales and PH Reggio, “An Update on Non-CB1, Non-CB2 Cannabinoid Related G-Protein-Coupled Receptors”, Cannabis Cannabinoid Research, (2017, Vol. 2, pp. 265-273). Therefore, it is useful to provide novel pharmaceuticals containing one or more cannabinoids that can be used to treat diseases known to be treatable by acting on or utilizing these physiological mechanisms.

[0005] The pharmacological effects of cannabinoids are expressed directly or indirectly via receptors, one example being mediated by CB1 and CB2, two G protein-coupled receptors that share 44% sequence homology in humans. The CB1 subtype is the most widely expressed G protein-coupled receptor in the brain, found in areas that control motor function, emotion, cognition, sensory responses, pain perception, thermoregulation, and physiological functions of the cardiovascular, digestive, and respiratory systems. Specifically, it is localized in the central nervous system (CNS) and peripheral nervous system, distributed in the olfactory bulb, cerebral cortex regions, parts of the basal ganglia, thalamus, hypothalamus, cerebellar cortex, brainstem, and spinal cord. It is also expressed in pituitary and thyroid cells, adipocytes, muscle cells, hepatocytes, and even in the lungs and kidneys. On the other hand, the CB2 subtype is expressed in immune cells, hematopoietic cells, osteoclasts, and osteoblasts, and mediates immune system responses, controls inflammation, modulates inflammatory and neuropathic pain, and is also involved in bone remodeling.

[0006] The pharmacology of CB1 and CB2 receptor modulators has been reviewed by Vemuri and Makriyannis (VK Vemuri and A. Makriyannis, “Medicinal Chemistry of Cannabinoids”, Clinical Pharmacology & Therapeutics, 2015, Vol. 97, pp. 553-558). 9 -Tetrahydrocannabinol (THC) and its major metabolite, 11-hydroxy-Δ 9-The psychoactive effects of tetrahydrocannabinol are expressed via partial agonist activity on central nervous system 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, Vol. 29, pp. 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, Vol. 153, pp. 199-215). THC is useful as an analgesic, an antiemetic, and in the treatment of anorexia in AIDS patients. Other CB1 receptor modulators include tetrahydrocannabivarin (THCV) (weak antagonist) and cannabinol (CBN) (weak agonist), both of which act as weak agonists for CB2. Non-psychoactive (?)-cannabidiol (CBD) and cannabidivarin (CBDV) do not interact significantly with any receptor subclass, and their mechanism of action is not clear (J. Fernandez-Ruiz et al., “Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?”, British Journal of Clinical Pharmacology, 2013, Vol. 75, pp. 323-333; S. Rosenthaler et al., “Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures”, Neurotoxicology and Teratology, 2014, Vol. 46, pp. 49-56). Δ 9 Combinations of Δ 9Tetrahydrocannabinol (THC) (dronabinol), administered as monotherapy or in combination with ondansetron (Zofran, a 5-HT3 antagonist) or prochlorperazine (a dopamine D2 receptor antagonist), has demonstrated clinical efficacy against chemotherapy-induced nausea and vomiting in cancer patients (MB May and AE Glode, “Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics”, Cancer Management and Research, 2016, Vol. 8, pp. 49-55).

[0007] Cannabinoids used as therapeutic drugs are primarily obtained by extracting cannabis plant material, fractionating Cannabis sativa oil, or by total synthesis, usually starting with aromatic compounds or terpenes. Because cannabis oil contains over 60 natural compounds, fractionation of this oil requires extensive chromatographic purification to obtain each component with virtually high purity (over 99%), and the large number of components makes reproducible manufacturing and storage difficult. For example, Δ 9 - Tetrahydrocannabinol (THC) is used to make other cannabis-derived components, especially its isomer Δ 8- Refinement from tetrahydrocannabinol is inefficient and costly. Furthermore, since many cannabinoids in cannabis oil have different effects on CB1 and CB2 receptors, such as full agonists, partial agonists, inverse agonists, neutral agonists, and antagonists, it is particularly important that each isolated natural product does not contain other cannabinoid natural products at significant levels (below ppm), in order to avoid undesirable biological effects and to efficiently reproduce the intended specifications. In addition, since many cannabinoid natural products are obtained as oils, they are difficult to crystallize and are susceptible to oxidative degradation in the atmosphere.Its isolation is complicated by the need for expensive and difficult-to-scale chromatography and / or derivatization (e.g., B. Trawick and MH Owens, “Process for the Preparation of (-)-delta 9-Tetrahydrocannabinol”, International Publication WO2009 / 099868 A1; E. Arslantas and U. Weigl, “Method for Obtaining Pure Tetrahydrocannabinol”, U.S. Patent 7,923,558 B2; JE Field, J. Oudenes, BI Gorin, R. Orprecio, FE Silva e Souza, NJ Ramjit and E.-L. Moore, “Separation of Tetrahydrocannabinols”, U.S. Patent 7,321,047 B2; P. Bhatarah, KJ Batchelor, D. McHattie and AK Greenwood, “Delta 9 Tetrahydrocannabinol Derivatives”, WO See 2008 / 099183 A1; DC Burdick, SJ Collier, F. Jos, B. Biolatto, BJ Paul, H. Meckler, MA Helle, and AJ Habershaw, “Process for Production of Delta-9-Tetrahydrocannabinol”, U.S. Patent 7,674,922 B2).

[0008] Cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabichromemenin (CBCV,3), and cannabichromemenic acid (CBCVA,4) have been isolated from Cannabis sativa oil at various purities, and their properties have been elucidated. Cannabichromene (CBC,1) is one of the most abundant components in cannabis oil. [ka] [ka]

[0009] Many synthetic routes for producing known cannabinoids are either not economical for large-scale use due to the use of expensive reagents, or they rely on condensation reactions under acidic conditions between monoterpene starting materials and alkylresorcinol derivatives (e.g., 5-n-pentylresorcinol [olivetol]). These reactions often produce byproducts resulting from carbenium ion rearrangement and other side reactions. For example, Δ using Brønsted or Lewis acid-catalyzed condensation reactions of olivetol and monoterpenes. 9 -The production of tetrahydrocannabinol (THC) is carried out by its isomer Δ 8- The process becomes more complicated because impurities containing tetrahydrocannabinol are simultaneously generated. Such impurities make it significantly more difficult to obtain cannabinoid active pharmaceutical ingredients in substantially high purity, and also increase costs (e.g., RK Razdan, “The Total Synthesis of Cannabinoids” in “The Total Synthesis of Natural Products”, edited by J. ApSimon, 1996, Vol. 4, pp. 185-262, Wiley and Sons, New York; C. Steup and T. Herkenroth, “Process for Preparing Synthetic Cannabinoids”, U.S. Patent Application Publication 2010 / 0298579 A1; RJ Kupper, “Cannabinoid Active Pharmaceutical Ingredient for Improved Dosage Forms”, International Publication WO2006 / 133941 A2; J. Erler and S. Heitner, “Method for the Preparation of Dronabinol”, U.S. Patent 8,324,408 B2; AL Gutman, M. Etinger, I. Fedotev, R. Khanolkar, GA Nisnevich, B. Pertsikov, I. Rukhman and B. Tishin, “Methods for Purifying trans-(-)-Δ 9 -Tetrahydrocannabinol and trans-(+)-Δ 9 -Tetrahydrocannabinol (see U.S. Patent 9,278,083 B2).

[0010] Cannabichromene (CBC,1) and related chromenes have been synthesized through oxidative cyclization reactions using 2,3-dichloro-5,6-dicyano-p-benzoquinone in benzene, or amine-catalyzed condensation cyclization reactions of 5-alkylresorcinol and citral (G. Cardillo, R. Cricchio, L. Merlini, “Synthesis of D,L-Cannabichromene, Franklinone and other Natural Chromenes”, Tetrahedron, 1968, Vol. 24, pp. 4825-4831), and reactions using 1,4-dioxane (K. Morimoto, S. Taura, “Enzymological Evidence for Cannabichromenic Acid Biosynthesis”, Journal of Natural Products, 1997, Vol. 60, pp. 854-867; T. Hashimoto, DN Quang, M. Nukada, Y. Asakawa, “Isolation, Synthesis and Biological "Activity of Grifolic Acid Derivatives from the Inedible Mushroom Albatrellus dispansus", Heterocycles, 2005, Vol. 65, pp. 2431-2439; Y. Shoyama, H. Hirano, I. Nishioka, "Biosynthesis of propyl cannabinoid acid and its biosynthetic relationship with pentyl and methyl cannabinoid acids", Phytochemistry, 1984, Vol. 23, pp. 1909-1912), or reactions using dichromate (G. Cardillo, M. Orena, G. Porzi, S.Sandri, “Simple Methods for Oxidation of o - Allylphenols to Chrom - 3 - enes”, Journal of the Chemical Society, Chemical Communications, 1979, pp. 836 - 837), or the reaction using N - iodosuccinimide (A. Bongini, G. Cardillo, M. Orena, G. Porzi, S. Sandri, “A New Synthesis of 2,2’ - Dialkylchrom - 3 - enes and Flav - 3 - enes”, Tetrahedron Letters, 1979, pp. 2545 - 2548; G.-N. Nguyen, E.N. Jordan, O. Kayser, “Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa”, Journal of Natural Products, 2022, Vol. 85, pp. 1555 - 1568; L.L. Anderson, A. Ametovski, J.L. Luo, D. Everett - Morgan, I.S. McGregor, S.D. Banister, J.C. Arnold, “Cannabichromene, Related Phytocannabinoids, and 5 - Fluoro - cannabichromene Have Anticonvulsant Properties in a Mouse Model of Dravet Syndrome”, ACS Chemical Neuroscience, 2021, Vol. 12, pp. 330 - 339; J.F. Quilez del Moral, C.R. Martinez, H.P. del Pulgar, J.E.M. Gonzalez, I. Fernandez, J.L. Lopez - Perez, A. Fernandez - Arteaga, A.F.Barrero, “Synthesis of Cannabinoids: “In Water” and “On Water”Approaches: Influence of SDS Micelles”, The Journal of Organic Chemistry, 2021, vol. 86, pp. 3344-3355; J. Vacek, J. Vostalova, B. Papouskova, D. Skarupova, M. Kos, M. Kabelac, J. Storch, “Antioxidant function of phytocannabinoids: Molecular basis of their stability and cytoprotective properties under UV-irradiation”, Free Radical Biology and Medicine, 2021, vol. 164, pp. 258-270; D. Brumar, B. Geiling, M. Haghdoost Manjili, “Cannabichromene compositions and methods of synthesizing cannabichromene”, International Publication WO 2021 / 127786 Small-scale synthesis has been reported in publications such as A1;CK Marlow, “Preparation of cannabichromene and related cannabinoids”, patent application WO 2021 / 133989, and A1;W.-C. Zhang, AP Honeycutt, “Methods of preparing synthetic cannabichromene and cannabicitran and derivatives thereof”, international publication WO 2021 / 222609). However, these reactions are not suitable for the large-scale production of numerous analogs with readily altered arene ring substituents, nor do they suggest methods for synthesizing single-enantiomer cannabinoids.

[0011] Cannabichromenic acid (CBCA,2) and related chromenic acids have been reported to date to be synthesized on a small scale by bromoalene / lithium exchange and carboxylation, alkali or amine-catalyzed condensation cyclization of 5-alkylresorsilate esters with citral, quinone-mediated oxidation of substituted cyclohexanone carboxylic acid esters, or oxidative cyclization using 2,3-dichloro-5,6-dicyano-p-benzoquinone (R. Davis, J. Black, T. Smeltzer, S. Colvin, “Methods of synthesizing halogenated cannabinoids and derivatives of cannabinoids”, International Publication WO 2022 / 192582; YR Lee, JH Choi, SH Yoon, “Efficient and general method for the synthesis of benzopyrans by ethylenediamine diacetate-catalyzed reactions of resorcinols with α,β-unsaturated aldehydes. One step synthesis of biologically M. Mondal, VG Puranik, NP Argade, “A Facile Phenol-Driven Intramolecular Diastereoselective Thermal / Base-Catalyzed Dipolar [2 + 2] Annulation Reactions: An Easy Access to Complex Bioactive Natural and Unnatural Benzopyran Congeners”, The Journal of Organic Chemistry, 2007, vol. 72, pp. 2068-2076; H. Hu, TJ Harrison, PDWilson, “A Modular and Concise Total Synthesis of (±)-Daurichromenic Acid and Analogues”, The Journal of Organic Chemistry, 2004, Vol. 69, pp. 3782-3786; S. Morimoto, K. Komatsu, F. Taura, Y. Shoyama, “Enzymological Evidence for Cannabichromenic Acid Biosynthesis”, Journal of Natural Products, 1997, Vol. 60, pp. 854-857). However, none of these reactions are suitable for the large-scale production of numerous analogues with readily altered arene ring substituents, nor do they offer any suggestions for the synthesis of single-enantiomer cannabinoids.

[0012] Studies on the synthesis and characterization of cocrystals derived from cannabinoids and cocrystal formation aids have been limited to date. Cocrystal derivatives of racemic quinone analogs of cannabichromene (CBC, 1) have already been disclosed. Cocrystallization of low molecular weight cannabinoids, namely cannabinol (CBN; melting point 75-77°C) and tetrahydrocannabinol (THC; melting point 63-66°C), with carnitine, aspartame, L-proline, D-proline, L-arginine, L-lysine, betaine, tetramethylpyrazine, 1H-imidazole, nicotinic acid, saccharin, urea, or nicotinamide is considered useful and is presumed to provide higher melting point solids. In particular, cocrystals of CBN with tetramethylpyrazine, L-proline, or D-proline have been most extensively studied by powder X-ray diffraction analysis. Furthermore, cocrystals of cannabinoids, including THC, cannabidiol (CBD), or CBN, with stilbenoids, including resveratrol, piceatannoline, pinosylvin, astringin, piseid, oxyresveratrol, ameropsin A, ameropsin B, viticin A, combretastatin, combretastatin B-1, isonotraenoic acid, combretastatin A-1, combretastatin A-4, gnetocreistol E, pinostilbene, pterostilbene, isoharpontigenin, gnetocreistol D, 4-methoxyresveratrol, lapontisin and lapontigenin, cavicuraline, 1-hydroxyphenanthrene, or anjuncosol, have been shown to be useful when used in combination with carbohydrate supplements in oral formulations (E. Munoz Blanco and G. Appendino, “Chromenic phytocannabinoids, their synthesis and use in treatment "or prevention of disease", European Public EP 3,666,765 A1; E. Munoz Blanco, G. Appendino and JDUniciti-Broceta, “Chromenic phytocannabinoids, their synthesis and use in treatment or prevention of Disease”, International Publication WO 2020 / 120582 A1; G. Mkrtchyan, JK Hoerner, RW Couch, JA Bis, and SAR Carino, “Cocrystals of Cannabinoids”, International Publication WO 2021 / 138610 A1; G. Rehman and KP Bushfield, “Compositions comprising co-crystals of stilbenoids and cannabinoids”, International Publication WO 2019 / 153088 A1; N. Tesson, C. Trilla, and AC Comely, “Solid compositions of cocrystals of cannabinoids”, International Publication WO 2020 / 089424 A1).

[0013] To date, no studies have utilized cocrystallization as a means of separating racemic cannabinoids. Furthermore, no specific studies have been reported on the formation of cocrystal derivatives for cannabichromene (CBC, 1), cannabichromenic acid (CBCA, 2), cannabiclomevalin (CBCV, 3), cannabiclomevalic acid (CBCVA, 4), or any of these structurally related non-quinone cannabinoids.

[0014] There are limited examples of studies that have isolated and studied the optical isomers of chromene-type cannabinoids. While it has been reported that naturally occurring cannabichromene (CBC, 1) can be optically resolved by chiral HPLC, there are no reports on the optical resolution of other chromene-type cannabinoids or cannabinoid acids, and the relative efficacy of each isolated optical isomer against biomedically relevant targets and their actions in cell assays remain unknown. Groudischaudic acid (5), a structurally related meliterpenoid, is a prenylated chromene that was isolated from Piper gaudichaudianu, separated by HPLC, and its (S)-enantiomer has been shown to have potent trypanosomiatic activity against Trypanosoma cruzi Y strain. In addition, several chromenes with anti-HIV activity have been obtained from methanol extracts of the Asian plant Rhododendron dauricum, and these are derived from the parent compound (+)-daurichromenic acid (6). This single enantiomer meriterpenoid chromene 6 is synthesized via a multi-step synthetic route from farnesar. [ka] [ka]

[0015] The following literature is relevant to studies on this type of separation. G. Mazzoccanti, OH Ismail, I. D'Acquarica, C. Villani, C. Manzo, M. Wilcox, A. Cavazzini and F. Gasparrini, “Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra-high performance supercritical fluid chromatography”, Chemical Communications, 2017, Paper 53, 12262-12265; JM Batista Jr., ANL Batista, D Rinaldo, W Vilegas, DL Ambrosio, RBM Cicarelli, VS Bolzani, MJ Kato, LA Nafie, SN Lopez and M. Furlan, “Absolute Configuration and Selective Trypanocidal Activity of Gaudichaudianic Acid Enantiomers,” Journal of Natural Products, 2011, page 74, pages 1154-1160; A. Mandi, MMM Swamy, T. Taniguchi, M. Anetai and K.S. Monde, “Reducing Molecular Flexibility by Cyclization for Elucidation of Absolute Configurations by CD Calculations: Daurochromenic Acid”, Chirality, 2016, page 28, pages 453-459; MMM Swamy, A. Mandi, M. Anetai, and K. Monde, “Stereochemistry of a Rhododaurochromanic Acid Derivative”, Natural Product Communications, 2016, Vol. 11, pp. 193-195; K. Liu and K. Woggon, “Enantioselective Synthesis of Daurichromenic Acid and Confluentin”, European Journal of Organic Chemistry, 2010, pp. 1033-1036; M. Okada, K. Saito, CP Wong, C. Li, D. Wang, M. Iijima, F. Taura, F. Kurosaki, T. Awakawa and I. Abe, “Combinatorial Biosynthesis of (+)-Daurichromenic Acid and Its Halogenated Analogue”, Organic Letters, 2017, Vol. 19, pp. 3183-3186; Z. Jin and Y. Kang, “Total Synthesis of Daurichromenic Acid”, U.S. Patent No. 7,102,020; AR Agua, PJ Barr, CK Marlowe, and MC Pirrung, “Cannabichromene Racemization and Absolute Stereochemistry Based on a Cannabicyclol Analog”, The Journal of Organic Chemistry, 2021, Vol. 86, pp. 8036-8040; JM Ferraro and WJ Umstead, “Chiral Separation of Cannabichromene, Cannabicyclol, and Their Acidic Analogs on Polysaccharide Chiral Stationary Phases”, Molecules, 2023, Vol. 28, Article No. 1164 (16 pages total); T. Onishi and WJ Umstead, “The Separation of Cannabinoids on Sub-2 μm Immobilized Polysaccharide Chiral Stationary Phases”, Pharmaceuticals, 2021, Vol. 14, Article No. 1250 (11 pages total); C. De Luca, A. Buratti, W. Umstead, P. Franco, A. Cavazzini, S. Felletti and M. Catani, “Investigation of retention behavior of natural cannabinoids on differently substituted polysaccharide-based chiral stationary phases under reversed-phase liquid chromatographic conditions”, Journal of Chromatography A, 2022, Volume 1672, Paper number 463076 (8 pages); Furthermore, this is also described in DC Metcalf, “Composition and methods to separate cannabinoids from impurities by crystallization”, International Publication WO 2022 / 020743 A1.

[0016] Regarding crystalline salts of cannabinoid carboxylic acids, salts have been synthesized with non-chiral amines such as triethylamine, tributylamine, N,N-diisopropylethylamine, methyldicyclohexylamine, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nona-5-ene, dicyclohexylamine, isopropylcyclohexylamine, and 2,2,6,6-tetramethylpiperidine. However, there have been no reported cases of separating racemic cannabinoid carboxylic acids with chiral amines (T. Durst and J. van der Vlugt, “Methods for extraction, processing, and purification of minor cannabinoid compounds from cannabis”, International Publication WO 2022 / 115971 A1).

[0017] Cannabichromene (CBC,1) does not show significant affinity for CB1 and CB2 receptors, but is known to inhibit the intracellular uptake of anandamide. CBC(1) is the most potent agonist of the TRPA1 cation channel among plant cannabinoids, and also acts on TRP channels, activating TRPV3 and TRPV4, inhibiting TRPV4 agonism, and activating TRPM8, although these effects have all been reported to be expressed with low potency. In addition, CBC has been reported to increase the survival rate of adult mouse neural stem / progenitor cells in the process of differentiation, and is known to have anti-inflammatory, antibacterial, and antifungal effects.Furthermore, CBC(9) has been shown to exhibit anti-inflammatory effects in activated macrophages, and this effect is negatively linked to constitutive CB1 cannabinoid signaling. It has also been shown to improve experimental mouse colitis. (SE Turner, CM Williams, L. Iversen and BJ Whalley, “Molecular Pharmacology of Phytocannabinoids”, Phytocannabinoids, 2017, pp.61-101; A. Tubaro, A. Giangaspero, S. Sosa, R. Negri, G. Grassi, S. Casano, RD Loggia and G. Appendino, “Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins”, Fitoterapia, 2010, vol.81, pp.816-819; CE Turner and MA Elsohly, “Biological activity of cannabichromene, its homologs and isomers”, Journal of Clinical) Pharmacology, 1981, vol.21, Supplement, pp.283-291; B. Romano, F. Borrelli, I. Fasolino, R. Capasso, F. Piscitelli, MG Cascio, RG Pertwee, D. Coppola, L. Vassallo, P. Orlando, V. Di Marzo and AA Izzo, “The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis”, British Journal of Pharmacology, 2013, vol.169, pp.213-229).

[0018] Studies on the biological effects of cannabichromevaline (CBCV,3) are limited. CBCV has been reported to have anti-inflammatory effects when used in combination with other cannabinoids, and is claimed to be useful in both monotherapy and combination therapy for the treatment of epilepsy. Furthermore, CBCV(3) has been shown to have a relatively weak inhibitory effect on homeodomain-interacting protein kinase 2, a conserved serine / threonine kinase that regulates transcription, cell differentiation, proliferation, and apoptosis (Y. Shoyama, H. Hirano, M. Oda, T. Somehara and I. Nishioka, “Cannabis IX Cannabichromevarin and cannabigerovarin, two new propyl homologs of cannabichromene and cannabigerol”, Chemical & Pharmaceutical Bulletin, 1975, vol.23, pp.1894-1895; A. Tubaro, A. Giangaspero, S. Sosa, R. Negri, G. Grassi, S. Casano, RD Loggia and G. Appendino, “Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins”, Fitoterapia, 2010, vol.81, pp.816-819; V. Stahl, “Cannabis and Derivatives Thereof for the Treatment of Pain and Inflammation Related with Dental Pulp and Bone Regeneration Related to Dental Jaw Bone Defects”, WO Patent Application 2019 / 030762 A2; G. Wang, L. Zhu, Y. Zhao, S. Gao, D. Sun, J. Yuan, Y. Huang, X. Zhang and X.Yao, “A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP+-induced apoptosis in human neuroblastoma SH-SY5Y cells”, Bioorganic Chemistry, 2017, vol.72, pp.64-73; B. Whalley, C. Williams, G. Stephens and T. Futamura, “Use of the Phytocannabinoid Cannabidivarin (CBDV) in the Treatment of Epilepsy”, U.S. Patent 9,125,859).

[0019] Cannabichromenic acid (CBCA, 2) and cannabichrome valic acid (CBCVA, 4) currently have limited biological or medical applications. Various biological effects have been reported for other cannabinoid carboxylic acids. For example, cannabigerolic acid (CBGA) is said to have a mild regulatory effect on the inhibition of ovarian, breast, lung, pancreatic, and other cancer cell proliferation by cannabidiol (CBD) and cannabigerol (CBG), and is also claimed to kill breast cancer cells itself. Furthermore, CBGA is known to act as an inverse agonist of the G protein-coupled receptor GPR55, an antagonist of monoacylglyceride lipase, and a PPARα / γ dual agonist, suggesting the possibility of analgesic effects. Cannabigerovalic acid (CBGVA) has been reported to have an anti-cancer cytostatic effect on leukemia cells at high concentrations. Furthermore, it has been claimed that mixtures of CBCA(2), CBCVA(4), or other cannabinoids with mitraginine, pseudoindoxyl, or 7-hydroxymitraginine, and other additives can be used to treat inflammation, spasms, or pain. In addition, CBCA(2), along with other acidic cannabinoids, has been shown to be useful in enhancing the natural resistance of animals, improving cellular resistance, treating diabetes or arteriosclerosis, and suppressing age-related decline in stress response, based on cell studies.Furthermore, formulations containing CBCA(2) or other cannabinoids, combined with isotonic agents, surfactants, and one or more stabilizers, are considered particularly useful as neuroprotective and anticonvulsant agents in the treatment of neonatal hypoxic-ischemic encephalopathy, status epilepticus, or stroke (E. D'Aniello et al., 2019; HAAJ Korthout et al., U.S. Patent 7,807,711; D. Parolaro et al., U.S. Patent 8,790,719; FA Javid et al., U.S. Patent 10,098,867; C. Stott et al., U.S. Patent 9,962,341; KA Scott et al., 2013; SA Ahmed et al., 2008; A. Kariman, U.S. Patent Publication 2018 / 0193399 A1; HAAJ Korthout, International Publication WO2012 / 144892 A1; S. Wright et al., UK Patent 2551986).

[0020] Numerous mixtures have been proposed involving one, two, or three cannabinoids, including cannabichromemenic acid (CBCA, 2) or cannabichrome varic acid (CBCVA, 4), and terpenes, but their specific applications remain unclear (K. Levy, JM Cooper, JR Martin and BG Reid, “Compositions Purposefully Selected Comprising Purified Cannabinoids and / or Purified Terpenes”, International Publication WO 2018 / 160827 A1).

[0021] In contrast to the currently limited biomedical applications of cannabinoid acids 2 and 4, tetrahydrocannabinolic acid (THCA), the carboxylic acid precursor of THC, has been widely studied. Several preclinical studies have shown that THCA is useful for controlling pain, including neuropathic pain and fibromyalgia, as well as for epilepsy, prostate cancer, breast cancer, colorectal cancer, lung cancer, and skin cancer, inflammatory diseases including encephalomyelitis, and autoimmune diseases, and also possesses antiemetic effects (e.g., RZ Dejana, M. Foli?, Z. Tantoush, M. Radovanovi?, G. Babi? and SM Jankovi?, “Investigational cannabinoids in seizure disorders, what have we learned thus far?” Expert Opinion on Investigational Drugs, 2018, Vol. 27, pp. 535-541; EM Rock, RL Kopstick, CL Limebeer and LA Parker, “Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus”, British Journal of Pharmacology, 2013, Vol. 170). pp. 641-648; HAAJ Korthout, KCM Verhoeckx, RF Witkamp, ​​RP Doornbos and M. Wang, “Medicinal Acidic Cannabinoids”, US Patent 7,807,711 B2; EM Rock, CL Limebeer, R. Navaratnam, MA Sticht, N. Bonner, K. Engeland, R. Downey, H. Morris, M. Jackson and LAParker, “A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping”, Psychopharmacology, 2014, Volume 231, pages 3207 - 3215; V. Di Marzo, L. De Petrocellis and A.S. Moriello, “New use for cannabinoid-containing plant extracts”, UK Patent 2,448,535; D. Parolaro, P. Massi, A. Antonio, F. Borelli, G. Aviello, V. Di Marzo, L. De Petrocellis, A.S. Schiano Moriello, A. Ligresti, A.; R.A. Ross, L.A. Ford, S. Anavi-Goffer, M. Guzman, G. Velasco, M. Lorente, S. Torres, T. Kikuchi, G. Guy, C. Stott, S. Wright, A. Sutton, D. Potter and E. De Meijer, “Phytocannabinoids in the Treatment of Cancer”, US Patent 8,790,719; T.P. Castor, L.C. Rosenberry, T.A. Tyler, R.J. Student, “Methods for Making Compositions and Compositions for Treating Pain and Cachexia”, US Publication 2008 / 0103193 A1; K. Kariman, “Compound and Method for Treating Spasms, Inflammation and Pain”, US Publication 2018 / 0193399 A1; A. Sinai and Z.Turner, “Use of Cannabis to Treat Fibromyalgia, Methods and Compositions Thereof”, International Publication WO 2016 / 181394 A1).

[0022] If cannabinoid acids 2 and 4 become readily available in larger quantities and higher purity, their applications in medicine can be more appropriately and thoroughly investigated, either as standalone therapeutic agents or in combination with other cannabinoids and other bioactive compounds. It is noteworthy that mixtures of cannabinoids may exhibit higher efficacy than single components (the so-called "entourage effect"), for example, the presence of THCA and other cannabinoids has been shown to enhance the efficacy of THC as an antitumor agent in cell culture and animal models of ER+ / PR+, HER2+, and triple-negative breast cancer (see, e.g., S. Blasco-Benito et al., Biochemical Pharmacology, 2018, vol. 157, pp. 285-293).

[0023] The present invention aims to solve the problem of difficulty in obtaining high-purity cannabinoids 1-4, and provides an efficient and highly reproducible manufacturing route for these compounds, as well as a flexible synthesis method for novel cannabinoid analogs. These compounds, when formulated alone or in combination with known cannabinoids or other drugs, are useful in the treatment of a wide range of diseases, including infections, pain, spasticity, nausea, loss of appetite associated with multiple sclerosis, epilepsy, Alzheimer's disease and neurodegenerative diseases, brain injury / concussion / traumatic brain injury, stroke, cancer, inflammation and immune-inflammatory diseases, glaucoma, dry eye, corneal injury or disease, eye diseases / injuries including retinal degeneration or disease, immune-inflammatory diseases, lung injury or disease, liver injury or disease, kidney injury or disease, pancreatitis and pancreatic diseases, cardiovascular injury or disease, suppression of inflammation after organ transplantation, reduction of postoperative inflammation, and treatment or prevention of skin diseases, and are also useful as antioxidants. [Prior art documents] [Patent Documents]

[0024] [Patent Document 1] International Publication No. 2016 / 181394 [Overview of the project] [Problems that the invention aims to solve]

[0025] In addition to the advantages and improvements disclosed herein, other objects and effects of the present invention will become apparent from the following description. In the drawings, the same reference numerals indicate the same parts. Detailed embodiments relating to cannabinoid compounds, intermediate compounds, and methods for producing cannabinoids and cannabimimeric compounds and their intermediates are disclosed here, but these embodiments are illustrative of the present invention and do not prevent the invention from being carried out in various forms. Furthermore, the examples shown in relation to each embodiment of the present invention are for illustrative purposes only and are not intended to be limiting.

[0026] In this specification and in the claims, unless the context clearly indicates otherwise, the following terms shall have the meanings expressly given herein. The expression “in one embodiment” in this specification does not necessarily refer to the same embodiment, but may be the same. Similarly, the expression “in another embodiment” does not necessarily refer to a different embodiment, but may be different. Thus, various embodiments can be readily combined without departing from the scope or spirit of the invention, as described below.

[0027] Furthermore, as used herein, the term "or" means inclusive "or" and is synonymous with "and / or" unless the context clearly indicates a different meaning. The term "based on" is not exclusive and may also be based on additional factors not mentioned. Also, throughout this specification, "a," "an," and "the" have a plural meaning. Furthermore, "in" has both the meaning of "inside (in)" and "on top of (on)."

[0028] Furthermore, as used herein, “substantially,” “effectively,” “similar,” “similarly,” “corresponding,” “equivalently,” “approximately,” “about,” and any combination thereof mean, unless otherwise specified, that the difference between the features or characteristics being compared is less than 25% of the respective values ​​or magnitudes of those features or characteristics as measured or defined.

[0029] The purpose of the combination or adjunctive therapies described herein is to enhance the efficacy of a drug by using a second or more drugs in combination, or to reduce the dose-limiting toxicity of a drug by using a second or more drugs in combination.

[0030] As used herein, "optionally substituted benzyl" means a benzyl group having one, two, or three independently selected C1-C4 alkyl groups, C1-C4 alkoxy groups, fluoro groups, chloro groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, methylenedioxy groups, cyano groups, or methoxymethyl groups optionally substituted on the aromatic ring, or a benzyl group having one or two independently selected C1-C4 alkyl groups optionally substituted on the benzylmethylene moiety.

[0031] As used herein, "optionally substituted 2-phenylethyl" means a 2-phenylethyl group having one, two, or three independently selected C1-C4 alkyl groups, C1-C4 alkoxy groups, fluoro groups, chloro groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, methylenedioxy groups, cyano groups, or methoxymethyl groups optionally substituted on the aromatic ring, or a 2-phenylethyl group having one or two independently selected C1-C4 alkyl groups optionally substituted on either or both of the methylene groups.

[0032] Unless otherwise defined herein, "arbitrarily substituted" means a phenyl ring as an aromatic ring, and includes those having one, two, or three independently selected C1-C4 alkyl groups, C1-C4 alkoxy groups, fluoro groups, or chloro groups substituted on the aromatic ring.

[0033] Unless otherwise defined herein, “substituted” means that at any position it may be optionally substituted with a C1-C4 alkyl group, a C1-C4 alkoxy group, a fluoro group, a chloro group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a methylenedioxy group, a cyano group, or a methoxymethyl group. [Means for solving the problem]

[0034] This invention relates to a method for preparing a variety of known and novel racemic cannabinoids 7 from a precursor 8 via a racemic intermediate 9. This includes racemic cannabichromene (CBC,1), racemic cannabichromenic acid (CBCA,2), racemic cannabiclomevalin (CBCV,3), racemic cannabiclomevalic acid (CBCVA,4), other naturally occurring racemic bicyclic cannabinoids, and other synthetic racemic bicyclic analogs. In this invention, using inexpensive and readily available starting materials, dioxinone 8 is prepared by a cascade reaction consisting of allyl rearrangement and aromatization reactions, and then dioxinone 9 is produced by oxidative cyclization, which is converted to racemic cannabinoid 7. Furthermore, the present invention relates to methods for separating racemic cannabichromene (CBC,1), racemic cannabiclomevalin (CBCV,3), racemic cannabichromenic acid (CBCA,2), racemic cannabiclomevalic acid (CBCVA,4), and other racemic bicyclic neutral cannabinoids and cannabinoid carboxylic acids. This includes direct separation of enantiomers by HPLC, or formation of diastereomerized cocrystals with a chiral cocrystallizing agent (CCA), separation and reconversion to the desired cannabinoid, or separation by formation of diastereomerized salts of racemic cannabichromenic acid (CBCA,2), racemic cannabiclomevalic acid (CBCVA,4) and related racemic cannabinoid acids with chiral amines (CA). These salts can be converted to single enantiomers of cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabiclomevalin (CBCV,3), cannabiclomevalic acid (CBCVA,4), and related single enantiomer cannabinoids by acid treatment (with decarboxylation if necessary) after alkali or base treatment. Non-racemic (scaremic) mixtures, such as single compounds of both enantiomer series and pairs of their enantiomers, can also be obtained.

[0035] [ka] Here, R AThis includes hydrogen, CO2H and its pharmaceutically acceptable salts or cocrystals, and CO2R C CONHR D CONR D R E That is the case. R B C1-C2 alkyl, linear or branched C3-C 10 Alkyl or double-branched C4 to C 10 Alkyl, which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, (CH2)o-C3 to C6 cycloalkyl, (CH2)p-OR F or C3 to C6 cycloalkyl (which may be optionally substituted with C1 to C8 alkyl groups). o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R C These are C1-C6 alkyl, (CH2)q-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. q is 0, 1, 2, 3, 4, 5, or 6. R D These are C1-C6 alkyl, (CH2)r-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. R E This is a C1-C6 alkyl, (CH2)r-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. Or, NR D R E The group is azetidinil, pyrrolidinil, morpholinil, or piperidinil, which may each be optionally substituted with one or two hydroxyl groups or one hydroxymethyl group. However, in the case of morpholine, hydroxyl groups may not be substituted on carbon atoms having heterocyclic nitrogen or heterocyclic oxygen. R FThese are C1 to C6 alkyl groups and (CH2)r-C3 to C6 cycloalkyl groups. Each r is independently 0, 1, 2, 3, 4, 5, or 6. Rα represents a C1 to C6 alkyl group or an optionally substituted aryl group, preferably methyl. Rβ represents a C1-C6 alkyl or optionally substituted aryl, preferably methyl. Or, Rα and Rβ combine to form (CH2)s, where s is 4, 5, or 6. Any hydroxyl group in the RB substituent in structural formulas 8 and 9 is protected.

[0036] The synthesis method of the present invention is applicable to large-scale production and manufacturing applications and can be used to produce racemic mixtures, single enantiomers, or non-racemic (scaremic) mixtures. Examples of known cannabinoids that can be obtained by the synthesis route of the present invention include cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabiclomevalin (CBCV,3), and cannabiclomevalic acid (CBCVA,4).

[0037] The synthesis method of the present invention is also applicable to the synthesis of racemic mixtures, single enantiomers, or non-racemic (scaremic) mixtures of novel cannabinoid 7, and these novel compounds also constitute part of the present invention. The racemic cannabinoid 7 described below are novel analogs of cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabiclomevalin (CBCV,3), and cannabiclomevalic acid (CBCVA,4), which can also be obtained by the synthesis route described herein, and these also constitute part of the present invention.

[0038] The synthesis method of the present invention is also applicable to the synthesis of known and novel cannabinoid 7 as single enantiomers of the (S) or (R) enantiomer series. Specifically, by direct separation of enantiomers by HPLC, or by the formation and separation of diastereoisomer cocrystals and their reconversion to cannabinoids, or by the reaction of cannabinoid carboxylic acid (7,RA=CO2H) with optically active amines or optically active alcohols to form diastereoisomer salts, esters, or amides, which are then treated with alkalis or bases, and further treated with acid (with decarboxylation if necessary), single enantiomer cannabinoid carboxylic acid (7,RA=CO2H) or neutral cannabinoid (7,RA=H), as well as related cannabinoids belonging to both enantiomer series, can be obtained. Such separation can also be used to produce scaremic mixtures (non-racemic mixtures) of cannabinoids (S)-7 and (R)-7, as well as single enantiomers.

[0039] These novel single-enantiomer cannabinoids (S)-7 and (R)-7 include single enantiomers of cannabichromemenic acid (CBCA,2) and cannabichrome varic acid (CBCVA,4), as well as all their analogues, which also constitute part of the present invention.

[0040] The chemical formulas for these novel single enantiomercannabinoids (S)-7 and (R)-7 are as follows: [ka] Here, R A H is H. R BThis refers to H, methyl, ethyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, which in any case may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, or n-propyl or n-hexyl which is substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, or branched C3 to C which is substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. 10 Alkyl or double-branched C4 to C 10 Alkyl, or (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F or a C3 to C6 cycloalkyl group optionally substituted with a C1 to C8 alkyl group. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R F C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl Each r is independently 0, 1, 2, 3, 4, 5, or 6.

[0041] or R A CO2H and its pharmaceutically acceptable salts or cocrystals, CO2R C CONHR D CONR D R E That is the case. R B This is H, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, which in any case are optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, or branched C3 to C which are optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. 10 Alkyl or double-branched C4 to C 10 Alkyl, or (CH2)o -C3 to C6 cycloalkyl, (CH2) p -OR F or a C3 to C6 cycloalkyl group optionally substituted with a C1 to C8 alkyl group. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R C C1 to C6 alkyl, (CH2) q -C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. q is 0, 1, 2, 3, 4, 5, or 6. R D C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. R E C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. Or NR D R E These are azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with one or two hydroxyl groups or one hydroxymethyl group, provided that the hydroxyl groups are not present on carbon atoms having heterocyclic nitrogen atoms or, in the case of morpholine, on carbon atoms having heterocyclic oxygen atoms. R F C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl Each r is independently 0, 1, 2, 3, 4, 5, or 6. However, R B In this compound, each hydroxyl group is not located on the carbon atom containing the fluoro group, nor on the carbon atom containing the second hydroxyl group.

[0042] The novel cannabinoid represented by the limited chemical formula 7 described above may be used alone or as a racemic mixture, a single enantiomer ((S)-7 or (R)-7), or a scaremic mixture, or as a known cannabinoid (e.g., Δ 9 -They can be used as active ingredients in combination with other pharmaceuticals (not limited to tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), or cannabidivarin (CBDV)). These can be used to treat infections, pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's disease-related brain injury / concussion, cancer, glaucoma and retinal degeneration, immune-inflammatory diseases, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, and other pathological conditions. In some embodiments, the novel cannabinoids represented by the limited chemical formula 7 described above can be used alone or in combination with Δ 9 -The drug is prepared as a formulation suitable for administration to patients by combining it with known cannabinoids such as tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabidivarin (CBDV), or other pharmaceuticals. Such formulations contain a combination therapeutic agent containing cannabinoids or a combination thereof, or other pharmaceuticals, as active ingredients, in addition to pharmaceutically acceptable diluents and excipients. The term “excipients” in this invention encompasses standard excipients well known to those skilled in the art (see, for example, Niazi, SK, “Handbook of Pharmaceutical Manufacturing Formulations, Compressed Solid Products, 2009, 2nd edition, Informa Healthcare, Vol. 1, p. 67, 99-169”), but may also include volatile components such as isolated monoterpenes derived from Cannabis sativa or citrus oil, or their synthesis or mixtures. The above-described drug compositions can be administered to patients orally, sublingually, intranasally, by inhalation, rectally, or parenterally, or by other well-known clinical administration methods. [Modes for carrying out the invention]

[0043] Large-scale synthesis methods and racemic separation of cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabichrome valine (CBCV,3), cannabichrome valine (CBCVA,4) and their analogues.

[0044] The present invention relates to a method for the large-scale preparation of a diverse range of known and novel cannabinoids 7, including cannabichromene (CBC,1), cannabichromenic acid (CBCA,2), cannabichrome valine (CBCV,3), cannabichrome valine (CBCVA,4), and other naturally occurring bicyclic cannabinoids. This method is characterized by the use of a cascade reaction series of oxidative cyclization and dioxynone ring cleavage from inexpensive and readily available starting materials. Furthermore, the present invention includes the synthesis of the target cannabinoid, including solvates, hydrates, and polymorphs, as needed, as oily substances or crystalline derivatives. This method includes the large-scale synthesis of racemic cannabinoid 7 and the separation thereof into single enantiomers, cannabinoids (S)-7 and (R)-7. [ka] [ka]

[0045] Here, R A This includes hydrogen (H), a carboxyl group (CO2H), and its pharmaceutically acceptable salts or cocrystals, CO2R C CONHR D , or CONR D R E That is the case. R B These are hydrogen (H), C1-C2 alkyl, linear or branched C3-C2 10 Alkyl, or double-branched C4 to C 10 The alkyl group is represented, and these may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. Also, R B(CH2)o-C3 to C6 cycloalkyl, (CH2)p-OR F or C3 to C6 cycloalkyl (which may be optionally substituted with C1 to C8 alkyl groups). o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R C These are C1-C6 alkyl, (CH2)q-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. q is 0, 1, 2, 3, 4, 5, or 6. R D C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. R E C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. Or, NR D R E These are azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with one or two hydroxyl groups or one hydroxymethyl group, except that, in the case of morpholine, the hydroxyl groups are not substituted on carbon atoms having a nitrogen or oxygen atom in the heterocyclic ring. R F C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl Each r is independently 0, 1, 2, 3, 4, 5, or 6.

[0046] The above manufacturing method includes the following: The first intermediate represented by chemical formula (8) is treated in a solvent at 40 to 100°C with a stoichiometric oxidizing agent, an optional secondary oxidizing agent, an optional additive or group of additives, and a palladium catalyst to obtain a racemic intermediate (9). Next, the racemic dioxinone (9) is hydrolyzed with an alkali or a base in a protic medium and acidified to obtain the racemic carboxylic acid (7) [R A =CO2H], or a step of obtaining the racemic neutral cannabinoid (7) [R A =H] separated by such hydrolysis and decarboxylation, or a step of obtaining the racemic cannabinoid ester (7) [CO2R C by such hydrolysis and esterification, or a step of obtaining the racemic cannabinoid amide (7) [CONHR D , CONR D R E by such hydrolysis and amidation.

[0047]

Chemical formula

[0048] Or, The racemic cannabinoid carboxylic acid 7 [R A =CO2H] is reacted with a single enantiomer chiral alcohol [R G OH] or a single enantiomer chiral amine [R H R I NH] to obtain the diastereomeric cannabinoid ester 7 [R A =CO2R G or the cannabinoid amide 7 [R A =CONR [[ID=3E]] H R B I is separated by normal phase chromatography (such as column chromatography or HPLC, etc.), and hydrolysis with decarboxylation is carried out as necessary to obtain the corresponding single enantiomer cannabinoids (S)-7 and (R)-7 (R A =CO2H or H). Or, The racemic carboxylic acid 7 [R A =CO2H], the racemic neutral cannabinoid 7 [R A =H], the racemic cannabinoid ester 7 [CO2R C , or the racemic cannabinoid amide 7 [CONHR D , CONR D R EThe mixture is treated with a chiral cocrystallization reagent (CCR), and the two resulting diastereomer cocrystals are separated and reconverted to their respective single enantiomers, cannabinoids (S)-7 and (R)-7.

[0049] or Racemic carboxylic acid 7[RA=CO2H] was treated with chiral amine (CA) to separate diastereomerated salts 10 and 11, and these salts 10 and 11 were treated with alkali or base to separate cannabinoid acids (S)-7 and (R)-7[R A By obtaining [=CO2H] or by decarboxylation after such hydrolysis, the separated cannabinoids (S)-7 and (R)-7[R A [=H] is obtained. Alternatively, by such hydrolysis and esterification, the separated cannabinoid esters (S)-7 and (R)-7[CO2RC] can be obtained, or by such hydrolysis and amidation, the separated cannabinoid amides (S)-7 and (R)-7[CONHR D CONR D R E Obtain ]. Here, R G -OH is a single enantiomer of chiral alcohol, not limited to menthol, 2-octanol, α-methylphenol, methylmandelate, or 1-phenylethanol. R H R I NH is a single, isolated enantiomer of a chiral amine, not limited to α-methylbenzylamine, α-methylnaphthylamine, leucine methyl ester, 1-amino-2-propanol, dimethylaspartate, ephedrine, dimethylglutamate, or phenylalanine methyl ester.

[0050] Generally, the two diastereomer salts 10 and 11 are separated by fractional recrystallization or by other techniques well known to those skilled in the art (see methods described in standard textbooks; for example, see Jaques, J.; Collet, A.; Wilen, SH, “Enantiomers, Racemates and Resolutions”, John Wiley & Sons, New York, 1981, Section 5.1.1 “Resolution of Acids”, pp. 257–259, 283–295, 299–328 and 329). Alternatively, the racemic carboxylic acid 7[R A =CO2H] is converted into chiral alcohol (R G -OH) or chiral amine (R H R I Condensation with NH) yields a mixture of the corresponding diastereomer esters 12 and 13 or diastereomer amides 14 and 15, and these two esters or amides are separated by fractional recrystallization, chromatography, or other techniques well known to those skilled in the art (as described by Jaques, Collet, Wilen, or known in general knowledge). The esters 12 or 13, or amides 14 or 15 are then hydrolyzed with appropriate deprotection to obtain single enantiomers of carboxylic acids (S)-7 and (R)-7[R] A [=CO2H] is obtained. Also, the single enantiomers of carboxylic acid (S)-7 and (R)-7[R A Decarboxylates [=CO2H] to obtain neutral cannabinoids (S)-7 and (R)-7[R A =H] may be obtained, or the carboxylic acid (S)-7 and (R)-7[R A Convert [=CO2H] by esterification or amidation, and R as needed. B The protecting hydroxyl group present on the substituent may be deprotected to obtain single enantiomers of cannabinoid esters and amides (S)-7 and (R)-7.

[0051] [ka] [ka] [ka] Here, The equivalent oxidizing agent is air, oxygen, quinone (preferably p-benzoquinone), hydrogen peroxide, or alkyl peroxide (preferably t-butyl hydroperoxide). Any secondary oxidizing agent is a quinone (preferably p-benzoquinone) used when air or oxygen is used as the equivalent oxidizing agent. Any optional additive is an alkali metal bicarbonate (preferably sodium bicarbonate or potassium bicarbonate). Any multiple additives include alkali metal bicarbonates (preferably sodium bicarbonate or potassium bicarbonate) and copper(II) carboxylates (preferably copper(II) acetate). The palladium catalyst is palladium(II) carboxylate (preferably palladium(II) acetate).

[0052] Here, R B Any hydroxy protecting group or any such group within the compound is a silyl protecting group. The hydroxy protecting group or any such group is preferably, independently, a t-butyldimethylsilyl group, a texyldimethylsilyl group, a t-butyldiphenylsilyl group, or a triisopropylsilyl group. In a preferred embodiment, the oxidative cyclization reaction is carried out at 60°C using p-benzoquinone as an optional second catalytic oxidizing agent, with air or oxygen as the equivalent oxidizing agent, sodium bicarbonate and copper(II) acetate as additives, and DMSO and water as solvents. CA is an optically active amine that is not limited to quinine, cinconidine, quinidine, cinconine, quinisine, cinconisine, ephedrine, α-methylbenzylamine, α-methylnaphthylamine, leucine methyl ester, or tyrosine hydrazide. R G-OH is an optically active alcohol, not limited to menthol, 2-octanol, α-methylphenol, methylmandelate, or 1-phenylethanol. R H R I NH is an optically active amine such as, but not limited to, α-methylbenzylamine, α-methylnaphthylamine, leucine methyl ester, 1-amino-2-propanol, dimethylaspartate, ephedrine, dimethylglutamate, and phenylalanine methyl ester.

[0053] Intermediates 8 and 9 (Rα and Rβ are both methyl; R B The small-scale synthesis of (Me) is known [DC Elliott, TK 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, 18, 1800-1803 and the references cited therein]. However, efficient and cost-effective large-scale synthesis methods for the novel cannabinoid 7 listed above have not been published to date. Furthermore, there is no prior art regarding the separation methods and compositions of single (S) and (R) forms of the single enantiomers of racemic cannabinoid 7, namely cannabichromemenic acid (CBCA,2), cannabichrome valic acid (CBCVA,4) and their similar neutral cannabinoids, as well as cannabinoid carboxylic acids and other synthetic analogs. [ka] [ka]

[0054] Protecting groups are widely known to those skilled in the art and are described in the textbooks of Greene and Wuts. (PGM Wuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, 4th edition, John Wiley, New York)

[0055] The dioxynone ring of intermediate 9 is cleaved by saponification or an equivalent method to produce cannabinoid carboxylic acid 7 (RA=CO2H). This method is described in the following literature and the literature cited therein: R. Cookson, TN Barrett and AGM Barrett, “b-Keto-dioxinones and b,d-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, Vol. 48, pp. 628-642.

[0056] Cannabinoid carboxylic acid 7(R A Decarboxylation of cannabinoid 7(R) =CO2H A The process of obtaining =H) is carried out according to the method described in the following literature and the literature cited therein: H. Perrotin-Brunel, W. Buijs, J. van Spronsen, MJE van Roosmalen, CJ Peters, R. Verpoorte and G.-J. Witkamp, ​​“Decarboxylation of D 9 -tetrahydrocannabinol: Kinetics and molecular modeling, Journal of Molecular Structure, 2011, Vol. 987, pp. 67-73.

[0057] Amide formation is carried out by activating carboxylic acids, for example, by forming N-hydroxysuccinimide esters and condensing them with the 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, Vol. 29, pp. 668-671)). Alternative amide bond-forming reagents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, Vol. 38, pp. 606-631).

[0058] The aforementioned novel cannabinoids (formula 7, (S)-7 or (R)-7, or non-racemic mixtures of (S)-7 and (R)-7 above) can be used alone or with known cannabinoids (e.g., Δ 9-It may be used in combination with other drugs (not limited to tetrahydrocannabinol (THC), tetrahydrocannabivarin (THBV), cannabidiol (CBD), cannabidivarin (CBDV), etc.) to treat infections, pain, multiple sclerosis-related spasticity, nausea, epilepsy, brain injury / concussion due to Alzheimer's disease, cancer, glaucoma and retinal degeneration, immune-inflammatory diseases, lung injury or lung disease, liver injury or liver disease, kidney injury or kidney disease, eye injury or eye disease, and other medical conditions. In some embodiments, the novel cannabinoids described above (Formula 7, (S)-7 or (R)-7) are formulated, either alone or in combination with known cannabinoids (not limited to, for example, Δ9-tetrahydrocannabinol (THC), tetrahydrocannabivarin (THBV), cannabidiol (CBD), cannabidivarin (CBDV), etc.) as pharmaceutical compositions suitable for administration to patients. Such formulations may include pharmaceutically acceptable diluents and excipients in addition to active cannabinoids and other agents in therapeutic combination formulations. This includes binders such as lactose, starch, cellulose, sorbitol, polyethylene glycol, polyvinyl alcohol, and other pharmaceutically acceptable oligosaccharides and polymers; disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose, and other pharmaceutically acceptable disintegrants; bases such as petrolatum, dimethyl sulfoxide, liquid paraffin, water-in-oil nanoemulsifications of omega-3 oils, and complexes with cyclodextrins such as hydroxypropyl-β-cyclodextrin; preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens, and other pharmaceutically acceptable preservatives; lubricants and fluidizers such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats and oils, cellulose ethers such as hydroxypropyl methylcellulose and gelatin, and other pharmaceutically acceptable coating agents; flavorings including volatile terpenes derived from cannabis and citrus fruits; and other pharmaceutically acceptable diluents and excipients. The pharmaceutical composition may be administered to a patient by oral administration (tablets, capsules, etc.), sublingual administration (tablets, strips, drops, sprays, lozenges, effervescent tablets, etc.), intranasal administration (spray or powder), inhalation administration (spray or powder), rectal administration (suppositories or solutions, etc.), or parenteral administration such as intramuscular, subcutaneous, or intravenous injection (solution, etc.), or by other known clinical administration methods.

[0059] Oxidative cyclization reactions are suitable for the synthesis of novel cannabinoids 7, (S)-7, or (R)-7, and these compounds also constitute part of the present invention. The present invention involves synthesizing the target cannabinoid as an oily substance or a crystalline derivative, and optionally including solvates, hydrates, and polymorphs. These novel racemic cannabinoids 7 have the following chemical formulas. [ka] Here: R A It is hydrogen (H). R B These are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, linear or branched C3, C4, C6 to C 10 Alkyl, or double-branched C4, C6 to C 10 It is alkyl, and in either case it is substituted with one or two hydroxyl groups, or one or more fluoro groups, (CH2)p-OR F It has been replaced with. p is 1, 2, 3, 4, 5, or 6. R F These are C1 to C6 alkyl groups and (CH2)r-C3 to C6 cycloalkyl groups. r is independently 0, 1, 2, 3, 4, 5, or 6. However, R B Each hydroxyl group contained in cannot be located on a carbon atom having a fluoro group or on a carbon atom having a secondary hydroxyl group.

[0060] or Here, R A This refers to a carboxyl group (CO2H) and its pharmaceutically acceptable salts or cocrystals, or CO2R C That is the case. R B hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-fluoroethyl, 2-fluoroethyl; or linear or branched C3 to C5 alkyl groups substituted with one or two hydroxyl groups or one or more fluoro groups; or linear or branched C6 to C 10 Alkyl, double-branched C4 to C 10 Alkyl groups, in either case optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups; (CH2)o-C3 to C6 cycloalkyl, (CH2)p-OR F or C3 to C6 cycloalkyl groups optionally substituted with C1 to C8 alkyl groups. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R C The compounds are C1 to C6 alkyl, (CH2)q-C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. q is 0, 1, 2, 3, 4, 5, or 6. R F These are C1 to C6 alkyl groups and (CH2)r-C3 to C6 cycloalkyl groups. r is independently 0, 1, 2, 3, 4, 5, or 6. However, R B Each hydroxyl group contained in cannot be located on a carbon atom having a fluoro group or on a carbon atom having a second hydroxyl group.

[0061] or Here, R A CONHR D CONR D R EThat is the case. R B is hydrogen (H) or C1-C2 alkyl, linear or branched C3-C 10 Alkyl, double-branched C4 to C 10 Alkyl groups, in either case optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, (CH2)o-C3 to C6 cycloalkyl groups, (CH2)p-OR F or C3 to C6 cycloalkyl groups optionally substituted with C1 to C8 alkyl groups. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R D These are C1 to C6 alkyl, (CH2)r-C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. R E These are C1-C6 alkyl, (CH2)r-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. or NR D R E These are azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each optionally substituted with one or two hydroxyl groups or one hydroxymethyl group. However, in the case of morpholine, the hydroxyl group cannot be located on a carbon atom having a ring nitrogen atom or a carbon atom having a ring oxygen atom. R F C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl r is independently 0, 1, 2, 3, 4, 5, or 6. However, R B Each hydroxyl group contained in cannot be located on a carbon atom having a fluoro group or on a carbon atom having a second hydroxyl group.

[0062] The separation following the oxidative cyclization reaction is suitable for the synthesis of novel single enantiomers of cannabinoids (S)-7 and (R)-7, as well as non-racemic (scalemic) mixtures of cannabinoids (S)-7 and (R)-7, which also constitute part of the present invention. The present invention includes synthesizing the desired cannabinoids as oily or crystalline derivatives (including solvates, hydrates, and polymorphs), as appropriate. These novel cannabinoids (S)-7 and (R)-7 have the following formulas: [ka]

[0063] Here, R A It is hydrogen (H). R B It is one of the following: Hydrogen (H), methyl, ethyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. Alternatively, it may be n-propyl or n-hexyl, which may be substituted with one or two hydroxyl groups, or with one or more fluoro groups. Alternatively, branch chain C3 to C 10 Alkyl or double-branched C4 to C 10 The alkyl group is optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. or (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR F or a C3 to C6 cycloalkyl group, which may be optionally substituted with a C1 to C8 alkyl group. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. RF C1 to C6 alkyl or (CH2) r -C3 to C6 cycloalkyl r is independently 0, 1, 2, 3, 4, 5, or 6.

[0064] or Here, R A CO2H and its pharmaceutically acceptable salts or cocrystals, CO2R C CONHR D , or CONR D R E That is the case. R B is hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl, each optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, or C3 to C 10 Branched alkyl or C4 to C 10 A double-branched alkyl group, each optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, or (CH2)o-C3 to C6 cycloalkyl, (CH2)p-OR F Alternatively, it is a C3 to C6 cycloalkyl group that is optionally substituted with a C1 to C8 alkyl group. o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R C These are C1-C6 alkyl, (CH2)q-C3-C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. q is 0, 1, 2, 3, 4, 5, or 6. R D C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. R E C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. or NR D R E This is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, which may be optionally substituted with one or two hydroxyl groups or one hydroxymethyl group, respectively. However, in the case of morpholine, the hydroxyl group must not be located on a carbon having heterocyclic nitrogen or a carbon having heterocyclic oxygen. R F C1 to C6 alkyl or (CH2) r -C3 to C6 cycloalkyl r is independently 0, 1, 2, 3, 4, 5, or 6. However, R B In this compound, each hydroxyl group is not located on the carbon atom containing the fluoro group, nor on the carbon atom containing the second hydroxyl group.

[0065] The oxidative cyclization reaction proceeds via intermediate 9, and these compounds are also part of the present invention. These novel intermediates 9 are represented by the following formula. [ka] Here, R B This includes hydrogen, a protected hydroxymethyl group, or a linear C2 to C2 group. 10 Alkyl, branched C3 to C 10 Alkyl, double-branched C4 to C 10 Alkyl, which in each case may be optionally substituted with one or two protecting hydroxyl groups, or may be optionally substituted with one or more fluoro groups, (CH2) o -C3 to C6 cycloalkyl, (CH2) p -OR FAlternatively, it may be a C3 to C6 cycloalkyl group (which may be optionally substituted with a C1 to C8 alkyl group). o is 0, 1, 2, 3, 4, 5, or 6. p is 1, 2, 3, 4, 5, or 6. R F C1 to C6 alkyl, (CH2) r -C3 to C6 cycloalkyl Rα is a C1 to C6 alkyl or optionally substituted aryl, preferably methyl. Rβ is a C1 to C6 alkyl or optionally substituted aryl, preferably methyl. Alternatively, Rα and Rβ combine to form (CH2) s It forms a , where s is 4, 5, or 6. However, R B None of the hydroxyl groups in the molecule are located on a carbon atom that has a fluoro group or a second hydroxyl group. [Examples]

[0066] (E)-3,7-dimethylocta-2,6-dien-1-yl4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate [ka]

[0067] N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10 g, 50 mmol) and 4-dimethylaminopyridine (6.1 g, 50 mmol) were sequentially added to a solution of 2-phenyl-1,3-dioxan-4,6-dione (9.6 g, 50 mmol) in ethyl acetate (250 mL). After 5 minutes, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (9.3 g, 50 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Then, aqueous HCl (2 M, 250 mL) was added, and the two-phase mixture was vigorously stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The obtained ethyl acetate extracts were combined, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was immediately dissolved in anhydrous toluene (PhMe, 250 mL), and geraniol (4.3 mL, 25 mmol) was added dropwise while vigorously stirring. The solution was heated to 60°C, and after confirming that the starting material had disappeared after 3 hours, it was concentrated under reduced pressure. The crude product was purified by flash column chromatography (siRNA:pentane = 1:10 to 1:5) to obtain (E)-3,7-dimethylocta-2,6-dien-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (8.1 g, 22 mmol, 88%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ: 5.43-5.27 (m, 2H), 5.11-5.04 (m, 1H), 4.71-4.63 (m, 2H), 3.51 (s, 2H), 3.50 (d, J = 0.5 Hz, 2H), 2.15-2.00 (m, 4H), 1.71 (s, 6H), 1.69 (s, 1H), 1.68 (d, J = 1.3 Hz, 4H), 1.60 (d, J = 1.4 Hz, 3H);^13C NMR (101 MHz, CDCl3) δ: 195.8, 166.5, 163.7, 143.8, 132.1, 123.7, 117.4, 107.5, 97.3, 62.8, 49.3, 47.1, 39.7, 26.4, 25.8, 25.2, 17.9, 16.7; 1270, 1200, 1014, 900cm -1 HRMS (ES - ): Calculated value [M + H] - C 20 H 29 O6 = 365.1959, measured value = 365.1968.

[0068] (E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one [ka]

[0069] (E)-3,7-dimethylocta-2,6-dienyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (3.6 g, 10 mmol) was added to (E)-3,7-dimethylocta-2,6-dienyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (50 mL) in anhydrous MeCN (acetonitrile), and magnesium chloride (0.95 g, 10 mmol) was added under stirring. The mixture was cooled to 0°C. Pyridine (1.6 mL, 20 mmol) was added dropwise while continuing to stir, and after 5 minutes, n-hexanoyl chloride (1.4 mL, 10 mmol) was added dropwise. After reacting at 0°C for 1 hour, saturated ammonium chloride aqueous solution (50 mL) was added, and the pH was further acidified to 1 with hydrochloric acid aqueous solution (1 M; 4 mL). The two-phase mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated saline solution (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue oil was immediately dissolved in anhydrous tetrahydrofuran (THF 50 mL), and tri(2-furyl)phosphine (116 mg, 0.5 mmol) and tris(dibenzylideneacetone)dipalladium(0) (116 mg, 0.126 mmol) were added sequentially under stirring. After 1 hour, triethylamine (Et3N 4.2 mL, 30 mmol) was added dropwise while continuing to stir, and the reaction was continued for a further 13 hours. Then, 10% citric acid aqueous solution (100 mL) was added to stop the reaction. The two-phase mixture was separated, the aqueous layer was extracted with ethyl acetate (RINKAN 100 mL × 3), and the organic extracts were combined. This was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (diethyl ether:pentane = 1:10) to obtain (E)-8-(3,7-dimethylocta-2,6-dienyl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (1.6 g, 4 mmol, 40%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 6.10 (s, 1H), 5.24 - 5.14 (m, 1H), 5.04 (dddd, J = 7, 5.5, 3.5, 1.5 Hz, 1H), 3.32 (dd, J = 7, 1 Hz, 2H), 3.04 - 2.94 (m, 2H), 2.16 - 1.99 (m, 5H), 1.79 (d, J = 1.3 Hz, 3H), 1.67 (s, 7H), 1.75 - 1.52 (m, 6H), 1.66 (d, J = 1.5 Hz, 3H), 1.58 (d, J = 1.5 Hz, 3H), 1.34 (tq, J = 5, 3 Hz, 5H), 0.93 - 0.82 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.6, 160.1, 156.1, 147.8, 138.6, 132.0, 123.7, 120.9, 112.9, 112.7, 105.0, 104.6, 39.7, 34.3, 31.9, 30.6, 26.4, 25.7, 22.6, 22.0, 17.7, 16.2, 14.1; IR (neat) 3291 (br), 2956, 2924, 2855, 1690, 1605, 1590, 1293, 1276, 1208, 1165, 1113, 1047 cm -1 HRMS (ES+) m / z calculation value [M + H] - C 25 H 37 O4= 401.2686, 401.2686, measured value 401.2686.

[0070] 2,2,8-Trimethyl-8-(4-methylpenta-3-en-1-yl)-5-pentyl-4H,8H-[1,3]dioxyno[4,5-f]chromen-4-one

change

[0071] To an oxygen-saturated solution of (E)-8-(3,7-dimethylocta-2,6-dienyl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (1.6 g, 4 mmol) dissolved in DMSO (100 mL) and water (10 mL), potassium bicarbonate (KHCO3 440 mg, 4.4 mmol) and palladium acetate (Pd(OAc) 290 mg, 0.40 mmol) were added under stirring. The reaction mixture was heated at 60°C for 18 hours under an oxygen atmosphere (1 atm). After the reaction was complete, the reaction solution was diluted with diethyl ether (Et2O 50 mL) and aqueous hydrochloric acid (1 M 50 mL) was added. The two-phase mixture was separated, and the aqueous phase was extracted with diethyl ether (50 mL x 3). The organic layers were combined, washed with water (50 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (diethyl ether:pentane = 1:10) to obtain 2,2,8-trimethyl-8-(4-methylpento-3-en-1-yl)-5-pentyl-4H,8H-[1,3]dioxyno[4,5-f]chromen-4-one (970 mg, 2.44 mmol, 61%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 6.54 (dd, J = 10.1, 0.7 Hz, 1H), 6.37 (s, 1H), 5.52 (d, J = 10.1 Hz, 1H), 5.08 (ddq, J = 8.5, 7, 1.5 Hz, 1H), 3.04 - 2.92 (m, 2H), 2.16 - 2.02 (m, 2H), 1.82 - 1.60 (m, 4H), 1.75 (m, 1H), 1.69 (s, 6H), 1.65 (d, J = 1.3 Hz, 3H), 1.56 (d, J = 1.3 Hz, 3H), 1.41 (s, 3H), 1.38 - 1.29 (m, 4H), 0.92 - 0.85 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 160.3, 158.9, 153.1, 150.0, 132.1, 127.9, 123.9, 116.0, 113.1, 107.5, 104.9, 104.5, 80.2, 41.7, IR (neat) 2921, 2956, 2856, 1726, 1563, 1387, 1280, 1150, 1129, 1037cm -1 ; HRMS (ES+) m / z calculated value C 25 H 34 O4[M+H]+ 393.2535, measured value 393.2558.

[0072] Cannabide chromium [ka]

[0073] 2,2,8-trimethyl-8-(4-methylpent-3-en-1-yl)-5-pentyl-4H,8H-[1,3]dioxyno[4,5-f]chromen-4-one (400 mg, 1 mmol) was dissolved in methanol (MeOH 5 mL), to which a 6 M sodium hydroxide aqueous solution (5 mL), degassed by three freeze-evaporation-thaw cycles under a nitrogen stream, was added dropwise with stirring. The reaction mixture was heated at 100 °C for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with diethyl ether (Et2O 10 mL), and then acidified with a 10% citric acid aqueous solution (10 mL). After 5 minutes, the two-phase solution was separated, and the aqueous phase was extracted with diethyl ether (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (diethyl ether:pentane = 1:10) to obtain cannabichromene (220 mg, 0.7 mmol, 70%) as an orange oily substance. 1H NMR (400 MHz, CDCl3) δ 6.63 (dd, J = 10.0, 0.8 Hz, 1H), 6.28 (s, 1H), 6.14 (d, J = 1.5 Hz, 1H), 5.52 (d, J = 10.0 Hz, 1H), 5.12 (tdq, J = 7.2, 2.9, 1.4 Hz, 1H), 4.68 (s, 1H), 2.46 (t, J = 7.8 Hz, 2H), 2.19 - 2.06 (m, 3H), 1.79 - 1.52 (m, 8H), 1.39 - 1.24 (m, 4H), 0.91 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 154.2, 151.1, 144.9, 131.8, 127.4, 124.3, 116.9, 109.3, 107.8, 107.1, 78.3, 41.2, 36.0, 31.6, 30.8, 30.5, 26.4, 25.8, 22.9, 22.7, 17.8, 14.2; IR (neat) 3410, 2958, 2924, 2855, 1622, 1576, 1429, 1142 1082, 1051 cm -1 ; HRMS (ES+) m / z calculated value C21H31O2 [M+H]+ 315.2324, measured value 315.2325.

[0074] CBC HPLC conditions (analytical analysis - CBC 1mg) Table 1 Table 2

[0075] CBC HPLC conditions (adjustment - CBC 4mg) Table 3

[0076] Cannabichromenic acid

change

[0077] t-BuOK (450 mg, 4 mmol) was suspended in Et2O (5 mL), and under stirring, a solution of 2,2,8-trimethyl-8-(4-methylpent-3-en-1-yl)-5-pentyl-4H,8H-[1,3]dioxyno[4,5-f]chromen-4-one (200 mg, 0.5 mmol) in Et2O (1 mL) was added. After 72 hours, water (10 mL) and Et2O (10 mL) were added, and the two-phase mixture was separated. The organic layer was extracted with water (10 mL × 5), and the resulting aqueous layer was combined and acidified to pH 1 with 4 M hydrochloric acid aqueous solution. The acidic solution was extracted with ethyl acetate (ethyl ethyl acetate 10 mL × 5). The combined organic extract was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Â:pentane = 1:6) to obtain cannabichromenic acid (102 mg, 0.28 mmol, 57%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 6.78 - 6.71 (m, 1H), 6.25 (s, 1H), 5.48 (d, J = 10.1 Hz, 1H), 5.09 (dddd, J = 8.6, 5.7, 2.8, 1.4 Hz, 1H), 2.92 - 2.85 (m, 2H), 2.09 (q, J = 7.9 Hz, 2H), 1.82 - 1.69 (m, 1H), 1.69 - 1.58 (m, 3H), 1.66 (d, J = 1.4 Hz, 3H), 1.57 (d, J= 1.3 Hz, 3H), 1.41 (s, 3H), 1.39 - 1.29 (m, 4H), 0.91 (td, J = 7.0, 5.9, 2.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 160.8, 159.1, 149.6, 132.0, 126.5, 124.0, 116.8, 111.7, 107.2, 103.0, 80.2, 41.8, 36.9, 32.2, IR (neat) 3310 (v. broad), 2958, 2924, 2858, 1615, 1565, 1453, 1259 1171 cm -1 ; HRMS (ES-) m / z calculated value C 22 H 29 O4[MH]+ 357.2066, measured value 357.2074.

Claims

1. A racemic compound with structural formula 7. 【Chemistry 01】 Here, R Ａ It is hydrogen. R Ｂ is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, or linear or branched C ２ , C ４ , C ６ from C １０ alkyl, or double-branched C ４ , C ６ from C １０ alkyl, either of which is substituted with one or two hydroxy groups or one or more fluoro groups, or (CH ２ ) ｐ -OR Ｆ and is selected from the group consisting of. p represents 1, 2, 3, 4, 5, or 6. R Ｆ C １ From C ６ Alkyl or (CH ２ ) ｒ -C ３ From C ６ Selected from the group consisting of cycloalkyl groups. r represents 0, 1, 2, 3, 4, 5, or 6. However, R Ｂ Each hydroxyl group in the compound must not be located on a carbon atom that has a fluoro group or another hydroxyl group. or Here, R Ａ CO ２ H, and its pharmaceutically acceptable salts or cocrystals, CO ２ R Ｃ That is the case. R Ｂ This includes hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-fluoroethyl, 2-fluoroethyl, linear or branched C ３ From C ５ Alkyl groups substituted with one or two hydroxyl groups, or substituted with one or more fluoro groups, linear or branched C ６ From C １０ Alkyl groups which are optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, double-branched C ４ From C １０ Alkyl groups which are optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and C ３ From C ６ Cycloalkyl and C as needed １ From C ８ It is selected from the group consisting of those substituted with alkyl groups. o is selected from 0, 1, 2, 3, 4, 5, 6. p is selected from 1, 2, 3, 4, 5, and 6. R Ｃ is C １ From C ６ Alkyl, (CH ２ ) q-C ３ From C ６ Selected from the group consisting of cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. q is selected from 0, 1, 2, 3, 4, 5, 6. R Ｆ is C １ From C ６ Alkyl, or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, 6. However, R Ｂ None of the hydroxyl groups in the molecule are located on carbon atoms that have a fluoro group or a secondary hydroxyl group. or Here, R Ａ is CONHR Ｄ Or CONR Ｄ R Ｅ That is the case. R Ｂ is hydrogen, C １ From C ２ Alkyl (substituted with one or two hydroxyl groups as needed, or with one or more fluoro groups as needed), linear or branched C ３ From C １０ Alkyl (substituted with one or two hydroxyl groups as needed, or with one or more fluoro groups as needed), double-branched C ４ From C １０ Alkyl (substituted with one or two hydroxyl groups as needed, or substituted with one or more fluoro groups as needed), (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and C ３ From C ６ Cycloalkyl (C as needed) １ From C ８ Selected from the group consisting of (those substituted with alkyl groups). o is selected from 0, 1, 2, 3, 4, 5, 6. p is selected from 1, 2, 3, 4, 5, and 6. R Ｄ is C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Cycloalkyl, C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. R Ｅ is C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. Or, NR Ｄ R Ｅ The group is selected from azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each of which may be substituted with one or two hydroxyl groups or one hydroxymethyl group as needed. However, in the case of morpholine, the hydroxyl group is not present on a carbon having heterocyclic nitrogen or heterocyclic oxygen. R Ｆ is C １ to C ６ alkyl, or (CH ２ )r - C ３ to C ６ cycloalkyl. r is selected from 0, 1, 2, 3, 4, 5, 6. However, R Ｂ None of the hydroxyl groups in the molecule are located on carbon atoms that have a fluoro group or a secondary hydroxyl group.

2. The racemic compound according to claim 1. Here, R Ａ is hydrogen. R Ｂ This includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, or linear or branched C ３ , C ４ , C ６ From C １０ Alkyl and double-branched C substituted with one or two hydroxyl groups ４ , C ６ From C １０ Selected from the group consisting of alkyl groups.

3. The racemic compound according to claim 1. Here, R Ａ is a carboxyl group (CO ２ H) and its pharmaceutically acceptable salts or cocrystals. R Ｂ This refers to hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-fluoroethyl, 2-fluoroethyl, linear or branched C2 substituted with one or two hydroxyl groups, or one or more fluoro groups. ３ From C ５ Alkyl, linear or branched carbon atoms optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ６ From C １０ Alkyl, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, double-branched C ４ From C １０ Alkyl, (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and optionally C １ From C ８ C substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl, or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6.

4. The racemic compound according to claim 1. Here, R Ａ CO ２ R Ｃ That is the case. R Ｂ This refers to hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-fluoroethyl, 2-fluoroethyl, linear or branched C molecules substituted with one or two hydroxyl groups, or one or more fluoro groups. ３ From C ５ Alkyl, linear or branched carbon atoms optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ６ From C １０ Alkyl, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, double-branched C ４ From C １０ Alkyl, (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and optionally C １ From C ８ C substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｃ C １ From C ６ Alkyl, (CH ２ ) q-C ３ From C ６ Selected from the group consisting of cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. q is selected from 0, 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl, or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6.

5. The racemic compound according to claim 1. Here, R Ａ is CONHR Ｄ Or CONR Ｄ R Ｅ That is the case. R Ｂ C is a hydrogen atom, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. １ From C ２ Alkyl, linear or branched carbon atoms optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ３ From C １０ Alkyl, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups, double-branched C ４ From C １０ Alkyl, (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and optionally C １ From C ８ C substituted with alkyl ３ From C ６ Selected from cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｄ C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Cycloalkyl, C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. R Ｅ C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. Or, NR Ｄ R Ｅ The compound is selected from azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each of which may optionally be substituted with one or two hydroxyl groups or one hydroxymethyl group. However, the hydroxyl group is not present on carbon atoms having heterocyclic nitrogen, or, in the case of morpholine, on carbon atoms having heterocyclic oxygen. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6.

6. A single enantiomer compound of structural formula (S)-7 or (R)-7, or a non-racemic mixture thereof. 【Chemical 02】 Here, R Ａ It is hydrogen. R Ｂ This includes hydrogen, methyl, ethyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl (all of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), n-propyl or n-hexyl (which may be substituted with one or two hydroxyl groups, or may be substituted with one or more fluoro groups), and branched C. ３ From C １０ Alkyl (which may be optionally substituted with one or two hydroxyl groups, or with one or more fluoro groups), double-branched C ４ From C １０ Alkyl (may be substituted with one or two hydroxyl groups, or with one or more fluoro groups), (CH ２ ) ｏ -C ３ From C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (which may be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl, or (CH ２ ) ｒ -C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6. or Here, R Ａ CO ２ H and its pharmaceutically acceptable salts or cocrystals, CO ２ R Ｃ CONHR Ｄ CONR Ｄ R Ｅ It is selected from the group consisting of the following. R Ｂ This includes hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl (all of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), and branched C. ３ From C １０ Alkyl or double-branched C ４ From C １０ Alkyl (each may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , or C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (which may be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｃ C １ From C ６ Alkyl, (CH ２ ) q-C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. q is selected from 0, 1, 2, 3, 4, 5, or 6. R Ｄ C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Cycloalkyl, C ３ From C ６ Selected from the group consisting of cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. R Ｅ C １ From C ６ Alkyl, (CH ２ ) ｒ -C ３ From C ６ The group is selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. Or, NR Ｄ R Ｅ The compound is selected from azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each of which may be optionally substituted with one or two hydroxyl groups or one hydroxymethyl group. However, in the case of morpholine, the hydroxyl group shall not be substituted on a carbon having heterocyclic nitrogen or a carbon having heterocyclic oxygen. R Ｆ C １ From C ６ Alkyl or (CH ２ ) ｒ -C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6. However, R Ｂ Each hydroxyl group contained herein shall not be substituted on a carbon atom having a fluoro group or on a carbon atom having a second hydroxyl group.

7. A single enantiomer compound of structural formula (S)-7 or (R)-7 as described in claim 6, or a non-racemic mixture thereof. Here, R Ａ It is hydrogen. R Ｂ This includes hydrogen, methyl, ethyl, n-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl (all of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), n-propyl or n-hexyl substituted with one or two hydroxyl groups, or substituted with one or more fluoro groups, and branched C ３ From C １０ Alkyl or double-branched C ４ From C １０ Alkyl (each optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), ((CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (those that can be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ C １ From C ６ Alkyl or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6.

8. A single enantiomer compound of structural formula (S)-7 or (R)-7 as described in claim 6, or a non-racemic mixture thereof. Here, R Ａ CO ２ H and its pharmaceutically acceptable salts or cocrystals. R Ｂ This includes hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl (in any case, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), and branched C. ３ From C １０ Alkyl or double-branched C ４ From C １０ Alkyl (in either case, optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (those that can be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is 0, 1, 2, 3, 4, 5, or 6.

9. A single enantiomer compound of structural formula (S)-7 or (R)-7 as described in claim 6, or a non-racemic mixture thereof. Here, R Ａ CO ２ R Ｃ That is the case. R Ｂ This includes hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl (all of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), and branched C. ３ From C １０ Alkyl or double-branched C ４ From C １０ Alkyl (each may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (which may be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｃ C １ From C ６ Alkyl, (CH ２ ) q-C ３ From C ６ The group is selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl. q is selected from 0, 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group.

10. A single enantiomer compound of structural formula (S)-7 or (R)-7 as described in claim 6, or a non-racemic mixture thereof. Here, R Ａ is CONR Ｄ R Ｅ That is the case. R Ｂ This includes hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl (all of which may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), and branched C. ３ From C １０ Alkyl or double-branched C ４ From C １０ Alkyl (each may be optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups), (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , C ３ From C ６ Cycloalkyl (C １ From C ８ Selected from the group consisting of (which may be optionally substituted with alkyl). o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｄ C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Cycloalkyl, C ３ From C ６ Selected from cycloalkyl, allyl, optionally substituted benzyl, and optionally substituted 2-phenylethyl, R Ｅ C １ From C ６ Alkyl, (CH ２ ) r-C ３ From C ６ Selected from the group consisting of cycloalkyl, allyl, optionally substituted benzyl, or optionally substituted 2-phenylethyl. Or, NR Ｄ R Ｅ The group is selected from azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, and each may be optionally substituted with one or two hydroxyl groups or one hydroxymethyl group. However, in the case of morpholine, the hydroxyl group must not be located on a carbon atom to which a heterocyclic nitrogen or heterocyclic oxygen is bonded. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) r-C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6.

11. An intermediate compound of structural formula 9. 【Chemistry 03】 Here, R Ｂ This is a linear C molecule optionally substituted with hydrogen, a protected hydroxymethyl group, one or two protected hydroxyl groups, or one or more fluoro groups. ２ From C １０ Alkyl, branched C optionally substituted with one or two protected hydroxyl groups, or optionally substituted with one or more fluoro groups ３ From C １０ Alkyl, optionally substituted with one or two protected hydroxyl groups, or optionally substituted with one or more fluoro groups, double-branched C ４ From C １０ Alkyl, (CH ２ ) ｏ -C ３ From C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , or C １ From C ８ C which is optionally substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C1 to C6 alkyl or (CH2) ｒ -C ３ From C ６ It is a cycloalkyl group. Rα is C １ From C ６ It is an alkyl or optionally substituted aryl. Rβ is C １ From C ６ It is an alkyl or optionally substituted aryl. However, R Ｂ None of the protected hydroxyl groups in the molecule are located on carbon atoms that have a fluoro group or a second protected hydroxyl group.

12. An intermediate compound of structural formula 9 as described in claim 11, Rα is methyl, Rβ is methyl.

13. An intermediate salt of structural formula 10 or structural formula 11. 【Chemical 04】 Here, R Ｂ C is optionally substituted with hydrogen, one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. １ From C ２ A linear or branched C molecule optionally substituted with alkyl, one or two hydroxyl groups, or one or more fluoro groups. ３ From C １０ Alkyl, double-branched carbon optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ４ From C １０ Alkyl, (CH ２ ) o-C ３ From C ６ Cycloalkyl, (CH ２ ) p-OR Ｆ , and C １ From C ８ C which is optionally substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) ｒ -C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6. CA is a single enantiomer of chiral amine. However, R Ｂ The hydroxyl group inside is not present on the carbon atom that has a fluoro group or a second hydroxyl group.

14. The intermediate salt according to claim 13, CA is selected from the group consisting of quinine, cinconidine, quinidine, cinconine, quinisine, and cinconisine.

15. The intermediate salt according to claim 15, CA is selected from the group consisting of ephedrine, α-methylbenzylamine, α-methylnaphthylamine, leucine methyl ester, and tyrosine hydrazide.

16. An intermediate ester of structural formula 12 or structural formula 13. 【Transformation 5】 Here, R Ｂ C is optionally substituted with hydrogen, one or two hydroxyl groups, or one or more fluoro groups. １ From C ２ Alkyl, linear or branched carbon atoms optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ３ From C １０ Alkyl, double-branched carbon optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ４ From C １０ Alkyl, (CH ２ ) ｏ -C ３ From C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , and C １ From C ８ C which is optionally substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) ｒ -C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6. OR Ｇ is R Ｇ It is formed from -OH groups. R Ｇ -OH is a single enantiomer of chiral alcohol. However, R Ｂ The hydroxyl group inside is not present on the carbon atom that has a fluoro group or a second hydroxyl group.

17. The intermediate ester according to claim 16, R Ｇ -OH is selected from the group consisting of menthol, 2-octanol, α-methylphenol, methylmandelate, or 1-phenylethanol.

18. An intermediate amide of structural formula 14 or structural formula 15. 【Transformation 6】 Here, R Ｂ C is optionally substituted with hydrogen, one or two hydroxyl groups, or one or more fluoro groups. １ From C ２ Alkyl, linear or branched carbon atoms optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ３ From C １０ Alkyl, double-branched carbon optionally substituted with one or two hydroxyl groups, or optionally substituted with one or more fluoro groups. ４ From C １０ Alkyl, (CH ２ ) ｏ -C ３ From C ６ Cycloalkyl, (CH ２ ) ｐ -OR Ｆ , and C １ From C ８ C which is optionally substituted with alkyl ３ From C ６ Selected from the group consisting of cycloalkyl groups. o is selected from 0, 1, 2, 3, 4, 5, or 6. p is selected from 1, 2, 3, 4, 5, or 6. R Ｆ is C １ From C ６ Alkyl or (CH ２ ) ｒ -C ３ From C ６ It is a cycloalkyl group. r is selected from 0, 1, 2, 3, 4, 5, or 6. R Ｈ R Ｉ NH is a single enantiomer of chiral amine. However, R Ｂ The hydroxyl group inside is not present on the carbon atom that has a fluoro group or a second hydroxyl group.

19. The intermediate amide according to claim 18, R Ｈ R Ｉ NH is either α-methylbenzylamine or α-methylnaphthylamine.

20. The intermediate amide according to claim 18, R Ｈ R Ｉ NH is selected from the group consisting of leucine methyl ester, 1-amino-2-propanol, dimethyl aspartate, ephedrine, dimethyl glutamate, or phenylalanine methyl ester.

Images