Ergolic acid derivatives and methods

Abstract

The invention relates to a preparation method of ergotic acid and derivatives thereof. Methods of use of ergolic acid and derivatives thereof, such as methods of treating neurodegenerative diseases. Ergolic acid derivatives and pharmaceutically acceptable salts thereof: # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 341,162, filed on May 12, 2022, which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to a method for preparing lysergic acid and its derivatives. The present disclosure also relates to novel derivatives of lysergic acid. The present disclosure also relates to a method for treating the same. Background Art

[0004] Since Hofmann discovered lysergic aciddiethylamide (LSD) in 1938, the medical applications of this natural product derivative have been considered interesting and controversial. For example, Sandoz Laboratories claimed in the 1940s that LSD was a "cure for everything," and the U.S. Congress, in part in response to the counterculture of the 1960s, made the possession and use of LSD illegal in 1968.

[0005] However, despite this past, some ergoline derivatives, such as pergolide and lisuride, have entered clinical use for the treatment of Parkinson's disease and migraine. In addition to the psychedelic drugs dimethyltryptamine (DMT) and 2,5-dimethoxy-4-iodoamphetamine, these ergoline structures are also 5-HT 2A GCPR ligand, 5-HT 2A GCPRs are key receptors responsible for many downstream neuropharmacological phenotypes. Due to the therapeutic potential of LSDs, several X-ray crystallographic structures have recently been obtained that allow the design of 5-HT2A ligands with novel neuropharmacological functions.

[0006] There are many known methods for synthesizing lysergic acid, including asymmetric and racemic syntheses. However, many methods are not reproducible and / or require an excessive number of steps. In addition to limiting the feasibility and efficiency of the method in producing a particular analog, these shortcomings also increase the additional waste generated by the method implementation.

[0007] There remains a need for a feasible synthesis of lysergic acid and its derivatives, including various LSD derivatives. Summary of the invention

[0008] Compounds including lysergic acid and lysergic acid derivatives, and methods of preparing compounds such as lysergic acid and its derivatives are described herein. The synthetic simplicity and malleability of embodiments of the methods described herein can allow for the development of non-natural analogs that can aid in the discovery of novel compounds with potentially important therapeutic indications for the treatment of various neurodegenerative diseases, psychological, cognitive, behavioral and / or mood disorders.

[0009] In one aspect, the present invention provides a method for synthesizing lysergic acid or its derivatives, for example, synthesizing lysergic acid or its derivatives from simple aromatic precursors. Lysergic acid derivatives may include those having substituents on the benzene ring of the lysergic acid indole nucleus. In some embodiments, the method includes coupling, dearomatization and cyclization of a halopyridine with a 4-haloindole derivative from commercial starting materials in six synthetic steps. In some embodiments, the method includes providing a compound of formula (A):

[0010]

[0011] Where ProtG is a protecting group, X is a halogen, and R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein as defined herein, C1-C 20 The hydrocarbyl group is unsubstituted or substituted; and contacting the compound of formula (A) with an annulating agent to produce an annulated compound. The method may further comprise contacting the annulated compound with an agent effective to remove the protecting group.

[0012] In another aspect, a compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical preparation comprising the compound or a pharmaceutically acceptable salt or solvate thereof are provided. In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof includes those of formula (I) or formula (I'):

[0013]

[0014] Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein as defined herein, the C1-C 20 The hydrocarbon group is unsubstituted or substituted. In some embodiments, R 1 -R 6 At least one of them is not hydrogen.

[0015] In another aspect, provided herein is a method for treating a neurodegenerative disease in a patient in need thereof. In some embodiments, the method comprises administering an effective amount of a compound or composition as described herein or a pharmaceutically acceptable salt or solvate thereof to a patient suffering from a neurodegenerative disease. In some embodiments, the compounds and compositions as described herein can be used to treat one or more neurodegenerative diseases and / or as intermediates and precursors for producing lysergic acid derivatives (e.g., prodrugs) for treating one or more neurodegenerative diseases.

[0016] Other objects, features and advantages of the methods and compounds described herein will become apparent from the following detailed description and the appended claims. However, it should be understood that although the detailed description and specific examples indicate specific embodiments, they are given by way of illustration only, as various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

[0017] Incorporated by Reference

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0019] In one embodiment, the present invention provides a method for synthesizing lysergic acid from simple aromatic precursors. In some embodiments, the method includes synthesizing derivatives of lysergic acid. In some embodiments, the compounds described herein can be used to treat neurodegenerative diseases, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. In some embodiments, the compounds described herein can be used to treat psychological, cognitive, behavioral and / or emotional disorders. In some embodiments, the present invention provides a method for treating a neurodegenerative disease in a patient in need thereof.

[0020] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof are administered in an amount of greater than about 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg. In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof are administered in an amount of 100 μg.

[0021] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount greater than about 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, or 10 mg.

[0022] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount greater than about 20 mg, 60 mg, 100 mg, 200 mg, 400 mg, or 500 mg.

[0023] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts or solvates are administered in an effective amount of about 10 μg to about 500 μg per kilogram of patient body weight (mg per kg, mpk). In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts or solvates can be administered according to a treatment regimen. The treatment regimen can be constructed to provide a therapeutically effective amount of the compound within a predetermined time period (e.g., administration time). The treatment regimen can be constructed to limit or prevent the side effects or undesirable complications of the compounds disclosed herein. The treatment regimen for the treatment of neurodegenerative diseases, psychological, cognitive, behavioral and / or emotional disorders can include administration of any number of days, and repeated administration can be performed if necessary. The administration period can be interrupted by a rest period that does not include administration. For example, the treatment regimen can include an administration period of 2, 3, 5, 7, 10, 15, 21, 28 or more days. These periods can be repeated. For example, a treatment regimen may include a set number of days as previously described, wherein the treatment regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more times.

[0024] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In one embodiment, pharmaceutical compositions comprising compounds described herein are administered to subjects in various ways via a variety of routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, oral, topical, or transdermal routes of administration.

[0025] In some embodiments, the pharmaceutical composition comprises about 30 μg to about 500 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 μg to about 400 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 70 μg to about 300 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 70 μg to about 100 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 80 μg to about 120 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 50 μg to about 100 μg of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof.

[0026] In some embodiments, the pharmaceutical composition does not contain additional excipients. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0027] In some embodiments, provided herein are pharmaceutical combinations comprising a pharmaceutical composition comprising a compound of the present disclosure and a commercially available drug for treating a neurodegenerative disease, a psychological, cognitive, behavioral and / or mood disorder. In some embodiments, the pharmaceutical combination achieves a synergistic effect, which can allow the use of a lower dose of one or more components of the combination.

[0028] In one embodiment, the compounds described herein are formulated as pharmaceutical compositions that are capable of crossing the blood-brain barrier.

[0029] Compound

[0030] In one embodiment, provided herein is a compound. In some embodiments, the compound has a compound of formula (I) or formula (I'), or a pharmaceutically acceptable salt or solvate thereof:

[0031]

[0032]

[0033] Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbon. C1-C 20 The hydrocarbon group can be C1-C 15 Hydrocarbon, C1-C 10Hydrocarbyl, C1-C5 hydrocarbyl or C1-C3 hydrocarbyl. As used herein, each "hydrocarbyl" may be unsubstituted or substituted, as defined herein.

[0034] In some embodiments, R 1 , R 2 , R 5 or R 6 In some embodiments, at least one of R 1 , R 2 , R 5 or R 6 In some embodiments, at least two of R 1 , R 2 , R 5 or R 6 At least three of are not hydrogen. In some embodiments, R 1 , R 2 , R 5 or R 6 Each of these is not hydrogen.

[0035] In some embodiments, R 3 and R 4 is not hydrogen. In some embodiments, R 3 and R 4 is not hydrogen, and R 1 , R 2 , R 5 or R 6 It's hydrogen.

[0036] In some embodiments, R 3 and R 4 In some embodiments, R 3 and R 4 (i) is not hydrogen, and (ii) is different.

[0037] In some embodiments, R 3 In some embodiments, R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, and R 3 In some embodiments, R 3 In some embodiments, R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, and R 3 It's a methoxy group.

[0038] In some embodiments, R 1 , R 3 , R 4 , R 5 and R 6 is hydrogen, and R 2 It's methyl.

[0039] In some embodiments, R 4 is a halogen substituent (e.g., chloro-, bromo-, iodo-). 1 , R 2 , R 3 , R 5 and R 6 is hydrogen, and R 4 is a halogen substituent (e.g., chloro-, bromo-, iodo-).

[0040] In some embodiments, the compound of formula (I) and its stereoisomers can be used to treat neurodegenerative diseases, or psychological, cognitive, behavioral and / or emotional disorders. In some embodiments, the compound of formula (I) can be further derivatized to produce an ester or amide prodrug of the compound of formula (I) or another analog of the compound of formula (I). Such esters, amides or other analogs of the compound of formula (I) can be used to treat one or more neurodegenerative diseases, or psychological, cognitive, behavioral and / or emotional disorders.

[0041] method

[0042] In some embodiments, provided herein are methods for producing lysergic acid and its derivatives.

[0043] In some embodiments, the methods comprise providing a compound of formula (a)-

[0044]

[0045]

[0046] Where R 1 To R 6 As defined herein. Although iodine is depicted as a substituent of formula (a), other halogens are also contemplated.

[0047] In some embodiments, the methods include contacting a compound of formula (a) or (c) with a metal-containing compound to form a Grignard reagent. In some embodiments, the Grignard reagent is formed by contacting (i) a compound of formula (a) or (c) with (ii) i-PrMgCl*LiCl.

[0048] After contacting the compound of formula (a) or formula (c) with a metal-containing compound to form a Grignard reagent, these methods include contacting the Grignard reagent with a compound of formula (b) or formula (d), respectively, to form a compound of formula (B):

[0049]

[0050] Where R 1 To R 6 As defined herein, and X is halogen, such as Br.

[0051] In some embodiments, the method includes providing a compound of formula (B); contacting the compound of formula (B) with a protecting group precursor to form a protected compound comprising a protected indole nitrogen; contacting the protected compound with a methylating agent to form a methylated compound comprising a methylated pyridine nitrogen; contacting the methylated compound with a reducing agent and then with a base to form a compound of formula (A). In some embodiments, the method includes contacting the compound of formula (B) with a methylating agent to form a methylated compound comprising a methylated pyridine nitrogen; contacting the methylated compound with a protecting group precursor to form a protected compound comprising a protected indole nitrogen; and contacting the protected compound with a base to form a compound of formula (A):

[0052]

[0053] Where R 1 To R 6 As defined herein, ProtG is a protecting group and X is a halogen.

[0054] Any reducing agent or base can be used in the methods described herein. In some embodiments, the reducing agent is NaBH4 and the base is LiTMP.

[0055] In some embodiments, the methods include providing a compound of formula (A); contacting the compound of formula (A) with a cyclizing agent to produce a cyclized compound; and contacting the cyclized compound with a reagent effective to remove the protecting group to form an acid of formula (I):

[0056]

[0057] In some embodiments, the cyclized compounds and stereoisomers thereof can be used to treat neurodegenerative diseases, psychological, cognitive, behavioral and / or mood disorders.

[0058] In some embodiments, the cyclizing agent is a Heck cyclizing agent. In some embodiments, the cyclizing agent comprises tris(dibenzylideneacetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0).

[0059] Any known protecting group can be used. In some embodiments, the protecting group is a tert-butyloxycarbonyl protecting group.

[0060] The reagent effective for removing the protecting group may be a base, such as KOH. The protecting group may be removed by contacting the compound with an aqueous KOH solution at a temperature of about 65°C to about 75°C.

[0061] Any combination of groups of the various variables described above is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0062] Pharmaceutical composition

[0063] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that aid in processing the active compounds disclosed herein into pharmaceutically acceptable preparations. Suitable formulations depend on the chosen route of administration. Pharmaceutical compositions described herein are summarized in, e.g., Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa., Mack Publishing Co., 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Easton, Pa., Mack Publishing Co., 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference for such disclosures.

[0064] The pharmaceutical composition used herein refers to a mixture of the compounds disclosed herein and other chemical components (i.e., pharmaceutically acceptable inactive ingredients), other chemical components such as carriers, excipients, adhesives, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates the administration of the compound to a subject in need.

[0065] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical, or transdermal routes of administration.

[0066] Treatment

[0067] Described herein are methods of treating neurodegenerative diseases. In some embodiments, described herein is a method of treating a neurodegenerative disease or disorder comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a derivative thereof.

[0068] Dosages used for adult human treatment are generally in the range of about 0.01 mg to about 5000 mg per day or about 0.01 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.

[0069] definition

[0070] When a compound or formula is depicted herein without indicating stereochemistry, it is intended that the compound or formula be interpreted and include all stereoisomers, and thus, Applicants reserve the right to claim any one or more stereoisomers of a compound or formula depicted or described herein.

[0071] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in a sense including "and / or" unless the content clearly dictates otherwise. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0072] When used herein to select substituents, the term "independently" means that: (i) the substituent at a particular position may be the same or different for each molecule of the formula (e.g., (i) a compound of formula (I) may include two molecules of formula (I), each molecule having R 1 Select the same or different C1-C20 and / or (ii) two differently labeled substituents selected from the same substituent pool may be the same or different (e.g., R 1 and R 2 Can be selected from "C1-C 20 Hydrocarbon", and R 1 and R 2 Select C1-C 20 The hydrocarbon groups may be the same or different).

[0073] Unless otherwise stated, the following terms used herein have the following meanings:

[0074] "Oxo" refers to a =O substituent. "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl groups containing up to 10 carbon atoms are referred to as C1-C 10 Alkyl groups, for example, having up to 6 carbon atoms are C1-C6 alkyl groups. Alkyl groups (and other moieties defined herein) having other numbers of carbon atoms are represented in a similar manner. Alkyl groups include, but are not limited to, C1-C6 alkyl groups. 10 In some embodiments, the alkyl group is methyl or ethyl. Preferably, the C1-C9 alkyl group, C1-C8 alkyl group, C1-C7 alkyl group, C1-C6 alkyl group, C1-C5 alkyl group, C1-C4 alkyl group, C1-C3 alkyl group, C1-C2 alkyl group, C2-C8 alkyl group, C3-C8 alkyl group and C4-C8 alkyl group. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethylpropyl, etc. In some embodiments, the alkyl group is methyl or ethyl. Preferably, the C1-C 10 The alkyl group is any one of methyl, ethyl, n-propyl, isopropyl and tert-butyl. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted.

[0075] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0076] "Alkoxy" refers to a radical of the formula -OR, where R is alkyl as defined. Unless otherwise specifically stated in the specification, alkoxy may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, alkoxy is methoxy. In some embodiments, alkoxy is ethoxy. The term "C1-C 10 "Alkoxy" alone or in combination means a group C1-C 10 Alkyl-O-, where "C1-C 10 “Alkyl” refers to as defined above, including but not limited to methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), and the like.

[0077] "Heteroalkyl" refers to an alkyl radical as described above, wherein one or more carbon atoms of the alkyl are replaced by O, N (i.e., NH, N-alkyl) or S atoms. "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain that connects the remainder of the molecule to a radical group. Unless otherwise expressly stated in this specification, heteroalkyl or heteroalkylene may be optionally substituted. Representative heteroalkyls include, but are not limited to, -OCHOMe, -OCHCHOMe or -OCHCHOCHCHNH. Representative heteroalkylenes include, but are not limited to, -OCHCHO-, -OCHCHOCHCHO- or -OCHCHOCHCHOCHCHO-.

[0078] "Alkylamino" refers to a group of the formula -NHR or -NRR wherein each R is independently an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.

[0079] The term "aromatic" refers to a planar ring having a non-localized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0080] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl can be optionally substituted. Examples of aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, aryl can be a monoradical or a diradical (i.e., arylene). Unless otherwise expressly stated in this specification, the term "aryl" or the prefix "ar" (e.g., "aralkyl") is intended to include optionally substituted aryl.

[0081] "Carboxyl" refers to -CO2H. In some embodiments, the carboxyl moiety can be replaced by a "carboxylic acid bioisomer," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisomer has similar biological properties as a carboxylic acid group. A compound having a carboxylic acid moiety can have a carboxylic acid moiety exchanged with a carboxylic acid bioisomer and have similar physical and / or biological properties compared to a carboxylic acid-containing compound. For example, in some embodiments, a carboxylic acid bioisomer has about the same degree of ionization at physiological pH as a carboxylic acid group. Examples of carboxylic acid bioisomers include, but are not limited to:

[0082] wait.

[0083] As used herein, the phrase “C1-C 20"Hydrocarbyl" and the like generally refer to aliphatic, aryl or aralkyl groups containing from 1 to 20 carbon atoms. In each case, examples of aliphatic groups include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkadienyl, cyclic groups, and the like, and include all substituted, unsubstituted, branched and straight chain analogs or derivatives thereof, in each case having from 1 to about 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, The cycloalkyl moiety may be monocyclic or polycyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. Other examples of alkyl moieties have straight chain, branched and / or cyclic moieties (e.g., 1-ethyl-4-methyl-cyclohexyl). Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl- 1-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl. Representative alkynyl moieties include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl , 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl. Examples of aryl or aralkyl moieties include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydronaphthalene, tolyl, xylyl, mesityl, benzyl, and the like, including any heteroatom-substituted derivatives thereof.

[0084] Unless otherwise indicated, the term "substituted" when used to describe a chemical structure or moiety refers to a derivative of that structure or moiety in which (i) a polyvalent non-carbon atom (e.g., oxygen, nitrogen, sulfur, phosphorus, etc.) is bonded to one or more carbon atoms of the chemical structure or moiety (e.g., a "substituted" C4 hydrocarbon group may include, but is not limited to, a diethyl ether moiety, a methyl propionate moiety, a N,N-dimethylacetamide moiety, a butoxy moiety, etc., a "substituted" aryl C 12The hydrocarbon group may include, but is not limited to, an oxybiphenyl moiety, a benzophenone moiety, etc.) or (ii) one or more of its hydrogen atoms (e.g., chlorobenzene can generally be characterized as an aryl C6 hydrocarbon group "substituted" with a chlorine atom) is substituted with a chemical moiety or functional group such as an alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, tert-butyl), alkynyl, alkylcarbonyloxy (-OC(O)-alkyl), amide (-C(O)NH-alkyl- or -alkyl-NHC(O)-alkyl), tertiary amine (e.g., alkylamino, arylamino, aralkylamino), aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl), alkylamino (-C(O)NH-alkyl- or -alkyl-NHC(O) ... alkyl-, -OC(O)NH-alkyl), carbamoyl (e.g., CONH2, as well as CONH-alkyl, CONH-aryl and CONH-aralkyl), carboxyl, carboxylic acid, cyano, ester, ether (e.g., methoxy, ethoxy), halogen, haloalkyl (e.g., -CCl3, -CF3, -C(CF3)3), heteroalkyl, isocyanate, isothiocyanate, nitrile, nitro, oxo, phosphodiester, sulfide, sulfonamide (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and aralkylsulfonyl), sulfoxide, thiol (e.g., mercapto, thioether) or urea (-NHCONH-alkyl-).

[0085] As used herein, the terms "comprising," "is," "includes," "has," and "include" are used in an open manner and should therefore be interpreted as "including but not limited to." When a compound or method is claimed or described in the form of "comprising" various steps or components, the device, system, or method may also "consist essentially of" or "consist of" the various steps or components, unless otherwise specified. As used herein, the term "about" refers to the numerical value of the number used plus or minus 10%.

[0086] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered that will alleviate one or more symptoms of the disease or condition being treated to a certain extent. The result can be a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition comprising a compound disclosed herein that is clinically required to significantly reduce the symptoms of the disease. Techniques such as dose escalation studies can be used to determine the appropriate "effective" amount for any individual case. "Effective amount" refers to an amount sufficient for the compound to achieve a given purpose relative to the absence of the compound (e.g., to achieve an administration effect, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathways, or alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to treat, prevent or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". The exact amount will depend on the purpose of the treatment, and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999).

[0087] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0088] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating at least one symptom of a disease or disorder, preventing other symptoms, inhibiting the disease or disorder, such as arresting the development of the disease or disorder, relieving the disease or disorder, causing regression of the disease or disorder, alleviating the condition caused by the disease or disorder, or prophylactically and / or therapeutically terminating the symptoms of the disease or disorder.

[0089] Various numerical ranges are disclosed herein. When the applicant discloses or claims any type of range, the applicant's intention is to disclose or claim each possible number that the range can reasonably cover, including the endpoints of the range and any sub-ranges and combinations of sub-ranges contained therein, unless otherwise stated. In addition, all numerical endpoints of the ranges disclosed herein are approximate values. As a representative example, the applicant discloses in some embodiments that the compound can be contacted with KOH at a temperature of about 65°C to about 75°C. The range should be interpreted as covering about 65°C and about 75°C, and also covering "about" 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C or 74°C, including any ranges and sub-ranges between these values.

[0090] In this specification, when a document, act or item of knowledge is mentioned or discussed, such mention or discussion does not constitute an admission that the document, act or item of knowledge or any combination thereof was publicly available, known to the public, part of the common general knowledge, or constituted prior art according to applicable laws and regulations on the priority date; or was known to be relevant to any problem attempted to be solved in this specification.

[0091] Implementation

[0092] The following is a non-limiting list of embodiments of the present disclosure:

[0093] Embodiment 1. A method for synthesizing lysergic acid or a derivative thereof, the method comprising providing a compound of formula (A) -

[0094]

[0095] Where ProtG is a protecting group, X is a halogen, and R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbon, where C1-C 20 The hydrocarbyl group is unsubstituted or substituted as defined herein; and contacting the compound of formula (A) with a cyclizing agent to form a cyclized compound.

[0096] Embodiment 2. The method of embodiment 1, further comprising contacting the cyclized compound with a reagent effective to remove the protecting group.

[0097] Embodiment 3. The method of any of the previous embodiments, wherein the cyclizing agent is a Heck cyclizing agent.

[0098] Embodiment 4. The method of any of the previous embodiments, wherein the cyclizing agent comprises tris(dibenzylideneacetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0).

[0099] Embodiment 5. The method of any of the previous embodiments, wherein the protecting group is a tert-butyloxycarbonyl protecting group.

[0100] Embodiment 6. The method of any of the preceding embodiments, further comprising providing a compound of formula (B) -

[0101]

[0102] The compound of formula (B) is contacted with (i) a protecting group precursor in any order to form a protected indole nitrogen, and (ii) a methylating agent in any order to form a methylated pyridine nitrogen; and then the compound of formula (B) is contacted with (a) a reducing agent and / or (b) a base in any order to form a compound of formula (A).

[0103] Embodiment 7. The method of any of the preceding embodiments, wherein the reducing agent is NaBH4.

[0104] Embodiment 8. The method of any of the previous embodiments, wherein the base is lithium tetramethylpiperidinium (LiTMP).

[0105] Embodiment 9. The method of any of the preceding embodiments, further comprising a compound of formula (a) -

[0106]

[0107] contacting a compound of formula (a) with a metal-containing compound to form a Grignard reagent; then contacting the Grignard reagent with a compound of formula (b) to form a compound of formula (B)

[0108]

[0109] Embodiment 10. The method of any of the preceding embodiments, wherein the metal-containing compound comprises i-PrMgCl*LiCl.

[0110] Embodiment 11. The method of any of the preceding embodiments, further comprising providing a compound of formula (c) -

[0111]

[0112] The compound of formula (c) is contacted with a metal-containing compound to form a Grignard reagent; the Grignard reagent is then contacted with a compound of formula (d) to form a compound of formula (B) -

[0113]

[0114] Embodiment 12. The method of any of the preceding embodiments, further comprising deacetylation to form a compound of formula (I):

[0115]

[0116] Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbon.

[0117] Embodiment 13. A compound or salt thereof formed by the method of any one of the preceding embodiments.

[0118] Embodiment 14. A compound or a salt thereof disclosed herein, such as any compound or a salt thereof disclosed in Scheme 1, Scheme 2, Scheme 3, Scheme 4, or Scheme 5.

[0119] Embodiment 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I') or a pharmaceutically acceptable salt thereof:

[0120]

[0121]

[0122] Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 A hydrocarbon group, and wherein R 1 -R 6 At least one of them is not hydrogen.

[0123] Embodiment 16. The compound of any of the preceding embodiments, wherein each C1-C 20 The hydrocarbon groups are independently C1-C 15 Hydrocarbon, C1-C 10 A hydrocarbon group, a C1-C5 hydrocarbon group or a C1-C3 hydrocarbon group.

[0124] Embodiment 17. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 5 or R 6 At least one of them is not hydrogen.

[0125] Embodiment 18. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 5 or R 6 At least two of them are not hydrogen.

[0126] Embodiment 19. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 5 or R 6At least three of them are not hydrogen.

[0127] Embodiment 20. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 5 or R 6 Each of is not hydrogen.

[0128] Embodiment 21. A compound according to any one of the preceding embodiments, wherein R 3 and R 4 Not hydrogen.

[0129] Embodiment 22. A compound according to any one of the preceding embodiments, wherein R 3 and R 4 is not hydrogen, and R 1 , R 2 , R 5 or R 6 It's hydrogen.

[0130] Embodiment 23. A compound according to any one of the preceding embodiments, wherein R 3 and R 4 are different.

[0131] Embodiment 24. A compound according to any one of the preceding embodiments, wherein R 3 and R 4 (i) is not hydrogen, and (ii) is different.

[0132] Embodiment 25. A compound according to any one of the preceding embodiments, wherein R 3 It's hydroxyl.

[0133] Embodiment 26. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, and R 3 It's hydroxyl.

[0134] Embodiment 27. A compound according to any one of the preceding embodiments, wherein R 3 It's a methoxy group.

[0135] Embodiment 28. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, and R 3 It's a methoxy group.

[0136] Embodiment 29. A compound according to any one of the preceding embodiments, wherein R 2 It's methyl.

[0137] Embodiment 30. A compound according to any one of the preceding embodiments, wherein R 1 , R 3 , R 4 , R 5 and R 6 is hydrogen, and R 2 It's methyl.

[0138] Embodiment 31. A compound according to any one of the preceding embodiments, wherein R 4 is a halogen (eg, chloro-, bromo-, iodo-).

[0139] Embodiment 32. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 3 , R 5 and R 6 is hydrogen, and R 4 is a halogen (eg, chloro-, bromo-, iodo-).

[0140] Embodiment 33. A compound according to any one of the preceding embodiments, wherein R 1 , R 2 , R 5 or R 6 At least one of them is not hydrogen.

[0141] Embodiment 34. A compound according to any one of the preceding embodiments, wherein R 3 and R 4 At least one of them is not hydrogen.

[0142] Embodiment 35. A compound according to any one of the preceding embodiments, wherein R 4 It is Cl.

[0143] Embodiment 36. The compound of any one of the preceding embodiments, wherein R 5 It's hydroxyl.

[0144] Embodiment 37. A compound according to any one of the preceding embodiments, wherein R 6 It's methyl.

[0145] Embodiment 38. A pharmaceutical composition comprising (i) a compound formed by the method of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and / or (ii) a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0146] Embodiment 39. The pharmaceutical composition of embodiment 38, wherein the pharmaceutical composition is used for one or more routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical or transdermal administration.

[0147] Embodiment 40. The pharmaceutical composition of any of the preceding embodiments further comprises one or more other components, such as one or more carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or one or more combinations thereof.

[0148] Embodiment 41. A method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to a patient suffering from a neurodegenerative disease an effective amount of a compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the preceding embodiments or any of the embodiments described herein.

[0149] Embodiment 42. The method of embodiment 41, wherein the compound or salt thereof or pharmaceutical composition is administered in an amount greater than about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, or about 100 μg.

[0150] Embodiment 43. The method of any of the preceding embodiments, wherein the compound or salt thereof or pharmaceutical composition is administered in an amount greater than about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, about 60 mg, about 100 mg, about 200 mg, about 400 mg, or about 500 mg.

[0151] Embodiment 44. The method of any of the preceding embodiments, wherein the compound or salt thereof or pharmaceutical composition is administered in an effective amount of about 10 μg to about 500 μg per kilogram of patient body weight (mg per kg, mpk).

[0152] Example

[0153] The present invention is further illustrated by the following examples, but these examples should not be interpreted in any way as imposing limitations on the scope of the present invention. On the contrary, it should be clearly understood that after reading the description herein, a person of ordinary skill in the art can think of various other aspects, embodiments, modifications and equivalents of the present invention without departing from the spirit of the present invention or the scope of the appended claims. Therefore, by considering the description and practice of the present invention disclosed herein, other aspects of the present invention will be apparent to those skilled in the art.

[0154] Example 1 - Synthesis of lysergic acid

[0155] Solution 1 Efforts to implement strategy 1 to synthesize 2 are described.

[0156]

[0157] Starting from bromopyridine 9, methylation of the pyridine nitrogen with MeOTf generated the intermediate N-methylpyridinium, which was subsequently trapped with Grignard reagent 11 to give dihydropyridine 15 as the major positional isomer in 82% overall yield at a C6 / C4 ratio of 2.6:1. It was predicted that addition at C6 would be preferred due to the addition directing effects of the ester and bromine substituents.

[0158] Next, the vinyl carbamate in 15 was reduced with LiAlH4 in 80% yield to afford a 1:1 mixture of diastereomers of the acetal 16. This mixture was considered ultimately inconsequential for the synthesis of 2, as the α-center of the ester can eventually be thermodynamically resolved after construction of the ergoline framework.

[0159] The acetal 16 was then treated with phenylhydrazine (10) and a 4% H2SO4 / EtOH mixture at elevated temperature to afford the indole 8 in 61% yield. It is noteworthy that this Fisher indolization reaction has been attempted with a variety of other phenylhydrazine derivatives, but none of them gave observable indole products. This observation hindered the ability to generate modified downstream intermediates in the pathway to 2.

[0160] After obtaining 8, a final C-H cyclization is required to close the last six-membered ring in lysergic acid (2). Initially, based on the precedent for this transformation, the only observable product was cyclization of the C2 position of the indole heterocycle. Attempts to sterically prevent this undesirable cyclization were frustrated by the inability to properly functionalize or protect the indole nitrogen under alkaline conditions. This may be due to the sensitivity of the tetrahydropyridine ring in 8 to base, where conditions that attempt to deprotonate the indole nitrogen result in an unproductive decomposition pathway. Further efforts to achieve vinyl bromide cyclization using Ni-catalysis or free radical propagation (e.g., PET, Bu3SnH, and AIBN) also largely resulted in only hydrodebromination of 8.

[0161] Furthermore, while reductive coupling strategies are possible via intermediates such as 18, the Fischer indolization of 16 can only be performed with phenylhydrazine (10), hampering the ability to prepare phenyl-functionalized indole analogs of 8. Importantly, since the same cyclization cleavage is required to form the critical C-C bond at the C4 position of the indole, strategically varying the position of the halogen may enable more efficient and reliable Pd-catalyzed cyclization.

[0162] Solution 2 The forward implementation of the second retrosynthetic strategy towards the synthesis of 2 is described.

[0163]

[0164] Starting from iodopyridine 13, magnesium-halogen exchange generated a heterocyclic nucleophile that was trapped by commercial aldehyde 14 to give the intermediate alcohol (not shown) in 85% yield. Upon exposure of this intermediate to Et3SiH and TFA, the Boc protecting group was cleaved, followed by reduction of the benzyl alcohol to give indole 19 in high gram yield.

[0165] The next step in the synthesis involves reductive dearomatization of the pyridine to the tetrahydropyridine. In this case, 19 was Boc-protected and the pyridine nitrogen was methylated in situ to form the intermediate pyridinium. This intermediate was not isolated but treated with NaBH4 to smoothly generate the dihydropyridine 20 in 60% one-pot yield. Isomerization of the enoate with LiTMP gave a 2:3 diastereomeric mixture of 12a and 12b, the latter of which would be used in the key Heck cyclization. Conveniently, 12a could be converted to 12b upon re-exposure to the isomerization conditions to give the same diastereomeric results. 0Treatment of 12b with the complex (generated in situ) readily afforded 21 in excellent yield, as well as two diastereomeric olefin isomers 22a and 22b in a 5:1:1 ratio, respectively. Although similar transformations have been reported, low yields and / or stoichiometric amounts of Pd were required to achieve this cyclization, which proved challenging to implement. Furthermore, the stereochemistry of the central α to the ester in 12b was critical to the success of the reaction, allowing for a syn-β-hydride elimination followed by migratory insertion of a putative arylpalladium(II) intermediate. Finally, a mixture of 21, 22a, and 22b was saponified and isomerized as previously reported to afford lysergic acid (2) in 50% yield. See, Oppolzer, W.; Francotte, E.; K. Total Synthesis of (±)-Lysergic Acid by an Intramolecular Imino-Diels-Alder Reaction. Preliminary Communication. Helv. Chim. Acta1981, 64(2), 478–481. https: / / doi.org / https: / / doi.org / 10.1002 / hlca.19810640212.

[0166] In summary, the concise synthesis of lysergic acid (2) has been completed from commercial raw materials through 6 steps, with a total yield of 14%. In addition, the final product is converted into lysergic acid methyl ester (see U.S. Patent Application Publication No. 2023 / 0116703A1), and then converted into hydrazide (see Bioorg.Med.Chem.Lett., 2008, 18, 979–982), which can achieve the resolution of enantiomers (see, for example, U.S. Patent No. 2,447,214). The core of the simplicity of this method is to strategically and redox-economically utilize heteroaromatic starting materials as functionalized precursors of the ergoline core. In addition, although this strategic approach was initially hindered by insurmountable tactical difficulties, the reversal of polar synthons enabled the final tetracyclic core to be constructed. This simple and potential modular platform can allow the synthesis and study of effective psychoplastic (psychoplastogenic) LSD derivatives, which is valuable for drug discovery and psychotherapy. The molecular space provided by this synthetic blueprint holds great promise for the increased utilization of psychedelic drugs and their derivatives as new neuropharmacological treatments.

[0167] Example 2—Synthesis of (±)-12-chlorolysergic acid

[0168]

[0169] Starting from iodopyridine 13, magnesium-halogen exchange followed by addition to aldehyde 14b (i.e., 4-bromo-5-chloro-1H-indole-3-carboxaldehyde) afforded the intermediate benzyl alcohol, which was reduced in two steps to give the biaryl 23 in moderate yield. After methylation and reduction of the intermediate, Boc protection of the indole afforded 24 in 81% yield (over two steps). Base-mediated isomerization of this intermediate afforded 25a / 25b in a 1:2 ratio in 83% yield. The minor undesired isomer (25a) was recovered again to afford a higher amount of 25b, which was subjected to Heck cyclization in excellent yield to give the enoate 26 in 57% yield. Hydrolysis of the mixture afforded 12-chlorolysergic acid (27) in good yield.

[0170] Example 3—Synthesis of (±)-13-hydroxylysergic acid

[0171] This example discloses a route to 13-hydroxy-LSD as shown below. Indole iodide is constructed from 3-bromo-5-methoxyaniline (B) in three steps. The iodide is then subjected to magnesium halogen exchange and then quenched with commercial pyridine aldehyde A. The resulting benzyl alcohol is reduced with TFA and triethylsilane to give the corresponding biaryl methylene. The intermediate is methylated, reduced and Boc protected to give the corresponding dihydropyridine in two steps in 29% yield.

[0172] The resulting tetrahydropyridine is isomerized with LiTMP to give the protoisomer, which serves as a substrate for intermolecular Heck cyclization to give the ergoline scaffold. The Heck product is treated with aqueous KOH to generate 13-OMe-lysergic acid, which is coupled with diethylamine and demethylated to generate 13-OH-LSD. Optically pure isomers can be obtained by the above-mentioned resolution of lysergic acid.

[0173]

[0174] Example 4—Synthesis of (±)-14-methyllysergic acid

[0175] This embodiment discloses a route to 14-Me-LSD, as shown below. The desired indole iodide is constructed from 4-bromo-2-nitrotoluene (B) in two steps. The iodide is subjected to magnesium halogen exchange and then quenched with commercial pyridine aldehyde A. The resulting benzyl alcohol is reduced with TFA and triethylsilane to obtain the corresponding biaryl methylene. The intermediate is methylated, reduced and Boc-protected to obtain the corresponding dihydropyridine, which is then isomerized with LiTMP to obtain olefin isomers, which serve as substrates for intermolecular Heck cyclization to obtain the ergoline scaffold. The Heck product is treated with KOH aqueous solution to generate 14-Me-lysergic acid, which is coupled with diethylamine to generate 13-Me-LSD. Optically pure isomers can be obtained by the above-mentioned decomposition method of lysergic acid.

[0176]

[0177] Example 5—General Experimental / Procedural Information

[0178] Unless otherwise stated, all reactions were performed using flame-dried round-bottom flasks or reaction vessels. Unless otherwise stated, reactions were performed using dry solvents under an inert atmosphere of nitrogen. Dry benzene (PhH), dichloromethane (CH2Cl2), diethyl ether (Et2O), dimethylformamide (DMF), 1,4-dioxane, methanol (MeOH), acetonitrile (MeCN), and tetrahydrofuran (THF) were obtained by passing previously degassed solvents through an activated alumina column. Unless otherwise stated, yields refer to chromatographic and spectral ( 1 H NMR) homogeneous material. The NMR yield is compared with the internal standard of trimethoxybenzene or dimethyl sulfone. The reaction is monitored by thin layer chromatography on Merck silica gel plates (glass backing, 60G, F-254) or Sigma-Aldrich alumina plates (glass backing, F-254). The commercial silica gel plates are treated with 50:1 hexane: triethylamine and then the basic silica plates are prepared by reduced pressure evaporation. The TLC plates are developed using ultraviolet light and appropriate developers. NMR spectra are recorded on a Bruker AvanceIII 400, 500 or 600MHz NMR spectrometer and calibrated using residual solvent as an internal reference (benzene-d6: 1 HNMRδ=7.16, 13 C NMR δ=128.06;CDCl3: 1 H NMR δ=7.26, 13 C NMR δ=77.16;CD2Cl2: 1 Hδ=5.32, 13 C NMR δ=53.84;DMSO-d6: 1 Hδ=2.50;Methanol-d4:1 Hδ=3.31). 19 F NMR spectra were calibrated using 3-fluoropyridine as an internal reference ( 19 F NMR δ = –125.7). The following abbreviations or combinations thereof are used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. In the analysis of dihydropyridine products, CDCl3 was passed through a pad of K2CO3 before use. The crude NMR spectrum was analyzed to determine the ratio of positional isomers of the dihydropyridine. 1 Selected peaks in H NMR were used to assign unresolved positional isomers. VWR silica gel (irregular, 40-60 μm), prepared basic silica gel or deactivated alumina (chromatographic alumina, neutral, Brockman I, 50-200 μm, ) were subjected to flash column chromatography. Basic silica gel was prepared by treating commercial silica gel with 50:1 hexane:triethylamine and then evaporating under reduced pressure. The alumina was deactivated to Brockman grade III alumina by adding pure water (5% w / w) to the solid alumina. The mixture was shaken and then left to stand in a sealed container to equilibrate overnight. Preparative TLC was performed on Merck silica gel plates (glass backing, 60G, F-254), basic silica gel plates or Sigma-Aldrich alumina plates (glass backing, F-254). High resolution mass spectra (HRMS) were recorded on an Agilent 6230TOF-MS spectrometer (DART). Unless otherwise stated, reagents were purchased and used without further purification. All reagents were purchased from the following suppliers. 2,2'-Azobis(2-methylpropionitrile) was recrystallized from methanol.

[0179] Acros Organics: Borane dimethyl sulfide complex

[0180] Amresco: Magnesium chloride (anhydrous)

[0181] Cambridge Isotope Laboratories: Chloroform-d1, Acetone-d6.

[0182] Fisher Scientific: Ammonium hydroxide (concentrated), phenylhydrazine, phosphorus oxychloride, pyridine, sodium chloride, sodium nitrite, and zinc metal.

[0183] Macron Fine Chemicals: Sodium hydroxide.

[0184] Oakwood Chemical: allyltributylstannane, di-tert-butyl dicarbonate, 4-(dimethylamino)pyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, lithium aluminum hydride, magnesium sulfate, methyl chloroformate, methyl trifluoromethanesulfonate, sodium bicarbonate, 2,2,6,6-tetramethylpiperidine.

[0185] Sigma Aldrich: n-Butyllithium (2.5 M in hexanes), copper(I) iodide, N,N-dicyclohexylmethylamine, N,N'-diethylenediamine, hydrogen peroxide, iodine, isopropylmagnesium chloride lithium chloride solution (13 M in THF), lithium chloride, pyridinium chlorochromate, sodium borohydride, sodium iodide, triethylsilane, trifluoroacetic acid, trifluoromethylsulfonic acid, tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate.

[0186] Spectrum Chemicals: Diatomaceous earth.

[0187] Strem: Bis(cyclooctadiene)nickel(0).

[0188] Synquest Laboratories:

[0189] VWR: Ammonium Chloride

[0190] Ward's Science: Hydrochloric Acid and Sulfuric Acid

[0191] 6-Iononicotinoic acid methyl ester 173157-33-0AA block 140 USD / g

[0192] 6-Bromonicotinate Methyl ester 26218-78-0AA Block $2.48 / g

[0193] 4-Bromo-3-formyl-1H-indole, N-BOC protected 303041-88-5AA block $91 / g

[0194] 4-Bromoindole-3-carboxaldehyde 98600-34-1AA block $12.88 / g

[0195] 4-Bromoindole 52488-36-5AA Block $4.67 / g

[0196]

[0197] In a 30mL test tube, pyridine XX (1.00mmol) was suspended in Et2O (1.0mL), and the mixture was placed under a N2 atmosphere. The reaction vessel was placed in a room temperature water bath and the mixture was gently stirred. MeOTf (1.0 equivalent) was added dropwise to the mixture and the reaction was stirred for 1 hour. After the disappearance of the starting material as determined by TLC, the thick white mixture was concentrated in vacuo, redissolved in THF (4.0mL), and then cooled to -78°C. Grignard reagent (1.0 equivalent) was added dropwise to the reaction, and the resulting yellow mixture was stirred for 2 hours. The reaction was then quenched by adding a saturated NaHCO3 solution (4mL), and the mixture was warmed to room temperature (rt). The product was extracted with EtOAc (3×10mL). The combined organic layers were washed with brine (15mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (gradient 4:1→7:3→3:2→1:1 hexanes:EtOAc, silica) to afford 203.9 mg (59% yield) of dihydropyridine XX.

[0198] 1H NMR(400MHz, CD2Cl2)δ7.26(s,1H),6.71(d,J=1.1Hz,1H),4.54–4.47(m,1H),4.38(t,J=3.8Hz,1H),4.05–4.00(m,2H),3.75–3.6 7(m,2H),3.60(s,3H),2.96(s,3H),2.02–1.94(m,1H),1.85–1.65(m,3H),1.65–1.55(m,1H),1.29(dtt,J=13.4,2.7,1.4Hz,1H).

[0199]

[0200] To a stirred suspension of dihydropyridine XX (1.00 g, 2.89 mmol) in THF (15 mL) at 0 ° C, a suspension of LAH (84.4 mg, 2.22 mmol) in THF (15 mL) at 0 ° C was added within 5 min. The reaction mixture was stirred at 0 ° C for more than 40 minutes. After completion of TLC, the mixture was cooled to -78 ° C, and then EtOAc (7 mL) was added at one time. The mixture was stirred at -78 ° C for 5 minutes, then warmed to 0 ° C and stirred for 5 minutes. The mixture was then cooled to -78 ° C, and then saturated Rochelle solution (7 mL) was added. The mixture was stirred at -78 ° C for 5 minutes, then warmed to 0 ° C and stirred for 5 minutes. Water (20 mL) was added to the mixture and the product was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (1:1 hexanes:EtOAc eluent, silica) to afford tetrahydropyridine XX (654 mg, 65% yield) in a 1.2:1 mixture of diastereoisomers.

[0201] Physical state: Pale yellow oil.

[0202] R f = 0.43 (1:1 hexanes:EtOAc eluent, silica).

[0203] 1 H NMR (500MHz, CDCl3): δ6.31 (q, J=1.5Hz, 1H), 6.21 (dt, J=3.2, 1.0Hz, 1H), 4.56–4.52 (m, 1.84H), 4. 11–4.05(m,3.68H),3.77–3.71(m,3.68H),3.70(s,2.52H),3.69(s,3H),3.42–3.36(m,1H),3.19–3. 09(m,2.84),2.96–2.91(m,0.84H),2.90–2.78(,2.84H),2.44(s,3H),2.37(s,2.52H),2.12–1.99(m ,1.84H),1.99–1.84(m,1.84H),1.82–1.72(m,1.84H),1.71–1.53(m,3.68H),1.35–1.78(m,1.84H).

[0204] 13C NMR (126MHz, CDCl3): δ172.4,172.1,128.0,126.9,126.1,124.6,102.4,102.4,67.0,67.0,6 6.4,66.2,52.3,52.3,50.1,46.5,43.1,42.5,42.3,39.8,32.0,30.2,26.0,25.9,25.9,24.7.

[0205] HRMS(DART):C 14 H 23 BrNO4 + [M+H] + The calculated value is 348.0805; the measured value is 348.0804.

[0206]

[0207] A solution mixture of 22:1 MeOH / concentrated H2SO4 (3.0 mL) was added to a scintillation vial containing acetal XX (155 mg, 0.444 mmol) and phenylhydrazine (131 μL). Initially, a white solid and a red solution were formed. The vial was flushed with N2 and sealed with a Teflon cap. The suspension was heated and stirred at 100°C. The solid dissolved and the reaction mixture turned dark red. The reaction mixture was heated and stirred at 100°C for 3 hours. Thereafter, the reaction mixture was cooled to room temperature and poured into a 1:1 mixture (6 mL) of saturated Na2CO3 solution and ice. The product was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (13:7 hexanes / EtOAc eluent, silica) to afford indole XX (94.7 mg, 59% yield) as a 1.8:1 mixture of diastereomers.

[0208] Physical state: Yellow oil.

[0209] R f = 0.39 (13:7 hexanes:EtOAc eluent, silica).

[0210] 1H NMR (600MHz, CDCl3): δ8.14 (s, 0.38H), 8.10 (s, 1H), 7.70 (app.d, J = 7.7Hz, 1.38H) ,7.33(app.d,J=8.0Hz,1.38H),7.18(app.t,J=7.5Hz,1.38H),7.15–7.09(m,2.76 H),6.39(s,0.38H),6.33(s,1H),3.71(s,1.14H),3.69(s,3H),3.54–3.44(m,1.38 H),3.41–3.25(m,4.14H),3.22–3.11(m,1H),3.09–2.8(m,3.14H),2.45(s,4.14H).

[0211] 13 C NMR (151MHz, CDCl3): δ172.2,136.2,136.2,127.7,125.8,125.0,122.9,122.0,121.9,119.4,119.4 ,119.2,119.1,111.3,111.2,67.3,67.3,52.5,52.3,48.7,45.9,43.3,42.3,41.7,39.5,27.5,26.8.

[0212] HRMS(DART):C 17 H 18 BrN2O2 + [MH] + The calculated value is 361.0546; the measured value is 361.0515.

[0213]

[0214] In CHCl3 / dry ice bath (-61 ℃) cooled pyridyl iodide XX (1.32g, 5.00mmol) THF (5.0mL) solution, i-PrMgCl LiCl solution (5.00mL, 1.00M, 5.00mmol) was added within 2 minutes. The mixture was stirred in a cooling bath for 1 hour. After XX consumption was determined by TLC, a THF (3.0mL) solution of XX (1.78, 5.50mmol) was added dropwise to the mixture within 2min. Additional THF (0.05mL) was used to transfer any residual XX, and the solution was added dropwise within 1min. The resulting solution was stirred in a cooling bath for 1 hour. Thereafter, the cooling bath was removed, and the reaction mixture was slowly warmed to room temperature. The reaction mixture became dark green after heating, and then eventually became amber. After about 1 hour at room temperature, the mixture was quenched with saturated NH4Cl solution (10 mL), water (10 mL) was added, and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (1:1:0.05 hexanes:EtOAc:DCM eluent, silica) to give alcohol XX (1.95 g, 85% yield).

[0215] Physical state: Light beige solid.

[0216] R f = 0.31 (11:9 hexanes:EtOAc eluent, silica).

[0217] 1 H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.28–8.18 (m, 2H), 7.46 (s, 1H), 7.42 (d, J = 7.8Hz, 2H), 6.75 (s, 1H), 3.95 (s, 2H), 1.61 (s, 9H).

[0218] 13 C NMR (151MHz, CDCl3) δ165.56,165.17,149.61,148.98,138.03,137.17,127.61,127.53 ,126.50,125.53,125.05,122.17,121.37,114.72,113.48,84.65,67.85,52.52,28.10.

[0219] HRMS(DART):C 21 H 22 BrN2O5 + [M+H] +The calculated value is 461.0707; the measured value is 461.0735.

[0220]

[0221] To a stirred solution of carbamate XX (1.95 g, 4.23 mmol) in THF (4.2 mL) at 0°C was added TFA (13 mL) in one portion, causing the mixture to turn dark amber. The mixture was warmed to room temperature, and after 30 minutes, Et3SiH (4.05 mL, 25.4 mmol) was added to the mixture and stirred at 35°C for 14 hours. Additional Et3SiH (2.03 mL, 12.7 mmol) was added to the mixture, and the reaction was stirred at 35°C for 1 hour. 1 After H NMR analysis confirmed completion, the reaction mixture was poured into saturated NaHCO solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with brine (15 mL), dried over MgSO, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (1:1 hexane: EtOAc eluent, silica) to give indole XX (1.02 g, 70% yield).

[0222] Physical state: Beige solid.

[0223] R f = 0.35 (1:1 hexanes:EtOAc eluent, silica).

[0224] 1 H NMR (400MHz, CDCl3) δ9.17 (s, 1H), 8.62 (s, 1H), 8.15 (dd, J = 8.2, 2.2Hz, 1H), 7.28 (d, J = 7.7Hz, 1H),7.23(d,J=7.8Hz,1H),7.18(d,J=8.2Hz,1H),7.04–6.96(m,2H),4.65(s,2H),3.93(s,3H).

[0225] 13 C NMR (151MHz, CDCl3) δ166.74,166.03,150.26,137.79,137.60,125.41,125. 31,124.07,123.54,123.11,122.67,114.16,113.12,110.72,52.29,35.12.

[0226] HRMS(DART):C 16 H 14 BrN2O2 + [M+H]+ The calculated value is 345.0233; the measured value is 345.0257.

[0227]

[0228] To a stirred solution of indole XX (85.0 mg, 246 μmol) and Boc2O (57.1 mg, 262 μmol) in CH2Cl2 (12 mL) was added DMAP (1.6 mg, 52.0 μmol). After 1.5 hours, the reaction was complete as determined by TLC. The reaction mixture was cooled to 0°C and MeOTf (28.7 μL, 262 μmol) was added in one portion. The mixture was stirred at 0°C for 1.5 hours. After completion as determined by TLC, the mixture was cooled to -78°C. A solution of NaBH4 (56.5 mg, 1.49 mmol) in MeOH (1.2 mL) was added to the pyridine reaction mixture within 1 min, causing the reaction mixture to turn yellow. The combined mixture was stirred at -78°C for 1 hour and then quenched with a 1:1 mixture of saturated NaHCO3 solution and acetone (2 mL). The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (3:2 EtOAc:hexanes eluent, silica) to afford enoate XX (63.3 mg, 56% yield).

[0229] Physical state: white foam.

[0230] R f = 0.40 (3:2 EtOAc:hexane eluent, silica).

[0231] 1 H NMR (400MHz, CDCl3): δ8.14(d,J=8.3Hz,1H),7.40(s,1H),7.35(d,J=7.7Hz,1H),7.09(t,J=8.1Hz,1H),6.96(s,1H),3.7 3(s,3H),3.52–3.31(m,3H),3.17(q,J=4.6Hz,1H),2.69(dd,J=14.2,10.0Hz,1H),2.54(s,3H),2.20(s,2H),1.65(s,9H).

[0232] 13C NMR (151MHz, CDCl3) δ166.36,149.10,137.22,137.03,128.42,128.08,127.29,125.80,1 25.08,117.93,114.54,114.07,84.26,56.74,51.58,51.03,40.81,28.41,28.18,25.87.

[0233] HRMS(DART):C 22 H 28 BrN2O4 + [M+H] + The calculated value is 463.1232; the measured value is 463.1234.

[0234]

[0235] At 0 ° C, n-BuLi (230 μ L, 2.35M, 0.54 mmol) was added to a stirred solution of HTMP (93.7 μ L, 0.55 mmol) in THF (1.0 mL). After stirring the solution for 50 minutes, it was cooled to -78 ° C, and then the enoate XX was added dropwise to THF (1.0 mL). After addition, the mixture turned from light yellow to amber. The reaction mixture was stirred at -78 ° C for 1 hour, then warmed to 0 ° C, and stirred for an additional 20 minutes. The reaction was quenched with saturated NH4Cl solution (1.0 mL). Water (10 mL) was added to the mixture and extracted with EtOAc (3x15 mL). The combined organic layer was washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on neutralized silica gel (4:1 hexanes:EtOAc eluent, silica) to give the minor isomer XX (16.6 mg, 33% yield) and the major isomer XX (27.2 mg, 54% yield) in a 3:2 ratio.

[0236] Physical state: Yellow oil.

[0237] R f = 0.17 (1:1 hexanes:EtOAc eluent, silica).

[0238] 1H NMR(600MHz,CDCl3)δ7.53(s,1H),7.37(dd,J=7.8,0.9Hz,1H),7.11(t,J=8.0Hz,1H),5.89(d,J=10.3Hz,1H),5.71(d,J=10.3Hz,1H),3.70(s,3H),3.59(dd,J=14.8,4.6Hz,1H),3.48–3.42(m,1H),3.30–3.25(m,1H),3.20(dd,J=11.7,5.3Hz,1H),2.86(dd,J=15.0,9.6Hz,1H),2.68(t,J=10.2Hz,1H),2.56(s,3H),1.66(s,9H).Iso B

[0239] 1H NMR(400MHz,CDCl3)δ8.17(d,J=8.6Hz,1H),7.48(s,1H),7.38(d,J=8.7Hz,1H),7.11(t,J=8.0Hz,1H),5.91(d,J=10.6Hz,1H),5.75(d,J=10.3Hz,1H),3.75(s,3H),3.53–3.45(m,1H),3.40–3.33(m,1H),3.32–3.22(m,2H),2.92–2.83(m,2H),2.56(s,3H),1.67(s,9H).Iso A

[0240] 13 C NMR(151MHz,CDCl3)δ172.99,149.15,136.92,130.44,128.69,127.28,126.27,125.03,123.06,117.07,114.50,114.03,84.17,61.09,53.99,51.99,43.02,41.57,29.27,28.19.Iso B

[0241] 13 C NMR(151MHz,CDCl3)δ173.49,149.16,137.04,130.42,128.57,127.23,126.24,124.98,122.54,117.51,114.51,114.02,84.14,60.32,52.08,50.31,42.66,38.48,29.44,28.20.Iso A

[0242] HRMS(DART):C 22 H 28 BrN2O4+ [M+H] + The calculated value is 463.1232; the measured value is 463.1229.

[0243]

[0244] In a 9 mL reaction vial, the major isomer XX (25.0 mg, 0.054 mmol) was added to Pd2(dba)3 (5.0 mg, 5.4 μmol) and P(t-Bu)3HBF4 (3.0 mg, 10.8 μmol) in degassed 1,4-dioxane (2.7 mL), followed by Cy2NMe (13.9 μL, 64.8 μmol). The mixture was heated to 100 °C for 12 hours. After completion as determined by TLC, water (15 mL) was added to the mixture and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1:2 hexanes:EtOAc eluent, silica) to give an insignificant mixture of tetracyclic XX and a 1:1 diastereomeric mixture of lysergic acid methyl esters and isolysergic acid methyl esters.

[0245] Physical state: Yellow oil.

[0246] R f = 0.23 (1:1 hexanes:EtOAc eluent, silica).

[0247] 1H NMR 1H NMR (400MHz, CDCl3) XXδ7.80 (s, 1H), 7.37–7.27 (m, 2H), 7.13 (d, J=7.3Hz, 1H), 7.04 (s, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.55–3.47 (m, 1H), 3.41–3.32 (m, 2H), 2.95 (dd, J=15.4, 4.6Hz, 1H), 2.73–2.65 (m, 1H), 2.60 (s, 3H), 1.66 (s, 9H). Diastereomer Aδ7.80 (s, 1H), 7.37–7.27 (m, 2H), 7.13 (d, J=7.3Hz, 1H) ,6.60(s,1H),3.78(s,3H),3.55–3.47(m,2H),3.41–3.32(m,2H),2.73–2.65(m,2H),2.58(s,3H),1.66(s,9H). Diastereoisomer Bδ7.80(s,1H),7.37–7.27(m,2H),7.13(d,J=7.3Hz,1H),6.55(d,J=4.0Hz,1H),3.73(s,3H),3.55–3.47(m,1H),3.41–3.32(m,3H),2.73–2.65(m,2H),2.55(s,3H),1.66(s,9H).

[0248] 13 C NMR(151MHz, CDCl3)XXδ165.97,150.01,140.44,135.82,131.51,128.87,126.92,125.61, 119.99,119.79,115.36,113.56,83.41,57.26,51.68,48.64,42.22,39.21,36.67,28.23.

[0249] HRMS(DART):C 22 H 27 N2O4 + [M+H] + The calculated value is 383.1970; the measured value is 383.1951.

[0250]

[0251] A stirred solution of compound XX (29.8 mg, 0.078 mmol) in ethanol (1 mL) and 1 N KOH (1 mL) was heated at 70 ° C for 3 hours. After completion of TLC determination, the mixture was cooled to room temperature and acidified to pH 5.8 with 1 N HCl. The resulting solution was concentrated, the residue was washed with cold water (3x1 mL) and acetone (1 mL), and then extracted with pyridine (1 mL). Evaporation of pyridine gave brown solid lysergic acid in a yield of 52%.

[0252] 1 H NMR 1 H NMR(600MHz,Pyr)δ11.73(s,1H),7.45(s,1H),7.43(d,J=8.7Hz,1H),7.31–7.28(m,1H),7.26(s,1H),4.11–4.04 (m,1H),3.63(dd,J=14.4,6.0Hz,1H),3.58–3.53(m,1H),3.31–3.26(m,1H),2.92(q,J=12.6Hz,2H),2.52(s,3H).

[0253] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art may make various modifications or changes accordingly, and these modifications or changes should be included in the spirit and scope of the present application and the scope of the appended claims. The entire contents of all publications, patents and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A method for synthesizing lysergic acid or a derivative thereof, the method comprising: Provided is a compound of formula (A) - Where ProtG is a protecting group, X is a halogen, and R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein the C1-C 20 The hydrocarbyl group is unsubstituted or substituted; contacting the compound of formula (A) with a cyclizing agent to produce a cyclized compound; as well as The cyclized compound is contacted with a reagent effective to remove the protecting group.

2. The method of claim 1, wherein the cyclizing agent comprises tris(dibenzylideneacetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0). The method according to claim 1 , wherein the protecting group is a tert-butyloxycarbonyl protecting group.

4. The method according to claim 1, further comprising: Provided is a compound of formula (B) - contacting the compound of formula (B) with (i) a protecting group precursor to form a protected indole nitrogen, and (ii) a methylating agent to form a methylated pyridine nitrogen, in any order; and then The compound of formula (B) is contacted with (a) a reducing agent and / or (b) a base in any order to form the compound of formula (A).

5. The method of claim 4, wherein the reducing agent is NaBH4 and the base is lithium tetramethylpiperidinium (LiTMP).

6. The method according to claim 4, further comprising: Provided is a compound of formula (a) - The compound of formula (a) is contacted with a metal-containing compound to form a Grignard reagent; and then the Grignard reagent is contacted with a compound of formula (b) to form the compound of formula (B) - 7. The method of claim 6, wherein the metal-containing compound comprises i-PrMgCl*LiCl.

8. The method according to claim 4, further comprising: Provided is a compound of formula (c): contacting the compound of formula (c) with a metal-containing compound to form a Grignard reagent; and then contacting the Grignard reagent with a compound of formula (d) to form the compound of formula (B)- 9. The method according to claim 1, further comprising deacetylation to form a compound of formula (I): Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein the C1-C 20 The hydrocarbyl group is unsubstituted or substituted.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I') or a pharmaceutically acceptable salt thereof: Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein the C1-C 20 The hydrocarbon group is unsubstituted or substituted, and wherein R 1 -R 6 At least one of them is not hydrogen.

11. The compound according to claim 10, wherein R 2 , R 3 or R 4 At least one of them is halogen, hydroxy, methoxy or C1-C6 hydrocarbon group.

12. The compound according to claim 10, wherein R 4 It is Cl.

13. The compound according to claim 10, wherein R 5 is a hydroxyl group, or R 6 It's methyl.

14. A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof.

15. A method for treating a neurodegenerative disease in a patient in need thereof, comprising administering to a patient suffering from a neurodegenerative disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I') or a pharmaceutically acceptable salt thereof: Where R 1 -R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen or C1-C 20 Hydrocarbyl, wherein the C1-C 20 The hydrocarbyl group is unsubstituted or substituted.

16. The method according to claim 15, wherein R 2 , R 3 or R 4 At least one of them is halogen, hydroxy, methoxy or C1-C6 hydrocarbon group.

17. The method according to claim 16, wherein R 4 It is Cl.

18. The method according to claim 15, wherein R 5 It's a hydroxyl group.

19. The method according to claim 15, wherein R 6 It's methyl.

20. The method of claim 15, wherein (i) R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, and R 3 is hydroxy or methoxy, or (ii) R 1 , R 3 , R 4 , R 5 and R 6 is hydrogen, and R 2 It's methyl.

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