Galanthamine intermediate compound and synthesis method thereof

Abstract

The invention discloses a galanthamine intermediate compound and a synthesis method thereof. The galanthamine intermediate compound is a compound as shown in a formula (I) or a stereoisomer, a tautomer, a solvate and a pharmaceutically acceptable salt of the compound as shown in the formula (I). The galanthamine intermediate compound disclosed by the invention is simple in preparation method, can be prepared without harsh conditions, and has the advantages of low price, easiness in obtaining and the like; moreover, when the galanthamine intermediate compound is used for preparing galanthamine or galanthamine hydrobromide, the preparation process is simple, and the total yield of the prepared galanthamine or galanthamine hydrobromide is high. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biopharmaceutical technology. Specifically, the present invention relates to a galanthamine intermediate compound and a method for synthesizing the same. More specifically, the present invention relates to a compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt of the compound represented by formula (I), a method for preparing a compound represented by formula (6), a method for preparing a compound represented by formula (9), and a method for preparing galanthamine or galanthamine hydrobromide. Background Art

[0002] Galantamine is an inhibitor of acetylcholinesterase, the enzyme responsible for breaking down the neurotransmitter acetylcholine. By inhibiting the activity of acetylcholinesterase, galantamine increases the concentration of acetylcholine in nerve synapses, thereby enhancing the neurotransmission effects of acetylcholine.

[0003] Galantamine has been shown to improve cognitive function, including memory, attention, and behavior, in patients with Alzheimer's disease. It may also have a positive impact on the progression of the disease through other mechanisms, such as regulating neuronal survival and neuroinflammatory responses. Galantamine has been approved for the treatment of Alzheimer's disease and is widely used in clinical practice.

[0004] However, the raw materials for synthesizing galanthamine are difficult to obtain, the reaction operation is complicated, the reaction conditions are harsh, and the yield is low. Therefore, there is an urgent need for a galanthamine intermediate compound so as to simplify the synthesis of galanthamine. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

[0006] The inventor unexpectedly discovered during the process of synthesizing galanthamine that the process of synthesizing galanthamine compounds in the prior art requires expensive raw materials and harsh reaction conditions to be carried out. However, the intermediate compound of formula (6) for synthesizing galanthamine is protected by the aldehyde group and then subjected to the alkylation ring-closing step, so that the synthesis reaction of the intermediate compound of formula (9) of galanthamine can be carried out without using harsh anhydrous conditions and expensive anhydrous cesium fluoride (CsF) as a base, and conventional potassium carbonate can be used for the synthesis reaction. The conditions required for the synthesis reaction are relatively loose, the required raw materials are cheap and easy to obtain, and the total yield of synthesizing galanthamine can be further improved on the basis of the prior art.

[0007] To this end, the present invention provides a galanthamine intermediate compound and a synthesis method thereof. The preparation method of the galanthamine intermediate compound is simple, the galanthamine intermediate compound can be prepared without harsh conditions, and has the advantages of being cheap and easy to obtain. Moreover, when the galanthamine or galanthamine hydrobromide is prepared by the galanthamine intermediate compound, the preparation process is simple, and the yield of the prepared galanthamine or galanthamine hydrobromide is high.

[0008] In one aspect of the present invention, the present invention further provides a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I):

[0009]

[0010] Wherein, X1 and X2 are each independently N or O;

[0011] R1 and R2 are each independently -C1-C6 alkyl optionally substituted by one or more Ra, or a 4-7 membered aromatic group optionally substituted by one or more Ra, each Ra being independently selected from halogen, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 haloalkyl; or, R1 and R2 together with the atoms to which they are attached form a 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 alkoxy, or -C1-C6 haloalkyl;

[0012] Ring A is empty or optionally substituted by one or more Rb 8-15 membered heterocycloalkyl, each Rb is independently selected from halogen, =O, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl;

[0013] R3 is empty, halogen, -C1-C6 alkyl optionally substituted by one or more Rc, -C1-C6 alkoxy optionally substituted by one or more Rc, -C1-C6 haloalkyl optionally substituted by one or more Rc, or 5-7 membered aromatic group optionally substituted by one or more Rc, each Rb is independently selected from halogen, -OH, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl;

[0014] R4 is -OH, or -OC(R5)(R6)H;

[0015] R5 is -C1-C6 alkoxy;

[0016] R6 is a halomethyl group.

[0017] The preparation method of the compound of the present invention is simple, the compound can be prepared without harsh conditions, and has the advantages of being cheap and easy to obtain; in addition, the compound can be used as an intermediate compound of galanthamine or galanthamine hydrobromide, the preparation process of galanthamine or galanthamine hydrobromide using the compound is simple, and the yield of the prepared galanthamine or galanthamine hydrobromide is high.

[0018] In another aspect of the present invention, the present invention also provides a method for preparing a compound represented by formula (6), comprising: subjecting compound 5 to a condensation reaction with a hydroxy compound to obtain a compound represented by formula (6);

[0019] Wherein, X1, X2, R1 and R2 of the compound represented by formula (6) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above;

[0020]

[0021] The method according to the embodiment of the present invention can prepare the compound represented by formula (6), which has the advantage of a simple preparation method.

[0022] In another aspect of the present invention, the present invention also provides a method for preparing a compound of formula (9), comprising: subjecting the compound of formula (8) to an alkylation ring-closing reaction under alkaline solution conditions to obtain a compound of formula (9);

[0023] Wherein, X1, X2, R1 and R2 in the compound represented by formula (8) and the compound represented by formula (9) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above, and X1, X2, R1 or R2 in the compound represented by formula (8) and the compound represented by formula (9) are the same;

[0024]

[0025] The above method of the present invention can prepare the compound represented by formula (9). In the alkylation ring-closing reaction, the method does not need to use harsh anhydrous conditions and expensive anhydrous cesium fluoride (CsF), but can use a conventional alkaline solution for the reaction. The reaction conditions are relaxed and the yield of the compound represented by formula (9) can be increased.

[0026] In another aspect of the present invention, the present invention provides a method for preparing galanthamine or galanthamine hydrobromide, which comprises: preparing the galanthamine or galanthamine hydrobromide using a compound represented by formula (9);

[0027] Wherein, X1, X2, R1 and R2 in the compound represented by formula (9) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above;

[0028]

[0029] According to the above method of the present invention, the compound represented by formula (9) is used as a raw material to synthesize galanthamine or galanthamine hydrobromide. The raw material is cheap and easy to obtain, and the total yield of galanthamine or galanthamine hydrobromide can be improved.

[0030] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION

[0031] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0032] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0033] Detailed description of the invention

[0034] Definitions and general terms

[0035] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0036] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0037] In this article, the terms "optionally substituted", "optionally substituted" and "substituted or unsubstituted" can be used interchangeably. In general, the term "optionally", whether or not it is preceded by the term "substituted", means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner. The substituents can be, but are not limited to, F, Cl, Br, etc.

[0038] In the present context, the term "one or more" means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, even more especially one or two".

[0039] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0040] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0041] In this document, the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b It means containing "a" to "b" carbon atoms. 1～n ” refers to a straight or branched saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, ... or n carbon atoms; further understand that “C 1～n " shall be interpreted as including any sub-ranges included therein, such as C 1～6 Including C 1～6 , C 1～3 , C 1～2 , C 2～6 , C 2～5 , C 2～4 , C 2～3 , C 3～6 , C 3～5 , C 3～4 , C 4～6 , C 4～5 .

[0042] In this context, the term "alkyl" has the general structure of The alkyl group may be a linear alkyl group or a branched alkyl group. Exemplarily, the term "C1-C6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms.

[0043] In this document, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms, i.e., one halogen atom is independent of another halogen atom, wherein "C1-C6 alkyl" is as defined above. In particular, the halogen atom is F, for example: the C1-C6 haloalkyl group may be -CF3, -CHF2, -CH2F, -CF2CF3 or -CH2CF3.

[0044] In the present context, the term "C1-C6 alkoxy" refers to a C1-C6 alkoxy group having the formula "-O-alkyl". 1～6 Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy and n-hexyloxy, or isomers of the above groups. In particular, the "C1-C6 alkoxyalkoxy" may contain 1, 2, 3, 4, 5, 6 carbon atoms ("C 1～6 Alkoxy”), preferably, may contain 1, 2 or 3 carbon atoms (“C 1～3 "alkoxy").

[0045] As used herein, the term "aromatic" refers to a carbon ring system containing monocyclic, bicyclic and tricyclic rings, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 5-7 atoms. The aromatic group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aromatic group. The term "aromatic" can be used interchangeably with the term "aromatic ring" or "aromatic ring". The aromatic group can include phenyl. The aromatic group is optionally substituted with one or more substituents described in the present disclosure.

[0046] In this article, the term "aromatic alcohol" refers to a class of organic compounds, which are alcohols with carbon chains with hydroxyl groups connected to benzene rings in the molecules, such as benzyl alcohol, o-phthalic acid, p-hydroxybenzyl alcohol, etc. Aromatic alcohols have hydroxyl compounds attached to the side chains of aromatic hydrocarbons, and their structures are different from phenols.

[0047] In this document, the term "heterocycloalkyl" or "heterocyclyl" refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing multiple ring atoms; wherein heteroatoms refer to nitrogen atoms, oxygen atoms, sulfur atoms, etc. It generally refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Unless otherwise specified, heteroatoms can be attached through carbon or nitrogen, wherein -CH 2- The group is optionally replaced by -C(O)-; and wherein, unless otherwise specified to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the -NH in the ring is optionally substituted by acetyl, formyl, methyl or mesyl; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic.

[0048] As used herein, the term "spirocycloalkyl" refers to a cycloalkyl group containing a spiro ring, wherein a spiro ring refers to a structure in which two or more rings share one or more carbon atoms, and the spiro ring may be an alicyclic ring (non-aromatic ring) or an aromatic ring.

[0049] As used herein, the term "heterospirocycloalkyl" refers to a "spirocycloalkyl" containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It generally refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon.

[0050] As used herein, the term "hydroxy compound" refers to any organic compound containing a hydroxyl (-OH) functional group, including alcohols and alcoholamines. A hydroxyl group is a functional group (-OH) consisting of a hydrogen atom and an oxygen atom, which is covalently bonded to a carbon atom.

[0051] The group description of the present invention It is used to describe the position of group substitution.

[0052] In the chemical structure of the ligand or compound described in the present disclosure, the bond "-" indicates that the configuration is not specified. If chiral isomerism exists in the chemical structure, the bond "-" can be or include both Although all of the above structural formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, for example, tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0053] As used herein, the term "stereoisomer" refers to isomers of a chemical substance that have the same molecular formula and bonding pattern, but different spatial arrangements. The main difference between stereoisomers is their three-dimensional configuration in three dimensions, such as chiral isomers (isomers with a chiral center or axis) and cis-trans isomers (stereoisomers at a double bond).

[0054] As used herein, the term "tautomer" refers to isomers of chemical species that are interconvertible, usually involving the migration of a proton (hydrogen ion) or an electrophile. Tautomers are interconvertible by internal proton transfer or electrophile migration without changing the molecular linkage.

[0055] As used herein, the term "solvate" refers to a physical combination of a compound and solvent molecules, usually bound by hydrogen bonds or other interactions. A solvate is a crystalline substance formed by a compound and a solvent, wherein the solvent is bound to the compound in the form of ions or molecules.

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to salts formed by the reaction of a compound with an inorganic or organic acid or base, which have appropriate stability, solubility and bioavailability in pharmaceutical terms. Pharmaceutically acceptable salts are often used to improve the physicochemical properties, solubility and stability of drugs, thereby improving the absorption and efficacy of drugs.

[0057] The present invention provides a compound represented by formula (I) or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt of the compound represented by formula (I), a method for preparing a compound represented by formula (6), a method for preparing a compound represented by formula (9), and a method for preparing galanthamine or galanthamine hydrobromide, which will be described in detail below.

[0058] The compound represented by formula (I) or the stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I)

[0059] In one aspect of the present invention, the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I):

[0060]

[0061] Wherein, X1 and X2 are each independently N or O;

[0062] R1 and R2 are each independently optionally replaced by one or more R a -C1-C6 alkyl, or optionally substituted with one or more R a Substituted 4- to 7-membered aromatic group, each R a are each independently selected from halogen, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 haloalkyl; or, R1 and R2 together with the atoms to which they are attached form a 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 alkoxy, or -C1-C6 haloalkyl;

[0063] Ring A is empty or optionally replaced by one or more R b Substituted 8- to 15-membered heterocycloalkyl, each R b are independently selected from halogen, =O, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl;

[0064] R3 is empty, halogen, optionally replaced by one or more R c -C1-C6 alkyl, optionally substituted with one or more Rc -C1-C6 alkoxy substituted, optionally with one or more R c -C1-C6 haloalkyl or optionally substituted with one or more R c Substituted 5- to 7-membered aromatic group, each R b are independently selected from halogen, -OH, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl;

[0065] R4 is -OH, or -OC(R5)(R6)H;

[0066] R5 is -C1-C6 alkoxy;

[0067] R6 is a halomethyl group.

[0068] The preparation method of the compound of the present invention is simple, the compound can be prepared without harsh conditions, and has the advantages of being cheap and easy to obtain; in addition, the compound can be used as an intermediate compound of galanthamine or galanthamine hydrobromide, the preparation process of galanthamine or galanthamine hydrobromide using the compound is simple, and the yield of the prepared galanthamine or galanthamine hydrobromide is high.

[0069] According to an embodiment of the present invention, X1 and X2 are both O.

[0070] According to an embodiment of the present invention, R1 and R2 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dimethylpropyl, tert-butyl or benzyl.

[0071] According to an embodiment of the present invention, R1 and R2 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0072] According to an embodiment of the present invention, R1 and R2 are each independently a methyl group or an ethyl group.

[0073] According to an embodiment of the present invention, R1 and R2 are methyl groups.

[0074] According to an embodiment of the present invention, R1 and R2 together with the atoms to which they are connected form a 5- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heterocycloalkyl group is optionally substituted by one or more -C1-C6 alkyl groups.

[0075] According to an embodiment of the present invention, R1 and R2 together with the atoms to which they are connected form a 5- to 6-membered heterocycloalkyl group, and the 5- to 6-membered heterocycloalkyl group is optionally substituted by one or more -C1-C3 alkyl groups.

[0076] According to an embodiment of the present invention, for

[0077] According to an embodiment of the present invention, for

[0078] According to an embodiment of the present invention, ring A is empty, and the compound represented by formula (I) has a structure represented by formula (II):

[0079]

[0080] According to an embodiment of the present invention, R3 is halogen, or is optionally replaced by one or more R c A substituted 5- to 7-membered aromatic group.

[0081] According to an embodiment of the present invention, each R b Each is independently selected from halogen or -OH.

[0082] According to an embodiment of the present invention, R4 is -OH or -OC(R5)(R6)H; R5 is -C1-C3 alkoxy; and R6 is a halomethyl group.

[0083] According to an embodiment of the present invention, the compound represented by formula (I) has the structure of the compound represented by formula (6), formula (7) or formula (8):

[0084]

[0085] According to an embodiment of the present invention, ring A is optionally substituted with one or more R b substituted 8- to 12-membered heterocycloalkyl, the 8- to 12-membered

[0086] The membered heterocycloalkyl group contains one or more O atoms.

[0087] According to an embodiment of the present invention, ring A is optionally substituted with one or more R b A substituted 8- to 12-membered heterospirocycloalkyl group, wherein the 8- to 12-membered heterospirocycloalkyl group contains one or more O atoms.

[0088] According to an embodiment of the present invention, each R b are each independently selected from halogen, =O, or -C 1～3 Alkoxy.

[0089] According to an embodiment of the present invention, the compound represented by formula (I) has the structure of the compound represented by formula (9):

[0090]

[0091] According to an embodiment of the present invention, the compound represented by formula (I) is as follows:

[0092]

[0093] In this article, compound 6-a, compound 6-b, compound 6-c, compound 6-d, compound 6-e, compound 6-f and compound 6-g all belong to the compound represented by formula (6).

[0094] In this article, compound 7-a, compound 7-b, compound 7-c, compound 7-d, compound 7-e, compound 7-f and compound 7-g all belong to the compound represented by formula (7).

[0095] In this article, compound 8-a, compound 8-b, compound 8-c, compound 8-d, compound 8-e, compound 8-f and compound 8-g all belong to the compound represented by formula (8).

[0096] In this article, compound 9-a, compound 9-b, compound 9-c, compound 9-d, compound 9-e, compound 9-f and compound 9-g all belong to the compound represented by formula (9).

[0097] Method for preparing the compound represented by formula (6)

[0098] In another aspect of the present invention, the present invention also provides a method for preparing a compound represented by formula (6), comprising: subjecting compound 5 to a condensation reaction with a hydroxy compound to obtain a compound represented by formula (6);

[0099] Wherein, X1, X2, R1 and R2 of the compound represented by formula (6) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above;

[0100]

[0101] The method according to the embodiment of the present invention can prepare the compound represented by formula (6), which has the advantage of a simple preparation method.

[0102] In this article, "X1, X2, R1 and R2 in compound 1 are consistent with X1, X2, R1 and R2 defined in the compound shown in formula (I)" means that X1 of compound 1 is consistent with X1 defined in the compound shown in formula (I), X2 of compound 1 is consistent with X2 defined in the compound shown in formula (I), R1 of compound 1 is consistent with R1 defined in the compound shown in formula (I), and R2 of compound 1 is consistent with R2 defined in the compound shown in formula (I). For example, compound 1 is a compound shown in formula (6), which means that "X1, X2, R1 and R2 in the compound shown in formula (6) and the compound shown in formula (I) are consistent with X1, X2, R1 and R2 defined in the compound shown in formula (I)" as pointed out in this article.

[0103] According to an embodiment of the present invention, the molar ratio of compound 5 to the hydroxy compound is 1:(2-10).

[0104] According to an embodiment of the present invention, the hydroxy compound includes an organic alcohol.

[0105] According to an embodiment of the present invention, the organic alcohol is selected from at least one of C1-C6 alkyl alcohol, 4-7-valent aromatic alcohol optionally substituted by C1-C6 alkyl, and C1-C4 alkyl glycol.

[0106] According to an embodiment of the present invention, the organic alcohol is selected from at least one of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol and 2,2-dimethyl-1,3-propylene glycol.

[0107] According to an embodiment of the present invention, in the compound represented by formula (I), R1 and R2 are each independently a -C1-C6 alkyl group, or a 4-7 membered aromatic group optionally substituted by a C1-C6 alkyl group, and the organic alcohol is selected from a C1-C6 alkyl alcohol, or a 4-7 membered aromatic alcohol optionally substituted by a C1-C6 alkyl group.

[0108] According to an embodiment of the present invention, the organic alcohol is selected from at least one of methanol, ethanol, n-propanol and isopropanol.

[0109] According to an embodiment of the present invention, in the compound represented by formula (6), R1 and R2 together with the atoms to which they are connected form a 5-7 membered heterocycloalkyl group, and the organic alcohol is selected from C1-C4 alkyl diols.

[0110] According to an embodiment of the present invention, the organic alcohol is selected from at least one of ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol and 2,2-dimethyl-1,3-propylene glycol.

[0111] According to an embodiment of the present invention, the water removing agent in the condensation reaction is selected from at least one of trimethyl orthoformate, triethyl orthoformate and toluene.

[0112] According to an embodiment of the present invention, the catalyst in the condensation reaction is selected from at least one of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid hydrate, phosphoric acid, pyridinium p-toluenesulfonate and tetrabutylammonium bromide.

[0113] According to an embodiment of the present invention, the organic alcohol is selected from at least one of methanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propanediol and neopentyl glycol, the dehydrating agent is trimethyl orthoformate or toluene, and the catalyst is p-toluenesulfonic acid or tetrabutylammonium bromide.

[0114] According to an embodiment of the present invention, the organic alcohol is ethylene glycol, the water removing agent is toluene, and the catalyst is p-toluenesulfonic acid.

[0115] According to an embodiment of the present invention, the organic alcohol is selected from at least one of methanol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propanediol and neopentyl glycol, the dehydrating agent is triethyl orthoformate, and the catalyst is tetrabutylammonium bromide.

[0116] According to an embodiment of the present invention, the compound 5 is obtained by the following steps:

[0117] The compound 4 is subjected to a first bromination reaction to obtain the compound 5;

[0118]

[0119] According to an embodiment of the present invention, the brominating agent of the first bromination reaction is selected from at least one of N-bromosuccinimide, dibromohydantoin, pyridinium tribromide and liquid bromine.

[0120] According to an embodiment of the present invention, the brominating agent of the first bromination reaction is N-bromosuccinimide.

[0121] According to an embodiment of the present invention, the first solvent of the first bromination reaction is selected from at least one of dichloromethane, chloroform and DMF.

[0122] According to an embodiment of the present invention, the first solvent of the first bromination reaction is dichloromethane.

[0123] Method for preparing the compound represented by formula (9)

[0124] In another aspect of the present invention, the present invention also provides a method for preparing a compound of formula (9), comprising: subjecting the compound of formula (8) to an alkylation ring-closing reaction under alkaline solution conditions to obtain a compound of formula (9);

[0125] Wherein, X1, X2, R1 and R2 in the compound represented by formula (8) and the compound represented by formula (9) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above, and X1, X2, R1 or R2 in the compound represented by formula (8) and the compound represented by formula (9) are the same;

[0126]

[0127] The above method of the present invention can prepare the compound represented by formula (9). In the alkylation ring-closing reaction, the method does not need to use harsh anhydrous conditions and expensive anhydrous cesium fluoride (CsF), but can use a conventional alkaline solution for the reaction. The reaction conditions are relaxed and the yield of the compound represented by formula (9) can be increased.

[0128] In this article, "X1, X2, R1 or R2 in Compound 2 and Compound 3 are the same" means that X1 of Compound 2 is the same as X1 of Compound 3, X2 of Compound 2 is the same as X2 of Compound 3, R1 of Compound 2 is the same as R1 of Compound 3, and R2 of Compound 2 is the same as R2 of Compound 3. For example, Compound 2 is a compound represented by Formula (8), and Compound 3 is a compound represented by Formula (9), which means that "X1, X2, R1 and R2 in the compounds represented by Formula (8) and Formula (9) are consistent with X1, X2, R1 and R2 defined in the aforementioned compound represented by Formula (I)" as stated in this article.

[0129] According to an embodiment of the present invention, the catalyst for the alkylation ring-closing reaction is selected from at least one of potassium carbonate and LiOH·H2O.

[0130] According to an embodiment of the present invention, the second solvent of the alkylation ring-closing reaction is selected from at least one of DMSO, DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide) and NMP (N-methylpyrrolidone).

[0131] According to an embodiment of the present invention, the second solvent for the alkylation ring-closure reaction is DMSO.

[0132] According to an embodiment of the present invention, the reaction temperature of the alkylation ring-closing reaction is 110° C. to 150° C., and the reaction time is 2 to 6 h.

[0133] According to an embodiment of the present invention, the compound represented by formula (8) is obtained by the following steps:

[0134] The compound represented by formula (7) is subjected to a condensation reaction with p-hydroxyphenylboronic acid to obtain a compound represented by formula (8);

[0135] Wherein, X1, X2, R1 or R2 in the compound represented by formula (7) and the compound represented by formula (8) are the same;

[0136]

[0137] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (7) to p-hydroxyphenylboronic acid is 1:(1-3).

[0138] According to an embodiment of the present invention, the catalyst for the condensation reaction is selected from at least one of PdCl2(dppf), PdCl2(PPh3)2 and Pd(PPh3)4.

[0139] According to an embodiment of the present invention, the catalyst for the condensation reaction is PdCl2(dppf).

[0140] According to an embodiment of the present invention, the third solvent for the condensation reaction is selected from at least one of TEA and THF.

[0141] According to an embodiment of the present invention, the surfactant for the condensation reaction is TPGS-750-M.

[0142] According to an embodiment of the present invention, the reaction temperature of the condensation reaction is 20° C. to 60° C., and the reaction time is 0.5 to 12 hours.

[0143] According to an embodiment of the present invention, the compound represented by formula (7) is obtained by the following steps:

[0144] The compound represented by formula (6) is subjected to etherification reaction to obtain a compound represented by formula (7);

[0145] Wherein, X1, X2, R1 or R2 in the compound represented by formula (6) and the compound represented by formula (7) are the same;

[0146]

[0147] According to an embodiment of the present invention, the etherification reaction is carried out in bromoacetaldehyde diethyl acetal, or in vinyl ethyl ether and Br2.

[0148] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (6) to bromoacetaldehyde diethyl acetal is 1:(1.5-2).

[0149] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (6), vinyl ethyl ether and Br2 is 1:(1-2):(1-1.5).

[0150] According to an embodiment of the present invention, the third solvent for the etherification reaction is selected from at least one of DCM and TEA.

[0151] According to an embodiment of the present invention, the catalyst for the etherification reaction is selected from at least one of DIPEA, zinc bromide and acetyl chloride.

[0152] Method for preparing galantamine or galantamine hydrobromide

[0153] In another aspect of the present invention, the present invention provides a method for preparing galanthamine or galanthamine hydrobromide, which comprises: preparing the galanthamine or galanthamine hydrobromide using a compound represented by formula (9);

[0154] Wherein, X1, X2, R1 and R2 in the compound represented by formula (9) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) above;

[0155]

[0156] According to the method of the embodiment of the present invention, the compound represented by formula (9) is used as a raw material to synthesize galanthamine or galanthamine hydrobromide. The raw material is cheap and easy to obtain, and the total yield of galanthamine or galanthamine hydrobromide can be increased.

[0157] According to an embodiment of the present invention, the preparation comprises: reacting the compound represented by formula (9) in a hydrochloric acid and 1,4-dioxane system to obtain compound 10;

[0158] Compound 10 and methylamine hydrochloride are reacted in a TEA and 1,4-dioxane system, and sodium cyanoborohydride is added to react to obtain compound 11;

[0159] Compound 11 is reacted in an acid catalyst and 1,4-dioxane system to obtain compound 12;

[0160] Compound 12 is reacted in a mixed solvent to obtain compound 2;

[0161] Compound 2 is subjected to a reduction reaction with a reducing agent in an inert solvent to obtain galanthamine;

[0162]

[0163] According to an embodiment of the present invention, the acid catalyst is selected from at least one of methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid.

[0164] According to an embodiment of the present invention, the acid catalyst is methanesulfonic acid.

[0165] According to an embodiment of the present invention, the mixed solvent includes ethanol and TEA, the volume ratio of ethanol to TEA is (8-10):(0.5-3), and the concentration of ethanol is 70%-100%.

[0166] According to an embodiment of the present invention, the reducing agent is selected from at least one of L-Selectride and K-Selectride.

[0167] According to an embodiment of the present invention, the reducing agent is L-Selectride.

[0168] According to an embodiment of the present invention, the inert solvent is diethyl ether or THF.

[0169] According to an embodiment of the present invention, the preparation further comprises: subjecting galanthamine to a second bromination reaction to obtain galanthamine hydrobromide.

[0170] According to an embodiment of the present invention, the brominating agent of the second bromination reaction includes hydrobromic acid.

[0171] According to an embodiment of the present invention, the fourth solvent of the second bromination reaction includes tetrahydrofuran.

[0172] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0173] Example 1: Preparation of Compound 5

[0174] The specific preparation steps of compound 5 are as follows:

[0175]

[0176] Compound 4 (51.8 g, 340 mmol, 1.0 equiv.) was added to a 1000 mL single-mouth bottle together with 500 mL of dichloromethane (DCM). N-bromosuccinimide (NBS, 60.6 g, 340 mmol, 1.0 equiv.) was added to the single-mouth bottle in 6 batches while stirring at room temperature of 27°C. The entire addition process lasted for 1 hour, and then the reaction was stirred at room temperature. During the reaction, thin layer chromatography (TLC, PE:EA=3:2) was used to monitor the reaction. After the reaction was carried out for 40 min, the filter cake was filtered and washed 3 times with DCM (50 mL), 300 mL of DCM was added, and the mixture was stirred at room temperature overnight and then filtered. After filtration, vacuum drying (T=55°C) was performed for 3 h to obtain 70.3 g of white solid compound 5 with a yield of 89.3%.

[0177] 1H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.88(s,1H),7.34(d,J=8.5Hz,1H),7.07(d,J=8.6Hz,1H),3.86(s,3H). 13 C NMR (101MHz, DMSO-d6) δ190.86,153.39,144.05,126.70,122.10,113.37,110.46,56.49.

[0178] HRMS (ESI) calculated value: C8H8BrO3 ([M+H] + ):230.9651, detection value:230.9640.

[0179] Example 2: Preparation of Compound 6

[0180] 2.1 The specific preparation steps of compound 6-a are as follows:

[0181]

[0182] Methanol (MeOH, 100 mL), compound 5 prepared in Example 1 (20.8 g, 90.2 mmol, 1.0 equiv.), trimethyl orthoformate (14.4 g, 135 mmol, 1.5 equiv.) and p-toluenesulfonic acid monohydrate (TsOH.H2O, 1.71 g, 9.02 mmol, 0.1 equiv.) were added to a reaction bottle. Thin layer chromatography (TLC, PE:EA=3:1) was used to monitor the reaction during the reaction, and the reaction was carried out at room temperature for 18 h; triethylamine (TEA, 18.2 g, 180 mmol, 2.0 equiv.) was added to the reaction solution, stirred for 30 min, and concentrated under reduced pressure at 40°C to obtain a crude compound 6-a. After high performance liquid chromatography (HPLC) detection, the purity was 83.10%, and it was dissolved in dichloromethane (DCM, 50 mL) for the next step of reaction.

[0183] 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),6.97(s,2H),5.40(s,1H),3.83(s,3H),3.24(s,6H). 13 C NMR (151 MHz, DMSO-d6) δ148.26,143.57,129.16,117.99,110.39,109.89,102.68,56.11,53.31.

[0184] 2.2 The specific preparation steps of compound 6-b are as follows:

[0185]

[0186] 10.00 g of compound 5 (10.0 g, 43.3 mmol, 1.0 equiv.) prepared in Example 1, toluene (200 mL), p-toluenesulfonic acid monohydrate (1.65 g, 8.66 mmol, 0.2 equiv.) and ethylene glycol (26.86 g, 433 mmol, 10.0 equiv.) were added to a 500 mL single-mouth bottle and stirred. The reaction bottle was heated to 130°C and the reaction was maintained for 6 h for hydrolysis reaction. Subsequently, the reaction bottle was cooled to 27°C. Solid sodium bicarbonate was added and stirred for 30 min at 27°C, and then filtered. The filter cake was washed three times with ethyl acetate (EA) (10 mL each time), and 100 mL of ethyl acetate (EA) was added to obtain the filtrate, and then washed 6 times with water (100 mL each time), and then washed once with saturated brine (100 mL). A yellow-brown oil was obtained by concentration under reduced pressure. After purification by silica gel column (PE:EA=3:1), a light yellow jelly was obtained. After standing at room temperature, 8.40 g of white solid compound 6-b was obtained, with a yield of 70.6%.

[0187] 1 H NMR (400 MHz, DMSO-d6) δ9.47 (s, 1H), 6.99 (q, J = 8.5 Hz, 2H), 5.89 (s, 1H), 4.03 (dd, J = 8.8, 5.0 Hz, 2H), 3.93 (dd, J = 8.7, 5.0 Hz, 2H), 3.83 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ148.74,143.58,129.04,117.91,110.27,110.18,102.09,64.73,56.17.

[0188] HRMS (ESI) calculated value: C 10 H 12 BrO4([M+H] + ):274.9913, Detection value:274.9917.

[0189] 2.3 The specific preparation steps of compound 6-d are as follows:

[0190]

[0191] Compound 5 (5.00 g, 21.6 mmol, 1.0 equiv.) prepared in Example 1, triethyl orthoformate (CH(OEt)3, 3.53 g, 23.8 mmol, 1.1 equiv.), 1,2-propylene glycol (6.59 g, 86.6 mmol, 4.0 equiv.) and tributyltin tert-butylbenzoate (TBATB, 104 mg, 0.216 mmol, 0.01 equiv.) were added to the reaction flask. The reaction was carried out at room temperature under nitrogen protection. After the reaction was allowed to proceed overnight, thin layer chromatography (TLC, EA:PE=1:3) was used for monitoring, and new spots were found to be generated, indicating that the raw materials were basically reacted. After stopping stirring, water (50 mL) was added to quench the reaction, and then ethyl acetate (EA, 50 mL) was used for extraction 3 times. The organic phase was washed once with saturated brine and concentrated under reduced pressure. It was purified by column chromatography (PE:EA=10:1) to obtain 4.6 g of compound 6-d with a yield of 76%.

[0192] 1 H NMR (400 MHz, DMSO-d6) δ9.47 (s, 1H), 7.01 (dt, J = 10.6, 5.4 Hz, 2H), 5.97 (d, J = 49.5 Hz, 1H), 4.35-4.17 (m, 1H), 4.04 (t, J = 7.0 Hz,1H),3.83(s,3H),3.54-3.43(m,1H),1.26(dd,J=14.6,6.0 Hz,3H). 13 C NMR(151 MHz, DMSO-d6)δ148.74,148.65,143.58,143.48,129.53,129.11,118.08,117.84,110.37,110 .32,110.15,110.12,102.15,101.47,72.79,71.73,71.25,70.49,56.18,56.16,18.29,18.13.

[0193] HRMS (ESI) calculated value: C 11 H 14 BrO4([M+H] + ):289.0070, detection value:289.0057.

[0194] 2.4 The specific preparation steps of compound 6-e are as follows:

[0195]

[0196] Compound 5 (50.0 g, 216 mmol, 1.0 equiv.) prepared in Example 1, triethyl orthoformate (CH(OEt)3, 48.1 g, 325 mmol, 1.5 equiv.), 1,3-propylene glycol (65.9 g, 866 mmol, 4.0 equiv.), tetrabutylammonium tribromide (1.04 g, 2.16 mmol, 0.01 equiv.) and dichloromethane (DCM, 100 mL) were added to the reaction flask. Under nitrogen protection, the reaction system was kept at room temperature for reaction.

[0197] After overnight, about 1.0 equiv. of triethylamine (TEA) was added, stirred for about 30 min, and dichloromethane (DCM) was evaporated under reduced pressure to obtain a reddish brown liquid. The liquid was dissolved in 200 mL of methyl ether, and 250 mL of water was added for washing, the two phases were separated, and the aqueous phase was extracted twice with ethyl acetate (EA, 50 mL). After the organic phases were combined, they were washed twice with water (100 mL). After the solvent was evaporated under reduced pressure, a solid precipitated. 200 mL of a mixed solvent of tert-methyl ether and n-ethane (PE) with a volume ratio of 1:1 was added, stirred at 0-10 ° C for 2 h, and then filtered. 30 mL of n-ethane (PE): tert-methyl ether = 1:1 was used for elution. The wet product was vacuum dried at 65 ° C to obtain an off-white solid of compound 6-e, weighing 45.0 g. After high performance liquid chromatography (HPLC) detection, its purity was 98.38% and the yield was 72.0%.

[0198] 1 H NMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 6.99 (dd, J=25.7, 8.5Hz, 2H), 5.58 (s, 1H), 4.12 (dd, J= 11.1,4.9Hz,2H),3.97-3.87(m,2H),3.82(s,3H),2.06-1.89(m,1H),1.42(d,J=13.4Hz,1H). 13 C NMR (151MHz, DMSO-d6) δ148.32,143.25,130.34,117.85,110.11,109.93,100.40,66.83,56.13,25.28.

[0199] HRMS (ESI) calculated value: C 11 H 14 BrO4([M+H] + ):289.0070, detection value:289.0062.

[0200] 2.5 The specific preparation steps of compound 6-f are as follows:

[0201]

[0202] Compound 5 (5.00 g, 21.6 mmol, 1.0 equiv.) prepared in Example 1, triethyl orthoformate (CH(OEt)3, 4.81 g, 32.5 mmol, 1.0 equiv.), 2-methyl-1,3-propanediol (7.80 g, 86.6 mmol, 4.0 equiv.) and tributyltin tert-butylbenzoate (TBATB, 104 mg, 0.216 mmol, 0.01 equiv.) were added to the reaction flask. Under nitrogen protection, the reaction was carried out at room temperature for 1.5 h. HPLC was sent for monitoring. After the reaction was allowed to proceed overnight, ethyl acetate (EA) (50 mL), triethylamine (TEA, 2.18 g, 21.6 mmol, 1.0 equiv.) and H2O (50 mL) were added. Liquid-liquid separation was performed, and the EA phase (50 mL) was washed with water three times. The organic phase was then concentrated under reduced pressure at 40°C and collected, and about 30 mL of tertiary methyl ether was added, and solids began to precipitate. After stirring at room temperature for about 3 hours, the wet product was filtered and dried overnight in vacuum at 65°C to obtain about 3.50 g of compound 6-f as a white powder solid. After high performance liquid chromatography (HPLC) detection, the purity was 87.3% and the yield was 53.4%.

[0203] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),7.06(d,J=8.5Hz,1H),6.97(d,J=8.5Hz,1H),5.58(s,1H ), 4.06 (d, J = 10.1Hz, 2H), 3.81 (d, J = 8.7Hz, 5H), 1.63 (d, J = 7.0Hz, 1H), 1.25 (d, J = 7.0Hz, 3H). 13 C NMR (151MHz, DMSO-d6) δ148.35,143.23,130.44,117.93,110.23,109.85,100.61,71.75,56.15,28.14,15.90.

[0204] HRMS (ESI) calculated value: C 12 H 16 BrO4([M+H] + ):303.0226, detection value:303.0222.

[0205] 2.5 The specific preparation steps of compound 6-g are as follows:

[0206]

[0207] Compound 5 (5.00 g, 21.6 mmol, 1.0 equiv.) prepared in Example 1, triethyl orthoformate (CH(OEt)3, 4.81 g, 32.5 mmol, 1.5 equiv.), neopentyl glycol (9.02 g, 86.6 mmol, 4.0 equiv.), tributyltin tert-butylbenzoate (TBATB, 104 mg, 0.216 mmol, 0.01 equiv.) and dichloromethane (DCM, 50 mL) were added to the reaction bottle. Under nitrogen protection, the reaction bottle was placed at room temperature for reaction. After the reaction was carried out overnight, it was monitored by thin layer chromatography (TLC) that the raw materials were basically reacted. Then triethylamine (TEA, 2.18 g, 21.6 mmol, 1.0 equiv.) was added, stirred for 30 minutes, and then concentrated under reduced pressure at 40°C. After adding about 30 mL of tert-methyl ether, solids began to precipitate. Then slowly add 30 mL of petroleum ether, lower the temperature to 0-10°C, and stir for 1 hour. Filter to obtain a wet product, and rinse with 5 mL of tertiary methyl ether. The wet product is vacuum dried at 65°C for 2 hours to obtain about 6.20 g of compound 6-g as an off-white solid. The purity is 98.3% and the yield is 99.0% as determined by high performance liquid chromatography (HPLC).

[0208] 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),7.07(d,J=8.5Hz,1H),6.98(d,J=8.6Hz,1 H),5.52(s,1H),3.82(s,3H),3.64(q,J=10.8Hz,4H),1.19(s,3H),0.74(s,3H). 13 C NMR (151MHz, DMSO-d6) δ148.39,143.27,130.11,117.91,110.25,109.96,100.44,56.15,29.77,22.84,21.30.

[0209] HRMS (ESI) calculated value: C 13 H 18 BrO4([M+H] + ):317.0383, detection value:317.0381.

[0210] Example 3: Preparation of Compound 7

[0211] 3.1 The specific preparation steps of compound 7-a are as follows:

[0212]

[0213] Add dichloromethane (DCM) (150 mL) and zinc bromide (81.2 mg, 0.361 mmol, 0.4% equiv) to a two-necked flask. Under nitrogen protection, lower the temperature to 0°C, slowly add bromoacetal diethanol (35.6 g, 180 mmol, 2.0 equiv), then slowly add acetyl chloride (14.2 g, 180 mmol, 2.0 equiv), and after the addition, raise the temperature to 45°C and stir to react for 3 h.

[0214] The temperature was lowered to 0°C, and a constant pressure dropping funnel was installed to slowly add triethylamine (TEA, 36.4 g, 361 mmol, 4.0 equiv). After the addition was completed, a solution of compound 6-a (continuous addition, theoretical amount 25.0 g, 90.2 mmol, 1.0 equiv) in dichloromethane (DCM) (50 mL) prepared in 2.1 of Example 2 was slowly added, and then the temperature was raised to 10°C for reaction.

[0215] After reacting overnight, thin layer chromatography (TLC, PE:EA=3:1) was used to detect that the raw materials were basically reacted. Water (100 mL) was added dropwise to the reaction solution, and the mixture was separated after stirring at room temperature for 20 min. The organic phase was then washed once with water (50 mL), and after being concentrated under reduced pressure at 40°C, it was purified by column chromatography (PE:EA=10:1) to obtain about 37.1 g of oily compound 7-a, which was detected by high performance liquid chromatography (HPLC) with a purity of 94.43% and a yield of 96.1%.

[0216] 1 H NMR (400MHz, DMSO-d6) δ7.27(d,J=8.7Hz,1H),7.13(d,J=8.7Hz,1H),5.43(s,1H),5.38(t,J=5.2 Hz,1H),3.86(s,3H),3.783.59(m,4H),3.35(s,3H),3.25(d,J=3.3Hz,6H),1.07(t,J=7.0Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ152.53,141.67,129.67,123.64,118.06,111.44,103.24,102.47,64.53,56.16,53.42,53.29,32.91,14.91.

[0217] 3.2 The specific preparation steps of compound 7-b are as follows:

[0218]

[0219] Dichloromethane (DCM, 100 mL) and bromine (Br2, 5.28 g, 33.0 mmol, 1.1 equiv.) were added to the reaction flask, cooled to 0°C under nitrogen protection, and vinyl ethyl ether (3.25 g, 45.0 mmol, 1.5 equiv.) was slowly added. After the addition was completed, when the reddish brown color disappeared, diisopropylethylamine (DIPEA, 7.76 g, 60.0 mmol, 2.0 equiv.) was added, and then compound 6-b (8.26 g, 30.0 mmol, 1.0 equiv.) obtained in 2.2 of Example 2 was added in batches. The addition was completed in about 1 hour, and the reaction was continued at 0°C overnight, and LC-MS was sent for detection. The detection results showed that the raw material was left and the target product was generated. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution to quench the reaction. The aqueous phase was extracted three times with dichloromethane (DCM) (30 mL), and the dichloromethane (DCM) phase was washed once with saturated brine (40 mL). The product of compound 7-b was obtained by concentration under reduced pressure, and purified by column chromatography (PE:EA=20:1) to obtain 2.60 g of white solid, with a yield of 20.3%.

[0220] 1 H NMR (400MHz, DMSO-d6) δ7.31(d,J=8.7Hz,1H),7.10(d,J=8.7Hz,1H),5.92(s,1H),5.38(t,J=5.1Hz ,1H),4.12-4.00(m,2H),4.00-3.92(m,2H),3.86(s,3H),3.81-3.59(m,4H),1.08(t,J=7.0Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ152.98,141.69,129.53,123.48,117.97,111.63,103.32,101.91,64.84,64.48,56.13,32.82,14.86.

[0221] HRMS (ESI) calculated value: C 14 H 19 Br2O5([M+H] + ):424.9594, detection value:424.9603.

[0222] 3.3 The specific preparation steps of compound 7-c are as follows:

[0223]

[0224] Dichloromethane (DCM, 25 mL) and bromine (Br2, 2.77 g, 17.3 mmol, 2.0 equiv.) were added to a 100 mL two-necked flask and cooled to 0°C under nitrogen protection. Ethyl vinyl ether (1.56 g, 21.6 mmol, 2.5 equiv.) was then added dropwise, and the reaction was continued for 15 min after the addition was completed. Diisopropylethylamine (DIPEA, 4.48 g, 34.6 mmol, 4.0 equiv.) was then added dropwise, and then the compound 5 prepared in Example 1 (dissolved in 5 mL DCM) was added dropwise. The reaction was continued for 5 h, and the mixture was concentrated and dried under reduced pressure at 40°C. The crude product was purified by silica gel column (PE:EA=5:1) to obtain 2.01 g of solid compound 7-c with a yield of 60.8%.

[0225] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),7.69(d,J=8.7Hz,1H),7.29(d,J=8.7Hz,1H), 5.43(dd,J=6.5,3.8Hz,1H),3.96(s,3H),3.80-3.62(m,4H),1.08(t,J=7.0Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ190.58,157.57,141.96,126.92,126.88,121.82,112.18,103.31,64.70,56.68,32.85,14.93.

[0226] HRMS (ESI) calculated value: C 12 H 15 Br2O4([M+H] + ):380.9332, detection value:380.9331.

[0227] 3.4 The specific preparation steps of compound 7-d are as follows:

[0228]

[0229] Dichloromethane (DCM, 80 mL) and bromine (Br2, 2.55 g, 16.0 mmol, 1.1 equiv.) were added to the reaction flask, the temperature was cooled to 0°C, and vinyl ethyl ether (1.57 g, 21.8 mmol, 1.5 equiv.) was slowly added under nitrogen protection. After the addition of vinyl ethyl ether, the reddish brown color disappeared, and diisopropylethylamine (DIPEA, 3.75 g, 29.0 mmol, 2.0 equiv.) was added, and then a dichloromethane (DCM) solution (20 mL) of the compound 6-d (4.60 g, 14.5 mmol, 1.0 equiv.) prepared in 2.3 of Example 2 was added. The addition was completed in about 1 hour, and the reaction was continued at 0°C overnight. Monitoring by thin layer chromatography (TLC, EA:PE=1:3) revealed the formation of product spots. During the reaction, saturated sodium bicarbonate solution (50 mL) was added to the reaction system for quenching, and then the aqueous phase was extracted twice with dichloromethane (DCM, 30 mL). After the organic phases were combined, they were washed once with saturated brine (30 mL), and then concentrated under reduced pressure at 40°C. The product was purified by column chromatography (PE:EA=20:1) to finally obtain 4.3 g of orange-red oily compound 7-d with a yield of 67%.

[0230] 1 H NMR (400MHz, DMSO-d6) δ7.33(dd,J=19.9,8.7Hz,1H),7.14(t,J=9.4Hz,1H),5.99(d,J=47.9Hz,1H),5.37(t,J=5.1Hz,1H),4.36-4.20(m,1H),4.10 -4.03(m,1H),3.86(s,3H),3.74(dq,J=14.2,7.1Hz,1H),3.69-3.59(m,3H ),3.55-3.45(m,1H),1.27(dd,J=15.0,6.0Hz,3H),1.08(t,J=7.0Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ153.03,152.91,141.72,141.60,129.96,129.53,123.71,123.47,117.99,117.80,11 1.92,111.72,103.31,101.95,101.26,72.92,71.91,71.32,70.56,64.47,56.23,32.90,18.28,18.10,14.92.

[0231] HRMS (ESI) calculated value: C 15 H 21Br2O5([M+H] + ):438.9750, detection value:438.9755.

[0232] 3.5 The specific preparation steps of compound 7-e are as follows:

[0233]

[0234] Add 200 mL of dichloromethane (DCM) and zinc bromide (125 mg, 0.545 mmol, 0.35% equiv.) to the reaction flask, and under nitrogen protection, reduce the temperature to 0°C. Slowly add bromoacetal diethanol (54.5 g, 277 mmol, 1.78 equiv.), and then slowly add acetyl chloride (21.7 g, 277 mmol, 1.78 equiv.). After the addition is complete, raise the temperature to 45°C and stir to react for 1 hour. Reduce the temperature to 0°C, install a constant pressure dropping funnel, and slowly add triethylamine (TEA, 56.0 g, 554 mmol, 3.56 equiv.), and the solution will become turbid. After the addition is complete, slowly add a dichloromethane (DCM, 100 mL) solution of compound 6-e (45.0 g, 156 mmol, 1.0 equiv.) prepared in 2.4 of Example 2. After the addition, the temperature was raised to 10°C and the reaction was stirred for 2h. Thin layer chromatography (TLC, PE: EA = 3: 1) was used for detection, and the results showed that the detection raw materials were basically reacted completely. 300mL of water was added dropwise to the reaction solution, stirred at room temperature for 30min, liquid-liquid separation, and then washed once with 100mL of water. The organic phase was concentrated under reduced pressure at 40°C to obtain a reddish-brown liquid crude product. After adding 100mL of n-heptane, it failed to completely dissolve and an oily substance appeared. In order to dissolve the oily substance, 20mL of tertiary methyl ether was added to make it dissolve clearly. The mixture was moved to 15°C and stirred, resulting in the precipitation of a solid product. After overnight stirring, the solid was separated by filtration. It was rinsed with 50mL of n-heptane, and the wet product was vacuum dried at 45°C for 5h to obtain 56g of white solid compound 7-e. After high performance liquid chromatography (HPLC) detection, its purity was 99.68% and the yield was 81.7%.

[0235] 1H NMR (400MHz, DMSO-d6) δ7.33(d,J=8.7Hz,1H),7.12(d,J=8.7Hz,1H),5.61(s,1H),5.36(t,J=5.1Hz,1H),4.13(dd,J=11.2,4.9Hz,2H),3.93(t, J=11.8Hz,2H),3.85(s,3H),3.74(tt,J=14.1,7.1Hz,1H),3.67-3.56(m,3H),2.08-1.91(m,1H),1.43(d,J=13.4Hz,1H),1.07(t,J=7.0Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ152.59,141.42,130.71,123.48,117.44,111.70,103.31,100.18,66.85,64.49,56.17,32.90,25.23,14.92.

[0236] HRMS (ESI) calculated value C 15 H 21 Br2O5([M+H] + ):438.9750, detection value:438.9774.

[0237] 3.6 The specific preparation steps of compound 7-f are as follows:

[0238]

[0239] Dichloromethane (DCM, 30 mL) and zinc bromide (8.90 mg, 0.04 mmol, 0.4% equiv.) were added to a two-necked flask and nitrogen was used for protection. After the temperature was lowered to 0°C, diethyl bromoacetal (3.90 g, 19.8 mmol, 1.0 equiv.) was slowly added, followed by acetyl chloride (1.55 g, 19.8 mmol, 2.0 equiv.). After the addition was completed, the temperature was raised to 45°C and stirred; after the reaction was carried out for 2 hours, the temperature was lowered to 0°C, and then a constant pressure dropping funnel was installed to slowly drop diisopropylethylamine (DIPEA, 5.11 g, 39.6 mmol, 4.0 equiv.). After the solution was dissolved, a dichloromethane (20 mL) solution of compound 6-f (3.00 g, 9.89 mmol, 1.0 equiv.) prepared in 2.5 of Example 2 was slowly added, and the temperature was raised to 10°C to continue the reaction. After the reaction was overnight, the raw material was basically reacted by thin layer chromatography (TLC). Water (30 mL) was added dropwise to the reaction, and liquid-liquid separation was performed after stirring at room temperature for 20 minutes, and then the organic phase (30 mL) was washed with water once. The organic phase was concentrated under reduced pressure at 40 ° C, and then purified by column chromatography (using a mixed solvent of n-hexane and ethyl acetate in a ratio of 8: 1) to obtain 4.30 g of compound 7-f as a white solid. Detected by high performance liquid chromatography (HPLC), the purity was 99.26% and the yield was 95.7%.

[0240] 1 H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.7Hz,1H),7.14(d,J=8.7Hz,1H),5.61(s,1H),5.36(t,J=5.1Hz,1H),4.08(d,J=11.2Hz,2H), 3.90-3.79(m,5H),3.77-3.69(m,1H),3.64(d,J=5.0Hz,3H),1.65(d,J=7.0Hz,1H),1.25(d,J=7.0Hz,3H),1.07(t,J=7.0Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ152.63,141.42,130.79,123.54,117.35,111.81,103.33,100.39,71.76,64.50,56.20,32.90,28.08,15.87,14.93.

[0241] HRMS (ESI) calculated value C 16 H 23 Br2O5([M+H] +):452.9907, detection value:452.9932.

[0242] 3.7 The specific preparation steps of compound 7-g are as follows:

[0243]

[0244] Dichloromethane (DCM, 30 mL) and zinc bromide (9.35 mg, 0.042 mmol, 0.4% equiv.) were added to a two-necked flask and nitrogen was used for protection. After the temperature was lowered to 0°C, diethyl bromoacetal (4.09 g, 20.76 mmol, 2.0 equiv.) was slowly added, followed by acetyl chloride (1.63 g, 20.8 mmol, 2.0 equiv.). After the addition was completed, the temperature was raised to 45°C and stirred; after 1 hour, the temperature was lowered to 0°C, and then a constant pressure dropping funnel was installed to slowly drop diisopropylethylamine (DIPEA, 5.36 g, 41.5 mmol, 4.0 equiv.). After the solution was dissolved, a dichloromethane (10 mL) solution of compound 6-g (3.30 g, 10.4 mmol, 1.0 equiv.) prepared in 2.5 of Example 2 was slowly added, and the temperature was raised to 10°C to continue the reaction. After the reaction was overnight, the raw material was basically reacted by thin layer chromatography (TLC). Water (30 mL) was added dropwise to the reaction, and liquid-liquid separation was performed after stirring at room temperature for 20 minutes, and then the organic phase (30 mL) was washed with water once. The organic phase was concentrated under reduced pressure at 40 ° C, and then purified by column chromatography (using a mixed solvent of ethyl acetate and n-hexane in a ratio of 1: 8) to obtain about 4.7 g of oily compound 7-g. After the product was left for about 48 hours, solids precipitated. Detected by high performance liquid chromatography (HPLC), the purity was 100% and the yield was 96.9%.

[0245] 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=8.7Hz,1H),7.14(d,J=8.8Hz,1H),5.55(s,1H),5.36(t,J= 5.1Hz,1H),3.86(s,3H),3.79-3.58(m,8H),1.20(s,3H),1.08(t,J=7.0Hz,3H),0.75(s,3H). 13 C NMR(151MHz,DMSO-d6)δ152.67,141.45,130.48,123.53,117.47,111.84, 103.34,100.22,76.73,64.51,56.20,32.89,29.76,22.80,21.26,14.93.

[0246] HRMS (ESI) calculated value C 17 H 25 Br2O5([M+H] + ):467.0063, detection value:467.0083.

[0247] Example 4: Preparation of Compound 8

[0248] 4.1 The specific preparation steps of compound 8-a are as follows:

[0249]

[0250] Compound 7-a (18.7 g, 43.7 mmol, 1.0 equiv.) prepared from 3.1 in Example 1, tetrahydrofuran (THF, 35 mL), DL-α-tocopheryl methoxy polyethylene glycol succinate-750-M (TPGS-750-M) (2% Wt, 70 mL), triethylamine (TEA, 9.04 g, 135 mmol, 3.0 equiv.), p-hydroxyphenylboronic acid (9.33 g, 65.5 mmol, 1.5 f) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl2(dppf), 1.27 g, 1.75 mmol, 0.04 equiv.) were added to a 250 mL single-mouth bottle. The reaction system was replaced with nitrogen three times, and the temperature was raised to 40°C for reaction; the reaction was carried out for about 2 h. During the reaction, thin layer chromatography (TLC, PE:EA=3:2) was used to monitor the reaction to ensure that the raw materials were completely reacted. The reaction system was cooled to room temperature, and then extracted with ethyl acetate (EA) for 3 times. The ethyl acetate (EA) phase was combined and washed with water for 2 times, and then concentrated under reduced pressure to obtain oily compound 8-a. After high performance liquid chromatography (HPLC) detection, its purity was 79.00%. The obtained compound 8-a can be directly used for the next step reaction.

[0251] 1 H NMR(400MHz, CDCl3)δ7.43(d,J=8.6Hz,1H),7.20-7.08(m,2H),6.96(d,J=8.7 Hz,1H),6.83(dd,J=5.1,2.7Hz,2H),4.97(dd,J=8.2,2.6Hz,1H),4.93(s,1H) ,3.89(s,3H),3.61(dq,J=9.4,7.1Hz,1H),3.33(dq,J=9.4,7.0Hz,1H),3.22( d, J=14.2Hz, 6H), 3.07 (ddd, J=18.9, 10.6, 5.5Hz, 2H), 1.06 (t, J=7.1Hz, 3H). 13C NMR (151MHz, CDCl3) δ155.89,152.59,141.93,136.52,132.01,131.74,129.82,126.70,12 2.92,115.16,115.04,111.07,103.93,102.11,64.81,55.85,53.90,53.88,32.18,15.03.

[0252] HRMS (ESI) calculated value C 20 H 25 BrNaO6([M+Na] + ):463.0727, detection value 463.0729.

[0253] 4.2 The specific preparation steps of compound 8-b are as follows:

[0254]

[0255] Compound 7-b (1.00 g, 2.35 mmol, 1.0 equiv.) prepared in 3.2 of Example 3, hydroxyphenylboronic acid (0.64 g, 4.70 mmol, 2.0 equiv.), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl2(dppf)) (68.8 mg, 0.094 mmol, 0.04 equiv.) were added to the reaction flask under nitrogen protection. Subsequently, triethylamine (TEA, 0.71 g, 7.02 mmol, 3.0 equiv.), tetrahydrofuran (THF, 4 mL) and DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% Wt, 20 mL) were added, and the reaction flask was heated to 40° C. and reacted for 8 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate (EA) (50 mL) three times to obtain a crude product. The crude product was dried by rotary evaporation at 50° C. Purification by silica gel column chromatography (PE:EA=7:1) gave 1.03 g of solid compound 8-b with a yield of 100%.

[0256] 1H NMR(400MHz, CDCl3) δ7.47(d,J=8.7Hz,1H),7.22(dd,J=16.4,8.8Hz,2H),6.98( d,J=8.7Hz,1H),6.83(d,J=8.5Hz,2H),5.41(s,1H),4.97(dd,J=8.3,2.5Hz,1H), 4.10(t,J=6.6Hz,2H),3.93-3.83(m,5H),3.61(dq,J=14.2,7.1Hz,1H),3.33(dq ,J=14.2,7.0Hz,1H),3.07(ddd,J=18.9,10.6,5.5Hz,2H),1.05(t,J=7.0Hz,3H). 13 C NMR (151MHz, CDCl3) δ155.43,153.11,141.81,136.97,132.45,132.24,128.91,126.79,12 3.35,114.90,114.80,111.50,103.95,101.42,65.40,65.40,64.97,55.93,32.22,15.06.

[0257] HRMS (ESI) calculated value: C 20 H 24 BrO6([M+H] + ):439.0751, detection value:439.0723.

[0258] 4.3 The specific preparation steps of compound 8-c are as follows:

[0259]

[0260] Compound 7-c (30.0 g, 78.5 mmol, 1.0 equiv.) prepared in 3.3 of Example 3, p-hydroxyphenylboronic acid (16.2 g, 118 mmol, 1.5 equiv.) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl2(dppf), 1.15 g, 1.5 mmol, 0.02 equiv.) were added to a 500 mL four-necked bottle and the reaction was carried out under nitrogen protection. Subsequently, triethylamine (TEA, 23.8 g, 236 mmol, 3.0 equiv.), tetrahydrofuran (THF, 75 mL) and DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% Wt, 150 mL) were added, and the reaction bottle was heated to 40° C. and reacted for 1 h. After the reaction, the temperature was lowered to room temperature, water (100 mL) was added, and then extracted with ethyl acetate (EA, 150 mL) for 3 times. The organic phases were combined and then concentrated to dryness under reduced pressure at 40°C to obtain a crude compound 8-c. The crude compound 8-c was purified by silica gel column chromatography (PE:EA=4:1) to obtain 12.1 g of a light yellow solid with a yield of 40.0%.

[0261] 4.4 The specific preparation steps of compound 8-d are as follows:

[0262]

[0263] In a 100 mL two-necked bottle, compound 7-d (2.00 g, 4.54 mmol, 1.0 equiv.) prepared in 3.4 of Example 3, p-hydroxyphenylboronic acid (0.941 g, 6.81 mmol, 1.5 equiv.), 1,1'-bis(diphenylphosphino)ferrocenedichloride palladium (PdCl2(dppf), 133 mg, 0.182 mmol, 0.04 equiv.), tetrahydrofuran (THF, 10 mL) and DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% Wt, 20 mL) were added. Under nitrogen protection, triethylamine (TEA, 1.38 g, 13.6 mmol, 3.0 equiv.) was added. The reaction system was heated to 45° C. for 3 h, and thin layer chromatography (TLC, HEX:EA=2:1) ​​showed that a small amount of raw materials remained. The reaction solution was cooled to room temperature and extracted three times with ethyl acetate (EA, 30 mL). The organic phases were combined, washed twice with water (40 mL), and concentrated under reduced pressure at 46 ° C to obtain a brown foamy solid. The crude product was purified by silica gel column chromatography (PE: EA = 3: 2) to obtain 0.72 g of compound 8-d as a light yellow solid, with a yield of 35.4%.

[0264] 1H NMR (400MHz, CDCl3) δ7.49 (dd, J=20.1, 8.7Hz, 1H), 7.257.15 (m, 2H), 6.98 (t, J=8.3Hz, 1H),6.83(d,J=8.5Hz,2H),5.53(s,1H),5.45(s,1H),4.95(dd,J=8.3,2.5Hz,1H),4.41 4.11(m,1H),3.96(t,J=7.0Hz,1H),3.90(s,3H),3.67-3.51(m,2H),3.43-3.26(m,1H), 3.15v2.97(m,2H),1.38(d,J=6.0Hz,2H),1.22(d,J=6.1Hz,1H),1.06(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ155.41,153.10,141.75,136.96,136.80,132.52,132.31,132.21,129.47,129.02,126.86,123.67,123.34 ,114.87,114.79,111.65,103.99,101.55,100.53,73.25,72.57,72.31,71.43,64.95,55.95,32.24,31.08,18.83,18.60,15.07.

[0265] HRMS (ESI) calculated value: C 21 H 25 BrNaO6([M+Na] + ):475.0727, detection value:475.0702.

[0266] 4.5 The specific preparation steps of compound 8-e are as follows:

[0267]

[0268] A 100 mL two-necked bottle was charged with compound 7-e (30.0 g, 68.2 mmol, 1.0 equiv.) prepared in 3.5 of Example 3, tetrahydrofuran (THF, 150 mL), p-hydroxyphenylboronic acid (14.1 g, 102 mmol, 1.5 equiv.), 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (PdCl2(dppf), 2.00 g, 2.70 mmol, 0.04 equiv.) and DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% Wt, 300 mL). The nitrogen atmosphere was replaced three times, and the nitrogen balloon was used for protection. Triethylamine (TEA, 20.7 g, 205 mmol, 3.0 equiv.) was added to the syringe, and the temperature was raised to 40°C for reaction for 2 h. During the reaction, thin layer chromatography (TLC, PE: EA = 3: 1) was used for reaction monitoring. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (EA, 150 mL) was added for extraction 3 times, and the organic phases were combined and washed with water (200 mL) 3 times, and concentrated under reduced pressure at 50°C to obtain a dark red oil. Ethanol (EtOH, 60 mL) was added to the crude product, and the temperature was raised to 55°C and stirred for about 20 min, and then water (120 mL) was added dropwise. After the addition was completed, the heating was turned off, and the temperature was gradually lowered to 15°C and stirred for 1 h, and then filtered. The filter cake was rinsed with EtOH: H2O = 1: 2 (20 mL). The wet product was vacuum dried at 65°C overnight to obtain 30.3 g of brown solid. After high performance liquid chromatography (HPLC) detection, its purity was 98.49%, and the yield was 98.0%.

[0269] 1 H NMR (400MHz, DMSO-d6) δ9.54 (s, 1H), 7.36 (d, J = 8.7Hz, 1H), 7.06 (dd, J = 11.2, 7.8Hz, 3H), 6.82(d,J=8.4Hz,2H),4.98-4.84(m,2H),4.01(d,J=9.9Hz,2H),3.83(s,3H),3.54(dd,J=2 3.2,11.3Hz,2H),3.42(dt,J=14.2,7.1Hz,1H),3.22(dq,J=14.1,7.0Hz,1H),3.09(ddd,J =18.5,10.6,5.3Hz,2H),2.03-1.85(m,1H),1.29(d,J=13.1Hz,1H),0.91(t,J=7.0Hz,3H). 13C NMR(151MHz,DMSO-d6)δ156.67,152.03,141.07,135.07,131.55,131.49,130.45,125.01,122 .91,114.49,111.35,102.86,99.19,69.80,66.64,66.61,63.21,55.72,32.41,25.16,14.85.

[0270] HRMS (ESI) calculated value: C 21 H 26 BrO6([M+H] + ):453.0907, detection value:453.0931.

[0271] 4.6 The specific preparation steps of compound 8-f are as follows:

[0272]

[0273] Compound 7-f (2.86 g, 6.30 mmol, 1.0 equiv.) prepared in 3.6 of Example 3, tetrahydrofuran (THF, 10 mL), triethylamine (TEA, 1.90 g, 18.9 mmol, 3.0 equiv.), p-hydroxyphenylboronic acid (1.30 g, 9.45 mmol, 1.5 equiv.) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl2(dppf), 184 mg, 0.252 mmol, 0.04 equiv.) were added to a 100 mL two-necked bottle. After nitrogen replacement three times, DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% weight, 20 mL) was added using a syringe. The temperature was raised to 40°C and the reaction was carried out overnight. The reaction was monitored by thin layer chromatography (TLC, PE:EA=3.1), and the reaction of the raw materials was basically completed. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate three times, and then the EA phase was washed with water twice. After vacuum concentration, it was purified by column chromatography (PE:EA=5:1) to obtain 1.58 g of a reddish brown oil. The purity was 100% and the yield was 53.7% as determined by high performance liquid chromatography (HPLC).

[0274] 1H NMR (400MHz, DMSO-d6) δ9.54 (s, 1H), 7.40 (d, J = 8.7Hz, 1H), 7.15-6.99 (m, 3H), 6.8 2(d,J=8.5Hz,2H),4.97-4.84(m,2H),3.84(s,3H),3.72(s,3H),3.44(ddd,J=17.1, 16.5,10.0Hz,2H),3.28-3.17(m,1H),3.13(dd,J=10.6,2.7Hz,1H),3.05(dd,J=10 .5,7.9Hz,1H),1.51(d,J=7.0Hz,1H),1.24(d,J=7.0Hz,3H),0.91(t,J=7.0Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ156.66,152.03,141.04,134.99,131.52,131.47,130.52,126.98,124.97,122.91 ,115.56,114.49,111.44,102.86,99.30,71.53,71.52,69.79,63.25,55.75,32.41,27.97,15.89,14.86.

[0275] HRMS (ESI) calculated value: C 22 H 28 BrO6([M+H] + ):467.1064, Detection value:467.1077.

[0276] 4.7 The specific preparation steps of compound 8-g are as follows:

[0277]

[0278] Compound 7-g (3.19 g, 6.82 mmol, 1.0 equiv.) prepared from 3.7 in Example 3, tetrahydrofuran (THF, 10 mL), triethylamine (TEA, 2.07 g, 20.5 mmol, 3.0 equiv.), p-hydroxyphenylboronic acid (1.41 g, 10.2 mmol, 1.5 equiv.) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl2(dppf), 0.200 g, 0.270 mmol, 0.04 equiv.) were added to a 100 mL two-necked bottle. After nitrogen replacement three times, DL-α-tocopheryl methoxypolyethylene glycol succinate-750-M (TPGS-750-M, 2% weight, 20 mL) was added using a syringe. The temperature was raised to 40°C for reaction; after 2 hours, the reaction was monitored by thin layer chromatography (TLC, PE:EA=3:1), and a small amount of raw materials remained in the reaction. The reaction solution was cooled to room temperature, extracted with ethyl acetate three times, and then the EA phase was washed with water twice. After vacuum concentration, column chromatography purification (EA:PE=1:5) was performed to obtain about 2.0 g of reddish brown oily compound 8-g. The purity was 99.87% and the yield was 61.0% as determined by high performance liquid chromatography (HPLC).

[0279] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=8.7Hz,1H),7.25-7.14(m,2H),6.99(d,J=8.7Hz,1H),6.83(d,J=8.6Hz,2H),4.97(s,1H),4.93(dd,J=8.3,2.5H z,1H),3.88(s,3H),3.68-3.56(m,3H),3.42-3.26(m,3H),3.06(ddd,J= 19.0,10.6,5.5Hz,2H),1.30(s,3H),1.05(t,J=7.1Hz,3H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ155.73,155.69,152.82,141.68,135.79,132.30,132.04,130.44,126.78,126.74,123 .02,114.94,114.86,111.64,104.05,99.73,77.64,77.60,65.05,55.93,32.17,30.16,23.21,21.77,15.02.

[0280] HRMS (ESI) calculated value: C 23 H 30 BrO6([M+H]+ ):481.1220, Detection value:481.1218.

[0281] Example 5: Preparation of Compound 9

[0282] 5.1 The specific preparation steps of compound 9-a are as follows:

[0283]

[0284] Compound 8-a (the crude product obtained in 4.1 of Example 4, 43.7 mmol, 1.0 equiv.), DMSO (200 mL), and potassium carbonate particles (18.1 g, 131 mmol, 3.0 equiv.) were added to the reaction flask and the reaction was carried out under nitrogen protection. The reaction flask was heated to 125°C and stirred. The reaction time was about 4 h. Thin layer chromatography (TLC) was used to detect that the raw materials were basically reacted completely, and heating and stirring were stopped. Ethyl acetate (EA, 100 mL) was added under stirring at 0°C, and then water (300 mL) was slowly added. Exothermic phenomenon occurred in this process. Liquid separation was performed, and the aqueous phase was extracted twice with ethyl acetate (EA) (100 mL each time), the organic phases were combined, washed twice with water (70 mL), and the organic phase was concentrated under reduced pressure at 40°C to obtain a crude product. After purification by column chromatography (PE:EA=5:1-2:1), 10.8 g of light yellow solid was obtained. After detection by high performance liquid chromatography (HPLC), the purity was 88.24%. The compound 5 prepared in Example 1 was used to generate methylal and then synthesized to the compound 9-a of this example in four steps, and the total yield was 80.8%.

[0285] 1 H NMR (400MHz, CDCl3) δ7.63 (dd, J=10.1, 2.8Hz, 1H), 7.23 (d, J=8.6Hz, 1H), 7.05 (dd, J=9.9, 2. 8Hz,1H),6.93(d,J=8.6Hz,1H),6.37(dd,J=9.9,1.8Hz,1H),6.30(dd,J=10.1,1.8Hz,1H),5. 43(t,J=2.6Hz,1H),4.98(s,1H),3.94-3.84(m,4H),3.65(dq,J=9.6,7.1Hz,1H),3.19(d,J=2 7.3Hz, 6H), 2.36 (dd, J=13.9, 2.6Hz, 1H), 1.92 (dd, J=13.9, 2.6Hz, 1H), 1.19 (t, J=7.1Hz, 3H). 13C NMR (151MHz, CDCl3) δ185.34,156.90,156.84,150.04,140.11,131.02,127.39,126.21,1 19.93,119.88,111.55,101.03,94.71,64.59,56.21,55.18,55.15,40.82,40.50,15.17.

[0286] HRMS (ESI) calculated value: C 20 H 24 NaO6([M+Na] + ):383.1465, detection value:383.1478.

[0287] 5.2 The specific preparation steps of compound 9-b are as follows:

[0288]

[0289] K2CO3 (440 mg, 3.18 mmol, 2.5 equiv.), DMSO (12 mL) and compound 8-b (560 mg, 1.27 mmol, 1.0 equiv.) prepared in 4.2 of Example 4 were added to the reaction flask. After the addition, the reaction flask was heated to 140°C for 6 h. The reaction solution was then cooled to room temperature, water (20 mL) was added, and then petroleum ether was extracted five times (20 mL each time). The organic phase was washed with brine and then rotary evaporated to dryness at 50°C. The obtained product compound 9-b was purified by silica gel column chromatography (PE:EA=5:3) to obtain 350 mg of a white solid with a yield of 86.5%.

[0290] 1 H NMR (400MHz, CDCl3) δ7.65(dd,J=10.1,2.8Hz,1H),7.28(d,J=2.0Hz,1H),7.07(dd,J=9.9,2.8Hz ,1H),6.94(d,J=8.6Hz,1H),6.34(dd,J=9.9,1.8Hz,1H),6.27(dd,J=10.2,1.8Hz,1H),5.57(s,1 H),5.45(t,J=2.6Hz,1H),4.09-4.03(m,2H),3.96-3.86(m,4H),3.84-3.76(m,2H),3.66(dq,J=9 .6,7.1Hz,1H),2.36(dd,J=13.9,2.6Hz,1H),1.93(dd,J=13.9,2.7Hz,1H),1.19(t,J=7.1Hz,3H). 13C NMR (151MHz, CDCl3) δ185.44,156.73,150.52,140.05,129.27,127.45,126.19,120. 69,120.45,111.47,99.17,94.76,65.25,65.22,64.52,56.19,40.80,40.37,15.15.

[0291] HRMS (ESI) calculated value: C 20 H 23 O6([M+H] + ):359.1489, detection value:359.1482.

[0292] 5.3 The specific preparation steps of compound 9-c are as follows:

[0293]

[0294] Compound 8-c (50 g, 126.5 mmol, 1.0 equiv.) prepared in 4.3 of Example 4 and dried cesium fluoride (61.2 g, 442.8 mmol) were added to a 1 L single-mouth bottle, and then dried N, N-dimethylformamide (DMF, 500 mL) was added. Under nitrogen protection, molecular sieves (50 g) were added. The reaction flask was heated to 130 ° C and the reaction was carried out for 2 h. After the reaction was completed, the temperature was lowered to room temperature, and then filtered through a diatomaceous earth pad, and the filter cake was washed with ethyl acetate (EA, 1.5 L). Then water (1.5 L) was added for separation. Concentrated and dried under reduced pressure at 40 ° C to obtain a crude compound 9-c. The crude product was purified by silica gel column chromatography (PE: EA = 3: 1), and 30.2 g of product was obtained by column, with a yield of 56.2%.

[0295] 1 H NMR (400MHz, CDCl3) δ9.91 (s, 1H), 7.72 (dd, J = 10.1, 2.9Hz, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.0 3(dd,J=9.9,2.9Hz,1H),6.95(d,J=8.6Hz,1H),6.34(dd,J=9.9,1.7Hz,1H),6.28(dd,J=10 .2,1.7Hz,1H),5.48(t,J=2.5Hz,1H),3.95(s,3H),3.93-3.83(m,1H),3.67(dq,J=9.6,7.1 Hz, 1H), 2.37 (dd, J=14.0, 2.6Hz, 1H), 1.99 (dd, J=14.0, 2.5Hz, 1H), 1.19 (t, J=7.1Hz, 3H). 13C NMR (151MHz, CDCl3) δ189.69,184.58,155.96,155.63,154.60,140.22,128.78,12 8.10,126.50,123.47,122.86,110.80,94.94,64.78,56.36,40.34,39.90,15.14.

[0296] HRMS (ESI) calculated value: C 18 H 19 O5([M+H] + ):315.1227, detection value:315.1213.

[0297] 5.3 The specific preparation steps of compound 9-d are as follows:

[0298]

[0299] K2CO3 (440 mg, 3.18 mmol, 2.5 equiv.), DMSO (12 mL) and compound 8-d (1.27 mmol, 1.0 equiv.) prepared in 4. of Example 4 were added to the reaction flask. After the addition was completed, the temperature was raised to 125°C for 2 hours. Then the temperature was lowered to room temperature, water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL) was extracted for 5 ci. The organic phase was washed with brine. The crude compound 9-d was obtained by concentrating under reduced pressure at 40°C. After purification by silica gel column chromatography (PE: EA = 5:3), a white solid was obtained with a yield of 98.4%.

[0300] 5.4 The specific preparation steps of compound 9-e are as follows:

[0301]

[0302] In the reaction flask, compound 8-e (29.6 g, 65.2 mmol, 1.0 equiv.) prepared in 4.5 of Example 4 and dimethyl sulfoxide (DMSO, 300 mL) were added respectively, and then lithium hydroxide monohydrate (LiOH·H2O, 8.21 g, 196 mmol, 3.0 equiv.) was added. Under nitrogen protection, the temperature was raised to 125°C and stirred for about 2 hours. The raw materials were basically reacted by monitoring by high performance liquid chromatography (HPLC). The reaction was placed at 15°C and continued to stir, and then water (500 mL) was added dropwise. After the addition was completed, the mixture was continued to stir at 15°C for 2 hours and then filtered. The solid was rinsed with water (50 mL) twice, and then the wet product was vacuum dried at 65°C overnight to obtain 21.1 g of brown solid of compound 9-e. The purity was 96.25% and the yield was 86.9% as determined by high performance liquid chromatography (HPLC).

[0303] 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=10.1, 2.7Hz, 1H), 7.32 (d, J=8.6Hz, 1H), 7.03 (dd, J=9. 9,2.7Hz,1H),6.92(d,J=8.6Hz,1H),6.41-6.26(m,2H),5.43(s,1H),5.29(s,1H),4.11- 4.00(m,2H),3.91-3.79(m,4H),3.69-3.51(m,3H),2.35(dd,J=13.9,2.4Hz,1H),2.19-2 .04(m,1H),1.92(dd,J=13.9,2.4Hz,1H),1.29(d,J=13.5Hz,1H),1.16(t,J=7.1Hz,3H). 13 C NMR (151MHz, CDCl3) δ185.56,157.15,157.02,150.17,139.86,131.18,127.10,125.95,120 .50,118.75,111.62,97.78,94.67,67.79,67.51,64.48,56.22,40.87,40.22,25.53,15.14.

[0304] HRMS (ESI) calculated value: C 21 H 25 O6([M+H] + ):373.1646, detection value:373.1651.

[0305] 5.5 The specific preparation steps of compound 9-f are as follows:

[0306]

[0307] K2CO3 (440 mg, 3.18 mmol, 2.5 equiv.), DMSO (12 mL) and compound 8-f (1.27 mmol, 1.0 equiv.) prepared from 4.6 in Example 4 were added to the reaction flask. After the addition was completed, the temperature was raised to 125°C for 2 hours. Then the temperature was lowered to room temperature, water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL) was extracted for 5 ci. The organic phase was washed with brine. The crude compound 9-f was obtained by concentrating under reduced pressure at 40°C. Purification by silica gel column chromatography (PE: EA = 5: 3) gave a yield of 74.6%.

[0308] 5.6 The specific preparation steps of compound 9-g are as follows:

[0309]

[0310] K2CO3 (440 mg, 3.18 mmol, 2.5 equiv.), DMSO (12 mL) and compound 8-g (1.27 mmol, 1.0 equiv.) prepared from 4.7 in Example 4 were added to the reaction flask. After the addition was completed, the temperature was raised to 125°C for 2 hours. Then the temperature was lowered to room temperature, water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL) was extracted for 5 ci. The organic phase was washed with brine. The crude compound 9-g was obtained by concentrating under reduced pressure at 40°C. After purification by silica gel column chromatography (PE: EA = 5: 3), a white solid was obtained with a yield of 91.0%.

[0311] From steps 5.1 to 5.6 of this example, it can be seen that the synthetic route of compound 9 in this example is:

[0312]

[0313] Among them, R7 is

[0314] Therefore, different compounds 8 were used to synthesize compound 9, and the reaction effects of different compounds 8 were compared. It was found that after examining the reaction results of different compounds 8 (8a-8g), the yield of the synthesized compound 9 was improved after the aldehyde group was protected and converted into acetal, and the reaction stability was improved, the impurities were less, and the yield was significantly improved. Among them, compound 9e, that is, the product protected by 1,3-propylene glycol, has the highest purity and yield. The yield of the compound and the purity of some compounds are exemplarily shown in the present invention, see Table 1 for details.

[0315] Table 1 Results of synthesizing compound 9 using different substrates

[0316] <![CDATA[R7]]> HPLC purity (%) Yield (%) c 86.08 56.2 a 88.24 80.8 b N / A 86.5 d N / A 98.4 e 96.25 86.9 f N / A 74.6 g N / A 91.0

[0317] Example 6: Preparation of Compound 10:

[0318] 6.1 The specific preparation steps for preparing compound 10 from compound 9-a are as follows:

[0319]

[0320] Add compound 9-a (1.0 g, 2.77 mmol, 1.0 equiv.) prepared in 5.1 of Example 5 and 1,4-dioxane (18 mL) into the reaction flask. Stir at 23°C under nitrogen protection. Then add 1M hydrochloric acid solution (18 mL), react for 2 hours, and perform high performance liquid chromatography (HPLC) detection. The raw materials are basically reacted, and the product content is 52.42%.

[0321] 6.2 The specific preparation steps for preparing compound 10 from compound 9-b are as follows:

[0322]

[0323] Add compound 9-b (750 mg, 2.09 mmol, 1.0 equiv.) prepared in 5.2 of Example 5, 1,4-dioxane (15 mL) and 1M hydrochloric acid solution (15 mL) to the reaction flask. React at room temperature for 2.5 hours, then heat to 100°C and react for 2 hours. Add water (20 mL) and extract with ethyl acetate (EA) (30 mL) 3 times. Wash once with saturated brine (50 mL). Concentrate the solution under reduced pressure at 50°C to obtain crude compound 10. Purify by silica gel column chromatography (PE: EA = 5: 4) to obtain 375 mg of a white solid product with a yield of 59.0%.

[0324] 6.3 The specific preparation steps for preparing compound 10 from compound 9-c are as follows:

[0325]

[0326] Add compound 9-c (30.0 g, 95.4 mmol, 1.0 equiv.) prepared in 5.3 of Example 5, 1M hydrochloric acid solution (600 mL) and 1,4-dioxane (600 mL) into a 2L single-mouth bottle. Under nitrogen protection, react at room temperature for 1 hour, then heat to 100°C and continue to react for 4 hours. Then cool to room temperature. Extract with ethyl acetate (EA) (600 mL) 3 times. Combine the organic phases and concentrate under reduced pressure to obtain a crude product. Purify by silica gel column chromatography (PE: EA = 1: 1) to obtain 15.6 g of a white solid product with a yield of 53.7%.

[0327] 6.4 The specific preparation steps for preparing compound 10 from compound 9-e are as follows:

[0328]

[0329] Compound 9-e (1.00 g, 2.69 mmol, 1.0 equiv.) prepared in 5.4 of Example 5 and 1,4-dioxane (18 mL) were added to the reaction flask and stirred at 23°C under nitrogen protection. Then 1M hydrochloric acid solution (18 mL) was added to react. After reacting at 23°C for 1 hour, the reaction mixture was sent to high performance liquid chromatography (HPLC) for monitoring. The raw material disappeared, but no target product was generated. The temperature was then raised to 100°C to continue the reaction. After about 2 hours of reaction, it was sent to HPLC for detection again. The raw material was basically reacted, and the product content was 52.42%.

[0330] In this example, compound 10 was synthesized from compound 9 (ag), and the 1H NMR, 13CNMR and HRMS (ESI) data of compound 10 were exemplified:

[0331] 1 H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.62(d,J=8.4Hz,1H),7.19(d,J=8.4Hz ,1H),6.70(d,J=6.5Hz,1H),5.69(dd,J=10.3,6.2Hz,1H),4.91(s,1H),4.23 (s,1H),3.88(s,3H),3.31-3.24(m,1H),2.78(dd,J=18.1,2.5Hz,1H),2.46( d,J=3.1Hz,1H),2.07(dd,J=17.9,1.9Hz,1H),1.72(dd,J=13.7,3.8Hz,1H). 13C NMR (151MHz, DMSO-d6) δ206.53,191.85,149.30,148.67,131.70,129.50,126.27,111.90,98.24,88.88,77.85,56.02,52.43,45.03,38.63.

[0332] HRMS (ESI) calculated value: C 16 H 16 NaO6([M+Na] + ):327.0839, detection value:327.0840.

[0333] Example 7: Preparation of Compound 11:

[0334] The specific preparation steps of compound 11 are as follows:

[0335]

[0336] Compound 10 (2.00 g, 6.57 mmol, 1.0 equiv.), methylamine hydrochloride (0.67 g, 9.87 mmol, 1.5 equiv.), 1,4-dioxane (40 mL) and triethylamine (TEA, 1.00 g, 9.86 mmol, 1.5 equiv.) prepared in Example 6 were added to a 100 mL single-mouth bottle. The mixture was reacted at room temperature for 15 hours under nitrogen protection. Sodium cyanoborohydride (0.62 g, 9.86 mmol, 1.5 equiv.) was then added to react for 18 hours. 40 mL of saturated sodium bicarbonate solution was added and stirred for 30 minutes. Extraction was performed with dichloromethane (DCM) (250 mL) twice. The organic phase was washed once with saturated brine (250 mL). Anhydrous sodium sulfate was added to dry, and after filtering, the filtrate was rotary evaporated to obtain a crude compound 11. The product was purified by silica gel column chromatography (PE:EA=1:2) to obtain 0.901 g of a white solid product with a yield of 40.1%.

[0337] 1H NMR (400MHz, CDCl3) δ6.59 (dd, J=23.3, 7.9Hz, 2H), 5.20 (s, 1H), 4.63 (s, 1H) ,4.43-4.19(m,2H),3.81(d,J=15.1Hz,1H),3.72(s,3H),3.61(t,J=13.8Hz, 1H),3.21(d,J=14.2Hz,1H),2.91-2.70(m,2H),2.56(s,1H),2.43(d,J=14.9 Hz,1H),2.32(s,4H),2.08(d,J=17.1Hz,1H),1.88(dd,J=15.3,11.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ206.86,146.99,145.25,131.18,124.31,121.09,112.02,88.09,65.63,63.52 ,59.35,55.77,50.34,43.39,42.34,40.43,40.22,40.06,40.01,39.80,39.59,39.38,39.17,29.56.

[0338] HRMS (ESI) calculated value: C 18 H 24 BN2O4([M+H] + ):343.1824, Detection value:343.1824.

[0339] Example 8: Preparation of Compound 12:

[0340] The specific preparation steps of compound 12 are as follows:

[0341]

[0342] Compound 11 (100 mg, 0.29 mmol, 1.0 equiv.), 1,4-dioxane (2 mL) and 20% methanesulfonic acid solution (0.25 mL) prepared in Example 7 were added to a 10 mL single-mouth bottle. Under nitrogen protection, the temperature was raised to 105 ° C for 4 hours. Then the temperature was lowered to room temperature, and the pH value was adjusted to 8-9 using a saturated sodium bicarbonate solution. Extraction with dichloromethane (DCM) (20 mL) was performed 3 times. The organic phase was rotary evaporated at 40 ° C to obtain a crude product. Purification by silica gel column chromatography (DCM: MeOH = 9: 1) gave 50 mg of a white solid product of compound 12 with a yield of 53%.

[0343] 1H NMR (400MHz, CDCl3) δ6.94(d,J=9.5Hz,1H),6.66(dd,J=19.2,8.2Hz,2H),6.02(d,J=10.4Hz,1H),4.75-4.68(m,1H),4.07(d,J=15.4Hz,1H),3.83(s,3 H),3.73(d,J=15.4Hz,1H),3.17(tt,J=9.9,8.5Hz,3H),2.74(dd,J=17.8,3 .8Hz,1H),2.43(s,3H),2.26(td,J=13.4,3.4Hz,1H),1.86(d,J=2.0Hz,1H).

[0344] 13 C NMR (151MHz, CDCl3) δ194.58,147.07,144.47,144.10,130.64,129.50,127. 22,122.14,111.99,88.09,60.78,56.12,54.22,49.09,42.54,37.43,33.35.

[0345] HRMS (ESI) calculated value: C 17 H 20 NO3([M+H] + ):286.1438, Detection value:286.1407.

[0346] Example 9: Preparation of Compound 2: Narwedine:

[0347] The specific preparation steps of compound 2: Narwedine are as follows:

[0348]

[0349] Add compound 12 (5.13 g, 18.0 mmol, 1.0 equiv.) prepared in Example 8 and 92 ml of a mixed solvent of 95% EtOH:TEA=(9:1, V / V) to a 250 mL single-mouth bottle. Raise the temperature to 85°C and stir until dissolved. Keep the temperature for about 30 minutes and then cool it down. Add an appropriate amount of seed crystals (Narwedine 2, 128 mg) to the reaction system. Solid begins to precipitate, continue to cool, keep stirring at 40°C for about 3 hours, then cool to 0-5°C and continue stirring for 3 hours. Filter and wash the solid with anhydrous ethanol. The product is vacuum dried at 35°C to obtain about 4.40 g of compound 2: Narwedine as an off-white solid. The product has a high performance liquid chromatography (HPLC) purity of 99.49%, an ee value of 99.7%, and a yield of 85.8%.

[0350] Other test data are the same as compound 12.

[0351] Example 10: Preparation of galanthamine and galanthamine hydrobromide:

[0352]

[0353] In a 100mL three-necked flask, 21mL of dry tetrahydrofuran (THF, 10mL) was added, and L-selectride (13.7ml 1.3eq) was added at -20°C under nitrogen protection, and after the addition, the solid compound 2 (3.0g 1eq) was slowly added when the temperature stabilized at -20°C; after 30min, the temperature was raised to 20°C, and the reaction was carried out at this temperature for 2h, followed by dropwise addition of 3.72g of 48% hydrobromic acid, and the temperature was lowered to 0°C, and the reaction was stopped after the reaction was carried out at this temperature for 1h; then the mixture was filtered and dried under vacuum by the wet method (60°C, 0.1MPa) for 15h to obtain 3.395g of galanthamine hydrobromide, with a yield of 87.7% and a purity of 99.31%.

[0354] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0355] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula (I) or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt of the compound represented by formula (I): in, X1 and X2 are each independently N or O; R1 and R2 are each independently optionally replaced by one or more R a -C1-C6 alkyl, or optionally substituted with one or more R a Substituted 4- to 7-membered aromatic group, each R a are each independently selected from halogen, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 haloalkyl; or, R1 and R2 together with the atoms to which they are attached form a 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C1-C6 alkoxy, or -C1-C6 haloalkyl; Ring A is empty or optionally replaced by one or more R b Substituted 8- to 15-membered heterocycloalkyl, each R b are independently selected from halogen, =O, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl; R3 is empty, halogen, optionally replaced by one or more R c -C1-C6 alkyl, optionally substituted with one or more R c -C1-C6 alkoxy substituted, optionally with one or more R c -C1-C6 haloalkyl or optionally substituted with one or more R c Substituted 5- to 7-membered aromatic group, each R c are independently selected from halogen, -OH, -C 1～6 Alkyl, -C 1～6 Alkoxy or -C 1～6 Haloalkyl; R4 is -OH or -OC(R5)(R6)H; R5 is -C1-C6 alkoxy; R6 is a halomethyl group.

2. The compound of formula (I) according to claim 1 or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt of the compound of formula (I), characterized in that: X1 and X2 are both O; Optionally, R1 and R2 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dimethylpropyl, tert-butyl or benzyl; Optionally, R1 and R2 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; Optionally, R1 and R2 together with the atoms to which they are attached form a 5- to 10-membered heterocycloalkyl group, which is optionally substituted with one or more -C1-C6 alkyl groups; Optionally, R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl group, which is optionally substituted with one or more -C1-C3 alkyl groups; Optionally, for Optionally, for 3. The compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound of formula (I), characterized in that: Ring A is empty, and the compound represented by formula (I) has a structure represented by formula (II): Optionally, R3 is halogen, or is optionally replaced by one or more R c Substituted 5- to 7-membered aromatic group; Optionally, each R c Each is independently selected from halogen or -OH; Optionally, R4 is -OH or -OC(R5)(R6)H; R5 is -C1-C3 alkoxy; R6 is a halomethyl group; Optionally, the compound represented by formula (I) has the structure of the compound represented by formula (6), formula (7) or formula (8):

4. The compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound of formula (I), characterized in that: Ring A is optionally substituted with one or more R b A substituted 8- to 12-membered heterocycloalkyl group, wherein the 8- to 12-membered heterocycloalkyl group contains one or more O atoms; Optionally, Ring A is optionally substituted with one or more R b A substituted 8- to 12-membered heterospirocycloalkyl group, wherein the 8- to 12-membered heterospirocycloalkyl group contains one or more O atoms; Optionally, each R b are each independently selected from halogen, =O, or -C 1～3 Alkoxy; Optionally, the compound represented by formula (I) has the structure of the compound represented by formula (9):

5. A method for preparing a compound represented by formula (6), characterized in that: include: Compound 5 is subjected to a condensation reaction with a hydroxy compound to obtain a compound represented by formula (6); Wherein, X1, X2, R1 and R2 of the compound represented by formula (6) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) according to any one of claims 1 to 4; 6. The method according to claim 5, characterized in that The molar ratio of the compound 5 to the hydroxy compound is 1:(2-10); Optionally, the hydroxy compound comprises an organic alcohol; Optionally, the organic alcohol is selected from at least one of a C1-C6 alkyl alcohol, a 4-7-membered aromatic alcohol optionally substituted with a C1-C6 alkyl group, and a C1-C4 alkyl glycol; Optionally, the organic alcohol is selected from at least one of methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol and 2,2-dimethyl-1,3-propylene glycol; Optionally, in the compound represented by formula (I), R1 and R2 are each independently -C1-C6 alkyl, or a 4-7 membered aromatic group optionally substituted by a C1-C6 alkyl group, and the organic alcohol is selected from a C1-C6 alkyl alcohol, or a 4-7 membered aromatic alcohol optionally substituted by a C1-C6 alkyl group; Optionally, the organic alcohol is selected from at least one of methanol, ethanol, n-propanol and isopropanol; Optionally, in the compound represented by formula (6), R1 and R2 together with the atoms to which they are connected form a 5-7 membered heterocyclic alkyl group, and the organic alcohol is selected from C1-C4 alkyl diols; Optionally, the organic alcohol is selected from at least one of ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol and 2,2-dimethyl-1,3-propylene glycol; Optionally, the dehydrating agent in the condensation reaction is selected from at least one of trimethyl orthoformate, triethyl orthoformate and toluene; Optionally, the catalyst in the condensation reaction is selected from at least one of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid hydrate, phosphoric acid, pyridinium p-toluenesulfonate and tetrabutylammonium bromide.

7. The method according to claim 6, characterized in that The organic alcohol is selected from at least one of methanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 2-methyl-1,3-propylene glycol and neopentyl glycol, the dehydrating agent is trimethyl orthoformate or toluene, and the catalyst is p-toluenesulfonic acid or tetrabutylammonium bromide.

8. The method according to any one of claims 5 to 7, characterized in that: The compound 5 is obtained by the following steps: The compound 4 is subjected to a first bromination reaction to obtain the compound 5; Optionally, the brominating agent of the first bromination reaction is selected from at least one of N-bromosuccinimide, dibromohydantoin, pyridinium tribromide and liquid bromine; Optionally, the first solvent of the first bromination reaction is selected from at least one of dichloromethane, chloroform and DMF.

9. A method for preparing a compound represented by formula (9), characterized in that: include: The compound represented by formula (8) is subjected to an alkylation ring-closing reaction under alkaline solution conditions to obtain a compound represented by formula (9); Wherein, X1, X2, R1 and R2 in the compound represented by formula (8) and the compound represented by formula (9) are the same as X1, X2, R1 and R2 defined in the compound represented by formula (I) according to any one of claims 1 to 4; 10. The method according to claim 9, characterized in that The catalyst for the alkylation ring-closing reaction is selected from at least one of potassium carbonate and LiOH·H2O; Optionally, the second solvent of the alkylation ring-closing reaction is selected from at least one of DMSO, DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide) and NMP (N-methylpyrrolidone); Optionally, the reaction temperature of the alkylation ring-closing reaction is 110° C. to 150° C., and the reaction time is 2 to 6 hours; Optionally, the compound represented by formula (8) is obtained by the following steps: The compound represented by formula (7) is subjected to a condensation reaction with p-hydroxyphenylboronic acid to obtain a compound represented by formula (8); Wherein, X1, X2, R1 or R2 in the compound represented by formula (7) and the compound represented by formula (8) are the same; Optionally, the molar ratio of the compound represented by formula (7) to p-hydroxyphenylboronic acid is 1:(1-3); Optionally, the catalyst for the condensation reaction is selected from at least one of PdCl2(dppf), PdCl2(PPh3)2 and Pd(PPh3)4; Optionally, the third solvent of the condensation reaction is selected from at least one of TEA and THF; Optionally, the surfactant of the condensation reaction is TPGS-750-M; Optionally, the reaction temperature of the condensation reaction is 20°C to 60°C, and the reaction time is 0.5 to 12h; Optionally, the compound represented by formula (7) is obtained by the following steps: The compound represented by formula (6) is subjected to etherification reaction to obtain a compound represented by formula (7); Wherein, X1, X2, R1 or R2 in the compound represented by formula (6) and the compound represented by formula (7) are the same; Optionally, the etherification reaction is carried out in bromoacetaldehyde diethyl acetal, or in vinyl ethyl ether and Br2; Optionally, the molar ratio of the compound represented by formula (6) to bromoacetaldehyde diethyl acetal is 1:(1.5-2); Optionally, the molar ratio of the compound represented by formula (6), vinyl ethyl ether and Br2 is 1:(1-2):(1-1.5); Optionally, the third solvent of the etherification reaction is selected from at least one of DCM and TEA; Optionally, the catalyst for the etherification reaction is selected from at least one of DIPEA, zinc bromide and acetyl chloride.

11. A method for preparing galantamine or galantamine hydrobromide, characterized in that: include: The galanthamine or galanthamine hydrobromide is prepared by using the compound represented by formula (9); Wherein, X1, X2, R1 and R2 in the compound represented by formula (9) are consistent with X1, X2, R1 and R2 defined in the compound represented by formula (I) according to any one of claims 1 to 4; 12. The method according to claim 11, characterized in that The preparation comprises: The compound represented by formula (9) is reacted in a hydrochloric acid and 1,4-dioxane system to obtain compound 10; The compound 10 and methylamine hydrochloride are reacted in a TEA and 1,4-dioxane system, and sodium cyanoborohydride is added for reaction to obtain a compound 11; The compound 11 is reacted in an acid catalyst and 1,4-dioxane system to obtain a compound 12; The compound 12 is reacted in a mixed solvent to obtain compound 2; The compound 2 is subjected to a reduction reaction with a reducing agent in an inert solvent to obtain the galanthamine; Optionally, the acid catalyst is selected from at least one of methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid; Optionally, the mixed solvent comprises ethanol and TEA, the volume ratio of the ethanol to TEA is (8-10): (0.5-3), and the concentration of the ethanol is 70%-100%; Optionally, the reducing agent is selected from at least one of L-Selectride and K-Selectride; Optionally, the inert solvent is diethyl ether or THF; Optionally, the preparation further comprises: The galanthamine is subjected to a second bromination reaction to obtain the galanthamine hydrobromide; Optionally, the brominating agent of the second bromination reaction comprises hydrobromic acid; Optionally, the fourth solvent of the second bromination reaction comprises tetrahydrofuran.

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