Process for the preparation of tetralins and intermediates thereof

Abstract

The present disclosure relates to a method for preparing tetrahydronaphthalene compounds and intermediates thereof. Specifically, the method of the present disclosure can convert S-configuration intermediates generated in the synthesis of tetrahydronaphthalene compounds into available intermediates or desired compounds, achieve high recovery efficiency, effectively improve the utilization rate of raw materials, and greatly reduce production costs.

Description

Technical Field

[0001] This disclosure belongs to the field of medicinal chemistry and relates to a method for preparing a tetrahydronaphthalene compound and its intermediates. Background Technology

[0002] Approximately 70% of breast cancer patients have estrogen receptor (ER) positive breast cancer. Endocrine therapy plays a crucial role in the treatment of these patients. Endocrine therapy is mainly divided into three categories: aromatase inhibitors (AIs), which inhibit the conversion of androgens into estrogens, thus lowering estrogen levels in the body; selective estrogen receptor modulators (SERMs), which antagonize the activity of estrogen receptors; and selective estrogen receptor degraders (SERDs), which not only antagonize estrogen receptor activity but also promote receptor degradation (J. Biol. Chem. 2006, 14, 9607-9615).

[0003] Compared with traditional small molecule inhibitors, protein proteolysis-targeting chimeras (PROTACs) exhibit unique advantages: 1) PROTACs do not require prolonged and high-intensity binding to the target protein, and the degradation process is similar to a catalytic reaction, allowing for cyclic binding and degradation of the target protein, thereby reducing systemic drug exposure and minimizing toxic side effects; 2) The target protein needs to be resynthesized after degradation to restore its function, therefore, degradation of the target protein shows a more efficient and durable anti-tumor effect than inhibition of its activity, and does not lead to drug resistance due to target protein mutations; 3) PROTACs also have therapeutic potential for targets currently considered untreatable, such as transcription factors, scaffold proteins, and regulatory proteins.

[0004] WO2022206737A1 discloses a novel class of PROTACs molecules that demonstrate their application as estrogen receptor degraders in the treatment of estrogen receptor-mediated or dependent diseases. The disclosed preparation method reveals... The recycling of the S-configuration isomer has not been disclosed. Therefore, if the S-configuration compound could be recycled and reused to convert it into usable intermediates or desired compounds, it would reduce the amount of waste generated, be more environmentally friendly, and significantly reduce production costs. Summary of the Invention

[0005] The purpose of this disclosure is to provide a method for preparing tetrahydronaphthalene compounds and their intermediates.

[0006] This disclosure provides a method for preparing a compound as shown in Formula IV, including the step of converting a compound as shown in Formula I into a compound as shown in Formula IV.

[0007]

[0008] Among them, R 1 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms and hydroxyl protecting groups;

[0009] R 2 and R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano, amino, hydroxyl, C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Each cycloalkyl group is independently selected from halogen, oxo group, C... 1-6 Alkyl, C 1-6 Alkoxy, cyano, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0010] R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 The alkyl group is replaced by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl and 5-10 membered heteroaryl;

[0011] R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 alkoxy, hydroxy, amino and C 1-6 Hydroxyalkyl;

[0012] R 6 Selected from -(CH2) p CH(OCH3)2;

[0013] X is an oxygen atom or -CH2-;

[0014] m can be 0, 1, 2, or 3;

[0015] n is 0, 1, 2, 3 or 4;

[0016] p can be 0, 1, 2, 3, or 4.

[0017] In some embodiments, the method further includes a step of converting the compound of Formula I into the compound of Formula II under oxidizing conditions.

[0018]

[0019] Among them, X and R 1 R 2 R 3 R 4a R 4b R 5 R 6 m and n are as defined above.

[0020] In some embodiments, the method further includes a step of converting the compound of formula II into the compound of formula IV under reducing conditions.

[0021]

[0022] Among them, X and R 1 R 2 R 3 R 4a R 4b R 5 R 6 R 7 m and n are as defined above.

[0023] In some embodiments, the method further includes a step of reducing the compound of Formula II to the compound of Formula III, and a step of converting the compound of Formula III to the compound of Formula IV.

[0024]

[0025] Among them, X and R 1 R 2R 3 R 4a R 4b R 5 R 6 R 7 m and n are as defined above.

[0026] In some embodiments, the method further includes a step of converting the compound of formula III into the compound of formula IV', and a step of chirally resolving the compound of formula IV' into the compound of formula IV.

[0027]

[0028] Among them, X and R 1 R 2 R 3 R 4a R 4b R 5 R 6 R 7 As defined above, R, m, n, and n 1 With R 7 They are not the same.

[0029] In some implementations, X is -CH2-.

[0030] In some embodiments, the hydroxyl protecting group is selected from acetyl (Ac), n-valeryl, tert-butyl, benzyl, and methoxybenzyl.

[0031] In some implementation schemes, R 1 and R 7 They may be the same or different, and each is independently selected from hydrogen, acetyl, n-valeryl, tert-butyl, benzyl, and methoxybenzyl.

[0032] In some implementation schemes, R 1 Selected from hydrogen atom, acetyl (Ac), n-valeryl, tert-butyl, benzyl, and methoxybenzyl (PMB).

[0033] In some implementation schemes, R 1 Selected from hydrogen atoms.

[0034] In some implementation schemes, R 1 Selected from acetyl groups.

[0035] In some implementation schemes, R 1 Selected from n-pentanoyl (Pe).

[0036] In some implementation schemes, R 1 Selected from tert-butyl.

[0037] In some implementation schemes, R 1 Selected from benzyl.

[0038] In some implementation schemes, R 7 Selected from hydrogen atom, acetyl (Ac), n-valeryl, tert-butyl, benzyl, methoxybenzyl.

[0039] In some implementation schemes, R 7 Selected from hydrogen atoms.

[0040] In some implementation schemes, R 7 Selected from acetyl groups.

[0041] In some implementation schemes, R 7 Selected from n-pentanoyl.

[0042] In some implementation schemes, R 7 Selected from tert-butyl.

[0043] In some implementation schemes, R 7 Selected from benzyl.

[0044] In some implementation schemes, R 1 and R 7 Same, R 1 and R 7 Selected from hydrogen, acetyl (Ac), n-valeryl, tert-butyl, benzyl, and methoxybenzyl. In some embodiments, R 1 and R 7 Same, R 1 and R 7 Selected from hydrogen atom, acetyl group, n-valeryl group, and tert-butyl group.

[0045] In some implementation schemes, R 1 and R 7 Same, R 1 and R 7 Selected from hydrogen atoms.

[0046] In some implementation schemes, R 1 and R 7 Same, R 1 and R 7 Selected from acetyl groups.

[0047] In some implementation schemes, R 1 and R 7 Same, R 1 and R 7 Selected from n-pentanoyl.

[0048] In some implementation schemes, R 1 and R 7 Same, R 1 and R 7 Selected from tert-butyl.

[0049] In some implementation schemes, R 1 and R 7 Different, R 1 and R 7 Each is independently selected from hydrogen, acetyl, n-valeryl, tert-butyl, benzyl, methoxybenzyl (e.g., when R...). 1 When selected from hydrogen, R 7 It can be selected from acetyl, n-valeryl, tert-butyl, benzyl, methoxybenzyl, but not hydrogen).

[0050] In some implementation schemes, R 1 and R 7 Different, R 1 Selected from hydrogen atoms, R 7 Selected from acetyl groups.

[0051] In some implementation schemes, R 1 and R 7 Different, R 1 Selected from n-pentanoyl, R 7 Selected from acetyl groups.

[0052] In some implementation schemes, R 2 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0053] In some implementation schemes, R 2 Selected from hydrogen atoms.

[0054] In some implementation schemes, R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 It is replaced by one or more substituents selected from alkyl, amino, nitro, and hydroxyl groups.

[0055] In some implementation schemes, R 3 Selected from phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, isobutyl, and 4-tetrahydropyranyl.

[0056] In some implementation schemes, R 3 Selected from isobutyl.

[0057] In some implementation schemes, R 3 Selected from phenyl.

[0058] In some implementation schemes, R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

[0059] In some implementation schemes, R 4a and R 4b Same, selected from hydrogen atoms.

[0060] In some implementation schemes, R 5 Selected from hydrogen, halogens and C 1-6 alkyl.

[0061] In some implementation schemes, R 5 Selected from hydrogen atoms and fluorine atoms.

[0062] In some implementation schemes, R 5 Selected from fluorine atoms.

[0063] In some implementation schemes, R 5 Selected from hydrogen atoms.

[0064] In some implementations, p is 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

[0065] In some implementation schemes, R 6 Selected from -CH(OCH3)2.

[0066] In some implementations, X is -CH2-; R 2 Selected from hydrogen, halogens and C 1-6 Alkyl group, preferably hydrogen; R 5 Selected from hydrogen, halogens and C 1-6 Alkyl groups, preferably hydrogen or fluorine; R 6 Selected from -CH(OCH3)2.

[0067] In some implementations, the oxidant is selected from quinone oxidants.

[0068] In some embodiments, the oxidant is selected from DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), benzoquinone, and tetrachlorobenzoquinone.

[0069] In some implementations, the oxidant is selected from DDQ.

[0070] In some implementations, the chiral separation method is hydrolytic enzyme separation.

[0071] In some embodiments, the hydrolytic enzyme is a lipase from Candida antarctica (CALB), namely CALB lipase.

[0072] In some embodiments, the CALB lipase is selected from at least one of immobilized CALB lipase and free CALB lipase.

[0073] In some embodiments, the free CALB lipase is selected from at least one of CALB lipase powder and CALB lipase solution.

[0074] In some embodiments, the CALB lipase is an immobilized CALB lipase.

[0075] In some embodiments, the immobilized CALB lipase is Novozym 435 or SZ-CALB-IMMO100 (e.g., SZ-CALB-IMMO100-A or SZ-CALB-IMMO100-B).

[0076] In some implementations, the chiral separation method is chromatographic separation (such as chiral high-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC)).

[0077] In some embodiments, the chiral resolution method is chemical resolution (e.g., using chiral resolving agents, such as L-tartaric acid, D-tartaric acid, benzoyl-L-tartaric acid (L-DBTA), benzoyl-D-tartaric acid (D-DBTA), toluene-L-tartaric acid (L-DTTA), or toluene-D-tartaric acid (D-DTTA), R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, etc.).

[0078] In some embodiments, the chiral resolving agent is selected from L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, L-aspartic acid, and D-aspartic acid.

[0079] In some embodiments, the chiral resolving agent is selected from D-DTTA.

[0080] In some embodiments, the reducing agent is selected from one or a combination of sodium cyanoborohydride, lithium cyanoborohydride, sodium triacetate borohydride, lithium triacetate borohydride, sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum tetrahydrogen, hydrogen, borane, palladium on carbon, and palladium hydroxide on carbon, preferably palladium on carbon.

[0081] In some embodiments, the reducing agent is selected from palladium on carbon.

[0082] In some embodiments, the preparation method includes the step of converting the compound represented by formula Ia into the compound represented by formula IVa.

[0083]

[0084] Among them, X and R 1 R 3 R 6 R 7 As defined above.

[0085] In some embodiments, the method further includes a step of converting the compound of formula Ia to the compound of formula IIa under oxidizing conditions.

[0086]

[0087] Among them, X and R 1 R 3 R 6 As defined above.

[0088] In some embodiments, the method further includes a step of converting the compound of formula IIa to the compound of formula IVa under reducing conditions.

[0089]

[0090] Among them, X and R 1 R 3 R 6 R 7 As defined above.

[0091] In some embodiments, the method further includes a step of reducing the compound of formula IIa to the compound of formula IIIa, and a step of converting the compound of formula IIIa to the compound of formula IVa.

[0092]

[0093] Among them, X and R 1 R 3 R 6 R 7 As defined in section 1 above.

[0094] In some embodiments, the method further includes a step of converting the compound of formula IIIa into the compound of formula IVa', and a step of chirally resolving the compound of formula IVa' into the compound of formula IVa.

[0095]

[0096] Among them, X and R 1 R 3 R6 R 7 As defined above, R 1 With R 7 They are not the same.

[0097] In some embodiments, a method for preparing compound 4 is provided, comprising the following steps:

[0098] 1) Compound 1 is converted to compound 2 in the presence of DDQ oxidant.

[0099]

[0100] 2) Compound 2 is converted to compound 4 under reducing agent conditions.

[0101]

[0102] Alternatively, compound 2 is converted to compound 3 under reducing conditions, and compound 3 is chirally resolved into compound 4.

[0103] .

[0104] In some embodiments, the method further includes the steps of converting compound 4 to compound 5, and compound 5 to compound 6 or a salt thereof.

[0105] .

[0106] In some embodiments, the conversion of compound 4 to compound 5 is carried out under acidic conditions (such as sulfuric acid or hydrochloric acid). The steps for the conversion of compound 5 to compound 6 are described in WO2022206737, the relevant content of which is incorporated herein for illustration.

[0107] In some embodiments, a method for preparing compound 11 is provided, comprising the following steps:

[0108] 1) Compound 7 is converted to compound 8 in the presence of DDQ oxidant.

[0109]

[0110] 2) Compound 8 is converted to compound 9 under reducing agent conditions.

[0111]

[0112] 3) Compound 9 is converted to compound 10 in the presence of acetyl chloride, and compound 10 is converted to compound 11 under the conditions of hydrolytic enzymes.

[0113] .

[0114] In some embodiments, the method further includes a step of converting compound 12 into compound 7.

[0115] .

[0116] In some embodiments, the method further includes the step of converting compound 11 to compound 5, and compound 5 to compound 6 or a salt thereof.

[0117] .

[0118] In some embodiments, the conversion of compound 11 to compound 5 is carried out under acidic conditions (such as sulfuric acid or hydrochloric acid).

[0119] In some embodiments, a method for preparing compound 4a is also provided, comprising the following steps:

[0120] 1) Compound 1a is converted to compound 2a in the presence of DDQ oxidant.

[0121]

[0122] 2) Compound 2a is converted to compound 4a under reducing conditions.

[0123]

[0124] Alternatively, compound 2a is converted to compound 3a under reducing conditions, and compound 3a is chirally resolved into compound 4a.

[0125] .

[0126] In some embodiments, the method further includes the step of converting compound 4a to compound 5a under acidic conditions, and then converting compound 5a to compound 6a or a salt thereof.

[0127] .

[0128] In some embodiments, the conversion of compound 4a to compound 5a is carried out under acidic conditions (such as sulfuric acid or hydrochloric acid). The procedure for the conversion of compound 5a to compound 6a is described in WO2018102725, the relevant content of which is incorporated herein by reference.

[0129] The preparation method disclosed herein can convert the S-configuration intermediates generated during the synthesis of tetrahydronaphthalene compounds into usable intermediates or desired compounds, achieving efficient recovery, effectively improving the utilization rate of raw materials, reducing waste and avoiding environmental pollution, increasing the total yield by more than 5%, and greatly reducing production costs.

[0130] Terminology Explanation

[0131] In this specification and claims, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this disclosure, definitions and explanations of some related terms are provided below. Furthermore, in the event of any discrepancy between the definitions and explanations of terms provided herein and their commonly understood meanings by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0132] The term "conversion" in this disclosure does not specifically refer to a single-step conversion reaction between two substrates; it can refer to a single-step or multi-step reaction between two substrates.

[0133] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations. In the chemical structure of the compounds described in this disclosure, the bond " "No configuration specified, i.e., key" The configuration of “” can be E-type or Z-type, or it can contain both E-type and Z-type configurations at the same time.

[0134] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0135] .

[0136] The compound salts described in this disclosure may be selected from inorganic or organic salts, such as hydrochloride, maleate, fumarate, L-tartrate, succinate, D-malate, L-malate, sulfate, phosphate and citrate.

[0137] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 10 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, isobutyl, etc. Alkyl groups can be substituted or unsubstituted.

[0138] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0139] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Unless otherwise specified, the cycloalkyl group may be substituted or unsubstituted.

[0140] "Heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, containing 3 to 8 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocyclic group. Unless otherwise specified, the heterocyclic group may be substituted or unsubstituted.

[0141] "Aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system. The aryl group may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl group. Unless otherwise specified, the aryl group may be substituted or unsubstituted.

[0142] "Heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. , , The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Unless otherwise specified, the heteroaryl group may be substituted or unsubstituted.

[0143] "Hydroxy protecting group" refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group and reacts on other functional groups of a compound, including but not limited to ester protecting groups, ether protecting groups, and acetal protecting groups. As an example, preferably, the hydroxyl protecting group can be (C... 1-10 Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as: formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, neopentanoyl, valeryl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 The aryloxy)carbonyl group can be 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), or methyl thiomethyl ether (MTM).

[0144] "Quinone oxidizing agents" refer to oxidizing agents whose molecular structure contains quinones, such as DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone); NQ (1,4-naphthoquinone); TCQ (2,3,4,5-tetrachloroquinone); TFQ (2,3,4,5-tetrafluoroquinone); BQ (1,4-benzoquinone); F4-TCNQ (2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinone dimethane); TCNQ (7,7,8,8-tetracyanoquinone dimethane); 2,3-dibromo-5,6-dicyano-1,4-benzoquinone; 2,5-dichloro-3,6-dicyano-1,4-benzoquinone; 2,6-dichloro-3,5-dicyano-1,4-benzoquinone; and 2,3-diiodo-5,6-dicyano-1,4-benzoquinone and its various complexes, etc.

[0145] The term "reducing agent" refers to a compound that loses (or "donates") electrons to an electron acceptor (oxidizing agent) in a redox chemical reaction. Reducing agents include those commonly known in the art, such as sodium hypophosphite (NaH2PO2), formaldehyde (CH2O) and other aldehydes, formic acid (HCOOH), salts of formic acid, salts of borohydrides (e.g., sodium borohydride (NaBH4)), salts of substituted borohydrides (e.g., sodium triacetoxyborohydride (Na(CH3CO2)3BH)), sodium alkoxide, lithium aluminum hydride (LiAlH4), diisobutylaluminum hydride (DIBAH), hydrazine (H2NNH2), and ammonia. Catalytic hydrogenation is also used for reduction.

[0146] "Alkoxy" refers to -O- (alkyl) and -O- (cycloalkyl), where alkyl and cycloalkyl are defined as described above. Unless otherwise specified, the alkoxy group may be substituted or unsubstituted.

[0147] "Haloalkoxy" refers to an alkoxy group that is replaced by one or more halogens, where the alkoxy group is as defined above.

[0148] "Hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0149] "alkyl acyl" refers to "alkyl-C(O)-", where alkyl is defined as described above.

[0150] "Amino" refers to -N(R) a )2, where R a Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally selected from one or more groups selected from halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, the "amino" can be an unsubstituted amino group (i.e., -NH2) or a substituted amino group (-N(R)). a )2, R a (Not all of it is hydrogen).

[0151] "Hydroxy" refers to the -OH group.

[0152] “Cyano” refers to the -CN group.

[0153] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0154] "Oxide" or "oxo group" refers to "=O".

[0155] "Nitro" refers to the -NO2 group.

[0156] When the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or alkoxy group is substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from halogens, oxo groups, and C... 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl and 5-10 membered heteroaryl.

[0157] "Optional" or "optional" means that the event or environment subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or environment may or may not occur. For example, "C optionally substituted with halogen or deuterium..." 1-6 "Alkyl" refers to the presence of halogens or deuterium, which may but are not required. This description includes C. 1-6 The case where alkyl groups are substituted with halogens or deuterium and C 1-6 The case where the alkyl group is not substituted by halogen or deuterium.

[0158] "Being replaced by one or more substituents selected from A, B, etc." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents or a combination of one or a plurality of different substituents. Detailed Implementation

[0159] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0160] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0161] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent.

[0162] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a WaterVbridge C18 150*4.6mm 5um column.

[0163] MS was determined using a liquid chromatography-mass spectrometry system (Vanquish-LTQXL, Thermo).

[0164] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0165] Normal column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh or 300~400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0166] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0167] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0168] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 L.

[0169] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0170] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0171] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0172] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0173] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0174] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0175] Example 1

[0176]

[0177] Under nitrogen protection, A1 (15.38 kg), A2 (13 kg, prepared according to Example 32 of WO2022206737A1), potassium carbonate (9.95 kg), and tetra(triphenylphosphine)palladium (833.4 g) were added to a 500 L reactor, along with 130 L of 1,4-dioxane and 26 L of water. The mixture was stirred until homogeneous, purged with nitrogen three times, and heated to 80-90 °C for 0.5-1 h. The reaction was stopped when TLC showed complete reaction.

[0178] Cool to room temperature, add water and ethyl acetate, stir and separate the liquids; extract the aqueous phase with ethyl acetate again, wash the organic phase with 20% sodium chloride solution, concentrate to obtain crude product, and purify the crude product by column chromatography (n-heptane-n-heptane:ethyl acetate = 30:1-10:1) to obtain compound 2 (15.36 kg), yield: 86.82%.

[0179] Compound 2:

[0180] MS-ESI: 492.30 [M+H] + .

[0181] 1 H-NMR (400 MHz, DMSO-d6): δ 6.95 (d, J = 8.8Hz, 2H), 6.89 (d, J = 8.8Hz, 2H), 6.75 (d, J = 2.4Hz, 1H), 6.60 (dd, J = 2.4, 8.4Hz, 1H), 6.35 (d, J = 8.4Hz, 1H), 4.11 (d, J = 6.4Hz, 1H), 3.73 (m, 2H), 3.29 (s, 6H), 2.75 (t, J = 7.6, 8.0Hz, 2H), 2.63 (m, 2H), 2.25 (t, J = 8.4, 7.2Hz, 2H), 1.91 (d, J = 7.2Hz, 2H), 1.66 (m, 4H), 1.40-1.33 (m, 2H), 1.26 (s, 9H), 0.76 (d, J = 6.4Hz, 6H).

[0182] Example 2

[0183]

[0184] Compound 2 (15.34 kg) was added to a 300 L high-pressure reactor, along with 75 L of methanol and 75 L of tetrahydrofuran. The mixture was stirred and dissolved, and the temperature was controlled below 20 °C. Palladium on carbon (wet) (3.07 kg) (Shaanxi Ruike) was added under nitrogen atmosphere. The mixture was purged with hydrogen three times. The pressure was set at 0.05~0.1 MPa, and the temperature was 20~25 °C for 24 h.

[0185] HPLC analysis showed no residue of compound 2, so the reaction was stopped. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain the racemic crude product. 75 L of methanol was added and heated until clear, then the mixture was slowly cooled to 0-50°C. o C. Filter and dry to obtain 14.92 kg of racemic compound 3, yield 96.88%. Compound 3 was resolved by SFC to obtain compound 4 (6.41 kg, yield: 41.61%); the byproduct fraction was collected and concentrated to obtain compound 1, which was used for further recovery to prepare compound 2.

[0186] Compound 4:

[0187] MS-ESI: 494.30 [M+H] + .

[0188] 1 H-NMR (400 MHz, DMSO-d6): δ 6.79-6.70 (m, 6H), 6.61 (dd, J = 2.4, 8.4Hz, 1H), 4.07 (d, J = 6.4Hz, 1H), 3.92 (d, J = 4.8Hz, 1H), 3.63-3.59 (m, 2H), 3.26 (s, 6H), 2.92-2.80 (m, 2H), 2.55-2.52 (m, 2H), 1.99-1.94 (m, 1H), 1.89-1.55 (m, 4H), 1.50-1.33 (m, 2H), 1.30 (m, 2H), 1.23 (s, 9H), 1.06-1.04 (m, 1H), 0.83 (t, J = 6.4Hz, 6H), 0.70-0.63 (m, 1H).

[0189] Compound 1:

[0190] MS-ESI: 494.30 [M+H] + .

[0191] 1 H-NMR (400 MHz, DMSO-d6): δ 6.79-6.70 (m, 6H), 6.61 (dd, J = 2.4, 8.4Hz, 1H), 4.07 (d, J = 6.4Hz, 1H), 3.92 (d, J = 4.8Hz, 1H), 3.63-3.59 (m, 2H), 3.26 (s, 6H), 2.92-2.80 (m, 2H), 2.55-2.52 (m, 2H), 1.99-1.94 (m, 1H), 1.89-1.55 (m, 4H), 1.50-1.33 (m, 2H), 1.30 (m, 2H), 1.23 (s, 9H), 1.06-1.04 (m, 1H), 0.83 (t, J = 6.4Hz, 6H), 0.70-0.63 (m, 1H).

[0192] Example 3

[0193]

[0194] Compound 1 (18.3 kg) was dissolved in 127.8 kg of toluene, 0~5 oA toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 10.1 kg dissolved in 191.4 kg toluene) was added dropwise at temperature C. After the addition was complete, the reaction was kept at this temperature for 2-4 hours under HPLC control. The reaction was stopped when compound 1 was less than 5.0%.

[0195] 0~10 o The reaction was quenched by adding 183 kg of semi-saturated sodium bicarbonate solution dropwise at C. Then, 165 kg of ethyl acetate was added, the mixture was stirred, and the aqueous phase was separated. The aqueous phase was extracted once with 165 kg of ethyl acetate. The organic phases were combined and washed successively with 183 kg of semi-saturated sodium bicarbonate solution and 183 kg of semi-saturated sodium chloride solution. The organic phase was then concentrated to obtain the crude product.

[0196] 108.6 kg of methanol was added to the crude product, stirred, and heated to 60°C to dissolve it; the product was cooled to crystallize, cooled to 0-5°C, centrifuged, washed with methanol, and the filter cake was dried to obtain compound 2 (15.92 kg), with a yield of 87.3%.

[0197] Example 4

[0198]

[0199] 23.5 g of compound 7 (obtained by the method disclosed in Example 26-2 of WO2022206737) and 100 mL of toluene were added to a 1 L reaction flask, followed by 100 mL of tetrahydrofuran. The mixture was stirred to dissolve the compounds, yielding reaction solution 1.

[0200] In a separate 250 mL reaction flask, add 11.4 g of DDQ and 200 mL of toluene, stir to dissolve, and obtain reaction solution 2.

[0201] Cool reaction solution 1 to 0-5°C in an ice bath, then add reaction solution 2 dropwise to reaction solution 1; add dropwise under controlled temperature, completing the addition in about 20 minutes, then keep the temperature at 0-5°C for 1-2 hours; take a sample for testing, and the reaction is complete when compound 7 is less than 5% remaining.

[0202] Control the temperature at 0~10℃, add 200 mL of semi-saturated sodium bicarbonate solution and 200 mL of ethyl acetate dropwise to the reaction solution, stir and separate the liquids; extract the aqueous phase with 100 mL of ethyl acetate; combine the organic phases, wash with 100 mL of semi-saturated sodium bicarbonate solution and 100 mL of saturated brine, concentrate the organic phase until no liquid droplets flow out, add a small amount of methanol and concentrate until no liquid droplets flow out, to obtain the crude product.

[0203] The crude product was added to 100 mL of methanol, heated to an external temperature of 60 °C, stirred for 1 h, cooled naturally to room temperature, stirred at 0-5 °C for 30 min, filtered, the filter cake was washed twice with 20 mL of ice-cold methanol, and dried under reduced pressure at 35 °C to constant weight to obtain compound 8 (12.6 g), with a two-step effective yield of 63.3%.

[0204] Compound 8:

[0205] MS-ESI: 436.25 [M+H] + .

[0206] 1 H-NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 6.94 (d, J = 8.4Hz, 2H), 6.87 (d, J = 8.8Hz, 2H), 6.55 (d, J = 2.4Hz, 1H), 6.38 (dd, J = 2.8, 8.4Hz, 1H), 6.26 (d, J = 8.4Hz, 1H), 4.11 (d, J = 6.4Hz, 1H), 3.63 (m, 2H), 3.29 (s, 6H), 2.70-2.58 (m, 4H), 2.21 (m, 2H), 1.89 (d, J = 7.2Hz, 2H), 1.78-1.67 (m, 4H), 1.39-1.30 (m, 2H), 0.75 (d, J = 6.0Hz, 6H).

[0207] Example 5

[0208]

[0209] Add 10% palladium on carbon (0.18 g, 15% wt), methanol (6 mL), and tetrahydrofuran (6 mL) to a 100 mL hydrogenation flask, evacuate, replace with hydrogen three times, purge with hydrogen to 0.3 MPa, heat to an external temperature of 50 °C, and stir for 1 h; allow to cool naturally to room temperature (25 °C), and under nitrogen protection, add compound 8 (1.20 g).

[0210] Vacuum was applied, hydrogen was purged three times, and hydrogen was added to 0.3 MPa. The external temperature was maintained at 25°C, and the reaction was carried out for 24 hours. Samples were taken for testing, and the reaction ended when the raw material content was less than 2%.

[0211] The mixture was filtered, and the filter cake was washed successively with 4.8 mL of tetrahydrofuran and 4.8 mL of methanol. The filtrate was concentrated under reduced pressure at 30 °C until no more droplets flowed out. 6 mL of methanol was added to the concentrate, and the mixture was heated to an external temperature of 60 °C and stirred for 1 h. The mixture was then allowed to cool naturally to room temperature and stirred at 0-5 °C for 30 min. After filtration, the filter cake was rinsed with cold methanol (1.2 mL × 2) and dried under reduced pressure at 35 °C to constant weight, yielding 1.11 g of compound 9, with a yield of 92% and a purity of 99.83%.

[0212] Compound 9:

[0213] MS-ESI: 438.25 [M+H] + .

[0214] 1 H-NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 6.77-6.73 (m, 4H), 6.60 (d, J = 8.4Hz, 1H), 6.50 (d, J = 2.4Hz, 1H), 6.42 (dd, J = 2.4, 8.4Hz, 1H), 4.07 (d, J = 6.4Hz, 1H), 3.85 (d, J = 4.8Hz, 1H), 3.60 (m, 2H), 3.26 (s, 6H), 2.85-2.75 (m, 2H), 2.51 (m, 2H), 1.96-1.77 (m, 1H) ), 1.78-1.60 (m, 4H), 1.52-1.40 (m, 2H), 1.33-1.23 (m, 2H), 1.04-0.97 (m, 1H), 0.76 (t, J = 6.0, 6.4Hz, 6H), 0.69-0.62 (m, 1H).

[0215] Example 6

[0216]

[0217] Compound 9 (31.0 g), 310 mL of tetrahydrofuran, and triethylamine (14.34 g) were added sequentially to the reaction flask; nitrogen was purged three times, and acetyl chloride (8.3 g) was added dropwise under water bath cooling, and the reaction was carried out at room temperature for 1 h.

[0218] TLC monitoring showed that the reaction of the raw materials was complete; the mixture was filtered, and the filter cake was washed with 62 mL of tetrahydrofuran. The filtrate was concentrated under reduced pressure. After concentration, 153 mL of methanol was added, and the mixture was heated to 55-60℃ and stirred for 1-2 h; the mixture was cooled to room temperature, and then cooled to 0-10℃ and stirred for 0.5-1 h; the mixture was filtered, and the filter cake was washed with 31 mL of methanol. The filter cake was dried under vacuum to obtain 31.9 g of compound 10, with a purity of 99.6% and an overall yield of 93.9%.

[0219] Compound 10: MS-ESI: 480.30 [M+H] + .

[0220] Example 7

[0221]

[0222] At room temperature, compound 10 (70 g), THF (154 mL) and MTBE (1246 mL) were added to a 3 L three-necked flask, along with deionized water (2.16 g) and immobilized CALB lipase (purchased from Shangke Biopharmaceutical (Shanghai) Co., Ltd., product code: SZ-CALB-IMMO100-A, 7 g, 10%wt), and the mixture was reacted at room temperature for 5-7 h.

[0223] Filter the solution, transfer the filtrate to a reaction flask, add 28 g of triethylamine dropwise, and after the addition is complete, cool the solution to 0-5°C in an ice bath. Add 26.4 g of valeryl chloride dropwise, and stir at 30°C for 1-2 hours. After the reaction is complete, add 5% sodium bicarbonate solution to the reaction solution, separate the layers, wash the organic phase with 8% sodium dihydrogen phosphate solution, then wash with water, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product.

[0224] The crude product was added to 105 mL of an ethanol:water (9:1) solution, heated until completely dissolved, cooled to allow crystallization, filtered, and dried to obtain 29.7 g of compound 11. The overall yield was 42%, the purity of related substances was 97.6%, the chiral purity was >99%, and the isomers were <0.3%. (The mother liquor mainly contained compound 12 and the lost compound 11, which can be used for subsequent recovery.)

[0225] Compound 11:

[0226] MS-ESI: 483.30 [M+H] + .

[0227] 1 H-NMR (400 MHz, DMSO-d6): δ 6.88 (d, J = 2.4Hz, 1H), 6.85 (d, J = 8.4Hz, 1H), 6.77-6.73 (m, 5H), 4.08 (d, J = 6.4Hz, 1H), 3.98 (d, J = 4.8Hz, 1H), 3.61 (m, 2H), 3.26 (s, 6H), 2.95-2.79 (m, 2H), 2.52 (m, 2H), 2.23 (s, 3H), 1.96-1.90 (m, 1H), 1.78-1.62 (m, 4H), 1.60-1.45 (m, 2H), 1.38-1.23 (m, 2H), 1.07-1.00 (m, 1H), 0.83 (t, J =6.4Hz, 6H), 0.72-0.65 (m, 1H).

[0228] Example 8

[0229]

[0230] At room temperature, lithium hydroxide monohydrate (132.2 g) was added to the crystallization filtrate (EtOH / water solution) of Example 7. After the addition was complete, the temperature was raised to 50°C and stirred for 3 h.

[0231] TLC analysis showed that compound 12 was present in excess. 33.1 g of lithium hydroxide monohydrate was added, and the mixture was stirred at 50°C for 0.5-1 h.

[0232] TLC analysis showed that the reaction of the raw materials was complete; the solvent was removed by vacuum concentration; 4800 mL of ethyl acetate and 1600 mL of water were added to the concentrate, and the mixture was stirred for 10 min and separated; 1600 mL of ethyl acetate was added to the aqueous phase for extraction twice; the organic phases were combined, washed with 2000 mL of 8% sodium dihydrogen phosphate aqueous solution, washed with 1600 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated until no more droplets flowed out, yielding 625 g of crude compound 7, which can be directly used to prepare compound 8.

[0233] Compound 7: MS-ESI: 438.25 [M+H] + .

[0234] Example 9

[0235]

[0236] Preparation of compound 5: Prepare a 2M sulfuric acid solution in a 200 L reactor (7.6 kg of sulfuric acid was slowly added to 35 L of water under controlled temperature), add tetrahydrofuran (51.2 L) and compound 4 (6.4 kg), stir well, and heat to 60 °C to react for 3-4 hours.

[0237] The reaction was detected by TLC, and compound 4 disappeared.

[0238] The system was cooled to below 10°C, neutralized with 38 L of 4M sodium hydroxide solution, and then the pH was adjusted to 7-8 with saturated sodium bicarbonate (the temperature should not exceed 30°C). 64 L of ethyl acetate was added for separation. The aqueous phase was extracted again with 32 L of ethyl acetate. The organic phases were combined, extracted again with 32 L of saturated brine, and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain 5.2 kg of reddish-brown solid (compound 5). The crude product yield was 102.4%, and the next reaction was carried out directly.

[0239] Compound 6:

[0240] MS-ESI: 390.20 [MH] + .

[0241] 1H-NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 9.10 (brs, 1H), 6.79-6.73 (m, 4H), 6.60 (d, J = 8.4Hz, 1H), 6.51 (d, J = 2.0Hz, 1H), 6.42 (dd, J = 2.4Hz, 8.4Hz, 1H), 3.86 (d, J = 4.8Hz, 1H), 3.53-3.48 (m, 2H), 2.85-2.69 (m, 4H), 2.50-2.40 (m, 1H), 1.92-1. 88 (m, 2H), 1.77-1.75 (m, 2H), 1.68-1.45 (m, 4H), 1.04-0.97 (m, 1H), 0.82 (t, J = 6.4Hz, 6H), 0.69-0.62 (m, 1H).

[0242] Compound 6 was prepared according to the method disclosed in WO2022206737.

[0243] Example 10

[0244]

[0245] Preparation of compound 5: At room temperature, compound 11 (4 g), 40 mL tetrahydrofuran, 10 mL water and 1.06 g lithium hydroxide monohydrate were added to a 250 mL three-necked flask and stirred to dissolve.

[0246] The temperature was raised to 50℃ and reacted for 2 hours. TLC monitoring showed that the starting material spot disappeared, so heating was stopped.

[0247] The system was cooled to <10℃, and 2M hydrochloric acid (87 mL) was added dropwise. After the addition was complete, the system was naturally heated to room temperature and stirred for 2 hours. The reaction was detected by TLC and found to be complete.

[0248] The reaction was stopped, cooled to room temperature, and the pH was adjusted to 6-7 with sodium bicarbonate solution. Dichloromethane was added, stirred, and separated. The aqueous phase was extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 3.3 g of product (compound 5). The product was not further purified before proceeding to the next step.

[0249] Compound 6 was prepared according to the method disclosed in WO2022206737.

Claims

1. A method for preparing a compound as shown in Formula IV, comprising the step of converting a compound as shown in Formula I into a compound as shown in Formula IV. in, R 1 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms and hydroxyl protecting groups; R 2 and R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano, amino, hydroxyl, C 3-8 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Each cycloalkyl group is independently selected from halogen, oxo group, C... 1-6 Alkyl, C 1-6 Alkoxy, cyano, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 One or more substituents in the cycloalkyl group are substituted; R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 cycloalkyl, 3-8-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are each independently selected from halogen, oxo group, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, cyano, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-8 The alkyl group is replaced by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl and 5-10 membered heteroaryl; R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 alkoxy, hydroxy, amino and C 1-6 Hydroxyalkyl; R 6 Selected from -(CH2) p CH(OCH3)2; X is an oxygen atom or -CH2-; m can be 0, 1, 2, or 3; n can be 0, 1, 2, 3, or 4; p can be 0, 1, 2, 3, or 4.

2. The preparation method according to claim 1, further comprising the step of converting the compound of formula I into the compound of formula II under oxidizing conditions. in, X, R 1 R 2 R 3 R 4a R 4b R 5 R 6 m and n are as defined in claim 1.

3. The preparation method according to claim 2, further comprising the step of converting the compound of formula II into the compound of formula IV under reducing agent conditions. in, X, R 1 R 2 R 3 R 4a R 4b R 5 R 6 R 7 m and n are as defined in claim 1.

4. The preparation method according to claim 3, further comprising the steps of reducing the compound of formula II to the compound of formula III, and the steps of converting the compound of formula III to the compound of formula IV. in, X, R 1 R 2 R 3 R 4a R 4b R 5 R 6 R 7 m and n are as defined in claim 1.

5. The preparation method according to claim 4, further comprising the steps of converting the compound of formula III into the compound of formula IV', and the chiral resolution of the compound of formula IV' into the compound of formula IV. in, X, R 1 R 2 R 3 R 4a R 4b R 5 R 6 R 7 As defined in claim 1, R 1 With R 7 different.

6. The preparation method according to any one of claims 1-5, wherein the hydroxyl protecting group is selected from acetyl (Ac), n-valeryl, tert-butyl, benzyl, and methoxybenzyl.

7. The preparation method according to any one of claims 1-6, wherein R 1 Selected from hydrogen, acetyl (Ac), n-valeryl, tert-butyl, benzyl, methoxybenzyl; R 7 Selected from hydrogen, acetyl (Ac), n-valeryl, tert-butyl, benzyl, and methoxybenzyl.

8. The preparation method according to any one of claims 1-7, wherein X is -CH2-; R 2 Selected from hydrogen, halogens and C 1-6 Alkyl group, preferably hydrogen; R 5 Selected from hydrogen, halogens and C 1-6 Alkyl groups, preferably hydrogen or fluorine; R 6 Selected from -CH(OCH3)2.

9. The preparation method according to any one of claims 1-8, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclic, 6-10-membered aryl, and 5-10-membered heteroaryl groups are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 It is substituted by one or more substituents selected from alkyl, amino, nitro, and hydroxyl groups; R 3 Preferred compounds include phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, isobutyl, and 4-tetrahydropyranyl; R 3 More preferably isobutyl.

10. The preparation method according to any one of claims 1-9, wherein R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; further, R 4a and R 4b The same, preferably hydrogen atoms.

11. The preparation method according to any one of claims 1-10, wherein the oxidant is selected from quinone oxidants; further preferably, DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), benzoquinone, or tetrachlorobenzoquinone.

12. The preparation method according to claim 1, wherein the preparation method includes the step of converting the compound of formula Ia into the compound of formula IVa. in, X, R 1 R 3 R 6 R 7 As defined in claim 1.

13. The preparation method according to claim 12, further comprising the step of converting the compound of formula Ia into the compound of formula IIa under oxidizing conditions. in, X, R 1 R 3 R 6 As defined in claim 1.

14. The preparation method according to claim 13, further comprising the step of converting the compound of formula IIa into the compound of formula IVa under reducing agent conditions. in, X, R 1 R 3 R 6 R 7 As defined in claim 1.

15. The preparation method according to claim 14, further comprising the steps of reducing the compound of formula IIa to the compound of formula IIIa, and the steps of converting the compound of formula IIIa to the compound of formula IVa. in, X, R 1 R 3 R 6 R 7 As defined in claim 1.

16. The preparation method according to claim 15, further comprising the step of converting the compound of formula IIIa into the compound of formula IVa', and the step of chirally resolving the compound of formula IVa' into the compound of formula IVa. in, X, R 1 R 3 R 6 R 7 As defined in claim 1, R 1 With R 7 different.

17. The preparation method according to claims 1-4 and 6-15, comprising the following reaction steps: 1) Compound 1 is converted to compound 2 in the presence of DDQ oxidant. 2) Compound 2 is converted to compound 4 under reducing agent conditions. Alternatively, compound 2 is converted to compound 3 under reducing conditions, and compound 3 is chirally resolved into compound 4. 。 18. The preparation method according to claims 1-16, comprising the following reaction steps: 1) Compound 7 is converted to compound 8 in the presence of DDQ oxidant. 2) Compound 8 is converted to compound 9 under reducing agent conditions. 3) Compound 9 is converted to compound 10 in the presence of acetyl chloride, and compound 10 is converted to compound 11 under the conditions of hydrolytic enzymes. 。 19. A method for preparing a tetrahydronaphthalene compound or a salt thereof, comprising the method of claim 17, and the steps of converting compound 4 to compound 5, and compound 5 to compound 6 or a salt thereof. 。 20. A method for preparing a tetrahydronaphthalene compound or a salt thereof, comprising the method of claim 18, and the steps of converting compound 11 to compound 5, and compound 5 to compound 6 or a salt thereof. 。

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