Preparation method of empagliflozin intermediate and analogue thereof

Abstract

The invention relates to a preparation method of an empagliflozin intermediate, an analogue thereof and a compound III, and the preparation method comprises the following steps: in the presence of a Ni catalyst, a ligand, Zn and an auxiliary agent, carrying out a coupling reaction on a compound I and a compound II to generate the compound III. The reaction formula is as follows. The ligand is terpyridine or a derivative thereof, and pyridine or a derivative thereof of which the 2 and 6 positions are simultaneously substituted by pyridine, imidazole, benzopyridine or benzimidazole, and the auxiliary agent is inorganic salt of Mg, Zn or Na. The target product obtained by the method disclosed by the invention is high in yield and good in selectivity.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis. Specifically, it relates to a method for preparing empagliflozin intermediates and their analogues. Background Technology

[0002] Squalifloxacin is a new class of oral hypoglycemic agents that lower blood glucose levels by inhibiting renal glucose reabsorption and promoting urinary glucose excretion, while also possessing cardiovascular and renal protective effects. These are novel diabetes treatment drugs, belonging to the SGLT2 inhibitor class. They lower plasma glucose levels by inhibiting SGLT-2 expression in the kidneys, reducing renal glucose reabsorption, and increasing urinary glucose excretion. Their hypoglycemic effect is independent of β-cell function and insulin resistance, exhibiting good safety and tolerability. Currently, commonly used squalifloxacin drugs in China include empagliflozin, canagliflozin, dapagliflozin, and etoragliflozin, whose structural formulas are as follows:

[0003] These glycosides all contain a β-configuration in their structural formulas and are prepared using similar methods. Taking empagliflozin as an example, there are currently several methods for its preparation:

[0004] Existing technologies WO2005092877A1 and WO2006120208A disclose the following route 1:

[0005]

[0006] Route 1 uses 5-bromo-2-chlorobenzoic acid as a starting material, which undergoes sequential acylation, Friedel-Crafts acylation, nucleophilic substitution, and reduction to yield the intermediate (S)-3-(4-(2-chloro-5-bromobenzene)phenoxy)tetrahydrofuran. This intermediate is then reacted with 2,3,4,6-tetra-O-trimethylsilyl-D-pyranoglobin-1,5-lactone via condensation, etherification, and demethylation to obtain the target product, with an overall yield of approximately 30%. The intermediate (A70) with a β-configuration glycosidic bond is the key compound in the preparation of empagliflozin. In this route, compound E50 undergoes lithium exchange with n-butyllithium to form an active lithium reagent, which then undergoes an addition reaction with the glycolactone. The resulting product is first methylated and then demethoxylated. After acetylation of the glycosyl group of the product, it is recrystallized and purified. The product is then deacetylated under alkaline conditions to give empagliflozin (β-configuration). This step involves the use and formation of reactive reagents, resulting in harsh process conditions, poor selectivity, cumbersome purification, and high production costs.

[0007] Prior art CN106905305A discloses a method for preparing empagliflozin as shown in route 2 below.

[0008]

[0009] Compound 5, after undergoing Grignard exchange, is coupled with compound 6 to obtain a β-glycosidic intermediate (compound 7). In this route, Grignard exchange requires low temperature, and the prepared Grignard reagent requires dropwise transfer, making the operation cumbersome and resulting in poor process stability.

[0010] Existing technologies, Org. Lett. 2018, 20, pp. 7991-7995 and Sci China Chem, 2019, 62: pp. 1492-1496, respectively reported the reductive cross-coupling of alkyl halides with aryl iodides / bromines using Ni catalysts, yielding the coupling products, with the reaction formulas as follows:

[0011]

[0012] However, in the prior art method used to prepare β-glycosidic intermediates for selenocillin drugs, the selectivity of the α and β configurations of the obtained product remains problematic.

[0013] The existing technology, *New Ligand Development for Nickel-Catalyzed Reductive Cross-Coupling Enabling Practical Synthesis of SGLT-2 Inhibitors*, Ding-Jun Chu, Xiao-Qiang Xie, et al., *Organic Process Research & Development*, Vol 29 / Issue 11, discloses the catalytic reaction of compound 1 with compounds 2, 4, or 6 to yield products 3, 5, or 7 using Ni(OAc)₂·4H₂O as a catalyst, L₁ as a ligand, and Zn and ZnBr₂ as promoters. However, the presence of water in the reaction system significantly affects the yield. The article also mentions that "adding 10 equivalents of H₂O completely stops the reaction, with no product formation, indicating that it is not moisture-resistant."

[0014] When the inventors repeated the reaction process described in the prior art, they found that the yield was unstable (ranging from 50% to 80%) when the scale reached a certain level (hundred-gram level). The reason for this is likely that the total water content of the catalyst itself increases with the increase in the amount added, thus affecting the reaction conversion. Furthermore, it was found that the catalyst Ni(OAc)₂·4H₂O has very poor solubility in the reaction solvent THF, which may also be a factor affecting the unstable yield. Therefore, the technical solution disclosed in this prior art carries significant risks when used in industrial-scale production.

[0015] In summary, existing techniques for preparing scutellarin-containing drugs with β-glycosidic bonds still present problems. Developing easy-to-operate, stable, and high-yield methods for preparing scutellarin-containing drugs is a pressing issue in this field. Summary of the Invention:

[0016] To address the problems existing in the preparation methods of levofloxacin intermediates containing β-glycosidic bonds in the prior art, the present invention provides a method for preparing compound III, the preparation method comprising the following steps:

[0017] In the presence of a catalyst, ligand, Zn, and an auxiliary agent, compound I and compound II undergo a coupling reaction to generate compound III, as shown in the following reaction formula:

[0018]

[0019] Wherein, R1, R2, R3, R4, and R5 are each independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, sulfonyl, amide, and carboxyl ester groups, wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heterocyclic, and alkoxy groups are optionally further substituted by one or more substituents selected from hydrogen atoms, alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, amide, sulfonyl, and carboxyl ester groups; or

[0020] Any combination or combination of R1 and R2, R2 and R3, R3 and R4, R4 and R5, together with the carbon atom to which they are attached, forms a 4- to 11-membered cyclic group, wherein all of the 4- to 11-membered cyclic groups are C or contain one or more N, O, S, or SO2 atoms. The cyclic group may optionally be further substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, sulfonyl, amide, and carboxylic acid ester groups.

[0021] X is either I or Br.

[0022] GP is a hydrogen atom or hydroxyl protecting group.

[0023] The catalyst is selected from NiCl2dme, NiBr2dme, NiCl2, NiBr2, or a combination thereof.

[0024] The structural formula of NiCl2dme is: The structural formula of NiBr2dme is:

[0025] The ligand is selected from one of the following compounds:

[0026]

[0027] In compounds 1, 2, 3, 4, and 5, R a R b R c R d R e Each is independently selected from hydrogen atoms, C1-C 12 Alkyl, phenyl, naphthyl, C1-C 12 alkoxy, heterocyclic, amino, hydroxyl, wherein the C1-C 12 Alkyl, phenyl, naphthyl, C1-C 12 The alkoxy group, heterocyclic group, and amino group may optionally be further selected from one or more C1-C6 groups. 12 Alkyl, phenyl, naphthyl, C1-C 12 Substituents include alkoxy, heterocyclic, amino, and hydroxyl groups.

[0028] The auxiliary agent is selected from ZnBr2, MgCl2, NaCl or ZnBr2, MgBr2, ZnCl2, or a combination thereof.

[0029] The ligand is selected from one or more of the following compounds:

[0030]

[0031]

[0032] In another preferred embodiment, GP is an acyl protecting group, a silyl ether protecting group, or a benzyl group.

[0033] In another preferred embodiment, the acyl protecting group is an acetyl group or a formyl group.

[0034] In another preferred embodiment, the silyl ether protecting group is trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), or tert-butyldiphenylsilyl (TBDPS).

[0035] In another preferred embodiment, the catalyst is selected from NiCl2dme.

[0036] In another preferred embodiment, the ligand is selected from one or more of the following compounds:

[0037]

[0038] In another preferred embodiment, the auxiliary agent is selected from MgCl2 and / or ZnBr2.

[0039] In another preferred embodiment, PG in compound I is a hydrogen atom, trimethylsilyl, triethylsilyl, acetyl, formyl, or benzyl.

[0040] In another preferred embodiment, the structural formula of compound II is shown below:

[0041]

[0042] In structural formulas (a), (b), (c), and (d), X is I or Br, and

[0043] In another preferred embodiment, the structural formula of compound III is shown below:

[0044]

[0045] In structural formulas A, B, C, and D, PG is a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, an acetyl group, a formyl group, or a benzyl group.

[0046] In another preferred embodiment, the molar ratio of compound II to compound I is 1:1.0 to 1.5, more preferably 1:1.1 to 1.3.

[0047] In another preferred embodiment, the molar ratio of compound II to the Ni catalyst is 1:0.01 to 0.5, more preferably 1:0.05 to 0.3.

[0048] In another preferred embodiment, the molar ratio of compound II to Zn is 1:1.0 to 3.0, more preferably 1:1.5 to 2.5.

[0049] In another preferred embodiment, the molar ratio of Ni catalyst to ligand is 1:1 to 3, more preferably 1:1.2 to 2.0.

[0050] In another preferred embodiment, the molar ratio of compound II to the adjuvant is 1:1.0 to 3.0, more preferably 1:1.1 to 1.5.

[0051] In another preferred embodiment, the coupling reaction temperature is 10–50°C, more preferably 20–30°C.

[0052] In another preferred embodiment, the solvent used for the coupling reaction is selected from tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, MeCN, DMI (isosorbitol dimethylhexahydrofuran[3,2-b]furan), 1,3-dimethyl-2-imidazolinone, or combinations thereof; more preferably, tetrahydrofuran.

[0053] This invention also provides a method for preparing an empagliflozin intermediate, compound A80, comprising the following steps:

[0054] In the presence of a Ni catalyst, ligand, Zn, and an auxiliary agent, compound M30 reacts with compound A50 to form compound A80, as shown in the following reaction formula:

[0055]

[0056] The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, the ligand is selected from T70, T85, T126, T138, T139, or a combination thereof, and the promoter is selected from MgCl2 and / or ZnBr2.

[0057] In another preferred embodiment, the catalyst is selected from NiCl2dme, the ligand is selected from T85, and the promoter is selected from ZnBr2.

[0058] This invention also provides a method for preparing a canagliflozin intermediate, compound DGL-A80, comprising the steps of: reacting compound M30 with compound DGL-A50 in the presence of a Ni catalyst, a ligand, Zn, and an auxiliary agent to generate compound DGL-A80, as shown in the following reaction formula:

[0059]

[0060] The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, the ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, the structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138 and EGL-T139 are as defined above, and the promoter is selected from MgCl2 and ZnBr2.

[0061] In another preferred embodiment, the catalyst is selected from NiCl2dme, the ligand is selected from T85, and the promoter is selected from ZnBr2.

[0062] This invention also provides a method for preparing a dapagliflozin intermediate, compound CGL-A80, comprising the steps of: reacting compound M30 with compound CGL-A50 in the presence of a catalyst, a ligand, Zn, and an auxiliary agent to generate compound CGL-A80, as shown in the following reaction formula:

[0063]

[0064] The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, the ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, the structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138 and EGL-T139 are as defined above, and the promoter is selected from MgCl2 and ZnBr2.

[0065] In another preferred embodiment, the catalyst is selected from NiCl2dme, the ligand is selected from T85, and the promoter is selected from ZnBr2.

[0066] This invention also provides a method for preparing the intermediate of eletogliflozin, compound BGL-A80, comprising the steps of: reacting compound M30 with compound BGL-A50 in the presence of a catalyst, a ligand, Zn, and an auxiliary agent to generate compound BGL-A80, as shown in the following reaction formula:

[0067]

[0068] The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, the ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, the structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138 and EGL-T139 are as defined above, and the promoter is selected from MgCl2 and ZnBr2.

[0069] In another preferred embodiment, the catalyst is selected from NiCl2dme, the ligand is selected from T85, and the promoter is selected from ZnBr2.

[0070] The present invention also provides a ligand compound, the structural formula of which is shown below:

[0071]

[0072] The ligand coordinates with the Ni catalyst to enable compounds I and II to undergo a coupling reaction, as shown in the following equation:

[0073]

[0074] Among them, R1, R2, R3, R4, R5, X, and GP are defined as above.

[0075] The Ni catalyst is selected from NiCl2dme, NiBr2dme, NiCl2, NiBr2, or a combination thereof.

[0076] The structural formula of NiCl2dme is: The structural formula of NiBr2dme is:

[0077] In another preferred embodiment, the coupling reaction system also contains Zn and an auxiliary agent selected from ZnBr2, MgCl2, NaCl, ZnBr2, MgBr2, and ZnCl2. Attached Figure Description

[0078] Figure 1 This is the 1H NMR spectrum of ligand T85.

[0079] Figure 2 This is the carbon NMR spectrum of ligand T85.

[0080] Figure 3 This is the mass spectrum of ligand T85.

[0081] Figure 4 This is the 1H NMR spectrum of ligand T126.

[0082] Figure 5 This is the carbon NMR spectrum of ligand T126.

[0083] Figure 6 This is the mass spectrum of ligand T126.

[0084] Figure 7 This is the 1H NMR spectrum of compound A80 obtained in Example 1.

[0085] Figure 8 This is the carbon NMR spectrum of compound A80 obtained in Example 1.

[0086] Figure 9 This is the mass spectrum of compound A80 obtained in Example 1.

[0087] Figure 10 This is the 1H NMR spectrum of ligand DGL-A80.

[0088] Figure 11 This is the mass spectrum of ligand DGL-A80.

[0089] Figure 12 This is the 1H NMR spectrum of ligand CGL-A80.

[0090] Figure 13 This is the mass spectrum of ligand CGL-A80. Detailed implementation method:

[0091] To address the problems existing in the preparation methods of β-glycoside intermediates of scutellarin-like drugs in the prior art, the inventors of this application, through in-depth research, modified and improved the ligands in the prior art based on the content disclosed in Org. Lett. 2018, 20, pp. 7991-7995, Sci China Chem, 2019, 62: pp. 1492-1496, and Ding-Jun Chu, et al., Organic Process Research & Development, and accordingly screened the catalysts and auxiliaries to obtain an ideal catalytic system. This catalytic system can obtain β-glycoside intermediates of scutellarin-like drugs with high selectivity and high yield.

[0092] Unless otherwise stated, some of the terms used in this invention are defined as follows:

[0093] "Alkyl" refers to compounds consisting of C1-C64 atoms. 20 A straight-chain or branched aliphatic hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, etc. The alkyl group can be substituted or unsubstituted.

[0094] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Examples include vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyl groups can be substituted or unsubstituted.

[0095] "Alynyl" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group can be substituted or unsubstituted.

[0096] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., are either substituted or unsubstituted.

[0097] "Heterocyclic group" refers to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic.

[0098] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, which may be fused together. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Aryl groups can be substituted or unsubstituted.

[0099] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples include furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, and pyrimidinyl.

[0100] "Alkoxy" refers to an (alkyl-O-) group. C1-C6 alkoxy groups are preferred. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0101] "Carboxyl group" refers to -C(O)OH. "Sulfoyl group" refers to -(O)S(O)-. "Amide group" refers to -C(O)NH-alkyl or -C(O)NH2. "Carboxylic acid ester group" refers to -C(O)O-alkyl.

[0102] In the preparation method of compound III of the present invention, the catalyst used includes, but is not limited to, NiCl2dme (i.e., a complex of nickel and dimethyl ethylene glycol ether), NiBr2dme, NiCl2, NiBr2, etc., which are simple to prepare, easy to separate, have good stability, and are widely used.

[0103] In the preparation method of compound III of the present invention, the auxiliary agent used includes, but is not limited to, ZnBr2, MgCl2, NaCl, ZnBr2, MgBr2, or ZnCl2. The role of the auxiliary agent is to adjust the ionic strength or solvent polarity of the reaction system, promote the reaction, and help improve the efficiency and selectivity of the coupling reaction.

[0104] In the preparation method of compound III of the present invention, the zinc used is used to reduce divalent nickel to a monovalent or zero-valent reduced state. The reduced nickel undergoes halogenation with the aryl halide, and the resulting transition state combines with the ligand, which then undergoes halogenation elimination with the alkyl group to obtain the coupling compound.

[0105] Compared with the prior art, the advantages of the method for preparing empagliflozin intermediates and their analogues of the present invention are as follows:

[0106] 1. It does not require reactive reagents, is simple to operate, has mild reaction conditions, and is easy to process, making it suitable for industrial-scale production.

[0107] 2. The catalysts, ligands and auxiliaries used are easy to obtain or have simple preparation methods, low cost, good reaction reproducibility, and easy-to-control reaction conditions.

[0108] 3. The combination of the tripyridine-based multidentate ligand and the Ni catalyst showed better catalytic coupling of compounds I and II. Moreover, compared with the common 4,4,4-tritert-butylbipyridine, this ligand has lower preparation cost, higher conversion rate, and stronger stereoselectivity.

[0109] 4. Compared with Ni(OAc)2·4H2O, the catalysts NiCl2dme and NiBr2dme used in this invention have better solubility in THF (0.1 equivalent of catalyst added to 10V of reaction solvent can obtain a basically clear solution), no water of crystallization, better catalytic effect, and stable yield of target product when scaled up to a certain scale (hundred-gram level).

[0110] The present invention will be further described below with reference to specific embodiments, and its application is not limited to the following examples.

[0111] The catalysts used in the following examples and their structures are shown in Table A below.

[0112] Table A

[0113]

[0114] The L-series ligands and their structures used in the following embodiments are as follows:

[0115]

[0116]

[0117] All of the above are compounds with known structures. For example, compound L-5 exhibits typical tripentate ligand characteristics. Its preparation method is as follows: substrate compound L1 and substrate compound L2 Compound L-5 was prepared by dehydration at 220°C under polyphosphoric acid conditions. This preparation method can be found in the reference: D. Gong et al., Journal of Organometallic Chemistry 702(2012)10-18.

[0118] The T-series ligands and their structures used in the following embodiments are as follows:

[0119]

[0120]

[0121]

[0122] The main characteristic of the above ligands is that they contain a terpyridine structure: The preparation method can be found in Angewandte Chemie-International Edition, 2020, vol.59(46), p.20697-20703L. The 2-acetylpyridine substrate was dissolved in THF. After adding potassium tert-butoxide and aldehyde, the mixture was stirred overnight. Acetic acid was added to adjust the pH to neutral, and then ammonium acetate was added and refluxed for 16 h. After the reaction was completed, the purity was separated to obtain the corresponding ligand.

[0123]

[0124] For example, the characterization spectra of ligand EGL-T85 obtained by the above method are shown below. Figure 1 , Figure 2 and Figure 3 The characterization spectra of EGL-T126 are shown below. Figure 4 , Figure 5 and Figure 6 ;

[0125] The structures of the new ligand-1, new ligand-2, new ligand-3 and new ligand-4 mentioned in the following embodiments are shown in Table D below.

[0126] Table D

[0127]

[0128] In the following examples, "isomer" refers to an isomer of compound A80, whose structure is as follows: "Raw material" refers to compound A50. The peak elution time of compound A80 is 22.28 min, the peak elution time of the isomer is 22.76 min, and the peak elution time of the raw material is 28.26 min. The structure of the "dehalogenation product" is...

[0129] In the following examples, "room temperature" refers to 25℃±2℃.

[0130] Example 1

[0131]

[0132] The following embodiments of the present invention use compounds M30 and A50 as raw materials, reacting them in the presence of a catalyst, a ligand, Zn, and an auxiliary agent to generate compound A80. The specific reaction process is as follows:

[0133] Compound A50 (100 mg, 1.0 eq), compound M30, catalyst, ligand, Zn, auxiliary agent, and THF (3 ml) were added to a reaction flask. The mixture was purged with nitrogen three times, stirred at room temperature, and the reaction was stopped after complete conversion of the reactants by TLC. The content of the target compound A80, its corresponding isomer, and dehalogenation byproducts in the reaction solution was determined by HPLC. The reaction conditions and results are shown in Table 1.

[0134] Table 1

[0135]

[0136]

[0137] In Table 1, "t-Bu-Terpy" is 4,4′,4″-tri-tert-butyl-2,2′,6′,2″-terpyridine, CAS number 115091-29-7; "Terpy" is 2,2',6',2"-terpyridine, CAS number 1148-79-4; "bipy" is 2,2'-bipyridine, CAS number 366-18-7; "t-Bu-Bipy" is 4,4'-di-tert-butyl-2,2'-dipyridine, CAS number 72914-19-3; DMAP is 4-dimethylaminopyridine; and pyridine is pyridine. " / " indicates not found; in the following tables, " / " indicates the same meaning.

[0138] As shown in Table 1, the overall conversion of product A80 obtained by using catalyst 7 (NiCl2dme) as the catalyst is high. Therefore, catalyst 7 was selected as the catalyst for screening with different ligands and different promoters.

[0139] Example 2

[0140] A50 (100 mg), M30, catalyst, ligand, Zn, auxiliary agent, and THF (2 ml) were added together to a reaction flask as solvent. The mixture was purged with nitrogen three times, and the reaction was stopped after complete conversion of the reactants by TLC. The content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution was detected by HPLC. The reaction conditions and results are shown in Table 2.

[0141] Table 2

[0142]

[0143]

[0144]

[0145] Table 2 shows that the combination of NiCl2dme as a catalyst and a multidentate ligand exhibits relatively good catalytic performance for the coupling conversion, and the new ligand-4 shows relatively good β-selectivity; however, the overall conversion is still not ideal. Analysis suggests that the catalyst or solvent may have some influence. Therefore, using A50 as the substrate and the new ligand-4 as the catalyst, the effects of the catalyst and solvent on the coupling reaction at room temperature were further investigated.

[0146] Example 3

[0147] A50 (100 mg), M30, catalyst NiCl2dme, new ligand 4, Zn, auxiliary agent, and solvent were added to a reaction flask. The mixture was purged with nitrogen three times and stirred at room temperature for 16 hours. When TLC showed almost no reactants, the reaction was stopped. HPLC was used to detect the content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution. The reaction conditions and results are shown in Table 3.

[0148] Table 3

[0149]

[0150]

[0151] As can be seen from Table 3, under the conditions of using NiCl2dme as catalyst, new ligand-4, magnesium chloride or zinc bromide as promoter, and THF as solvent, the proportion of β-configuration product (compound A80) is greater than that of α-configuration product (isomeric form of compound A80), and the β / α ratio can reach about 5 / 1.

[0152] Due to the low overall conversion rate, further screening of ligands is needed based on this reaction system. Therefore, using A50 as the substrate and NiCl2dme as the catalyst, the effect of polydentate ligands with structures similar to ligand-4 on the coupling reaction was further investigated at room temperature.

[0153] Example 4

[0154] A50 (100 mg, 1.0 eq), M30 (1.5 eq), catalyst NiCl2dme (0.15 eq), ligand, Zn (2.0 eq), auxiliary agent, and solvent were added to a reaction flask. The mixture was purged with nitrogen three times, stirred at room temperature, and the reaction was stopped after the reactants were completely converted using TLC. The content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution was determined by HPLC. The reaction conditions and results are shown in Table 4.

[0155] Table 4

[0156]

[0157]

[0158] Table 4 shows that terpyridines are more universally applicable, and most terpyridine ligands show relatively good effects with MgCl2 / ZnBr2 auxiliary combinations. Therefore, EGL-A50 was selected as the substrate, NiCl2dme as the catalyst, and THF as the solvent to further investigate the effect of terpyridine ligands with different substituents on the coupling reaction at room temperature.

[0159] Example 5

[0160] Compound A50 (100 mg, 1.0 eq), compound M30 (1.5 eq), catalyst NiCl2dme (0.2 eq), ligand, Zn (2.0 eq), auxiliary agent, and THF (2 mL) were added to a reaction flask. The mixture was purged with nitrogen three times, stirred at room temperature, and the reaction was stopped after the reactants were completely converted using TLC. The content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution was determined by HPLC. The reaction conditions and results are shown in Table 5.

[0161] Table 5

[0162]

[0163]

[0164] Table 5 shows that terpyridines with substituted methyl groups at different positions on both ends and an isopropyl or tert-butyl group at the para position of the central pyridine (N) exhibit better ligand performance. Terpyridines without substituents on both ends and with aromatic ring substituents in the central pyridine generally perform poorly as ligands. This performance may be related to the steric hindrance or electron-richness of the pyridine substituents, which affect the catalyst's approach direction to the substrate and its electron-donating effect.

[0165] Example 6

[0166] To further verify the influence of terpyridine ligands with the above two characteristics on coupling reactions, the inventors designed a series of terpyridine ligands with substituents at different positions on both ends of the pyridine (to increase steric hindrance) and different alkane substituents in the middle pyridine (to increase electron donation), and experimentally verified their influence on coupling reactions. The specific implementation is as follows:

[0167] Compound A50 (100 mg, 1.5 eq), compound M30 (1.5 eq), catalyst NiCl2dme (0.2 eq), ligand, Zn (2.0 eq), auxiliary agent, and THF (2 mL) were added to a reaction flask. The mixture was purged with nitrogen three times, stirred at room temperature, and the reaction was stopped after the reactants were completely converted by TLC. The content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution was detected by HPLC. The reaction conditions and results are shown in Table 6.

[0168] Table 6

[0169]

[0170]

[0171] As shown in Table 6, using EGL-T51, EGL-T68, EGL-T85, EGL-T106, EGL-T126, EGL-T127, EGL-T138, and EGL-T139 as ligands yields better coupling effects than the common nickel coupling ligand T70. Among these, EGL-T51, EGL-T68, EGL-T85, and EGL-T106 have dimethyl substitutions at the 4, 5, and 6 positions of the pyridine on both sides, and the pyridine in the middle is substituted with different alkyl groups, resulting in greater steric hindrance and a higher proportion of β-configured products. EGL-T126, EGL-T127, EGL-T138, and EGL-T139 have no substitutions on both sides, but a straight-chain alkyl substituent in the middle, making them more electronegative and producing fewer dehalogenated products.

[0172] The characteristics of the ligands described above, to some extent, verify that the preparation of leucine intermediates containing β-glycosidic bonds via coupling reactions catalyzed by NiCl2dme is significantly influenced by the ligands. Ligands with large spatial positions and high electronegativity result in better stereoselectivity and coupling efficiency in the coupling reaction. EGL-T85 is a representative ligand possessing these two characteristics.

[0173] Example 7

[0174] To further investigate the stability of the reaction, reaction conditions with and without water and air were examined, as detailed below:

[0175] Compound A50 (100 mg, 1.0 eq), compound M30 (1.5 eq), catalyst NiCl2dme (0.2 eq), EGL-T85 (0.2 eq), Zn (2.0 eq), auxiliaries, and THF (2 mL) were added to a reaction flask and stirred at room temperature. The reaction mixture was monitored by TLC until the reactants were completely converted, at which point the reaction was stopped. The content of the target compound A80, its corresponding isomer, and the reactants in the reaction solution was determined by HPLC. The reaction conditions and results are shown in Table 7.

[0176] Table 7

[0177]

[0178] “ND” indicates that it was not detected.

[0179] As shown in Table 7, the moisture content in the reaction system has a significant impact on the products obtained from the coupling reaction. Higher water content results in lower substrate conversion and a lower concentration of the target product in the reaction solution. Furthermore, the coupling reaction conducted in air is less effective than that conducted in nitrogen.

[0180] A production run experiment was conducted based on the optimal catalytic combination obtained from the previous examples.

[0181] Example 8

[0182] Compound A50 (50.0 g, 0.12 mol), compound M30 (74.4 g, 0.18 mol), NiCl2dme (2.6 g, 12 mmol), T85 (4.16 g, 12 mmol), Zn (15.7 g, 0.24 mol), and ZnBr2 (27.15 g, 0.12 mol) were added to a reaction flask. THF (500 mL) was used as the solvent. The mixture was purged three times with nitrogen and stirred at room temperature for approximately 16 h. When TLC showed almost no starting material, stirring was stopped, and water was added to the reaction mixture for extraction and separation. The separated organic phase was dried with Na2SO4 and concentrated. The residue was then slurried with ethanol to obtain compound A80 (50 g, yield 67.0%) with an HPLC purity of 98.9%. The 1H NMR spectrum, 1C NMR spectrum, and mass spectrum of compound A80 are shown below. Figure 7 , Figure 8 and Figure 9 The data for the hydrogen NMR spectra are attributed as follows:

[0183] 1 H NMR(400MHz, CDCl3)δ7.37(d,J=8.1Hz,1H),7.21(s,1H),7.16–7.03(m,3H),6.80( d,J=8.0Hz,2H),5.31(t,J=9.3Hz,1H),5.22(t,J=9.5Hz,1H),5.07(t,J=9.5Hz,1H ),4.90(s,1H),4.41–4.23(m,2H),4.16(d,J=12.0Hz,1H),4.11–3.94(m,5H),3.94 –3.79(m,2H),2.24–2.13(m,2H),2.08(d,J=8.8Hz,6H),2.00(s,3H),1.73(s,3H).

[0184] Example 9

[0185]

[0186] DGL-A50 (50 g, 0.13 mol), M30 (82.7 g, 0.20 mol), NiCl2dme (3.0 g, 13 mmol), T85 (4.63 g, 13 mmol), Zn (17.5 g, 0.24 mol), and ZnBr2 (30.21 g, 0.13 mol) were added to a reaction flask. THF (500 mL) was used as the solvent. The mixture was purged three times with nitrogen and stirred at room temperature for 5–16 h. When TLC showed almost no reactants remaining, stirring was stopped, and water was added to the reaction mixture for extraction and separation. The separated organic phase was dried with Na2SO4 and concentrated. The residue was then slurried with ethanol to obtain compound DGL-A80 (42 g, 51.1%), with an HPLC purity of 99.0%. The 1H NMR spectrum and mass spectrum of compound DGL-A80 are shown below. Figure 10 and Figure 11 The data for the hydrogen NMR spectra are attributed as follows: 1 H NMR (400MHz, CDCl3) δ7.39 (d, J=8.2Hz, 1H), 7.22 (dd, J=8.2, 1.8Hz, 1H), 7.09 (d, J=8.6Hz, 3H),6.85(d,J=8.5Hz,2H),5.32(t,J=9.4Hz,1H),5.23(t,J=9.6Hz,1H),5.08(t,J=9.6Hz, 1H),4.38–4.26(m,2H),4.17(dd,J=12.3,1.9Hz,1H),4.08–3.98(m,4H),3.83(ddd,J=9.7, 4.6, 2.1Hz, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.74 (s, 3H), 1.43 (t, J = 7.0Hz, 3H).

[0187] Example 10

[0188]

[0189] CGL-A50 (50 g, 0.12 mol), M30 (75.5 g, 0.12 mol), NiCl2dme (2.9 g, 12 mmol), T85 (4.22 g, 12 mmol), Zn (16.0 g, 0.24 mol), and ZnBr2 (27.57 g, 0.12 mol) were added to a reaction flask. THF (500 ml) was used as the solvent, and the mixture was purged with nitrogen three times. The mixture was stirred at room temperature for 5-16 hours. When TLC showed almost no reactants, stirring was stopped, and water was added to the reaction mixture for extraction and separation. The separated organic phase was dried with Na2SO4 and concentrated. The residue was then slurried with ethanol to obtain CGL-A80 (45 g, 60.3%), with an HPLC purity of 99.3%. The 1H NMR spectrum and mass spectrum of compound CGL-A80 are shown below. Figure 12 and Figure 13 The data for the product's 1H NMR spectrum are assigned as follows:

[0190] 1 H NMR(400MHz, CDCl3) δ7.51(dd,J=8.6,5.3Hz,2H),7.22(dd,J=11.6,6.8Hz,3H),7.06(dd,J=10.4,6 .8Hz,3H),6.65(d,J=3.5Hz,1H),5.35(t,J=9.4Hz,1H),5.27(t,J=9.6Hz,1H),5.17(t,J=9.6Hz,1H ),4.40(d,J=9.8Hz,1H),4.32(dd,J=12.3,4.7Hz,1H),4.19(dd,J=12.2,1.9Hz,1H),4.14(s,2H),3 .86(ddd,J=9.8,4.6,2.1Hz,1H),2.33(s,3H),2.10(s,3H),2.09(s,3H),2.03(s,3H),1.79(s,3H).

[0191] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Various variations can be made to the above embodiments of the present invention. That is, all simple and equivalent changes and modifications made in accordance with the claims and description of this application fall within the protection scope of the claims of this patent.

Claims

1. A method for preparing compound III, characterized in that, The preparation method includes the following steps: In the presence of a Ni catalyst, ligands, Zn, and promoters, compounds I and II undergo a coupling reaction to generate compound III, as shown in the following reaction formula: Wherein, R1, R2, R3, R4, and R5 are each independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, sulfonyl, amide, and carboxyl ester groups, wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heterocyclic, and alkoxy groups are optionally further substituted by one or more substituents selected from hydrogen atoms, alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, amide, sulfonyl, and carboxyl ester groups; or Any combination or combination of R1 and R2, R2 and R3, R3 and R4, R4 and R5, together with the carbon atom to which they are attached, forms a 4- to 11-membered cyclic group, wherein all of the 4- to 11-membered cyclic groups are C or contain one or more N, O, S, or SO2 atoms. The cyclic group may optionally be further substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, phenyl, cyano, halogen, nitro, hydroxyl, amino, carboxyl, sulfonic acid, mercapto, cycloalkyl, heterocyclic, alkoxy, sulfonyl, amide, and carboxylic acid ester groups. X is either I or Br. GP is a hydrogen atom or hydroxyl protecting group. The catalyst is selected from NiCl2dme, NiBr2dme, NiCl2, NiBr2, or a combination thereof. The structural formula of NiCl2dme is: The structural formula of NiBr2dme is: The ligand is selected from one of the following compounds: In compounds 1, 2, 3, 4 and 5, R a R b R c R d R e Each is independently selected from hydrogen atoms, C1-C 12 Alkyl, phenyl, naphthyl, C1-C 12 alkoxy, heterocyclic, heteroaryl, amino, hydroxyl, wherein the C1-C 12 Alkyl, phenyl, naphthyl, C1-C 12 The alkoxy group, heterocyclic group, and amino group may optionally be further selected from one or more C1-C6 groups. 12 Alkyl, phenyl, naphthyl, C1-C 12 Substituents include alkoxy, heterocyclic, amino, and hydroxyl groups. The auxiliary agent is selected from ZnBr2, MgCl2, NaCl or ZnBr2, MgBr2, ZnCl2, or a combination thereof.

2. The preparation method according to claim 1, characterized in that, The ligands are selected from one or more of the following compounds:

3. The preparation method according to claim 1 or 2, characterized in that, The preparation method satisfies one or more of the following conditions: (i)GP is an acyl protecting group, a silyl ether protecting group, or a benzyl group. Preferably, the acyl protecting group is an acetyl or a formyl group. Preferably, the silyl ether protecting group is a trimethylsilyl (TMS), a triethylsilyl (TES), a triisopropylsilyl (TIPS), a tert-butyldimethylsilyl (TBS), or a tert-butyldiphenylsilyl (TBDPS). (ii) The catalyst is selected from NiCl2dme. (iii) The ligand is selected from one or more of the following compounds: The additives are selected from MgCl2 and / or ZnBr2.

4. The preparation method according to claim 1 or 2, characterized in that, The preparation method satisfies one or more of the following conditions: In compound I, PG is a hydrogen atom, trimethylsilyl group, triethylsilyl group, acetyl group, formyl group, or benzyl group. The structural formula of compound II is shown below: In equations (a), (b), (c), and (d), X is I or Br, and The structural formula of compound III is shown below: In structural formulas A, B, C, and D, PG is a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, an acetyl group, a formyl group, or a benzyl group.

5. The preparation method according to claim 1 or 2, characterized in that, The coupling reaction satisfies one or more of the following conditions: (i) The molar ratio of compound II to compound I is 1:1.0 to 1.5, more preferably 1:1.1 to 1.

3. (ii) The molar ratio of compound II to the Ni catalyst is 1:0.01 to 0.5, more preferably 1:0.05 to 0.

3. (iii) The molar ratio of compound II to Zn is 1:1.0 to 3.0, more preferably 1:1.5 to 2.

5. (iv) The molar ratio of Ni catalyst to ligand is 1:1 to 3, more preferably 1:1.2 to 2.

0. (v) The molar ratio of compound II to the adjuvant is 1:1.0 to 3.0, more preferably 1:1.1 to 1.

5. (vi) The coupling reaction temperature is 10–50 °C, more preferably 20–30 °C. (vii) The solvent used in the coupling reaction is selected from tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, MeCN, DMI (isosorbitol dimethyl hexahydrofuran[3,2-b]furan), 1,3-dimethyl-2-imidazolinone, or combinations thereof; more preferably, tetrahydrofuran.

6. A method for preparing an intermediate of the compound empagliflozin, compound A80, characterized in that, The preparation method includes the following steps: In the presence of a Ni catalyst, ligand, Zn, and an auxiliary agent, compound M30 reacts with compound A50 to form compound A80, as shown in the following reaction formula: The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, more preferably NiCl2dme. The ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, preferably EGL-T85. The structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138, and EGL-T139 are as defined in claim 2. The additive is selected from MgCl2 and / or ZnBr2, more preferably ZnBr2.

7. A method for preparing a canagliflozin intermediate, compound DGL-A80, characterized in that, The preparation method includes the following steps: In the presence of a Ni catalyst, ligands, Zn, and an auxiliary agent, compound M30 reacts with compound DGL-A50 to form compound DGL-A80, as shown in the following reaction formula: The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, more preferably NiCl2dme. The ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, preferably EGL-T85. The structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138, and EGL-T139 are as defined in claim 2. The additive is selected from MgCl2 and / or ZnBr2, more preferably ZnBr2.

8. A method for preparing a dapagliflozin intermediate, compound CGL-A80, characterized in that, The preparation method includes the following steps: In the presence of a catalyst, ligand, Zn, and an auxiliary agent, compound M30 reacts with compound CGL-A50 to form compound CGL-A80, as shown in the following reaction formula: The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, more preferably NiCl2dme. The ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, preferably EGL-T85. The structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138, and EGL-T139 are as defined in claim 2. The additive is selected from MgCl2 and / or ZnBr2, more preferably ZnBr2.

9. A method for preparing an eletogliflozin intermediate, compound BGL-A80, characterized in that, The preparation method includes the following steps: In the presence of a catalyst, ligand, Zn, and an auxiliary agent, compound M30 reacts with compound BGL-A50 to form compound BGL-A80, as shown in the following reaction formula: The Ni catalyst is selected from NiCl2dme and / or NiBr2dme, more preferably NiCl2dme. The ligand is selected from EGL-T70, EGL-T85, EGL-T126, EGL-T138, EGL-T139, or combinations thereof, preferably EGL-T85. The structural formulas of EGL-T70, EGL-T85, EGL-T126, EGL-T138, and EGL-T139 are as defined in claim 2. The additive is selected from MgCl2 and / or ZnBr2, more preferably ZnBr2.

10. A ligand compound having the following structural formula: The ligand coordinates with the Ni catalyst to enable compounds I and II to undergo a coupling reaction, as shown in the following equation: in, R1, R2, R3, R4, R5, X, and GP are as defined in claim 1. The Ni catalyst is selected from NiCl2dme, NiBr2dme, NiCl2, NiBr2, or a combination thereof, and the structural formula of NiCl2dme is as follows: The structural formula of NiBr2dme is:

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