Process for the preparation of gemcitabine intermediates and intermediates thereof

Abstract

The application provides a preparation method of an intermediate of gepotidacin, 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-formaldehyde, which uses compound I (2-bromopyridine substituted at the 5-position) as raw material, sequentially undergoes 3-methylation or propenylization, 3-propanolization, ring closure and 5-formaldehyde alkylation to obtain the target compound. The method has a short route, high yield, easily available raw material and is suitable for industrial production. 1 , R 2 are each independently selected from halogen, the halogen being selected from F, Cl, Br, I.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis, and more specifically, relates to the intermediate of giberdalin, the preparation method of compound IV and the intermediate thereof. Background Technology

[0002] Blujepa (generic name gepotidacin) is a novel triazaacenaphthene-based bacterial topoisomerase inhibitor (including bacterial topoisomerase II and topoisomerase IV) developed by GlaxoSmithKline (GSK). It inhibits bacterial DNA replication and exhibits proven antibacterial activity in the treatment of uncomplicated urinary tract infections and uncomplicated urogenital gonorrhea caused by susceptible bacteria (when there are limited or no alternative treatment options). It received initial market approval from the U.S. Food and Drug Administration (FDA) in 2025. Its chemical structure is shown below:

[0003]

[0004] The prior art WO2008128942 A1 discloses several methods for preparing gipodacin. These methods use different pyridine substitutes as raw materials. Among them, scheme 4a (route 1) uses 2-chloro-6-methoxy-3-nitropyridine as raw material and obtains key intermediate 9 through multiple reaction steps. Intermediate 9 is then subjected to a substitution reaction with piperidineamine and the amino protecting group is removed to obtain intermediate 11. Intermediate 11 is then subjected to reductive amination with compound 12 (i.e., aldehyde compound V described herein) to obtain the final product.

[0005]

[0006] Route 1

[0007] Another route (Route 2) disclosed in WO2008128942A1 involves synthesizing intermediate 9 using similar steps, followed by reductive amination with compound 2a to obtain the final product, wherein compound 2a is derived from compound 12 ( It was prepared by [method name missing]. Therefore, it can be seen that compound 12 (i.e., aldehyde compound V described herein) is crucial to the synthesis of gipodacin.

[0008]

[0009] Route 2

[0010] Prior art US8759523B2 reports a method for preparing 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxaldehyde (compound V), as shown in route 3 below:

[0011]

[0012] Route 3

[0013] In Route 3, compound V is prepared using N-Boc glycine (compound 1) as a starting material. The process involves sequential esterification, amidation, and double bond [4+2] cycloaddition to construct a pyridine ring, followed by reduction or reduction-oxidation to obtain the target product. This route is lengthy, has a low overall yield, and uses expensive N-Boc glycine, making it costly and unsuitable for industrial production.

[0014] Therefore, there is a need in the art for a method for the industrial production of 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxaldehyde that is short in route, high in yield, and suitable for industrial production. Summary of the Invention

[0015] To address the shortcomings of existing methods for preparing compound V, an intermediate of gibbadacin, this invention provides a novel method for preparing compound V. This method utilizes inexpensive and readily available starting materials, has a short route, and achieves high yields, making it suitable for industrial production.

[0016] The present invention provides an intermediate for gipodacin, compound V. The preparation method includes the following steps: Compound I reacts with a methyl reagent or an allyl reagent to generate Compound II, as shown in the following reaction formula:

[0017] ,

[0018] Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, or I; R 3 It is methyl or allyl.

[0019] In another, more preferred example, R 1 For Br, R 2 It can be Br or F.

[0020] In another preferred embodiment, the methyl reagent is selected from iodomethane, bromomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, dimethyl carbonate, or combinations thereof, more preferably iodomethane.

[0021] In another preferred embodiment, the allyl reagent is selected from allyl bromide, allyl iodide, allyl chloride, allyl methanesulfonate, allyl p-toluenesulfonate, or combinations thereof, more preferably, allyl bromide.

[0022] In another preferred embodiment, the reaction of compound I with the methyl reagent or the allyl reagent is carried out in the presence of a strong base.

[0023] In another preferred embodiment, the strong base is selected from lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), or combinations thereof. In another more preferred embodiment, the strong base is selected from LDA.

[0024] In another preferred embodiment, the molar ratio of compound I to the methyl reagent or allyl reagent is 1:1.0 to 3.0, more preferably 1:1.1 to 1.5.

[0025] In another preferred embodiment, the molar ratio of compound I to the strong base is 1:1.0 to 3.0, more preferably 1:1.05 to 1.2.

[0026] In another preferred embodiment, the solvent used for reacting compound I with the methyl or allyl reagent is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, hexane, cyclohexane, heptane, or combinations thereof, more preferably tetrahydrofuran. In another preferred embodiment, the weight-to-volume ratio of compound I to solvent is 50-200 mg / mL, more preferably 80-120 mg / mL.

[0027] In another preferred embodiment, the reaction of compound I with the methyl reagent or the allyl reagent comprises: first adding a solution of the strong base dropwise to a solution of compound I at -78°C to -40°C and reacting at this temperature for 0.5 to 2 hours; then adding the methyl reagent or the allyl reagent dropwise at -78°C to -40°C and reacting at this temperature for 0.5 to 2 hours.

[0028] In another preferred embodiment, the preparation method of compound V further includes the step of converting compound II into compound III, as shown in the following reaction formula:

[0029] .

[0030] In another preferred embodiment, R in equation II 3 The process by which compound II is converted to compound III is as follows: compound II reacts with an electrophilic reagent in the presence of a strong base to produce compound III.

[0031] In another preferred embodiment, the strong base is selected from lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), or combinations thereof, more preferably LDA.

[0032] In another preferred embodiment, the electrophilic agent is selected from ethylene oxide, ethylene carbonate, ethylene sulfate, or combinations thereof, more preferably ethylene oxide.

[0033] In another preferred embodiment, the molar ratio of compound II to the electrophilic reagent is 1:1.0 to 3.0, more preferably 1:1.2 to 1.6.

[0034] In another preferred embodiment, the molar ratio of compound II to the strong base is 1:1.0 to 3.0, more preferably 1:1.05 to 1.2.

[0035] In another preferred embodiment, the reaction solvent used to generate compound III by reacting compound II with an electrophilic reagent in the presence of a strong base is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, hexane, cyclohexane, heptane, or combinations thereof, more preferably tetrahydrofuran.

[0036] In another preferred embodiment, the weight-to-volume ratio of compound II to solvent is 80-300 mg / mL, more preferably 80-150 mg / mL.

[0037] In another preferred embodiment, the process of reacting compound II with an electrophilic reagent in the presence of a strong base includes: first, adding the strong base dropwise to a solution of compound II at -78°C to -40°C and reacting at this temperature for 0.5 to 2 hours; then, adding the electrophilic reagent dropwise at -78°C to -40°C and reacting at this temperature for 0.5 to 2 hours; and finally, reacting the mixture at 0 to 40°C for 5 to 12 hours.

[0038] In another preferred embodiment, R in equation II 3 The process by which compound II is converted to compound III is as follows: compound II first reacts with a boron reagent, and then is oxidized under alkaline conditions using an oxidizing agent to generate compound III.

[0039] In another preferred embodiment, the boron reagent is selected from borane-tetrahydrofuran complexes, borane-dimethyl sulfide complexes, 9-boronbicyclo[3.3.1]nonane (9-BBN), diisocyanate camphorane (Ipc2BH), catechol borane (HBcat), or pinacol borane (HBpin), or combinations thereof. In another more preferred embodiment, the boron reagent is selected from borane-tetrahydrofuran complexes or 9-boronbicyclo[3.3.1]nonane. In another more preferred embodiment, the boron reagent is selected from 9-boronbicyclo[3.3.1]nonane.

[0040] In another preferred embodiment, the oxidant is selected from hydrogen peroxide, peroxytert-butanol, m-chloroperoxybenzoic acid, peracetic acid, potassium persulfate, sodium chlorite, sodium periodate, oxygen, or combinations thereof, more preferably, hydrogen peroxide.

[0041] In another preferred embodiment, the base providing the alkaline conditions is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, or combinations thereof, more preferably sodium hydroxide.

[0042] In another preferred embodiment, the molar ratio of compound II to the boron reagent is 1:1.0 to 2.0, more preferably 1:1.05 to 1.2.

[0043] In another preferred embodiment, the molar ratio of compound II to the oxidant is 1:1.0 to 10.0, more preferably 1:2.0 to 5.0.

[0044] In another preferred embodiment, the alkali providing the alkaline conditions is selected from sodium hydroxide, and the oxidant is selected from hydrogen peroxide. In another preferred embodiment, the concentration of hydrogen peroxide is 10-50%, and the sodium hydroxide is provided by a 2-4M aqueous solution of sodium hydroxide, wherein the volume ratio of the aqueous solution of sodium hydroxide to the volume ratio of hydrogen peroxide is 1:0.5-1.5.

[0045] In another preferred embodiment, the reaction solvent used in the process of reacting compound II with a boron reagent and then oxidizing it with an oxidizing agent to generate compound III is selected from tetrahydrofuran, diethyl ether, dioxane, toluene, xylene, or combinations thereof, more preferably tetrahydrofuran. In another preferred embodiment, the weight-to-volume ratio of compound II to solvent is 80-250 mg / mL, more preferably 80-150 mg / mL.

[0046] In another preferred embodiment, the process of reacting compound II with a boron reagent and then oxidizing it with an oxidant to generate compound III includes: first adding the boron reagent dropwise to a solution of compound II at -10℃ to 10℃ (more preferably, -5℃ to 4℃) and reacting at this temperature for 1 to 3 hours; then adding an aqueous solution of alkali and an oxidant dropwise at -10℃ to 10℃ (more preferably, -5℃ to 4℃) and reacting at 0℃ to 40℃ for 0.5 to 2 hours.

[0047] In another preferred embodiment, the preparation method of compound V further includes the step of: intramolecular cyclization of compound III to generate compound IV-A, as shown in the following reaction formula:

[0048] .

[0049] In another preferred embodiment, the intramolecular cyclization of compound III is carried out in the presence of a copper catalyst, a ligand, and a base.

[0050] In another preferred embodiment, the copper catalyst is selected from CuI, CuBr, CuCl, Cu2O, CuOTf, Cu(OTf)2, Cu(OAc)2, or combinations thereof, preferably CuI.

[0051] In another preferred embodiment, the ligand is selected from oxalidium diamines and their derivatives, 1,10-phenanthroline diamines and their derivatives, bipyridine diamines and their derivatives, N,N'-dimethylethylenediamine and their derivatives, or combinations thereof, more preferably oxalidium diamine or 1,10-phenanthroline diamines.

[0052] In another preferred embodiment, the base is selected from K2CO3, Cs2CO3, Na2CO3, K3PO4, Na3PO4, t-BuOK, t-BuONa or combinations thereof, more preferably t-BuONa.

[0053] In another preferred embodiment, the molar ratio of compound III to the catalyst is 1:0.01 to 0.3, more preferably 1:0.1 to 0.2.

[0054] In another preferred embodiment, the molar ratio of the copper catalyst to the ligand is 1:0.5 to 2.0, more preferably 1:1.

[0055] In another preferred embodiment, the molar ratio of compound III to the base is 1:1.0 to 3.0, more preferably 1:1.5 to 2.0.

[0056] In another preferred embodiment, the solvent used for intramolecular cyclization of compound III is selected from toluene, DMF, DMSO, dioxane, NMP, or combinations thereof, more preferably dioxane. In another preferred embodiment, the weight-to-volume ratio of compound III to the solvent is 40-300 mg / mL, more preferably 60-150 mg / mL.

[0057] In another preferred embodiment, the reaction temperature for intramolecular cyclization of compound III is 60-150°C, more preferably 80-120°C.

[0058] In another preferred embodiment, the reaction time for intramolecular cyclization of compound III is 4 to 48 hours, more preferably 6 to 24 hours.

[0059] In another preferred embodiment, R in compound III 2 For F, the intramolecular cyclization of compound III is carried out in the presence of a base. In another preferred embodiment, the base is selected from Na2CO3, K2CO3, CsCO3, K3PO4, Na3PO4, NaOH, KOH, CH3ONa, CH3OK, CH3CH2ONa, CH3CH2OK, t-BuONa, t-BuOK, NaH, DBU, TEA, DIPA, or combinations thereof, more preferably t-BuOK. In another preferred embodiment, the molar ratio of compound III to the base is 1:0.5 to 1.5, more preferably 1:0.8 to 1.0.

[0060] In another preferred embodiment, R in compound III 2 For F, the solvent used for intramolecular cyclization of compound III is selected from tetrahydrofuran, DMF, DMSO, dioxane, NMP, or combinations thereof, more preferably tetrahydrofuran. In another preferred embodiment, the weight-to-volume ratio of compound III to the solvent is 80-400 mg / mL, more preferably 100-300 mg / mL.

[0061] In another preferred embodiment, R in compound III 2 For F, the intramolecular cyclization process of compound III is as follows: first, a mixture of compound III and solvent is added to the mixture of base and solvent at -20℃ to 0℃ and reacted at this temperature for 0.5 to 2 hours, and then reacted at 0℃ to 40℃ for 12 to 24 hours.

[0062] In another preferred embodiment, the preparation method of compound V further includes the step of: compound IV-A undergoing an aldehyde reaction to generate compound V, as shown in the following reaction formula.

[0063] .

[0064] In another preferred embodiment, compound IV-A is first reacted with an alkyllithium reagent or a Grignard reagent, and then reacted with a carbonyl reagent to generate compound V.

[0065] In another preferred embodiment, the alkyllithium reagent is selected from n-butyllithium, sec-butyllithium or tert-butyllithium, more preferably n-butyllithium.

[0066] In another preferred embodiment, the Grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, allyl magnesium chloride, allyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, or combinations thereof. More preferably, isopropyl magnesium chloride.

[0067] In another preferred embodiment, the carbonyl reagent is selected from N,N-dimethylformamide, N-formylmorpholine, ethyl formate, methyl formate, trimethyl orthoformate, or combinations thereof, more preferably, N,N-dimethylformamide.

[0068] In another preferred embodiment, the molar ratio of compound IV to the alkyllithium reagent or Grignard reagent is 1:1.0 to 3.0, more preferably 1:1.05 to 1.3.

[0069] In another preferred embodiment, the molar ratio of compound IV to the carbonyl reagent is 1:1.0 to 5.0, more preferably 1:2.0 to 3.0.

[0070] In another preferred embodiment, the solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, dioxane, toluene, xylene, or combinations thereof, more preferably tetrahydrofuran. In another preferred embodiment, the weight-to-volume ratio of compound II to the solvent is 50-200 mg / mL, more preferably 60-150 mg / mL.

[0071] In another preferred embodiment, the step of aldehyde hydration of compound IV-A to generate compound V is as follows: first, an alkyl lithium reagent or a Grignard reagent is added dropwise to a solution of compound IV-A at -78℃ to -40℃ and the reaction is carried out at this temperature for 0.2 to 1.0 hours; then, a carbonyl reagent is added dropwise at -78℃ to -40℃; after the addition is complete, the mixture is reacted at 0℃ to 40℃ for 1 to 4 hours.

[0072] In another preferred embodiment, the preparation method further includes the step of reacting compound III with a cyano reagent to generate compound III', as shown in the following reaction formula:

[0073] .

[0074] In another preferred embodiment, the cyano reagent is selected from cuprous cyanide, potassium cyanide, sodium cyanide, zinc cyanide, trimethylsilane, acetone cyanohydrin, potassium ferrocyanide, or combinations thereof, more preferably, cuprous cyanide.

[0075] In another preferred embodiment, the molar ratio of compound III to the cyano reagent is 1:0.8 to 1:3.0, more preferably 1:1.0 to 1:1.5, and even more preferably 1:1.1.

[0076] In another preferred embodiment, the solvent used in the reaction is selected from DMF, NMP, DMSO, DMAc, HMPA, or combinations thereof, more preferably DMF. In another preferred embodiment, the weight-to-volume ratio of compound III to the solvent is 30-200 mg / mL, more preferably 50-90 mg / mL.

[0077] In another preferred embodiment, the reaction temperature is 60°C to 180°C, more preferably 80°C to 150°C, and even more preferably 130°C.

[0078] In another preferred embodiment, the reaction time is 1 to 24 hours, more preferably 2 to 8 hours.

[0079] In another preferred embodiment, the preparation method further includes the step of: intramolecular cyclization of compound III' to generate compound IV-B, as shown in the following reaction formula:

[0080] .

[0081] In another preferred embodiment, the intramolecular cyclization of compound III' is carried out in the presence of a copper catalyst, a ligand, and a base.

[0082] In another preferred embodiment, the copper catalyst is selected from CuI, CuBr, CuCl, Cu2O, CuOTf, Cu(OTf)2, Cu(OAc)2, or combinations thereof, more preferably CuI. In another preferred embodiment, the ligand is selected from oxalyl diamine or its derivatives, 1,10-phenanthroline or its derivatives, bipyridine or its derivatives, N,N'-dimethylethylenediamine or its derivatives, or combinations thereof, more preferably oxalyl diamine or 1,10-phenanthroline ligands. In another preferred embodiment, the base is selected from K2CO3, Cs2CO3, Na2CO3, K3PO4, Na3PO4, t-BuOK, t-BuONa, or combinations thereof, more preferably t-BuONa.

[0083] In another preferred embodiment, the molar ratio of compound III' to the catalyst is 1:0.01 to 0.3, more preferably 1:0.1 to 0.2.

[0084] In another preferred embodiment, the molar ratio of the copper catalyst to the ligand is 1:0.5 to 2.0, more preferably 1:1.

[0085] In another preferred embodiment, the molar ratio of compound III' to the base is 1:1.0 to 3.0, more preferably 1:1.5 to 2.0.

[0086] In another preferred embodiment, the solvent used in the reaction is selected from toluene, DMF, DMSO, dioxane, NMP, or combinations thereof, more preferably dioxane. The weight-to-volume ratio of compound III' to the solvent is 40-200 mg / mL, more preferably 50-100 mg / mL.

[0087] In another preferred embodiment, the reaction temperature is 60~150℃, more preferably 80~120℃.

[0088] In another preferred embodiment, the reaction time is 2 to 48 hours, more preferably 6 to 24 hours.

[0089] In another preferred embodiment, R in equation III' 2 For F, the intramolecular cyclization of compound III' is carried out in the presence of a base. In another preferred embodiment, the base is selected from Na2CO3, K2CO3, CsCO3, K3PO4, Na3PO4, NaOH, KOH, CH3ONa, CH3OK, CH3CH2ONa, CH3CH2OK, t-BuONa, t-BuOK, NaH, DBU, TEA, DIPA, or combinations thereof, more preferably t-BuOK. In another preferred embodiment, the molar ratio of compound III' to the base is 1:0.5 to 2.0, more preferably 1:0.8 to 1.2.

[0090] In another preferred embodiment, R in equation III' 2 For F, the solvent used for intramolecular cyclization of compound III' is selected from tetrahydrofuran, DMF, DMSO, dioxane, NMP, or combinations thereof, more preferably tetrahydrofuran. In another preferred embodiment, the weight-to-volume ratio of compound III' to the solvent is 15-150 mg / mL, more preferably 20-60 mg / mL.

[0091] In another preferred embodiment, R in equation III' 2 For F, the molecular weight cyclization of compound III' is first carried out by adding a mixture of compound III' and solvent to the mixture of base and solvent at -20℃ to 0℃ and reacting at this temperature for 0.5 to 2 hours, and then reacting at 0℃ to 40℃ for 12 to 24 hours.

[0092] In another preferred embodiment, the preparation method further includes the following step: compound IV-B is reduced to generate compound V, as shown in the following reaction formula:

[0093] ,

[0094] In another preferred embodiment, the reducing agent used for reduction is selected from diisobutylaluminum hydride (DIBAL-H), triethylsilane / palladium on carbon, Raney nickel / ammonium formate, Red-Al (i.e., sodium dihydrobis(2-methoxyethoxy)aluminate), borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium tri(tert-butoxy)aluminum hydride, a mixture of lithium aluminum hydride with morpholine or N-methylpiperazine, or combinations thereof, more preferably, diisobutylaluminum hydride.

[0095] In another preferred embodiment, the molar ratio of compound IV to the reducing agent is 1:1.0 to 2.0, more preferably 1:1.1 to 1.2.

[0096] In another preferred embodiment, the solvent used for reduction is selected from dichloromethane, tetrahydrofuran, diethyl ether, dioxane, toluene, or combinations thereof, more preferably dichloromethane. In another preferred embodiment, the weight-to-volume ratio of compound IV to the solvent is 50-200 mg / mL, more preferably 60-150 mg / mL.

[0097] In another preferred embodiment, the reaction temperature for reducing the cyano group of compound IV is -78°C to -40°C.

[0098] In another preferred embodiment, the method for preparing compound V provided by the present invention includes the following steps:

[0099] i) Compound III undergoes intramolecular cyclization to generate compound IV-A, and

[0100] ii) Compound IV-A undergoes an aldehyde reaction to generate compound V.

[0101] The reaction formula is as follows:

[0102] ,

[0103] Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, and I.

[0104] In another, more preferred example, R 1 For Br, R 2 It can be Br or F.

[0105] In another preferred embodiment, the preparation method of compound V includes the following steps:

[0106] i) Compound III reacts with a cyano reagent to form compound III'.

[0107] ii) Compound III' undergoes intramolecular cyclization to generate compound IV-B, and

[0108] iii) Compound IV-B is reduced to form compound V.

[0109] The reaction formula is as follows:

[0110] ,

[0111] Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, and I.

[0112] In another, more preferred example, R 1 For Br, R 2 It can be Br or F.

[0113] In another preferred embodiment, the method for preparing compound III includes the steps of:

[0114] Compound II is converted into compound III, according to the following reaction:

[0115] .

[0116] The present invention also provides a compound having the structural formula shown in Formula III or Formula III':

[0117] , ,

[0118] In Equation III, R 1 R 2Each is independently selected from halogens, said halogens being selected from F, Cl, Br or I, more preferably, R 1 For Br, R 2 For Br or F,

[0119] In Equation III', R 2 The halogen is selected from halogens, wherein the halogen is selected from F, Cl, Br or I, and more preferably, R 2 It can be Br or F. Attached Figure Description

[0120] Figure 1 The 1H NMR spectrum of compound II-Aa prepared in Example 1 is shown.

[0121] Figure 2 The hydrogen NMR spectrum of compound III-A prepared in Example 2 is shown.

[0122] Figure 3 The 1H NMR spectrum of compound II-Ab prepared in Example 3 is shown.

[0123] Figure 4 The 1H NMR spectrum of compound IV-A prepared in Example 5 is shown.

[0124] Figure 5 The 1H NMR spectrum of compound V prepared in Example 6 is shown.

[0125] Figure 6 The 1H NMR spectrum of compound II-Ba prepared in Example 7 is shown.

[0126] Figure 7 The 1H NMR spectrum of compound III-B prepared in Example 8 is shown.

[0127] Figure 8 The hydrogen NMR spectrum of compound IV-A prepared in Example 9 is shown.

[0128] Figure 9 The hydrogen NMR spectrum of compound III'-A prepared in Example 10 is shown.

[0129] Figure 10 The 1H NMR spectrum of compound IV-B prepared in Example 11 is shown.

[0130] Figure 11 The 1H NMR spectrum of compound V prepared in Example 12 is shown.

[0131] Figure 12 The 1H NMR spectrum of compound III'-B prepared in Example 13 is shown. Detailed Implementation

[0132] To address the shortcomings of existing methods for preparing the intermediate compound V of gipodacin, such as high starting material costs, lengthy steps, low overall yield, and unavailability of some raw materials, making them unsuitable for industrial production, the inventors of this application, through in-depth research, discovered that using readily available and inexpensive compound I (5-substituted 2-bromopyridine) as the starting material, and sequentially undergoing 3-position methylation, 3-position methylation or propenylation, propanolization, ring closure, and 5-position aldehyde methylation, yields the target compound. This method has a shorter route, higher yield, and readily available raw materials, making it suitable for industrial production.

[0133] In some specific embodiments of the present invention, the preparation method of compound V includes the following steps:

[0134] (1) Compound I reacts with a methyl reagent or an allyl reagent to form compound II.

[0135] (2) Compound II is converted into compound III.

[0136] (3) Compound III undergoes intramolecular cyclization to generate compound IV-A, or

[0137] Compound III undergoes a nucleophilic reaction with a cyano reagent to form compound III', which then undergoes intramolecular cyclization to form compound IV-B.

[0138] (4) Compound IV-A undergoes an aldehyde reaction or compound IV-B is reduced to form compound V.

[0139] The reaction formula is as follows:

[0140] ,

[0141] Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, I; R 3 It is methyl or allyl.

[0142] Each step (1) to (4) of the preparation method of compound V of the present invention is preferably carried out in an inert gas atmosphere, such as a nitrogen atmosphere.

[0143] In a specific embodiment of the present invention, in step (1), the reaction of compound I with a methyl reagent or an allyl reagent is carried out in the presence of a strong base, which includes, but is not limited to, LDA, LiHMDS, NaHMDS, and KHMDS. The methyl reagent includes, but is not limited to, iodomethane, bromomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, or dimethyl carbonate. The allyl reagent includes, but is not limited to, allyl bromide, allyl iodide, allyl chloride, allyl methanesulfonate, or allyl p-toluenesulfonate. The reaction conditions, solvents, reagents, and amounts of compound I reacting with the methyl reagent or allyl reagent can be carried out according to conventional methods for such reactions in the art.

[0144] In step (2), R in equation II 3 When the compounds are methyl and allyl, different methods are used to convert compound II into compound III.

[0145] When R 3 When the methyl group is present, compound II reacts with an electrophilic reagent in the presence of a strong base to form compound III. The strong base includes, but is not limited to, LDA, LiHMDS, NaHMDS, and KHMDS. The electrophilic reagent includes, but is not limited to, ethylene oxide, ethylene carbonate, and ethylene sulfate.

[0146] When R 3 When the compound is allyl, compound II first reacts with a boron reagent, and then is oxidized under alkaline conditions using an oxidizing agent to generate compound III. The boron reagent includes, but is not limited to, borane-tetrahydrofuran complexes, borane-dimethyl sulfide complexes, 9-boronbicyclo[3.3.1]nonane, diisocyanuronylborane, catecholborane, or pinacolborane. The oxidizing agent includes, but is not limited to, hydrogen peroxide, peroxytert-butanol, m-chloroperoxybenzoic acid, peracetic acid, potassium persulfate, sodium chlorite, sodium periodate, and oxygen. The base includes, but is not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.

[0147] In step (3), the intramolecular cyclization of compound III in formula III is carried out in the presence of a copper catalyst, a ligand, and a base. The copper catalyst includes, but is not limited to, CuI, CuBr, CuCl, Cu2O, CuOTf, Cu(OTf)2, and Cu(OAc)2. Ligands of copper catalysts commonly used in the art can be used in this invention. The ligands used in this invention include, but are not limited to, oxalyl diamine and its derivatives, 1,10-phenanthroline and its derivatives, bipyridine and its derivatives, and N,N'-dimethylethylenediamine and its derivatives. The base includes, but is not limited to, K2CO3, Cs2CO3, Na2CO3, K3PO4, Na3PO4, t-BuOK, and t-BuONa.

[0148] When R 2 For F, intramolecular cyclization of compound III can be carried out in the presence of a copper catalyst, a ligand, and a base, or it can be carried out in the presence of a base alone, including but not limited to Na2CO3, K2CO3, CsCO3, K3PO4, Na3PO4, NaOH, KOH, CH3ONa, CH3OK, CH3CH2ONa, CH3CH2OK, t-BuONa, t-BuOK, NaH, DBU, TEA, and DIPA.

[0149] In step (3), compound III first undergoes a nucleophilic substitution reaction with a cyano reagent to generate compound III', which then undergoes intramolecular cyclization to obtain compound IV-B. The nucleophilic substitution reaction of compound III with the cyano reagent can be carried out using conventional cyano reagents used in the art for this type of reaction, and under conventional reagents and reaction conditions used in the art for this type of reaction. The cyano reagent includes, but is not limited to, cuprous cyanide, potassium cyanide, sodium cyanide, zinc cyanide, trimethylsilane, acetone cyanohydrin, and potassium ferrocyanide. The reaction conditions and reagents used for the intramolecular cyclization of compound III' to obtain compound IV-B are the same as those for the intramolecular cyclization of compound III, carried out in the presence of a copper catalyst, ligand, and base. When R... 2 Intramolecular cyclization of compound III' (F) can occur in the presence of a copper catalyst, ligand, and base, or it can occur solely in the presence of a base, just like compound III.

[0150] In step (4), compound IV-A or compound IV-B are converted into compound V using different methods.

[0151] In the conversion of compound IV-A to compound V, the halogen in IV-A first undergoes halogen-metal exchange with an alkyllithium reagent or a Grignard reagent, and then reacts with a carbonyl reagent to generate compound V. The alkyllithium reagent includes, but is not limited to, n-butyllithium, sec-butyllithium, or tert-butyllithium. The Grignard reagent includes, but is not limited to, isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, allyl magnesium chloride, allyl magnesium bromide, n-butyl magnesium chloride, and n-butyl magnesium bromide. The carbonyl reagent includes, but is not limited to, N,N-dimethylformamide, N-formylmorpholine, ethyl formate, methyl formate, and trimethyl orthoformate.

[0152] In the process of converting compound IV-B to compound V, the cyano group is reduced to an aldehyde group. The reducing agents used include, but are not limited to, diisobutylaluminum hydride, triethylsilane / palladium on carbon, Raney nickel / ammonium formate, red aluminum, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium tris(tert-butoxy)aluminum hydride, and mixtures of lithium aluminum hydride with morpholine or N-methylpiperazine.

[0153] In one specific embodiment of the present invention, the preparation method of compound V includes the following steps:

[0154] (1) Compound I-1 reacts with a methylating agent or an allylating agent to form compound II-1.

[0155] (2) Compound II-1 reacts with an electrophilic reagent or with a boron reagent and then is oxidized to form compound III-1.

[0156] (3) Compound III-1 undergoes intramolecular cyclization to generate compound IV-A.

[0157] (4) Compound IV-A reacts first with an alkyllithium reagent or a Grignard reagent, and then with a carbonyl reagent to form compound V.

[0158] The reaction formula is as follows:

[0159] ,

[0160] Where R 3 It is methyl or allyl, R 2 It can be Br or F.

[0161] In one specific embodiment of the present invention, the preparation method of compound V includes the following steps:

[0162] (1) Compound I-1 reacts with a methylating agent or an allylating agent to form compound II-A.

[0163] (2) Compound II-1 reacts with an electrophilic reagent or with a boron reagent and then is oxidized to form compound III-1.

[0164] (3) Compound III-1 first reacts with a cyano reagent to form compound III'-1, and then undergoes intramolecular ring closure to form compound IV-B.

[0165] (4) Compound IV-B is reduced to form compound V.

[0166] The reaction formula is as follows:

[0167] ,

[0168] Where R 3 It is methyl or allyl, R 2 It can be Br or F.

[0169] Compared with the prior art, the preparation method of compound V, the intermediate of gibbadacin, of the present invention has the following advantages:

[0170] 1) The starting materials used are readily available.

[0171] 2) The reaction route is short, the yield is high, the cost is low, and it is suitable for industrial production.

[0172] The invention will be further described below with reference to specific implementations. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0173] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared according to methods disclosed in the prior art.

[0174] Example 1: Preparation of compound II-Aa from compound IA

[0175]

[0176] 2,5-Dibromopyridine, compound IA (23.7 g, 0.10 mol), was added to a reaction flask, followed by 200 mL of THF to obtain a solution. The air in the flask was purged three times with nitrogen, and the solution was cooled to -78 °C. At this temperature, LDA (2.0 M in THF, 55 mL, 0.11 mol) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. Then, iodomethane (17.0 g, 0.12 mol) was added dropwise to the solution at this temperature. After the addition was complete, the reaction was kept at this temperature for 2 hours. TLC monitoring showed that compound IA had essentially completed the reaction, at which point the reaction was stopped. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give 22.5 g of a pale yellow oil, with a yield of 89.7%. The 1H NMR spectrum of the product, compound II-Aa, is shown in [reference needed]. Figure 1 The data is as follows:

[0177] 1 H NMR (400 MHz, CDCl3) d 8.37 (s, 1H), 7.35 (s, 1H), 2.35 (s, 3H).

[0178] The mass spectrometry data of the obtained product, compound II-Aa, are as follows: MS (ESI): m / z 251.9 [M+H] + .

[0179] Example 2: Preparation of compound III-A from compound II-Aa

[0180]

[0181] In a reaction flask, 25.1 g (0.10 mol) of 4-methyl-2,5-dibromopyridine prepared in Example 1 was dissolved in 200 mL of THF. After purging the air in the reaction flask three times with nitrogen, the solution was cooled to -78 °C. At this temperature, LDA (2.0 M in THF, 55 mL, 0.11 mol) was added dropwise to the solution. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. At this temperature (-78 °C), ethylene oxide solution (3.0 M in THF, 50 mL, 0.15 mol) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour, then allowed to rise naturally to room temperature and stirred overnight. The reaction was stopped after TLC monitoring showed that the reactants had essentially reacted completely. Water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 25.1 g of a pale yellow solid, with a yield of 85.1%. The resulting product, the 1H NMR spectrum of compound III-A (see...) Figure 2 The data is as follows:

[0182] 1 H NMR (400 MHz, CDCl3) d 8.39 (s, 1H), 7.37 (s, 1H), 3.71 (t, J = 6.1Hz, 2H), 2.80 (dd, J = 8.8, 6.9 Hz, 2H), 1.91-1.83 (m, 2H), 1.78 (br s, 1H).

[0183] The mass spectrometry data of the obtained product, compound III-A, are as follows: MS (ESI): m / z 296.0 [M+H] + .

[0184] Example 3: Preparation of compound II-Ab from compound IA

[0185]

[0186] 2,5-Dibromopyridine IA (23.7 g, 0.10 mol) was added to a reaction flask, followed by THF (200 mL) to obtain a solution. The air in the flask was purged three times with nitrogen, and the solution was cooled to -78°C. At this temperature, LDA (2.0 min THF, 55 mL, 0.11 mol) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. Allyl bromide (14.5 g, 0.12 mol) was then added dropwise at this temperature (-78°C). After the addition was complete, the mixture was kept at this temperature and stirred for 2 hours. The reaction was stopped after TLC monitoring showed that the reactants had essentially reacted completely. The reaction solution was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give 15.2 g of a pale yellow oil, with a yield of 54.9%. The 1H NMR data of the obtained product and compound II-Ab are shown in [reference needed]. Figure 3 )for: 1 H NMR (400 MHz, CDCl3) d 8.42(s, 1H), 7.35 (s, 1H), 6.16-5.67 (m, 1H), 5.34-5.02 (m, 2H), 3.44 (d, J = 6.4Hz, 2H).

[0187] The mass spectrometry data of the obtained product, compound II-Ab, are as follows: MS (ESI): m / z 278.0 [M+H] + .

[0188] Example 4: Preparation of compound III-A from compound II-Ab

[0189]

[0190] In a reaction flask, 27.7 g (0.10 mol) of 4-allyl-2,5-dibromopyridine, compound II-Ab, prepared in Example 3, was dissolved in 200 mL of THF to obtain a solution. After purging the air in the reaction flask three times with nitrogen, the solution was cooled to 0 °C, and 0.11 mol of 9-BBN (0.5 M in THF, 220 mL) was added dropwise at this temperature. After the addition was complete, the reaction solution was allowed to rise naturally to room temperature and stirred for 2 hours. TLC monitoring showed that compound II-B had reacted completely. The reaction solution was then cooled to 0 °C, and 33 mL of 3 M NaOH and 33 mL of 30% H₂O₂ were added sequentially. The system was allowed to rise naturally to room temperature and stirred for another hour at room temperature. TLC monitoring showed that the intermediate formed by the reaction of compound II-B and 9-BBN had reacted completely, and the reaction was stopped. The reaction solution was extracted with ethyl acetate. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give 22.4 g of a pale yellow solid, yield 76.0%. The obtained product is the compound III-A. 1 The H NMR spectrum and mass spectra are consistent with the product of Example 2.

[0191] Example 5: Preparation of compound IV-A from compound III-A

[0192]

[0193] The following compounds, prepared in Examples 2 or 4: 4-(3-hydroxypropyl)-2,5-dibromopyridine (10.0 g, 33.9 mmol), CuI (0.65 g, 3.4 mmol, 10 mol%), 1,10-phenanthroline (0.61 g, 3.4 mmol, 10 mol%), t-BuONa (65.2 g, 67.8 mmol), and dioxane (100 mL), were added to a reaction flask. The air in the flask was purged three times with nitrogen. The mixture was heated to 100°C and stirred for 16 hours. TLC monitoring showed that starting material III-A had essentially completed the reaction, at which point the reaction was stopped. The reaction solution was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated to dryness, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give 5.8 g of a pale yellow solid, yield 79.9%. The product and the 1H NMR spectrum of compound IV-A were obtained. Figure 4 The data is as follows: 1 H NMR (400 MHz, CDCl3) d 7.89 (s, 1H), 7.12 (s, 1H), 4.21-4.18 (m, 2H), 2.75 (t, J = 6.5 Hz, 2H), 2.01-1.98 (m, 2H).

[0194] The mass spectrometry data for compound IV-A are as follows: MS (ESI): m / z 214.1 [M+H] + .

[0195] Example 6: Preparation of compound V from compound IV-A

[0196]

[0197] In a reaction flask, 5.0 g (23.4 mmol) of 6-bromo-3,4-dihydro-2H-pyrano[2,3-c]pyridine, prepared in Example 5, was dissolved in 50 mL of THF to obtain a solution. The air in the reaction flask was purged three times with nitrogen, and the solution was cooled to -78 °C. At this temperature, n-butyllithium (2.5 M in hexane, 11.2 mL, 28.1 mmol) was added dropwise to the solution. After the addition was complete, the mixture was stirred for another 30 minutes. Then, DMF (4.3 g, 58.5 mmol) was added dropwise to the reaction solution at -78 °C. After the addition was complete, the reaction solution was allowed to rise naturally to room temperature and stirred for another 2 hours at room temperature. The reaction was stopped when the starting materials were found to be substantially complete by TLC. The reaction solution was quenched with water and then extracted with ethyl acetate. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 2.1 g of a white solid, with a yield of 55.1%. The product and the 1H NMR spectrum of compound V are shown below. Figure 5 The data is as follows: 1 H NMR (400 MHz, CDCl3) d 9.88 (s, 1H), 8.21 (s, 1H), 7.66(s, 1H), 4.27 (dd, J = 5.8, 4.5 Hz, 2H), 2.81 (t, J = 6.4 Hz, 2H), 2.17-1.88(m, 2H).

[0198] The mass spectrometry data for compound V are as follows (MS (ESI): m / z 164.2 [M+H) + .

[0199] Example 7: Preparation of compound II-Ba from compound IB

[0200]

[0201] Compound IB (30 g, 0.17 mol, 1.0 eq) was added to a reaction flask and dissolved in THF (250 mL). The air in the flask was then purged three times with nitrogen. The solution was cooled to -78°C, and LDA (2.0 M in THF, 95 mL, 1.1 eq) was added dropwise at this temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 1 h. CH3I (29 g, 0.20 mol, 1.2 eq) was added dropwise to the solution at -78°C. After the addition was complete, the reaction was kept at this temperature for 1–3 h. HPLC monitoring showed that compound IB had essentially completed the reaction. Stirring was stopped, and the reaction was quenched with saturated ammonium chloride solution and then extracted. The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography to give a pale yellow oil, II-Ba (27 g, yield 84%). The product and the 1H NMR spectrum of compound II-Ba are shown. Figure 6 The data is as follows: 1 H NMR (200 MHz, CDCl3) δ 8.18 (s, 1H), 7.38 (d, J = 5.8 Hz, 1H), 2.35 (s, 3H).

[0202] The mass spectrometry data for compound II-Ba are as follows: MS (ESI): m / z 190.1 [M+H] + .

[0203] Example 8: Preparation of compound III-B from compound II-Ba

[0204]

[0205] Compound II-Ba (27 g, 0.14 mol, 1.0 eq) was added to a reaction flask and dissolved in THF (220 mL). The air in the flask was then purged three times with nitrogen, and the solution was cooled to -78 °C. At this temperature, LDA (2.0 M in THF, 95 mL, 1.1 eq) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 h. Then, ethylene oxide solution (3.0 M in THF, 67 mL, 0.2 mol) was added dropwise. After the addition was complete, the reaction was kept at this temperature for 1–3 h. After HPLC monitoring showed that the reactants had essentially reacted completely, stirring was stopped, and water was added to quench the reaction. The organic phase was extracted with ethyl acetate, dried, and concentrated to dryness. The residue was purified by column chromatography to give a pale yellow oil (23.5 g, yield 71.8%). The product and the 1H NMR spectrum of compound III-B are shown below. Figure 7 The data is as follows: 1H NMR (200 MHz, CDCl3) δ 8.16 (s, 1H),7.36 (d, J = 5.5 Hz, 1H), 3.70 (q, J = 5.8 Hz, 2H), 2.77 (t, J = 9.5 Hz, 2H),2.05 – 1.79 (m, 2H), 1.48 (br s, 1H).

[0206] The mass spectrometry data for compound III-A are as follows: MS (ESI): m / z 234.1 [M+H] + .

[0207] Example 9: Preparation of compound IV-A from compound III-B

[0208]

[0209] Compound III-B (10.0 g, 42.7 mmol, 1.0 eq) was added to a reaction flask and dissolved in THF (300 mL). The mixture was purged three times with nitrogen and cooled to -10°C. Under nitrogen protection, potassium tert-butoxide (5.27 g, 47.0 mmol, 1.1 eq) was added, and the mixture was stirred at this temperature for 1 hour. The mixture was then allowed to warm to room temperature and reacted for 12–24 hours. HPLC monitoring showed that the reactants were essentially complete, at which point the reaction was stopped. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to dryness. The residue was purified by column chromatography to give a white solid (6.4 g, 70% yield). The product and the 1H NMR spectrum of compound IV-A are shown below. Figure 8 The data is as follows: 1 H NMR (200 MHz, CDCl3) δ 8.05 (s, 1H), 7.27 (s, 1H), 4.41 – 4.29 (m, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.29 – 2.00 (m, 2H).

[0210] The mass spectrometry data for compound IV-A are as follows: MS (ESI): m / z 214.1 [M+H] + .

[0211] Example 10: Preparation of compound III'-A from compound III-A

[0212]

[0213] In a reaction flask, compound III-A (10.0 g, 33.9 mmol) was dissolved in DMF (150 mL), and cuprous cyanide (3.3 g, 37.3 mmol, 1.1 eq) was added under nitrogen protection. The mixture was heated to 130 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, it was cooled to room temperature, and ammonia (50 mL, 28% aqueous solution) and ethyl acetate (100 mL) were added to the system. The mixture was stirred for 30 minutes. The insoluble matter was removed by filtration, and the filter cake was washed with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 5.72 g of a yellow solid, with a yield of 70%. The product and the 1H NMR spectrum of compound III'-A were obtained. Figure 9 The data is as follows: 1 H NMR (200 MHz, CDCl3) δ 8.71 (s,1H), 7.60 (s, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.89 (dd, J = 9.2, 6.3 Hz, 2H), 2.13 – 1.79 (m, 3H).

[0214] The mass spectrometry data for compound III'-A are as follows: MS (ESI): m / z 240.9 [M+H] + .

[0215] Example 11: Preparation of compound IV-B from compound III'-A

[0216]

[0217] Compound III'-A (8.2 g, 34.0 mmol), CuI (0.65 g, 3.4 mmol, 10 mol%), 1,10-phenanthroline (0.61 g, 3.4 mmol, 10 mol%), t-BuONa (65.3 g, 68.0 mmol), and dioxane (100 mL) prepared in Example 10 were added to a reaction flask. The air in the reaction flask was purged three times with nitrogen. The mixture was heated to 100 °C and stirred for 16 hours. TLC monitoring showed that starting material III'-A had essentially reacted completely, and the reaction was stopped. The reaction solution was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated to dryness, and the residue was purified by column chromatography to give 3.98 g of a pale yellow solid, with a yield of 73%. The product and the 1H NMR spectrum of compound IV-B were obtained. Figure 10 The data is as follows: 1H NMR (400 MHz, CDCl3) δ 8.18 (s,1H), 7.38 (s, 1H), 4.31 (t, J = 6.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.20 –1.91 (m, 2H).

[0218] The mass spectrometry data for compound IV-B are as follows: MS (ESI): m / z 161.1 [M+H] + .

[0219] Example 12: Preparation of compound V from compound IV-B

[0220]

[0221] In a reaction flask, 4.0 g (25.0 mmol) of 6-cyano-3,4-dihydro-2H-pyrano[2,3-c]pyridine, prepared in Example 10, was dissolved in 40 mL of dichloromethane to obtain a solution. The air in the reaction flask was replaced three times with nitrogen. The solution was cooled to -78°C, and at this temperature, diisobutylaluminum hydride (1.0 M in toluene, 30.0 mL, 30.0 mmol) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. TLC monitoring showed that the starting compound IV-B had essentially completed the reaction, and the reaction was stopped. At this temperature, methanol was slowly added to the reaction solution to quench the reaction. The quenched reaction solution was allowed to rise naturally to room temperature, and dilute hydrochloric acid was added, followed by extraction with ethyl acetate. After drying the organic phase, it was concentrated to dryness, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 2.4 g of a white solid, with a yield of 58.8%. The obtained product, compound V... 1 HNMR spectra (see) Figure 11 The product is consistent with that of Example 6.

[0222] Example 13: Preparation of compound IV-B from compound III-B

[0223]

[0224] In a reaction flask, compound III-B (10.0 g, 42.7 mmol) was dissolved in DMF (150 mL), and cuprous cyanide (3.3 g, 47.0 mmol, 1.1 eq) was added under nitrogen protection. The mixture was heated to 130 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and ammonia (50 mL, 28% aqueous solution) and ethyl acetate (100 mL) were added to the system. The mixture was stirred for 30 minutes. The insoluble matter was removed by filtration, and the filter cake was washed with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 6.54 g of a yellow solid, with a yield of 85%. The product and the 1H NMR spectrum of compound III'-B were obtained. Figure 12 The data is as follows: 1 H NMR (200 MHz, CDCl3) δ 8.46(s, 1H), 7.64 (d, J = 5.7 Hz, 1H), 3.71 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 7.8Hz, 2H), 2.07 – 1.81 (m, 2H), 1.55 (br s, 1H).

[0225] The mass spectrometry data for compound III'-B are as follows: MS (ESI): m / z 181.1 [M+H] + .

[0226] Compound III'-B (10.0 g, 55.5 mmol, 1.0 eq) was added to a reaction flask, dissolved in THF (300 mL), and purged three times with nitrogen. The solution was then cooled to -10°C. Under nitrogen protection, potassium tert-butoxide (6.85 g, 61.1 mmol, 1.1 eq) was added, and the mixture was stirred at this temperature for 1 hour. The mixture was then allowed to warm naturally to room temperature for 12–24 hours. HPLC monitoring showed that the reactants were essentially complete, at which point the reaction was stopped. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to dryness. The residue was purified by column chromatography to give a white solid (6.93 g, 78% yield). The obtained product is the derivative of compound IV-B. 1 The H NMR spectrum and mass spectra are consistent with the product of Example 11.

[0227] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made using the content of the present invention specification and claims, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. Compound V The preparation method of the [method] is characterized by, The preparation method includes the step of reacting compound I with a methyl reagent or an allyl reagent to generate compound II, as shown in the following reaction formula: ， Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, or I; R 3 It is methyl or allyl. Better yet, R 1 For Br, R 2 It can be Br or F.

2. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: (i) The reaction of compound I with a methyl or allyl reagent is carried out in the presence of a strong base selected from lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino), sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or combinations thereof, preferably lithium diisopropylamino. (ii) The methyl reagent is selected from iodomethane, bromomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, dimethyl carbonate, or combinations thereof, preferably iodomethane. (iii) The allyl reagent is selected from allyl bromide, allyl iodide, allyl chloride, allyl methanesulfonate, allyl p-toluenesulfonate, or combinations thereof, preferably allyl bromide.

3. The preparation method according to claim 1, characterized in that, The preparation method further includes the step of converting compound II into compound III, as shown in the following reaction formula: 。 4. The preparation method according to claim 3, characterized in that, The preparation method satisfies one or more of the following conditions: (i)R 3 The methyl group is present. Compound II reacts with an electrophilic reagent in the presence of a strong base to form compound III. The strong base is selected from lithium diisopropylamino (LDA), lithium bis(trimethylsilylamino)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), or combinations thereof, more preferably lithium diisopropylamino, and The electrophilic reagent is selected from ethylene oxide, ethylene carbonate, ethylene sulfate, or a combination thereof, preferably ethylene oxide; (ii)R 3 Compound II is allyl. It first reacts with a boron reagent, and then is oxidized under alkaline conditions using an oxidizing agent to produce compound III. The boron reagent is selected from borane-tetrahydrofuran complexes, borane-dimethyl sulfide complexes, 9-boronbicyclo[3.3.1]nonane, diisocyanate-camphorane, catecholborane, or pinacolborane, or combinations thereof, more preferably, borane-tetrahydrofuran complexes or 9-boronbicyclo[3.3.1]nonane, and most preferably, 9-boronbicyclo[3.3.1]nonane. The oxidant is selected from hydrogen peroxide, tert-butanol peroxide, m-chloroperoxybenzoic acid, peracetic acid, potassium persulfate, sodium chlorite, sodium periodate, oxygen, or combinations thereof, preferably hydrogen peroxide, and... The alkaline condition provided is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, or combinations thereof, preferably sodium hydroxide.

5. The preparation method according to claim 3, characterized in that, The preparation method further includes the step of: intramolecular cyclization of compound III to generate compound IV-A, as shown in the following reaction formula: 。 6. The preparation method according to claim 5, characterized in that, The preparation method further includes the step of: compound IV-A undergoing an aldehyde reaction to generate compound V, as shown in the following reaction formula. 。 7. The preparation method according to claim 6, characterized in that, Compound IV-A reacts first with an alkyllithium reagent or a Grignard reagent, and then with a carbonyl reagent to form compound V. Preferably, the alkyllithium reagent is selected from n-butyllithium, sec-butyllithium, or tert-butyllithium; more preferably, n-butyllithium... Preferably, the Grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, allyl magnesium chloride, allyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, or combinations thereof; more preferably, isopropyl magnesium chloride, and... Preferably, the carbonyl reagent is selected from N,N-dimethylformamide, N-formylmorpholine, ethyl formate, methyl formate, trimethyl orthoformate, or combinations thereof, and more preferably, N,N-dimethylformamide.

8. The preparation method according to claim 3, characterized in that, The preparation method further includes the step of reacting compound III with a cyano reagent to generate compound III', as shown in the following reaction formula: ， Preferably, the cyano reagent is selected from cuprous cyanide, potassium cyanide, sodium cyanide, zinc cyanide, trimethylsilane, acetone cyanohydrin, potassium ferrocyanide, or combinations thereof, and more preferably, cuprous cyanide.

9. The preparation method according to claim 8, characterized in that, The preparation method further includes the step of: intramolecular cyclization of compound III' to generate compound IV-B, as shown in the following reaction formula. 。 10. The preparation method according to claim 5 or 9, characterized in that, The intramolecular cyclization was carried out in the presence of a copper catalyst, ligands, and a base. Preferably, the copper catalyst is selected from CuI, CuBr, CuCl, Cu2O, CuOTf, Cu(OTf)2, Cu(OAc)2, or combinations thereof, more preferably CuI. Preferably, the ligand is selected from oxalyl diamine and its derivatives, 1,10-phenanthroline and its derivatives, bipyridine and its derivatives, N,N'-dimethylethylenediamine and its derivatives, or combinations thereof; more preferably, oxalyl diamine or 1,10-phenanthroline, and Preferably, the alkali is selected from K2CO3, Cs2CO3, Na2CO3, K3PO4, Na3PO4, t-BuOK, t-BuONa, or combinations thereof, more preferably t-BuONa.

11. The preparation method according to claim 5 or 9, characterized in that, In equations III and III', R 2 For F, the intramolecular cyclization of compound III occurs in the presence of a base. Preferably, the alkali is selected from Na2CO3, K2CO3, CsCO3, K3PO4, Na3PO4, NaOH, KOH, CH3ONa, CH3OK, CH3CH2ONa, CH3CH2OK, t-BuONa, t-BuOK, NaH, DBU, TEA, DIPA, or combinations thereof, more preferably t-BuOK.

12. The preparation method according to claim 9, characterized in that, The preparation method further includes the following step: compound IV-B is reduced to generate compound V, as shown in the following reaction formula: ， Preferably, the reducing agent used for reduction is selected from diisobutylaluminum hydride, triethylsilane / palladium on carbon, Raney nickel / ammonium formate, red aluminum, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium tris(tert-butoxy)aluminum hydride, a mixture of lithium aluminum hydride with morpholine or N-methylpiperazine, or combinations thereof, and more preferably, diisobutylaluminum hydride.

13. A method for preparing compound V, characterized in that, The preparation method includes the following steps: i) Compound III undergoes intramolecular cyclization to generate compound IV-A, and ii) Compound IV-A undergoes aldehyde alkylation to generate compound V. The reaction formula is as follows: , Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, and I. Better yet, R 1 For Br, R 2 It can be Br or F.

14. A method for preparing compound V, characterized in that, The preparation method includes the following steps: i) Compound III reacts with a cyano reagent to form compound III'. ii) Compound III' undergoes intramolecular cyclization to generate compound IV-B, and iii) Compound IV-B is reduced to form compound V. The reaction formula is as follows: , Where R 1 R 2 Each is an independent halogen, selected from F, Cl, Br, and I. Better yet, R 1 For Br, R 2 It can be Br or F.

15. The method according to claim 13 or 14, characterized in that, The preparation method of compound III includes the following steps: Compound II is converted into compound III, according to the following reaction: ， R 3 It is methyl or allyl.

16. A compound having the structural formula shown in Formula III or Formula III': 、 ， In Equation III, R 1 R 2 Each is independently selected from halogens, said halogens being selected from F, Cl, Br or I, more preferably, R 1 For Br, R 2 For Br or F, In formula III', R 2 The halogen is selected from halogens, wherein the halogen is selected from F, Cl, Br or I, and more preferably, R 2 It can be Br or F.

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