Method for synthesizing aryl-substituted chiral tetrahydropyran ring by means of de-symmetrization

Abstract

The present invention provides a method for synthesizing an aryl-substituted chiral tetrahydropyrane ring by means of de-symmetrization. The method comprises subjecting a cyclic anhydride represented by formula I or a symmetric dicarboxylate represented by formula II to catalytic alcoholysis so as to obtain an intermediate having a high ee value and a target spatial configuration represented by formula III, reacting same with a methyl metal reagent to obtain a lactone represented by formula IV, reducing same to obtain an ether represented by formula V, subjecting the substance represented by formula V-A to copper catalysis to obtain a corresponding aryl hydrazine represented by formula VI, and performing indole ring closure on same and a pyruvic acid derivative under acid catalysis to obtain a target product; or subjecting a compound represented by formula V-B to functional group conversion to form an intermediate represented by formula VIII, and then reacting same with an acrylic acid derivative to produce a target compound. The present invention avoids the use of a transition metal catalyst and SFC splitting in reported methods, thereby reducing the reaction cost and facilitating scaled-up production. The present method is a technical route that is economical, environmentally friendly, simple in post-treatment, and suitable for scaled-up production.

Description

A method for synthesizing aryl-substituted chiral tetrahydropyran rings via desymmetry Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and relates to a method for synthesizing chiral tetrahydropyran rings, particularly a method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry. Background Technology

[0002] Applications of aryl-substituted chiral tetrahydropyran rings: This structure and its derivatives, such as lactones and hemiacetals, can be further derived to obtain more complex molecules. Among them, highly chiral pure structures can serve as key synthons in pharmaceutical molecule synthesis. For example, oxaliplatin and ECC5004, as small-molecule GLP-1 receptor agonists, exert effective antidiabetic effects by enhancing glucose-dependent insulin secretion and improving energy balance, and possess pharmacokinetic characteristics favorable for oral administration, demonstrating significant advantages and a potential pharmaceutical market.

[0003] As the core module of oxaliplatin and ECC5004 (see Figure 1), and also one of the difficulties in their synthesis, the synthetic improvement of the aryl-substituted chiral tetrahydropyran ring segments in their structure, namely (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid and (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-indazine-2-carboxylic acid and their derivatives, is particularly important.

[0004] Currently, the construction of chiral centers in aryl-substituted chiral tetrahydropyran ring fragments mainly relies on transition metal palladium catalysis to build carbon-carbon bonds between the aryl group and the tetrahydropyran ring, followed by chromatographic separation or transition metal asymmetric hydrogenation to obtain enantiomers with high chiral purity. Some methods also utilize enzyme catalysis or transition metal catalysis to obtain aryl-substituted chiral tetrahydropyran ring precursor structures from specific substrates.

[0005] Currently, there are few publicly disclosed patents regarding the synthesis of aryl-substituted chiral tetrahydropyran ring fragments, with only a few original research patents involving this topic. For example, patent (WO2018056453A1) uses bromoindole as a substrate and a readily available organozinc reagent with a tetrahydropyran structure to construct carbon-carbon bonds via a palladium-catalyzed Negishi reaction, obtaining a racemic form of the target structure. This racemic form is then resolved using SFC (Super Critical Fluid Chromatography) to obtain the desired configuration. Other examples include patents WO / 2022 / 017338 and US11584751B1, which involve a Pd-catalyzed Suzuki reaction between bromoindole and a borate ester of a dihydropyran ring, followed by Pd / C reduction of the double bonds in the dihydropyran ring to obtain a racemic form of the target structure. Finally, SFC chiral resolution yields the target structure with the desired stereoconfiguration. The fragment in the ECC5004 molecule was also synthesized using this method. The recently published patent (CN117777111A) uses bromoindole raw material and α,β-unsaturated lactone to construct carbon-carbon bonds via palladium-catalyzed Heck coupling, constructs the key chiral center via ruthenium-catalyzed asymmetric hydrogenation, and then constructs the target molecular structure through two steps.

[0006] However, in existing methods, the use of transition metals not only increases the cost of synthesis, but also leads to metal residue problems in subsequent drug synthesis. Furthermore, the equipment required for SFC resolution is expensive and unsuitable for industrial production, and unwanted configurations are discarded, which greatly increases the cost of synthesizing the target structure. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a method for synthesizing aryl-substituted chiral tetrahydropyran rings via desymmetry. This invention synthesizes cyclic anhydrides as shown in Formula I or symmetrical dicarboxylic acid esters as shown in Formula II using methods commonly found in the literature. The resulting intermediates, with a high ee value and a target stereoconfiguration as shown in Formula III, are obtained via alcoholysis catalyzed by ethylenediamine-based small organic molecules (or, under organic small molecule or enzyme catalysis, the symmetrical dicarboxylic acid ester shown in Formula II is hydrolyzed to obtain an intermediate with a high ee value and a target stereoconfiguration as shown in Formula III). These intermediates are then reacted with a methyl metal reagent to obtain a dimethylated lactone as shown in Formula IV, which is subsequently reduced to obtain an ether as shown in Formula V.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] This invention provides a method for synthesizing aryl-substituted chiral tetrahydropyran rings via desymmetry, the method comprising the following steps:

[0010] a) The compound shown in Formula I is given by alcoholysis with high chiral purity by organic small molecule catalysis or enzyme catalysis;

[0011] b) The compound shown in Formula III reacts with a methyl metal reagent to give the compound shown in Formula IV;

[0012] c) The compound shown in formula IV is reduced with lactone to obtain the compound shown in formula V;

[0013] d) The compound represented by formula VA is subjected to a copper-catalyzed hydrazination reaction to give the compound represented by formula VI;

[0014] e) The compound shown in Formula VI undergoes acid-catalyzed Fisher cyclization with a pyruvate derivative to yield the compound shown in Formula VII.

[0015] Alternatively, step d) can be replaced with step f):

[0016] f) The compound shown in formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to give the compound shown in formula VIII;

[0017] g) The compound shown in Formula VIII is cyclized with an acrylic acid derivative to obtain the compound shown in Formula IX;

[0018] Among them, the compound represented by formula I: The compound represented by Formula III:

[0019] The compound represented by Formula IV: The compound shown in formula V:

[0020] Compounds represented by formula VA: The compound shown in Formula VI:

[0021] The compound represented by formula VII: The compound represented by formula VB:

[0022] The compound represented by formula VIII: The compound represented by Formula IX:

[0023] In the formula, X is Halogen (Cl, Br, I), -OTf, -OMs, or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group; R 2 For H, Me, Et, iPr, or Bn; R 3 H or Boc; Z is -OR 4 ;R 4 C1-C6 alkyl or -NR 5 R6 ;R 5 It is a C1-C3 alkyl group; R 6 It is a phenyl or a substituted phenyl group.

[0024] As a preferred embodiment of the present invention, step a) is replaced by step a1): the compound shown in formula II is subjected to single hydrolysis by organic small molecule catalysis or enzyme catalysis to obtain the compound shown in formula III with high chiral purity.

[0025] The compound represented by Formula II:

[0026] In the formula, X is Halogen (Cl, Br, I), -OTf, -OMs, or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group.

[0027] As a preferred embodiment of the present invention, in step a) or step a1), the substrate for the alcoholysis reaction includes one of methanol, ethanol, benzyl alcohol or other alkyl alcohols, and the amount of substrate used for the alcoholysis reaction is 1.0-10.0 equivalents.

[0028] As a preferred embodiment of the present invention, in step b), the methyl metal reagent includes one of methyllithium, methylmagnesium bromide, methylmagnesium chloride, and methylmagnesium iodide; the amount of the methyl metal reagent used is 3.0-5.0 equivalents.

[0029] In a preferred embodiment of the present invention, in step c), the reducing agent used to reduce the lactone includes DIBAL-H and Et3SiH.

[0030] In a preferred embodiment of the present invention, in step d), the copper catalyst includes CuI or CuBr, and the amount of copper catalyst used is 0.01-1.0 equivalents.

[0031] As a preferred embodiment of the present invention, in step d), the ligands used in the reaction include N-(2,6-dimethylphenyl)-6-hydroxypyridine amide or N1,N2-bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide; the substrates for the hydrazideation reaction include hydrazine hydrate, 1-tert-butoxycarbonyl-1-methylhydrazine, 1-tert-butoxycarbonyl-1-ethylhydrazine or 1-tert-butoxycarbonyl-1-benzylhydrazine.

[0032] As a preferred embodiment of the present invention, in step e), the acid used for acid catalysis includes HCl, PPA, TsOH or TfOH; the acetone derivative includes ethyl pyruvate, methyl pyruvate or N-methyl-2-oxo-N-phenylpropionamide.

[0033] As a preferred embodiment of the present invention, in step f), the metal reagent includes n-butyllithium, sec-butyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide.

[0034] As a preferred embodiment of the present invention, in step g), the acrylic derivative includes ethyl acrylate, methyl acrylate, benzyl acrylate or N-methyl-N-phenylacrylamide.

[0035] This invention uses cyclic anhydrides as shown in Formula I or symmetrical dicarboxylic acid esters as shown in Formula II, synthesized by methods commonly used in the literature, to undergo alcoholysis catalyzed by ethylenediamine-based small organic molecules to obtain an intermediate with a high ee value and a target stereoconfiguration as shown in Formula III (or a symmetrical dicarboxylic acid ester can be hydrolyzed under organic small molecule or enzyme catalysis to obtain an intermediate with a high ee value and a target stereoconfiguration as shown in Formula III). The intermediate is then reacted with a methyl metal reagent to obtain a dimethylated lactone as shown in Formula IV, which is then reduced to obtain an ether as shown in Formula V.

[0036] Furthermore, the compound shown in Formula VA was catalyzed by copper to give the corresponding arylhydrazine shown in Formula VI, and finally reacted with a pyruvate derivative via Fisher ring closure under acid catalysis to give the target product shown in Formula VII.

[0037] Alternatively, the compound shown in Formula VB is functionalized into an aldehyde shown in Formula VIII, which is then cyclized by a Balis-Hillman reaction with an acrylic acid derivative to generate a compound shown in Formula IX.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1) The starting materials of this invention have simple structures and are readily available for commercial production. This invention uses inexpensive and readily available chiral ethylenediamine organic small molecules or commercial enzyme catalysis to construct a chiral center at the 4-position of the tetrahydropyran ring through a desymmetry method.

[0040] 2) In this invention, substrate I or II is desymmetrized by chiral ethylenediamine organic small molecule catalysis or commercial enzyme catalysis (including but not limited to) to obtain the desired key chiral center and synthesize the intermediate as shown in Formula III. This step is the key step to realize this process route.

[0041] 3) This invention avoids the use of transition metal catalysts and SFC resolution in reported methods, reduces reaction costs, and is conducive to scale-up production. It is an economical, environmentally friendly, simple post-processing, and easy-to-scale production technical route. Attached Figure Description

[0042] Figure 1 is a schematic diagram of Oglione and ECC5004.

[0043] Figure 2 is a synthetic route diagram of the present invention.

[0044] Figure 3 shows the NMR spectrum of the compound shown in VII.

[0045] Figure 4 is a chirality diagram of the racemic form of the compound shown in VII.

[0046] Figure 5 is a chirality diagram of the single chiral target compound shown in VII. Detailed Implementation

[0047] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0048] In this invention, all raw materials, reagents, or equipment used can be purchased from the market, as shown in Table 1.

[0049] Table 1. Raw Materials

[0050] In Table 1, the materials numbered 28-33 are the raw materials for chiral catalysts. The starting materials and some catalysts are from the exploration platform, Anaiji Chemical and Network Technology platform. Some catalysts are synthesized in-house. Reference: Highly enantioselective desymmetrizations of meso-anhydrides. Carsten Bolm. [J] Tetrahedron 2010, 66 6349. DOI:10.1016 / j.tet.2010.04.121 Enantioselective Alcoholysis of meso-Glutaric Anhydrides Catalyzed by Cinchona-Based Sulfonamide Catalysts. Choong Eui Song. [J] Adv.Synth.Catal.2010, 352, 2211. DOI:10.1002 / adsc.201000289.

[0051] This invention provides a method for synthesizing aryl-substituted chiral tetrahydropyran rings via desymmetry, the method comprising the following steps:

[0052] a) The compound shown in Formula I is given by alcoholysis with high chiral purity by organic small molecule catalysis or enzyme catalysis;

[0053] b) The compound shown in Formula III reacts with a methyl metal reagent to give the compound shown in Formula IV;

[0054] c) The compound shown in formula IV is reduced with lactone to obtain the compound shown in formula V;

[0055] d) The compound represented by formula VA is subjected to a copper-catalyzed hydrazination reaction to give the compound represented by formula VI;

[0056] e) The compound shown in Formula VI undergoes acid-catalyzed Fisher cyclization with a pyruvate derivative to yield the compound shown in Formula VII.

[0057] Alternatively, step d) can be replaced with step f).

[0058] f) The compound shown in formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to give the compound shown in formula VIII;

[0059] g) The compound shown in Formula VIII is cyclized with an acrylic acid derivative to obtain the compound shown in Formula IX;

[0060] Among them, the compound represented by formula I: The compound represented by Formula III:

[0061] The compound represented by Formula IV: The compound shown in formula V:

[0062] Compounds represented by formula VA: The compound shown in Formula VI:

[0063] The compound represented by formula VII: The compound represented by formula VB:

[0064] The compound represented by formula VIII: The compound represented by Formula IX:

[0065] In the formula, X is Halogen (Cl, Br, I), -OTf, -OMs, or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group; R 2 For H, Me, Et, iPr, or Bn; R 3 H or Boc; Z is -OR 4 ;R 4 C1-C6 alkyl or -NR 5 R 6 ;R 5 It is a C1-C3 alkyl group; R 6It is a phenyl or a substituted phenyl group.

[0066] Referring to Figure 2, the specific steps of the method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry in this invention are as follows:

[0067] 1. The compound shown in Formula I was synthesized according to the literature “Pilot-Plant Preparation of 3,4-Dihydropyridin-2-one Derivatives, the Core Structures of P2X7 Receptor Antagonists” (By: Shu-Hai Zhao; et al, Organic Process Research & Development 2010, 14, 612–616).

[0068] 2. Dissolve the compound shown in Formula I in a solvent, add methanol and a catalyst, and react at 0-50°C until the reaction is complete. After post-treatment, obtain the intermediate shown in Formula III.

[0069] Alternatively, the compound shown in Formula II can be dissolved in a solvent, an enzyme catalyst can be added, and the reaction can be carried out in a buffer salt system until the reaction is complete. After post-treatment, the intermediate shown in Formula III can be obtained.

[0070] The compound represented by Formula II:

[0071] In the formula, X is Halogen (Cl, Br, I), -OTf, -OMs, or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group.

[0072] In one embodiment of the present invention, the substrate for the alcoholysis reaction includes one of methanol, ethanol, benzyl alcohol or other alkyl alcohols, and the amount of substrate used for the alcoholysis reaction is 1.0-10.0 equivalents.

[0073] The catalyst used in this step is selected from commercially available enzymes, such as Novozym 435 and CAL-B, and small molecules including but not limited to those with the following structural features:

[0074] Preferably, the catalyst used in this step is selected from commercially available enzymes, such as Novozym 435, aminolipase AYS, lipase PPL, etc.

[0075] 3. Dissolve the intermediate shown in Formula III in the solvent tetrahydrofuran, add a methyl metal reagent dropwise at low temperature, and after the reaction is complete, obtain the compound shown in Formula IV through post-treatment.

[0076] In Figure 2, Me-M represents MeLi and MeMgX (where X represents Cl, Br, or I).

[0077] In one embodiment of the present invention, the methyl metal reagent includes one of lithium methyl, magnesium methyl bromide, magnesium methyl chloride, and magnesium methyl iodide; the amount of the methyl metal reagent used is 3.0-5.0 equivalents.

[0078] 4. Dissolve the substance shown in Formula IV in a solvent, add a reducing agent, and then perform post-treatment to obtain the compound shown in Formula V.

[0079] In one embodiment of the present invention, the reducing agent used to reduce the lactone includes DIBAL-H and Et3SiH.

[0080] 5. Dissolve the substance shown in Formula VA in a solvent, add the substrate hydrazine, copper catalyst and ligand, and react at 40-100℃ under a nitrogen protective atmosphere until the reaction is complete. After post-treatment, obtain the compound shown in Formula VI.

[0081] In one embodiment of the present invention, the copper catalyst comprises CuI or CuBr, and the amount of copper catalyst used is 0.01-1.0 equivalents; the ligand used in the reaction comprises N-(2,6-dimethylphenyl)-6-hydroxypyridine amide or N1,N2-bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide; the substrate of the hydrazideation reaction comprises hydrazine hydrate, 1-tert-butoxycarbonyl-1-methylhydrazine, 1-tert-butoxycarbonyl-1-ethylhydrazine or 1-tert-butoxycarbonyl-1-benzylhydrazine.

[0082] 6. Dissolve the substance shown in Formula VI in a solvent, add a pyruvate derivative, add an acid catalyst, and react at 40-100℃ until the reaction is complete. After post-treatment, obtain the compound shown in Formula VII.

[0083] In one embodiment of the invention, the acid used for acid catalysis includes HCl, PPA, TsOH or TfOH; the acetone derivative includes ethyl pyruvate, methyl pyruvate or N-methyl-2-oxo-N-phenylpropionamide.

[0084] 7. Dissolve the substance shown in Formula VB in a solvent, add a metal reagent dropwise at low temperature to lithiate it, then react it with DMF, and after post-treatment, obtain the compound shown in Formula VIII.

[0085] In one embodiment of the present invention, the metal reagent includes n-butyllithium, sec-butyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide.

[0086] 8. Dissolve the substance shown in Formula VIII in a solvent, add an acrylic acid derivative, catalytically cyclize the compound, and then post-process it to obtain the compound shown in Formula IX.

[0087] In one embodiment of the present invention, the acrylic acid derivative includes ethyl acrylate, methyl acrylate, benzyl acrylate, or N-methyl-N-phenylacrylamide.

[0088] The following specific examples provide the synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate ethyl ester (VII) and (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indazine-2-carboxylate ethyl ester (IX).

[0089] Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0090] Example 1

[0091] Synthesis from starting materials:

[0092] Synthesis of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA):

[0093] Under nitrogen protection, 285 g of p-bromobenzaldehyde, 1500 mL of ethanol, and 400 g of ethyl acetoacetate were added sequentially to a 5 L four-necked flask at room temperature. Nitrogen was then introduced, followed by the addition of 20 g of piperidine, and the reaction was continued at room temperature for 1 day. The reaction was confirmed by LCMS. The mixture was directly filtered, and the filter cake was washed with 550 mL of ethanol, dried under vacuum, and air-dried to obtain 460 g of diethyl 2,4-diacetyl-3-(4-bromophenyl)glutarate, an off-white solid with a yield of 70.0% and a purity of 93.9%. At room temperature, 460 g of diethyl 2,4-diacetyl-3-(4-bromophenyl)glutarate and 1400 mL of ethanol were added sequentially to a 5 L four-necked flask. 259.2 g of sodium hydroxide was dissolved in 1400 mL of water and added to the reaction mixture. The temperature was raised to 80 °C, and the system gradually dissolved and clarified. The reaction was continued at 80 °C for 2 hours. The reaction was confirmed to be complete by LCMS. After cooling to room temperature, most of the ethanol was removed by desolvation under reduced pressure in a 40°C water bath. Then, 5000 mL of water was added for dilution, and the mixture was cooled with ice. 594 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3, resulting in the precipitation of a large amount of light yellow solid. The solid was filtered, and the filter cake was washed with 1000 mL of water, dried under vacuum, and then dried. The sample was then dried at 45°C for 4 hours to obtain 278 g of 3-(4-bromophenyl)glutaric acid, a light yellow solid, with a yield of 90.6% and a purity of 98.2%.

[0094] Under nitrogen protection, 1600 mL of acetyl chloride was added to a 5 L four-necked flask at room temperature, followed by the partial addition of 275 g of 3-(4-bromophenyl)glutaric acid. The temperature was then raised to 80 °C, and the starting material gradually dissolved at an internal temperature of 58 °C. The reaction was continued at 80 °C for 2 hours. The reaction was confirmed to be complete by methanol-derived LCMS. The mixture was cooled to room temperature and then dissolved under reduced pressure in a 40 °C water bath. 1000 mL of n-heptane was added, the mixture was stirred, filtered, washed with 500 mL of n-heptane, and dried. The solid was then dissolved under reduced pressure in a 40 °C water bath to obtain 212 g of off-white solid, with a yield of 81.4% and a purity of 97.4%.

[0095] The structural formula of the substance represented by formula IA:

[0096] Synthesis of dimethyl 3-(4-bromophenyl)glutarate (II-A):

[0097] In a 250 mL three-necked flask under nitrogen protection, 10 g of 3-(4-bromophenyl)glutaric acid, 100 mL of methanol, and 300 mg of concentrated sulfuric acid were added sequentially, and the mixture was refluxed overnight at 70 °C. After the reaction was complete, the mixture was cooled to room temperature and dissolved under reduced pressure in a 40 °C water bath. The crude residue was diluted with 200 mL of ethyl acetate and washed with 50 mL of semi-saturated sodium bicarbonate aqueous solution and saturated brine, respectively. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was dissolved under reduced pressure in a 40 °C water bath to give 9 g of dimethyl 3-(4-bromophenyl)glutaric acid, a light brown solid, with a yield of 82% and a purity of 96.5%.

[0098] The structural formula of the substance shown in Formula II-A: In the formula R 1 For Me.

[0099] Example 2

[0100] The structural formula of the substance shown in Formula III-A: In the formula R 1 For Me.

[0101] Step 1: See Figure 2, Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0102] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)thiourea were added sequentially to a 500 mL three-necked flask at room temperature and reacted for 1 day at room temperature. The reaction was confirmed by LCMS. After washing with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dissolved under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.7 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 76.8%, purity of 99.5%, and ee value of 92.3%.

[0103] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0104] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)thiourea were added sequentially to a 500 mL three-necked flask at room temperature and reacted for 1 day at room temperature. The reaction was confirmed by LCMS. After washing with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dissolved under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.4 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 63.3%, purity of 99.1%, and ee value of 97.7%.

[0105] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0106] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)thiourea were added sequentially to a 500 mL three-necked flask at room temperature and reacted for 1 day at room temperature. The reaction was confirmed by LCMS. After washing with 0.1N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was desolventized under reduced pressure. Crystallization was performed using a heptane and toluene system. The mixture was filtered, and the filtrate was collected and desolventized to a white solid, yielding 1.6 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxovaleric acid (III-A), with a yield of 71.4%, purity of 99.0%, and ee value of 92.5%.

[0107] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0108] Under nitrogen protection, at room temperature, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of N-((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)-3,5-bis(trifluoromethyl)benzenesulfonamide were added sequentially to a 500 mL three-necked flask and reacted at room temperature for 1 day. The reaction was confirmed by LCMS. After washing with 0.1N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was desolventized under reduced pressure. Crystallization was performed using a heptane and toluene system. The mixture was filtered, and the filtrate was collected and desolventized to a white solid, yielding 1.52 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 67.9%, purity of 98.6%, and ee value of 93.5%.

[0109] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0110] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-phenylthiourea were added sequentially to a 500 mL four-necked flask at room temperature. The reaction was carried out at room temperature for 1 day. The reaction was confirmed by LCMS. After washing with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dissolved under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.54 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 69.0%, purity of 98.5%, and ee value of 94.1%.

[0111] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0112] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) prepared in Example 1, 240 mL of methyl tert-butyl ether, 2.4 g of methanol, and 200 mg of Novozym 435 lipase were added sequentially to a 500 mL four-necked flask at room temperature. The reaction was allowed to proceed for 5 days at room temperature. The reaction was confirmed by LCMS. After filtration, the mixture was washed with 40 mL of methyl tert-butyl ether. The filtrate was washed with 0.1 N hydrochloric acid and saturated brine, respectively. The upper organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the filtrate was dissolved under reduced pressure and crystallized using a heptane and toluene system. After filtration, the filtrate was collected and dissolved until a white solid was obtained, yielding 1.14 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxovaleric acid (III-A), with a yield of 51.0%, purity of 96%, and ee value of 98.5%.

[0113] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0114] In a 100 mL three-necked flask under nitrogen protection, 2 g of dimethyl 3-(4-bromophenyl)glutarate (II-A) prepared in Example 1, 16 mL of buffer solution (pH = 7.2), and 200 mg of aminolipase AYS were added sequentially, and the reaction was carried out overnight at room temperature. The reaction was confirmed by LC-MS. The pH was lowered to 5, adjusted to pH = 2 with concentrated hydrochloric acid, filtered, washed with 50 mL of ethyl acetate, extracted with ethyl acetate, washed with saturated brine, and the upper organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was filtered, and the solvent was removed under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.35 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxovalerate (III-A), with a yield of 71.0%, purity of 95%, and ee value of 94.2%.

[0115] Alternatively, step 1: See Figure 2, synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0116] In a 100 mL three-necked flask under nitrogen protection, 2 g of diethyl 3-(4-bromophenyl)glutarate (II-B) prepared in Example 1, 16 mL of buffer solution (pH = 7.2), and 200 mg of aminolipase AYS were added sequentially, and the reaction was carried out overnight at room temperature. The reaction was confirmed by LC-MS. The pH was lowered to 5, adjusted to pH = 2 with concentrated hydrochloric acid, filtered, washed with 50 mL of ethyl acetate, extracted with ethyl acetate, washed with saturated brine, and the upper organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was filtered, and the solvent was removed under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.14 g of (S)-3-(4-bromophenyl)-5-ethoxy-5-oxovalerate (III-A), with a yield of 62.0%, purity of 96%, and ee value of 94.4%.

[0117] Example 3

[0118] The structural formula of the substance shown in Formula IV-A:

[0119] Step 2: See Figure 2, Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0120] In a 1000 mL three-necked flask under nitrogen protection, 10 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 was added sequentially, followed by 100 mL of tetrahydrofuran. The mixture was cooled to -30 °C, and 44.5 mL of methylmagnesium chloride (3 mol / L in THF) was added dropwise, maintaining the temperature below -10 °C. After the addition was complete, the reaction was carried out at 0 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was then quenched in 150 mL of ice-cold 1N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and dissolved under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was dried to give 10.4 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A), a white solid with a yield of 75.3%, a purity of 98.7%, and an ee value of 96.8%.

[0121] Alternatively, step 2: See Figure 2, Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0122] In a 1000 mL three-necked flask under nitrogen protection, 10 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 was added sequentially, followed by 100 mL of tetrahydrofuran. The mixture was cooled to -40 °C, and 45 mL of methylmagnesium chloride (3 mol / L in THF) was added dropwise, maintaining the temperature below -10 °C. After the addition was complete, the reaction was carried out at 10 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was then quenched in 150 mL of ice-cold 1N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and dissolved under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was dried to give 11.5 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A), a white solid with a yield of 83.3%, purity of 97.8%, and ee value of 94.8%.

[0123] Alternatively, step 2: See Figure 2, Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0124] In a 1000 mL three-necked flask under nitrogen protection, 10 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 was added sequentially, followed by 100 mL of tetrahydrofuran. The mixture was cooled to -40 °C, and 130 mL of methyllithium (1 mol / L in 2-MeTHF) was added dropwise, maintaining the temperature below -10 °C. After the addition was complete, the reaction was carried out at 0 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was then quenched in 150 mL of ice-cold 1N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and dissolved under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was dried to give 12.3 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A), a white solid with a yield of 89.1%, purity of 95.8%, and ee value of 91.8%.

[0125] Example 4

[0126] The structural formula of the substance represented by formula VA:

[0127] Step 3: See Figure 2, Synthesis of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA):

[0128] In a 250 mL three-necked flask, 10 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A) prepared in Example 3 and 100 mL of dichloromethane were added sequentially. The mixture was cooled to -70 °C in a dry ice ethanol bath, and 50 mL of DIBAL-H solution (1 mol / L in hexane) was added dropwise, with the temperature controlled not to exceed -65 °C. After the addition was complete, the mixture was kept at -70 °C for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in 300 mL of 10% wt potassium sodium tartrate aqueous solution and stirred for 1 hour until clear and separated into layers. The solution was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure to obtain 9.6 g of (4R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-ol, a white solid. This solid was added to a 250 mL three-necked flask with 100 mL of DCM and 11 g of triethylsilane. The mixture was cooled to 0 °C in an ice-water bath, and 5.7 g of boron trifluoride ether was added dropwise. The mixture was then reacted at 0 °C for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in 100 mL of ice-cold semi-saturated sodium bicarbonate aqueous solution and stirred until no more bubbles were generated. The solution was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolventized under reduced pressure to obtain a colorless oil. Crystallization from n-heptane and ethyl acetate yielded 8.2 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA), with a yield of 94.2% and a purity of 93.0%.

[0129] Example 5

[0130] The structural formula of the substance shown in Formula VI: In the formula, R 2 =H,R 3 =H.

[0131] Step 4: See Figure 2, Synthesis of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI):

[0132] In a 100 mL three-necked flask under nitrogen protection and magnetic stirring, 18 mg of cuprous iodide, 41 mg of N1,N2 bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide, 95 mg of potassium phosphate, 41 mg of cetyltrimethylammonium bromide, followed by 1 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4 and 0.25 mL of water. The mixture was purged with nitrogen three times and reacted at 80 °C for 15 minutes. The mixture was then cooled to room temperature, and 853 mg of potassium phosphate and 450 mg of 85% wt hydrazine hydrate were added. The mixture was purged with nitrogen three times and reacted overnight at 80 °C. The solution was cooled to room temperature, diluted with 20 mL of dichloromethane, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrate was washed once with 20 mL of water and once with semi-saturated saline solution. The organic phase was collected, and concentrated hydrochloric acid was added to adjust the pH to 3, resulting in the precipitation of a large amount of solid. The solution was filtered, and the filter cake was washed with 10 mL of dichloromethane. The solution was dried under vacuum and then dissolved under reduced pressure in a water bath at 40 °C to obtain 670 mg of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI), an off-white solid with a yield of 70.1% and a purity of 96.5%.

[0133] Alternatively, step 4: See Figure 2, synthesis of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI):

[0134] In a 100 mL three-necked flask under nitrogen protection and magnetic stirring, 62 mg of cuprous iodide, 143 mg of N1,N2 bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide, 332 mg of potassium phosphate, 143 mg of cetyltrimethylammonium bromide, 3.5 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4, and 0.9 mL of water were added. The mixture was purged with nitrogen three times and reacted at 80 °C for 15 minutes. The mixture was then cooled to room temperature, and 2987 mg of potassium phosphate and 1.54 mg of 85% wt hydrazine hydrate were added. The mixture was purged with nitrogen three times and reacted overnight at 80 °C. The solution was cooled to room temperature, diluted with 60 mL of dichloromethane, filtered, and the filter cake was washed with 60 mL of dichloromethane. The filtrate was washed once with 30 mL of water and once with 30 mL of semi-saturated saline solution. The organic phase was collected, and concentrated hydrochloric acid was added to adjust the pH to 3, resulting in the precipitation of a large amount of solid. The solution was filtered, and the filter cake was washed with 30 mL of dichloromethane. The solution was dried under vacuum and then dissolved under reduced pressure in a water bath at 40 °C to obtain 2.78 g of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI), an off-white solid with a yield of 83.2% and a purity of 96.5%.

[0135] The structural formula of the substance shown in Formula VI: R 2 =Me,R 3 =Boc.

[0136] Step 4: See Figure 2, Synthesis of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI):

[0137] In a 100 mL three-necked flask, under nitrogen protection and magnetic stirring, 57 mg of cuprous iodide, 61 mg of N1,N2-bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide, and 772 mg of potassium carbonate were added sequentially. The mixture was purged with nitrogen three times. Then, 1 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4, 0.68 g of tert-butyl 1-methylhydrazine-1-carboxylate, and 20 mL (10 V) of dimethyl sulfoxide were added. The mixture was purged with nitrogen three times, and then the reaction was carried out overnight at 80 °C. LCMS analysis showed that most of the raw materials were converted into the product. The reaction was cooled to room temperature, filtered, and the filter cake was washed with 40 mL of ethyl acetate. The filtrate was quenched in 60 mL of ice water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure in a 40°C water bath. The crude product was wet-processed through a silica gel column (heptane / EA = 6:1) to give 475 mg of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B), a colorless oil, with a yield of 19.1% and a purity of 95%.

[0138] Step 4: See Figure 2, Synthesis of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI):

[0139] In a 250 mL three-necked flask, under nitrogen protection and magnetic stirring, 50 mg of cuprous bromide, 108 mg of N-(2,6-dimethylphenyl)-6-hydroxypyridine amide, and 1.54 g of potassium carbonate were added sequentially. The mixture was purged with nitrogen three times. Then, 2 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4, 1.36 g of tert-butyl 1-methylhydrazine-1-carboxylate, and 20 mL of dimethyl sulfoxide were added. The mixture was purged with nitrogen three times, and then the reaction was carried out overnight at 80 °C. The reaction was detected by LCMS. After cooling to room temperature, the mixture was filtered. The filter cake was washed with 40 mL of ethyl acetate, and the filtrate was quenched in 60 mL of ice water. The mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure in a 40 °C water bath. The crude product was wet-processed by silica gel column chromatography (heptane / EA = 6:1) to give 2.0 g of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B), a colorless oil with a yield of 80.3% and a purity of 96%.

[0140] Example 6

[0141] The structural formula of the substance shown in Formula VII: In the formula, Z represents OEt.

[0142] Step 5: See Figure 2, Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0143] In a 250 mL three-necked flask, 20 mL of ethanol and 4 g of concentrated sulfuric acid were mixed. After cooling to room temperature, 2 g of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine (VI) prepared in Example 5 and 760 mg of ethyl pyruvate were added, and the mixture was reacted at 80 °C for 4 hours. After the reaction was complete as detected by LCMS, the mixture was cooled to room temperature, and most of the ethanol was removed by desolvation under reduced pressure in a 40 °C water bath. The solution was then quenched in 50 mL of water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography was used to obtain 820 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII), with a yield of 45.4%, a purity of 97.2%, and an ee value of 95.7%.

[0144] Alternatively, step 5: See Figure 2, synthesis (VII) of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate:

[0145] In a 250 mL three-necked flask, 20 mL of toluene and 5 g of polyphosphoric acid were mixed, followed by 2 g of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine (VI) prepared in Example 5, and 750 mg of ethyl pyruvate. The mixture was then reacted at 100 °C for 4 hours. After the reaction was complete as detected by LCMS, the mixture was cooled to room temperature, quenched in 50 mL of water, extracted with toluene, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 870 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII), with a yield of 48.2%, purity of 97.2%, and ee value of 96.9%.

[0146] Alternatively, step 5: See Figure 2, synthesis (VII) of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate:

[0147] In a 250 mL three-necked flask, 20 mL of ethanol and 4 g of concentrated sulfuric acid were mixed. After cooling to room temperature, 2 g of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B) prepared in Example 5 and 760 mg of ethyl pyruvate were added. The mixture was then reacted at 80 °C for 4 hours. After the reaction was complete as detected by LCMS, the mixture was cooled to room temperature and subjected to desolvation under reduced pressure in a 40 °C water bath to remove most of the ethanol. The solution was then quenched in 50 mL of water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography was used to obtain 980 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII), with a yield of 54.4%, purity of 95.2%, and ee value of 94.7%. The NMR spectrum of the prepared (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) is shown in Figure 3. The chirality diagram of the racemic mixture is shown in Figure 4 and Table 2. The chirality diagram of the single chiral target is shown in Figure 5 and Table 3.

[0148] Table 2

[0149] Table 3

[0150] Alternatively, step 5: See Figure 2, synthesis (VII) of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate:

[0151] In a 250 mL three-necked flask, under nitrogen protection and magnetic stirring, 2 g of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B) prepared in Example 5, 765 mg of ethyl pyruvate, 20 mL of ethanol were added sequentially, and 1 g of trimethylchlorosilane was added dropwise at room temperature. The mixture was then reacted at 80 °C for 4 hours. After the reaction was complete as detected by LCMS, the solution was cooled to room temperature and then desolvated under reduced pressure in a 40°C water bath to remove most of the ethanol. The solution was then quenched in 50 mL of water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was then crystallized from n-heptane and ethyl acetate to give 732 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII), an off-white solid with a yield of 40.6%, a purity of 96.27%, and an ee value of 93.9%.

[0152] Synthesis of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indazine-2-carboxylic acid ethyl ester (IX):

[0153] Example 7

[0154] Synthesis from starting materials:

[0155] Synthesis of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB):

[0156] Under nitrogen protection, 200 g of 2-bromoisonital, 1000 mL of ethanol, and 421.6 g of ethyl acetoacetate were added sequentially in a 5 L four-necked flask with mechanical stirring at room temperature. Nitrogen was then introduced, followed by the addition of 13.8 g of piperidine, and the reaction was allowed to proceed for 1 day at room temperature. The reaction was confirmed by LCMS. The mixture was directly filtered, and the filter cake was washed with 400 mL of ethanol, dried under vacuum, and air-dried to obtain 365 g of diethyl 2,4-diacetyl-3-(2-bromopyridin-4-yl)glutarate, an off-white solid with a yield of 79.1% and a purity of 96%. In a 5 L four-necked flask at room temperature, 365 g of diethyl 2,4-diacetyl-3-(2-bromopyridin-4-yl)glutarate and 1095 mL of ethanol were added sequentially. 205.1 g of sodium hydroxide was dissolved in 1095 mL of water, cooled to room temperature, and then added to the reaction mixture. The temperature was raised to 40 °C, and the system gradually dissolved and became clear. The reaction was continued at 40 °C for 2 hours. LC-MS analysis showed the reaction was complete. The mixture was cooled to room temperature, and most of the ethanol was removed by desolvation under reduced pressure in a 40 °C water bath. Then, 1825 mL of water was added for dilution, and the mixture was cooled with ice. 448 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3, resulting in the precipitation of a large amount of off-white solid. The solid was filtered, and the filter cake was washed with 1000 mL of water, dried under vacuum, and then dried at 45 °C for 4 hours to obtain 182.5 g of 3-(2-bromopyridin-4-yl)glutaric acid, an off-white solid with a yield of 74.4% and a purity of 96%.

[0157] Under nitrogen protection, 180 g of 3-(2-bromopyridin-4-yl)glutaric acid, 1800 mL of toluene, and 191.2 g of acetic anhydride were added in portions to a 5 L four-necked flask at room temperature. The temperature was then raised to 110 °C, and the starting material gradually dissolved. The reaction was continued at 110 °C for 5 hours. The reaction was confirmed to be complete by methanol-derived LCMS. The mixture was cooled to room temperature, and the solution was removed under reduced pressure in a 40 °C water bath. 1000 mL of n-heptane was added, the mixture was stirred, filtered, washed with 500 mL of n-heptane, and dried. The solid was then removed under reduced pressure in a 40 °C water bath to finally obtain 126.5 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB), a pale yellow solid, with a yield of 75.0% and a purity of 94%.

[0158] The structural formula of the substance represented by formula IB:

[0159] Example 8

[0160] The structural formula of the substance shown in Formula III-B: In the formula, R 1 For Me.

[0161] Step 1: See Figure 2, Synthesis of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxovaleric acid (III-B):

[0162] Under nitrogen protection, 2 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB) prepared in Example 7, 200 mL of methyl tert-butyl ether, 2.4 g of methanol, and 0.04 g of 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-phenylthiourea were added sequentially to a 500 mL four-necked flask at room temperature. The reaction was carried out at room temperature for 1 day. The reaction was confirmed by LCMS. After washing with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dissolved under reduced pressure. Crystallization was performed using a heptane and toluene system, filtered, and the filtrate was collected and dissolved until a white solid was obtained, yielding 1.45 g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxovaleric acid (III-B), with a yield of 65.0%, purity of 99.5%, and ee value of 94.5%.

[0163] Alternatively, step 1, see Figure 2, synthesis of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B):

[0164] Under nitrogen protection, at room temperature, 2 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB) prepared in Example 7, 200 mL of methyl tert-butyl ether, 2.4 g of methanol, and 0.04 g of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)thiourea were added sequentially to a 500 mL four-necked flask, and the reaction was carried out at room temperature for 1 day. The reaction was confirmed by LCMS. After washing with 0.1N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was desolventized under reduced pressure. Crystallization was performed using a heptane and toluene system. The mixture was filtered, and the filtrate was collected and desolventized to a white solid, yielding 1.15 g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxovaleric acid (III-B), with a yield of 51.5%, purity of 98.5%, and ee value of 92.5%.

[0165] Example 9

[0166] The structural formula of the substance shown in Formula IV-B:

[0167] Step 2: See Figure 2, Synthesis of (R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-B):

[0168] In a 1000 mL three-necked flask under nitrogen protection, 10 g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxovaleric acid (III-B) prepared in Example 8 was added sequentially, followed by 100 mL of tetrahydrofuran. The mixture was cooled to -40 °C, and 38 mL of methylmagnesium chloride (3 mol / L in THF) was added dropwise, maintaining the temperature below -10 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was then quenched in 150 mL of ice-cold 1N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was dissolved under reduced pressure in a 40 °C water bath. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was dried to give 6.8 g of (R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-B), a white solid with a yield of 73.1%, purity of 98.7%, and ee value of 96.2%.

[0169] Example 10

[0170] The structural formula of the substance shown in formula VB:

[0171] Step 3: See Figure 2, Synthesis of (S)-2-bromo-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine (VB):

[0172] In a 250 mL three-necked flask, 10 g of (R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-B) prepared in Example 9 and 100 mL of dichloromethane were added sequentially. The mixture was cooled to -70 °C in a dry ice ethanol bath, and 48 mL of DIBAL-H solution (1 mol / L in hexane) was added dropwise, with the temperature controlled not to exceed -65 °C. After the addition was complete, the mixture was kept at -70 °C for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in 300 mL of 10% wt potassium sodium tartrate aqueous solution and stirred for 1 hour until clear and separated into layers. The solution was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure to obtain 10 g of (4R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-ol, a white solid. This solid was added to a 250 mL three-necked flask with 100 mL of DCM and 11 g of triethylsilane. The mixture was cooled to 0 °C in an ice-water bath, and 5.7 g of boron trifluoride ether was added dropwise. The mixture was then reacted at 0 °C for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in 100 mL of ice-cold semi-saturated sodium bicarbonate aqueous solution and stirred until no more bubbles were generated. The solution was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure in a 40 °C water bath to obtain a colorless oil. Crystallization from n-heptane and ethyl acetate yielded 8.6 g of (S)-2-bromo-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine (VB), with a yield of 90.5% and a purity of 96.0%.

[0173] Example 11

[0174] The substance represented by Formula VIII:

[0175] Step 4: See Figure 2, Synthesis of (S)-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridinecarboxaldehyde (VIII):

[0176] In a 500 mL three-necked flask, 10 g of (S)-2-bromo-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine (VB) prepared in Example 10 was added sequentially, along with 100 mL of tetrahydrofuran. The mixture was cooled to -70 °C in a dry ice ethanol bath, and 55.7 mL of n-butyllithium solution (1 mol / L in THF) was added dropwise. After the addition was complete, the mixture was kept at -70 °C for half an hour. Then, 27.1 g of DMF was added dropwise, with the temperature controlled not to exceed -65 °C. After the addition was complete, the temperature was slowly raised to 0 °C and the reaction was carried out for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in 100 mL of ice-cold saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure in a 40 °C water bath. Crystallization from n-heptane and ethyl acetate yielded 5.7 g of (S)-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridinecarboxaldehyde (VIII), with a yield of 70.0% and a purity of 94.3%.

[0177] Example 12

[0178] The substance represented by Formula IX: In the formula, Z represents OEt.

[0179] Step 5: See Figure 2, Synthesis of ethyl indene-2-carboxylate in (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) (IX):

[0180] In a 100 mL three-necked flask under nitrogen protection and magnetic stirring, 5 g of (S)-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridinecarboxaldehyde (VIII) prepared in Example 11, 4.6 g of ethyl acrylate, and 1.7 g of DABCO were added sequentially, and the mixture was reacted at room temperature for 12 hours. The reaction was confirmed to be complete by LCMS. Ethyl acrylate was removed under reduced pressure in a 40°C water bath. The crude residue was dissolved in 100 mL of ethyl acetate, washed with water and saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure in a 40°C water bath to obtain 7.3 g of ethyl 2-((4-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridin-2-yl)(hydroxy)methyl)acrylate. This was added to a 250 mL three-necked flask, followed by 40 mL of dichloromethane and 2.7 g of pyridine. The mixture was then cooled to 0°C in an ice-water bath, and 2.7 g of acetyl chloride was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in an ice-cold saturated sodium bicarbonate solution, stirred at room temperature for half an hour, extracted with DCM, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure in a 40°C water bath to obtain the crude residue. The crude residue was dissolved in 100 mL of toluene and refluxed for 16 hours. The reaction was confirmed to be complete by LCMS. The residue was then dissolved under reduced pressure in a 40 °C water bath and purified by silica gel column chromatography (n-heptane / ethyl acetate = 3:1) to give 3.87 g of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl) indene-2-carboxylic acid ethyl ester (IX), with a yield of 55.3% and a purity of 95.5%.

[0181] As can be seen, the cyclic anhydride as shown in Formula I or the symmetrical dicarboxylic acid ester as shown in Formula II, synthesized by the method described in the literature, is catalytically alcoholyzed to obtain an intermediate with a high ee value and a target stereoconfiguration as shown in Formula III. This intermediate then reacts with a methyl metal reagent to obtain a lactone as shown in Formula IV. The lactone as shown in Formula IV reacts with a methyl metal reagent to obtain a ring-closed dimethylated compound as shown in Formula VA or Formula VB. The compound as shown in Formula VA is then copper-catalyzed to obtain the corresponding arylhydrazine as shown in Formula VI. Finally, under acid catalysis, it reacts with a pyruvate derivative via Fisher ring closure to obtain the target product as shown in Formula VII; or the compound as shown in Formula VB is functionalized to an aldehyde as shown in Formula VIII, which is then reacted with an acrylic acid derivative via a Balis-Hillman reaction to form a ring-closed compound as shown in Formula IX.

[0182] This invention avoids the use of transition metal catalysts and SFC resolution in reported methods, reduces reaction costs, and facilitates scale-up production. It is an economical, environmentally friendly, and simple post-processing technology that is easy to scale up.

[0183] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing aryl-substituted chiral tetrahydropyran rings via desymmetry, characterized in that, The method includes the following steps: a) The compound shown in Formula I is subjected to alcoholysis via small organic molecule catalysis or enzymatic catalysis to yield the compound shown in Formula III with high chiral purity; the catalyst is 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)thiourea, 1-(3,5-bis(trifluoromethyl)phenyl)-3- ((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)thiourea, N-((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)-3,5-bis(trifluoromethyl)benzenesulfonamide, 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-benzenethiourea or Novozym 435 lipase; b) The compound shown in Formula III reacts with a methyl metal reagent to give the compound shown in Formula IV; c) The compound shown in formula IV is reduced with lactone to obtain the compound shown in formula V; d) The compound represented by formula VA is subjected to a copper-catalyzed hydrazination reaction to give the compound represented by formula VI; e) The compound shown in Formula VI undergoes acid-catalyzed Fisher cyclization with a pyruvate derivative to yield the compound shown in Formula VII. Alternatively, step d) can be replaced with step f): f) The compound shown in formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to give the compound shown in formula VIII; g) The compound shown in Formula VIII is cyclized with an acrylic acid derivative to obtain the compound shown in Formula IX; Among them, the compound represented by formula I: The compound represented by Formula III: The compound represented by Formula IV: The compound represented by formula V: Compounds represented by formula VA: The compound shown in Formula VI: The compound represented by formula VII: The compound represented by formula VB: The compound represented by formula VIII: The compound represented by Formula IX: In the formula, X is Cl, Br, I, -OTf, -OMs or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group; R 2 For H, Me, Et, iPr, or Bn; R 3 H or Boc; Z is -OR 4 ;R 4 C1-C6 alkyl or -NR 5 R 6 ;R 5 It is a C1-C3 alkyl group; R 6 It is a phenyl or a substituted phenyl group.

2. The method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1, characterized in that, Step a) is replaced by step a1): The compound shown in Formula II is hydrolyzed by organic small molecule catalysis or enzyme catalysis to obtain the compound shown in Formula III with high chiral purity. The compound represented by Formula II: In the formula, X is Cl, Br, I, -OTf, -OMs or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl or benzyl group.

3. The method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1, characterized in that, In step a), the substrate for the alcoholysis reaction is one of methanol, ethanol, benzyl alcohol, or other alkyl alcohols, and the amount of substrate used for the alcoholysis reaction is 1.0-10.0 equivalents.

4. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step b), the methyl metal reagent is one of lithium methyl, magnesium methyl bromide, magnesium methyl chloride, and magnesium methyl iodide; the amount of the methyl metal reagent used is 3.0-5.0 equivalents.

5. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step c), the reducing agents used to reduce the lactone are DIBAL-H and Et3SiH.

6. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step d), the copper catalyst is CuI or CuBr, and the amount of copper catalyst used is 0.01-1.0 equivalents.

7. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step d), the ligand used in the reaction is N-(2,6-dimethylphenyl)-6-hydroxypyridine amide or N1,N2-bis(2,5-dimethyl-1H-pyrrolo-1-yl)oxalamide; the substrate for the hydrazideation reaction is hydrazine hydrate, 1-tert-butoxycarbonyl-1-methylhydrazine, 1-tert-butoxycarbonyl-1-ethylhydrazine or 1-tert-butoxycarbonyl-1-benzylhydrazine.

8. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step e), the acid used for acid catalysis is HCl, H2SO4, PPA, TsOH or TfOH; the acetone derivative is ethyl pyruvate, methyl pyruvate or N-methyl-2-oxo-N-phenylpropionamide.

9. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step f), the metal reagent is n-butyllithium, sec-butyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide.

10. A method for synthesizing aryl-substituted chiral tetrahydropyran rings by desymmetry according to claim 1 or 2, characterized in that, In step g), the acrylic acid derivative is ethyl acrylate, methyl acrylate, benzyl acrylate, or N-methyl-N-phenylacrylamide.

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