A method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization

Abstract

The present invention provides a method for synthesizing a chiral tetrahydropyran ring substituted with an aromatic group by desymmetrization, such as a cyclic anhydride as shown in Formula I or a symmetrical dicarboxylic acid ester as shown in Formula II, catalytic alcoholysis to obtain an intermediate as shown in Formula III with a high ee value, reacting with a methyl metal reagent to obtain a lactone as shown in Formula IV, reducing to obtain an ether as shown in Formula V, and obtaining the corresponding aromatic hydrazine as shown in Formula VI through copper catalysis as shown in Formula V-A, and closing the indole ring with a pyruvic acid derivative under acid catalysis to obtain the target product; or a compound as shown in Formula V-B is converted into an intermediate as shown in Formula VIII through a functional group, and reacting with an acrylic acid derivative to generate a target compound. The present invention avoids the use of transition metal catalysts and SFC splitting in the 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 technical route.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, relates to a method for synthesizing a chiral tetrahydropyran ring, and particularly relates to a method for synthesizing an aromatic-substituted chiral tetrahydropyran ring through desymmetrization. Background Art

[0002] Application background of chiral tetrahydropyran ring substituted with aromatic groups: This structure and its derivatives, such as lactone, hemiacetal, etc., can be further derived to obtain molecules with more complex structures, among which highly chirally pure structures can be used as key synthons in the synthesis of pharmaceutical molecules. For example, oglerone and ECC5004, as a small molecule GLP-1 receptor agonist, play an effective anti-diabetic effect by enhancing glucose-dependent insulin secretion and improving energy balance, and have pharmacokinetic characteristics that are conducive to oral administration, which have huge advantages and potential drug markets.

[0003] As the core module of Oglelon and ECC5004 (see Figure 1 ), which is also one of the difficulties in its synthesis. The improvement of the synthesis of the aromatic-substituted chiral tetrahydropyran ring fragments in its 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)-indolizine-2-carboxylic acid and their derivatives is particularly important.

[0004] At present, the construction of chiral centers of aromatic-substituted chiral tetrahydropyran ring fragments mainly relies on transition metal palladium catalysis to construct the carbon-carbon bond between the aromatic group and the tetrahydropyran ring, and then uses chromatography to separate or uses transition metal asymmetric hydrogenation to obtain high chiral purity enantiomers. Some also use enzyme catalysis or transition metal catalysis to obtain aromatic-substituted chiral tetrahydropyran ring precursor structures from specific substrates.

[0005] At present, there are few patents disclosed for the synthesis method of aromatically substituted chiral tetrahydropyran ring fragments, and only a few original research patents are involved. For example, in patent (WO2018056453A1), the substrate bromoindole and the ready-made tetrahydropyran structure organic zinc reagent are used to construct the carbon-carbon bond through the palladium-catalyzed Negishi reaction to obtain the racemate of the target structure, which is then separated by SFC (Super Critical Fluid) to obtain the desired configuration target structure.

[0006] For example, patents WO / 2022 / 017338 and US11584751B1, etc., use Pd-catalyzed Suzuki reaction of substrate bromoindole and boric acid ester of dihydropyran ring, and then reduce the double bond in dihydropyran ring by Pd / C to obtain the racemate of target structure, and finally obtain the target structure with required stereo configuration by SFC chiral separation. Among them, this fragment in ECC5004 molecule is also synthesized based on this method.

[0007] The recently published patent (CN117777111A) uses bromoindole raw materials and α,β-unsaturated lactones to construct carbon-carbon bonds through palladium-catalyzed Heck coupling, constructs key chiral centers through ruthenium-catalyzed asymmetric hydrogenation, and then constructs the target molecular structure through two steps.

[0008] However, in the existing methods, the use of transition metals not only increases the synthesis cost, but also causes the problem of metal residues in the subsequent drug synthesis. In addition, the equipment required for SFC splitting is relatively expensive and not suitable for industrial production. It also discards unnecessary configurations, greatly increasing the synthesis cost of the target structure. Summary of the invention

[0009] In order to solve the above problems, the present invention provides a method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization. The present invention synthesizes a cyclic anhydride as shown in formula I or a symmetrical dicarboxylic acid ester as shown in formula II by a commonly used method in literature, and obtains an intermediate with a target stereo configuration of high ee value as shown in formula III by alcoholysis catalyzed by an organic small molecule of ethylenediamine (or the symmetrical dicarboxylic acid ester as shown in formula II is hydrolyzed under organic small molecule or enzyme catalysis to obtain an intermediate with a target stereo configuration of high ee value as shown in formula III), and reacts with a methyl metal reagent to obtain a dimethylated lactone as shown in formula IV, and obtains an ether as shown in formula V by reduction.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] The present invention provides a method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization, the method comprising the following steps:

[0012] a) the compound represented by formula I is subjected to alcoholysis catalyzed by organic small molecules or enzymes to obtain a compound represented by formula III with high chiral purity;

[0013] b) the compound represented by formula III is reacted with a methyl metal reagent to obtain a compound represented by formula IV;

[0014] c) reducing the compound represented by formula IV to obtain the compound represented by formula V;

[0015] d) the compound represented by formula VA is subjected to copper-catalyzed hydrazine reaction to obtain the compound represented by formula VI;

[0016] e) the compound represented by formula VI is subjected to acid-catalyzed Fisher ring closure with a pyruvic acid derivative to obtain a compound represented by formula VII;

[0017] Alternatively, step d) is replaced by step f):

[0018] f) the compound represented by formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to obtain a compound represented by formula VIII;

[0019] g) the compound represented by formula VIII is cyclized with an acrylic acid derivative to obtain a compound represented by formula IX;

[0020] Wherein, the compound shown in formula I: ;

[0021] The compound shown in formula III: ;

[0022] The compound shown in formula IV: ;

[0023] The compound represented by formula V: ;

[0024] The compound represented by formula VA: ;

[0025] The compound shown in formula VI: ;

[0026] The compound shown in formula VII: ;

[0027] The compound represented by formula VB: ;

[0028] The compound represented by formula VIII: ;

[0029] The compound represented by formula IX: ;

[0030] Wherein, X is Halogen (Cl, Br, I), -OTf, -OMs or -OTs; Y is C or N; R 1 is C1-C6 alkyl or benzyl; R 2 is H, Me, Et, iPr or Bn; R 3 is H or Boc; Z is -OR 4 ; R 4 C1-C6 alkyl or -NR 5 R6 ; R 5 is a C1-C3 alkyl group; R 6 It is phenyl or substituted phenyl.

[0031] As a preferred embodiment of the present invention, the step a) is replaced by step a1): the compound represented by formula II is hydrolyzed by organic small molecule catalysis or enzyme catalysis to obtain a compound represented by formula III with high chiral purity;

[0032] The compound shown in formula II: ;

[0033] Wherein, X is Halogen (Cl, Br, I), -OTf, -OMs or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl group or a benzyl group.

[0034] As a preferred embodiment of the present invention, in step a) or step a1), the substrate for alcoholysis reaction includes one of methanol, ethanol, benzyl alcohol or other alkyl alcohols, and the amount of the substrate for alcoholysis reaction is 1.0-10.0 equivalents.

[0035] As a preferred embodiment of the present invention, in step b), the methyl metal reagent includes one of methyl lithium, methyl magnesium bromide, methyl magnesium chloride, and methyl magnesium iodide; and the amount of the methyl metal reagent used is 3.0-5.0 equivalents.

[0036] As a preferred embodiment of the present invention, in step c), the reducing agent used to reduce the lactone includes DIBAL-H and Et3SiH.

[0037] As a preferred embodiment of the present invention, in step d), the copper catalyst includes CuI or CuBr, and the amount of the copper catalyst is 0.01-1.0 equivalent.

[0038] As a preferred embodiment of the present invention, in the step d), the ligand used in the reaction includes N-(2,6-dimethylphenyl)-6-hydroxypicolinamide or N1,N2-bis(2,5-dimethyl-1H-pyrrol-1-yl)oxalamide; the substrate of the hydrazine reaction includes hydrazine hydrate, 1-tert-butoxycarbonyl-1-methylhydrazine, 1-tert-butoxycarbonyl-1-ethylhydrazine or 1-tert-butoxycarbonyl-1-benzylhydrazine.

[0039] 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.

[0040] As a preferred embodiment of the present invention, in step f), the metal reagent includes n-butyl lithium, sec-butyl lithium, isopropyl magnesium chloride or isopropyl magnesium bromide.

[0041] As a preferred embodiment of the present invention, in step g), the acrylic acid derivative includes ethyl acrylate, methyl acrylate, benzyl acrylate or N-methyl-N-phenylacrylamide.

[0042] The present invention uses a cyclic anhydride as shown in formula I or a symmetrical dicarboxylic acid ester as shown in formula II synthesized by a common method in literature, and undergoes alcoholysis catalyzed by an organic small molecule such as ethylenediamine to obtain an intermediate with a target stereo configuration of high ee value as shown in formula III (or the symmetrical dicarboxylic acid ester is hydrolyzed under organic small molecule or enzyme catalysis to obtain an intermediate with a target stereo configuration of high ee value as shown in formula III), which is reacted with a methyl metal reagent to obtain a dimethylated lactone as shown in formula IV, and then reduced to obtain an ether as shown in formula V.

[0043] Furthermore, the compound shown in Formula VA is subjected to copper catalysis to obtain the corresponding aryl hydrazine shown in Formula VI, and finally reacted with a pyruvic acid derivative under acid catalysis to obtain the target product shown in Formula VII via Fisher closure of the indole ring.

[0044] Alternatively, the compound represented by formula VB is converted into an aldehyde represented by formula VIII through functional group conversion, and the latter is then subjected to Balis-Hillman reaction with an acrylic acid derivative to form a compound represented by formula IX after ring closure.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] 1) The starting materials of the present invention have simple structures and are easily available in commercial quantities. The present invention uses cheap 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 desymmetrization method.

[0047] 2) The present invention uses chiral ethylenediamine organic small molecule catalysis or commercial enzyme catalysis (including but not limited to) to desymmetrize substrate I or II to obtain the required key chiral center and synthesize the intermediate shown in formula III. This step is a key step in realizing the present process route.

[0048] 3) The present invention avoids the use of transition metal catalysts and SFC separation in the reported methods, reduces the reaction cost, and is conducive to scale-up production. It is an economical, environmentally friendly, simple post-processing, and easy-to-scale technical route. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is a schematic diagram of Oglelon and ECC5004.

[0050] Figure 2 It is the synthesis route diagram of the present invention.

[0051] Figure 3 This is the NMR spectrum of the compound shown in VII.

[0052] Figure 4 This is the chiral diagram of the racemate of the compound shown in VII.

[0053] Figure 5 This is a chiral diagram of a single chiral target compound shown in VII. DETAILED DESCRIPTION

[0054] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0055] In the present invention, the raw materials, reagents or equipment used can be purchased from the market, see Table 1.

[0056] Table 1. Raw materials

[0057] Serial number Material Name CAS.NO batch number factory 1 Ethyl acetoacetate 141-97-9 P2099679 Titan 2 p-Bromobenzaldehyde 1122-91-4 P1948667 Titan 3 Acetyl chloride 75-36-5 P2791990 Titan 4 Methylmagnesium chloride 676-58-4 230706 Shangyu Hualun 5 Boron trifluoride etherate 109-63-7 P1775474 Titan 6 Triethylsilane 617-86-7 P2517733 Titan 7 O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 148893-10-1 DMU930 Peter 8 Hydrogen chloride 1,4-dioxane solution 7647-01-0 P2192569 Titan 9 Polyphosphoric acid 8017-16-1 P1856081 Titan 10 Diisobutylaluminum hydride 1.0M in n-hexane solution 1191-15-7 C15759865 Maclean 11 Sodium hydroxide 1310-73-2 C2427250 Aladdin 12 Methyl tert-butyl ether 1634-04-4 P2563275 Titan 13 Oxalyl chloride 79-37-8 C14978996 Maclean 14 Cuprous Bromide 7787-70-4 C14302174 Maclean 15 Cuprous iodide 7681-65-4 A2218355 Aladdin 16 Potassium Carbonate Anhydrous, Granular 584-08-7 P2857341 Titan 17 6-Hydroxypyridine-2-carboxylic acid 19621-92-2 D23040055 Shanghai Shaoyuan 18 2,6-Dimethylaniline 87-62-7 P2954244 Titan 19 Dimethyl sulfoxide 67-68-5 P3174042 Titan 20 1-tert-Butyloxycarbonyl-1-methylhydrazine 21075-83-2 R23093769 Shanghai Shaoyuan 21 N1, N2-Bis(2,5-dimethyl-1H-pyrrol-1-yl)oxalamide 289708-48-1 Titan 22 Hexadecyltrimethylammonium bromide 57-09-0 PIBURXAX Anaiji 23 Ethyl pyruvate 617-35-6 P2432559 Titan 24 2-Bromopyridine-4-carboxaldehyde 118289-17-1 FLX681 Peter 25 n-Butyl lithium (1.6M / 15%) n-hexane solution 109-72-8 PG5URJDR Anaiji 26 dimethylformamide 68-12-2 K2321131 Aladdin 27 Ethyl acrylate 140-88-5 J2121251 Aladdin 28 (1R, 2R)-1-Amino-2-(dimethylamino)cyclohexane 320778-92-5 P2832979 Titan 29 Phenyl thioisocyanate 103-72-0 C16515779 Maclean 30 Quinine 130-95-0 DGU980 Peter 31 Quinidine 56-54-2 R23083839 Shanghai Shaoyuan 32 3,5-Bis(trifluoromethyl)benzenesulfonyl chloride 39234-86-1 CNC497 Peter 33 3,5-Bis(trifluoromethyl)phenylisothiocyanate 23165-29-9 DSV644 Peter 34 3-[[3,5-Bis(trifluoromethyl)phenyl]amino]-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-3-cyclobutene-1,2-dione 1263205-96-4 P2141437 Titan 35 Novozym 435 9001-62-1

[0058] In Table 1, the materials No. 28-33 are raw materials for chiral catalysts. The starting materials and some catalysts come from the exploration platform, Anaiji Chemical and Network Technology Platform. Some catalysts are synthesized by ourselves. References: 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.

[0059] The present invention provides a method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization, the method comprising the following steps:

[0060] a) the compound represented by formula I is subjected to alcoholysis catalyzed by organic small molecules or enzymes to obtain a compound represented by formula III with high chiral purity;

[0061] b) the compound represented by formula III is reacted with a methyl metal reagent to obtain a compound represented by formula IV;

[0062] c) reducing the compound represented by formula IV to obtain the compound represented by formula V;

[0063] d) the compound represented by formula VA is subjected to copper-catalyzed hydrazine reaction to obtain the compound represented by formula VI;

[0064] e) the compound represented by formula VI is subjected to acid-catalyzed Fisher ring closure with a pyruvic acid derivative to obtain a compound represented by formula VII;

[0065] Alternatively, step d) is replaced by step f),

[0066] f) the compound represented by formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to obtain a compound represented by formula VIII;

[0067] g) the compound represented by formula VIII is cyclized with an acrylic acid derivative to obtain a compound represented by formula IX;

[0068] Wherein, the compound shown in formula I: ;

[0069] The compound shown in formula III: ;

[0070] The compound shown in formula IV: ;

[0071] The compound represented by formula V: ;

[0072] The compound represented by formula VA: ;

[0073] The compound shown in formula VI: ;

[0074] The compound shown in formula VII: ;

[0075] The compound represented by formula VB: ;

[0076] The compound represented by formula VIII: ;

[0077] The compound represented by formula IX: ;

[0078] Wherein, X is Halogen (Cl, Br, I), -OTf, -OMs or -OTs; Y is C or N; R 1 is C1-C6 alkyl or benzyl; R 2 is H, Me, Et, iPr or Bn; R 3 is H or Boc; Z is -OR 4 ; R 4 C1-C6 alkyl or -NR 5 R 6 ; R 5 is a C1-C3 alkyl group; R 6 It is phenyl or substituted phenyl.

[0079] See also Figure 2 The specific steps of the method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization of the present invention are:

[0080] 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-HaiZhao; et al, Organic Process Research&Development 2010, 14, 612–616).

[0081] 2. Dissolve the compound shown in formula I in a solvent, add methanol and a catalyst, react at 0-50° C. until the reaction is completed, and obtain an intermediate shown in formula III through post-treatment;

[0082] Alternatively, the compound shown in formula II is dissolved in a solvent, an enzyme catalyst is added, and the reaction is carried out in a buffer salt system until the reaction is completed, and then the intermediate shown in formula III is obtained through post-treatment.

[0083] The compound shown in formula II: ;

[0084] Wherein, X is Halogen (Cl, Br, I), -OTf, -OMs or -OTs; Y is C or N; R 1 It is a C1-C6 alkyl group or a benzyl group.

[0085] 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 the substrate for the alcoholysis reaction is 1.0-10.0 equivalents.

[0086] The catalyst used in this step is selected from commercial enzymes, such as enzyme Novozym 435, CAL-B, and small molecules including but not limited to having the following structural features:

[0087] .

[0088] Preferably, the catalyst used in this step is selected from commercial enzymes, such as enzyme Novozym 435, aminolipase AYS, lipase PPL and the like.

[0089] 3. The substance represented by the intermediate represented by formula III is dissolved in a solvent tetrahydrofuran, and a methyl metal reagent is added dropwise at low temperature. After the reaction is completed, a compound represented by formula IV is obtained by post-treatment.

[0090] Figure 2 In the above, Me-M is MeLi, MeMgX (X is Cl, Br or I).

[0091] In one embodiment of the present invention, the methyl metal reagent includes one of methyl lithium, methyl magnesium bromide, methyl magnesium chloride, and methyl magnesium iodide; and the amount of the methyl metal reagent used is 3.0-5.0 equivalents.

[0092] 4. Dissolve the substance shown in Formula IV in a solvent, add a reducing agent, and obtain a compound shown in Formula V through post-treatment.

[0093] In one embodiment of the present invention, the reducing agent used to reduce the lactone includes DIBAL-H and Et3SiH.

[0094] 5. The substance shown in formula VA is dissolved in a solvent, and the substrate hydrazine, copper catalyst and ligand are added. The reaction is carried out at 40-100° C. under a nitrogen atmosphere until the reaction is completed, and the compound shown in formula VI is obtained after post-treatment.

[0095] In one embodiment of the present invention, the copper catalyst includes CuI or CuBr, and the amount of the copper catalyst is 0.01-1.0 equivalent; the ligand used in the reaction includes N-(2,6-dimethylphenyl)-6-hydroxypyridine amide or N1, N2-bis(2,5-dimethyl-1H-pyrrol-1-yl)oxalamide; the substrate of the hydrazine reaction includes hydrazine hydrate, 1-tert-butoxycarbonyl-1-methylhydrazine, 1-tert-butoxycarbonyl-1-ethylhydrazine or 1-tert-butoxycarbonyl-1-benzylhydrazine.

[0096] 6. Dissolve the substance shown in Formula VI in a solvent, add a pyruvic acid derivative, add an acid catalyst, react at 40-100° C. until the reaction is completed, and obtain a compound shown in Formula VII through post-treatment.

[0097] In one embodiment of the present 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.

[0098] 7. The substance represented by formula VB is dissolved in a solvent, a metal reagent is added dropwise at low temperature for lithiation, and then reacted with DMF, and the compound represented by formula VIII is obtained after post-treatment.

[0099] In one embodiment of the present invention, the metal reagent includes n-butyl lithium, sec-butyl lithium, isopropyl magnesium chloride or isopropyl magnesium bromide.

[0100] 8. The substance represented by formula VIII is dissolved in a solvent, an acrylic acid derivative is added, and the ring is closed by catalytic reaction, and the compound represented by formula IX is obtained by post-treatment.

[0101] In one embodiment of the present invention, the acrylic acid derivative includes ethyl acrylate, methyl acrylate, benzyl acrylate or N-methyl-N-phenylacrylamide.

[0102] The following provides the synthesis of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (VII) and the synthesis of ethyl (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate (IX) through specific examples.

[0103] Synthesis of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (VII).

[0104] Example 1

[0105] Starting material synthesis:

[0106] Synthesis of (4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA):

[0107] Under nitrogen protection, 285 grams of p-bromobenzaldehyde, 1500 mL of ethanol, and 400 grams of ethyl acetoacetate were added to a 5L four-necked bottle at room temperature. Nitrogen replacement, 20 grams of piperidine were added, and the reaction was carried out at room temperature for 1 day. LCMS detection showed that the reaction was complete, and the filter cake was directly filtered, and the filter cake was washed with 550 mL of ethanol, dried and air-dried to obtain 460 grams of 2,4-diacetyl-3-(4-bromophenyl) glutaric acid diethyl ester, an off-white solid, with a yield of 70.0% and a purity of 93.9%; 460 grams of 2,4-diacetyl-3-(4-bromophenyl) glutaric acid diethyl ester and 1400 mL of ethanol were added to a 5L four-necked bottle at room temperature. 259.2 grams of sodium hydroxide were dissolved in 1400 mL of water, and then added to the reaction, and the temperature was raised to 80°C. The system gradually dissolved and clarified, and the reaction was continued at 80°C for 2 hours. LCMS detected that the reaction was complete, and the temperature was cooled to room temperature. First, most of the ethanol was removed by decompression in a 40°C water bath, then 5000mL of water was added for dilution, ice was cooled, and 594mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3. A large amount of light yellow solid was precipitated, which was filtered and the filter cake was washed with 1000mL of water, drained and air-dried. The sample was then dried at 45°C for 4 hours to obtain 278g of 3-(4-bromophenyl)pentanedioic acid as a light yellow solid with a yield of 90.6% and a purity of 98.2%.

[0108] Under nitrogen protection, 1600 mL of acetyl chloride was added to a 5L four-necked bottle at room temperature, and 275 g of 3-(4-bromophenyl)pentanedioic acid was added in batches, and then the temperature was raised to 80°C, the raw materials gradually dissolved, and the internal temperature was 58°C; the reaction was continued at 80°C for 2 hours. The reaction was complete as detected by methanol-derived LCMS, and the mixture was cooled to room temperature, desolventized in a 40°C water bath, and then 1000 mL of n-heptane was added for pulping and filtration, washed with 500 mL of n-heptane, and dried. The solid was desolventized in a 40°C water bath, and finally 212 g of off-white solid was obtained, with a yield of 81.4% and a purity of 97.4%.

[0109] The structural formula of the substance shown in Formula IA: .

[0110] Synthesis of dimethyl 3-(4-bromophenyl)glutarate (II-A):

[0111] In a 250mL three-necked flask, under nitrogen protection, 10 g of 3-(4-bromophenyl)pentanedioic acid, 100 mL of methanol, and 300 mg of concentrated sulfuric acid were added in sequence, and refluxed at 70°C overnight. After the reaction was completed, the mixture was cooled to room temperature and desolventized in a 40°C water bath. The crude residue was diluted with 200 mL of ethyl acetate, washed with 50 mL of a half-saturated sodium bicarbonate aqueous solution and saturated brine, respectively, the organic phase was collected, dried and filtered with anhydrous sodium sulfate, and the filtrate was desolventized in a 40°C water bath to obtain 9 g of dimethyl 3-(4-bromophenyl)pentanedioate as a light brown solid with a yield of 82% and a purity of 96.5%.

[0112] The structural formula of the substance shown in formula II-A: , where R 1 For me.

[0113] Example 2

[0114] The structural formula of the substance shown in formula III-A: , where R 1 For me.

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

[0116] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained 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 to a 500 mL three-necked flask at room temperature and reacted for 1 day. The reaction was completed by LCMS detection, and the mixture was washed with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The mixture was crystallized using a n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.7 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 76.8%, a purity of 99.5%, and an ee value of 92.3%.

[0117] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0118] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained 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 to a 500 mL three-necked flask at room temperature and reacted for 1 day. The reaction was completed by LCMS detection, and the mixture was washed with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The mixture was crystallized using a n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.4 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 63.3%, a purity of 99.1%, and an ee value of 97.7%.

[0119] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0120] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained 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-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)thiourea were added in sequence into a 500 mL three-necked flask at room temperature and reacted for 1 day. The reaction was completed by LCMS detection. The product was washed with 0.1N hydrochloric acid and saturated brine, and the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The product was crystallized using an n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.6 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) with a yield of 71.4%, a purity of 99.0%, and an ee value of 92.5%.

[0121] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0122] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained in Example 1, 200 mL of methyl tert-butyl ether, 2 g of methanol, and 0.04 g of N-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)-3,5-bis(trifluoromethyl)benzenesulfonamide were added in sequence into a 500 mL three-necked flask at room temperature and reacted for 1 day. The reaction was completed by LCMS detection. The product was washed with 0.1N hydrochloric acid and saturated brine, and the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The product was crystallized using an n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.52 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) with a yield of 67.9%, a purity of 98.6%, and an ee value of 93.5%.

[0123] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0124] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained 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 to a 500 mL four-necked bottle at room temperature, and the mixture was reacted at room temperature for 1 day. The reaction was completed by LCMS detection, and the mixture was washed with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The mixture was crystallized using a n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.54 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 69.0%, a purity of 98.5%, and an ee value of 94.1%.

[0125] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0126] Under nitrogen protection, 2 g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione (IA) obtained in Example 1, 240 mL of methyl tert-butyl ether, 2.4 g of methanol, and 200 mg of Novozym435 lipase were added to a 500 mL four-necked bottle at room temperature, and reacted at room temperature for 5 days. The reaction was completed by LCMS detection, filtered, washed with 40 mL of methyl tert-butyl ether, and the filtrate was washed with 0.1 N hydrochloric acid and saturated brine respectively. The upper organic phase was collected and dried with anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The filtrate was crystallized using a n-heptane and toluene system, filtered, and the filtrate was desolvated to an off-white solid to obtain 1.14 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 51.0%, a purity of 96%, and an ee value of 98.5%.

[0127] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0128] In a 100 mL three-necked flask, under nitrogen protection, 2 g of 3-(4-bromophenyl) dimethyl glutarate (II-A) obtained in Example 1, 16 mL of buffer solution (pH = 7.2), and 200 mg of aminolipase AYS were added in sequence, and the reaction was allowed to react overnight at room temperature. LCMS detected that the reaction was complete, and the reaction pH dropped to 5. The pH was adjusted to 2 with concentrated hydrochloric acid, filtered, washed with 50 mL of ethyl acetate, the filtrate was extracted with ethyl acetate, washed with saturated brine, the upper organic phase was collected and dried with anhydrous sodium sulfate, filtered, the filtrate was desolvated under reduced pressure, and a n-heptane and toluene system was used for crystallization, filtered, the filtrate was collected, and desolvated to an off-white solid to obtain 1.35 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A), with a yield of 71.0%, a purity of 95%, and an ee value of 94.2%.

[0129] Alternatively, step 1: see Figure 2 , Synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0130] In a 100 mL three-necked flask, under nitrogen protection, 2 g of 3-(4-bromophenyl) diethyl glutarate (II-B) obtained in Example 1, 16 mL of buffer solution (pH = 7.2), and 200 mg of aminolipase AYS were added in sequence, and the reaction was allowed to react overnight at room temperature. LCMS detected that the reaction was complete, and the reaction pH dropped to 5. The pH was adjusted to 2 with concentrated hydrochloric acid, filtered, washed with 50 mL of ethyl acetate, the filtrate was extracted with ethyl acetate, washed with saturated brine, the upper organic phase was collected and dried with anhydrous sodium sulfate, filtered, the filtrate was desolvated under reduced pressure, and a n-heptane and toluene system was used for crystallization, filtered, the filtrate was collected, and desolvated to an off-white solid to obtain 1.14 g of (S)-3-(4-bromophenyl)-5-ethoxy-5-oxopentanoic acid (III-A), with a yield of 62.0%, a purity of 96%, and an ee value of 94.4%.

[0131] Example 3

[0132] The structural formula of the substance shown in formula IV-A is: .

[0133] Step 2: See Figure 2 , Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0134] In a 1000mL three-necked flask, under nitrogen protection, 10g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 and 100mL tetrahydrofuran were added in sequence, the temperature was lowered to -30°C, 44.5mL methylmagnesium chloride (3mol / L in THF) was added dropwise, the temperature was controlled not to exceed -10°C, and the reaction was carried out at 0°C for 2 hours after the addition was completed. After the reaction was completed by LCMS detection, the reaction solution was poured into 150mL of ice 1N hydrochloric acid aqueous solution to quench, extracted with ethyl acetate, and then washed with saturated brine, the organic phase was collected, dried and filtered with anhydrous sodium sulfate, the filtrate was spin-dried, and desolventized under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was drained to obtain 10.4 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A) as a white solid with a yield of 75.3%, a purity of 98.7%, and an ee value of 96.8%.

[0135] Alternatively, step 2: see Figure 2 , Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0136] In a 1000mL three-necked flask, under nitrogen protection, 10g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 and 100mL tetrahydrofuran were added in sequence, the temperature was lowered to -40°C, 45mL methylmagnesium chloride (3mol / L in THF) was added dropwise, the temperature was controlled not to exceed -10°C, and the reaction was carried out at 10°C for 2 hours after the addition was completed. After the reaction was completed by LCMS detection, the reaction solution was poured into 150mL of ice 1N hydrochloric acid aqueous solution to quench, extracted with ethyl acetate, and then washed with saturated brine, the organic phase was collected, dried and filtered with anhydrous sodium sulfate, the filtrate was spin-dried, and desolventized under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was drained to obtain 11.5 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A) as a white solid with a yield of 83.3%, a purity of 97.8%, and an ee value of 94.8%.

[0137] Alternatively, step 2: see Figure 2 , Synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A):

[0138] In a 1000mL three-necked flask, under nitrogen protection, 10g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) prepared in Example 2 and 100mL tetrahydrofuran were added in sequence, the temperature was lowered to -40°C, 130mL methyl lithium (1mol / L 2-MeTHF) was added dropwise, the temperature was controlled not to exceed -10°C, and the reaction was carried out at 0°C for 2 hours after the addition was completed. After the reaction was completed by LCMS detection, the reaction solution was poured into 150mL of ice 1N hydrochloric acid aqueous solution to quench, extracted with ethyl acetate, and then washed with saturated brine, the organic phase was collected, dried and filtered with anhydrous sodium sulfate, the filtrate was spin-dried, and desolventized under reduced pressure. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was drained to obtain 12.3 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-A) as a white solid with a yield of 89.1%, a purity of 95.8%, and an ee value of 91.8%.

[0139] Example 4

[0140] The structural formula of the substance shown in formula VA is: .

[0141] Step 3: See Figure 2 , Synthesis of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA):

[0142] 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 in sequence, 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 completed, the mixture was kept at -70°C for 1 hour. LCMS detected that the reaction was complete, and the reaction solution was poured into 300 mL of 10% wt potassium sodium tartrate aqueous solution to quench, stirred for 1 hour until clarified and layered, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure to obtain 9.6 g of (4R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-ol as a white solid. The solid was added to a 250 mL three-necked flask, 100 mL of DCM, 11 g of triethylsilane, cooled to 0°C in an ice-water bath, 5.7 g of boron trifluoride ether was added dropwise, and then reacted at 0°C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was poured into 100 mL of iced half-saturated sodium bicarbonate aqueous solution to quench, stirred until no bubbles were generated, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure to obtain a colorless oil, which was crystallized from n-heptane and ethyl acetate to obtain 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%.

[0143] Example 5

[0144] The structural formula of the substance shown in formula VI is: , where R 2 =H,R 3 =H.

[0145] Step 4: See Figure 2 , Synthesis of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI):

[0146] In a 100 mL three-necked flask, magnetic stirring and nitrogen protection were used to sequentially add 18 mg of cuprous iodide, 41 mg of N1, N2 bis(2,5-dimethyl-1H-pyrrol-1-yl)oxamide, 95 mg of potassium phosphate, 41 mg of hexadecyltrimethylammonium bromide, and then 1 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4 and 0.25 mL of water, and nitrogen was replaced 3 times, and the reaction was carried out at 80°C for 15 minutes. Then the temperature was lowered to room temperature, and 853 mg of potassium phosphate and 450 mg of 85%wt hydrazine hydrate were added, and nitrogen was replaced 3 times, and then the reaction was carried out at 80°C overnight. The mixture 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 brine. The organic phase was collected, and concentrated hydrochloric acid was added dropwise to adjust the pH to 3. A large amount of solid was precipitated, filtered, and the filter cake was washed with 10 mL of dichloromethane, dried, and desolventized 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) as an off-white solid with a yield of 70.1% and a purity of 96.5%.

[0147] Alternatively, step 4: see Figure 2 , Synthesis of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VI):

[0148] In a 100 mL three-necked flask, magnetic stirring and nitrogen protection were used to sequentially add 62 mg of cuprous iodide, 143 mg of N1, N2 bis(2,5-dimethyl-1H-pyrrol-1-yl)oxamide, 332 mg of potassium phosphate, 143 mg of hexadecyltrimethylammonium bromide, and then 3.5 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 4 and 0.9 mL of water, and nitrogen was replaced 3 times, and the reaction was carried out at 80°C for 15 minutes. Then the mixture was cooled to room temperature, and 2987 mg of potassium phosphate and 1.54 mg of 85%wt hydrazine hydrate were added, and nitrogen was replaced 3 times, and then the reaction was carried out at 80°C overnight. The mixture 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. The organic phase was collected, and concentrated hydrochloric acid was added dropwise to adjust the pH to 3. A large amount of solid was precipitated, filtered, and the filter cake was washed with 30 mL of dichloromethane, dried, and desolventized 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) as an off-white solid with a yield of 83.2% and a purity of 96.5%.

[0149] The structural formula of the substance shown in formula VI is: , R 2 =Me,R 3 =Boc.

[0150] 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):

[0151] In a 100 mL three-necked flask, 57 mg of cuprous iodide, 61 mg of N1, N2-bis(2,5-dimethyl-1H-pyrrol-1-yl)oxamide, and 772 mg of potassium carbonate were added in sequence with magnetic stirring and nitrogen protection. The nitrogen atmosphere was replaced 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 nitrogen atmosphere was replaced three times, and then the reaction was carried out at 80° C. overnight. LCMS detected that most of the raw materials were converted into products. The reaction temperature was cooled to room temperature and filtered. The filter cake was washed with 40 mL of ethyl acetate, and the filtrate was poured into 60 mL of ice water for quenching. The mixture was extracted with ethyl acetate and washed with saturated brine. 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-filtered on a silica gel column (heptane / EA=6:1) to obtain 475 mg of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B) as a colorless oil with a yield of 19.1% and a purity of 95%.

[0152] 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):

[0153] In a 250 mL three-necked flask, 50 mg of cuprous bromide, 108 mg of N-(2,6-dimethylphenyl)-6-hydroxypicolinamide, and 1.54 g of potassium carbonate were added in sequence under magnetic stirring and nitrogen protection. The nitrogen atmosphere was replaced 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 nitrogen atmosphere was replaced three times, and the reaction was carried out at 80° C. overnight. The reaction was completed by LCMS detection, and the temperature was cooled to room temperature and filtered. The filter cake was washed with 40 mL of ethyl acetate, and the filtrate was poured into 60 mL of ice water for quenching. The mixture was extracted with ethyl acetate and washed with saturated brine. 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-filtered on a silica gel column (heptane / EA=6:1) to obtain 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) as a colorless oil with a yield of 80.3% and a purity of 96%.

[0154] Example 6

[0155] The structural formula of the substance shown in formula VII: , where Z is OEt.

[0156] Step 5: See Figure 2 , Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0157] In a 250 mL three-necked flask, 20 mL of ethanol and 4 g of concentrated sulfuric acid were mixed, cooled to room temperature, and then 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 then reacted at 80°C for 4 hours. After LCMS detection, the reaction was completed, cooled to room temperature, and most of the ethanol was removed by decompression in a 40°C water bath, and then poured into 50 mL of water for quenching, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected and dried and filtered with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and 820 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) was obtained, with a yield of 45.4%, a purity of 97.2%, and an ee value of 95.7%.

[0158] Alternatively, step 5: see Figure 2 , Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0159] In a 250 mL three-necked flask, 20 mL of toluene and 5 g of polyphosphoric acid were mixed, and 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 were added, and then reacted at 100°C for 4 hours. After the reaction was completed by LCMS detection, the mixture was cooled to room temperature, poured into 50 mL of water for quenching, extracted with toluene, washed with saturated brine, and concentrated under reduced pressure. 870 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) was obtained by silica gel column chromatography, with a yield of 48.2%, a purity of 97.2%, and an ee value of 96.9%.

[0160] Alternatively, step 5: see Figure 2 , Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0161] In a 250 mL three-necked flask, 20 mL of ethanol and 4 g of concentrated sulfuric acid were mixed, cooled to room temperature, and then 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, and then reacted at 80°C for 4 hours. After LCMS detection, the reaction was completed, cooled to room temperature, and most of the ethanol was removed by decompression in a 40°C water bath, and then poured into 50 mL of water for quenching, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected and dried and filtered with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and 980 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) was obtained, with a yield of 54.4%, a purity of 95.2%, and an ee value of 94.7%. The NMR spectrum of the obtained (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) is shown in Figure 3 , see the chiral diagram of the racemate Figure 4 See Table 2 for the chirality diagram of a single chiral target. Figure 5 Table 3.

[0162] Table 2

[0163] Retention time Peak area Peak area ratio Peak height 1 4.929 9582978 49.44 1017767 2 8.160 9799399 50.56 611174

[0164] Table 3

[0165] Retention time Peak area Peak area ratio Peak height 1 4.937 120780 1.55 14758 2 8.198 7678013 98.45 483093

[0166] Alternatively, step 5: see Figure 2 , Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII):

[0167] In a 250 mL three-necked flask, with magnetic stirring and nitrogen protection, 2 g of (S)-2-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (VI-B) obtained in Example 5, 765 mg of ethyl pyruvate, and 20 mL of ethanol were added in sequence, and 1 g of trimethylsilyl chloride was added dropwise at room temperature, followed by reaction at 80°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and desolventized on a 40°C water bath to remove most of the ethanol. The mixture was then poured into 50 mL of water to quench, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and crystallized from n-heptane and ethyl acetate to obtain 732 mg of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VII) as an off-white solid with a yield of 40.6%, a purity of 96.27%, and an ee value of 93.9%.

[0168] Synthesis of ethyl (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate (IX).

[0169] Example 7

[0170] Synthesis of starting materials:

[0171] Synthesis of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB):

[0172] Under nitrogen protection, mechanical stirring and nitrogen protection were performed in a 5L four-necked bottle at room temperature, and 200 grams of 2-bromoisonicotinaldehyde, 1000 mL of ethanol, and 421.6 grams of ethyl acetoacetate were added in sequence. Nitrogen replacement was performed, and 13.8 grams of piperidine were added and reacted at room temperature for 1 day. LCMS detected that the reaction was complete, and the filter cake was directly filtered, and 400 mL of ethanol was added to wash the filter cake, and it was drained and dried to obtain 365 grams of 2,4-diacetyl-3-(2-bromopyridin-4-yl) glutaric acid diethyl ester, an off-white solid, with a yield of 79.1% and a purity of 96%; 365 grams of 2,4-diacetyl-3-(2-bromopyridin-4-yl) glutaric acid diethyl ester and 1095 mL of ethanol were added in a 5L four-necked bottle at room temperature. 205.1 grams of sodium hydroxide was dissolved in 1095 mL of water, cooled to room temperature and then added to the reaction, heated to 40°C, the system gradually dissolved and clarified, and continued to react at 40°C for 2 hours. LCMS detected that the reaction was complete, cooled to room temperature, first desolventized on a 40°C water bath to remove most of the ethanol, then diluted with 1825 mL of water, cooled with ice, and 448 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3, a large amount of off-white solid was precipitated, filtered, the filter cake was washed with 1000 mL of water, drained and dried, and the sample was dried at 45°C for 4 hours to obtain 182.5 grams of 3-(2-bromopyridin-4-yl)pentanedioic acid, an off-white solid, with a yield of 74.4% and a purity of 96%.

[0173] Under nitrogen protection, 180 g of 3-(2-bromopyridin-4-yl)pentanedioic acid, 1800 mL of toluene, and 191.2 g of acetic anhydride were added in batches in a 5L four-necked bottle at room temperature, and then the temperature was raised to 110°C, and the raw materials gradually dissolved; the reaction was continued at 110°C for 5 hours. The reaction was complete as detected by methanol-derived LCMS, and the mixture was cooled to room temperature, desolventized in a 40°C water bath, and then 1000 mL of n-heptane was added for pulping and filtration, washed with 500 mL of n-heptane, and dried. The solid was desolventized in a 40°C water bath, and finally 126.5 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB) was obtained as a light yellow solid with a yield of 75.0% and a purity of 94%.

[0174] The structural formula of the substance shown in Formula IB: .

[0175] Example 8

[0176] The structural formula of the substance shown in formula III-B: , where R 1 For me.

[0177] Step 1: See Figure 2 , Synthesis of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B):

[0178] Under nitrogen protection, 2 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB) obtained 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 to a 500 mL four-necked bottle at room temperature, and the mixture was reacted at room temperature for 1 day. The reaction was completed by LCMS detection, and the mixture was washed with 0.1 N hydrochloric acid and saturated brine, the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The mixture was crystallized using a n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.45 g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B), with a yield of 65.0%, a purity of 99.5%, and an ee value of 94.5%.

[0179] Alternatively, for step 1, see Figure 2 , Synthesis of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B):

[0180] Under nitrogen protection, 2 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione (IB) obtained 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-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)thiourea were added in sequence into a 500 mL four-necked flask at room temperature and reacted at room temperature for 1 day. The reaction was completed by LCMS detection. The product was washed with 0.1N hydrochloric acid and saturated brine, and the upper organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure. The product was crystallized using an n-heptane and toluene system, filtered, and the filtrate was collected and desolvated to an off-white solid to obtain 1.15 g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B) with a yield of 51.5%, a purity of 98.5%, and an ee value of 92.5%.

[0181] Example 9

[0182] The structural formula of the substance shown in formula IV-B is: .

[0183] Step 2: See Figure 2 , Synthesis of (R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-B):

[0184] In a 1000mL three-necked flask, under nitrogen protection, 10g (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B) obtained in Example 8 and 100mL tetrahydrofuran were added in sequence, the temperature was lowered to -40°C, 38mL methylmagnesium chloride (3mol / L in THF) was added dropwise, the temperature was controlled not to exceed -10°C, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed by LCMS detection, the reaction solution was poured into 150mL of iced 1N hydrochloric acid aqueous solution to quench, extracted with ethyl acetate, and then washed with saturated brine, the organic phase was collected, dried and filtered with anhydrous sodium sulfate, and the filtrate was desolvated 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 drained to obtain 6.8 g of (R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-one (IV-B) as a white solid with a yield of 73.1%, a purity of 98.7%, and an ee value of 96.2%.

[0185] Example 10

[0186] The structural formula of the substance shown in formula VB is: .

[0187] Step 3: See Figure 2 , Synthesis of (S)-2-bromo-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine (VB):

[0188] 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 in sequence, 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 completed, the mixture was kept at -70°C for 1 hour. LCMS detected that the reaction was complete, and the reaction solution was poured into 300 mL of 10% wt potassium sodium tartrate aqueous solution to quench, stirred for 1 hour until clarified and layered, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure to obtain 10 g of (4R)-4-(2-bromopyridin-4-yl)-6,6-dimethyltetrahydro-2H-pyran-2-ol as a white solid. The solid was added to a 250 mL three-necked flask, 100 mL of DCM, 11 g of triethylsilane, cooled to 0°C in an ice-water bath, 5.7 g of boron trifluoride etherate was added dropwise, and then reacted at 0°C for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was poured into 100 mL of iced half-saturated sodium bicarbonate aqueous solution to quench, stirred until no bubbles were generated, 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, which was crystallized from n-heptane and ethyl acetate to obtain 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%.

[0189] Embodiment 11

[0190] The substance represented by formula VIII: .

[0191] Step 4: See Figure 2 , Synthesis of (S)-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridinecarboxaldehyde (VIII):

[0192] In a 500 mL three-necked flask, 10 g of (S)-2-bromo-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine (VB) obtained in Example 10 and 100 mL of tetrahydrofuran were added in sequence, the temperature was cooled to -70°C in a dry ice ethanol bath, 55.7 mL of n-butyl lithium solution (1 mol / L in THF) was added dropwise, and the temperature was kept at -70°C for half an hour after the addition was completed. Then 27.1 g of DMF was added dropwise, and the temperature was controlled not to exceed -65°C. After the addition was completed, the temperature was slowly raised to 0°C and reacted for 1 hour. LCMS detected that the reaction was complete. The reaction solution was poured into 100 mL of ice-cold saturated ammonium chloride aqueous solution to quench, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure in a 40°C water bath and crystallized with n-heptane and ethyl acetate to obtain 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%.

[0193] Example 12

[0194] The substance represented by formula IX: , where Z is OEt.

[0195] Step 5: See Figure 2 , Synthesis of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester (IX):

[0196] In a 100 mL three-necked flask, with magnetic stirring and nitrogen protection, 5 g of (S)-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridinecarboxaldehyde (VIII) obtained in Example 11, 4.6 g of ethyl acrylate, and 1.7 g of DABCO were added in sequence and reacted at room temperature for 12 hours. The reaction was complete by LCMS detection. Ethyl acrylate was removed under reduced pressure on a 40°C water bath. The crude residue was dissolved in 100 mL of ethyl acetate, washed with water and saturated brine respectively, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure on 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, which was added to a 250 mL three-necked flask, and then 40 mL of dichloromethane and 2.7 g of pyridine were added. Then, the mixture was cooled to 0°C in an ice-water bath, 2.7 g of acetyl chloride was added dropwise, and then reacted at room temperature for 1 hour. The reaction was complete by LCMS detection. The reaction solution was poured into an ice-saturated sodium bicarbonate aqueous solution to quench, stirred at room temperature for half an hour, extracted with DCM, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure on a 40°C water bath to obtain a crude residue. The crude residue was dissolved in 100 mL of toluene and refluxed for 16 hours. The reaction was complete when detected by LCMS. The solvent was removed under reduced pressure in a 40°C water bath and purified by silica gel column chromatography (n-heptane / ethyl acetate = 3:1) to obtain 3.87 g of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester (IX) with a yield of 55.3% and a purity of 95.5%.

[0197] It can be seen that the cyclic anhydride as shown in formula I or the symmetrical dicarboxylic acid ester as shown in formula II synthesized by the method in the literature in the present invention is subjected to catalytic alcoholysis to obtain the target stereo configuration of high ee value as shown in formula III intermediate, which is reacted with a methyl metal reagent to obtain a lactone as shown in formula IV, and the lactone as shown in formula IV is reacted with a methyl metal reagent to obtain a ring-closed dimethylated compound as shown in formula VA or a compound as shown in formula VB, and the compound as shown in formula VA is subjected to copper catalysis to obtain the corresponding aryl hydrazine as shown in formula VI, and finally under acid catalysis, it is reacted with a pyruvic acid derivative to obtain the target product as shown in formula VII through Fisher indole ring closure; or the compound as shown in formula VB is converted into an aldehyde as shown in formula VIII through functional group conversion, and the latter is then subjected to Balis-Hillman reaction with an acrylic acid derivative and then ring-closed to generate a compound as shown in formula IX.

[0198] The present invention avoids the use of transition metal catalysts and SFC separation in the 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 technical route.

[0199] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization, characterized in that: The method comprises the following steps: a) The compound represented by formula I is subjected to organic small molecule catalysis or enzyme catalysis alcoholysis to obtain a compound represented by 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-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)thiourea, N-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinolin-2-yl)methyl)-3,5-bis(trifluoromethyl)benzenesulfonamide, 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-phenylthiourea, or Novozym 435 lipase; b) the compound represented by formula III is reacted with a methyl metal reagent to obtain a compound represented by formula IV; c) reducing the compound represented by formula IV to obtain the compound represented by formula V; d) the compound represented by formula VA is subjected to copper-catalyzed hydrazine reaction to obtain the compound represented by formula VI; e) the compound represented by formula VI is subjected to acid-catalyzed Fisher ring closure with a pyruvic acid derivative to obtain a compound represented by formula VII; Alternatively, step d) is replaced by step f): f) the compound represented by formula VB is treated with a metal reagent and reacted with N,N-dimethylformamide to obtain a compound represented by formula VIII; g) the compound represented by formula VIII is cyclized with an acrylic acid derivative to obtain a compound represented by formula IX; Wherein, the compound shown in formula I: ; The compound shown in formula III: ; The compound shown in formula IV: ; The compound represented by formula V: ; The compound represented by formula VA: ; The compound shown in formula VI: ; The compound shown in formula VII: ; The compound represented by formula VB: ; The compound represented by formula VIII: ; The compound represented by formula IX: ; Wherein, X is Cl, Br, I, -OTf, -OMs or -OTs; Y is C or N; R 1 is C1-C6 alkyl or benzyl; R 2 is H, Me, Et, iPr or Bn; R 3 is H or Boc; Z is -OR 4 ; R 4 C1-C6 alkyl or -NR 5 R 6 ; R 5 is a C1-C3 alkyl group; R 6 It is phenyl or substituted phenyl.

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

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

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

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

6. A method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization according to claim 1 or 2, characterized in that: In the step d), the copper catalyst is CuI or CuBr, and the amount of the copper catalyst is 0.01-1.0 equivalent.

7. A method for synthesizing an aromatic-substituted chiral tetrahydropyran ring by desymmetrization according to claim 1 or 2, characterized in that: In the step d), the ligand used in the reaction is N-(2,6-dimethylphenyl)-6-hydroxypyridine amide or N1,N2-bis(2,5-dimethyl-1H-pyrrol-1-yl)oxalamide; the substrate of the hydrazine 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 an aromatic-substituted chiral tetrahydropyran ring by desymmetrization according to claim 1 or 2, characterized in that: In the 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 an aromatic-substituted chiral tetrahydropyran ring by desymmetrization according to claim 1 or 2, characterized in that: In the step f), the metal reagent is n-butyl lithium, sec-butyl lithium, isopropyl magnesium chloride or isopropyl magnesium bromide.

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

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