Method for constructing Orforglipron pyran ring chirality through enzyme catalysis

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for constructing Orforglipron pyran ring chirality through enzyme catalysis, which comprises the following steps: step S1, taking SM1 and SM2 as raw materials, and reacting under the action of a palladium catalyst and a ligand to obtain INT-1; step S2; carrying out hydrogenation reduction on double bonds of the INT-1 under the catalysis of Pd / C to obtain INT-2; s3, carrying out hydrolysis resolution on the INT-2 in a solvent, a buffer salt system and enzyme catalysis to obtain a chiral pure intermediate INT-3; step S4, performing ring closing on the INT-3 through a Grignard reaction to synthesize a lactone intermediate INT-4; and S5, carrying out Diball-H reduction, quenching, dichloromethane extraction and anhydrous sodium sulfate drying on the INT-4, and then reducing by using triethyl silane to obtain the compound with the general formula A. Chirality is constructed through enzyme catalysis, isomer impurities do not need to be split and separated through SFC when the chirality is constructed, loss is reduced, the yield is increased, and a target product is obtained with high yield and high chiral selectivity; meanwhile, the cost is relatively reduced, and the cost is saved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for constructing orforglipron pyran ring chirality through enzyme catalysis. Background Art

[0002] The current GLP-1 agonists are basically subcutaneous injections, with different injection forms such as multiple injections per day, once a day, and once a week. They may be more troublesome to use. According to information provided by Novo Nordisk, Novoxin is currently (as of January 2024) the world's first and only oral glucagon-like peptide-1 receptor agonist (GLP-1RA), but because it is a peptide substance, the absorption rate is relatively low, and the bioavailability is only 1%; therefore, everyone is also looking for other drugs with similar effects and not easy to degrade. Orforglipron was developed in this context. It is a chemical substance, a small molecule that also acts on the GLP-1 receptor, but because it is not a protein, it will not be degraded by enzymes. Early pharmacokinetic studies have shown that whether or not to eat will not affect absorption. Because this drug is a non-peptide substance, it is easier to produce and has a lower cost, which also means that it has a price advantage and may be used by more people.

[0003] Compound A is a key chiral intermediate for the synthesis of Orforglipron. Currently, there are two patent documents for the synthesis of this intermediate. Patent WO2018056453A1 reports the preparation method of route 1, using 5-bromoindole-2-carboxylic acid ethyl ester as a raw material and (2,2-dimethyltetrahydro-2H-pyran-4-yl) zinc iodide to couple to obtain a racemic pyran intermediate, and then separate the isomers by SFC chiral resolution, and then obtain the target product by hydrolysis condensation;

[0004]

[0005] Another patent WO2022017338A1 reports the preparation method of route 2, using 5-bromoindole-2-carboxylic acid ethyl ester and 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as raw materials to obtain the product by coupling, and then hydrogenating to obtain the racemic pyran intermediate, and then separating the isomers by SFC chiral resolution, and then obtaining the target product by hydrolysis condensation;

[0006]

[0007] At present, these two methods mainly use SFC splitting to separate isomeric impurities when constructing chirality, which will inevitably lead to a loss of half, a relatively low yield, and a relatively high separation cost.

[0008] Another recent patent WO2024137426 reported a method for constructing chirality by Evans cofactor induction using 5-bromo-1H-indole-2-carboxylic acid as a raw material (route three). This method constructs chirality by cofactor induction, avoiding a large amount of material waste. However, this route uses a relatively expensive allylpalladium chloride dimer catalyst. Through our reference to the literature method preparation process, we also found that the chiral purity induced by Evans cofactor was only 85%.

[0009] Summary of the invention

[0010] The purpose of the present invention is to provide a method for constructing the chirality of Orforglipron pyran ring by enzyme catalysis, so as to solve the problem in the prior art that when constructing the chirality, the isomer impurities are mainly separated by SFC splitting, which will inevitably lead to a loss of half, a relatively low yield, and a relatively high separation cost.

[0011] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0012] A method for constructing orforglipron pyran ring chirality by enzyme catalysis, including intermediates

[0013]

[0014] The specific preparation steps are as follows:

[0015] Step S1, using SM1 and SM2 as raw materials, reacting under the action of palladium catalyst and ligand to obtain INT-1; step S2: INT-1 is hydrogenated and reduced to double bonds under Pd / C catalysis to obtain INT-2; step S3, INT-2 is hydrolyzed and resolved under solvent, buffer salt system and enzyme catalysis to obtain chiral pure intermediate INT-3; step S4, INT-3 is ring-closed to synthesize lactone intermediate INT-4 through Grignard reaction; step S5, INT-4 is reduced by Dibal-H, quenched, extracted with dichloromethane, dried with anhydrous sodium sulfate, and then reduced with triethylsilane to obtain a compound of general formula A; the reaction formula is as follows,

[0016]

[0017] ; wherein R1 is selected from -COOC 0-10 Alkyl, -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(substituted phenyl), -CONH(C 0-10 alkyl) or -CONH(substituted phenyl); R2 is selected from C 0-10 Alkyl; R3 is selected from C0-5 Alkyl; X is selected from Cl, Br, I or OTf.

[0018] A further technical solution is that in step S3, the enzyme is R9600, R9100, LIPASEAY30 or Lipozyme435.

[0019] A further technical solution is that in step S3, the solvent comprises one of water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile or a combination thereof.

[0020] A further technical solution is that in step S3, the buffer salt system comprises one or a combination of sodium bicarbonate solution, potassium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium acetate solution, potassium acetate solution, sodium phosphate solution, disodium hydrogen phosphate solution, sodium hydrogen phosphate solution, potassium phosphate solution, dipotassium hydrogen phosphate solution, and potassium hydrogen phosphate solution.

[0021] A further technical solution is that in step S1, the palladium catalyst is Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd(CN)2Cl2, allylpalladium(II) chloride dimer, 1,4-bis(diphenylphosphinobutane)palladium dichloride or dichlorobis(tricyclohexylphosphine)palladium.

[0022] A further technical solution is that in step S1, the ligand is XPhos, XantPhos, SPhos, BrettPhos, DaveSPhos, tBuXPhos, RuPhos, JoneSPhos, QPhos, AmPhos, MePhos, tetramethyltBuXPhos, P(tBu)3HBF4, PCy3HBF4, CataCXiumA, BINAP, DPEPhos, Dpbp, Dppb or Dppe.

[0023] A further technical solution is that in step S1, the combination of the palladium catalyst and the ligand is a combination of any palladium catalyst selected from the group consisting of Pd(OAc)2, Pd(CN)2Cl2, and allylpalladium(II) chloride dimer and the ligand XantPhos or RuPhos.

[0024] A further technical solution is that in step S1, the reaction condition is a coupling reaction under nitrogen protection at 90-110°C.

[0025] Compared with the prior art, the present invention has the following beneficial effects: the present invention constructs chirality through enzyme catalysis, and when constructing chirality, it is not necessary to separate isomeric impurities through SFC splitting, thereby reducing losses and improving yields. The yield of some steps can reach 95%, and the target product can be obtained with high chiral selectivity; at the same time, the cost is relatively reduced, saving costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the NMR of the final product of the example (wherein X is Br, R1 is -CONMePh, R2 is Et, and R3 is Me). DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0028] The following are two examples and a comparative example of constructing the chirality of the Orforglipron pyran ring by enzyme catalysis using the present invention.

[0029] The reaction formulas of the two embodiments are:

[0030]

[0031] Embodiment 1: wherein X is Br, R1 is -CONMePh, R2 is Et, and R3 is Me.

[0032] Step 1: At room temperature, 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (10 g), potassium carbonate (12.6 g), DMF (150 mL), purified water (15 mL), and diethyl glutaconate (6.8 g) were added to a 250 mL three-necked flask in sequence. After nitrogen substitution, Pd(OAc)2 (35 mg) and XantPhos (60 mg) were added to the reaction system. The temperature was raised to 110 °C and the reaction was carried out for 15 h. Samples were taken for monitoring. After confirming that the reaction is complete, cool to room temperature, add to 500 mL of ice water, and extract twice with ethyl acetate. After combining the ethyl acetate phases, wash twice with saturated brine, add activated carbon and anhydrous sodium sulfate, stir and dry to decolorize, remove color and residual palladium, filter on diatomaceous earth, and concentrate to remove ethyl acetate to obtain 11.1 g of white solid product (3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)pent-2-enedioic acid diethyl ester), with a yield of 86%.

[0033] Step 2: Add diethyl 3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)pent-2-enedioate (11.1 g), methanol (200 mL) and Pd / C (0.2 g) into a 500 mL single-mouth bottle, replace the gas with hydrogen, and react at room temperature for 20 h. Sampling and monitoring are performed to ensure that the reaction of the raw materials is complete. Filter the mixture with diatomaceous earth pad, add activated carbon to the filtrate, stir for 1 h, filter the mixture with diatomaceous earth pad, and concentrate under reduced pressure to obtain 10.8 g of white solid product (diethyl 3-(2-(phenyl)carbamoylmethyl)-1H-indol-5-yl)pentanedioate), with a yield of 97%.

[0034] Step 3: Add 3-(2-(phenyl)carbamoylmethyl)-1H-indol-5-yl)glutaric acid diethyl ester (10.8 g) and 1,4-dioxane (50 mL) into a 500 mL three-necked flask. After nitrogen substitution, add enzyme R9600 and 10% potassium dihydrogen phosphate solution (250 mL) and stir at room temperature for 24 hours. Then, remove the unreacted raw materials by MTBE extraction. The pH of the aqueous phase is adjusted to 5-6 with 4M hydrochloric acid. The product is extracted with ethyl acetate, dried and concentrated with sodium sulfate to obtain 9.0 g of product (5-ethoxy-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)-5-oxopentanoic acid), with a yield of 89% and a chiral purity of 98.9%.

[0035] Step 4: Add 5-ethoxy-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)-5-oxopentanoic acid (9.0 g) to a 500 mL three-necked flask, add THF (150 mL), replace with nitrogen three times, cool to 10 ° C, and add methyl bromide (2M in 2-Me-THF, 67 mL) was slowly added dropwise to the reaction system, the reaction temperature was controlled at 10-15°C, and the reaction was continued at 10-15°C for 5 h after the addition was completed. The reaction solution was poured into ice-cold dilute hydrochloric acid to quench the reaction, and extracted with ethyl acetate. The organic phases were combined and washed once with aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated to obtain a crude oil, which was then crystallized with ethanol and water to obtain 6.5 g of a white solid ((R)-5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide) with a yield of 78%, and the chiral purity was further increased to 99.5%.

[0036] Step 5: Add (R)-5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (6.5 g) and DCM (100 mL) into a 250 mL three-necked flask, replace with nitrogen and cool to -40°C, slowly drop Dibal-H (25 mL, 1 M) into the reaction system, control the reaction temperature not to exceed -40°C, naturally warm to room temperature after the addition is complete, and react for 3 h, pour the reaction solution into an ice-cold potassium sodium tartrate solution, stir and quench for 0.5 h, extract and separate, extract the aqueous phase twice with DCM, combine the organic phases, dry with sodium sulfate, transfer to a 1 L three-necked flask, add triethylsilane (6.5 g), stir and react at room temperature overnight, concentrate under reduced pressure to remove the solvent, and crystallize the residue with n-heptane to obtain 5.8 g of white solid with a yield of 92% and a chiral purity of 99.5%.

[0037] Example 2: Wherein X is Br, R1 is -CO2 i Pr, R2 is Et, and R3 is Me.

[0038] Step 1: At room temperature, add isopropyl 5-bromo-1H-indole-2-carboxylate (10 g), potassium carbonate (14.7 g), DMF (150 mL), purified water (15 mL), and diethyl glutaconate (7.9 g) into a 250 mL three-necked flask in sequence. After nitrogen substitution, add Pd(OAc)2 (35 mg) and XantPhos (60 mg) into the reaction system. After heating to 110 °C and reacting for 15 h, take samples for monitoring and determine After the reaction, the mixture was cooled to room temperature, added to 500 mL of ice water, and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed twice with saturated brine. Activated carbon and anhydrous sodium sulfate were added, stirred, dried and decolorized to remove color and residual palladium. The mixture was filtered through diatomaceous earth and concentrated to remove ethyl acetate to obtain 11.5 g of a white solid product ((E)-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pent-2-enedioic acid diethyl ester) with a yield of 83%.

[0039] Step 2: Add diethyl (E)-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pent-2-enedioate (11.5 g), methanol (200 mL) and Pd / C (0.2 g) into a 500 mL single-mouth bottle, replace the gas with hydrogen, and react at room temperature for 20 h. Sampling and monitoring are performed to ensure that the reaction of the raw materials is complete. Filter the mixture with diatomaceous earth pad, add activated carbon to the filtrate, stir for 1 h, filter the mixture with diatomaceous earth pad, and concentrate under reduced pressure to obtain 11 g of white solid product (diethyl 3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pentanedioate) with a yield of 96%.

[0040] Step 3: Add diethyl 3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)glutarate (11 g) and 1,4-dioxane (50 mL) into a 500 mL three-necked flask. After nitrogen substitution, add enzyme R9600 and 10% potassium dihydrogen phosphate solution (250 mL) and stir at room temperature for 24 hours. Then, remove the unreacted raw materials by MTBE extraction. The pH of the aqueous phase is adjusted to 5-6 with 4M hydrochloric acid. The product is extracted with ethyl acetate, dried and concentrated with sodium sulfate to obtain 8.1 g of product (5-ethoxy-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)-5-oxopentanoic acid (8.1 g)), with a yield of 79% and a chiral purity of 98.5%.

[0041] Step 4: Add 5-ethoxy-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)-5-oxopentanoic acid (8.1 g) to a 500 mL three-necked flask, add THF (150 mL), replace with nitrogen three times, cool to 10 ° C, and add methyl bromide (2M in 2-Me-THF, 56 mL) was slowly added dropwise to the reaction system, the reaction temperature was controlled at 10-15 ° C. After the addition was completed, the reaction was continued at 10-15 ° C for 5 hours, the reaction solution was poured into ice-cold dilute hydrochloric acid to quench the reaction, and extracted with ethyl acetate. The organic phases were combined and washed once with sodium bicarbonate aqueous solution, dried over sodium sulfate, and concentrated to obtain a crude oil, which was then crystallized with ethanol and water to obtain 4.8 g of a white solid (5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid isopropyl ester) with a yield of 65%, and the chiral purity was further improved to 99.1%.

[0042] Step 5: Add 5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid isopropyl ester (4.8 g) and DCM (100 mL) into a 250 mL three-necked flask, replace with nitrogen and cool to -40°C, slowly drop Dibal-H (17 mL, 1 M) into the reaction system, control the reaction temperature not to exceed -40°C, naturally warm to room temperature after the addition is complete and react for 3 h, pour the reaction solution into a frozen potassium sodium tartrate solution and stir to quench for 0.5 h, extract and separate, extract the aqueous phase twice with DCM, combine the organic phases, dry with sodium sulfate, transfer to a 1 L three-necked flask, add triethylsilane (4 g), stir and react at room temperature overnight, concentrate under reduced pressure to remove the solvent, and crystallize the residue with n-heptane to obtain 4 g of white solid with a yield of 87%.

[0043] Comparative Example:

[0044]

[0045] Step 1: Add 5-bromo-1H-indole-2-carboxylic acid (10 g), DMF (1.6 mL) and ACN (100 mL) to the reactor. Oxalyl chloride solution (4.8 mL) was mixed with ACN (20 mL) and added at a certain rate, and the temperature was kept below 30°C. After addition, the reaction was stirred vigorously at room temperature for 60 minutes. The reaction temperature was then adjusted to 5°C, and N-methylaniline (5.5 mL) was slowly added until the internal temperature was below 10°C. After stirring for 10 minutes, TEA (14 mL) was slowly added to the mixture while keeping the internal temperature below 30°C. The mixture was stirred at room temperature for 2 hours and quenched with water. Filter, and the resulting wet slurry was washed with ACN and water in turn. The wet material was dried in vacuo at 70°C for 24 hours to give the title compound as a solid (13 g, 90%)

[0046] Step 2: Charge 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxylic acid (13 g) and NN-dimethylacetamide (65 mL) into the reactor. The mixture was heated to 50-60 ° C and purged with nitrogen. Tri-tert-butylphosphonium tetrafluoroborate (130 mg) and allylpalladium chloride dimer (40 mg) were purged with nitrogen, and NN-dicyclohexylmethylamine (28 g) and acrylic acid (4 g) were added. Nitrogen protection and stirred at 50-70 ° C for 18 hours. 1M sulfuric acid aqueous solution was added at 50-70 ° C to pH 3.68. Water was added and the temperature was adjusted to 5-15 ° C within 5 hours. The mixture was stirred for 1-3 hours, filtered, and the resulting wet cake was rinsed with water, and then vacuum dried at 50-80 ° C to constant weight to obtain the target compound as a solid (10 g, 71%).

[0047] Step 3: Add (E)-3-(2-(methyl(phenyl)carbamoyl)-1H-indole-5-acyl)acrylic acid (10 g) and ACN (100 mL), CDI (6.1 g) to the reactor. Stir the reactants at 5-10°C for 2 h, filter and rinse the resulting wet cake with ACN (50 mL). Add the wet cake, NN-dimethylacetamide (80 mL), (R)-4-benzyl-2-oxazolidinone (6.8 g), and 1,8-diazabicyclo[5.4.0]undec-7-ene (15 g) to the reactor. Stir the reactants at 10-25°C for 1 hour and then quench with 5N HCl to pH 4. Stir the resulting suspension for 6-12 hours and filter. Soak the wet cake with water (60 mL) and dry in a vacuum dryer at 50-80°C to a constant temperature to obtain the title compound (11.8 g, 65%) as a solid.

[0048] Step 4: Add 0.5M 2-methylallylmagnesium chloride in THF solution (132 g) and lithium chloride (3.1 g) to the reactor. Cool the mixture to -42°C, then add copper (I) iodide (1.40 g) and (RE)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (11.8 g) at below -30°C. The reaction is stirred at -40 to -20°C for 8 hours, then quenched with 10% aqueous ammonium chloride solution (40 mL). Add MTBE (20 mL), stir the contents for 1 hour, separate the layers, add ethylenediamine (0.63 g) to the organic layer, and stir the mixture at 20°C-30°C for 2 hours. Add 10% aqueous ammonium chloride solution (40 mL) and stir the mixture at 20-30°C for 30-60 minutes. Separate the liquid and filter the organic phase through a pad of diatomaceous earth. Rinse the filter cake with THF (90 mL) and combine the filtrates. Concentrate the organic phase under reduced pressure at 40-50°C and concentrate to 5 volumes with ethanol (90 mL). Heat the resulting mixture with ethanol (23.70 g) at 80°C until a clear solution is obtained. Subsequently, the mixture is cooled to 5-10°C within 3 hours, filtered and the filter cake is rinsed with ethanol (100 mL). The solid is vacuumed to constant weight at 50-80°C to obtain the title compound as a solid (8.5 g, 65%).

[0049] Step 5: Add 5-(R)-1-(R)-4-benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (8.5 g) and THF (60 mL) to the reactor. Adjust the reaction temperature to 20-30°C and stir the mixture until a clear solution is obtained. Add glacial acetic acid (0.087 g), water (0.16 g, 5.556 mol) and ethanol (2.5 g). Cool to -20°C, add 2M lithium borohydride in THF solution (7.2 g) at below -5°C, and then stir at 0-10°C for 15 hours. Quench the reaction with 10% aqueous ammonium chloride solution at below 10°C. Extract the mixture with MTBE, separate the layers, and concentrate the organic phase in vacuo and remove it twice with methanol. The mixture was then heated at 65°C until a clear solution was obtained, then cooled to 5-10°C over 5 hours and filtered. The filter cake was rinsed with water and dried under vacuum at 50-80°C to constant weight to give the title compound as a solid (4 g, 67%).

[0050] Step 6: Charge (R)-5-(1-hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (4 g), p-toluenesulfonic acid monohydrate (5.2 g) and cyclopentyl methyl ether (30 mL) into the reactor. The reaction was reacted at 60-70 ° C for 12 hours, and then quenched with 1N sodium hydroxide aqueous solution (10.72 ml). IPA and n-heptane were added successively for crystallization. The filter cake was vacuum dried at 50-80 ° C to constant weight to obtain the title compound as a solid (3 g, 75%), with a chiral purity of only 85.0%. The chiral purity can be increased to 97% by crystallization purification with dichloromethane and n-heptane, but only 1.9 grams of product were obtained, and the yield was reduced to 48%.

[0051] Table 1 Comparison of experimental data between Example 1 and Comparative Example

[0052] Overall steps Total yield Chiral purity Embodiment 1 5 53％ 99.5％ Comparative Example 6 13％ 85.0％

[0053] Although the present invention is described herein with reference to a number of illustrative embodiments of the present invention, it will be appreciated that those skilled in the art may devise many other modifications and implementations that fall within the scope and spirit of the principles disclosed herein. More specifically, within the scope of the present disclosure, drawings, and claims, a variety of variations and modifications may be made to the components and / or layout of the subject combination layout. In addition to the variations and modifications made to the components and / or layout, other uses will also be apparent to those skilled in the art.

Claims

1. A method for constructing orforglipron pyran ring chirality by enzyme catalysis, characterized in that: Including intermediates The specific preparation steps are as follows: Step S1, using SM1 and SM2 as raw materials, reacting under the action of palladium catalyst and ligand to obtain INT-1; Step S2: INT-1 is subjected to hydrogenation reduction of double bonds under Pd / C catalysis to obtain INT-2; Step S3, INT-2 is hydrolyzed and resolved under the catalysis of a solvent, a buffer salt system and an enzyme to obtain a chirally pure intermediate INT-3; Step S4, INT-3 is ring-closed to synthesize lactone intermediate INT-4 through a Grignard reaction; Step S5, INT-4 is reduced by Dibal-H, quenched, extracted with dichloromethane, dried over anhydrous sodium sulfate, and then reduced with triethylsilane to obtain a compound of formula A; The reaction formula is as follows: ； Wherein, R1 is selected from -COOC 0-10 Alkyl, -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(substituted phenyl), -CONH(C 0-10 alkyl) or -CONH(substituted phenyl); R2 is selected from C 0-10 Alkyl; R3 is selected from C 0-5 Alkyl; X is selected from Cl, Br, I or OTf.

2. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In step S3, the enzyme is R9600, R9100, LIPASEAY30 or Lipozyme435.

3. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In step S3, the solvent includes one of water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile or a combination thereof.

4. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In step S3, the buffer salt system comprises one of sodium bicarbonate solution, potassium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium acetate solution, potassium acetate solution, sodium phosphate solution, disodium hydrogen phosphate solution, sodium hydrogen phosphate solution, potassium phosphate solution, dipotassium hydrogen phosphate solution, and potassium hydrogen phosphate solution, or a combination thereof.

5. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In the step S1, the palladium catalyst is Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd(CN)2Cl2, allylpalladium(II) chloride dimer, 1,4-bis(diphenylphosphinobutane)palladium dichloride or dichlorobis(tricyclohexylphosphine)palladium.

6. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 5, characterized in that: In step S1, the ligand is XPhos, XantPhos, SPhos, BrettPhos, DaveSPhos, tBuXPhos, RuPhos, JoneSPhos, QPhos, AmPhos, MePhos, tetramethyltBuXPhos, P(tBu)3HBF4, PCy3HBF4, CataCXiumA, BINAP, DPEPhos, Dpbp, Dppb or Dppe.

7. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 6, characterized in that: In the step S1, the combination of the palladium catalyst and the ligand is a combination of any palladium catalyst selected from the group consisting of Pd(OAc)2, Pd(CN)2Cl2, and allylpalladium(II) chloride dimer and the ligand XantPhos or RuPhos.

8. The method of constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In the step S1, the reaction conditions are coupling reaction under nitrogen protection at 90-110°C for 13-18 hours; in the step S2, the reaction conditions are reaction at room temperature for 17-23 hours; in the step S3, the reaction conditions are stirring reaction at room temperature for 22-26 hours; in the step S4, the Grignard reagent is methylmagnesium bromide, and the reaction temperature is controlled at 10-15°C; in the step S5, Dibal-H is added to the reaction system by dropwise addition, and the reaction temperature is controlled not to exceed -40°C.

9. A method for constructing orforglipron pyran ring chirality by enzyme catalysis according to claim 1, characterized in that: In the step S1, the mass ratio of the palladium catalyst to the ligand is 3-4:5-7.

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