Method for constructing chirality of pyran ring in orforglipron by means of enzymatic catalysis

Abstract

The present invention relates to the technical field of organic synthesis, and specifically relates to a method for constructing the chirality of a pyran ring in Orforglipron by means of enzymatic catalysis, the method comprising the following steps: step S1, by using SM1 and SM2 as starting materials, carrying out a reaction under the action of a palladium catalyst and a ligand to obtain INT-1; step S2, under the catalysis of Pd / C, subjecting INT-1 to double bond hydrogenation reduction to obtain INT-2; step S3, in the presence of a solvent, a buffer salt system and enzymatic catalysis, subjecting INT-2 to hydrolysis and resolution to obtain a chirally pure intermediate INT-3; step S4, subjecting INT-3 to a Grignard reaction for cyclization, so as to synthesize a lactone intermediate INT-4; and step S5, subjecting INT-4 to reduction by means of Dibal-H, quenching same, performing extraction with dichloromethane, drying same with anhydrous sodium sulfate, and then performing reduction by means of triethylsilane to obtain a compound of general formula A. In the present invention, the chirality is constructed by means of enzymatic catalysis without the need of SFC resolution for separating isomeric impurities during the construction of the chirality, thereby reducing losses and improving yield, obtaining the target product at high yield and high chiral selectivity, and further saving expenses and reducing costs.

Description

A method for constructing chiral Orforglipron pyran rings via enzymatic catalysis Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to a method for constructing the chiral Orforglipron pyran ring via enzyme catalysis. Background Technology

[0002] Currently, GLP-1 agonists are primarily administered subcutaneously, with various injection methods including multiple daily doses, once-daily doses, and once-weekly doses. This can be somewhat cumbersome. According to Novo Nordisk, Novozymes is currently (as of January 2024) the world's first and only oral glucagon-like peptide-1 receptor agonist (GLP-1RA). However, because it is a peptide, its absorption rate is relatively low, with a bioavailability of only 1%. Therefore, researchers are searching for other drugs with similar effects that are less prone to degradation. Orforglipron was developed under these circumstances. It is a chemical substance, a small molecule that also acts on the GLP-1 receptor, but because it is not a protein, it is not degraded by enzymes. Early pharmacokinetic studies showed that absorption is not affected by food intake. Because this drug is a non-peptide substance, it is easier to produce and has a lower cost, meaning it has a price advantage and may be used by more people.

[0003] Compound A is a key chiral intermediate in the synthesis of Orforglipron. Currently, there are two patent documents that mainly describe the synthesis of this intermediate. Patent WO2018056453A1 reports the preparation method of Route 1, which uses ethyl 5-bromoindole-2-carboxylate as a raw material and (2,2-dimethyltetrahydro-2H-pyran-4-yl)zinc iodide to obtain a racemic pyran intermediate. Then, the isomers are separated by chiral resolution via SFC, and the target product is obtained by hydrolysis and condensation.

[0004] Route 1

[0005] Another patent, WO2022017338A1, reports a preparation method using route two. The product is obtained by coupling ethyl 5-bromoindole-2-carboxylate and 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as raw materials. The product is then obtained by hydrogenation, followed by separation of isomers by chiral resolution using SFC, and finally by hydrolysis and condensation to obtain the target product.

[0006] Route 2

[0007] Currently, both methods mainly separate isomer impurities by SFC when constructing chirality, which inevitably leads to a loss of about 50%, resulting in relatively low yields and high separation costs.

[0008] Another recent patent, WO2024137426, reported a method (route 3) for constructing chirality using 5-bromo-1H-indole-2-carboxylic acid as a raw material via Evans cofactor induction. This method avoids the waste of a large amount of materials by constructing chirality through cofactor induction. However, this route uses a relatively expensive allyl palladium chloride dimer catalyst. In our preparation process based on the literature method, we also found that the purity of the chirality induced by Evans cofactor is only 85%.

[0009] Route 3 Summary of the Invention

[0010] The purpose of this invention is to provide a method for constructing the chiral pyran ring of Orforglipron through enzyme catalysis, which solves the problem that in the prior art, isomer impurities are mainly separated by SFC during chiral construction, which inevitably leads to a loss of about 50%, resulting in low yields and high separation costs.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] A method for constructing the chiral Orforglipron pyran ring via enzymatic catalysis, comprising intermediates

[0013] The specific preparation steps are as follows:

[0014] Step S1: Using SM1 and SM2 as raw materials, INT-1 is obtained by reacting under the action of palladium catalyst and ligand; Step S2: INT-1 undergoes hydrogenation reduction of the double bond 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 undergoes cyclization via Grignard reaction to synthesize lactone intermediate INT-4; 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 compound of general formula A; the reaction formula is as follows.

[0015] Where 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 0-10Alkyl group or -CONH (substituted phenyl); R2 is selected from C 0-10 Alkyl group; R3 is selected from C 0-5 Alkyl group; X is selected from Cl, Br, I or OTf.

[0016] A further technical solution is that, in step S3, the enzyme is R9600, R9100, LIPASEAY30, or Lipozyme435.

[0017] A further technical solution is that, in step S3, the solvent comprises one or a combination of water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, and acetonitrile.

[0018] 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.

[0019] 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, allyl palladium(II) chloride dimer, 1,4-bis(diphenylphosphine)palladium dichloride, or dichlorobis(tricyclohexyl)palladium.

[0020] 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.

[0021] A further technical solution is that, in step S1, the combination of the palladium catalyst and the ligand is any one of the palladium catalysts selected from Pd(OAc)2, Pd(CN)2Cl2, and allyl palladium(II) chloride dimer, combined with the ligand XantPhos or RuPhos.

[0022] A further technical solution is that, in step S1, the reaction conditions are a coupling reaction under nitrogen protection at 90-110℃.

[0023] Compared with the prior art, the beneficial effects of the present invention are: the present invention constructs chirality through enzyme catalysis, which eliminates the need to separate isomer impurities by SFC during chirality construction, reducing losses and increasing yield. Some steps can achieve a yield of 95%, and the target product is obtained with high chiral selectivity; at the same time, the cost is also relatively reduced, saving costs. Attached Figure Description

[0024] Figure 1 shows the NMR of the final product of the example (where X is Br, R1 is -CONMePh, R2 is Et, and R3 is Me). Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0026] The following are two examples and a comparative example of constructing Orforglipron pyran ring chirality by enzyme catalysis using the present invention.

[0027] The reaction formulas for the two embodiments are as follows:

[0028] Example 1: Where X is Br, R1 is -CONMePh, R2 is Et, and R3 is Me.

[0029] Step 1: At room temperature, 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (10g), potassium carbonate (12.6g), DMF (150mL), purified water (15mL), and diethyl penteneate (6.8g) were added sequentially to a 250mL three-necked flask. After nitrogen purging, Pd(OAc)2 (35mg) and XantPhos (60mg) were added to the reaction system. The mixture was heated to 110℃ and reacted for 15 hours. Samples were then taken for monitoring. After confirming the reaction was complete, 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, and the mixture was stirred, dried, and decolorized to remove color and residual palladium. The mixture was filtered through diatomaceous earth, concentrated, and ethyl acetate was removed to obtain 11.1 g of a white solid product (3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)pent-2-enediaric acid diethyl ester), with a yield of 86%.

[0030] Step 2: 11.1 g of 3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)pent-2-enedia dicitate, 200 mL of methanol, and 0.2 g of Pd / C were added to a 500 mL single-necked flask. After hydrogen purging, the mixture was reacted at room temperature for 20 h. Samples were taken for monitoring. After confirming that the reactants had reacted completely, the mixture was filtered through a diatomaceous earth liner. Activated carbon was added to the filtrate and the mixture was stirred for 1 h. After filtration through a diatomaceous earth liner, the mixture was concentrated under reduced pressure to obtain 10.8 g of a white solid product (3-(2-(phenyl)carbamoylmethyl)-1H-indol-5-yl)pentyl dicitate), with a yield of 97%.

[0031] Step 3: 10.8 g of 3-(2-(phenyl)carbamoylmethyl)-1H-indol-5-yl)glutaric acid diethyl ester and 50 mL of 1,4-dioxane were added to a 500 mL three-necked flask. After nitrogen purging, enzyme R9600 and 250 mL of 10% dipotassium hydrogen phosphate solution were added. The mixture was stirred at room temperature for 24 h. Unreacted raw materials were removed by MTBE extraction. The pH of the aqueous phase was adjusted to 5-6 with 4 M hydrochloric acid. The product was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to obtain 9.0 g of product (5-ethoxy-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)-5-oxovalerate), with a yield of 89% and a chiral purity of 98.9%.

[0032] Step 4: Add 9.0 g of 5-ethoxy-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)-5-oxovaleric acid to a 500 mL three-necked flask, add 150 mL of THF, purge with nitrogen three times, cool to 10 °C, and then add methyl bromide (2 M in). 2-Me-THF (67 mL) was slowly added dropwise to the reaction system, and the reaction temperature was controlled at 10–15 °C. After the addition was complete, the reaction was continued at 10–15 °C for 5 h. The reaction solution was then quenched in frozen dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed once with sodium bicarbonate aqueous solution, dried with sodium sulfate, and concentrated to obtain a crude oily product. The product was then crystallized with ethanol and water to obtain 6.5 g of 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 further improved to 99.5%.

[0033] Step 5: (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) were added to a 250 mL three-necked flask. After purging with nitrogen, the temperature was lowered to -40 °C. Dibal-H (25 mL, 1 M) was slowly added dropwise to the reaction system, controlling the reaction temperature not to exceed -40 °C. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was allowed to proceed for 3 h. The reaction solution was then poured into a frozen sodium potassium tartrate solution and stirred for 0.5 h. The solution was extracted and separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined, dried over sodium sulfate, and transferred to a 1 L three-necked flask. Triethylsilane (6.5 g) was added and the mixture was stirred overnight at room temperature. The solvent was removed by concentration under reduced pressure. The residue was crystallized from n-heptane to obtain 5.8 g of white solid, with a yield of 92% and a chiral purity of 99.5%.

[0034] Example 2: Where X is Br and R1 is -CO2 i Pr, R2 is Et, and R3 is Me.

[0035] Step 1: At room temperature, isopropyl 5-bromo-1H-indole-2-carboxylic acid (10g), potassium carbonate (14.7g), DMF (150mL), purified water (15mL), and diethyl pentanoate (7.9g) were added sequentially to a 250mL three-necked flask. After nitrogen purging, Pd(OAc)₂ (35mg) and XantPhos (60mg) were added to the reaction system. The mixture was heated to 110℃ and reacted for 15 hours. Samples were taken for monitoring to determine the reaction status. After the reaction was complete, 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, and the mixture was stirred, dried, and decolorized to remove color and residual palladium. The mixture was filtered through diatomaceous earth and concentrated to remove ethyl acetate, yielding 11.5 g of a white solid product ((E)-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pent-2-enediol diethyl ester), with a yield of 83%.

[0036] Step 2: Diethyl (E)-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pent-2-enediacid (11.5 g), methanol (200 mL), and Pd / C (0.2 g) were added to a 500 mL single-necked flask. After hydrogen purging, the mixture was reacted at room temperature for 20 h. Samples were taken for monitoring. After confirming that the reactants had reacted completely, the mixture was filtered through a diatomaceous earth liner. Activated carbon was added to the filtrate and the mixture was stirred for 1 h. After filtration through a diatomaceous earth liner, the mixture was concentrated under reduced pressure to obtain 11 g of white solid product (diethyl 3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)pentanoic acid), with a yield of 96%.

[0037] Step 3: Diethyl 3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)glutarate (11 g) and 1,4-dioxane (50 mL) were added to a 500 mL three-necked flask. After nitrogen purging, enzyme R9600 and 10% dipotassium hydrogen phosphate solution (250 mL) were added. The mixture was stirred at room temperature for 24 h. Unreacted raw materials were removed by MTBE extraction. The pH of the aqueous phase was adjusted to 5-6 with 4 M hydrochloric acid. The product was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to obtain 8.1 g of product (5-ethoxy-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)-5-oxovalerate (8.1 g)), with a yield of 79% and a chiral purity of 98.5%.

[0038] Step 4: Add 8.1 g of 5-ethoxy-3-(2-(isopropoxycarbonyl)-1H-indol-5-yl)-5-oxovaleric acid to a 500 mL three-necked flask, add 150 mL of THF, purge with nitrogen three times, cool to 10 °C, and then add 2 MnO-methyl bromide. 2-Me-THF (56 mL) was slowly added dropwise to the reaction system, and the reaction temperature was controlled at 10–15 °C. After the addition was complete, the reaction was continued at 10–15 °C for 5 h. The reaction solution was then quenched in frozen dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed once with sodium bicarbonate aqueous solution, dried with sodium sulfate, and concentrated to obtain a crude oily product. The product was then crystallized with ethanol and water to obtain 4.8 g of white solid (isopropyl 5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid), with a yield of 65% and a chiral purity further improved to 99.1%.

[0039] Step 5: 4.8 g of 5-(2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid isopropyl ester and 100 mL of DCM were added to a 250 mL three-necked flask. After purging with nitrogen, the temperature was lowered to -40 °C. Dibal-H (17 mL, 1 M) was slowly added dropwise to the reaction system, controlling the reaction temperature not to exceed -40 °C. After the addition was complete, the temperature was naturally raised to room temperature and reacted for 3 h. The reaction solution was poured into a frozen sodium potassium tartrate solution and stirred for 0.5 h. The solution was extracted and separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined, dried over sodium sulfate, and transferred to a 1 L three-necked flask. Triethylsilane (4 g) was added and the mixture was stirred overnight at room temperature. The solvent was removed by concentration under reduced pressure. The residue was crystallized from n-heptane to obtain 4 g of white solid, with a yield of 87%.

[0040] Comparative Example:

[0041] Step 1: Add 5-bromo-1H-indole-2-carboxylic acid (10g), DMF (1.6mL), and ACN (100mL) to the reactor. Oxaloyl chloride solution (4.8mL) is mixed with ACN (20mL) and added at a controlled rate, maintaining the temperature below 30°C. After addition, the reaction is vigorously stirred at room temperature for 60 minutes. Then, the reaction temperature is adjusted to 5°C, and N-methylaniline (5.5mL) is slowly added while the internal temperature remains below 10°C. After stirring for 10 minutes, TEA (14mL) is slowly added to the mixture while maintaining the internal temperature below 30°C. The mixture is stirred at room temperature for 2 hours and then quenched with water. Filter the mixture, and wash the filter cake sequentially with ACN and water. Dry the wet mixture under vacuum at 70°C for 24 hours to obtain the title compound in solid form (13g, 90%).

[0042] Step 2: 5-Bromo-N-methyl-N-phenyl-1H-indole-2-carboxylamide (13g) and N / N-dimethylacetamide (65mL) were charged into the reactor. The mixture was heated to 50-60°C and purged with nitrogen. Tri-tert-butylphosphonium tetrafluoroborate (130mg) and allyl palladium chloride dimer (40mg) were added, followed by N / N-dicyclohexylmethylamine (28g) and acrylic acid (4g) under nitrogen protection and stirring at 50-70°C for 18 hours. A 1M aqueous sulfuric acid solution was added at 50-70°C to adjust the pH to 3.68. Water was added, and the temperature was adjusted to 5-15°C over 5 hours. The mixture was stirred for 1-3 hours, filtered, and the resulting wet cake was washed with water and then vacuum dried at 50-80°C to constant weight to obtain the target compound in solid form (10g, 71%).

[0043] 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 wash the resulting wet filter cake with ACN (50 mL). Add the wet filter 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 h, then quench with 5N HCl to pH 4. Stir the resulting suspension for 6-12 h and filter. Soak the wet filter cake in water (60 mL) and dry it in a vacuum desiccator at 50-80 °C until constant to obtain the title compound in solid form (11.8 g, 65%).

[0044] Step 4: Add 132 g of 0.5 M 2-methylallyl magnesium chloride THF solution and 3.1 g of lithium chloride to the reactor. Cool the mixture to -42 °C, then add 1.40 g of copper iodide (I) and 11.8 g of (RE)-5-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide at below -30 °C. Stir the reaction between -40 and -20 °C for 8 hours, then quench with 40 mL of 10% ammonium chloride aqueous solution. Add 20 mL of MTBE, stir the contents for 1 hour, separate the layers, add 0.63 g of ethylenediamine to the organic layer, and stir the mixture at 20-30 °C for 2 hours. Add 40 mL of 10% ammonium chloride aqueous solution and stir the mixture at 20–30 °C for 30–60 minutes. Separate the liquid and filter the organic phase through a diatomaceous earth filter. Wash the filter cake with THF (90 mL) and combine the filtrates. Concentrate the organic phase under reduced pressure at 40–50 °C and concentrate with ethanol (90 mL) to 5 volumes. Heat the resulting mixture with ethanol (23.70 g) at 80 °C until a clear solution is obtained. Subsequently, cool the mixture to 5–10 °C over 3 hours, filter, and wash the filter cake with ethanol (100 mL). The solid is heated under vacuum to constant weight at 50–80 °C to give the title compound (8.5 g, 65%) in solid form.

[0045] Step 5: Add 8.5 g of 5-(R)-1-(R)-4-benzyl-2-oxooxazolidine-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide and 60 mL of THF to the reactor. Adjust the reaction temperature to 20-30 °C and stir the mixture until a clear solution is obtained. Add 0.087 g of glacial acetic acid, 0.16 g of water (5.556 mol), and 2.5 g of ethanol. Cool to -20 °C, add 7.2 g of 2 M lithium borohydride in THF solution below -5 °C, and then stir at 0-10 °C for 15 hours. Quench the reaction with 10% ammonium chloride aqueous solution below 10 °C. Extract the mixture with MTBE, separate the layers, concentrate the organic phase under vacuum, and carry it twice with methanol. The mixture was then heated at 65°C until a clear solution was obtained, and then cooled to 5-10°C over 5 hours and filtered. The filter cake was washed with water and dried under vacuum at 50-80°C to constant weight to give the title compound solid (4 g, 67%).

[0046] Step 6: (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) were charged into the reactor. The reaction was carried out at 60-70 °C for 12 hours, then quenched with 1N sodium hydroxide aqueous solution (10.72 mL). IPA and n-heptane were added sequentially 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%. Purification by crystallization with dichloromethane and n-heptane could increase the chiral purity to 97%, but only 1.9 g of product was obtained, resulting in a yield of 48%.

[0047] Table 1 Comparison of experimental data between Example 1 and Comparative Example 2

[0048] Although the invention has been described herein with reference to several illustrative embodiments, it should be understood that many other modifications and implementations can be devised by those skilled in the art, which will fall within the scope and spirit of the principles disclosed herein. More specifically, various variations and modifications can be made to the components and / or layout of the subject matter arrangement within the scope of the disclosure, drawings, and claims. Besides variations and modifications to the components and / or layout, other uses will be apparent to those skilled in the art.

Claims

1. A method for constructing a chiral Orforglipron pyran ring via enzymatic catalysis, characterized in that, Including intermediates The specific preparation steps are as follows: Step S1: Using SM1 and SM2 as raw materials, INT-1 is obtained by reacting them under the action of palladium catalyst and ligand. Step S2; INT-1 is hydrogenated and reduced to obtain INT-2 under Pd / C catalysis; In step S3, INT-2 is hydrolyzed and separated in a solvent, buffer salt system and under enzyme catalysis to obtain the chiral pure intermediate INT-3; In step S4, INT-3 synthesizes lactone intermediate INT-4 via Grignard reaction cyclization; In 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 with the general formula A. The reaction formula is as follows: Where 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 group or -CONH (substituted phenyl); R2 is selected from C 0-10 Alkyl group; R3 is selected from C 0-5 Alkyl group; X is selected from Cl, Br, I or OTf.

2. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 1, characterized in that: In step S3, the enzyme is R9600, R9100, LIPASEAY30, or Lipozyme435.

3. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 1, characterized in that: In step S3, the solvent comprises one or a combination of water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, and acetonitrile.

4. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 1, characterized in 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.

5. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 1, characterized in that: In step S1, the palladium catalyst is Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd(CN)2Cl2, allyl palladium(II) chloride dimer, 1,4-bis(diphenylphosphine)palladium dichloride, or dichlorobis(tricyclohexyl)palladium.

6. The method for constructing a chiral Orforglipron pyran ring via 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. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 6, characterized in that: In step S1, the combination of the palladium catalyst and ligand is any one of the palladium catalysts selected from Pd(OAc)2, Pd(CN)2Cl2, and allyl palladium(II) chloride dimer, combined with the ligand XantPhos or RuPhos.

8. The method for constructing a chiral Orforglipron pyran ring via enzyme catalysis according to claim 1, characterized in that: In step S1, the reaction conditions are a coupling reaction at 90-110℃ under nitrogen protection for 13-18 hours; in step S2, the reaction conditions are a reaction at room temperature for 17-23 hours; in step S3, the reaction conditions are a stirred reaction at room temperature for 22-26 hours; in step S4, the Grignard reagent is methyl magnesium bromide, and the reaction temperature is controlled at 10-15℃; in step S5, Dibal-H is added to the reaction system dropwise, and the reaction temperature is controlled not to exceed -40℃.

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

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