Preparation method of GLP-1 receptor agonist Orforglipron

Abstract

The invention relates to a synthesis method of a GLP-1R agonist Orforglipron, and the synthesis method is as shown in the following formula. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical synthesis and relates to a new preparation method of a GLP-1 receptor agonist Orforglipron. Background Art

[0002] GLP-1R (glucagon-like peptide-1 receptor) is a receptor located on the cell membrane, mainly expressed in tissues such as pancreatic beta cells, digestive tract, heart and brain. After binding to the incretin hormone GLP-1, it can inhibit glucagon secretion, promote insulin secretion, delay gastric emptying, and affect appetite and body weight. Due to these effects of GLP-1R, GLP-1 receptor agonists are used to treat type 2 diabetes and obesity, becoming a vital player in the treatment of these metabolic diseases. Science magazine ranked GLP-1 drugs as the top scientific breakthrough of 2023.

[0003] Orforglipron is a small molecule GLP-1 receptor agonist currently in phase 3 clinical trials. It showed good results in a 26-week phase 2 double-blind randomized controlled clinical trial (NCT05048719). After oral administration of Orforglipron, the average change in HbA1c was significant, reaching -2.10%, while the positive control dulaglutide group was -1.10%. Orforglipron is not only superior to dulaglutide in terms of efficacy in type 2 diabetes, but also shows potential as an anti-obesity drug. In another phase 2 double-blind randomized controlled trial (NCT05051579), a weight loss of up to 14.7% was observed at week 36, which is completely comparable to semaglutide. These findings show that Orforglipron has multiple benefits and can significantly improve the quality of life of patients with type 2 diabetes. Moreover, these non-peptide small molecule drugs are less expensive and easy to take, which can enable a wider range of people to obtain high-quality treatment and revolutionize the management of type 2 diabetes and obesity in many ways. Therefore, research on the synthesis and structural optimization of Orforglipron is of great significance. Summary of the invention

[0004] The inventors have solved the technical problem of the compound through experimental research, and the reaction route is as follows:

[0005]

[0006]

[0007] The present invention comprises the following steps:

[0008] (1) Using indole-2-carboxylic acid ethyl ester / methyl ester (1) as the starting material, in the presence of a suitable base, a palladium catalyst and an organic phosphine ligand, Heck coupling with acrylic acid is carried out to introduce an acrylic acid group at the C-5 position of the indole compound to obtain an intermediate (2):

[0009]

[0010] The base is preferably selected from triethylamine, tributylamine, N,N-dicyclohexylmethylamine, sodium acetate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium tert-butoxide; the palladium catalyst is preferably selected from allylpalladium (II) chloride dimer, tetrakis(triphenylphosphine)palladium, palladium dichloride, sodium tetrachloropalladate and palladium diacetate; the organic phosphine ligand is preferably selected from triphenylphosphine, tri-o-tolylphosphine, SPhos, sPSPhos, tri-tert-butylphosphine tetrafluoroborate and the like.

[0011] (2) The acrylic acid derivative (2) is condensed with the (R)-Evens reagent (3) to introduce a chiral auxiliary group to obtain compound (4):

[0012]

[0013] Indole-5-acrylic acid (2) is used as a substrate, and its carboxyl group is first activated to become an acyl chloride or an acyl imidazole, and then a mixture of Evens reagent (3) and a base is added to undergo a condensation reaction at room temperature to obtain compound (4). The carboxyl group activation method can be to convert the carboxyl group into an acyl imidazole using CDI, or to convert the carboxyl group into an acyl chloride using oxalyl chloride, thionyl chloride or pivaloyl chloride; the Evens auxiliary group can be selected from The base is selected from butyl lithium, LiHMDS, KHMDS, NaHMDS, DBU, triethylamine or tributylamine.

[0014] (3) Under the induction of Evens chiral auxiliary group, the substrate compound (4) is subjected to 1,4-addition reaction with 2-methylallyl copper lithium reagent to introduce 2-methylallyl side chain and construct (S) configuration chiral center to obtain compound (5):

[0015]

[0016] The Gilman reagent is generated from 2-methylallylmagnesium chloride, and the generated Gilman reagent is subjected to asymmetric 1,4-addition to the substrate (4), thereby efficiently introducing a 2-methylallyl side chain, constructing a chiral center, and obtaining compound (5).

[0017] (4) Reduction and elimination of the Evens chiral auxiliary group to obtain compound (6):

[0018]

[0019] The Evens chiral auxiliary group of compound (5) is selectively reduced with sodium borohydride or lithium borohydride.

[0020] (5) Substrate (6) undergoes rearrangement and ring-closing reaction to obtain intermediate (7):

[0021]

[0022] Under acidic conditions, compound (6) undergoes a ring-closure reaction to construct a (S)-configuration tetrahydropyran module to synthesize intermediate (7). The acidic catalyst is selected from sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid or an acidic cation exchange resin.

[0023] (6) Replacement of indole-2-carboxylic acid ethyl / methyl ester (7) with tert-butyl ester to obtain intermediate (8):

[0024]

[0025] In the presence of a suitable base, the ester group of intermediate (7) is hydrolyzed and converted into a tert-butyl ester to obtain intermediate (8), wherein the base is selected from LiOH, NaOH, KOH, KOBu t or NaOBu t ; The tert-butylating agent that releases the carboxyl group is selected from N,N-dimethylformamide di-tert-butyl acetal reagent, or 2,2,2-trichloroacetimidic acid tert-butyl ester reagent.

[0026] (7) Alkylate compound (8) with chloroacetonitrile or bromoacetonitrile to obtain intermediate (9):

[0027]

[0028] The key intermediate (8) is alkylated with chloroacetonitrile or bromoacetonitrile in the presence of a suitable base to obtain intermediate (9), wherein the base is selected from NaH, KOBu t 、NaOBu t , K2CO3, Cs2CO3, NaHMDS, LiHDMS or KHMDS.

[0029] (8) Under appropriate base catalysis, the intermediate (9) is reacted with (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide

[0030] (10) to obtain intermediate (11):

[0031]

[0032] The base is selected from KHMDS, NaHMDS, LiHMDS, LiOBu t or KOBu t .

[0033] (9) treating the nitrile compound (11) with hydroxylamine hydrochloride, and then cyclizing the crude product (12) with CDI in the presence of a base.

[0034] The intermediate (13) is obtained:

[0035]

[0036] The base is selected from DBU, pyridine, pyrrolidine, pyrrole, triethylamine, DIPEA, methylamine, diethylamine, ethyldimethylamine, imidazole, diisopropylamine, Barton base, NaOH, NaOMe, NaOEt or KOBu t .

[0037] (10) Hydrolysis and removal of the tert-butyl protection of compound (13) to obtain intermediate (14):

[0038]

[0039] The hydrolysis can be carried out under acid catalysis, and the catalyst is selected from dilute hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, formic acid or acidic ion exchange resin; the hydrolysis can also be carried out under base catalysis, and the catalyst is selected from NaOH, KOH, KOBu t or NaH, etc. (11) Compound (14) and (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-

[0040] The target compound Orforglipron (LY3502970) was obtained by condensation reaction of 4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (15).

[0041]

[0042] The condensing agent is selected from carbodiimide, phosphonium cation or urea cation condensing agents such as EDC, CDIC, DCC, HATU, HBTU, PyBOP, PyAOP, HOBt, HOAt, Oxyma derivatives, etc. Specific embodiments

[0043] The present invention is further described below by way of examples, but the contents of the present invention are not limited thereby.

[0044] Example 1

[0045]

[0046] Intermediate 2

[0047] Sodium tetrachloropalladate (16 mg, 50 μmol), sSPhos (66 mg, 125 μmol) and 10 mL of a mixed solvent of water / acetonitrile (1:1) were added to a 20 mL microwave reaction bottle at room temperature, purged with nitrogen three times and stirred for 15 minutes. Compound (1) (268 mg, 1 mmol), Na2CO3 (220 mg, 2 mmol) and acrylic acid (110 mg, 1.5 mmol) were then added to the reaction bottle, and the reaction mixture was microwaved at 80°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with 20 mL of saturated NaHCO3 solution, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layer was dried, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain product (2) (248 mg, 95%); MS m / z: 260 (M+H).

[0048] Intermediate 4

[0049] CDI (3.60 g, 22.2 mmol) was added to a solution of compound (2) (4.76 g, 18.3 mmol) in acetonitrile (100 mL) at room temperature. The reaction mixture was stirred for 3 hours and then filtered. The filter cake was rinsed with acetonitrile (30 mL) and transferred to a single-mouth bottle for vacuum drying for one hour. N, N-dimethylacetamide (50 mL) was added to dissolve the filter cake. Evens reagent (3) (3.68 g, 22.6 mmol) and DBU (7.18 g, 47.2 mmol) were added at room temperature. Stirring was continued for 1 hour. Then, the reaction was quenched with 5N HCl (8 mL) and the pH was adjusted to 4. The resulting suspension was stirred overnight and then filtered. The wet filter cake was rinsed with water (10 mL) and vacuum dried at 50°C to constant weight to obtain a solid product (4) (5.54 g, 75%), MS: m / z=405 (M+1).

[0050] Intermediate 5

[0051] Lithium chloride (3.0 g, 70.8 mmol) was dissolved in THF (100 mL), 2-methylallylmagnesium chloride (0.5 M, 125 mL, 68.3 mmol) was added at room temperature and stirred for 90 minutes, then cooled to -78 ° C and a solution of cuprous bromide-dimethyl sulfide (7.28 g, 35.4 mmol) in diisopropyl sulfide (20 mL) was slowly added, the reaction was stirred at -50 to -30 ° C for 30 minutes, and compound (4) (8.0 g, 19 .8mmol) in THF (25mL), the reaction solution was stirred at -30°C for 4 hours, and then the reaction was quenched with saturated aqueous ammonium chloride (50mL). The reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethyl acetate (50mL), the combined filtrate was washed with saturated brine, dried, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE:EA=5:1) to give a white solid product (5) (7.29 g, 80%), MS: m / z=461 (M+1).

[0052] Intermediate 6

[0053] Below 0°C, lithium borohydride (348 mg, 15.8 mmol) was added in portions to anhydrous ether (100 mL) of compound (5) (7.04 g, 15.3 mmol). After removing the ice bath, the mixture was stirred at room temperature overnight. 1N KHSO4 aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with ether (50 mL×3). The organic phase was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give a solid product (6) (4.42 g, 96%); MS: m / z=302 (M+1).

[0054] Intermediate 7

[0055] A THF solution (30 mL) of compound (6) (1.22 g, 4.05 mol) and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) was heated at 60-70°C for 12 hours, then quenched with 10% aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with saturated brine, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give a white solid product (7) (1.13 g, 93%); MS: m / z=302 (M+1).

[0056] Intermediate 8

[0057] The intermediate (7) (9.48 g, 31.5 mmol) was dissolved in a solution of LiOH in MeOH (0.5 M, 125 mL) and stirred at room temperature overnight. After TLC detection, the reaction was completed and concentrated in vacuo. Water (15 mL) was added to the residue. The resulting suspension was acidified with 1N HCl aqueous solution, the solid was collected by filtration, and then dissolved in ethyl acetate. The organic solution was dried, filtered, and concentrated. The resulting residue was resuspended in anhydrous toluene (150 mL) at 80°C, and N,N-dimethylformamide di-tert-butyl acetal (20 mL, 84.0 mmol) was added dropwise to the heated suspension. The reaction mixture was stirred at 80°C for 3 hours and then cooled to room temperature. The mixture was diluted with toluene and washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (50 mL), respectively. The organic layer was dried, filtered, and concentrated. The residue was slurried and ground from hexane to give a white powder product (8) (9.56 g, 92%). 1 H NMR (400MHz, DMSO-d6) δ11.58 (s, 1H), 7.47 (s, 1H), 7.39 (d, J=8.6Hz, 1H), 7.18 (d, J=8.6Hz, 1H), 7.00 (s, 1H), 3.70-3. 72 (m, 2H), 3.00 (t, j=12.6Hz, 1H), 1.71-1.67 (m, 2H), 1.59-1.54 (m, 11H), 1.28 (s, 3H), 1.19 (s, 3H); MS: m / z=330 (M+1).

[0058] Intermediate 9

[0059] At 0°C, NaH (60%, 220 mg, 5.46 mmol) was slowly added to a DMF (10 mL) dry solution of the intermediate (8) (600 mg, 1.82 mmol). After reacting for 0.5 h, bromoacetonitrile (190 μL, 2.73 mmol) was added dropwise at 0°C. The reaction was continued for 2 h until TLC showed that the reaction was complete. Saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (100 mL) and water (50 mL) were added to extract and wash away DMF. The organic phase was dried and then spin-dried. The residue was purified by silica gel column chromatography (EA: PE = 1: 20) to obtain a white oily product (9) (500 mg, 75%). 1H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 7.41-7.30 (m, 2H), 7.28-7.23 (m, 2H), 5.58 (d, j=1.8Hz, 2H), 3.91- 3.80(m,2H),3.08-3.00(m,1H)),1.79-1.73(m,2H),1.66-1.60(m,11H),1.35(s,3H),1.29(s,3H);MS m / z: 369(M+H).

[0060] Intermediate 11

[0061] At 0°C, under nitrogen protection, the intermediate (9) (300 mg, 0.82 mmol) and the sulfate (10) (550 mg, 3.28 mmol) were dissolved in dry THF (20 mL), and LiHMDS (1 M THF solution, 4.92 mL, 4.92 mmol) was slowly added dropwise, and the reaction was carried out at 0°C for 1-2 h. After the raw material was exhausted by TLC monitoring, saturated aqueous ammonium chloride solution (10 mL) was added to quench, and ethyl acetate (100 mL) and water (40 mL) were added for extraction. The organic phase was dried and then spin-dried. The residue was separated by silica gel column chromatography (EA: PE = 1: 10) to obtain a colorless oil (11) (260 mg, 79%). 1 H NMR (400MHz, DMSO-d6) δ7.55-7.61 (m, 2H), 7.37-7.39 (m, 1H), 7.26 (s, 1H), 3.71-3.73 (m, 2H), 3.02-3.09 (m, 1H), 2.31-2. MS m / z: 409(M+H).

[0062] Intermediate 13

[0063] Intermediate (11) (220 mg, 0.54 mmol), hydroxylamine hydrochloride (190 mg, 2.73 mmol) and sodium bicarbonate (230 mg, 2.73 mmol) were added to DMSO (5 mL) in sequence and reacted at 80 ° C for 5 h. After cooling, ethyl acetate (50 mL) and water (30 mL) were added to extract and wash away DMSO. The organic phases were combined, dried, filtered and concentrated to obtain a white solid crude product (12), which can be used for the next step without purification.

[0064] At room temperature, carbonyldiimidazole (165 mg, 1 mmol) was added to a solution of the intermediate (12) (220 mg, 0.5 mmol) and DBU (230 mg, 1.5 mmol) in DMSO (5 mL). After stirring at room temperature for 1 h, the starting material disappeared after monitoring by TLC. Ethyl acetate (50 mL) and water (20 mL) were added to extract and wash away DMSO. The organic phase was dried, filtered, and spin-dried. The crude product was separated by Pre-TLC (EA: PE = 1: 4) to obtain a light yellow solid product (13) (200 mg, 78% two steps); 1 H NMR (400MHz, CDCl3) δ7.50 (s, 1H), 7.42 (m, 1H), 7.30-7.25 (m, 1H), 7.22 (d, J=13.8Hz, 1H), 3.83 (td, j=9.2, 8.6, 3.4Hz, 2H), 3.01 (dq, j=12.3, 4.6, 4.1Hz, 1H), 2.36-2.13 (m, 1H), 1.97-1.81 (m, 1H), 1.74 (m, 4H), 1.66-1.53 ​​(m, 12H), 1.33 (s, 3H), 1.27 (d, j=3.7Hz, 3H); MS m / z: 468(M+H).

[0065] Intermediate 14

[0066] At room temperature, the intermediate (13) (50 mg, 0.11 mmol) was dissolved in TFA / DCM (1 / 2, v / v, 2 mL) solution and stirred at room temperature for 6 h. The starting material disappeared after TLC monitoring. The solvent was removed by rotary evaporation under reduced pressure to give a crude light yellow oily product (14) (30 mg) which was directly used in the next step reaction; MS m / z: 412 (M+H).

[0067] Preparation of Orforglipron

[0068] At room temperature, HATU (42 mg, 0.11 mmol) was added to a solution of compound (14) (30 mg, 0.07 mmol) and triethylamine (30 μL, 0.22 mmol) in DMF (1 mL). After stirring at room temperature for 1 h, compound (15) (40 mg, 0.08 mmol) was added and stirring was continued overnight. Ethyl acetate (20 mL) and water (5 mL) were added to extract and wash away DMF. The organic phase was dried, filtered and concentrated. The residue was separated by Pre-TLC (EA: PE = 4: 1) to obtain Orforglipron (41 mg, 66%) as a white solid. 1H NMR (400MHz, CDCl3) δ11.27 (s, 1H), 8.06 (s, 1H), 7.41-7.53 (m, 4H), 7.19-7.23 (m, 3H), 6.63 (s, 1 H), 6.52-6.53 (m, 1H), 6.24 (d, J=3.0Hz, 1H), 5.73-5.75 (m, 1H), 4.40-4.51 (m, 1H), 4.05 (s, 3H), 4 .00(s, 1H), 3.78-3.92(m, 1H), 3.48-3.64(m, 1H), 2.96-3.20(m, 2H), 2.29(s, 6H), 1.90-1.93(m, 1 H),1.75-1.780(m,3H),1.34(s,3H),1.28(s,3H),1.25(s,3H),1.23(d,3H),0.85-0.92(m,2H); m / z: 883(M+H).

[0069] The synthetic method of Orforglipron provided by the invention has the following advantages: the key intermediate (7) carboxylic acid protecting group is selected from tert-butyl alcohol ester, which has the advantages that on the one hand, the removal method of tert-butyl carboxylate is mild, and it can be hydrolyzed to release the carboxyl group under acidic or alkaline conditions; on the other hand, it is stable enough to withstand alkaline reagents such as NaH, LiHMDS and KHMDS, and can achieve efficient preparation of Orforglipron. Tert-butyl carboxylate The protection effect is better than that of carboxylic acid N-methyl-N-phenylamide protecting group Even if the cost advantage of tert-butyl alcohol ester over N-methylaniline is ignored, the chemical transformation of tert-butyl ester, whether it is the introduction or removal of the protecting group, is more convenient and flexible. In particular, due to the mildness of the tert-butyl protection and removal method, the structural modification of the base-sensitive functional group on the Orforglipron molecule can be carried out, which is conducive to its more extensive structure-activity relationship research. The synthetic method of the present invention is simple to operate, the raw materials are cheap and easy to obtain, and no expensive separation instruments and methods are required, so it is suitable for large-scale production.

[0070] The examples are only used to illustrate the embodiments of the present invention, but the present invention is not limited to the above examples. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected, and the scope of the present invention to be protected is defined by the claims and their equivalents.

Claims

1. A method for preparing a GLP-1 receptor agonist Orforglipron, characterized in that: The specific steps are: (1) Using indole-2-carboxylic acid ethyl ester / methyl ester (1) as the starting material, an acrylic acid group is introduced at the C-5 position of the indole compound by a Heck coupling reaction to obtain an intermediate (2); (2) The acrylic acid derivative (2) is condensed with the (R)-Evens reagent (3) to introduce a chiral auxiliary group to obtain a compound (4); (3) Under the induction of Evens chiral auxiliary group, the substrate compound (4) is subjected to 1,4-addition reaction with 2-methylallyl copper lithium reagent to introduce 2-methylallyl side chain and construct (S) configuration chiral center to obtain compound (5); (4) Reduction and elimination of the Evens chiral auxiliary group to obtain compound (6); (5) Substrate (6) undergoes rearrangement and ring-closure reaction to obtain key intermediate (7); (6) replacing indole-2-carboxylic acid ethyl / methyl ester (7) with tert-butyl ester to obtain intermediate (8); (7) Alkylation of compound (8) with chloroacetonitrile or bromoacetonitrile to obtain intermediate (9); (8) reacting the intermediate (9) with (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide (10) under appropriate base catalysis to obtain the intermediate (11); (9) treating the cyano compound (11) with hydroxylamine hydrochloride to obtain an intermediate (12), and then subjecting the crude product (12) to a cyclization reaction with CDI in the presence of a base to obtain an oxadiazolone intermediate (13); (10) hydrolyzing and removing the tert-butyl protection of compound (13) to obtain intermediate (14); (11) Compound (14) is subjected to condensation reaction with (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (15) to obtain the target compound Orforglipron (LY3502970).

2. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (1), compound (1) is used as a substrate and Heck coupling is carried out with acrylic acid in the presence of a suitable base, a palladium catalyst and an organic phosphine ligand to obtain compound (2): The base is preferably selected from triethylamine, tributylamine, N,N-dicyclohexylmethylamine, sodium acetate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium tert-butoxide; the palladium catalyst is preferably selected from allylpalladium (II) chloride dimer, tetrakis(triphenylphosphine)palladium, palladium dichloride, sodium tetrachloropalladate and palladium diacetate; the organic phosphine ligand is preferably selected from SPhos, sSPhos, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine tetrafluoroborate and the like.

3. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (2), indole-5-acrylic acid (2) is used as a substrate, and its carboxyl group is first activated to form an acyl chloride or acyl imidazole, and then a mixture of Evens reagent (3) and a base is added to perform a condensation reaction at room temperature to obtain compound (4): The activation method of the carboxyl group can be to convert the carboxyl group into an acyl imidazole by using CDI, or to convert the carboxyl group into an acyl chloride by using oxalyl chloride, thionyl chloride or pivaloyl chloride; the Evens auxiliary group can be selected from The base is selected from butyl lithium, LiHMDS, KHMDS, NaHMDS, DBU, triethylamine or tributylamine.

4. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (3), Gilman copper lithium reagent is generated from 2-methylallyl magnesium chloride, and the generated Gilman reagent is subjected to asymmetric 1,4-addition to substrate (4), thereby efficiently introducing a 2-methylallyl side chain, constructing a chiral center, and obtaining compound (5).

5. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (4), sodium borohydride or lithium borohydride is used to selectively reduce and eliminate the Evens chiral auxiliary group of compound (5) to obtain compound (6).

6. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (5), compound (6) undergoes an acid-catalyzed rearrangement ring-closing reaction to construct a (S)-configuration tetrahydropyran module to obtain intermediate (7): The acidic catalyst is selected from sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid or acidic cation exchange resin.

7. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (6), the ester group of intermediate (7) is hydrolyzed in the presence of a suitable base and converted to a tert-butyl ester to obtain intermediate (8): The base is selected from LiOH, NaOH, KOH, KOBu t or NaOBu t ; The tert-butylating agent is selected from N,N-dimethylformamide di-tert-butyl acetal reagent, or 2,2,2-trichloroacetimidic acid tert-butyl ester reagent.

8. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (7), the key intermediate (8) is alkylated with chloroacetonitrile or bromoacetonitrile in the presence of a suitable base to give intermediate (9). Base is selected from NaH, KOBu t 、NaOBu t , K2CO3, Cs2CO3, NaHMDS, LiHDMS or KHMDS.

9. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (8), compound (9) is reacted with (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide (10) under base catalysis to obtain compound (11): The base is selected from KHMDS, LiHMDS, LiOBu t or KOBu t .

10. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (9), the nitrile intermediate (11) is treated with hydroxylamine hydrochloride, and then the crude product (12) is intramolecularly cyclized using a cyclization reagent CDI and an appropriate base in a solvent to obtain an intermediate (13): The base is selected from DBU, pyridine, pyrrolidine, pyrrole, triethylamine, DIPEA, methylamine, diethylamine, ethyldimethylamine, imidazole, diisopropylamine, Barton base, NaOH, NaOMe, NaOEt or KOBu t .

11. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (10), the tert-butyl group of compound (13) is hydrolyzed to obtain compound (14): The hydrolysis can be carried out under acid catalysis, the catalyst being selected from dilute hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, formic acid or acidic ion exchange resin, etc. The hydrolysis can also be carried out under base catalysis, the catalyst being selected from NaOH, KOH or KOBu t wait.

12. The method for preparing the GLP-1 receptor agonist Orforglipron according to claim 1, characterized in that: In step (11), the intermediate (14) is subjected to dehydration condensation with (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (15) in the presence of an appropriate condensing agent to obtain the target product Orforglipron: The condensing agent is selected from carbodiimide, phosphorus cation or urea cation condensing agents such as EDC, CDIC, DCC, HATU, HBTU, PyBOP, PyAOP, HOBt, HOAt, Oxyma derivatives.

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