Preparation method of GLP-1R agonist Orforglipron

Abstract

The invention discloses a preparation method of a GLP-1R agonist Orforglipron, which comprises the following reaction steps: carrying out four-step reaction on an oxopiperidine compound (1) and (4-fluoro-3, 5-dimethylphenyl) hydrazine (2) to obtain a compound 8, and carrying out seven-step reaction on 5-bromo-indolecarboxylic acid (9) to obtain a compound 17. Then, the compound 8 and a compound 17 are subjected to an acid amine condensation reaction, and Orforglipron (LY3502970) is obtained. The preparation method is relatively low in cost, easy to operate, relatively short in synthetic route and suitable for industrial production and application, and the total yield can reach 32%.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an efficient preparation method of a GLP-1R agonist Orforglipron (chemical name: 3-((1R,2R)-1-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one). Background Art

[0002] Glucagon-like peptide-1 receptor (GLP-1R) agonists have become core drugs in the field of metabolic diseases due to their significant efficacy in the treatment of type 2 diabetes and obesity. They play a multi-dimensional role by promoting insulin secretion, inhibiting glucagon release, delaying gastric emptying and regulating appetite. In 2023, "Science" even rated GLP-1 drugs as the top scientific breakthrough of the year. However, the existing mainstream GLP-1R agonists (such as semaglutide and tilportide) are all peptide drugs that need to be administered by injection or rely on complex oral preparations (such as absorption enhancers), resulting in low patient compliance, high production costs, and limited production capacity that seriously restricts market supply.

[0003] Orforglipron (LY3502970), the first oral small-molecule GLP-1RA to complete Phase III clinical trials, is expected to address these pain points. Its advantages include convenient, once-daily oral administration, independent of dietary restrictions. Its efficacy has been demonstrated in a Phase III study (ACHIEVE-1) showing that after 40 weeks of treatment with a 36mg dose, patients experienced a 1.5% reduction in glycated hemoglobin (A1C) and a 7.9% (7.3kg) average weight loss, with the weight loss trend not reaching a plateau. Its small molecule structure also facilitates scalable synthesis, breaking through the biofermentation capacity bottleneck of peptide-based drugs. Eli Lilly anticipates that its approval will allow for global, unconstrained market access.

[0004] Despite the promising prospects of Orforglipron, its industrial production still faces significant challenges: the original patent (US20250042899) uses a 28-step synthesis route with low yield and complex operation; the cost of key intermediates is high; and the yield of some reactions is low.

[0005] The current orforglipron synthesis process has significant drawbacks in terms of process economy, intermediate costs, scale-up feasibility, and impurity control, hindering its potential as an accessible drug. Therefore, there is an urgent need to develop a highly efficient, low-cost, and industrially scalable preparation method. Summary of the Invention

[0006] The purpose of the present invention is to solve the above problems existing in the prior art and provide a method for preparing the GLP-1R agonist Orforglipron.

[0007] The technical solution adopted in the present invention is as follows:

[0008] A method for preparing a GLP-1R agonist, Orforglipron, comprises the following steps:

[0009] S1. An oxopiperidine compound (1) and (4-fluoro-3,5-dimethylphenyl)hydrazine (2) undergo a Knorr pyrazole synthesis reaction to obtain an intermediate compound (3);

[0010]

[0011] S2, compound (3) and carbonyl imidazole compound (4) are reacted under alkaline conditions and ring-closed to obtain dihydroimidazolone compound (5);

[0012]

[0013] S3, compound (5) undergoes Goldberg coupling reaction with 5-bromo-4-fluoro-1-methyl-1H-indazole (6) to obtain intermediate compound (7);

[0014]

[0015] S4, intermediate compound (7) is subjected to removal of the amino protecting group under acidic conditions to obtain (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 (8);

[0016]

[0017] S5, 5-bromoindolecarboxylic acid (9) and ethanol are subjected to esterification reaction to obtain compound (10);

[0018]

[0019] S6. Compound (10) is alkylated under alkaline conditions to obtain cyano compound (11);

[0020]

[0021] S7, compound (11) and (4R)-4-methyl-1,3,2-dioxathiazolin-2,2-dioxide (12) are reacted under strong alkaline conditions to form a methylcyclopropane group to obtain compound (13);

[0022]

[0023] S8, the methylcyclopropane compound (13) is functionalized to obtain the amidoxime compound (14);

[0024]

[0025] S9 and the amidoxime compound (14) are condensed to obtain the oxadiazole compound (15);

[0026]

[0027] S10 and the oxadiazole compound (15) are then reacted with a cyclic ether organozinc reagent through a Negishi coupling reaction to obtain compound (16);

[0028]

[0029] S11, compound (16) is subjected to ester hydrolysis under strong alkaline conditions to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (17);

[0030]

[0031] S12, compound (8) and compound (17) undergo amide condensation under the catalysis of a condensing agent to obtain Orforglipron;

[0032]

[0033] Reaction formula of the present invention is as follows:

[0034]

[0035] Preferably, in S1, the organic solvent is one or more of methanol, ethanol, acetonitrile, acetic acid, and tetrahydrofuran; the reaction temperature is 0-120° C., and the reaction time is 0-24 h.

[0036] Preferably, in S2, the organic solvent is one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), tetrahydrofuran, methanol, ethanol, toluene, and 1,4-dioxane; the alkaline condition is one or more of sodium hydride, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium bicarbonate, 4-dimethylaminopyridine, and N,N-diisopropylethylamine; the acidic condition is one or more of hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, and trifluoroacetic acid; the reaction temperature is 10-150°C, and the reaction time is 3-24h.

[0037] Preferably, in S3, the organic solvent is one or more of toluene, xylene, THF, DMA, 1,4-dioxane, DMF, NMP, and DMSO; the base is a metal-containing base selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; the amine-containing ligand is selected from one or more of N,N'-dimethylethylenediamine, N,N'-dimethylcyclohexanediamine, and ethylenediamine; the catalyst is selected from one or more of Cu, CuI, CuCl, CuCl2, Cu2O, Cu(OAc)2, and Cu(acac)2; the molar ratio of the aromatic compound to the amine, Cu catalyst, amine ligand, and base is 1:(1.2-1.8):(0.05-0.08):(0.06-0.1):(1.5-2.5).

[0038] Preferably, in S4, the organic solvent is selected from one or more of acetonitrile, THF, DMF, DME, 1,4-dioxane, methanol, ethanol, NMP, DMA, DMSO, toluene, and DCM; and the acid is selected from one or more of methanesulfonic acid, trifluoroacetic acid, acetic acid, hydrochloric acid, and sulfuric acid.

[0039] Preferably, in S5, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol; the esterification reagent is selected from one or more of thionyl chloride, oxalyl chloride, and concentrated sulfuric acid; the reaction temperature is 40-80°C, and the reaction time is 1-8h.

[0040] Preferably, in S6, the organic solvent is selected from one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP); the alkaline condition is one or more of potassium tert-butoxide, sodium hydride, and potassium hexamethyldisilazide; the cyanation reagent is selected from chloroacetonitrile and bromoacetonitrile; the reaction temperature is 0–40°C, and the reaction time is 1–6h.

[0041] Preferably, in S7, the organic solvent is selected from one or more of tetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and N,N-dimethylformamide; the strong base is selected from one or more of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide; the reaction temperature is -20–25°C, and the reaction time is 1–4h.

[0042] Preferably, in S8, the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and water; the hydroxylamine source is selected from hydroxylamine hydrochloride and hydroxylamine sulfate; the neutralizing base is selected from sodium carbonate, potassium carbonate, and sodium bicarbonate; the reaction temperature is 50-80°C, and the reaction time is 2-6h.

[0043] Further preferably, in S9, the organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and 1,4-dioxane; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI) and 1,1'-carbonylbis(1,2,4-triazole); the catalyst is selected from 1,8-diazabicycloundec-7-ene (DBU) and triethylamine; the reaction temperature is 10-40°C, and the reaction time is 4-12h.

[0044] Further preferably, in S10, the cyclic ether organozinc reagent is prepared via an iodinated cyclic ether intermediate and zinc powder; the solvent is selected from tetrahydrofuran and N,N-dimethylformamide; the catalyst is selected from Pd2(dba)3 and Pd(OAc)2; the ligand is selected from triphenylphosphine and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (S-Phos); the reaction temperature is 60–80°C, and the reaction time is 3-8h.

[0045] Further preferably, in S11, the alkaline condition is one of an aqueous solution or an alcohol solution of sodium hydroxide, lithium hydroxide, or potassium hydroxide; the reaction temperature is 40-70° C., and the reaction time is 4-12 h; and the acidifying agent is selected from one of hydrochloric acid, sulfuric acid, and acetic acid.

[0046] Further preferably, in S12, the condensing agent is selected from 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU); the base is selected from N,N-diisopropylethylamine, triethylamine; the solvent is selected from dichloromethane, N,N-dimethylformamide, acetonitrile; the reaction temperature is 0-30°C, and the reaction time is 2-8h.

[0047] The present invention has the following beneficial effects: Commercially available compounds 1 and 9 are used to synthesize compounds 8 and 17, respectively. The two compounds are then combined through acid-amine condensation to obtain the target compound, orforglipron. This compound can then undergo a Pd-catalyzed Negishi coupling to obtain the target compound 16 in a substrate-induced manner. The required raw materials in this route are all commercially available and easily accessible. Compared to existing routes, this route offers lower costs, more environmentally friendly conditions, and all synthetic operations suitable for industrial scale-up. Compared to existing routes, this route is easier to implement and shorter, with an overall yield of 32% (compared to 12.5% ​​for existing routes). BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is a framework diagram of the convergent synthesis strategy of Orforglipron in the present invention. DETAILED DESCRIPTION

[0049] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0050] Example 1

[0051]

[0052] Step S1

[0053] In a 250 mL three-necked flask, (4-fluoro-3,5-dimethylphenyl)hydrazine (2.17 g, 14.1 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (4.04 g, 16.9 mmol) were dissolved in 100 mL of ethanol. Py·HCl (0.244 g, 2.11 mmol) was then added and allowed to react at 75°C for 12 h. After completion of the reaction, the mixture was cooled and a large amount of water was added. The pH was adjusted to 9 with NaOH(aq). Extraction was performed with ethyl acetate, and the crude product was concentrated under reduced pressure. Rapid separation and purification by column chromatography removed most impurities and pigments. After concentration, the product was dissolved in 20 mL of EA and slurried in 200 mL of industrial hexane. Filtration and drying yielded 5.17 g of a pale yellow powder. The yield was 98%. 1 H NMR(600MHz,Chloroform-d)δ7.1(d,J=6.2Hz,2H),5.1(d,J=105.0Hz,1H),4.4–4.1(m,1H),3 .6(s,2H),3.1(s,1H),2.7–2.6(m,2H),2.3(d,J=2.2Hz,6H),1.5(s,9H),1.3(d,J=6.6Hz,3H). 13C NMR(150MHz,Chloroform-d)δ158.9(d,J CF =244.7Hz),154.6,147.1,139.5,133.7,125.9,125.8,124.7,124.7,79.9,58.4,44.5,37.9,28.6,24.1,18.7,14.8,14.8.

[0054] Step S2

[0055] In a 250 mL three-necked flask, (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.84 g, 13 mmol) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (5.18 g, 26 mmol) were dissolved in 100 mL of DMA and mixed well. 4.4 g, 39 mmol) was added to the solution at 25°C in four portions. The reaction was maintained at this temperature for 4 h, and then quenched by adding aqueous NH4Cl solution. The solution was extracted with ethyl acetate, washed with saturated NaCl(aq), and finally dried over anhydrous sodium sulfate. After concentration under reduced pressure, a dark brown viscous liquid was obtained, which was then rapidly separated and purified by column chromatography to remove most impurities and pigments. A small amount of solution remained after concentration, and was placed in an ice bath to precipitate hairy needle-like white crystals. The filtered crystals were dissolved in 100 mL of THF. MsOH was slowly added at 60°C and stirred for 2 h. The mixture was cooled, water was added, and the pH was adjusted to >9 with NaOH (aq). The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The mixture was then dissolved in THF and Et3N (3.23 g, 32 mmol) and Boc2O (7 g, 32 mmol) were added at 25°C. The mixture was mixed and reacted for 1 h. After completion of the reaction, water was added to quench the mixture and the mixture was extracted with ethyl acetate. The mixture was washed with saturated NaCl (aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid. Purification by column chromatography afforded 3.00 g of a light yellow solid with a yield of 85.95%. 1 H NMR(600MHz,Chloroform-d)δ7.0(d,J=6.1Hz,2H),6.7(d,J=3.5Hz,1H),6.1(s,1H),5.2(d,J=68.3Hz,1H), 4.3(d,J=102.5Hz,1H),3.1(s,1H),2.8–2.7(m,2H),2.2(d,J=2.1Hz,6H),1.4(s,9H),1.2(d,J=6.8Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ159.2(d,J CF=245.4Hz),154.4,148.9,147.2,133.2,133.2,128.3,125.6,125.5,124.5,124.5,1 13.0,110.1,85.1,80.0,45.5,44.4,37.8,37.0,28.5,27.9,24.2,19.5,14.7,14.6.

[0056] Step S3

[0057] Take a 150 mL three-necked flask, prepare it in advance to be anhydrous and oxygen-free, and under the protection of argon, add (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (2.2 g, 5 mmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (1.7 g, 7. 5mmol), (1S,2S)-(+)-N,N-dimethyl-1,2-cyclohexanediamine (0.355g, 2.5mmol), and K2CO3 (2.07g, 15mmol) were dissolved in 50mL of NMP and mixed thoroughly. CuI (0.476g, 2.5mmol) was added and the reaction was stirred at 130°C for 3h. Water and saturated NH4Cl(aq) were then added to quench the reaction, and extraction was performed with ethyl acetate. The product was washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a reddish-black liquid. Purification by column chromatography afforded 2.21g of a brown oily liquid. The yield was 75%. 1 HNMR(600MHz,Chloroform-d)δ8.1(d,J=1.0Hz,1H),7.4(t,J=7.7Hz,1H),7.2(d,J=8.8Hz,1H),7.1(d,J=6.1Hz,2H),6.6(t,J=2.3Hz,1H),6.3( s,1H),5.4–5.2(m,1H),4.4(d,J=111.0Hz,1H),4.1(s,3H),3.2(s,1H), 2.8–2.7(m,2H),2.2(d,J=2.1Hz,6H),1.5(s,9H),1.3(d,J=6.7Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ159.2(d,J CF =245.2Hz),151.4,149.8(d,J CF=258.5Hz),141.7,141.6,133.6,129.9,129.1,126.0,125.7,125.6,124.1,124.1,115.0, 114.9,114.8,114.7,112.1,105.7,105.6,80.1,36.1,29.8,28.6,24.4,19.5,14.8,14.8.

[0058] Step S4

[0059] In a 250 mL three-necked flask, (S)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.89 g, 10 mmol) was dissolved in 100 mL of methanol. MsOH (3.84 g, 40 mmol) was slowly added dropwise. After mixing thoroughly, the mixture was placed in a 50°C oil bath for 4 h. The mixture was then cooled to room temperature and quenched with 100 mL of water. The pH of the reaction solution was adjusted to >8 with sodium hydroxide solution. The mixture was extracted with dichloromethane, washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown solid. The solid was filtered and washed with ethyl acetate to obtain 4.33 g of an off-white solid. The yield was 88.5%. 1 H NMR(600MHz,Chloroform-d)δ8.1(d,J=1.0Hz,1H),7.4(dd,J=8.8,6.7Hz,1H),7.2(dd ,J=8.8,1.0Hz,1H),7.1(d,J=6.1Hz,2H),6.5(dd,J=3.1,1.5Hz,1H),6.2(d,J=3.1Hz,1 H),4.2(q,J=6.6Hz,1H),4.1(s,3H),3.4(m,J=13.0,5.4,3.7Hz,1H),3.1(m,J=12.9,9 .4,5.1Hz,1H),2.9–2.8(m,2H),2.5(s,1H),2.2(d,J=2.1Hz,6H),1.3(d,J=6.6Hz,3H). 13 CNMR(150MHz,Chloroform-d)δ159.1(d,J CF =245.1Hz),151.5,149.9(d,J CF=258.4Hz),147.7,141.7,141.6,133.6,133.6,129.9,128.9,126.0,125.7,125.5,124.3,124.2,117.8, 115.0,114.9,114.8,114.7,114.4,114.4,112.3,105.6,105.6,47.4,42.5,36.1,24.7,20.2,14.8,14.7.

[0060]

[0061] Step S5

[0062] In a 500mL three-necked flask, 5-bromoindole-2-carboxylic acid (10g, 41.6mmol) was mixed with 200mL of ethanol to form a suspension. After heating to 70°C, SOCl2 (9.91g, 83.3mmol) was slowly added dropwise using a constant pressure dropping funnel. After 4 hours of reaction, water was added to quench the mixture. The mixture was extracted with ethyl acetate, and the organic phases were combined and neutralized with saturated NaHCO3 until the aqueous phase was free of bubbles. Finally, the mixture was washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown solid. The solid was then filtered and washed with a hexane / EA mixture (10:1) to obtain a yellow solid. The solid was then dissolved in 40mL of DCM and recrystallized at 50°C. After ice-cooling, 9.99g of off-white crystals were obtained. The yield was 89.6%. 1 H NMR(600MHz,Chloroform-d)δ9.1(s,1H),7.8(dd,J=1.9,0.8Hz,1H),7.4(dd,J=8.7,1.9Hz, 1H),7.3–7.3(m,1H),7.1(dd,J=2.1,1.0Hz,1H),4.4(t,J=7.2Hz,2H),1.4(t,J=7.1Hz,3H). 13 C NMR (150MHz, Chloroform-d) δ161.9,135.5,129.2,128.7,128.4,125.1,114.1,113.5,108.0,61.4,14.5.

[0063] Step S6

[0064] Ethyl 5-bromo-1H-indole-2-carboxylate (8 g, 30 mmol) was dissolved in 100 mL of DMF, followed by the addition of t-BuOK (5 g, 45 mmol) in portions. The mixture was stirred at room temperature for 1 hour, and then chloroacetonitrile (3.4 g, 45 mmol) was slowly added dropwise. The mixture was heated to 40°C and reacted for 4 hours. Water and saturated NH4Cl(aq) were added to quench the reaction. The resulting gray filter cake was then dissolved in ethyl acetate, filtered through celite, and concentrated to yield 4.94 g of white needle-like crystals. The yield was 86%. 1 H NMR (600MHz, Chloroform-d) δ7.8(d,J=1.9Hz,1H),7.5(dd,J=9.0,1.9Hz,1H),7.3–7.3(m,2H),5.6(s,2H),4.4(q,J=7.1Hz,2H),1.4(t,J=7.1Hz,3H). 13 C NMR (150MHz, Chloroform-d) δ161.6,137.3,129.4,128.0,127.7,125.7,115.4,114.7,111.8,111.3,61.6,32.6,14.4.

[0065] Step S7

[0066] In a 250 mL three-necked flask, ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (3.07 g, 10 mmol) was dissolved in dry DMPU / THF (10 mL / 100 mL) under argon. The mixture was stirred in an ice bath to pre-cool. (4R)-4-methyl-1,3,2-dioxathiazolin-2,2-dioxide (2.76 g, 20 mmol) was then added. After stirring, the solution turned pale yellow. Subsequently, 2 mL of a THF solution of LiHMDS was added dropwise every 5 minutes (20 mL total) under an ice bath. After the additions were complete, the mixture was allowed to react for 2.5 hours under an ice bath. After the reaction was complete, a large amount of saturated NH4Cl(aq) and water was added to quench the mixture, and the mixture was stirred for 1 hour. The product was then extracted with EA (250 mL x 3), washed with saturated NaCl (aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a black viscous liquid. After purification by column chromatography, the product was concentrated to obtain a bright yellow solid. Finally, the solid was rinsed with petroleum ether to obtain 1.45 g of a white solid. The yield was 42%.

[0067] Step S8

[0068] In a 250 mL three-necked flask, ethyl 5-bromo-1-((1S,2S)-1-cyano-2-methylcyclopropyl)-1H-indole-2-carboxylate (2.4 g, 6.9 mmol) was dissolved in 100 mL of DMSO. Hydroxylamine hydrochloride (2.4 g, 34.5 mmol) and sodium carbonate (3.66 g, 34.5 mmol) were added and reacted at 70°C for 3 h. The mixture was then quenched with a large amount of water. Extraction with ethyl acetate was performed, followed by washing with water and saturated NaCl(aq), drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain a pale yellow oily crude product. The crude product was dissolved by heating in 50 mL of a 10:1 PE / EA mixture, filtered while hot, and the filtrate was collected and placed in an ice bath for crystallization, ultimately yielding 2.15 g of white crystals. The yield was 82%. 1 H NMR (600MHz, Methanol-d4) δ7.7(d,J=1.9Hz,1H),7.7(d,J=8.9Hz,1H),7.3(dd,J=8.9,1.9Hz,1H),7.1(d,J=0.8Hz,1H),4.4(dq,J= 7.3,3.4Hz,2H),1.6(dd,J=7.2,5.5Hz,1H),1.5–1.5(m,1H),1.4(t,J=7.1Hz,3H),1.2(d,J=6.3Hz,3H),0.9(dd,J=9.6,5.5Hz,1H). 13 C NMR (150MHz, Methanol-d4) δ164.1,153.6,140.0,130.7,129.0,128.8,125.8,115.7,115.4,111.9,62.7,41.9,23.8,19.3,14.6,14.2.

[0069] Step S9

[0070] Ethyl 5-bromo-1-((1S,2S)-1-(N-hydroxyaminocarbamimidoyl)-2-methylcyclopropyl)-1H-indole-2-carboxylate (3.8 g, 10 mmol) was dissolved in 100 mL of DMSO. CDI (3.24 g, 20 mmol) was then added to the reaction system and stirred until uniform. DBU (0.304 g, 20 mmol) was then slowly added dropwise. After stirring at room temperature (25°C) for 8 h, the mixture was quenched by addition of saturated NH4Cl(aq) and a large amount of water. The mixture was extracted with ethyl acetate, washed with water and saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid. Purification by column chromatography afforded 3.91 g of pure white crystals. The yield was 96.35%. 1HNMR(600MHz,Chloroform-d)δ9.7(s,1H),7.8(d,J=1.8Hz,1H),7.5(d,J=8.9Hz,1H),7.5(dd,J=8.8,1.9Hz,1H),7.2(d,J=0.9Hz, 1H),4.5(t,J=7.1Hz,2H),1.9(dd,J=7.5,6.1Hz,1H),1.7–1.7(m,1H),1.5(t,J=7.2Hz,3H),1.4–1.4(m,1H),1.2(d,J=6.4Hz,3H). 13 C NMR (150MHz, Chloroform-d) δ163.4,158.4,156.8,138.5,129.5,129.1,127.6,125.5,116.1,113.6,112.3,62.5,36.15,24.2,19.3,14.3,14.1.

[0071] Step S10

[0072] In a 500mL three-necked flask, acetone (5.8g, 100mmol), 3-butene-1-ol (7.2g, 100mmol), and NaI (14.9g, 100mmol) were added to 150mL of MeCN. After stirring, TMSCl (10.86g, 100mmol) was slowly added dropwise to generate TMSI in situ. The reaction mixture was stirred at room temperature (25°C) for 1h. After completion, saturated Na2S2O3 (aq) and 200mL of water were added to quench the reaction. The mixture was filtered and extracted with ethyl acetate. The organic phase was then washed with saturated NaCl (aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a yellow to red liquid with a distinctive aroma. Purification by column chromatography yielded 22.80g of a colorless, oily liquid with a distinctive aroma.

[0073] Zinc powder (3.25 g, 50 mmol) and anhydrous LiCl (2.1 g, 50 mmol) were weighed and placed in a 100 mL round-bottom flask. 50 mL of ultra-dry DMF was added and stirred. The reaction system was placed under an argon atmosphere and heated to 40°C. TMSCl (1.08 g, 10 mmol) and 1,2-dibromoethane (1.87 g, 10 mmol) were then added via syringe. After stirring, the temperature was raised to 60°C. The reaction solution was stirred for 0.5 h, and the iodide compound (4.8 g, 20 mmol) prepared above was slowly added dropwise. The reaction was allowed to react for 3 h, and then cooled to room temperature.

[0074] In a dry round-bottom flask, Pd2(dba)3 (10 mmol%) and PPh3 (20 mmol%) were weighed into a glove box and added to 100 mL of ultra-dry THF. After stirring at room temperature, 5-bromo-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid ethyl ester (4.06 g, 10 mmol) was added. After mixing thoroughly, the organozinc reagent prepared above was added to the reaction solution. The reaction was allowed to react at 70°C for 4 h. After quenching with saturated NH4Cl(aq) and water, 100 mL of ethyl acetate was added, and the mixture was filtered through celite and cotton to remove insoluble matter. The filtrate was separated into an organic phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated NaCl(aq), dried, and concentrated. After purification by column chromatography, 3.96 g of a white solid was obtained. The yield was 90.2%. 1 H NMR(600MHz,Chloroform-d)δ9.8(s,1H),7.6(d,J=8.6Hz,1H),7.5(d,J=1.7Hz,1H),7.3(dd,J=8.7,1.7 Hz,1H),7.2(s,1H),4.4(q,J=7.1Hz,2H),3.9–3.8(m,2H),3.0(qd,J=8.6,5.9Hz,1H),1.9(dd,J=7.5,6.1 Hz,1H),1.7(d,J=5.1Hz,1H),1.7–1.7(m,1H),1.7(d,J=2.9Hz,1H),1.7(d,J=9.7Hz,1H),1.6(t,J=12.9H z,1H),1.5(d,J=7.5Hz,1H),1.4(d,J=7.1Hz,3H),1.3(s,3H),1.3(d,J=1.8Hz,3H),1.2(d,J=6.3Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ163.7,158.8,157.1,140.2,138.9,128.2,126.4,126.3,120.3 ,113.2,112.2,72.0,62.2,61.9,44.9,37.55,35.1,34.0,31.9,24.1,21.9,19.2,14.4,14.1.

[0075] Step S11

[0076] In a 250 mL three-necked flask, ethyl 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylate (4.39 g, 10 mmol) was dissolved in 100 mL of methanol. NaOH (1.6 g, 40 mmol) was dissolved in 20 mL of water and slowly added to the reaction flask. After mixing thoroughly, the mixture was reacted in a 50°C oil bath for 6 h. The mixture was then cooled to room temperature and quenched with 100 mL of water. The reaction mixture was then adjusted to a pH <6 with 2 mol / L hydrochloric acid. Extraction was performed with ethyl acetate, washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a yellow solid. Purification by column chromatography afforded 3.53 g of an off-white solid. The yield was 86%. 1 HNMR(600MHz,Chloroform-d)δ7.6(d,J=8.4Hz,1H),7.5(s,1H),7.3(d,J=8.6Hz,1H),7.3–7.2(m,1H),3.9–3.8(m,2H),3.0(s ,1H),1.9(s,1H),1.8–1.8(m,2H),1.7(d,J=3.9Hz,2H),1.6(t,J=12.9Hz,1H),1.5(s,1H),1.4(s,3H),1.3(s,3H),1.2(s,3H). 13 C NMR(150MHz,Chloroform-d)δ166.4,161.5,157.5,140.1,138.7,128.9,126.5,126.1, 120.4,113.4,112.1,72.2,61.9,44.9,37.6,34.9,34.0,31.8,23.6,21.9,19.5,14.5.

[0077] Step S12

[0078] In a 500 mL three-necked flask, under argon, 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (4.89 g, 10 mmol), HATU (4.56 g, 12 mmol), and DIPEA (2.58 g, 20 mmol) were dissolved in 200 mL of DCM. After stirring at 25°C for 30 min, compound 8 (4.93 g, 12 mmol) was added to the reaction system. The reaction was continued at room temperature for 4 h before being quenched by the addition of 200 mL of water. The organic phase was separated and the aqueous phase was extracted once with DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a reddish-brown viscous liquid. After separation and purification by chromatographic column, 7.06 g of grayish yellow solid was obtained, with a yield of 80%. 1 H NMR (600MHz, DMSO-d6) δ11.8(s,1H),8.3(d,J=2.4Hz,1H),7.6(d,J=8.8Hz,1H),7.5(s,1H),7.5(t,J=7.8Hz,1H),7.4(d,J=8.5Hz,1H),7. 3(d,J=9.5Hz,1H),7.2(d,J=6.1Hz,2H),7.1(d,J=3.1Hz,1H),6.9(d,J=22.5Hz,2H),5.6–5.5(m,1H),4.4(d,J=12.9Hz,1H),4.1(s,3H),3. 7–3.7(m,2H),3.6(t,J=12.9Hz,1H),3.2(t,J=13.8Hz,1H),3.0(d,J=12.8Hz,1H),2.9(d,J=15.6Hz,1H),2.3(s,6H),1.8(q,J=7.4Hz,1H), 1.7(t,J=6.7Hz,1H),1.7(d,J=10.7Hz,2H),1.6–1.6(m,2H),1.5(d,J=13.0Hz,1H),1.4(d,J=6.7Hz,3H),1.3(s,3H),1.2(d,J=9.4Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ163.0,158.9,158.5,157.5(d,J CF =244.4Hz),150.9,150.0(d,J CF=255.8Hz),146.3,141.5,141.4,139.5,136.2,133.5,131.6,129.7,129. 3,126.7,126.4,125.2,125.0,124.2,123.6,116.2,115.4,114.5,114.4,1 13.6,113.5,112.7,110.6,106.8,104.6,79.2,70.9,59.6,44.6,44.4,41.5,36.7,35.9,35.6,33.9,32.2,24.3,21.7,19.5,18.3,14.4,14.4,12.6.

[0079] Example 2

[0080] The preparation method of this embodiment is the same as that of Example 1, except that:

[0081] Step S1-1

[0082] Step S1-1 differs from Step S1 in that (4-fluoro-3,5-dimethylphenyl)hydrazine is replaced with the corresponding hydrochloride, dissolved in methanol, and reacted with sodium hydroxide. The resulting mixture is then reacted with tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate at 70°C for 15 hours. After the reaction is complete, the mixture is cooled, a large amount of water is added, and extraction is performed with ethyl acetate. The crude product is concentrated under reduced pressure and purified by column chromatography to yield a pale yellow powder solid. The yield is 81%.

[0083] Step S5-1

[0084] Step S5-1 differs from Step S5 in that 5-bromoindole-2-carboxylic acid and methanol are mixed and stirred to form a suspension. After heating to 70°C, oxalyl chloride is slowly added dropwise using a constant pressure dropping funnel. After 8 hours of reaction, water is added for quenching. Extraction is performed with ethyl acetate, and the organic phases are combined and then neutralized with saturated NaHCO3 until the aqueous phase is free of bubbles. Finally, the product is washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow-brown solid. Column chromatography yields an off-white solid. The yield is 73.6%.

[0085] Step S6-1

[0086] Step S6-1 differs from step S6 in that ethyl 5-bromo-1H-indole-2-carboxylate is dissolved in THF, followed by the addition of NaH. After stirring at room temperature for 1 hour, chloroacetonitrile is slowly added dropwise. After reacting at room temperature for 4 hours, the mixture is quenched with water and saturated NH4Cl(aq). The reaction is then extracted with ethyl acetate, washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a dark gray solid, which is purified by column chromatography to a white solid. The yield is 53%.

[0087] Step S7-1

[0088] The difference between step S7-1 and step S7 is that 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylic acid ethyl ester is dissolved in THF under argon protection, placed in an ice bath and stirred for pre-cooling, and then (4R)-4-methyl-1,3,2-dioxathiazolin-2,2-dioxide is added. Subsequently, a THF solution of LiHMDS is added dropwise under an ice bath, and the mixture is reacted at room temperature for 5 hours. After the reaction is completed. A large amount of saturated NH4Cl(aq) and water are added to quench the mixture and stirred for 1 hour. Then, the mixture is extracted with ethyl acetate, washed with saturated NaCl(aq), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a black viscous liquid, which is separated and purified by a chromatographic column and concentrated to obtain a yellow solid. The yield is 17%.

[0089] Step S10-1

[0090] Step S10-1 differs from step S10 in that Pd(dba) is replaced with Pd(OAc). All other steps remain unchanged. The reaction solution is quenched and extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl(aq), dried, concentrated, and purified by column chromatography to yield a white solid. The yield is 78.7%.

[0091] The description and drawings of the present invention are considered to be illustrative rather than restrictive. On the basis of the present invention, those skilled in the art can make some substitutions and modifications to some of the technical features according to the disclosed technical content without creative work, and all of them are within the scope of protection of the present invention.

Claims

1. A method for preparing a GLP-1R agonist Orforglipron, characterized in that: The following steps are involved: S1. An oxopiperidine compound (1) and (4-fluoro-3,5-dimethylphenyl)hydrazine (2) undergo a Knorr pyrazole synthesis reaction to obtain an intermediate compound (3); S2, compound (3) and carbonyl imidazole compound (4) are reacted under alkaline conditions and ring-closed to obtain dihydroimidazolone compound (5); S3, compound (5) undergoes Goldberg coupling reaction with 5-bromo-4-fluoro-1-methyl-1H-indazole (6) to obtain intermediate compound (7); S4, intermediate compound (7) is subjected to removal of the amino protecting group under acidic conditions to obtain (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 (8); S5, 5-bromoindolecarboxylic acid (9) and ethanol are subjected to esterification reaction to obtain compound (10); S6. Compound (10) is alkylated under alkaline conditions to obtain cyano compound (11); S7, compound (11) and (4R)-4-methyl-1,3,2-dioxathiazolin-2,2-dioxide (12) are reacted under strong alkaline conditions to form a methylcyclopropane group to obtain compound (13); S8, the methylcyclopropane compound (13) is functionalized to obtain the amidoxime compound (14); S9 and the amidoxime compound (14) are condensed to obtain the oxadiazole compound (15); S10 and the oxadiazole compound (15) are then reacted with a cyclic ether organozinc reagent through a Negishi coupling reaction to obtain compound (16); S11, compound (16) is subjected to ester hydrolysis under strong alkaline conditions to give 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (17); S12, compound (8) and compound (17) undergo amide condensation under the catalysis of a condensing agent to obtain Orforglipron; The reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that In S1, the organic solvent is one or more of methanol, ethanol, acetonitrile, acetic acid, and tetrahydrofuran; the reaction temperature is 0-120°C, and the reaction time is 0-24h; In S2, the organic solvent is one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), tetrahydrofuran, methanol, ethanol, toluene, and 1,4-dioxane; the alkaline condition is one or more of sodium hydride, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium bicarbonate, 4-dimethylaminopyridine, and N,N-diisopropylethylamine; the acidic condition is one or more of hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, and trifluoroacetic acid; the reaction temperature is 10-150°C, and the reaction time is 3-24h.

3. The preparation method according to claim 1, characterized in that In the S3, the organic solvent is one or more of toluene, xylene, THF, DMA, 1,4-dioxane, DMF, NMP, and DMSO; the base is a metal-containing base selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; the amine-containing ligand is one or more of N,N'-dimethylethylenediamine, N,N'-dimethylcyclohexanediamine, and ethylenediamine; the catalyst is one or more of Cu, CuI, CuCl, CuCl2, Cu2O, Cu(OAc)2, and Cu(acac)2; and the molar ratio of the aromatic compound to the amine, Cu catalyst, amine ligand, and base is 1:(1.2-1.8):(0.05-0.08):(0.06-0.1):(1.5-2.5).

4. The preparation method according to claim 1, characterized in that In S4, the organic solvent is selected from one or more of acetonitrile, THF, DMF, DME, 1,4-dioxane, methanol, ethanol, NMP, DMA, DMSO, toluene, and DCM; the acid is selected from one or more of methanesulfonic acid, trifluoroacetic acid, acetic acid, hydrochloric acid, and sulfuric acid; In S5, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol; the esterification reagent is selected from one or more of thionyl chloride, oxalyl chloride, and concentrated sulfuric acid; the reaction temperature is 40-80°C, and the reaction time is 1-8 hours.

5. The preparation method according to claim 1, characterized in that In S6, the organic solvent is selected from one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP); the alkaline condition is one or more of potassium tert-butoxide, sodium hydride, and potassium hexamethyldisilazide; the cyanation reagent is selected from chloroacetonitrile and bromoacetonitrile; the reaction temperature is 0–40°C, and the reaction time is 1–6h.

6. The preparation method according to claim 1, characterized in that In S7, the organic solvent is selected from one or more of tetrahydrofuran, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and N,N-dimethylformamide; the strong base is selected from one or more of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide; the reaction temperature is -20–25°C, and the reaction time is 1–4 hours.

7. The preparation method according to claim 1, characterized in that In said S8, the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and water; the hydroxylamine source is selected from hydroxylamine hydrochloride and hydroxylamine sulfate; the neutralizing base is selected from sodium carbonate, potassium carbonate, and sodium bicarbonate; the reaction temperature is 50-80°C, and the reaction time is 2-6h.

8. The preparation method according to claim 1, characterized in that In S9, the organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and 1,4-dioxane; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI) and 1,1'-carbonylbis(1,2,4-triazole); the catalyst is selected from 1,8-diazabicycloundec-7-ene (DBU) and triethylamine; the reaction temperature is 10-40°C, and the reaction time is 4-12h.

9. The preparation method according to claim 1, characterized in that In S10, the cyclic ether organozinc reagent is prepared via an iodinated cyclic ether intermediate and zinc powder; the solvent is selected from tetrahydrofuran and N,N-dimethylformamide; the catalyst is selected from Pd2(dba)3 and Pd(OAc)2; the ligand is selected from triphenylphosphine and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos); the reaction temperature is 60-80°C, and the reaction time is 3-8 hours; In S11, the alkaline condition is one of an aqueous solution or an alcohol solution of sodium hydroxide, lithium hydroxide, or potassium hydroxide; the reaction temperature is 40-70° C., and the reaction time is 4-12 hours; and the acidifying agent is selected from one of hydrochloric acid, sulfuric acid, and acetic acid.

10. The preparation method according to claim 1, characterized in that In S12, the condensing agent is selected from 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU); the base is selected from N,N-diisopropylethylamine and triethylamine; the solvent is selected from dichloromethane, N,N-dimethylformamide and acetonitrile; the reaction temperature is 0-30°C and the reaction time is 2-8h.

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