A method for synthesizing a small molecule drug intermediate of ostarine and similar glp-1ra

Abstract

The application discloses a synthesis method of alogliptin and similar GLP-1RA small molecule drug intermediates, and the synthesis method takes the compound shown in intermediate formula I, the compound shown in intermediate formula II and the compound shown in intermediate formula VI as starting materials; the compound shown in intermediate formula I and the compound shown in intermediate formula II are first synthesized into the compound shown in core intermediate formula V through three steps, then the strategy of the patent of Henan Academy of Sciences is referred to, amide condensation is carried out with the compound shown in intermediate formula VI, and three steps of reactions such as late-stage modification of cyano and five-membered ring synthesis are carried out; through the synthesis strategy of the convergent method, the compound shown in intermediate formula IX can be obtained only through six linear steps, and the technical route is economical, environment-friendly, simple in post-treatment and convenient for scale-up production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and relates to the GLP-1 receptor agonist orforglipron and similar GLP-1RA small molecule drugs, and particularly to a convergent synthesis method for the core chiral substituted indole intermediate of orforglipron and similar GLP-1 small molecule drugs. Background Technology

[0002] Mainstream injectable GLP-1 drugs often suffer from poor patient compliance and demanding storage requirements, while oral small-molecule GLP-1RA drugs typically offer advantages in terms of ease of administration and portability. In April 2026, the FDA approved the world's first oral small-molecule GLP-1 receptor agonist, Orforglipron (brand name FOUNDAYO™), marking a milestone in the field of small-molecule GLP-1RAs. Simultaneously, several similar small-molecule oral GLP-1RA molecules are rapidly progressing in the market, with Aleniglipron and ASC30, shown below, already in Phase II clinical trials.

[0003]

[0004] These molecules have broad application prospects in the global weight loss market, which also creates an urgent need for the large-scale production of the already approved Orforglipron active pharmaceutical ingredient and other similar molecules under development. As shown above, the substituted indole structure circled is the core module of several investigational oral small molecule GLP-1RA molecules, including Orforglipron. However, the original synthetic process has a lengthy linear route—more than 10 chemical transformations, the construction of the chiral three-membered ring is selective, and the removal of isomers requires multiple crystallizations. Furthermore, the construction of the final product from this fragment suffers from severe intramolecular amidation side reactions (as shown below), low yield, and difficult purification, which seriously restricts the accessibility and commercialization of such drugs (see patent [PCT / US2023 / 084487]).

[0005]

[0006] Publication number CN121378229A, published on January 23, 2026, entitled "An Invention on an Orforglipron Intermediate and Its Synthetic Method and Application," addresses the aforementioned pain points in existing Orforglipron synthesis processes by proposing a new synthetic approach. The core innovation lies in generating indole carboxylic acid intermediate 2 from compound 1 via amide hydrolysis, retaining the cyano group, and then condensing it with another chiral secondary amine fragment to construct a five-membered ring. This avoids the intramolecular amidation side reaction under amide condensation conditions. This approach increases the overall yield by more than 8% and avoids the use of environmentally unfriendly reagents, making it a strong competitive route for the commercial production of Orforglipron or other similar molecules. In this report, the starting material compound 1 (shown below) still employs the original route's 9-step linear synthesis, combined with the subsequent condensation and cyano group modification to construct the five-membered ring in 3 steps, resulting in a total linear route of 12 steps—lengthy and uneconomical. Therefore, there is an urgent need to develop a new synthetic process that can efficiently and conveniently obtain compound 1.

[0007] . Summary of the Invention

[0008] To address the shortcomings of existing synthetic routes for the key intermediate 1-N-substituted-2-carboxylic acid-5-substituted indole, such as lengthy synthesis routes, high synthesis costs, and long production cycles, this invention provides a synthetic method for omaglione and similar GLP-1RA small molecule drug intermediates. This invention uses compounds represented by intermediate formula I, intermediate formula II, and intermediate formula VI as starting materials. The compounds represented by intermediate formula I and intermediate formula II are first synthesized in three steps to form the core intermediate formula V. Then, following the strategy of a patent from the Henan Academy of Sciences Institute of Chemistry, a three-step reaction involving amide condensation and cyano group modification to form a five-membered ring is performed with the core intermediate formula V. Using a convergent synthesis strategy, the longest linear step is only six steps, yielding the compound represented by intermediate formula IX (taking IX-1: Orforglipron as an example).

[0009] To achieve the above objectives, the present invention adopts the following technical solution: This invention first provides a method for synthesizing a compound represented by intermediate formula V, the method comprising the following steps: 1) The compound shown in Formula I is dissolved in a solvent, and the compound shown in Formula II, base and catalyst are added. The mixture is heated until the reaction is complete, and after post-treatment, the compound shown in Formula III is obtained. 2) The compound shown in Formula III is dissolved in a solvent, and an aqueous solution of hydrochloric acid is added to react with an aqueous solution of sodium nitrite to obtain a nitrosamine intermediate. Ammonium chloride and zinc powder are added, and the mixture is heated to reduce it. After the reaction is completed, the compound shown in Formula IV is obtained through post-treatment. 3) The compound shown in Formula IV is dissolved in a solvent and reacts with ethyl pyruvate to form a hydrazone intermediate. After desolvation under reduced pressure, a solvent and an acid catalyst are added, and the indole ring is synthesized by heating. After the reaction is complete, ethyl carboxylic acid is hydrolyzed, and the intermediate compound shown in Formula V is obtained after post-treatment. Among them, the compound represented by formula I: ; The compound represented by Formula II: ; The compound represented by Formula III: ; The compound represented by Formula IV: ; The compound shown in formula V: ; In the formula, R1 is H or Me, R2 is H or Me, and R3 is H or Me.

[0010] In a preferred embodiment of the present invention, in step 1), the solvent is one of dimethyl sulfoxide, 1,4-dioxane, or toluene, and the volume of the solvent is 5.0V-30.0V; the amount of the compound represented by formula II is 1.0-3.0 equivalents; and the catalyst is methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II). The catalyst is selected from the following: tetra-triphenylphosphine palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, cuprous iodide, or copper acetate, with a catalyst dosage of 0.001-0.2 equivalents; the ligand is selected from the following: 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, [1,1'-bis(diphenylphosphine)ferrocene], N1,N2-bis(2,6-dimethylphenyl)oxalamide, N-(2,6-dimethylphenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide, or benzoin oxime, with a ligand dosage of 0.002-0.4 equivalents; the base is selected from the following: cesium carbonate, potassium carbonate, sodium tert-butoxide, or potassium tert-butoxide, with a base dosage of 1.0-5.0 equivalents.

[0011] In a preferred embodiment of the present invention, in step 2), the solvent is one of dimethyl sulfoxide, 1,4-dioxane, or toluene, and the volume of the solvent is 5.0V-30.0V; the amount of hydrochloric acid is 2.0-10.0 equivalents, the amount of sodium nitrite is 0.95-1.5 equivalents, the amount of ammonium chloride is 1.0-5.0 equivalents, the amount of zinc powder is 1.0-5.0 equivalents, and the hydrogenation reduction catalyst used for reduction is 5% palladium on carbon and 5% platinum on carbon.

[0012] In a preferred embodiment of the present invention, in step 3), the solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, or toluene; the acid catalyst is one of sulfuric acid, boron trifluoride ether, trifluoroacetic acid, or p-toluenesulfonic acid, and the amount of acid catalyst used is 1.0-5.0 equivalents; the alkali used for hydrolysis is one of sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, or lithium hydroxide, and the amount of alkali used for hydrolysis is 1.0-5.0 equivalents.

[0013] This invention also provides a method for synthesizing oxaliplatin and similar GLP-1RA small molecule drug intermediates, the method comprising the following steps: a) Dissolve the compound of intermediate formula V obtained by the above synthesis method in a solvent, add the compound of chiral amine intermediate formula VI, base and condensing agent to carry out amide condensation reaction, and after post-treatment, obtain the compound of intermediate formula VII. b) Dissolve the compound of intermediate formula VII in a solvent, add hydroxylamine, heat until the reaction is complete, and then post-process to obtain the compound of intermediate formula VIII; c) The compound shown in intermediate formula VIII was placed in a solvent, and a base and a carbonylating agent were added to carry out a five-membered ring reaction. After post-treatment, ozoglieron and the compound shown in intermediate formula IX, which is similar to GLP-1RA small molecule drug intermediate, were obtained. Among them, the compound represented by formula VII: ; The compound represented by formula VIII: ; The compound represented by Formula IX: ; In the formula, R1 is H or Me, R2 is H or Me, and R3 is Me.

[0014] In a preferred embodiment of the present invention, in step a), the solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, or N,N-dimethylpropenylurea, and the volume of the solvent is 3.0V-20.0V; the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The condensing agent is one of (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the amount of condensing agent is 1.0-2.0 equivalents; the base is one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or 1,8-diazabicyclo[5.4.0]undec-7-ene, and the amount of base is 1.0-5.0 equivalents.

[0015] As a preferred embodiment of the present invention, in step b), the solvent is one of methanol, ethanol, isopropanol or tetrahydrofuran; the hydroxylamine species is one of 50% hydroxylamine aqueous solution or hydroxylamine hydrochloride, and the amount of hydroxylamine species used is 1.5-5.0 equivalents.

[0016] In a preferred embodiment of the present invention, in step c), the solvent is one of tetrahydrofuran, 1,4-dioxane, or dichloromethane; the cyclization carbonylating agent is one of N,N'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or triphosgene, and the amount of the cyclization carbonylating agent is 1.5-5.0 equivalents; the base is one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, and the amount of the base is 1.0-5.0 equivalents.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1) The starting materials of this invention have a simple structure and are readily available for commercial mass production.

[0018] 2) This invention uses the compound represented by intermediate formula II with high chiral purity as the starting material for the aggregation method to completely convert the compound represented by intermediate formula I. This can avoid the 5%-7% SRS diastereomers generated during the original synthesis route, and avoid the additional production costs and yield losses caused by recrystallization, thus greatly improving the synthesis efficiency.

[0019] 3) The hydrolysis of the ester group in this invention is carried out under mild conditions and the cyano group is well tolerated, thus avoiding the risk of cyano group intolerance during strong alkaline hydrolysis of compound 1 in the original patent.

[0020] 4) The convergent synthesis method of the present invention only requires 6 steps, which is an economical, environmentally friendly, simple post-processing, and easy-to-scale production technical route.

[0021] 5) The convergence method of the present invention, with its unique advantages of open structure and late-stage cyano modification, can be extended to the synthesis of other similar GLP-1 small molecule drugs, showing great synthetic advantages and commercial application prospects. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is a synthetic route diagram of omaglione and similar GLP-1RA small molecule drug intermediates of the present invention.

[0024] Figure 2 This is a synthetic route diagram of the compound represented by intermediate formula V of the present invention.

[0025] Figure 3 This is the 1H NMR spectrum of the compound represented by Formula III-3.

[0026] Figure 4 This is the 1H NMR spectrum of the compound represented by Formula IV-3.

[0027] Figure 5 This is the 1H NMR spectrum of the compound represented by formula V-3.

[0028] Figure 6 This is the 1H NMR spectrum of the compound represented by Formula III-4.

[0029] Figure 7 This is the 1H NMR spectrum of the compound represented by Formula IV-4.

[0030] Figure 8 This is the 1H NMR spectrum of the compound represented by formula V-4.

[0031] Figure 9 This is the 1H NMR spectrum of the compound represented by Formula VII-1.

[0032] Figure 10 This is the 1H NMR spectrum of the compound represented by formula VIII-1.

[0033] Figure 11 This is the 1H NMR spectrum of the compound represented by Formula IX-1. Detailed Implementation

[0034] To further understand the content of this invention, the invention will be described in detail with reference to the embodiments.

[0035] The present application will be further described in detail below with reference to embodiments. It is understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Furthermore, it should be noted that, for ease of description, only the parts relevant to the invention are shown in the accompanying drawings. The terms "first," "second," etc., used in this invention are for the convenience of describing the technical solutions of the invention and have no specific limiting effect; they are all general terms and do not constitute a limitation on the technical solutions of the invention. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of this application can be combined with each other. Multiple technical solutions in the same embodiment, as well as multiple technical solutions in different embodiments, can be arranged and combined to form new technical solutions that do not contradict or conflict, all of which are within the scope of protection claimed by this invention.

[0036] This invention first provides a method for synthesizing the compound represented by intermediate formula V, such as... Figure 2 As shown, this invention uses readily available and inexpensive chiral or achiral 4-substituted bromobenzene (the compound shown in intermediate formula I, refer to CN_119101040_B) and the compound shown in intermediate formula II via metal-catalyzed CN coupling to obtain the compound shown in intermediate formula III; then, through diazotization, a nitrosamine intermediate is generated, which is then reduced by zinc powder and ammonium chloride to obtain the compound shown in intermediate formula IV; then, it is reacted with ethyl pyruvate to generate a hydrazone intermediate, and finally, an indole ring is catalyzed to obtain the compound shown in core intermediate formula V.

[0037] Furthermore, this invention also provides methods for synthesizing omaglione and similar GLP-1RA small molecule drug intermediates, such as... Figure 2 As shown, the compound of intermediate formula V obtained by the above synthetic method is used in a convergent synthesis strategy to synthesize each GLP-1RA molecule. The compound of intermediate formula V, along with other different compounds of formula VI, undergoes an amide condensation reaction to obtain the compounds of intermediate formula VII; then reacts with hydroxylamine to generate the compounds of each amine oxime intermediate formula VIII; and then reacts with a carbonylating agent to construct a five-membered ring to obtain the compounds of each GLP-1RA molecule of formula IX.

[0038] In this invention, the compound represented by Formula I-1: ; The compound shown in Formula I-2: ; The compound represented by Formula II-1: ; The compound shown in Formula II-2: ; The compound shown in Formula III-1: ; The compound shown in Formula III-2: ; The compound shown in Formula III-3: ; The compound shown in Formula III-4: ; The compound shown in Formula IV-1: ; The compound shown in Formula IV-2: ; The compound shown in Formula IV-3: ; The compound shown in Formula IV-4: ; The compound shown in Formula V-1: ; The compound shown in formula V-2: ; The compound shown in Formula V-3: ; The compound shown in formula V-4: ; The compound shown in Formula VI-1: ; The compound shown in Formula VI-2: ; The compound shown in Formula VI-3: ; The compound shown in Formula VI-4: ; The compound shown in Formula VI-5: ; The compound shown in Formula VI-6: ; The compound shown in Formula VI-7: ; The compound shown in Formula VI-8: ; The compound shown in Formula VI-9: ; The compound represented by formula VII-1: ; The compound represented by formula VII-2: ; The compound represented by formula VII-3: ; The compound represented by formula VII-4: ; The compound represented by formula VII-5: ; The compounds represented by formula VII-6: ; The compounds represented by formula VII-7: ; The compounds represented by formula VII-8: ; The compounds represented by formula VII-9: ; The compound shown in Formula VIII-1: ; The compound shown in Formula VIII-2: ; The compound shown in Formula VIII-3: ; The compound shown in Formula VIII-4: ; The compound shown in Formula VIII-5: ; The compound shown in Formula VIII-6: ; The compound shown in Formula VIII-7: ; The compound shown in Formula VIII-8: ; The compound shown in Formula VIII-9: ; The compound represented by Formula IX-1 (Orforglipron): ; The compound represented by formula IX-2: ; The compound represented by Formula IX-3: ; The compound represented by Formula IX-4: ; The compound represented by Formula IX-5: ; The compound represented by Formula IX-6: ; The compound shown in Formula IX-7: ; The compound represented by Formula IX-8: ; The compound represented by Formula IX-9: .

[0039] Example 1

[0040] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the following compounds were added sequentially: 10.00 g (37.15 mmol) of intermediate formula I-2, 1-aminocyclopropane-1-carboxynitrile hydrochloride (6.61 g (55.73 mmol) of intermediate formula II-1), cesium carbonate (36.31 g (111.45 mmol), and dimethyl sulfoxide (100 mL, 10V). 1 N 2-Bis(2,6-dimethylphenyl)oxalamide (2.20 g, 7.43 mmol), purged three times with nitrogen; then cuprous iodide (0.71 g, 3.72 mmol); then heated to 80 °C for 16 h. After most of the reaction was detected, the temperature was lowered to 20-30 °C, quenched with water (100 mL, 10 V), extracted with ethyl acetate (50 mL x 3, 5 V x 3), the combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5 V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), filtered, and the filtrate was desolvated under reduced pressure in a 40 °C water bath to dryness. Wet column chromatography (n-heptane / ethyl acetate = 5:1) yielded the compound of intermediate formula III-3 (1.6 g, yield 15.9%), a pale yellow solid with a purity of 86.9%. MS (ESI) Calcd for C 17 H 22 N2O [M+H] + : 271.17, found 271.20.

[0041] Example 2

[0042] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the following compounds were added sequentially: the compound shown in intermediate formula I-2 (10.00 g, 37.15 mmol), 1-aminocyclopropane-1-carboxynitrile hydrochloride (the compound shown in intermediate formula II-1) (6.62 g, 55.73 mmol), sodium tert-butoxide (10.71 g, 111.45 mmol), dimethyl sulfoxide (100 mL, 10 V), and N-(2,6-dimethylphenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide (1.80 g, 7.43 mmol). The mixture was purged with nitrogen three times. Then, cuprous iodide (0.71 g, 3.72 mmol) was added. The mixture was then heated to 80 °C and reacted for 16 hours. After most of the reaction was detected, the temperature was lowered to 20-30°C, and the mixture was quenched with water (100 mL, 10V). Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), filtered, and the filtrate was desolvated under reduced pressure in a 40°C water bath until dry. Wet column chromatography (n-heptane / ethyl acetate = 5:1) yielded the compound of intermediate formula III-3 (2.8 g, yield 28.1%), a yellow solid with a purity of 80.8%. MS (ESI) Calcd for C 17 H 22 N2O [M+H] +: 271.17, found271.20.

[0043] Example 3

[0044] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the following compounds were added sequentially: the compound shown in intermediate formula I-2 (10.00 g, 37.15 mmol), 1-aminocyclopropane-1-carboxynitrile hydrochloride (the compound shown in intermediate formula II-1) (6.61 g, 55.73 mmol), cesium carbonate (36.31 g, 111.45 mmol), dimethyl sulfoxide (100 mL, 10V), and benzoxime (0.85 g, 3.72 mmol). The mixture was purged with nitrogen three times. Then, copper acetate (0.68 g, 3.72 mmol) was added. The mixture was then heated to 80 °C and reacted for 16 hours. After most of the reaction was detected, the temperature was lowered to 20-30°C, and the mixture was quenched with water (100 mL, 10V). Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), filtered, and the filtrate was desolvated under reduced pressure in a 40°C water bath until dry. Wet column chromatography (n-heptane / ethyl acetate = 5:1) yielded the compound of intermediate formula III-3 (2.2 g, yield 21.5%) as a yellow solid with a purity of 79.3%. MS (ESI) Calcd for C 17 H 22 N2O [M+H] + : 271.17, found 271.20.

[0045] Example 4

[0046] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the following compounds were added sequentially: 10.00 g (37.15 mmol) of intermediate formula I-2, 1-aminocyclopropane-1-carboxynitrile hydrochloride (6.60 g (55.73 mmol) of intermediate formula II-1), cesium carbonate (36.30 g (111.45 mmol)), and toluene (100 mL, 10V). The mixture was purged with nitrogen three times. Then, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (2.15 g (1.86 mmol)) was added, and the mixture was purged with nitrogen three times. The mixture was then heated to 80 °C and reacted for 16 hours. After the reaction was complete, the temperature was lowered to 20-30°C, and the mixture was quenched with water (100 mL, 10V). Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), and dissolved under reduced pressure in a 40°C water bath until dry. Wet column chromatography (n-heptane / ethyl acetate = 5:1) yielded the compound shown in intermediate III-3 (5.81 g, yield 57.5%), a pale yellow solid with a purity of 98.7%. Figure 3 As shown, 1 H NMR (500 MHz, DMSO) δ7.11 - 7.05 (m, 2H), 6.74 (s, 1H), 6.73 - 6.68 (m, 2H), 3.70 - 3.61 (m, 2H), 2.81 (tt, J = 12.5, 3.7 Hz, 1H), 1.60 (dddd, J = 13.0, 5.8, 3.8, 1.9 Hz, 2H),1.54 - 1.45 (m, 3H), 1.40 (t, J = 12.9 Hz, 1H), 1.23 (s, 3H), 1.16 (s, 3H),1.15 - 1.11 (m, 2H). 13 C NMR (126 MHz, DMSO) δ 144.61, 136.44, 127.81, 122.27,113.81, 71.68, 61.26, 44.77, 36.29, 34.00, 32.09, 23.36, 22.14, 16.60. MS(ESI) Calcd for C 17 H 22 N2O [M+H] + : 271.17, found 271.20.

[0047] Example 5

[0048] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the compound shown in intermediate formula I-2 (10.00 g, 37.15 mmol), 1-aminocyclopropane-1-carboxynitrile hydrochloride (the compound shown in intermediate formula II-1) (6.60 g, 55.73 mmol), potassium carbonate (15.30 g, 111.45 mmol), and 1,4-Dioxane (100 mL, 10 V) were added sequentially. The mixture was purged with nitrogen three times. Then, methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (tBuXphos-Pd-G3) (1.48 g, 1.86 mmol) and (0.79 g, 1.86 mmol) were added, and the mixture was purged with nitrogen three times. The mixture was then heated to 80 °C and reacted for 16 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and water (100 mL, 10V) was added for quenching. Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), and dissolved under reduced pressure in a 40℃ water bath until dry. Ethyl acetate / n-heptane was slurried in a 5:1 ratio, filtered, and dried to give the intermediate compound (8.11 g, yield 80.8%), a pale yellow solid with a purity of 99.0%. MS (ESI) Calcd for C 17 H 22 N2O [M+H] + : 271.17, found 271.20.

[0049] Example 6

[0050] This embodiment provides the synthesis of (S)-1-[[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino]cyclopropane-1-carboxynitrile (the compound shown in Formula III-3). In a 250 mL three-necked flask, the following compounds were added sequentially: 10.00 g (37.15 mmol) of intermediate formula I-2, 1-aminocyclopropane-1-carboxynitrile hydrochloride (6.60 g (55.73 mmol) of intermediate formula II-1), potassium tert-butoxide (12.50 g (111.45 mmol), and dimethyl sulfoxide (100 mL, 10 V). The mixture was purged with nitrogen three times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex [abbreviation: Pd(dppf)Cl2 CH2Cl2] (1.36 g (1.86 mmol) was added, and the mixture was purged with nitrogen three times. The mixture was then heated to 80 °C and reacted for 16 hours. After the reaction was complete, the temperature was lowered to 20-30°C, and the mixture was quenched with water (100 mL, 10V). Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10 g, 1 w), and dissolved under reduced pressure in a 40°C water bath until dry. Wet column chromatography (n-heptane / ethyl acetate = 5:1) yielded the compound of intermediate formula III-3 (6.03 g, yield 59.8%), a pale yellow solid with a purity of 99.5%. MS (ESI) Calcd for C 17 H 22 N2O [M+H] + : 271.17, found 271.20.

[0051] Example 7

[0052] This embodiment provides the synthesis of (S)-1-[2-[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]hydrazyl]cyclopropane-1-carboxynitrile (the compound shown in Formula IV-3). Method (1) Add the compound (4.50 g, 16.64 mmol) of intermediate formula III-3 and water (27 mL, 6V) to a 100 mL three-necked flask. After dissolving, cool the mixture to 0-10 °C in an ice-water bath. Add concentrated hydrochloric acid (6.7 mL, 79.87 mmol) dropwise and stir for 10-20 minutes. Dissolve sodium nitrite (1.21 g, 17.47 mmol) in water (4.5 mL) to prepare a solution. Add the solution dropwise to the reaction mixture at 0-10 °C and continue to react at 0-10 °C until the starting material disappears. Then add ammonium chloride (1.96 g, 36.61 mmol) and zinc powder (3.26 g, 49.92 mmol) and heat to 40-45 °C for 2-4 hours. After the reaction was complete, the insoluble matter was removed by filtration. The filtrate was poured into a saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane, precipitating a large amount of white insoluble matter. This white insoluble matter was removed by filtration. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to give the intermediate compound of formula IV-3 (3.72 g, yield 78.4%), a white powder solid with a purity of 99.5%. Figure 4 As shown, 1 H NMR (500 MHz, DMSO) δ 7.18 - 7.09 (m, 4H), 4.65 (s, 2H), 3.71 - 3.64 (m, 2H), 2.86 (tt, J = 12.4, 3.7 Hz, 1H), 1.68 - 1.55 (m, 4H), 1.50 (tdd, J = 12.8, 9.3, 7.8 Hz, 1H), 1.42 (t, J = 12.9 Hz, 1H), 1.38 (q, J= 5.0 Hz, 2H), 1.24 (s, 3H), 1.16 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 148.29,137.96, 127.43, 120.90, 115.13, 71.69, 61.24, 44.67, 36.24, 34.57, 33.91,32.09, 22.14, 18.01. MS(ESI) Calcd for C 17 H 23 N3O [M+H] + : 286.18, found 269.10 / 286.10.

[0053] Example 8

[0054] This embodiment provides the synthesis of (S)-1-[2-[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]hydrazyl]cyclopropane-1-carboxynitrile (the compound shown in Formula IV-3). Add the compound (7.98 g, 29.58 mmol) of intermediate formula III-3 and water (48 mL, 6V) to a 100 mL three-necked flask. After dissolving, cool the mixture to 0-10 °C in an ice-water bath. Add concentrated hydrochloric acid (12 mL, 141.98 mmol) dropwise while stirring for 10-20 minutes. Dissolve sodium nitrite (2.15 g, 31.05 mmol) in water (8 mL) to prepare a solution. Add the solution dropwise to the reaction mixture at 0-10 °C and continue the reaction at 0-10 °C until the starting material disappears. Then, toluene (80 mL, 10V) was added for dilution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was stirred and allowed to stand for separation, and the lower aqueous phase was discharged. The lower aqueous phase was then diluted again with toluene (80 mL, 10V), stirred, and allowed to stand for separation, and the lower aqueous phase was discharged. The organic phases were combined and transferred to a 250 mL single-necked flask. The mixture was magnetically stirred, purged twice with nitrogen, and 5% platinum carbon (0.08 g, 1% wt) was added. The mixture was purged three times with hydrogen at 1 atm, and the hydrogenation reduction reaction was carried out at 1 atm for 16 hours. After the reaction was complete, the platinum carbon was filtered, and the filter cake was washed with toluene (16 mL, 2V). The filtrate was desoluble under reduced pressure in a water bath at 40-50℃ until dry to obtain the compound shown in intermediate formula IV-3 (7.61 g, yield 90.2%), an off-white solid with a purity of 98.8%. MS (ESI) Calcd for C 17 H 23 N3O [M+H] + : 286.18, found 269.10 / 286.10.

[0055] Example 9

[0056] This embodiment provides the synthesis of (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (the compound shown in Formula V-3). To a 30 mL reaction flask, compound of intermediate formula IV-3 (1.50 g, 5.26 mmol), anhydrous ethanol (13.5 mL, 9V), and ethyl pyruvate (0.67 g, 5.79 mmol) were added sequentially. The mixture was heated to 80 °C and refluxed until the starting material disappeared. Concentrated sulfuric acid (0.75 mL, 0.5V) was added, and the mixture was heated to 80 °C and refluxed. After the reaction was complete, ethyl acetate was added to dilute the mixture. The reaction solution was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The solvent was removed under reduced pressure to obtain 1.20 g of brown solid intermediate. Tetrahydrofuran (12 mL) and potassium tert-butoxide (0.74 g, 6.57 mmol) were then added, and the reaction was maintained at room temperature. After the reaction was complete, 10% citric acid aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed successively with water and saturated brine, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to give the intermediate compound of formula V-3 (0.78 g, yield 43.8%), a pale yellow powder with a purity of 99.2%. Figure 5 As shown, 1 H NMR (500 MHz, CDCl3) δ 7.54 -7.46 (m, 2H), 7.40 (d, J = 0.9 Hz, 1H), 7.29 (dd, J = 8.7, 1.7 Hz, 1H), 3.84(dt, J = 12.0, 3.0 Hz, 1H), 3.82 - 3.72 (m, 1H), 2.98 (ddt, J = 12.5, 9.2,4.2 Hz, 1H), 1.99 (dd, J = 5.0, 2.8 Hz, 2H), 1.70 (ddd, J = 17.6, 10.2, 3.3Hz, 4H), 1.67 - 1.52 (m, 2H), 1.29 (s, 3H), 1.24 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 164.16, 139.10, 137.72, 126.60, 125.50, 125.30, 119.69, 118.46,114.12, 110.39, 71.23, 60.74, 43.68, 36.38, 32.75, 30.65, 24.04, 20.82. MS(ESI) Calcd for C 20 H 22 N₂O₃ [M+H] + : 339.16, found 339.30.

[0057] Example 10

[0058] This embodiment provides the synthesis of (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (the compound shown in Formula V-3). To a 30 mL reaction flask, compound of intermediate formula IV-3 (1.50 g, 5.26 mmol), anhydrous ethanol (13.5 mL, 9V), and ethyl pyruvate (0.67 g, 5.79 mmol) were added sequentially. The mixture was heated to 80 °C and refluxed until the starting material disappeared. Concentrated sulfuric acid (0.75 mL, 0.5V) was added, and the mixture was heated to 80 °C and refluxed. After the reaction was complete, ethyl acetate was added to dilute the mixture. The reaction solution was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The solvent was removed under reduced pressure to obtain 1.20 g of brown solid intermediate. Tetrahydrofuran (12 mL) and lithium hydroxide (0.16 g, 6.57 mmol) were then added, and the reaction was maintained at room temperature. After the reaction was complete, the mixture was quenched with 10% citric acid aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to give the intermediate compound of formula V-3 (1.16 g, yield 65.5%), a pale yellow powder with a purity of 99.5%. MS (ESI) Calcd for C 20 H 22 N₂O₃ [M+H] + : 339.16, found 339.30.

[0059] Example 11

[0060] This embodiment provides the synthesis of (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (the compound shown in Formula V-3). To a 30 mL reaction flask, compound of intermediate formula IV-3 (1.50 g, 5.26 mmol), anhydrous ethanol (13.5 mL, 9V), and ethyl pyruvate (0.67 g, 5.79 mmol) were added sequentially. The mixture was heated to 80 °C and refluxed until the starting material disappeared. The temperature was then lowered to 20-30 °C, and the mixture was dissolved under reduced pressure in a 40 °C water bath until dry. Toluene was added for dilution (15 mL, 10V), followed by p-toluenesulfonic acid (0.91 g, 5.26 mmol). The mixture was then heated to 100 °C and refluxed. After the reaction was complete, ethyl acetate was added for dilution. The reaction solution was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The solvent was removed under reduced pressure to yield 1.20 g of a brown solid intermediate. Tetrahydrofuran (12 mL) and sodium tert-butoxide (0.63 g, 6.57 mmol) were then added, and the reaction was maintained at room temperature. After the reaction was complete, the mixture was quenched with a 10% citric acid aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The solvent was removed by rotary evaporation, and crystallization was performed using ethyl acetate / n-heptane at a ratio of 1V / 5V to give the intermediate compound of formula V-3 (1.30 g, yield 73.2%), a pale yellow powder with a purity of 99.6%. MS (ESI) Calcd for C 20 H 22 N₂O₃ [M+H] + :339.16, found 339.30.

[0061] Example 12

[0062] This embodiment provides the synthesis of (1S,2S)-1-{[4-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl]amino}-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula III-4). In a 250 mL three-necked flask, under mechanical stirring and nitrogen protection, the following compounds were added sequentially: compound I-2 (10 g, 37.15 mmol), (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (compound II-2) (7.39 g, 55.73 mmol), potassium carbonate (15.38 g, 111.45 mmol), and dioxane (100 mL, 10V). The mixture was purged with nitrogen three times. Then, tBuXphos-Pd-G3 (1.48 g, 1.86 mmol) was added, and the mixture was purged with nitrogen three times. The mixture was then heated to 80 °C and reacted for 16 hours. After the reaction was complete, the temperature was lowered to 20-30℃, and water (100 mL, 10V) was added for quenching. Extraction was performed with ethyl acetate (50 mL x 3, 5V x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (150 mL x 2, 5V x 2), dried over anhydrous sodium sulfate (10.00 g, 1 w), and dissolved under reduced pressure in a 40℃ water bath until dry. A mixture of n-heptane and ethyl acetate (5:1) was stirred, filtered, and dried under vacuum. The solution was then dissolved under reduced pressure in a 40℃ water bath until dry, yielding the intermediate compound of formula III-4 (7.15 g, yield 67.6%), a white powder with a purity of 99.2%. Figure 6 As shown, 1 H NMR (500 MHz, CDCl3) δ 7.14 - 7.09 (m, 2H), 6.81 -6.77 (m, 1H), 6.74 - 6.68 (m, 1H), 4.18 (s, 1H), 3.87 - 3.75 (m, 2H), 2.89 -2.81 (m, 1H), 1.72 - 1.63 (m, 4H), 1.55 (td, J = 12.9, 2.2 Hz, 1H), 1.44 -1.39 (m, 2H), 1.31 (s, 3H), 1.26 (s, 3H), 1.21 (dd, J = 15.0, 5.6 Hz, 3H). 13 CNMR (126 MHz, CDCl3) δ 142.23, 136.47, 126.72, 126.68, 120.67, 113.05,112.90, 70.89, 60.81, 43.55, 35.65, 32.64, 30.75, 26.18, 22.47, 21.80, 20.77,10.83.. MS(ESI) Calcd for C 18 H 24 N2O [M+H] + : 285.19, found 285.10.

[0063] Example 13

[0064] This embodiment provides the synthesis of (1S,2S)-1-[1-[4-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]phenyl]hydrazyl]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula IV-4). Add the compound shown in intermediate formula III-4 (1.35 g, 4.75 mmol) and water (8 mL, 6V) to a 100 mL three-necked flask. After dissolving, cool the mixture to 0-10 °C in an ice-water bath. Add concentrated hydrochloric acid (1.9 mL, 22.80 mmol) dropwise while stirring for 10-20 minutes. Dissolve sodium nitrite (0.34 g, 4.99 mmol) in water (1.3 mL) and add it dropwise to the reaction mixture at 0-10 °C. Continue to react at 0-10 °C until the starting material disappears. Then add ammonium chloride (0.56 g, 10.45 mmol) and zinc powder (0.93 g, 14.25 mmol) and heat to 40-45 °C for 2-4 hours. After the reaction was complete, the insoluble matter was removed by filtration. The filtrate was poured into a saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane, resulting in the precipitation of a large amount of white insoluble matter. This white insoluble matter was removed by filtration. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to give the intermediate compound of formula IV-4 (0.87 g, yield 61.2%), a colorless oil with a purity of 99.7%. Figure 7 As shown, 1 H NMR (500MHz, CDCl3) δ 7.09 (q, J = 8.9 Hz, 4H), 3.80 - 3.69 (m, 2H), 2.82 (tt, J =12.4, 4.1 Hz, 1H), 1.77 (dt, J = 13.5, 7.7 Hz, 1H), 1.65 (s, 4H), 1.49 (t, J= 12.9 Hz, 1H), 1.24 (s, 3H), 1.20 (s, 3H), 1.18 (t, J = 3.6 Hz, 3H), 0.98(dd, J = 7.8, 5.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 146.84, 137.87, 126.44,126.38, 119.22, 114.56, 70.87, 60.77, 59.38, 43.45, 35.63, 32.54, 30.74,20.76, 13.18, 13.10, 11.47.. MS(ESI) Calcd for C 18 H 25 N3O1 [M+H] + : 300.20, found283.30 / 300.30.

[0065] Example 14

[0066] This embodiment provides the synthesis of (1S,2S)-1-[1-[4-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]phenyl]hydrazyl]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula IV-4). Add the compound shown in intermediate formula III-4 (1.35 g, 4.75 mmol) and water (8 mL, 6V) to a 100 mL three-necked flask. After dissolving, cool the mixture to 0-10 °C in an ice-water bath. Add concentrated hydrochloric acid (1.9 mL, 22.80 mmol) dropwise while stirring for 10-20 minutes. Dissolve sodium nitrite (0.34 g, 4.99 mmol) in water (1.3 mL) and add it dropwise to the reaction mixture at 0-10 °C. Continue to react at 0-10 °C until the starting material disappears. Then, toluene (13.5 mL, 10V) was added for dilution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was stirred and allowed to stand for separation, and the lower aqueous phase was discharged. The lower aqueous phase was then diluted again with toluene (13.5 mL, 10V), stirred, and allowed to stand for separation, and the lower aqueous phase was discharged. The organic phases were combined and transferred to a 100 mL single-necked flask. The mixture was magnetically stirred, purged twice with nitrogen, and 5% platinum carbon (0.01 g, 1% wt) was added. The mixture was purged three times with hydrogen at 1 atm, and the hydrogenation reduction reaction was carried out at 1 atm for 16 hours. After the reaction was complete, the platinum carbon was filtered, and the filter cake was washed with toluene (2.7 mL, 2V). The filtrate was desoluble under reduced pressure in a water bath at 40-50℃ until dry to obtain the intermediate compound of formula IV-4 (1.32 g, yield 93.1%), a colorless oil with a purity of 99.1%. MS (ESI) Calcd for C 18 H 25 N3O1 [M+H] + : 300.20, found 283.30 / 300.30.

[0067] Example 15

[0068] This embodiment provides the synthesis of 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (the compound shown in Formula V-4). To a 30 mL reaction flask, compound of intermediate formula IV-4 (0.5 g, 1.67 mmol), anhydrous ethanol (4.5 mL, 9V), and ethyl pyruvate (0.21 g, 1.84 mmol) were added sequentially. The mixture was heated to 80 °C and refluxed until the starting material disappeared. The solvent was removed by desolvation under reduced pressure. Toluene (4.5 mL, 9V) and p-toluenesulfonic acid (0.34 g, 2.00 mmol) were added to the residue, and the mixture was heated to 110 °C and refluxed. After the reaction was complete, ethyl acetate was added to dilute the mixture. The reaction solution was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The solvent was removed by rotary evaporation to obtain 0.4 g of a brown solid. Tetrahydrofuran (4 mL) and sodium tert-butoxide (0.27 g, 2.09 mmol) were then added, and the reaction was maintained at room temperature. After the reaction was complete, the mixture was quenched with a 10% citric acid aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The solvent was removed by rotary evaporation, and the mixture was slurried with n-heptane / ethyl acetate at a ratio of 1:5. After filtration, the wet product was desolvated under reduced pressure in a 40°C water bath until dry to give the intermediate compound (0.46 g, yield 78.0%), a pale yellow powder with a purity of 98.1%. Figure 8 As shown, 1 H NMR (500 MHz, DMSO) δ 13.16(s, 1H), 7.64 - 7.30 (m, 3H), 7.24 (s, 1H), 3.71 (dd, J = 8.8, 2.2 Hz, 2H), 3.04 (tt, J = 12.6, 3.7 Hz, 1H), 2.01 - 1.63 (m, 5H), 1.61 - 1.46 (m, 3H), 1.41 (d, J = 5.0 Hz, 2H), 1.27 (s, 3H), 1.18 (s, 3H). 13 C NMR (126 MHz, DMSO)δ 162.24, 140.09, 137.85, 129.68, 126.34, 125.99, 120.53, 119.15, 112.30,111.69, 71.75, 61.24, 44.87, 36.99, 34.10, 32.07, 30.90, 25.62, 25.17, 22.15,15.74.. MS(ESI) Calcd for C 21 H24 N₂O₃ [M+H] + : 353.18, found 353.30.

[0069] Example 16

[0070] This embodiment provides the synthesis of (1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula VII-1). Add (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 (the compound shown in intermediate formula VI-1) (2.50 g, 5.11 mmol) and 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (the compound shown in intermediate formula V-4) (1.98 g, 5.62 mmol) to a 50 mL three-necked flask. 1,3-Dimethyl-2-imidazolone (15 mL) was added dropwise with N,N-diisopropylethylamine (2.64 g, 20.44 mmol) at 20-25 °C and stirred for 5 h. After the reaction was completed, the reaction solution was poured into an aqueous solution of sodium carbonate (15% wt, 25 mL), extracted with ethyl acetate (22.5 mL x 2), and the combined organic phases were washed with brine (20% wt, 25 mL x 3). The solvent was removed under reduced pressure by rotary evaporation, and the residue was purified by silica gel column chromatography to give the intermediate compound of formula VII-1 (3.20 g, yield 76.0%), a pale yellow powder with a purity of 99.4%. Figure 9 As shown, 1H NMR (500MHz, DMSO) δ 8.32 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 19.6 Hz,3H), 7.31 (dd, J = 8.6, 1.7 Hz, 1H), 7.14 (dd, J = 44.9, 4.6 Hz, 3H), 6.92(d, J = 50.8 Hz, 2H), 5.76 (s, 1H), 4.28 (d, J = 12.2 Hz, 1H), 4.12 (s, 3H),3.77 - 3.64 (m, 2H), 3.57 (s, 1H), 3.14 - 2.78 (m, 3H), 2.26 (s, 6H), 1.99(s, 1H), 1.80 (s, 1H), 1.75 (s, 1H), 1.69 (d, J = 10.3 Hz, 2H), 1.53 (t, J =12.9 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H), 1.37 (s, 2H), 1.28 (s, 4H), 1.18 (d,J = 7.2 Hz, 3H). 13 C NMR (126 MHz, DMSO) δ 170.81, 162.24, 159.63, 157.69,151.37, 148.59, 146.79, 141.88, 140.02, 136.14, 133.97, 130.06, 129.75,127.06, 126.85, 125.55, 125.40, 124.46, 123.99, 119.91, 118.89, 116.73,115.79, 114.86, 114.07, 113.20, 110.89, 107.23, 104.37, 71.77, 60.23, 55.39,45.05, 37.10, 36.34, 34.27, 32.10, 31.74, 30.78, 23.86, 22.18, 18.80, 15.40,14.80, 14.77, 14.56, 14.43. MS(ESI) Calcd for C 47 H 47 F2N9O3 [M+H]+: 824.38, found 824.40.

[0071] Example 17

[0072] This embodiment provides the synthesis of (1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula VII-1). Add (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 (the compound shown in intermediate formula VI-1) (2.50 g, 5.11 mmol) and 1-[(1S,2S)-1-cyano-2-methylcyclopropyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (the compound shown in intermediate formula V-4) (1.98 g, 5.62 mmol) to a 50 mL three-necked flask. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (2.20 g, 5.77 mmol) and N,N-dimethylpropenylurea (15 mL) were added dropwise at 20-25 °C, and the reaction was stirred at 20-25 °C for 5 h. After the reaction was complete, the reaction solution was poured into an aqueous solution of sodium carbonate (15% wt, 25 mL), extracted with ethyl acetate (22.5 mL x 2), and the combined organic phases were washed with brine (20% wt, 25 mL x 3). The solution was removed under reduced pressure in a rotary evaporator, dissolved in tetrahydrofuran (11.3 mL, 4.5 V), and crystallized by adding formic acid (22.5 mL, 9 V) and water (30 mL, 12 V). The mixture was filtered, and the filter cake was washed with water (20 mL, 8 V). The solution was then removed under reduced pressure in a water bath at 40-50 °C until dry to give the intermediate compound (3.65 g, yield 86.7%), a pale yellow powder with a purity of 98.2%. MS (ESI) Calcd for C47H47F2N9O3 [M+H]+: 824.38, found 824.40.

[0073] Example 18

[0074] This embodiment provides the synthesis of (1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-N-hydroxy-2-methylcyclopropane-1-formamidinium (the compound shown in intermediate formula VIII-1). Method (1) Compound of intermediate formula VII-1 (2.00 g, 2.43 mmol) and ethanol (20 mL, 10V) were added to a 40 mL reaction flask. The mixture was heated to 70 °C to dissolve the precipitate. Then, 50% hydroxylamine aqueous solution (0.48 g, 7.29 mmol) was added, and the reaction was maintained at 65–70 °C for 18 h. After the reaction was complete, the mixture was cooled in an ice-water bath, filtered at 0–5 °C, and the filter cake was dried to obtain compound of intermediate formula VIII-1 (1.70 g, yield 81.7%), a white powder with a purity of 98.7%. Figure 10 As shown, 1H NMR(500 MHz, DMSO) δ 9.26 (s, 1H), 8.33 - 8.17 (m, 1H), 7.64 (dd, J = 8.9, 0.9Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.19 (dd, J = 6.9,1.5 Hz, 3H), 7.12 - 7.06 (m, 1H), 7.00 - 6.87 (m, 1H), 6.77 (d, J = 18.8 Hz,1H), 5.60 (q, J = 6.7 Hz, 1H), 4.20 - 4.05 (m, 4H), 3.74 - 3.65 (m, 2H), 3.58(t, J = 12.5 Hz, 1H), 3.17 - 3.06 (m, 1H), 3.06 - 2.96 (m, 1H), 2.87 - 2.77(m, 1H), 2.24 (dd, J = 22.3, 2.0 Hz, 6H), 1.71 - 1.64 (m, 2H), 1.60 - 1.50(m, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.37 (dt, J = 9.2, 6.4 Hz, 1H), 1.27 (d, J= 5.8 Hz, 3H), 1.17 (d, J = 7.5 Hz, 3H), 1.08 (dd, J = 18.3, 6.6 Hz, 3H),1.04 (d, J = 6.1 Hz, 3H).。 13C NMR (126 MHz, DMSO) δ 164.45, 157.72, 151.35,150.12, 148.59, 146.76, 141.88, 141.81, 139.18, 136.84, 133.95, 132.20,130.09, 129.75, 126.86, 125.57, 125.42, 124.04, 123.44, 119.19, 116.55,115.83, 114.94, 114.86, 114.07, 113.91, 113.16, 112.39, 107.24, 102.52,71.76, 62.49, 61.32, 45.08, 44.55, 41.60, 37.19, 36.35, 34.36, 32.12, 25.97,24.65, 22.19, 20.85, 18.39, 14.81, 14.78, 13.55. MS(ESI) Calcd for C 47 H 50 F2N 10 O4[M+H] + : 857.40, found 857.50.

[0075] Example 19

[0076] This embodiment provides the synthesis of (1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-N-hydroxy-2-methylcyclopropane-1-formamidinium (the compound shown in intermediate formula VIII-1). Method (2) Compound of intermediate formula VII-1 (2.00 g, 2.43 mmol) and tetrahydrofuran (10 mL, 5V) were added to a 40 mL reaction flask. The mixture was heated to 70 °C to dissolve the precipitate. 50% hydroxylamine aqueous solution (0.48 g, 7.29 mmol) was added, and the reaction was maintained at 65–70 °C for 6 h. After the reaction was complete, the mixture was cooled to 0–5 °C in an ice-water bath. Water (30 mL, 15V) was added dropwise to induce crystallization. The filter cake was dried to obtain compound of intermediate formula VIII-1 (1.92 g, yield 92.5%), a white powder solid with a purity of 99.1%. MS (ESI) Calcd for C47 H 50 F2N 10 O4 [M+H] + : 857.40, found 857.50.

[0077] Example 20

[0078] This embodiment provides the synthesis of 3-[(1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (the compound shown in Formula IX-1: Orforglipron). Method (1) Compound (1.0 g, 1.12 mmol) of intermediate formula VIII-1, tetrahydrofuran (7 mL, 7V), and N,N'-disuccinimidyl carbonate (0.72 g, 2.80 mmol) were added dropwise to a 40 mL reaction flask. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 g, 3.36 mmol) was added dropwise at 20–25 °C, and the reaction was maintained at 20–25 °C for 7 h. After the reaction was complete, the temperature was lowered to 0–10 °C, and formic acid (8 mL, 8V) and water (12 mL, 12V) were added dropwise. Crystallization was maintained at 0–10 °C. The mixture was filtered, and the filter cake was slurried once with water (20 mL) at room temperature. The wet product was dried to obtain (compound (Intermediate Formula IX-1): Orforglipron) (0.77 g, yield 74.8%), a white powdery solid with a purity of 92.6%. Figure 11 As shown, 1H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.95 (s, 2H), 5.58 (d, J = 7.0 Hz, 1H), 4.38 (d, J = 12.6 Hz, 1H), 4.11 (s, 4H), 3.75 - 3.66 (m, 3H), 3.19 (s, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.89 (d, J = 15.2 Hz, 1H), 2.26 (s, 6H), 1.72 - 1.54 (m, 7H), 1.44 (d, J = 6.7 Hz, 2H), 1.27 (s, 4H), 1.17 (d, J = 7.7 Hz, 6H). 13 C NMR (126 MHz, DMSO) δ 163.52, 159.65, 159.29, 158.98, 157.71, 148.58, 146.73, 139.86, 136.61, 133.95, 132.08, 130.07, 129.76, 127.09, 126.85, 125.59, 125.43, 124.57, 124.00, 119.92, 116.58, 115.86, 114.84, 114.07, 113.90, 113.13, 110.98, 107.25, 105.01, 71.75, 61.28, 45.01, 44.75, 37.12, 36.35, 36.04, 34.32, 32.10, 24.73, 22.18, 19.99, 18.71, 14.81, 14.78, 13.00. MS (ESI) Calcd for C 48 H 48 F2N 10 O5 [M+H] + : 883.38, found 883.50.

[0079] Example 21

[0080] This embodiment provides the synthesis of 3-[(1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (the compound shown in Formula IX-1: Orforglipron). Method (2) The compound shown in intermediate formula VIII-1 (1.0 g, 1.12 mmol), 1,4-dioxane (7 mL, 7V), and N,N'-carbonyldiimidazole (0.45 g, 2.80 mmol) were added dropwise to a 40 mL reaction flask. N,N-diisopropylethylamine (0.43 g, 3.36 mmol) was added dropwise at 20-25 °C, and the reaction was maintained at 20-25 °C for 7 h. After the reaction was completed, the temperature was lowered to 0-10 °C, and formic acid (8 mL, 8V) and water (12 mL, 12V) were added dropwise. Crystallization was carried out at 0-10 °C. The mixture was filtered, and the filter cake was slurried once with water (20 mL) at room temperature. The wet product was dried to obtain (the compound shown in intermediate formula IX-1: Orforglipron) (0.93 g, yield 90.2%), a white powder solid with a purity of 99.2%. MS (ESI) Calcd for C 48 H 48 F2N 10 O5 [M+H] + :883.38, found 883.50.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a compound of intermediate formula V, characterized in that, The synthesis method includes the following steps: 1) The compound shown in Formula I is dissolved in a solvent, and the compound shown in Formula II, base and catalyst are added. The mixture is heated until the reaction is complete, and after post-treatment, the compound shown in Formula III is obtained. 2) The compound shown in Formula III is dissolved in a solvent, and an aqueous solution of hydrochloric acid is added to react with an aqueous solution of sodium nitrite to obtain a nitrosamine intermediate. Ammonium chloride and zinc powder are added, and the mixture is heated to reduce it. After the reaction is completed, the compound shown in Formula IV is obtained through post-treatment. 3) The compound shown in Formula IV is dissolved in a solvent and reacts with ethyl pyruvate to form a hydrazone intermediate. After desolvation under reduced pressure, a solvent and an acid catalyst are added, and the indole ring is synthesized by heating. After the reaction is complete, ethyl carboxylic acid is hydrolyzed, and the intermediate compound shown in Formula V is obtained after post-treatment. Among them, the compound represented by formula I: ； The compound represented by Formula II: ； The compound represented by Formula III: ； The compound represented by Formula IV: ； The compound represented by formula V: ； In the formula, R1 is H or Me, R2 is H or Me, and R3 is H or Me.

2. The method for synthesizing the compound of intermediate formula V according to claim 1, characterized in that, In step 1), the solvent is one of dimethyl sulfoxide, 1,4-dioxane, or toluene, and the volume of the solvent is 5.0V-30.0V; the amount of the compound represented by formula II is 1.0-3.0 equivalents; the catalyst is methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) The catalyst is selected from the following: tetra-triphenylphosphine palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, cuprous iodide, or copper acetate, with a catalyst dosage of 0.001-0.2 equivalents; the ligand is selected from the following: 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl, [1,1'-bis(diphenylphosphine)ferrocene], N1,N2-bis(2,6-dimethylphenyl)oxalamide, N-(2,6-dimethylphenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide, or benzoin oxime, with a ligand dosage of 0.002-0.4 equivalents; the base is selected from the following: cesium carbonate, potassium carbonate, sodium tert-butoxide, or potassium tert-butoxide, with a base dosage of 1.0-5.0 equivalents.

3. The method for synthesizing the compound of intermediate formula V according to claim 1, characterized in that, In step 2), the solvent is one of dimethyl sulfoxide, 1,4-dioxane or toluene, and the volume of the solvent is 5.0V-30.0V; the amount of hydrochloric acid is 2.0-10.0 equivalents, the amount of sodium nitrite is 0.95-1.5 equivalents, the amount of ammonium chloride is 1.0-5.0 equivalents, the amount of zinc powder is 1.0-5.0 equivalents, and the hydrogenation reduction catalyst used for reduction is 5% palladium on carbon and 5% platinum on carbon.

4. The method for synthesizing the compound of intermediate formula V according to claim 1, characterized in that, In step 3), the solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane or toluene; the acid catalyst is one of sulfuric acid, boron trifluoride ether, trifluoroacetic acid, p-toluenesulfonic acid, and the amount of acid catalyst used is 1.0-5.0 equivalents; the base used for hydrolysis is one of sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilanolate, lithium hydroxide, and the amount of base used for hydrolysis is 1.0-5.0 equivalents.

5. A method for synthesizing oxaliplatin and similar GLP-1RA small molecule drugs, characterized in that, The synthesis method includes the following steps: a) The compound of intermediate formula V is synthesized by the synthetic method according to any one of claims 1-4, wherein the compound of intermediate formula V is dissolved in a solvent, and the compound of chiral amine intermediate formula VI, a base and a condensing agent are added to carry out an amide condensation reaction, and the compound of intermediate formula VII is obtained after post-treatment. b) Dissolve the compound of intermediate formula VII in a solvent, add hydroxylamine, heat until the reaction is complete, and then post-process to obtain the compound of intermediate formula VIII; c) The compound shown in intermediate formula VIII is placed in a solvent, and a base and a carbonylating agent are added to carry out a five-membered ring reaction. After post-treatment, ozoglieron and a compound shown in formula IX, a small molecule drug similar to GLP-1RA, are obtained. Among them, the compound represented by formula VII: ； The compound represented by formula VIII: ； The compound represented by Formula IX: ； In the formula, R1 is H or Me, R2 is H or Me, and R3 is Me; The compound shown in Formula VI is selected from: The compound shown in Formula VI-1: ； The compound shown in Formula VI-2: ； The compound shown in Formula VI-3: ； The compound shown in Formula VI-4: ； The compound shown in Formula VI-5: ； The compound shown in Formula VI-6: ； The compound shown in Formula VI-7: ； The compound shown in Formula VI-8: ； The compound shown in Formula VI-9: ； In Equations VII, VIII, and IX The structural group representing the compound of formula VI, a chiral amine intermediate, after condensation reaction.

6. The method for synthesizing omaglione and similar GLP-1RA small molecule drugs according to claim 5, characterized in that, In step a), the solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, or N,N-dimethylpropenylurea, and the volume of the solvent is 3.0V-20.0V; the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, or 2-(7-azobenzotriazole)-N The condensing agent is one of N,N',N'-tetramethylurea hexafluorophosphate, (2-oxime-cyanoethyl acetate)-N,N-dimethyl-morpholinourea hexafluorophosphate, or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the amount of condensing agent is 1.0-2.0 equivalents; the base is one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, and the amount of base is 1.0-5.0 equivalents.

7. The method for synthesizing omaglione and similar GLP-1RA small molecule drugs according to claim 5, characterized in that, In step b), the solvent is one of methanol, ethanol, isopropanol or tetrahydrofuran; the hydroxylamine species is one of 50% hydroxylamine aqueous solution or hydroxylamine hydrochloride, and the amount of hydroxylamine species used is 1.5-5.0 equivalents.

8. The method for synthesizing omaglione and similar GLP-1RA small molecule drugs according to claim 5, characterized in that, In step c), the solvent is one of tetrahydrofuran, 1,4-dioxane, or dichloromethane; the cyclization carbonylating agent is one of N,N'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or triphosgene, and the amount of the cyclization carbonylating agent is 1.5-5.0 equivalents; the base is one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, and the amount of the base is 1.0-5.0 equivalents.

9. The method for synthesizing omaglione and similar GLP-1RA small molecule drugs according to claim 5, characterized in that, The compound represented by Formula IX is selected from: The compound represented by Formula IX-1: ； The compound shown in Formula IX-2: ； The compound represented by Formula IX-3: ； The compound represented by Formula IX-4: ； The compound represented by Formula IX-5: ； The compound represented by Formula IX-6: ； The compound shown in Formula IX-7: ； The compound represented by Formula IX-8: ； The compound represented by Formula IX-9: 。

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