A method for the synthesis of a GLP-1 receptor agonist core chiral intermediate

Abstract

The application provides a synthesis method of a GLP-1 receptor agonist core chiral intermediate, which comprises the following steps: synthesizing a three-membered ring under alkaline conditions by using commercially available benzhydrylideneaminoacetonitrile or N-acetonitrile phthalimide and a compound shown in formula II which is a commercially available chiral pure intermediate; separating and purifying by recrystallization; removing a benzophenone protecting group under acidic conditions or removing a phthaloyl protecting group under a hydrazine hydrolysis condition; and forming a hydrochloride salt to obtain a target product. The application provides a relatively economical and environment-friendly synthesis technical route which is beneficial to scale-up production. The starting material of the application has a simple structure and is easily purchased in a commercial batch.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and relates to GLP-1 receptor agonists, specifically to a method for synthesizing a high-chiral-purity (1S,2S)-1-amino-2-methylcyclopropane-1-carboxylon hydrochloride, the core chiral intermediate of the GLP-1 receptor agonist Orforglipron (also known as ozoglipron). Background Technology

[0002] Orforglipron (trade name FOUNDAYO™), developed by Eli Lilly, is the world's first oral small-molecule GLP-1 receptor agonist, approved by the FDA in April 2026. Its remarkable clinical efficacy and broad market prospects have created an urgent need for large-scale production of the active pharmaceutical ingredient. However, the existing linear synthetic route is too long (as shown below, [Original process patent: PCT / US2023 / 084487]), severely restricting the accessibility and commercialization of this drug.

[0003]

[0004] The chiral methylcyclopropane-1-carboxynitrile structure in compound 9 provides two chiral centers for the final product. Its construction process generates 5-7% isomers, which need to be removed by recrystallization. Recrystallization removes the isomers but also results in the loss of compound 7 obtained through the seven-step transformation. Therefore, synthesizing (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile or its hydrochloride form with high chiral purity will be beneficial in promoting process improvements for the convergent synthesis of Orforglipron.

[0005] Meanwhile, existing synthetic routes for (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile have many limitations, such as: In 1991 (Synlett, 1991(3), 151) and 1994 (Canadian Journal of Chemistry, 1994, 1332), the French team Salaun reported a route for synthesizing (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile from methyl (2S)-3-hydroxy-2-methylpropionate (compound 1 shown below). This route involved hydroxyl protection, ester reduction to aldehyde, Strecker reaction to construct aminonitrile intermediate 4, conversion of the protected hydroxyl group to a halogen or leaving group such as p-toluenesulfonyl ester, and finally, base-induced diastereoselective cyclization. The key step, controlled by the conformation of imine nitrile intermediate 6, achieved a cyclization diastereoselectivity of 84:16, which could be improved to 94:6 by column chromatography purification. Removal of the protecting group yielded the target molecule, compound 8. However, the entire route involved multiple chemical transformations, was overly lengthy, and resulted in low synthetic yields.

[0006]

[0007] Patent WO2025 / 133396A reports that 2-[(diphenylmethylene)amino]acetonitrile (compound 1 shown below) cyclizes with 1,3-dibromopropane under alkaline conditions to give a mixture of cis and trans isomers. After preparative HPLC separation, (trans)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxylonitrile (compound trans-3 shown below) was given in 3.55% yield, and (cis)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxylonitrile (compound cis-3 shown below) was given in 8.09% yield.

[0008] In this process, (cis)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile is deprotected in hydrochloric acid to yield (cis)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (compound cis-4 shown below). The primary objective of patent WO2025 / 133396A is to obtain the cis racemic hydrochloride. While this method has a short synthetic route, it yields a racemic mixture with extremely low separation yield, making it unsuitable for industrial-scale production.

[0009]

[0010] Therefore, there is an urgent need to develop a synthetic method that can efficiently synthesize (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile with high chiral purity from commercially available raw materials. Summary of the Invention

[0011] To address the shortcomings of existing synthetic routes for (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile, which are lengthy, have low synthetic yields, and extremely low separation yields, making them unsuitable for industrial-scale production, this invention provides a method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist. This invention uses commercially available diphenylmethyleneaminoacetonitrile, or synthesized via known methods (Chemistry - A European Journal, 2010, 16(18)).

[5286] Starting from the intermediate compound of formula I, which is synthesized from aminoacetonitrile methanesulfonate and benzophenone, a three-membered ring is synthesized in a step under basic conditions with the commercially available chiral pure intermediate compound of formula II, to obtain a set of diastereomers of RS and SS (SS configuration is predominant). After recrystallization and purification, the intermediate compound of formula III with high chiral purity is obtained. Then, under acidic conditions, the benzophenone protecting group is removed, and the high-purity target product IV, namely (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride, can be successfully obtained.

[0012] Alternatively, this invention starts with commercially available N-acetonitrile phthalimide, or with the intermediate compound of formula V synthesized from bromoacetonitrile and potassium phthalimide by a known method (WO2005 / 92856), and synthesizes a three-membered ring with the commercially available chiral pure intermediate compound of formula II under basic conditions in a next step, to obtain a set of diastereomers of RS and SS (SS configuration predominant). After recrystallization and purification, the compound of formula VI with high chiral purity is obtained. Under hydrazine hydrate conditions, the phthaloyl protecting group is removed by hydrazine desorption, and then the hydrochloride is formed, which can successfully obtain the high-purity target product IV, namely (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride.

[0013] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist, the method comprising: 1) Dissolve the compound of intermediate formula I in a solvent, add the compound of intermediate formula II and a base, and continue the reaction until it is complete. After post-treatment and separation and purification, the compound of intermediate formula III is obtained. 2) Dissolve the compound shown in intermediate formula III in a solvent, add hydrochloric acid solution dropwise at 0-5℃, and after the reaction is complete, obtain the compound shown in intermediate formula IV through post-treatment; Alternatively, the synthesis method is as follows: a) Dissolve the compound shown in intermediate formula V in a solvent, add intermediate formula II and a base, and continue the reaction until it is complete. After post-treatment and separation and purification, obtain the compound shown in intermediate formula VI. b) Dissolve the compound of intermediate formula VI in a solvent, add hydrazine hydrate, and after the reaction is complete, post-treatment is performed to obtain the compound of intermediate formula IV. 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: ; The compound shown in Formula VI: .

[0014] In a preferred embodiment of the present invention, in step 1), the solvent is one of tetrahydrofuran, 1,4-dioxane, or dichloromethane. The amount of solvent used is 5-20 times its volume, and the reaction temperature is 0-50°C.

[0015] As a preferred embodiment of the present invention, in step 1), the alkali is one of lithium tert-butoxide, lithium bis(trimethylsilylamine), sodium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride, and the amount of the alkali used is 2-10 times the volume.

[0016] As a preferred embodiment of the present invention, in step 2), the solvent is one of methanol, ethanol, 1,4-dioxane or tetrahydrofuran.

[0017] In a preferred embodiment of the present invention, in step 2), the amount of hydrochloric acid used is 1-10 equivalents, and the reaction temperature is 0-50°C.

[0018] As a preferred embodiment of the present invention, in step a), the solvent is one of tetrahydrofuran, 1,4-dioxane or dichloromethane, and the amount of solvent used is 5-20 times the volume.

[0019] As a preferred embodiment of the present invention, in step a), the alkali is one of lithium tert-butoxide, DBU or potassium carbonate, and the amount of alkali used is 2-10 times the volume.

[0020] In a preferred embodiment of the present invention, the reaction temperature in step a) is 0-50°C.

[0021] As a preferred embodiment of the present invention, in step b), the solvent is one of methanol, ethanol, 1,4-dioxane or tetrahydrofuran.

[0022] In a preferred embodiment of the present invention, in step b), the amount of hydrochloric acid used is 1-10 equivalents, and the reaction temperature is 0-50°C.

[0023] Compared with the prior art, the present invention has the following beneficial effects: 1) In this invention, the compound represented by intermediate formula I is dissolved in a solvent, and the compound represented by intermediate formula II and a base are added. The reaction is carried out at 0-30°C until the reaction is complete. After post-processing and separation and purification, the compound represented by intermediate formula III is obtained. The compound represented by intermediate formula III was dissolved in a solvent, and hydrochloric acid solution was added dropwise at 0-5℃. After the reaction was completed, the compound represented by intermediate formula IV was obtained through post-treatment. The present invention also uses an inexpensive and readily available method to dissolve the compound represented by intermediate formula V in a solvent, add the compound represented by intermediate formula II and a base, and after the reaction is completed, obtain the compound represented by intermediate formula VI through post-processing and separation and purification. The compound represented by intermediate formula VI was dissolved in a solvent, hydrazine hydrate was added, and after the reaction was completed, post-treatment was performed to obtain the compound represented by intermediate formula IV.

[0024] 2) This invention provides a relatively economical and environmentally friendly synthesis technology route that is conducive to large-scale production. 3) The starting materials of this invention have a simple structure and are readily available for commercial bulk purchase. Attached Figure Description

[0025] 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.

[0026] Figure 1 This is the synthetic route diagram of the present invention.

[0027] Figure 2 This is the HPLC chromatogram of a mixture of diastereomers of the compound represented by intermediate formula III.

[0028] Figure 3 This is the HPLC chromatogram of the monomer of the compound represented by intermediate formula III.

[0029] Figure 4 This is the 1H NMR spectrum of the compound represented by intermediate formula III.

[0030] Figure 5 This is the carbon NMR spectrum of the compound represented by intermediate formula III.

[0031] Figure 6 This is the 1H NMR spectrum of the compound represented by intermediate formula IV.

[0032] Figure 7 This is the carbon NMR spectrum of the compound represented by intermediate formula IV. Detailed Implementation

[0033] To further understand the content of this invention, the invention will be described in detail with reference to the embodiments.

[0034] 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.

[0035] In this invention, all raw materials, reagents, or equipment used can be purchased from the market.

[0036] This invention provides a method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist. See Figure 1 The synthesis method is as follows: 1) Dissolve the compound represented by intermediate formula I in a solvent, add the compound represented by intermediate formula II and a base, and continue the reaction until it is complete. After post-processing and separation and purification, the compound represented by intermediate formula III is obtained. 2) Dissolve the compound shown in intermediate formula III in a solvent, add hydrochloric acid solution dropwise at 0-5℃, and after the reaction is complete, obtain the compound shown in intermediate formula IV through post-treatment.

[0037] Right now: .

[0038] Or see Figure 1 The synthesis method is as follows: a) Dissolve the compound shown in intermediate formula V in a solvent, add intermediate formula II and a base, and continue the reaction until it is complete. After post-treatment and separation and purification, obtain the compound shown in intermediate formula VI. b) The compound of intermediate formula VI was dissolved in a solvent, hydrazine hydrate was added, and after the reaction was completed, the compound of intermediate formula IV was obtained by post-treatment.

[0039] Right now: .

[0040] Example 1

[0041] This embodiment provides the synthesis of (1S,2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula III). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, 2-[(diphenylmethylene)amino]acetonitrile (intermediate formula I) (10.00 g, 45.40 mmol), (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (intermediate formula II) (12.54 g, 90.80 mmol), and tetrahydrofuran (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 20-30 °C, and lithium tert-butoxide (29.07 g, 363.20 mmol) was added in portions. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with toluene (100 mL, 10 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower aqueous phase was removed, and the organic phase was washed with a semi-saturated sodium chloride aqueous solution (50 mL, 5 V). The lower aqueous phase was removed, and the mixture was washed again with a saturated sodium chloride aqueous solution (50 mL, 5 V). The lower aqueous phase was removed, and the organic phase was desolvated under reduced pressure at 40 °C to dryness using a rotary evaporator. The mixture was then prepared under medium pressure in a 10 mmol NH4HCO4(aq) / acetonitrile system to obtain the compound shown in formula III (7.00 g, 59.2%), a light brown solid with a purity of 99.5%. 1 H NMR (500MHz, CDCl3) δ 7.54 (dt, J = 8.2, 1.1 Hz, 2H), 7.45 (dd, J = 5.0, 1.9 Hz, 3H), 7.36 (td, J = 7.2, 1.2 Hz, 1H), 7.30 - 7.25 (m, 4H), 1.82 - 1.74 (m, 1H),1.69 (dd, J = 9.4, 5.0 Hz, 1H), 1.34 (d, J = 6.1 Hz, 3H), 1.19 (dd, J = 7.8,5.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 170.83, 138.50, 135.06, 129.66,128.74, 127.63, 127.59, 127.50, 127.09, 119.24, 33.26, 26.13, 26.09, 11.72. MS(ESI) Calcd for C 18 H 16 N2 [M+H] + 261.13, found 261.20. See also Figure 2 , Figure 3 , Figure 4 and Figure 5 .

[0042] Example 2

[0043] This embodiment provides the synthesis of (1S,2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula III). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, 2-[(diphenylmethylene)amino]acetonitrile (intermediate formula I) (10.00 g, 45.40 mmol), (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (intermediate formula II) (12.54 g, 90.80 mmol), and 1,4-dioxane (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 0-10 °C, and a 1 M solution of LiHMDS in tetrahydrofuran (363.2 mL, 363.20 mmol) was added dropwise. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with toluene (200 mL, 20 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower aqueous phase was discarded, and the organic phase was washed with a semi-saturated sodium chloride aqueous solution (100 mL, 10 V). The lower aqueous phase was discarded, and the mixture was washed again with a saturated sodium chloride aqueous solution (100 mL, 10 V). The lower aqueous phase was discarded, and the organic phase was desolvated under reduced pressure at 40 °C to dryness using a rotary evaporator. Crystallization was then performed using (ethyl acetate / n-heptane = 0.5 V: 10 V) to give the intermediate compound of formula III (8.20 g, 69.4%), a light brown solid with a purity of 98.5%. MS (ESI) Calcd for C 18 H 16 N2 [M+H] + : 261.13, found 261.20.

[0044] Example 3

[0045] This embodiment provides the synthesis of (1S,2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile (the compound shown in Formula III). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, 2-[(diphenylmethylene)amino]acetonitrile (the compound shown in intermediate formula I) (10.00 g, 45.40 mmol), (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (the compound shown in intermediate formula II) (12.54 g, 90.80 mmol), and dichloromethane (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 0-10 °C, and a 1 M solution of KHMDS in tetrahydrofuran (363.2 mL, 363.20 mmol) was added dropwise. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with dichloromethane (200 mL, 20 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower organic phase was collected and washed with a semi-saturated sodium chloride aqueous solution (100 mL, 10 V). The lower organic phase was collected again and washed with a saturated sodium chloride aqueous solution (100 mL, 10 V). The lower organic phase was collected and dissolved under reduced pressure at 40 °C on a rotary evaporator until dry. Crystallization (ethyl acetate / n-heptane = 0.5 V: 10 V) yielded the compound of intermediate formula III (10.53 g, 89.1%), a light brown solid with a purity of 98.5%. MS (ESI) Calcd for C 18 H 16 N2 [M+H] + : 261.13, found 261.20.

[0046] Example 4

[0047] This embodiment provides the synthesis of (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (the compound shown in Formula IV). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, (1S,2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile (the compound shown in intermediate formula III) (3.00 g, 11.52 mmol) and 4M hydrogen chloride ethanol solution (12.0 mL, 4V, 48.00 mmol) were added sequentially, and the mixture was reacted at 20-30 °C for 3 h. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure at 30 °C on a rotary evaporator, and then slurried with n-heptane (15 mL, 5V) for 0.5 h. After filtration, the filter cake was washed with n-heptane (3 mL, 1V), and the wet filter cake was evaporated to dryness under reduced pressure at 40 °C on a rotary evaporator to obtain the compound shown in intermediate formula IV (1.45 g, 94.8%), an off-white solid. 1 H NMR (500 MHz, DMSO) δ 9.53 (s, 3H), 1.81 (dddd, J = 12.8, 10.1,7.3, 5.0 Hz, 1H), 1.68 (dd, J = 10.1, 6.2 Hz, 1H), 1.41 - 1.36 (m, 1H), 1.28(d, J = 6.4 Hz, 3H). 13 C NMR (126 MHz, DMSO) δ 119.19, 24.32, 20.29, 18.91,11.45. MS(ESI) Calcd for C 18 H 16 N2 [M+H] + 97.07, found 97.10. See also Figure 6 and Figure 7 .

[0048] Example 5

[0049] This embodiment provides the synthesis of (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (the compound shown in Formula IV). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, (1S,2S)-1-[(diphenylmethylene)amino]-2-methylcyclopropane-1-carboxynitrile (the compound shown in intermediate formula III) (3.00 g, 11.52 mmol), methanol (12 mL, 4V), and a 4M solution of 1,4-dioxane in hydrogen chloride (12.0 mL, 4V, 48.00 mmol) were added sequentially. The mixture was then reacted at 20–30 °C for 3 h. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure at 30 °C on a rotary evaporator. The mixture was then slurried with n-heptane (15 mL, 5V) for 0.5 h, filtered, and the filter cake was washed with n-heptane (3 mL, 1V). The wet filter cake was then evaporated to dryness under reduced pressure at 40 °C on a rotary evaporator to obtain the compound shown in intermediate formula IV (1.48 g, 96.8%), an off-white solid. MS(ESI) Calcd for C 18 H 16 N2 [M+H] + : 97.07, found 97.10.

[0050] Example 6

[0051] This embodiment provides the synthesis of (1S,2S)-N-(1-cyano-2-methylcyclopropyl)phthalimide (the compound shown in Formula VI). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, phthalimide acetonitrile (the compound shown in intermediate formula V) (10.00 g, 53.71 mmol), (R)-4-methyl-1,3,2-dioxathiacyclopentane 2,2-dioxide (the compound shown in intermediate formula II) (14.84 g, 107.42 mmol), and tetrahydrofuran (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 20-30 °C, and lithium tert-butoxide (34.40 g, 429.68 mmol) was added in portions. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with toluene (100 mL, 10 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower aqueous phase was removed, and the organic phase was washed with a semi-saturated sodium chloride aqueous solution (50 mL, 5 V). The lower aqueous phase was removed, and the mixture was washed again with a saturated sodium chloride aqueous solution (50 mL, 5 V). The lower aqueous phase was removed, and the organic phase was desolvated under reduced pressure at 40 °C to dryness using a rotary evaporator. The mixture was then reacted under medium pressure in a 10 mmol NH₄HCO₄(aq) / acetonitrile system to prepare the intermediate compound (6.87 g, 56.5%), a light brown solid with a purity of 99.5%. MS (ESI) Calcd for C 18 H 16 N2 [M+H] +: 227.07, found 227.20.

[0052] Example 7

[0053] This embodiment provides the synthesis of (1S,2S)-N-(1-cyano-2-methylcyclopropyl)phthalimide (the compound shown in Formula VI). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, phthalimide acetonitrile (intermediate formula V) (10.00 g, 53.71 mmol), (R)-4-methyl-1,3,2-dioxane-2,2-dioxide (intermediate formula II) (14.84 g, 107.42 mmol), and 1,4-dioxane (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 0-10 °C, and DBU (49.06 g, 322.26 mmol) was added in portions. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with toluene (200 mL, 20 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower aqueous phase was discarded, and the organic phase was washed with a semi-saturated sodium chloride aqueous solution (100 mL, 10 V). The lower aqueous phase was discarded, and the mixture was washed again with a saturated sodium chloride aqueous solution (100 mL, 10 V). The lower aqueous phase was discarded, and the organic phase was desolvated under reduced pressure at 40 °C to dryness using a rotary evaporator. Crystallization (ethyl acetate / n-heptane = 1 V: 5 V) yielded the intermediate compound of formula VI (9.19 g, 75.6%), a light brown solid with a purity of 98.5%. MS (ESI) Calcd for C 18 H 16 N2 [M+H] + : 227.07, found 227.20.

[0054] Example 8

[0055] This embodiment provides the synthesis of (1S,2S)-N-(1-cyano-2-methylcyclopropyl)phthalimide (the compound shown in Formula VI). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, phthalimide acetonitrile (intermediate formula V) (10.00 g, 53.71 mmol), (R)-4-methyl-1,3,2-dioxathiacyclopentane 2,2-dioxide (intermediate formula II) (14.84 g, 107.42 mmol), and dichloromethane (60 mL, 6V) were added sequentially. The mixture was purged with nitrogen twice, cooled to 0-10 °C, and potassium carbonate (29.69 g, 214.84 mmol) was added in portions. The mixture was then reacted at 20-30 °C for 16 h. After the reaction was complete, the mixture was diluted with dichloromethane (200 mL, 20 V), cooled to 0-10 °C, and quenched dropwise with 5% sodium bicarbonate (100 mL, 10 V). After stirring for 15 minutes, the mixture was allowed to stand for 15 minutes to separate into layers. The lower organic phase was collected and washed with a semi-saturated sodium chloride aqueous solution (100 mL, 10 V). The lower organic phase was collected again and washed with a saturated sodium chloride aqueous solution (100 mL, 10 V). The lower organic phase was collected and dissolved under reduced pressure at 40 °C on a rotary evaporator until dry. Crystallization (ethyl acetate / n-heptane = 1 V: 5 V) yielded the intermediate compound of formula VI (10.48 g, 86.2%), a light brown solid with a purity of 99.2%. MS (ESI) Calcd for C 18 H 16 N2 [M+H] + : 227.07, found 227.20.

[0056] Example 9

[0057] This embodiment provides the synthesis of (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (the compound shown in Formula IV). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, (1S,2S)-N-(1-cyano-2-methylcyclopropyl)phthalimide (intermediate compound VI) (5.00 g, 22.10 mmol), methanol (25.0 mL, 5V), and 80% wt hydrazine hydrate (3.45 g, 55.25 mmol) were added sequentially, and the mixture was reacted at 70-80 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with methanol (25.0 mL, 5V). The filtrate was desoluble in a 20-30°C water bath until no flow was observed, and then distilled under reduced pressure. Hydrazine hydrate was first distilled off to remove the product. The free amine was added to a 4M hydrogen chloride ethanol solution (10 mL, 2V, 40.00 mmol) to form a hydrochloride salt, which was then desoluble in a 40°C water bath under reduced pressure until dry. Heptane (15 mL, 3V) was added and the mixture was stirred. The mixture was filtered, and the filter cake was desoluble in a 40°C water bath under reduced pressure until dry, yielding the compound of intermediate formula IV (1.90 g, 64.8%), an off-white solid. MS(ESI)Calcd for C 18 H 16 N2 [M+H] + : 97.07, found 97.10.

[0058] Example 10

[0059] This embodiment provides the synthesis of (1S,2S)-1-amino-2-methylcyclopropane-1-carboxynitrile hydrochloride (the compound shown in Formula IV). In a 250 mL three-necked flask, under magnetic stirring and nitrogen protection, (1S,2S)-N-(1-cyano-2-methylcyclopropyl)phthalimide (intermediate compound VI) (5.00 g, 22.10 mmol), ethanol (25.0 mL, 5V), and 80% hydrazine hydrate (3.45 g, 55.25 mmol) were added sequentially, and the mixture was reacted at 70-80 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (25.0 mL, 5V). The filtrate was desoluble in a water bath at 20-30°C until no flow was observed, and then water (10 mL, 2V, 20.00 mmol) was added. Methyl tert-butyl ether (50 x 3 mL, 10V x 3) was added for extraction. The organic phase was combined and washed with an aqueous solution (25 mL, 5V). A 4M hydrogen chloride ethanol solution (10 mL, 2V, 40.00 mmol) was added to the organic phase to form a hydrochloride salt, which was then desoluble under reduced pressure in a water bath at 40°C until dry. Heptane (15 mL, 3V) was added and the mixture was stirred. The mixture was filtered, and the filter cake was desoluble under reduced pressure in a water bath at 40°C until dry, yielding the compound of intermediate formula IV (2.41 g, 82.4%), an off-white solid. MS (ESI) Calcd for C 18 H 16N2[M+H] + : 97.07, found 97.10.

[0060] 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 core chiral intermediate of a GLP-1 receptor agonist, characterized in that, The synthesis method is as follows: 1) Dissolve the compound represented by intermediate formula I in a solvent, add the compound represented by intermediate formula II and a base, and continue the reaction until it is complete. After post-processing and separation and purification, the compound represented by intermediate formula III is obtained. 2) Dissolve the compound shown in intermediate formula III in a solvent, add hydrochloric acid solution dropwise at 0-5℃, and after the reaction is complete, obtain the compound shown in intermediate formula IV through post-treatment; Alternatively, the synthesis method is as follows: a) Dissolve the compound shown in intermediate formula V in a solvent, add intermediate formula II and a base, and continue the reaction until it is complete. After post-treatment and separation and purification, obtain the compound shown in intermediate formula VI. b) Dissolve the compound of intermediate formula VI in a solvent, add hydrazine hydrate, and after the reaction is complete, post-treatment is performed to obtain the compound of intermediate formula IV. 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: ； The compound shown in Formula VI: .

2. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step 1), the solvent is one of tetrahydrofuran, 1,4-dioxane, or dichloromethane. The amount of solvent used is 5-20 times its volume, and the reaction temperature is 0-50℃.

3. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step 1), the alkali is one of lithium tert-butoxide, lithium bis(trimethylsilylamine), sodium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride, and the amount of alkali used is 2-10 times the volume.

4. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step 2), the solvent is one of methanol, ethanol, 1,4-dioxane or tetrahydrofuran.

5. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step 2), the amount of hydrochloric acid used is 1-10 equivalents, and the reaction temperature is 0-50℃.

6. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step a), the solvent is one of tetrahydrofuran, 1,4-dioxane or dichloromethane, and the amount of solvent used is 5-20 times the volume.

7. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step a), the alkali is one of lithium tert-butoxide, DBU, or potassium carbonate, and the amount of alkali used is 2-10 times the volume.

8. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step a), the reaction temperature is 0-50℃.

9. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step b), the solvent is one of methanol, ethanol, 1,4-dioxane or tetrahydrofuran.

10. The method for synthesizing a core chiral intermediate of a GLP-1 receptor agonist according to claim 1, characterized in that, In step b), the amount of hydrochloric acid used is 1-10 equivalents, and the reaction temperature is 0-50℃.

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