Chiral resolution method and application of 3-aryl substituted glutaric acid monoester compound

Abstract

The invention provides a chiral resolution method and application of a 3-aryl substituted glutaric acid monoester compound, and the method comprises the following steps: taking a substance as shown in a formula I as a starting raw material, and carrying out alcoholysis to obtain a racemic intermediate as shown in a formula IV; and splitting the intermediate shown in the formula IV, and then dissociating to obtain the compound shown in the formula III, which has a single spatial configuration and an ee value of more than 99%. A cyclic anhydride substrate with a symmetrical structure is used and reacts with alcohol to obtain racemic 3-aryl substituted glutaric acid monoester, a target configuration with high chiral purity is obtained by screening some resolution reagents and solvents and performing salifying resolution on the 3-aryl substituted glutaric acid monoester, the operation is simple, the resolution reagents are easily available in the market and can be recycled, and the method is suitable for industrial production. The method has the advantages that an expensive chiral catalyst or a harsh enzyme catalysis condition is avoided, the reaction cost is reduced, amplified production is facilitated, the ee value of a target configuration can be increased to 99% or above, and the method is an economic and environment-friendly technical route which is simple in post-treatment and convenient for amplified production.

Description

Technical Field

[0001] The present invention belongs to the technical fields of organic synthetic chemistry and medicinal chemistry, relates to glutaric acid monoester compounds, and in particular to an efficient chiral resolution method for 3-aryl substituted glutaric acid monoester compounds and applications thereof. Background Art

[0002] As the core module of Orforglipron and ECC5004 (shown below), and also one of the difficulties in their synthesis, the improved synthesis of the aromatic-substituted chiral tetrahydropyran ring fragments in their structures, namely (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid and (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-indolizine-2-carboxylic acid and their derivatives is particularly important.

[0003]

[0004] 3-Aryl-substituted glutaric acid monoesters are an important class of chiral intermediates with widespread applications in medicinal chemistry, functional materials, and asymmetric catalysis. Industry is increasingly demanding the stereoisomeric purity of these compounds, particularly for active pharmaceutical ingredients, which often require an enantiomeric excess (EE) of ≥99%. This fragment serves as a key chiral intermediate in the synthesis of Orforglipron and ECC5004.

[0005] In the prior art, the methods for obtaining optically pure 3-aryl substituted glutaric acid monoester products are concentrated in the following two categories:

[0006] (1) Chiral organic small molecules or enzyme-catalyzed alcoholysis of cyclic anhydrides.

[0007] (2) Hydrolysis of glutaric acid diester catalyzed by chiral organic small molecules or enzymes.

[0008] These reactions generally require the reaction system to be carried out under dilution conditions below 0.05 mol / L, and generally only products with ee values of about 80% to 90% can be obtained, which still need to be purified to the target purity through multiple splitting or recrystallization. In addition, the enzyme catalysts and organic small molecule catalysts used are relatively expensive and require strict pH control conditions. These two types of methods generally have process scale-up bottlenecks: the former has a reactor volume utilization rate of less than 30% due to the low reaction concentration, and the latter requires the configuration of precise pH adjustment equipment and the catalyst recovery cost is high, which significantly increases the production cost.

[0009] The existing process flow is as follows:

[0010]

[0011] Through cyclic anhydride substrate I or diester substrate II, a certain proportion of the target stereo configuration is obtained through small molecule or enzyme catalysis, and then after purification, the target product with improved ee value is finally obtained. The ee value is generally around 96% to 97%. Methods for obtaining products with higher ee value are rarely reported. Summary of the Invention

[0012] In order to solve the above technical problems, the present invention provides a chiral resolution method and application of 3-aryl substituted glutaric acid monoester compounds. The present invention directly obtains a target configuration product with an ee value of >99% from a racemic substrate by using a chiral reagent that can be directly purchased on the market. Compared with traditional methods, the present invention has the following breakthrough advantages: (1) no chiral small molecules or enzyme catalysis are required; (2) the reaction concentration is increased to 0.8 mol / L level, which improves the utilization rate of equipment production capacity; (3) the recovery rate of the resolution reagent used is ≥90%, which greatly reduces the reagent cost; (4) no special conditions such as low temperature (below -20°C) or precision pH meter are required, which simplifies the equipment configuration requirements; (5) the target product with an ee value of >99% can be finally obtained. The process conditions used in the present invention provide a reliable technical path for industrial scale-up.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for chiral resolution of 3-aryl substituted glutaric acid monoester compounds, the method comprising:

[0015] 1) dissolving the substance represented by formula I in an alcohol solvent, adding 4-dimethylaminopyridine, reacting until completion, and post-processing to obtain the intermediate represented by formula IV;

[0016] 2) dissolving the intermediate represented by formula IV in a solvent, heating, adding a resolving agent, and post-treating to obtain the compound represented by formula III;

[0017] 3) Repeat step 2) until a compound of formula III having a single stereo configuration and an ee value greater than 99% is obtained;

[0018] Among them, the substance shown in formula I:

[0019] The intermediate shown in formula IV:

[0020] The compound shown in formula III:

[0021] Where Ar:

[0022]

[0023] X is Cl, Br, I, -OTF, -OMs or -OTs; Y is C or N; R 1 is a C1-C6 alkyl group or a benzyl group; R 2 is C1-C6 alkoxy or benzyloxy or -NR 5 R 6 ; R 3 is H, -CNCH2, Boc, Cbz, Bn or Ts; R 4 is H or -CNCH2; R 5 is H, C1-C6 alkyl or phenyl; R 6 is H, C1-C6 alkyl or phenyl.

[0024] As a preferred embodiment of the present invention, in step 1), the alcohol solvent is one of methanol, ethanol, benzyl alcohol and benzene mercaptan.

[0025] As a preferred embodiment of the present invention, in step 1), the amount of 4-dimethylaminopyridine used is 0.01-1 equivalent, and the reaction temperature is 0-80°C.

[0026] As a preferred embodiment of the present invention, in step 2), the temperature is raised to 30-80°C.

[0027] As a preferred embodiment of the present invention, in step 2), the amount of the resolving agent used is 0.1-1.2 equivalents.

[0028] As a preferred embodiment of the present invention, in step 2), the resolving agent is cinchonidine, cinchonine, quinidine, quinine, (R)-α-phenylethylamine, (R)-1-(1-naphthyl)ethylamine or (R)-1-cyclohexylethylamine.

[0029] As a preferred embodiment of the present invention, in step 2), the solvent is one or two or more of ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, tetrahydrofuran, isopropanol or dichloromethane.

[0030] The present invention also provides the use of 3-aryl substituted glutaric acid monoester compounds obtained by the above chiral resolution method in synthesizing key chiral intermediates of Orforglipron and ECC5004.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1) The present invention uses a symmetrically structured cyclic anhydride substrate to react with an alcohol to obtain a racemic 3-aryl-substituted glutaric acid monoester. By screening a number of resolution agents and solvents, the 3-aryl-substituted glutaric acid monoester is resolved by salt formation to obtain the target configuration with high chiral purity.

[0033] 2) The present invention is simple to operate, and the resolution reagents are readily available and recyclable in the market, thus avoiding expensive chiral catalysts or harsh enzyme catalysis conditions, reducing reaction costs, and facilitating scale-up production.

[0034] 3) The present invention can increase the ee value of the target configuration to more than 99%, which is an economical, environmentally friendly, simple post-processing and easy-to-scale production technical route. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0036] Figure 1 It is the synthesis route diagram of the present invention.

[0037] Figure 2 This is a roadmap for the synthesis of Formula III-A from Formula IA.

[0038] Figure 3 is a route to synthesize Formula X from Formula III-A.

[0039] Figure 4 This is a roadmap for the synthesis of Formula III-B from Formula IB.

[0040] Figure 5 This is a roadmap for synthesizing formula III-C from formula IC.

[0041] Figure 6 This is a roadmap for synthesizing Formula III-D from Formula ID.

[0042] Figure 7 is a chiral diagram of the racemate of formula IV-A in Example 1.

[0043] Figure 8 : is the chirality diagram of the single chiral target compound of formula III-A in Example 9. DETAILED DESCRIPTION

[0044] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0045] In the present invention, all the raw materials, reagents or equipment used can be purchased from the market.

[0046] Example 1

[0047] See also Figure 2 , this example provides the synthesis of 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (IV-A):

[0048] Under nitrogen protection, 500g of 4-(4-bromophenyl)dihydro-2H-pyran-2,6(3H)-dione, 2L of methanol, and 11.3g of 4-dimethylaminopyridine were added to a 5L three-necked flask at room temperature and reacted for 2h. After LCMS detection, the reaction was completed, and the mixture was distilled under reduced pressure to 2V. 500mL of 1N hydrochloric acid aqueous solution was added, and the mixture was beaten at room temperature for 1h. The mixture was filtered and rinsed with 500mL of water. The filter cake was collected and dried under vacuum to obtain 545g of 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with a yield of 97.5% and a purity of 98.7%. Figure 7 As shown in Table 1.

[0049] Table 1

[0050]

[0051] Example 2

[0052] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0053] Under nitrogen protection, 10g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200mL ethyl acetate were added to a 500mL three-necked flask at room temperature, the temperature was raised to 50-60°C to dissolve, 5.86g cinchonidine was added, the mixture was stirred at this temperature for 3h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 50mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after testing, the ee value was 85%), transferred to a 500mL three-necked flask, the temperature was raised to 50°C to dissolve, 4.75g cinchonidine was added, the mixture was stirred at this temperature for 2 ... 1N hydrochloric acid aqueous solution, extraction and separation, the organic phase was collected (after testing, the ee value was 97.3%), transferred to a 500mL three-necked flask, heated to 50°C to dissolve, 4.2g of cinchonidine was added, and the mixture was stirred for 2h at this temperature. Then, the mixture was slowly cooled to room temperature and filtered. The filter cake was rinsed with 50mL of ethyl acetate, the filter cake was collected, 100mL of ethyl acetate and 100mL of 1N hydrochloric acid aqueous solution were added, the layers were extracted and separated, the organic phase was collected (after testing, the ee value was 99.2%), concentrated, and dried to obtain 3.9g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 99.1%.

[0054] Example 3

[0055] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0056] Under nitrogen protection, 10g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200mL acetonitrile were added to a 500mL three-necked flask at room temperature, the temperature was raised to 50-60℃ to dissolve, 5.9g cinchonidine was added, the temperature was kept warm and stirred for 3h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 50mL acetonitrile, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after detection, the ee value was 82%), the solvent was concentrated and transferred to a 500mL three-necked flask, 100mL acetonitrile was added, the temperature was raised to 50℃ to dissolve, 4.1g cinchonidine was added, the temperature was kept warm and stirred for 2 ... 1N hydrochloric acid aqueous solution, extraction and separation, collecting the organic phase (after testing, ee value is 95.3%), concentrating to remove the solvent, transferring to a 500mL three-necked flask, adding 100mL acetonitrile, transferring to a 500mL three-necked flask, heating to 50°C to dissolve, adding 3.0g cinchonidine, keeping warm and stirring for 2h, then slowly cooling to room temperature, filtering, rinsing the filter cake with 50mL acetonitrile, collecting the filter cake, adding 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution, extraction and separation, collecting the organic phase (after testing, ee value is 97.8%), concentrating, and drying to obtain 2.4g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid, ee value is 97.8%.

[0057] Example 4

[0058] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0059] Under nitrogen protection, 10 g of 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200 mL of methyl tert-butyl ether were added to a 500 mL three-necked flask at room temperature. The temperature was raised to 50-60° C. to dissolve the mixture. 5.86 g of cinchonidine was added, the mixture was stirred at this temperature for 3 h, and the temperature was slowly lowered to room temperature. The mixture was filtered, and the filter cake was rinsed with 50 mL of methyl tert-butyl ether. The filter cake was collected, and 100 mL of methyl tert-butyl ether and 100 mL of 1N aqueous hydrochloric acid were added. The mixture was extracted and separated into layers. The organic phase was collected (the ee value was 65.1% after testing), concentrated, and dried to obtain 3.6 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 65.4%.

[0060] Example 5

[0061] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0062] Under nitrogen protection, 10 g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200 mL ethyl acetate were added to a 500 mL three-necked flask at room temperature, the temperature was raised to 50-60 ° C to dissolve, 2.41 g (R) -α-phenylethylamine was added, the mixture was stirred for 3 h, and then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50 mL ethyl acetate, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after testing, the ee value was 23%), transferred to a 500 mL three-necked flask, the temperature was raised to 50 ° C to dissolve, 2.0 g R-phenylethylamine was added, the mixture was stirred for 2 h, and then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50 mL ethyl acetate, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after testing, the ee value was 23%), transferred to a 500 mL three-necked flask, the temperature was raised to 50 ° C to dissolve, 2.0 g R-phenylethylamine was added, the mixture was stirred for 2 h, and then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50 mL ethyl acetate, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N aqueous hydrochloric acid solution was used for extraction and stratification. The organic phase was collected (after detection, the ee value was 47.3%), concentrated and dried to obtain 4.3 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 46.5%.

[0063] Example 6

[0064] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0065] Under nitrogen protection, 10 g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200 mL ethyl acetate were added to a 500 mL three-necked flask at room temperature, and the temperature was raised to 50-60 ° C to dissolve. 3.4 g (R)-1-(1-naphthyl)ethylamine was added, and the mixture was stirred for 3 h. The mixture was then slowly cooled to room temperature and filtered. The filter cake was rinsed with 50 mL ethyl acetate, the filter cake was collected, and 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution, extraction and stratification, the organic phase was collected (after testing, the ee value was 65%), transferred to a 500mL three-necked flask, heated to 50°C to dissolve, 2.75g (R) -1- (1-naphthyl) ethylamine was added, the mixture was stirred for 2h, then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate was added, 100mL 1N hydrochloric acid aqueous solution, extraction and stratification, the organic phase was collected (after testing, the ee value was 87%), transferred to a 500mL three-necked flask, heated to 50°C to dissolve, 2.6g (R) -1- (1-naphthyl) ethylamine was added, the mixture was stirred for 2h, then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate, 100mL 1N aqueous hydrochloric acid solution was used for extraction and separation. The organic phase was collected (the ee value was 95.8% after detection), concentrated and dried to obtain 2.6 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 96.0%.

[0066] Example 7

[0067] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0068] Under nitrogen protection, 10 g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200 mL acetonitrile were added to a 500 mL three-necked flask at room temperature, the temperature was raised to 50-60 ° C to dissolve, 3.4 g (R) -1- (1-naphthyl) ethylamine was added, the temperature was kept warm and stirred for 3 h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 50 mL acetonitrile, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after detection, the ee value was 75%), the solvent was concentrated and transferred to a 500 mL three-necked flask, 100 mL acetonitrile was added, the temperature was raised to 50 ° C to dissolve, 2.75 g (R) -1- (1-naphthyl) ethylamine was added, the temperature was kept warm and stirred for 2 h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 50 mL acetonitrile, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected, the solvent was concentrated and removed, the product was transferred to a 500 mL three-necked flask, 100 mL acetonitrile was added, the temperature was raised to 50 ° C to dissolve, 2.75 g (R) -1- (1-naphthyl) ethylamine was added, the temperature was kept warm and stirred for 2 h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 50 mL acetonitrile, the filter cake was collected, 100 mL ethyl acetate and 100 mL 1N hydrochloric acid aqueous solution, extraction and separation, the organic phase was collected (after testing, the ee value was 90.2%), concentrated to remove the solvent, transferred to a 500mL three-necked flask, added 100mL acetonitrile, transferred to a 500mL three-necked flask, heated to 50°C to dissolve, added 2.4g (R)-1-(1-naphthyl)ethylamine, kept warm and stirred for 2h, then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50mL acetonitrile, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, extraction and separation, the organic phase was collected (after testing, the ee value was 95.8%), concentrated, and dried to obtain 2.8g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 95.8%.

[0069] Example 8

[0070] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0071] Under nitrogen protection, 10 g of 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 200 mL of ethyl acetate were added to a 500 mL three-necked flask at room temperature, and the temperature was raised to 50-60 ° C to dissolve. 2.82 g of (R)-1-cyclohexylethylamine was added, and the mixture was stirred for 3 h. The temperature was then slowly lowered to room temperature and filtered. The filter cake was rinsed with 50 mL of ethyl acetate, the filter cake was collected, and 100 mL of ethyl acetate and 100 mL of ethanol were added. 1N hydrochloric acid aqueous solution, extraction and stratification, the organic phase was collected (after testing, the ee value was 73%), transferred to a 500mL three-necked flask, heated to 50-60°C to dissolve, 2.35g (R) -1- (1-naphthyl) ethylamine was added, the mixture was stirred for 2h, then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate was added, 100mL 1N hydrochloric acid aqueous solution, extraction and stratification, the organic phase was collected (after testing, the ee value was 92%), transferred to a 500mL three-necked flask, heated to 50-60°C to dissolve, 1.72g (R) -1- (1-naphthyl) ethylamine was added, the mixture was stirred for 2h, then slowly cooled to room temperature, filtered, the filter cake was rinsed with 50mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate was added, 100mL 1N aqueous hydrochloric acid solution was used for extraction and separation. The organic phase was collected (the ee value was 96.1% after detection), concentrated and dried to obtain 3.5 g of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid with an ee value of 96.2%.

[0072] Example 9

[0073] See also Figure 2 , this example provides the synthesis of (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A):

[0074] Under nitrogen protection, 1000g 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid and 20L ethyl acetate were added to a 50L reactor at room temperature, the temperature was raised to 50-60°C to dissolve, 600g cinchonidine was added, the mixture was stirred at this temperature for 3h, and the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 1L ethyl acetate, (filtrate recovery) the filter cake was collected, 5L ethyl acetate and 5L1N hydrochloric acid aqueous solution were added, the extraction was performed, (aqueous phase recovery) the organic phase was collected (after testing, the ee value was 82%), transferred to a 50L reactor, the temperature was raised to 50-60°C, 520g cinchonidine was added, the mixture was stirred at this temperature for 2h, and the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 1L ethyl acetate, (filtrate recovery) the filter cake was collected, 5L ethyl acetate and 5L1N hydrochloric acid aqueous solution were added, the extraction was performed, and the organic phase was collected (after testing, the ee value was 82%). 1N hydrochloric acid aqueous solution, extraction and stratification, (aqueous phase recovery) collect the organic phase (after detection, ee value is 96.8%), transfer to a 50L reactor, heat to 50-60 ° C, add 430g cinchonidine, keep warm and stir for 2h, then slowly cool to room temperature, filter, rinse the filter cake with 1L ethyl acetate, (filtrate recovery) collect the filter cake, add 5L ethyl acetate, 5L 1N hydrochloric acid aqueous solution, extraction and stratification, (aqueous phase recovery) collect the organic phase (after detection, ee value is 99.5%), concentrate and dry to obtain 435g (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid, ee value is 99.4%, as shown Figure 8 As shown in Table 2.

[0075] Table 2

[0076]

[0077] The filtrate and the extracted aqueous phase were combined, stirred and separated, and the organic phase was concentrated and dried to recover 560 g of 3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid. Solid sodium carbonate was added to the aqueous phase to adjust the pH to 8-12 to precipitate cinchonidine, which was filtered, washed, and dried to recover 1426 g of cinchonidine.

[0078] In addition, (S)-3-(4-bromophenyl)-5-methoxy-5-oxopentanoic acid (III-A) can be used as a raw material for synthesizing the key intermediate X of Orforglipron. The specific examples are as follows:

[0079] Example 10

[0080] See also Figure 3 , this example provides the synthesis of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (V):

[0081] In a 1000mL three-necked flask, nitrogen protection, 20 grams of (S) -3- (4- bromophenyl) -5- methoxy -5- oxopentanoic acid (III-A) obtained in Example 2, 200mL tetrahydrofuran, cooled to -30 ° C, 90mL methylmagnesium chloride (3mol / Lin THF) was added dropwise, and the temperature was controlled to be no more than -20 ° C. After dripping, the temperature was slowly raised to 0 ° C and the reaction was reacted for 2 hours. LCMS detection was completed, and the reaction solution was poured into 300mL of ice 1N hydrochloric acid aqueous solution for quenching, extracted with ethyl acetate, and then washed with saturated brine. The organic phase was collected and dried with anhydrous sodium sulfate and filtered. The filtrate was spin-dried and desolventized. The crude product was slurried with ethyl acetate and n-heptane, filtered, and the filter cake was drained to obtain 24.2 grams of (R) -4- (4- bromophenyl) -6,6- dimethyltetrahydro -2H- pyran-2-one (V), a white solid with a purity of 99.5%.

[0082] Example 11

[0083] See also Figure 3 , this example provides the synthesis of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VI):

[0084] In a 500 mL three-necked flask, 20 g of (R)-4-(4-bromophenyl)-6,6-dimethyltetrahydro-2H-pyran-2-one (VI) prepared in Example 1 and 200 mL of dichloromethane were added in sequence. The temperature was cooled to -70°C in a dry ice ethanol bath. 100 mL of DIBAL-H solution (1 mol / L hexane) was added dropwise, and the temperature was controlled not to exceed -65°C. After the addition was complete, the temperature was kept at -70°C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was poured into 500 mL of 10% wt potassium sodium tartrate aqueous solution to quench the reaction. The mixture was stirred for 1 hour until the layers were clear and separated. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure to obtain 20.6 g of (4R)-4-(4-bromophenyl)

[0085] 6,6-Dimethyltetrahydro-2H-pyran-2-ol, a white solid, was added to a 500 mL three-necked flask, 200 mL of DCM, 22 g of triethylsilane, and cooled to 0°C in an ice-water bath. 11.5 g of boron trifluoride etherate was added dropwise, and the mixture was allowed to react at 0°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was quenched by pouring it into 200 mL of ice-cold, half-saturated aqueous sodium bicarbonate solution. The mixture was stirred until no bubbles were generated, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure to obtain a colorless oil. Crystallization from n-heptane and ethyl acetate gave 16.8 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VI) with a purity of 98.8%.

[0086] Example 12

[0087] See also Figure 3 , this example provides the synthesis of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VII):

[0088] In a 500 mL three-necked flask, under magnetic stirring and nitrogen protection, 266 mg of cuprous iodide, 615 mg of N1,N2 bis(2,5-dimethyl-1H-pyrrol-1-yl)oxamide, 1.43 g of potassium phosphate, and 615 mg of hexadecyltrimethylammonium bromide were added in sequence. Then, 15 g of (S)-4-(4-bromophenyl)-2,2-dimethyltetrahydro-2H-pyran (VA) prepared in Example 1 and 3.9 mL of water were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 80°C for 15 minutes. The mixture was then cooled to room temperature, and 12.8 g of potassium phosphate and 6.62 g of 85% wt hydrazine hydrate were added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 80°C overnight. The mixture was cooled to room temperature, diluted with 200 mL of dichloromethane, filtered, and the filter cake was washed with 200 mL of dichloromethane. The filtrate was washed once with 200 mL of water and once with 150 mL of semi-saturated brine. The organic phase was collected and adjusted to pH = 3 by dropwise addition of concentrated hydrochloric acid. A large amount of solid was precipitated, filtered, and the filter cake was washed with 150 mL of dichloromethane, dried, and desolvated under reduced pressure in a 40°C water bath to obtain 12.5 g of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine hydrochloride (VII) as an off-white solid with a purity of 97.5%.

[0089] Example 13

[0090] See also Figure 3 This example provides the synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VIII):

[0091] In a 250 mL three-necked flask, 100 mL of ethanol and 20 g of concentrated sulfuric acid were mixed. After cooling to room temperature, 10 g of (S)-(4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)phenyl)hydrazine (VI-A) obtained in Example 5 and 4 g of ethyl pyruvate were added, and the mixture was reacted at 75 ° C for 3 hours. LCMS detection showed that the reaction was complete, cooled to room temperature, and most of the ethanol was removed by decompression desolventizing in a 40 ° C water bath. The mixture was then poured into 200 mL of water for quenching, extracted with ethyl acetate, washed with saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, 50 mL of n-heptane was added for slurrying, and the filter cake was collected by filtration and dried to give 7.2 g of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (VIII) with a purity of 95.2%.

[0092] Example 14

[0093] See also Figure 3This example provides the synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (IX):

[0094] In a 250 mL three-necked flask, 5 g of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester was added, 50 mL of tetrahydrofuran was added, and the mixture was stirred to dissolve. 17 mL of 1 M lithium hydroxide aqueous solution was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was completed by LCMS detection. 100 mL of methyl tert-butyl ether and 50 mL of water were added, and the layers were extracted. The aqueous phase was collected and washed with 50 mL of methyl tert-butyl ether. The pH of the aqueous phase was then adjusted to 3-4 with 1N hydrochloric acid aqueous solution. Solid precipitated, and the filter cake was collected by filtration and dried to obtain 4.6 g of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (IX) with a purity of 98.9%.

[0095] Example 15

[0096] See also Figure 3 , this example provides (S)-5-2,2-dimethyltetrahydro-2H-pyran-4-yl-N-methyl-N-phenyl-1H-indole-2-carboxamide (X):

[0097] In a 250 mL three-necked flask, 4.5 g of (S)-5-2,2-dimethyltetrahydro-2H-pyran-4-yl-N-methyl-N-phenyl-1H-indole-2-carboxamide was added, 50 mL of dichloromethane was added, and the mixture was stirred to dissolve. 2.5 g of oxalyl chloride and 2 drops of N,N-dimethylformamide were added dropwise under ice bath, and the mixture was stirred in ice bath for 2 hours. The solvent was removed by concentration under reduced pressure, and the mixture was redissolved in 50 mL of acetonitrile. 3.5 g of N-methylaniline and 5 g of triethylamine were added, and the mixture was stirred at room temperature for 4 hours. 100 mL of water was added, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was then hot-beaten with a mixed solution of isopropanol and water. The filter cake was collected by filtration and dried to obtain 5.5 g of (S)-5-2,2-dimethyltetrahydro-2H-pyran-4-yl-N-methyl-N-phenyl-1H-indole-2-carboxamide (X) with a purity of 99.3% and an ee value of 99.1%.

[0098] Example 16:

[0099] See also Figure 4 This example provides the synthesis of 3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (IV-B):

[0100] Under nitrogen, 10 g of 4-(2-bromopyridin-4-yl)dihydro-2H-pyran-2,6(3H)-dione, 50 mL of methanol, and 400 mg of 4-dimethylaminopyridine were added sequentially to a 250 mL three-necked flask at room temperature. The mixture was allowed to react for 6 h. LCMS confirmed the reaction was complete, and the mixture was evaporated to 2 V under reduced pressure. 100 mL of water and 100 mL of dichloromethane were added, and the layers were separated by extraction. The organic phase was collected and washed with saturated brine. The organic phase was concentrated to yield 7.6 g of 3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid, with a yield of 68.4% and a purity of 95.5%.

[0101] Example 17

[0102] See also Figure 4 This example provides the synthesis of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid (III-B):

[0103] Under nitrogen protection, 5g 3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid and 150mL ethyl acetate were added to a 250mL three-necked flask at room temperature, the temperature was raised to 50-60℃ to dissolve, 2.7g cinchonidine was added, the mixture was stirred at this temperature for 2h, and the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (the ee value was 47% after detection), transferred to a 250mL three-necked flask, the temperature was raised to 50℃ to dissolve, 2.1g cinchonidine was added, the mixture was stirred at this temperature for 2h, and the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (the ee value was 47% after detection), transferred to a 250mL three-necked flask, the temperature was raised to 50℃ to dissolve, 2.1g cinchonidine was added, the mixture was stirred at this temperature for 2h, and the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution, extraction and separation, the organic phase was collected (after testing, the ee value was 75.3%), transferred to a 250mL three-necked flask, heated to 50°C to dissolve, 1.5g of cinchonidine was added, and the mixture was stirred for 2h at this temperature. Then, the mixture was slowly cooled to room temperature and filtered. The filter cake was rinsed with 30mL of ethyl acetate, the filter cake was collected, 100mL of ethyl acetate and 100mL of 1N hydrochloric acid aqueous solution were added, extraction and separation were carried out, the organic phase was collected (after testing, the ee value was 92.2%), concentrated, and dried to obtain 1.4g of (S)-3-(2-bromopyridin-4-yl)-5-methoxy-5-oxopentanoic acid with an ee value of 92.1%.

[0104] Example 18

[0105] See also Figure 5 This example provides the synthesis of 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid (IV-C):

[0106] Under nitrogen, 10 g of ethyl 5-(2,6-dioxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate, 50 mL of methanol, and 400 mg of 4-dimethylaminopyridine were added sequentially to a 250 mL three-necked flask at room temperature and allowed to react for 12 h. After LCMS analysis, the reaction was complete and the mixture was distilled to 2 V under reduced pressure. 100 mL of 1N aqueous hydrochloric acid was added, and the mixture was slurried at room temperature for 1 h. The mixture was filtered and rinsed with 100 mL of water. The filter cake was collected and dried under vacuum to yield 9.6 g of 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid, with a yield of 87.3% and a purity of 97.2%.

[0107] Example 19

[0108] See also Figure 5 This example provides the synthesis of (S)-3-(2-(ethoxycarbonyl)-1H-indol-5-yl)-5-methoxy-5-oxopentanoic acid (III-C):

[0109] Under nitrogen protection, 5g 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid and 150mL ethyl acetate were added to a 250mL three-necked flask at room temperature, the temperature was raised to 50-60°C to dissolve, 2.5g cinchonidine was added, the mixture was stirred at this temperature for 3h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (the ee value was 35% after detection), transferred to a 250mL three-necked flask, the temperature was raised to 50°C to dissolve, 1.4g cinchonidine was added, the mixture was stirred at this temperature for 2h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (the ee value was 35% after detection), transferred to a 250mL three-necked flask, the temperature was raised to 50°C to dissolve, 1.4g cinchonidine was added, the mixture was stirred at this temperature for 2h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution, extraction and separation, the organic phase was collected (after testing, the ee value was 67.3%), transferred to a 250mL three-necked flask, heated to 50°C to dissolve, 1.2g of cinchonidine was added, and the mixture was stirred for 2h at this temperature. The mixture was then slowly cooled to room temperature and filtered. The filter cake was rinsed with 30mL of ethyl acetate, the filter cake was collected, 100mL of ethyl acetate and 100mL of 1N hydrochloric acid aqueous solution were added, extraction and separation were carried out, the organic phase was collected (after testing, the ee value was 87.2%), concentrated, and dried to obtain 1.1g of (S)-3-(2-(ethoxycarbonyl)-1H-indol-5-yl)-5-methoxy-5-oxopentanoic acid with an ee value of 87.5%.

[0110] Example 20

[0111] See also Figure 6This example provides the synthesis of 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid (IV-B):

[0112] Under nitrogen, 10 g of ethyl 5-(2,6-dioxotetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate, 50 mL of methanol, and 400 mg of 4-dimethylaminopyridine were added sequentially to a 250 mL three-necked flask at room temperature. The reaction was allowed to react for 12 h. LCMS confirmed the reaction was complete, and the mixture was evaporated to 2 V under reduced pressure. 100 mL of water and 100 mL of dichloromethane were added, and the layers were separated by extraction. The organic phase was collected and washed with saturated brine. The organic phase was concentrated to yield 9.6 g of 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid, with a yield of 86.7% and a purity of 96.5%.

[0113] Example 21

[0114] See also Figure 6 This example provides the synthesis of (S)-3-(2-(ethoxycarbonyl)-1H-indol-5-yl)-5-methoxy-5-oxopentanoic acid (III-B):

[0115] Under nitrogen protection, 5g 3-[2-(ethoxycarbonyl)-1H-indol-5-yl]-5-methoxy-5-oxopentanoic acid and 150mL ethyl acetate were added to a 250mL three-necked flask at room temperature, the temperature was raised to 50-60°C to dissolve, 2.5g cinchonidine was added, the mixture was stirred at this temperature for 3h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after testing, the ee value was 41%), transferred to a 250mL three-necked flask, the temperature was raised to 50°C to dissolve, 1.4g cinchonidine was added, the mixture was stirred at this temperature for 2h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution were added, the organic phase was collected (after testing, the ee value was 41%), transferred to a 250mL three-necked flask, the temperature was raised to 50°C to dissolve, 1.4g cinchonidine was added, the mixture was stirred at this temperature for 2h, and then the temperature was slowly lowered to room temperature, filtered, the filter cake was rinsed with 30mL ethyl acetate, the filter cake was collected, 100mL ethyl acetate and 100mL 1N hydrochloric acid aqueous solution, extraction and separation, the organic phase was collected (after testing, the ee value was 77%), transferred to a 250mL three-necked flask, heated to 50°C to dissolve, 1.2g of cinchonidine was added, and the mixture was stirred for 2h at this temperature. Then, the mixture was slowly cooled to room temperature and filtered. The filter cake was rinsed with 30mL of ethyl acetate, the filter cake was collected, 100mL of ethyl acetate and 100mL of 1N hydrochloric acid aqueous solution were added, extraction and separation were carried out, the organic phase was collected (after testing, the ee value was 90.9%), concentrated and dried to obtain 1.3g of (S)-3-(2-(ethoxycarbonyl)-1H-indol-5-yl)-5-methoxy-5-oxopentanoic acid with an ee value of 91.1%.

[0116] As can be seen, the present invention uses a symmetrically structured cyclic anhydride substrate to react with an alcohol to produce a racemic 3-aryl-substituted glutaric acid monoester. By screening a number of resolution reagents and solvents, the 3-aryl-substituted glutaric acid monoester is resolved by salt formation to obtain the target configuration with high chiral purity. The operation is simple, the resolution reagents are readily available and recyclable, and expensive chiral catalysts or harsh enzymatic conditions are avoided, reducing reaction costs and facilitating scale-up production. The present invention can increase the ee value of the target configuration to over 99%, providing an economical, environmentally friendly, simple post-processing, and easy-to-scale production technology route. The 3-aryl-substituted glutaric acid monoester obtained by the present invention can be used as a key chiral intermediate in the synthesis of Orforglipron and ECC5004.

[0117] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for chiral resolution of 3-aryl substituted glutaric acid monoester compounds, characterized in that: The method is: 1) dissolving the substance represented by formula I in an alcohol solvent, adding 4-dimethylaminopyridine, reacting until completion, and post-processing to obtain the intermediate represented by formula IV; 2) dissolving the intermediate represented by formula IV in a solvent, heating, adding a resolving agent, and post-treating to obtain the compound represented by formula III; 3) Repeat step 2) until a compound of formula III having a single stereo configuration and an ee value greater than 99% is obtained; Among them, the substance shown in formula I: The intermediate shown in formula IV: The compound shown in formula III: Where Ar: X is Cl, Br, I, -OTF, -OMs or -OTs; Y is C or N; R 1 is a C1-C6 alkyl group or a benzyl group; R 2 is C1-C6 alkoxy or benzyloxy or -NR 5 R 6 ; R 3 is H, -CNCH2, Boc, Cbz, Bn or Ts; R 4 is H or -CNCH2; R 5 is H, C1-C6 alkyl or phenyl; R 6 is H, C1-C6 alkyl or phenyl.

2. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 1), the alcohol solvent is one of methanol, ethanol, benzyl alcohol and benzene mercaptan.

3. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 1), the amount of 4-dimethylaminopyridine used is 0.01-1 equivalent, and the reaction temperature is 0-80°C.

4. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 2), the temperature is raised to 30-80°C.

5. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 2), the amount of the resolving agent used is 0.1-1.2 equivalents.

6. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 2), the resolving agent is cinchonidine, cinchonine, quinidine, quinine, (R)-α-phenylethylamine, (R)-1-(1-naphthyl)ethylamine or (R)-1-cyclohexylethylamine.

7. The chiral resolution method of a 3-aryl substituted glutaric acid monoester compound according to claim 1, characterized in that: In step 2), the solvent is one or two or more of ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, tetrahydrofuran, isopropanol or dichloromethane.

8. A 3-aryl substituted glutaric acid monoester compound, characterized in that: Prepared by the method according to any one of claims 1 to 7.

9. Application of 3-aryl substituted glutaric acid monoester compounds, characterized in that: Use of a 3-aryl-substituted glutaric acid monoester compound obtained by the chiral resolution method according to any one of claims 1 to 7 or a 3-aryl-substituted glutaric acid monoester compound according to claim 8 in the synthesis of key chiral intermediates of Orforglipron and ECC5004.

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