(S)-3-halo-5-substituted pyridine derivative and asymmetric catalytic synthesis method thereof

Abstract

The invention relates to a (S)-3-halo-5-substituted pyridine derivative and an asymmetric catalytic synthesis method thereof.The compound has a specific chiral center structure and can be used as an important medical intermediate, and the preparation process adopts three-step continuous reaction: firstly, performing Grignard reaction under a low-temperature condition to construct an acetyl framework; then, high-selectivity asymmetric reduction is realized by using a ruthenium catalyst with a specific configuration; and finally, carrying out mild methylation reaction to obtain a target product. By optimizing the catalyst system, the reaction temperature and the material ratio, the optical purity and the reaction yield of the product are remarkably improved, and meanwhile, the common side reaction problem in the traditional process is avoided. The method is easy and convenient to operate, mild in condition and suitable for industrial production, and an efficient and reliable synthesis path is provided for preparation of chiral drug intermediates.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis chemistry, in particular to a kind of (S)-3-halogenated-5-substituted pyridine derivative and its asymmetric catalytic synthesis method. BACKGROUND

[0002] Pyridine derivatives are an important class of heterocyclic compounds, widely used in the fields of medicine, pesticide, material science, etc. Among them, chiral pyridine derivatives have important value in drug molecule design due to their unique stereoconfiguration. However, the existing methods for synthesizing such compounds still have many problems, such as insufficient chiral control, harsh reaction conditions, and complicated steps. At present, the synthesis of chiral pyridine derivatives mainly relies on the following methods: (1) metal-catalyzed asymmetric hydrogenation: such as ruthenium or rhodium-catalyzed asymmetric reduction of pyridine ring. Although this method can construct chiral centers, it usually requires high-pressure hydrogen conditions, and the nitrogen atom in the pyridine ring easily leads to catalyst poisoning and inactivation, affecting the reaction efficiency. (2) asymmetric synthesis induced by chiral auxiliary: by introducing chiral auxiliary groups to control stereoselectivity, but additional steps are required to remove the chiral auxiliary, increasing the process complexity and the overall yield is low. (3) enzyme catalysis or biotransformation: although it has high stereoselectivity, the substrate range is limited, and the reaction conditions (such as pH, temperature) are strict, which is difficult to be applied in large-scale industrialization.

[0003] CN111499558A discloses a method for asymmetric reduction of chiral spiro-bis-boron catalyzed substituted pyridine, which comprises preparing a chiral spiro-bis-boron catalyst: in a nitrogen-filled glove box, a chiral spiro-bis-diene and a diaryl boron hydride compound are sequentially added to a reaction bottle, a solvent is added to the reaction bottle, and stirring is performed to allow them to react fully, thereby obtaining a chiral spiro-bis-boron catalyst; catalytic reduction of pyridine: pyridine, secondary amine, tri-n-butylbenzylammonium chloride, pinacol borane and the solvent are added to the above reaction bottle, and stirring is performed under a nitrogen atmosphere until the reaction is completed; the solvent is removed by reduced pressure distillation, and column chromatography is used to separate to obtain a chiral piperidine; the method uses a chiral spiro-bis-boron catalyst to reduce pyridine, but does not solve the substrate compatibility problem of halogenated pyridine, and the ee value is only 90%-95%.

[0004] CN103351333B discloses an aryl pyridine derivative compound and a preparation method thereof, which comprises a suzuki reaction of halogenated pyridine and substituted phenylboronic acid under the action of inorganic base, with a palladium-containing catalyst as catalyst and a phosphorus compound as ligand, to obtain a disubstituted pyridine compound of formula I; R1 in formula I is aryl or substituted aryl; R2 is selected from halogen, methyl, aryl, aryloxy, arylthio or alkynyl; the preparation method constructs aryl pyridine through Suzuki coupling, requires pre-activation of boronic acid reagent and cannot introduce chiral center.

[0005] CN115038690A discloses a method for manufacturing haloalkyl-substituted pyridine compounds. The method requires high temperature (>100℃) and palladium catalysis, resulting in high industrialization costs.

[0006] Existing technologies suffer from drawbacks such as insufficient chiral control, harsh reaction conditions, and poor substrate compatibility. Therefore, it is of great significance to develop an efficient and highly selective synthetic process for (S)-3-halo-5-substituted pyridine derivatives. Summary of the Invention

[0007] The purpose of this invention is to provide a (S)-3-halo-5-substituted pyridine derivative and its asymmetric catalytic synthesis method, so as to solve the problems of low stereoselectivity, harsh reaction conditions and complicated process steps in the synthesis of chiral pyridine derivatives in the prior art.

[0008] The objective of this invention can be achieved through the following technical solutions: In a first aspect, the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: (S)-3-R1-5-R2-2-(1-R3O-ethyl)pyridine (Formula (I)): R1 is selected from bromine, chlorine, or iodine; R2 is selected from fluorine, cyano, or trifluoromethyl; R3 is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl.

[0009] The (S)-3-halo-5-substituted pyridine derivative provided by this invention has a core structure (S)-3-R1-5-R2-2-(1-R3O-ethyl)pyridine that achieves functional optimization through the synergistic effect of three key sites: the halogen at C-3 provides a subsequent derivatization site, the electron-withdrawing group at C-5 regulates the electron cloud density, and the chiral ethoxy group at C-2 stabilizes the configuration through steric hindrance. In particular, R3 is limited to C1-C4 alkyl, with methyl being the most suitable, which can balance solubility and steric hindrance. This design enables the compound to have both crystallinity and reactivity.

[0010] Preferably, R1 is bromine; R2 is fluorine; and R3 is methyl, with the chemical name: (S)-3-bromo-5-fluoro-2-(1-methoxyethyl)pyridine.

[0011] The present application provides (S)-3-halogenated-5-substituted pyridine derivatives, and (S)-3-bromo-5-fluoro-2-(1-methoxyethyl)pyridine is the most preferred embodiment, the bromine atom provides the best coupling reactivity, the fluorine atom produces a moderate electronic effect, stronger than CN but weaker than CF3, and the methoxy group ensures the stability of chirality while controlling the LogP value in the ideal range of 2.5-3.0. Experiments show that this combination increases the crystallization yield by more than 15%.

[0012] In a second aspect, the present application provides a method for preparing the compound of formula (I) in the first aspect, comprising the following steps: (1) Grignard reaction: reacting the compound of formula (II) 3-R1-2-cyano-5-R2-pyridine with Grignard reagent R4MgX under inert gas protection to obtain the compound of formula (III) 3-R1-2-acetyl-5-R2-pyridine; (2) Asymmetric reduction: reducing the compound of formula (III) to the chiral alcohol (S)-3-R1-2-(1-hydroxyethyl)-5-R2-pyridine of formula (IV) under the action of a ruthenium catalyst; (3) Methylation: reacting the compound of formula (IV) with an alkylating agent R3Y under basic conditions to obtain the compound of formula (I); wherein R1, R2 and R3 are defined as in claim 1, R4 is methyl, X is halogen, and Y is a leaving group.

[0013] The present application provides a method for preparing (S)-3-halogenated-5-substituted pyridine derivatives, which innovatively combines Grignard reaction, asymmetric reduction and methylation in three steps: first, selectively protecting the cyano group and constructing an acetyl group through low-temperature Grignard reaction; then, realizing hydrogen transfer reduction using [(S,S)-TsDPEN-Ru] catalyst, which can directionally bind to the pyridine nitrogen atom through N-p-toluenesulfonyl, making the reduction face selective to 99%; finally, methylation under weak base conditions to avoid racemization of the chiral center. The key to improving the total yield to 75% in the three steps is to directly use the intermediates without purification.

[0014] Preferably, in step (1), the Grignard reagent is methyl magnesium iodide, the reaction solvent is anhydrous tetrahydrofuran, the reaction temperature is -10℃-5℃, and the molar ratio of Grignard reagent to the compound of formula (II) is (1.0-1.2):1.

[0015] Preferably, in step (2), the ruthenium catalyst is (S,S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium (II) chloride, the reduction system is a mixed solution of formic acid and triethylamine with a volume ratio of (3-5):1, and the catalyst is used in an amount of 0.1%-5% of the molar amount of the substrate, and the reaction temperature is 45℃-65℃.

[0016] The application provides a preparation method of (S)-3-halogenated-5-substituted pyridine derivatives, which is carried out in an asymmetric reduction system, and a [(S, S)-TsDPEN-Ru] catalyst, in which the steric hindrance of the isopropyl phenyl group forces the substrate to approach the ruthenium center from the Re side, and when formic acid / triethylamine (5:2) is used as a hydrogen source, the triethylamine can neutralize the generated CO2, preventing bubbles from causing catalyst deactivation, and the optimal temperature range of 45-65 DEG C enables the reaction to be completed within 3 hours, and the ee value is stable at 99% ± 0.5%.

[0017] Preferably, in step (3), the alkylating agent is dimethyl sulfate, methyl iodide or methyl bromide, potassium tert-butoxide is used as a base, the molar ratio of the base to the compound of formula (IV) is (2.0-2.5):1, and the reaction solvent is 2-methyltetrahydrofuran.

[0018] Preferably, the enantiomeric excess value of the compound of formula (IV) obtained in step (2) is greater than or equal to 98% ee, which is determined by chiral HPLC detection.

[0019] The application provides a preparation method of (S)-3-halogenated-5-substituted pyridine derivatives, which realizes mild methylation in 2-MeTHF by using KOtBu (2.0-2.5 equivalents), and the advantages are as follows: ① the steric hindrance of tert-butoxy prevents beta-elimination; ② the high boiling point of 2-MeTHF allows room temperature reaction, and compared with THF, the solvent loss is reduced by 50%; ③ when dimethyl sulfate is used as a methylation agent, its bifunctional characteristics can be precisely controlled, and the proportion of only monomethylated product is greater than 95%; wherein, the guarantee of greater than or equal to 98% ee is derived from the synergistic control of three steps: the regioselectivity of Grignard reaction (>99:1), the face selectivity of ruthenium catalyst (99% ee) and the protection effect of KOtBu on the configuration during methylation. When chiral HPLC uses an AD-H column, n-hexane / isopropyl alcohol (90:10) can make the retention time difference between (S)-type and (R)-type reach 2.3 minutes, so that the detection accuracy is ensured to be ± 0.1%.

[0020] Preferably, the reaction products of steps (1), (2) and (3) are optionally directly used for the next step reaction without isolation and purification.

[0021] The application provides a preparation method of (S)-3-halogenated-5-substituted pyridine derivatives, and the feasibility of directly using intermediates without isolation is based on: ① the Mg 2 ⁺ salt quenched after Grignard reaction can be complexed with formic acid; ② the water (<3%) produced by reduction can be removed by 2-MeTHF azeotrope; ③ the excess KOtBu during methylation can neutralize the acidic impurities in the previous step. This design shortens the production cycle by 60% and reduces the solvent consumption by 40%.

[0022] In a third aspect, the present application provides a method for purifying the compound of the first aspect, comprising the following steps: (a) extracting the reaction solution with ethyl acetate or dichloromethane; (b) drying the organic phase with anhydrous sodium sulfate; (c) removing the solvent by distillation under reduced pressure to obtain a crude product; (d) further purifying by column chromatography or crystallization.

[0023] The purification method of the (S)-3-halogenated-5-substituted pyridine derivative provided by the present application can remove polar and non-polar impurities respectively by alternating extraction with ethyl acetate / dichloromethane, and the moisture is controlled to be less than 50 ppm when dried with anhydrous Na2SO4 to prevent product hydrolysis. Gradient heating is used in the distillation under reduced pressure to avoid bumping, so that the purity of the crude product is more than 92%.

[0024] Preferably, the chiral HPLC detection uses a Chiralpak AD-H column with a volume ratio of n-hexane to isopropanol (85-95):(5-15) as the mobile phase, and the flow rate is 0.8-1.2 mL / min.

[0025] The purification method of the (S)-3-halogenated-5-substituted pyridine derivative provided by the present application uses HPLC detection, and the amylose stationary phase of the Chiralpak AD-H column produces π-π stacking with the pyridine ring. The n-hexane / isopropanol forms the best separation degree at a flow rate of 1.0 mL / min, and the ratio of 85:15 to 95:5 can be adjusted to adapt to the polarity difference of different R1 / R2 substituents, ensuring the accuracy of detection of all derivatives.

[0026] The beneficial effects of the present application are: (1) The (S)-3-halogenated-5-substituted pyridine derivative provided by the present application realizes efficient construction of the C-2 chiral center through the (S,S)-TsDPEN-Ru catalyst, with an ee value of ≥98%, which is significantly better than the prior art; (2) The preparation method of the (S)-3-halogenated-5-substituted pyridine derivative provided by the present application has a total yield of ≥75% in three steps, which is more than 50% higher in efficiency than the traditional 5-6 step process; (3) The preparation method of the (S)-3-halogenated-5-substituted pyridine derivative provided by the present application avoids high-pressure hydrogenation and heavy metal residues, and uses a 2-methyltetrahydrofuran and formic acid / triethylamine reduction system, which meets the requirements of green chemistry. DETAILED DESCRIPTION

[0027] To further illustrate the technical means and effects taken by the present application to achieve the predetermined object, the following embodiments are combined to illustrate the specific embodiments, structures, features and effects of the present application in detail.

[0028] In one embodiment, the present application provides a (S)-3-halogenated-5-substituted pyridine derivative or a pharmaceutically acceptable salt thereof, having the structure of formula (I): (S)-3-R1-5-R2-2-(1-R3O-ethyl)pyridine, wherein R1 is selected from bromine, chlorine or iodine; R2 is selected from fluorine, cyano or trifluoromethyl; R3 is selected from methyl, ethyl, n-propyl, isopropyl or n-butyl; preferably, R1 is bromine, R2 is fluorine, and R3 is methyl, i.e. (S)-3-bromo-5-fluoro-2-(1-methoxyethyl)pyridine.

[0029] In another embodiment, the present application provides a preparation and purification method of the (S)-3-halogenated-5-substituted pyridine derivative, which specifically comprises: (1) Grignard reaction: under inert gas protection, a compound of formula (II) 3-R1-2-cyano-5-R2-pyridine is reacted with a Grignard reagent R4MgX in anhydrous tetrahydrofuran at -10°C to 5°C, the molar ratio of the Grignard reagent to the compound of formula (II) is 1.0:1 to 1.2:1, to obtain a compound of formula (III) 3-R1-2-acetyl-5-R2-pyridine, wherein R4 is methyl and X is halogen; (2) asymmetric reduction: the compound of formula (III) is reacted in a mixed solution of a ruthenium catalyst [(S,S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium (II) chloride] and formic acid and triethylamine (volume ratio 3:1 to 5:1) at 45°C to 65°C, the catalyst is used in an amount of 0.1% to 5% of the molar amount of the substrate, to obtain a compound of formula (IV) (S)-3-R1-2-(1-hydroxyethyl)-5-R2-pyridine, with an enantiomeric excess value ≥98% ee; (3) methylation: the compound of formula (IV) is reacted with an alkylating agent R3Y in the presence of potassium tert-butoxide in 2-methyltetrahydrofuran, the molar ratio of the base to the compound of formula (IV) is 2.0:1 to 2.5:1, to obtain a compound of formula (I), wherein Y is a leaving group; (4) purification: the reaction solution is extracted with ethyl acetate or dichloromethane, the organic phase is dried with anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product is purified by column chromatography or crystallization, and the final product is detected for optical purity by chiral HPLC using a Chiralpak AD-H chromatographic column with n-hexane and isopropanol (volume ratio 85:15 to 95:5) as the mobile phase at a flow rate of 0.8 to 1.2 mL / min; wherein the reaction products of steps (1)-(3) are optionally purified without separation for the next step.

[0030] Example 1 The embodiment provides a preparation and purification method of (S)-3-bromo-5-fluoro-2-(1-methoxyethyl)pyridine, and specifically comprises the following steps: (1) 3-bromo-2-cyano-5-fluoropyridine 1.0 mmol is dissolved in anhydrous tetrahydrofuran 10 mL, and a 3M methyl magnesium bromide solution 1.1 mmol is added dropwise under nitrogen protection at-5 ℃; after dropwise addition is completed, the reaction is carried out at 0 ℃ for 1 hour; after the reaction is completed, 5 mL of water is added for quenching, the organic phase is separated, the water phase is extracted with ethyl acetate 10 mL twice; the combined organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-bromo-5-fluoro-2-acetylpyridine, with a yield of 95%; (2) asymmetric reduction: the above product 1.0 mmol is dissolved in a formic acid and triethylamine mixed solution 4:1 ratio 5 mL, and S,S-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium chloride 0.5 mol% is added; the reaction is carried out at 55 ℃ for 3 hours; after the reaction is completed, 20 mL of ethyl acetate is added for dilution, filtration is carried out, the filtrate is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain S-3-bromo-5-fluoro-2-1-hydroxyethylpyridine, with a yield of 88% and an ee value of 99%; (3) methylation: the above alcohol 1.0 mmol is dissolved in 2-methyltetrahydrofuran 5 mL, 2.2 mmol of potassium tert-butoxide and 1.2 mmol of dimethyl sulfate are added, and the reaction is carried out at room temperature for 1 hour; 10 mL of water is added for quenching, and the reaction is extracted with ethyl acetate 20 mL twice; the combined organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure; the crude product is purified by silica gel column chromatography, petroleum ether and ethyl acetate 5:1 are used, and the target product is obtained, with a yield of 76%.

[0031] Example 2 The embodiment provides a preparation and purification method of (S)-3-chloro-5-cyano-2-(1-ethoxyethyl)pyridine, and specifically comprises the following steps: (1) Grignard reaction: 3-chloro-2-cyano-5-cyanopyridine 1.0 mmol is dissolved in anhydrous tetrahydrofuran 10 mL, and a 3M methylmagnesium chloride solution 1.2 mmol is added dropwise under nitrogen protection at-10 ℃; after dropwise addition is completed, the reaction is carried out at-5 ℃ for 1.5 hours; after the reaction is completed, saturated ammonium chloride solution 5 mL is added for quenching, the organic phase is separated, the aqueous phase is extracted with dichloromethane 10 mL twice; the combined organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-chloro-5-cyano-2-acetylpyridine, with a yield of 93%; (2) asymmetric reduction: the above product 1.0 mmol is dissolved in a formic acid and triethylamine mixed solution 3:1 ratio 5 mL, and S,S-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium chloride 0.1 mol% is added; the reaction is carried out at 45 ℃ for 5 hours; after the reaction is completed, dichloromethane 20 mL is added for dilution, filtration is carried out, the filtrate is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain S-3-chloro-5-cyano-2-1-hydroxyethylpyridine, with a yield of 85% and an ee value of 98%; (3) methylation: the above alcohol 1.0 mmol is dissolved in 2-methyltetrahydrofuran 5 mL, potassium tert-butoxide 2.5 mmol and iodoethane 1.5 mmol are added, and the reaction is carried out at room temperature for 1.5 hours; water 10 mL is added for quenching, dichloromethane 20 mL is extracted twice; the combined organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure; the crude product is purified by silica gel column chromatography, petroleum ether and ethyl acetate 4:1 are used, and the target product is obtained, with a yield of 72%.

[0032] Example 3 The embodiment provides a preparation and purification method of (S)-3-iodo-5-trifluoromethyl-2-(1-isopropoxyethyl) pyridine, and specifically comprises the following steps: (1) Grignard reaction: 3-iodo-2-cyano-5-trifluoromethyl pyridine 1.0 mmol is dissolved in anhydrous tetrahydrofuran 10 mL, and a 3M methyl magnesium bromide solution 1.0 mmol is added dropwise at 0 DEG C under nitrogen protection; after dropwise addition is completed, 5 DEG C reaction is carried out for 0.5 hours; after reaction is completed, water 5 mL is added for quenching, an organic phase is separated, and an aqueous phase is extracted with ethyl acetate 10 mL twice; the organic phase is combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-iodo-5-trifluoromethyl-2-acetyl pyridine, with a yield of 90%; (2) asymmetric reduction: the above product 1.0 mmol is dissolved in a formic acid and triethylamine mixed solution 5:1 ratio 5 mL, and S,S-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium chloride 5 mol% is added; 65 DEG C reaction is carried out for 2 hours; after reaction is completed, ethyl acetate 20 mL is added for dilution, filtration is carried out, the filtrate is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain S-3-iodo-5-trifluoromethyl-2-1-hydroxyethyl pyridine, with a yield of 82% and an ee value of 98.5%; (3) methylation: the above alcohol 1.0 mmol is dissolved in 2-methyl tetrahydrofuran 5 mL, potassium tert-butoxide 2.0 mmol and bromoisopropane 1.0 mmol are added, and room temperature reaction is carried out for 2 hours; water 10 mL is added for quenching, ethyl acetate 20 mL is extracted twice; the organic phase is combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure; the crude product is purified by silica gel column chromatography, petroleum ether and ethyl acetate 3:1 ratio is used, and the target product is obtained, with a yield of 70%.

[0033] Example 4 The embodiment differs from example 1 only in that the Grignard reaction temperature is 5 DEG C, and other components and parameters remain unchanged.

[0034] Example 5 The embodiment differs from example 1 only in that the Grignard reaction temperature is -10 DEG C, and other components and parameters remain unchanged.

[0035] Example 6 The embodiment differs from example 1 only in that the amount of potassium tert-butoxide used in the methylation step is 2.5 mmol, and other components and parameters remain unchanged.

[0036] Example 7 The embodiment differs from example 1 only in that 1 mol% of 2,2'-bipyridine is additionally added as a synergistic ligand in the catalytic system in the asymmetric reduction step, and other components and parameters remain unchanged.

[0037] Example 8 The difference between this example and Example 1 is only that the methylation step uses a 2-methyltetrahydrofuran / acetonitrile (3:1) mixed solvent system, and other components and parameters remain unchanged.

[0038] Example 9 The difference between this example and Example 1 is only that the asymmetric reduction stage uses a gradient temperature strategy, i.e. 45°C for 1 hour, then raised to 60°C for 2 hours, and other components and parameters remain unchanged.

[0039] Comparative Example 1 The difference between this comparative example and Example 1 is only that the asymmetric reduction step uses a (R,R)-configuration TsDPEN ligand, and other components and parameters remain unchanged.

[0040] Comparative Example 2 The difference between this comparative example and Example 1 is only that the methylation step uses pure acetonitrile as the solvent, and other components and parameters remain unchanged.

[0041] Comparative Example 3 The difference between this example and Example 1 is only that the methylation step uses 2.5 mmol of potassium tert-butoxide, and other components and parameters remain unchanged.

[0042] Comparative Example 4 The difference between this comparative example and Example 1 is only that [RuCl2(p-cymene)]2 is used instead of the original catalyst, and other components and parameters remain unchanged.

[0043] Comparative Example 5 The difference between this comparative example and Example 1 is only that 1 mol% of lithium chloride is added as an additive in the Grignard reaction, and other components and parameters remain unchanged.

[0044] The reaction indicators of Examples 1-9 and Comparative Examples 1-5 are shown in Table 1.

[0045] Table 1

[0046] Note: Total yield = Grignard yield x reduction yield x methylation yield / 10000, ee value change reflects stereoselectivity Through systematic analysis and comparison of the above experimental data, we can draw the following important conclusions: (1) The synthesis method of (S)-3-halogenated-5-substituted pyridine derivatives provided by the present application has obvious technical advantages. The total yield of examples 1-9 is stably in the range of 51.7%-66.9%, and the ee value is maintained above 98%, which fully proves the reliability and reproducibility of the process. In contrast, the total yield of comparative examples 1-5 is generally low (<55%), and the key indicator ee value in comparative example 1 is as low as 15%, which clearly shows that the (S,S)-TsDPEN-Ru catalyst system, the accurate control of the reaction temperature range (-10℃ to 5℃), and the optimized material ratio (such as Grignard reagent 1.0-1.2 equivalents) are the key factors to ensure the high efficiency and high selectivity of the reaction.

[0047] (2) The study on the influence of reaction temperature shows that the Grignard reaction has the best effect in the range of -5℃ to 0℃. Specifically, although the reaction rate of example 4 (5℃) is accelerated, the yield is reduced to 90% due to the increase of by-products; and although the yield of example 5 (-10℃) is slightly increased to 96%, the reaction time is prolonged by 50%. This temperature effect verifies the necessity of limiting the reaction temperature range in claim 4.

[0048] (3) The optimization study of material ratio shows that the amount of potassium tert-butoxide in the methylation step is most suitable when controlled in the range of 2.0-2.5 equivalents. The methylation yield of example 6 (2.5 equivalents) is increased to 78%, while the methylation yield of comparative example 3 (3.0 equivalents) is decreased to 65%, which shows that excessive base will cause the increase of side reactions, which is completely consistent with the protection range of claim 6.

[0049] (4) The process optimization scheme shows good improvement effect. Example 7 (adding 1mol% bipyridine) increases the reduction yield to 92%; example 8 (MeTHF / acetonitrile mixed solvent) increases the methylation yield to 80%; and example 9 (gradient temperature rise) increases the reduction yield to 90%. These improvements not only verify the rationality of the dependent claims, but also indicate the direction for subsequent process optimization.

[0050] (5) The comparative example study strongly proves the necessity of the technical scheme of the present application. Comparative example 1 ((R,R)-ligand) causes the ee value to be completely out of control; comparative example 2 (pure acetonitrile) reduces the methylation yield to 60%; comparative example 4 ([RuCl2(p-cymene)]2 catalyst) reduces the reduction yield to 75%; and comparative example 5 (adding LiCl) reduces the Grignard yield to 80%. These results fully show that there is a close synergistic relationship between the technical features.

[0051] (6) The comprehensive evaluation shows that the standard process conditions of Example 1 (total yield 63.5%, ee value 99%) have reached the industry-leading level, and Example 8 further improves the total yield to 66.9% by optimizing the mixed solvent, showing excellent prospects for industrial application.

[0052] The present application successfully realizes the efficient synthesis of high stereoselectivity pyridine derivatives through an innovative catalytic system and optimized process conditions. The combination of a chiral catalyst with a specific configuration and precise control of reaction parameters significantly improves the optical purity and reaction yield of the product, while avoiding the common side reactions and racemization problems in traditional methods. This technical solution not only solves the problems of poor selectivity and complicated steps in existing processes, but also provides a reliable and environmentally friendly synthesis path for the industrial production of chiral drug intermediates.

[0053] The above is only a preferred embodiment of the present application, not any form of limitation on the present application, although the present application has been disclosed as above with a preferred embodiment, however, not to limit the present application, any person skilled in the art, within the scope of the technical solution of the present application, can make some changes or modifications to the above disclosed technical content to make equivalent embodiments with equivalent changes, but as long as it does not deviate from the technical solution content of the present application, any concise modification, equivalent change and modification made to the above embodiments according to the technical essence of the present application are still within the scope of the technical solution of the present application.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: (S)-3-R1-5-R2-2-(1-R3O-ethyl)pyridine (Formula (I)) Its features are: R1 is selected from bromine, chlorine, or iodine; R2 is selected from fluorine, cyano, or trifluoromethyl; R3 is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl.

2. The compound of claim 1, wherein: R1 is bromine; R2 is fluorine; R3 is methyl, and its chemical name is (S)-3-bromo-5-fluoro-2-(1-methoxyethyl)pyridine.

3. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that, Includes the following steps: (1) Grignard reaction: Compound (II) 3-R1-2-cyano-5-R2-pyridine was reacted with Grignard reagent R4MgX under inert gas protection to obtain compound (III) 3-R1-2-acetyl-5-R2-pyridine; (2) Asymmetric reduction: The compound of formula (III) is reduced to the chiral alcohol (S)-3-R1-2-(1-hydroxyethyl)-5-R2-pyridine of formula (IV) under the action of ruthenium catalyst; (3) Methylation: The compound of formula (IV) is reacted with the alkylating agent R3Y under basic conditions to obtain the compound of formula (I); The definitions of R1, R2, and R3 are the same as in claim 1, R4 is methyl, X is halogen, and Y is a leaving group.

4. The method of claim 3, wherein, In step (1), the Grignard reagent is methyl magnesium iodide, the reaction solvent is anhydrous tetrahydrofuran, the reaction temperature is -10℃ to 5℃, and the molar ratio of the Grignard reagent to the compound of formula (II) is (1.0-1.2):

1.

5. The method of claim 3, wherein, In step (2), the ruthenium catalyst is (S,S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine ruthenium(II) chloride, the reduction system is a mixed solution of formic acid and triethylamine with a volume ratio of (3-5):1; the amount of catalyst used is 0.1%-5% of the molar amount of the substrate, and the reaction temperature is 45℃-65℃.

6. The method of claim 3, wherein, In step (3), the alkylating agent is dimethyl sulfate, iodomethane or bromomethane, potassium tert-butoxide is used as the base, the molar ratio of the base to the compound of formula (IV) is (2.0-2.5):1, and the reaction solvent is 2-methyltetrahydrofuran.

7. The method according to any one of claims 3-6, characterized in that, The enantiomeric excess value of the compound of formula (IV) obtained in step (2) is ≥98% ee, which is determined by chiral HPLC detection.

8. The method of claim 3, wherein, The reaction products of steps (1), (2), and (3) may optionally be used directly in the next step of the reaction without separation and purification.

9. A method of purifying a compound according to any one of claims 1-2, characterized in that, Includes the following steps: (a) Extract the reaction solution with ethyl acetate or dichloromethane; (b) Dry the organic phase with anhydrous sodium sulfate; (c) Remove the solvent by vacuum distillation to obtain the crude product; (d) Further purification by column chromatography or crystallization.

10. The purification method of claim 9, wherein, The chiral HPLC detection was performed using a Chiralpak AD-H column with a mobile phase of (85-95):(5-15) hexane to isopropanol at a flow rate of 0.8-1.2 mL / min.

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