Alpha-carbonyl gamma-chiral methyl carboxylate compound and analogue thereof, and preparation method and application of alpha-carbonyl gamma-chiral methyl carboxylate compound and analogue thereof

Abstract

The invention discloses an alpha-carbonyl gamma-chiral methyl carboxylate compound and an analogue thereof as well as a preparation method and application of the alpha-carbonyl gamma-chiral methyl carboxylate compound. The alpha-carbonyl gamma-chiral methyl carboxylate compound comprises a compound as shown in a formula I or a formula II, wherein R1 is selected from H, phenyl, t-butyloxycarboryl or meta-position cyano substituted phenyl; r2 is selected from H, alkyl with 1-6 carbon atoms, hydroxyl, tertiary butyl, benzyl or benzhydryl. According to the alpha-carbonyl gamma-chiral methyl carboxylate compound provided by the invention, ester groups with different steric hindrances are selected, so that a Dieckmann condensation reaction with high regioselectivity is realized under a low-temperature condition; the product obtained by the reaction does not need to be subjected to chiral resolution to obtain a single component, the purification step is simplified, and the method is suitable for being widely used in actual production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an α-carbonylγ-chiral methyl carboxylic acid ester compound and its analogues, their preparation methods and applications. Background Technology

[0002] α-Carbonyl-γ-chiral methyl carboxylate esters are the molecular basis and key structure of many bioactive drug molecules. Intramolecular Dieckmann ester condensation is one of the effective methods for their synthesis. The literature "High-yield condensation method for preparation of carbocyclic or N-containing heterocyclic β-keto esters used in situ activated sodium hydride in dimethyl sulphoxide" reports the preparation of α-carbonyl-γ-chiral methyl carboxylate esters based on a six-membered ring skeleton via Dieckmann ester condensation. The synthetic reaction formula is as follows:

[0003]

[0004] The above process results in two cyclization pathways, yielding two components: α-carbonylγ-methylcarboxylate and α-carbonylα'-methylcarboxylate, in a near 1:1 ratio. Each component also includes two corresponding isomers. Due to their structural similarity, it is difficult to obtain a single component through simple separation methods; chiral resolution is required to obtain a single product.

[0005] The literature "High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydridein dimethyl sulphoxide" reports the synthesis of α-carbonyl carboxylic acid esters based on a five-membered ring skeleton using Dieckmann ester condensation with different ester groups. The molecular formula does not contain a γ-chiral methyl group. The reaction formula is as follows:

[0006]

[0007] Furthermore, the base used in the relevant reactions in the aforementioned literature is sodium hydride (NaH), and the solvent is DMSO, which is not easy to scale up and poses certain risks. Summary of the Invention

[0008] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention proposes an α-carbonylγ-chiral methyl carboxylic acid ester compound and its analogues.

[0009] The present invention also proposes a method for preparing α-carbonyl-γ-chiral methyl carboxylic acid ester compounds.

[0010] The present invention also proposes an analogue of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound and its salt.

[0011] The present invention also proposes a method for preparing analogs of α-carbonyl-γ-chiral methyl carboxylic acid esters and their salts.

[0012] The present invention also proposes applications of the above-mentioned compounds or similar substances.

[0013] According to a first aspect of the present invention, an α-carbonylγ-chiral methyl carboxylic acid ester compound and its salt, its tautomer, or a salt of its tautomer, wherein the α-carbonylγ-chiral methyl carboxylic acid ester compound comprises a compound as shown in Formula I or Formula II; the structural formula of Formula I or Formula II is as follows:

[0014]

[0015] Among them, R 1 Selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups; R 2 It is selected from H, alkyl with 1 to 6 carbon atoms, hydroxyl, tert-butyl, benzyl or diphenylmethyl.

[0016] In some embodiments of the present invention, the α-carbonylγ-chiral methyl carboxylic acid ester compound comprises one of the following formulas:

[0017]

[0018] According to a second aspect of the present invention, a method for preparing α-carbonyl-γ-chiral methyl carboxylic acid ester compounds is provided, the method comprising the following steps:

[0019] α-carbonyl-γ-chiral methyl carboxylic acid esters were obtained by reacting compounds of formula (I-1) or (I-2) under alkaline conditions.

[0020] The α-carbonyl-γ-chiral methyl carboxylic acid esters include compounds as shown in Formula I or Formula II and their derivatives; the structural formulas of Formula I or Formula II are as follows:

[0021]

[0022] The structural formulas of compounds (I-1) and (I-2) are as follows:

[0023]

[0024] In the formula, R 1 Selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups; R 2 Selected from methyl, tert-butyl, benzyl, and diphenylmethyl.

[0025] In some embodiments of the present invention, the reaction includes at least one of the following conditions:

[0026] 1) The reaction is carried out in solution, and the method further includes the step of dissolving the raw material in an organic solvent to prepare a solution, wherein the organic solvent includes at least one of tetrahydrofuran, toluene and 1,4-dioxane;

[0027] 2) The alkaline conditions are generated by adding an alkali, wherein the alkali includes at least one of potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino and lithium bistrimethylsilylamino.

[0028] Preferably, the alkali is added in the form of an alkaline solution, wherein the concentration of the alkali in the alkaline solution is 0.2–2 mol / L;

[0029] Preferably, the molar ratio of the compound of formula (I-1) or the compound of formula (I-2) to the base is 1:(0.5-2).

[0030] 3) The reaction time is 2–8 hours;

[0031] 4) The reaction temperature is -80℃ to -60℃.

[0032] In some preferred embodiments of the present invention, the concentration of alkali in the alkaline solution is 0.8 to 1.2 mol / L.

[0033] In some more preferred embodiments of the present invention, the concentration of alkali in the alkaline solution is 1 mol / L.

[0034] In some preferred embodiments of the present invention, the molar ratio of the compound of formula (I-1) or the compound of formula (I-2) to the base is 1:(1 to 1.5).

[0035] In some more preferred embodiments of the present invention, the molar ratio of the compound of formula (I-1) or the compound of formula (I-2) to the base is 1:1.2.

[0036] In some preferred embodiments of the present invention, the reaction temperature is -75°C to -65°C.

[0037] In some more preferred embodiments of the present invention, the reaction temperature is -70°C.

[0038] According to a third aspect of the invention, an analogue of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, a salt thereof, a tautomer thereof, or a salt thereof, wherein the structural formula of the analogue is shown in one of the following formulas:

[0039]

[0040] In the formula, R 1 Phenyl groups selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups;

[0041] R 2 Selected from H, alkyl groups with 1 to 6 carbon atoms, hydroxyl groups, tert-butyl groups, benzyl groups, or diphenylmethyl groups.

[0042] R3 is selected from H, OTf, or amino groups;

[0043] R4 is selected from alkyl, pyridyl, halophenyl, phenylenediamine or haloaniline groups with 1 to 6 carbon atoms;

[0044] R5 is selected from halogens, nitrile groups, or alkyl groups with 1 to 4 carbon atoms;

[0045] R6 is selected from alkyl groups having 1 to 6 carbon atoms;

[0046] R7 is selected from benzyl formate group;

[0047] R8 is selected from Boc;

[0048] R9 is selected from H or alkyl groups with 1 to 4 carbon atoms.

[0049] Throughout the text, R1 and R2 refer to the same thing.

[0050] In some embodiments of the present invention, the salt is selected from hydrochloride, sulfate or nitrate.

[0051] In some preferred embodiments of the present invention, analogues of the α-carbonyl-γ-chiral methyl carboxylic acid ester compound and their salts, tautomers thereof, or salts of their tautomers comprise one of the following formulas:

[0052]

[0053] According to a fourth aspect of the present invention, a method for preparing analogs of α-carbonyl-γ-chiral methyl carboxylic acid esters and their salts, tautomers thereof, or salts of their tautomers is provided, the method comprising the following steps:

[0054] The α-carbonylγ-chiral methyl carboxylic acid esters described in the first aspect of the present invention are used as raw materials for reducing reactions and / or salt formation reactions.

[0055] In some embodiments of the present invention, the reaction includes at least one of the following conditions:

[0056] 1) The reaction is carried out in solution, and the method further includes the step of preparing a solution by dissolving the substance in an organic solvent, wherein the organic solvent includes at least one of tetrahydrofuran, methanol, ethyl acetate, dichloromethane and ethanol;

[0057] 2) The reducing reaction includes reducing hydrogenation, reducing alkylation, reducing amination, or reducing cyclization;

[0058] 3) The reaction time is 16–24 hours;

[0059] 4) The reaction temperature is 20℃~110℃.

[0060] According to a fifth aspect of the present invention, the use of a compound in the preparation of a pyrimidinone and piperidine bioactive drug is provided, said compound being selected from α-carbonylγ-chiral methyl carboxylate compounds and their salts, tautomers thereof or salts thereof as described in the first aspect of the present invention, or analogs of α-carbonylγ-chiral methyl carboxylate compounds and their salts, tautomers thereof or salts thereof as described in the third aspect of the present invention.

[0061] The present invention has at least the following beneficial effects:

[0062] 1) The method for preparing α-carbonyl-γ-chiral methyl carboxylic acid esters provided by the present invention achieves highly regioselective Dieckmann condensation reaction at low temperature by selecting ester groups with different steric hindrances; the product obtained by the reaction does not require chiral resolution to obtain a single component, thus simplifying the purification steps.

[0063] 2) The preparation method of α-carbonylγ-chiral methyl carboxylic acid esters provided by the present invention uses inexpensive and readily available raw materials and adopts simple reaction steps to obtain high-purity gram-scale R-configuration α-carbonylγ-chiral methyl carboxylic acid esters.

[0064] 3) The preparation method of α-carbonylγ-chiral methyl carboxylic acid esters provided by this invention uses a reaction temperature that is much lower than that of existing technologies, ensuring safety during the reaction process. Detailed Implementation

[0065] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0066] Materials and Definitions

[0067] In the following examples and comparative examples, the analytical data of the samples were determined by the following instruments: nuclear magnetic resonance was measured by an AVANCENEO 500 NMR spectrometer, with tetramethylsilane (TMS) as an internal standard, chemical shift in ppm, and coupling constant in Hz; mass spectrometry was measured by a G6125C mass spectrometer; and liquid chromatography-mass spectrometry was measured by an Agilent G6125 / 35 mass spectrometer.

[0068] In the following examples and comparative examples, the silica gel used for column chromatography was 200-300 mesh (produced by Titan); the silica gel plate used for TLC (thin-layer chromatography) was the HSGF-254 type thin-layer chromatography pre-prepared plate produced by Yantai Chemical Plant; the boiling range of petroleum ether was 60-90°C; and ultraviolet light and an iodine tank were used for color development.

[0069] Unless otherwise stated, all conventional reagents and chemicals used in the following examples and comparative examples were purchased from Bidex, Energie, and Titan. Reagents and solvents used in the experiments were handled according to the specific reaction conditions.

[0070] Example 1

[0071] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 1a, the structural formula of which is shown below:

[0072]

[0073] The synthetic route is shown below:

[0074]

[0075] Specifically, the following steps are included:

[0076] 1) Add 35g (228mmol) of (R)-3-aminobutyric acid methyl hydrochloride, 33.4mL (228mmol) of tert-butyl acrylate, 300mL of dichloromethane (DCM), 38mL (273mmol) of triethylamine (Et3N) and 3.4mL (22.8mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to a flask;

[0077] The reaction system was refluxed at 40°C for 48 hours;

[0078] After the reaction was completed, water (100 mL) was added for dilution, DCM was extracted three times, the organic phases were combined and washed with saturated NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 45.0 g of crude product 3, which is a pale yellow oily liquid with a crude yield of 81%.

[0079] 2) Dissolve 34.0g of crude product 3 (139mmol) obtained in step 1) and 24.0g of 3-cyanobenzaldehyde (183mmol) in 300mL of anhydrous DCM, slowly add 10.5mL of glacial acetic acid (183mmol), and stir at room temperature for 2h.

[0080] 44.2 g NaBH(OAc)3 (209 mmol) was added in portions, and the reaction was carried out overnight at room temperature.

[0081] After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and DCM was used for extraction. The organic layers were combined and washed with saturated NaCl. The mixture was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 15.5 g of pale yellow oily liquid 4, i.e. intermediate 4, with a yield of 31%.

[0082] NMR data for intermediate 4: 1 H NMR (500MHz, CDCl3) δ7.61(s,1H),7.52(d,J=1.7Hz,1H),7.51(d,J=1.7Hz,1H),7.38(t,J=7.7Hz,1H),3.67(s,3H),3.65(d,J=14.7Hz,1H), 3.52(d,J=14.7Hz,1H),3.24(m,1H),2.76–2.64(m,2H),2.55(dd,J=14.5,7.6Hz,1H),2.40–2.21(m,3H),1.43(s,9H),1.07(d,J=6.6Hz,3H).

[0083] 3) Dissolve 72.0 mg of intermediate 4 (0.2 mmol) obtained in step 2) in 2.0 mL of anhydrous tetrahydrofuran (THF), add 240 μL of THF solution containing 1 mol / L potassium tert-butoxide (tBuOK) dropwise to the system at -70 °C, and stir at -70 °C for 3 h.

[0084] LC-MS monitoring showed that the molar ratio of compound 1a to compound 1b was greater than 50:1. After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate, and extracted three times with 5 mL of water. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) gave 50.7 mg of pale yellow solid 1, with a yield of 77%.

[0085] TLC results for compound 1a: Rf = 0.4;

[0086] LC-MS results for compound 1a: m / z 329.3 [M+H] + ;

[0087] NMR data of compound 1a: 1 H NMR (500MHz, CDCl3) δ12.12(s,1H),7.66(s,1H),7.58(d,J=7.8Hz,1H),7.54(d,J=7.9Hz,1H),7.42(t,J=7.8Hz,1H),3.74(d,J=13.9Hz,1H),3. 56(d,J=13.9Hz,1H),3.12(s,2H),2.99(m,1H),2.55(dd,J=17.7,5.7Hz,1H),2.06(dd,J=17.9,4.4Hz,1H),1.45(s,9H),1.08(d,J=6.6Hz,3H);

[0088] TLC results for compound 1b: Rf = 0.3;

[0089] LC-MS results for compound 1b: m / z 287.2 [M+H] + .

[0090] 4) Gram-level preparation of compound 1a: 12.4 g of crude product 3 (34.4 mmol) obtained in step 1) was dissolved in 340 mL of anhydrous THF and placed at -70 °C. 41.3 mL of THF solution containing 1 mol / L tBuOK was added dropwise to the system and stirred at -70 °C for 3 h.

[0091] LC-MS monitoring showed that the molar ratio of compound 1a to compound 1b was 15.8:1. After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate, and extracted three times with water (50 mL). The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 15:1) to give 6.2 g of pale yellow solid 1a, with a yield of 55%.

[0092] Example 2

[0093] This embodiment provides a method for preparing an α-carbonylγ-chiral methyl carboxylic acid ester compound, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 5a, the structural formula of which is shown below:

[0094]

[0095] The synthetic route is shown below:

[0096]

[0097] Specifically, the following steps are included:

[0098] 1) Add 4.6 g (30 mmol) of (R)-3-aminobutyric acid methyl ester hydrochloride, 4.9 g (30 mmol) of benzyl acrylate, 60 mL of DCM, 5 mL (36 mmol) of Et3N and 0.8 mL (6.8 mmol) of DBU to a flask; reflux the reaction system at 40 °C for 24 h;

[0099] After the reaction was completed, water was added for dilution, and the product was extracted three times with DCM. The organic phases were combined and washed with saturated NaCl. The product was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8.0 g of crude pale yellow oily liquid product 6, with a crude yield of 96%.

[0100] 2) Dissolve 8.0g of crude product 6 (28.7mmol) obtained in step 1) and 5.6g of 3-cyanobenzaldehyde (43mmol) in 100mL of anhydrous DCM, slowly add 2.5mL of glacial acetic acid (43mmol), and stir at room temperature for 2h.

[0101] 13.0 g NaBH(OAc)3 (61 mmol) was added in portions, and the reaction was carried out overnight at room temperature.

[0102] After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and the mixture was extracted with DCM. The organic layers were combined and washed with saturated NaCl. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 7.8 g of pale yellow oily liquid 7, i.e., intermediate 7, with a yield of 69%.

[0103] 3) Dissolve 720.0 mg of intermediate 7 (2 mmol) obtained in step 2) in 20.0 mL of anhydrous THF, add 2.4 mL of THF solution containing 1 mol / L potassium tert-butoxide (tBuOK) dropwise to the system at -70 °C, and stir at -70 °C for 3 h.

[0104] LC-MS monitoring showed that the molar ratio of compound 5a to compound 5b was 1.6:1. After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate, and extracted three times with 5 mL of water. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) yielded 360 mg of pale yellow solid 5a, with a yield of 50%.

[0105] Example 3

[0106] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 8a, the structural formula of which is shown below:

[0107]

[0108] The synthetic route is shown below:

[0109]

[0110] Specifically, the following steps are included:

[0111] 1) Add 5.2 g (34 mmol) of (R)-3-aminobutyric acid methyl ester hydrochloride, 8 g (34 mmol) of diphenyl acrylate, 100 mL of DCM, 5.7 mL (41 mmol) of Et3N and 0.8 mL (6.8 mmol) of DBU to a flask; reflux the reaction system at 40 °C for 24 h;

[0112] After the reaction was completed, water was added for dilution, and the product was extracted three times with DCM. The organic phases were combined and washed with saturated NaCl. The product was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10.0 g of crude pale yellow oily liquid, crude product 9, with a crude yield of 83%.

[0113] 2) Dissolve 10.0g of crude product 9 (28.1mmol) obtained in step 1) and 3.7g of 3-cyanobenzaldehyde (28.1mmol) in 100mL of anhydrous DCM, slowly add 3.2mL of glacial acetic acid (39.3mmol), and stir at room temperature for 2h;

[0114] 11.9 g NaBH(OAc)3 (56.2 mmol) was added in portions, and the reaction was carried out overnight at room temperature.

[0115] After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and the mixture was extracted with DCM. The organic layers were combined and washed with saturated NaCl. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 2.8 g of pale yellow oily liquid 10, i.e., intermediate 10, with a yield of 21%.

[0116] 3) Dissolve 941.0 mg of intermediate 10 (2 mmol) obtained in step 2) in 20.0 mL of anhydrous THF, add 2.4 mL of THF solution containing 1 mol / L potassium tert-butoxide (tBuOK) dropwise to the system at -70 °C, and stir at -70 °C for 3 h.

[0117] LC-MS monitoring showed that the molar ratio of compound 8a to compound 8b was 3.2:1. After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate, and extracted three times with 5 mL of water. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) yielded 359 mg of pale yellow solid 8a, with a yield of 41%.

[0118] Example 4

[0119] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 11a, the structural formula of which is shown below:

[0120]

[0121] The synthetic route is shown below:

[0122]

[0123] Specifically, the following steps are included:

[0124] 1) Dissolve 12.3g of crude product 3 (50mmol) obtained in step 1) of Example 1 and 7g of benzaldehyde (66mmol) in 200mL of anhydrous DCM, slowly add 4.0mL of glacial acetic acid (66mmol), and stir at room temperature for 2h.

[0125] 16.0 g NaBH(OAc)3 (75 mmol) was added in portions, and the reaction was carried out overnight at room temperature.

[0126] After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and the mixture was extracted with DCM. The organic layers were combined and washed with saturated NaCl. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 40:1) to obtain 8.5 g of pale yellow oily liquid 12, i.e., intermediate 12, with a yield of 51%.

[0127] 2) Dissolve 8.5g of intermediate 12 (25.3mmol) obtained in step 1) in 250mL of anhydrous THF, add 30.4mL of THF solution containing 1mol / L tBuOK dropwise to the system at -70℃, and stir at -70℃ for 4h.

[0128] LC-MS monitoring showed that the molar ratio of compound 11a to compound 11b was 29:1. After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate, and extracted three times with water (5 mL). The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (mobile phase: petroleum ether: ethyl acetate = 40:1) yielded 5.5 g of pale yellow solid 11a, with a yield of 72%.

[0129] Example 5

[0130] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 13, the structural formula of which is shown below:

[0131]

[0132] The preparation method of this embodiment is the same as that of Example 1, except that the (R)-3-aminobutyric acid methyl ester hydrochloride in step 1) is replaced with an equimolar amount of (S)-3-aminobutyric acid methyl ester hydrochloride to prepare a pale yellow solid compound 13.

[0133] Example 6

[0134] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 14, the structural formula of which is shown below:

[0135]

[0136] The synthetic route is shown below:

[0137]

[0138] Specifically, the following steps are included:

[0139] 1) Dissolve 5.1 g of crude product 3 (20.8 mmol) obtained in step 1) of Example 1 in 100 mL of anhydrous DCM, then add 5.9 mL of Et3N (42 mmol) and 4.5 mL of Boc2O (31.2 mmol), and react overnight at 40 °C;

[0140] After the reaction was complete, water (50 mL) was added and extracted with DCM. The organic layers were combined and washed with saturated NaCl. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1) to obtain 6.3 g of pale yellow oily liquid 40, i.e. intermediate 40, with a yield of 88%.

[0141] 2) Dissolve 2.9g of intermediate 40 (8.3mmol) obtained in step 1) in 85mL of anhydrous THF, add 10mL of THF solution containing 1mol / L tBuOK dropwise to the system at -70℃, and stir at -70℃ for 8h.

[0142] After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, diluted with ethyl acetate, and extracted three times with water (5 mL). The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (mobile phase: petroleum ether: ethyl acetate = 50:1) to give 1.8 g of white solid compound 39, with a yield of 69%.

[0143] Example 7

[0144] This embodiment provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 15, the structural formula of which is shown below:

[0145]

[0146] Specifically, the following steps are included:

[0147] 1) Add 35g (228mmol) of (S)-3-aminobutyric acid methyl hydrochloride, 33.4mL (228mmol) of tert-butyl acrylate, 300mL of dichloromethane (DCM), 38mL (273mmol) of triethylamine (Et3N) and 3.4mL (22.8mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to a flask;

[0148] The reaction system was refluxed at 40°C for 48 hours;

[0149] After the reaction was completed, water (50 mL) was added for dilution, DCM was extracted three times, the organic phases were combined and washed with saturated NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the S-isomer of crude product 3.

[0150] 2) The S-isomer of crude product 3 obtained in step 1) was synthesized according to steps 1) to 2) of Example 6 to obtain white solid compound 15, with an overall yield of 38%.

[0151] Example 8

[0152] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 11a prepared in Example 4, the structural formula of which is shown below:

[0153]

[0154] The synthetic route is shown below:

[0155]

[0156] Specifically, the following steps are included:

[0157] 1464 mg of compound 11a (4.8 mmol) prepared in Example 4 was dissolved in 40 mL of MeOH, 100 mg of palladium on carbon catalyst (palladium content 10%) was added, the mixture was purged three times under a hydrogen atmosphere, and then stirred at room temperature for 2 h.

[0158] After the reaction was completed, the insoluble matter was filtered off using diatomaceous earth, the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (20 mL) was added for dilution, water (10 mL) was added and the mixture was extracted three times with ethyl acetate, the organic phases were combined and washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to give 905 mg of pale yellow solid compound 16, with a yield of 88%.

[0159] LC-MS results for compound 16: m / z 214.2 [M+H] + .

[0160] Example 9

[0161] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0162]

[0163] The synthetic route is shown below:

[0164]

[0165] Specifically, the following steps are included:

[0166] 300 mg of compound 1a (1.0 mmol) prepared in Example 1 was dissolved in 5 mL of ethyl acetate solution of hydrochloric acid (hydrochloric acid concentration of 1.0 mmol / L) and stirred at room temperature for 3 h.

[0167] After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 230 mg of white solid compound 17, with a yield of 93%.

[0168] Example 10

[0169] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 17 prepared in Example 9, the structural formula of which is shown below:

[0170]

[0171] The synthetic route is shown below:

[0172]

[0173] Specifically, the following steps are included:

[0174] 100 mg of compound 17 (0.4 mmol) prepared in Example 9 was dissolved in 5 mL of MeOH, and then 1 mL of SOCl2 was added. The mixture was stirred at 60 °C for 4 h.

[0175] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of ethyl acetate, and extracted three times with 10 mL of water and ethyl acetate. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 99 mg of pale yellow oily liquid compound 18, with a yield of 95%.

[0176] Example 11

[0177] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0178]

[0179] The synthetic route is shown below:

[0180]

[0181] Specifically, the following steps are included:

[0182] 1.0 g of compound 1a (3.3 mmol) prepared in Example 1 was dissolved in 10 mL of 30% HCl aqueous solution and refluxed for 3 h;

[0183] After the reaction was completed, 20% NaOH solution was slowly added at low temperature until the pH reached 10. 10 mL of dichloromethane was added for extraction three times. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 610 mg of pale yellow oily liquid compound 19, with a yield of 91%.

[0184] Example 12

[0185] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0186]

[0187] The synthetic route is shown below:

[0188]

[0189] Specifically, the following steps are included:

[0190] Under argon protection, 657 mg of compound 1a (2 mmol) prepared in Example 1 was dissolved in 10 mL of anhydrous THF, and NaH (4 mmol) was added in batches. The mixture was stirred at room temperature for 30 min, and then 677 mg of Tf2O (2.4 mmol) was added and stirred overnight.

[0191] After the reaction was completed, 5 mL of water was added to quench the reaction, and 10 mL of dichloromethane was added to extract the mixture three times. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 703 mg of pale yellow oily solid compound 20, with a yield of 96%.

[0192] Example 13

[0193] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0194]

[0195] The synthetic route is shown below:

[0196]

[0197] Specifically, the following steps are included:

[0198] 657 mg of compound 1a (2 mmol) prepared in Example 1 was dissolved in 10 mL of MeOH, and 113 mg of NaBH4 (3 mmol) was added at 0 °C. The mixture was then stirred at room temperature for 1 h. The solvent was then removed by rotary evaporation, diluted with dichloromethane, quenched with water, extracted, and concentrated to obtain a yellow oily liquid. The yellow oily liquid was dissolved in DCM, and then Et3N (2.4 mmol, 0.3 mL) and MsCl (2.4 mmol, 275 mg) were added. The mixture was reacted overnight at room temperature.

[0199] After the reaction was completed, 5 mL of water was added to quench the reaction, and 10 mL of dichloromethane was added to extract the mixture three times. After concentration, the mixture was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 399 mg of pale yellow oily liquid compound 21, with a yield of 64%.

[0200] Example 14

[0201] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0202]

[0203] The synthetic route is shown below:

[0204]

[0205] Specifically, the following steps are included:

[0206] 1.5 g of compound 1a (4.9 mmol) prepared in Example 1 was dissolved in 20 mL of MeOH, and 1.9 g of NH4Oac (24.45 mmol) was added. The mixture was stirred at 40 °C for 4 h.

[0207] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 10 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 7:1) to give 1.4 g of pale yellow solid compound 22, with a yield of 91%.

[0208] Example 15

[0209] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0210]

[0211] The synthetic route is shown below:

[0212]

[0213] Specifically, the following steps are included:

[0214] 328 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, and 236 mg of compound 24 (1.5 mmol) and 81.0 mg of sodium methoxide (1.5 mmol) were added. The mixture was refluxed and stirred overnight at 100 °C.

[0215] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 10 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: DCM:MeOH = 20:1) to obtain 200 mg of pale yellow solid compound 23, with a yield of 56%.

[0216] Example 16

[0217] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0218]

[0219] The synthetic route is shown below:

[0220]

[0221] Specifically, the following steps are included:

[0222] 328 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, and 398 mg of compound 26 (1.5 mmol) and 81.0 mg of sodium methoxide (1.5 mmol) were added. The mixture was refluxed and stirred overnight at 100 °C.

[0223] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 10 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: DCM:MeOH = 20:1) to give 265 mg of pale yellow solid compound 25, with a yield of 61%.

[0224] Example 17

[0225] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0226]

[0227] The synthetic route is shown below:

[0228]

[0229] Specifically, the following steps are included:

[0230] 328 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, and 162 mg of compound 28 (1.5 mmol) and 85.9 mL of glacial acetic acid (1.5 mmol) were added. The mixture was refluxed and stirred overnight at 100 °C.

[0231] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, extracted three times with 10 mL of water, dried and concentrated, and then separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1) to give 347 mg of pale yellow solid compound 27, with a yield of 83%.

[0232] Example 18

[0233] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0234]

[0235] The synthetic route is shown below:

[0236]

[0237] Specifically, the following steps are included:

[0238] 208 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, 258 mg of compound 30 (1.5 mmol) and 85.9 mL of glacial acetic acid (1.5 mmol) were added, and the mixture was refluxed and stirred overnight at 100 °C.

[0239] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, extracted three times with 10 mL of water, dried and concentrated, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to give 415 mg of pale yellow solid compound 29, with a yield of 86%.

[0240] Example 19

[0241] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0242]

[0243] The synthetic route is shown below:

[0244]

[0245] Specifically, the following steps are included:

[0246] 208 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, and 328 mg of compound 32 (1.5 mmol) and 85.9 mL of glacial acetic acid (1.5 mmol) were added. The mixture was refluxed and stirred overnight at 100 °C.

[0247] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, extracted three times with 10 mL of water, dried and concentrated, and then separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to give 439 mg of pale yellow solid compound 31, with a yield of 83%.

[0248] Example 20

[0249] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0250]

[0251] The synthetic route is shown below:

[0252]

[0253] Specifically, the following steps are included:

[0254] 208 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, 195 mg of compound 34 (1.5 mmol) and 0.5 mL of polyphosphoric acid were added, and the mixture was refluxed and stirred overnight at 80 °C.

[0255] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 10 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: dichloromethane:methanol = 20:1) to give 168 mg of pale yellow solid compound 33, with a yield of 46%.

[0256] Example 21

[0257] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0258]

[0259] The synthetic route is shown below:

[0260]

[0261] Specifically, the following steps are included:

[0262] 208 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of DCE, 259 mg of compound 36 (1.5 mmol) and 0.5 mL of polyphosphoric acid were added, and the mixture was refluxed and stirred overnight at 80 °C.

[0263] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 5 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: dichloromethane:methanol = 20:1) to give 233 mg of pale yellow solid compound 35, with a yield of 57%.

[0264] Example 22

[0265] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 1a prepared in Example 1, the structural formula of which is shown below:

[0266]

[0267] The synthetic route is shown below:

[0268]

[0269] Specifically, the following steps are included:

[0270] 208 mg of compound 1a (1 mmol) prepared in Example 1 was dissolved in 5 mL of MeOH, and 184 mg of compound 38 (1.5 mmol) and 81.0 mg of sodium methoxide (1.5 mmol) were added. The mixture was refluxed and stirred overnight at 100 °C.

[0271] After the reaction was completed, the solvent was removed by rotary evaporation, diluted with 10 mL of dichloromethane, and extracted three times with 5 mL of water. After drying and concentration, the mixture was separated by column chromatography (mobile phase: DCM:MeOH = 20:1) to give 213 mg of pale yellow solid compound 37, with a yield of 66%.

[0272] Example 23

[0273] This embodiment provides a salt of an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically a salt of an analog of compound 14 prepared in Example 6, the structural formula of which is shown below:

[0274]

[0275] The synthetic route is shown below:

[0276]

[0277] Specifically, the following steps are included:

[0278] 313 mg of compound 14 (1 mmol) prepared in Example 6 was dissolved in 5 mL of 4.0 M hydrochloric acid in ethyl acetate and reacted overnight at room temperature.

[0279] After the reaction was complete, the solvent was removed by rotary evaporation to obtain 190 mg of white solid compound 39, with a yield of 99%.

[0280] Example 24

[0281] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 14 prepared in Example 6, the structural formula of which is shown below:

[0282]

[0283] The synthetic route is shown below:

[0284]

[0285] Specifically, the following steps are included:

[0286] 313 mg of compound 14 (1 mmol) prepared in Example 6 was dissolved in 5 mL of EtOH, and 5 mL of hydrazine hydrate (50% content) was added. The mixture was then refluxed overnight at 80 °C.

[0287] After the reaction was complete, dichloromethane was added for dilution, followed by the addition of water (5 mL) and extraction three times. After drying and concentration, the mixture was subjected to column chromatography (mobile phase: DCM:MeOH = 20:1) to give 180 mg of yellow solid compound 40, with a yield of 71%.

[0288] Example 25

[0289] This embodiment provides an analog of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, specifically an analog of compound 16 prepared in Example 8, the structural formula of which is shown below:

[0290]

[0291] The synthetic route is shown below:

[0292]

[0293] Specifically, the following steps are included:

[0294] 213 mg of compound 16 (1 mmol) prepared in Example 8 was then added to 205 mg of benzyl chloroformate (1.2 mmol) and 167 μL of triethylamine (1.2 mmol), and stirred overnight at room temperature.

[0295] After the reaction was completed, water was added and the mixture was extracted three times. After drying and concentration, column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) was performed to give 302 mg of yellow solid compound 41, with a yield of 87%.

[0296] Comparative Example 1

[0297] This comparative example provides a method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds, and obtains an α-carbonylγ-chiral methyl carboxylic acid ester compound 42a, the structural formula of which is shown below:

[0298]

[0299] The synthetic route is shown below:

[0300]

[0301] Specifically, the following steps are included:

[0302] 1) Add 2.0 g of compound 43 (10 mmol) dissolved in THF to a flask, then add 2.1 g of K2CO3 (15 mmol) and compound 44 (15 mmol);

[0303] The reaction system was allowed to react overnight at room temperature;

[0304] After the reaction was complete, the solvent was removed by rotary evaporation, 40 mL of dichloromethane was added for dilution, 30 mL of water was added and the mixture was extracted three times. The organic phases were combined and washed with saturated NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.2 g of crude product 45, with a crude yield of 89%.

[0305] 2) Dissolve the obtained crude product in 10 mL of ethyl acetate solution of hydrochloric acid (1.0 mmol / L); react at room temperature for 6 h;

[0306] After the reaction was complete, the solvent was removed under reduced pressure to give 2.4 g of intermediate 46, with a yield of 91%.

[0307] 3) 48 was synthesized according to the synthesis method of compound 4 in Example 1.

[0308] 4) 92.4 mg of compound 48 (0.2 mmol) was dissolved in 2.0 mL of anhydrous THF, and 0.24 mL of THF solution containing 1 mol / L potassium tert-butoxide (tBuOK) was added dropwise to the system at -70 °C. The mixture was stirred at -70 °C for 3 h. LC-MS monitoring showed that the molar ratio of compound 42a to compound 42b was 1.6:1.

[0309] Although this comparative example also has a certain degree of reactivity selectivity, compared with Example 1, the raw materials for Comparative Example 1 are more expensive and the synthesis steps are longer, making it unsuitable for industrial production.

[0310] Comparative Example 2

[0311] This comparative example provides another method for preparing α-carbonyl-γ-chiral methyl carboxylic acid ester compound 42a, the structural formula of which is shown below:

[0312]

[0313] The synthetic route is shown below:

[0314]

[0315] Specifically, the following steps are included:

[0316] 1) Add 1.5 g (10 mmol) of (R)-3-aminobutyric acid methyl ester hydrochloride, 860 mg (10 mmol) of methyl acrylate, 30 mL of DCM, 1.6 mL (12 mmol) of Et3N and 0.3 mL (2 mmol) of DBU to a flask;

[0317] The reaction system was refluxed at 40°C for 24 hours;

[0318] After the reaction was completed, water was added for dilution, and the product was extracted three times with DCM. The organic phases were combined and washed with saturated NaCl. The product was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.9 g of crude pale yellow oily liquid, with a crude yield of 96%.

[0319] 2) Dissolve 1.9g of crude product 45 (9.6mmol) obtained in step 1) and 1.5g of 3-cyanobenzaldehyde (11.5mmol) in 30mL of anhydrous DCM, slowly add 680μL of glacial acetic acid (11.5mmol), and stir at room temperature for 2h.

[0320] 4.9 g NaBH(OAc)3 (23 mmol) was added in portions, and the reaction was carried out overnight at room temperature.

[0321] After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and DCM was used for extraction. The organic layers were combined and washed with saturated NaCl. The mixture was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 2.1 g of pale yellow oily liquid 46, i.e. intermediate 46, with a yield of 69%.

[0322] 3) Dissolve 637 mg of intermediate 46 (2 mmol) obtained in step 2) in 20 mL of anhydrous THF, add 2.4 mL of THF solution containing 1 mol / L tBuOK dropwise to the system at -70 °C, and stir at -70 °C for 3 h.

[0323] After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was extracted with 5 mL of water and 10 mL of DCM. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain a mixture of compounds 47a and 47b. 1 H-NMR showed that the ratio of compound 47a to compound 47b was 1.1:1.

[0324] The results of this comparative example show that when using ester groups with the same steric hindrance for Dieckmann ester condensation, the regioselectivity of the reaction products is extremely low. Combined with the results of the previous examples, it can be seen that the method for preparing α-carbonylγ-chiral methyl carboxylic acid ester compounds provided by this invention can achieve high regioselectivity, requires no purification step, and is suitable for widespread use in actual production.

[0325] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

Claims

1. An α-carbonyl-γ-chiral methyl carboxylic acid ester compound and its salt, its tautomer, or a salt of its tautomer, characterized in that, The α-carbonyl-γ-chiral methyl carboxylic acid esters include compounds as shown in Formula I or Formula II; the structural formulas of Formula I or Formula II are as follows: Among them, R 1 Selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups; R 2 It is selected from H, alkyl with 1 to 6 carbon atoms, hydroxyl, tert-butyl, benzyl or diphenylmethyl.

2. The α-carbonylγ-chiral methyl carboxylic acid ester compound and its salt, its tautomer or salt of its tautomer according to claim 1, characterized in that, The α-carbonylγ-chiral methyl carboxylic acid ester compounds include one of the following formulas:

3. A method for preparing an α-carbonyl-γ-chiral methyl carboxylic acid ester compound, characterized in that, The preparation method includes the following steps: α-carbonyl-γ-chiral methyl carboxylic acid esters were obtained by reacting compounds of formula (I-1) or (I-2) under alkaline conditions. The α-carbonyl-γ-chiral methyl carboxylic acid esters include compounds as shown in Formula I or Formula II and their analogues; the structural formulas of Formula I or Formula II are as follows: The structural formulas of compounds (I-1) and (I-2) are as follows: In the formula, R 1 Selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups; R 2 Selected from methyl, tert-butyl, benzyl, and diphenylmethyl; When preparing the compound shown in Formula I, the compound of Formula (I-1) is used as the starting material; when preparing the compound shown in Formula II, the compound of Formula (I-2) is used as the starting material.

4. The preparation method according to claim 3, characterized in that, The reaction includes at least one of the following conditions: 1) The reaction is carried out in solution, and the method further includes the step of dissolving the raw material in an organic solvent to prepare a solution, wherein the organic solvent includes at least one of tetrahydrofuran, toluene and 1,4-dioxane; 2) The alkaline conditions are generated by adding an alkali, wherein the alkali includes at least one of potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, and lithium bistrimethylsilylamino. Preferably, the alkali is added in the form of an alkaline solution, wherein the concentration of the alkali in the alkaline solution is 0.2–2 mol / L; Preferably, the molar ratio of the compound of formula (I-1) or the compound of formula (I-2) to the base is 1:(0.5-2). 3) The reaction time is 2–8 hours; 4) The reaction temperature is -80℃ to -60℃.

5. An analogue of an α-carbonyl-γ-chiral methyl carboxylic acid ester compound and its salt, its tautomer, or a salt of its tautomer, characterized in that, The structural formula of the analogue is shown in one of the following formulas: In the formula, R 1 Phenyl groups selected from H, phenyl, tert-butoxycarbonyl, or meta-cyano-substituted phenyl groups; R 2 Selected from H, alkyl groups with 1 to 6 carbon atoms, hydroxyl groups, tert-butyl groups, benzyl groups, or diphenylmethyl groups. R 3 Selected from H, OTf, or amino; R 4 Selected from alkyl, pyridyl, halophenyl, phenylenediamine or haloaniline groups with 1 to 6 carbon atoms; R 5 Selected from halogens, nitrile groups, or alkyl groups with 1 to 4 carbon atoms; R 6 Selected from alkyl groups having 1 to 6 carbon atoms; R 7 Selected from benzyl formate; R 8 Selected from Boc; R 9 Selected from H or alkyl groups with 1 to 4 carbon atoms.

6. Analogs of the α-carbonylγ-chiral methyl carboxylic acid esters according to claim 5, their salts, their tautomers, or salts of their tautomers, characterized in that, The salt is selected from hydrochloride, sulfate or nitrate.

7. Analogs of α-carbonyl-γ-chiral methyl carboxylic acid esters according to claim 5 or 6, their salts, their tautomers, or salts of their tautomers, characterized in that, The analogues of the α-carbonylγ-chiral methyl carboxylic acid esters and their salts, their tautomers, or salts of their tautomers include any one of the following formulas:

8. A method for preparing an analogue of an α-carbonylγ-chiral methyl carboxylic acid ester compound and its salt, its tautomer, or a salt of its tautomer, characterized in that, The preparation method includes the following steps: The α-carbonyl-γ-chiral methyl carboxylic acid ester compound described in claim 1 or 2 is used as a raw material for a reducing reaction and / or a salt-forming reaction.

9. The preparation method according to claim 8, characterized in that, The reaction includes at least one of the following conditions: 1) The reaction is carried out in solution, and the method further includes the step of preparing a solution by dissolving the substance in an organic solvent, wherein the organic solvent includes at least one of tetrahydrofuran, methanol, ethyl acetate, dichloromethane and ethanol; 2) The reducing reaction includes reducing hydrogenation, reducing alkylation, reducing amination, or reducing cyclization; 3) The reaction time is 16–24 hours; 4) The reaction temperature is 20℃~110℃.

10. The use of a compound in the preparation of pyrimidinone and piperidine bioactive drugs, characterized in that, The compound is selected from the α-carbonylγ-chiral methyl carboxylic acid esters and their salts, their tautomers or salts of their tautomers as described in claim 1 or 2, or analogs of the α-carbonylγ-chiral methyl carboxylic acid esters and their salts, their tautomers or salts of their tautomers as described in any one of claims 5 to 7.

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