Brivaracetam intermediate and preparation method thereof

Abstract

The invention discloses a brivaracetam intermediate and a preparation method thereof, and belongs to the field of pharmacy. The preparation method has the advantages of mild reaction, simple operation, low cost, high yield, high purity, short reaction route, easily available raw materials and excellent technical effect.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a brivaracetam intermediate and a preparation method thereof. Background Art

[0002] Brivaracetam (English name: brivaracetam, trade name: ), chemical name is (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide, a 2-pyrrolidone derivative, and its structural formula is as follows:

[0003]

[0004] Brivaracetam is a novel high-affinity ligand for synaptic vesicle protein 2A (SV2A). It can be used clinically as an adjuvant treatment for adult patients with refractory partial-onset epilepsy with or without secondary systemic seizures, and can also be used to treat childhood epilepsy.

[0005] The brivaracetam side chain (see compound BVT04) is a key intermediate in the synthesis of brivaracetam. The difficulty of preparing the side chain, the mildness of the reaction, the cost, the yield, the purity, the length of the reaction route, the ease of obtaining raw materials, etc. directly affect the synthesis efficiency of brivaracetam.

[0006]

[0007] Organic Process Research & Development 2016, 20, 1566-1575 and Chinese patent CN109266630 reported the synthesis of the above side chain by esterase splitting. The substrate raw material diethyl propylmalonate used in this method is not easy to obtain, and tert-butyl bromoacetate is expensive, resulting in high production costs. CN109266630 also discloses an alkylation step using methyl valerate and tert-butyl bromoacetate, but the reaction needs to be carried out under ultra-low temperature conditions (-78°C), requiring special reaction equipment.

[0008] Patent CN109535107 adopts a chiral auxiliary method to directly introduce a chiral center to prepare the above-mentioned side chain, thereby avoiding chiral separation. However, the chiral auxiliary used is expensive, and the alkylation reaction needs to be carried out at ultra-low temperature conditions (-78°C) when introducing chirality, requiring special reaction equipment.

[0009] Patent applications CN106279074A, WO2016191435A1, and CN105646319A disclose the following synthetic routes:

[0010]

[0011] This route uses cheap chiral epichlorohydrin to react with diethyl malonate to form a ring, then reacts with ethyl Grignard reagent to open the ring to construct a chiral center, and then hydrolyzes and decarboxylates to close the ring to obtain the buvacetam side chain. This method has a short reaction step, but the Grignard reagent is expensive, and due to the high reactivity of the Grignard reagent, the reaction system is complicated and the product purification is difficult, resulting in poor quality of the final product.

[0012] Therefore, there is still an urgent need for a method for preparing the side chain of brivaracetam with mild reaction, simple operation, low cost, high yield, high purity, short reaction route and readily available raw materials. Summary of the invention

[0013] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0014] In a first aspect, the present invention provides a method for preparing the compound BVT02.

[0015] A method for preparing compound BVT02, characterized by comprising:

[0016]

[0017] Compound BVT01 and compound A undergo Michael addition reaction in the presence of an alkaline reagent in a solvent to obtain compound BVT01-A. Compound BVT01-A, water and a decarboxylation reagent undergo decarboxylation reaction in a solvent to obtain compound BVT02.

[0018] in,

[0019] R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl;

[0020] R 1 , R 2 Each is independently selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

[0021] In some embodiments, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0022] In some embodiments, R, R 1 , R 2 It is methyl.

[0023] In some embodiments, R is methyl or phenyl; R 1 , R 2 are independently selected from methyl or ethyl.

[0024] In some embodiments, the decarboxylation agent is at least one of lithium bromide, sodium bromide, sodium iodide, and sodium chloride.

[0025] In some embodiments, the alkaline agent includes an organic alkaline agent or an inorganic alkaline agent.

[0026] In some embodiments, the organic alkaline agent includes at least one of diethylamine, dipropylamine, diisopropylamine, morpholine, piperidine, pyrrolidine, and 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene.

[0027] In some embodiments, the inorganic alkaline agent includes at least one of potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, and potassium tert-butoxide.

[0028] In some embodiments, the solvent for the Michael addition reaction includes at least one of water, dichloromethane, DMF, DMSO, N-methylpyrrolidone and dioxane.

[0029] In some embodiments, the molar ratio of the compound BVT01 to the compound A is 1.0:1.0. to 1.0:3.0. In some embodiments, the molar ratio of the compound BVT01 to the compound A is 1.0:1.0, 1.0:1.2, 1.0:1.5, 1.0:2.0, 1.0:2.5 or 1.0:3.0.

[0030] In some embodiments, the molar ratio of the compound BVT01 to the alkaline agent is 1.0:0.1 to 1.0:2.0. In some embodiments, the molar ratio of the compound BVT01 to the alkaline agent is 1.0:0.1, 1.0:0.2, 1.0:0.3, 1.0:0.4, 1.0:0.5, 1.0:0.6, 1.0:0.7, 1.0:0.8, 1.0:0.9, 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9 or 1.0:2.0.

[0031] In some embodiments, the reaction temperature of the Michael addition reaction is 10°C-40°C. In some embodiments, the reaction temperature of the Michael addition reaction is 15°C-35°C. In some embodiments, the reaction temperature of the Michael addition reaction is 20°C-35°C. In some embodiments, the reaction temperature of the Michael addition reaction is 20°C-30°C. In some embodiments, the reaction temperature of the Michael addition reaction is 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0032] In some embodiments, the reaction temperature of the decarboxylation reaction is 60° C. to 180° C. In some embodiments, the reaction temperature of the decarboxylation reaction is 150° C. to 180° C. In some embodiments, the reaction temperature of the decarboxylation reaction is 60° C., 70° C., 80° C., 90° C., 100° C., 110° C., 140° C., 145° C., 150° C., 155° C., 160° C., 165° C., 170° C., 175° C., or 180° C.

[0033] In some embodiments, the molar ratio of the compound BVT01-A to the decarboxylation agent is 1.0:1.0-1.0:3.0. In some embodiments, the molar ratio of the compound BVT01-A to the decarboxylation agent is 1.0:1.0-1.0:2.5. In some embodiments, the molar ratio of the compound BVT01-A to the decarboxylation agent is 1.0:1.0, 1.0:1.5, 1.0:2.0, 1.0:2.5, 1.0:3.0.

[0034] In some embodiments, the solvent for the decarboxylation reaction includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0035] In some embodiments, the preparation method further includes the preparation method of BVT01, and the preparation method of BVT01 includes:

[0036]

[0037] Compound BVT00 and n-butyraldehyde undergo condensation reaction in a solvent in the presence of an alkaline reagent to obtain compound BVT01.

[0038] In some embodiments, the basic agent is a secondary amine.

[0039] In some embodiments, the alkaline reagent is at least one of diethylamine, dipropylamine, diisopropylamine, morpholine, piperidine, and pyrrolidine.

[0040] In some embodiments, the solvent for the condensation reaction includes at least one of n-hexane, cyclohexane, n-heptane, toluene, dichloromethane, and chloroform.

[0041] In some embodiments, the reaction temperature of the condensation reaction is 50° C. to 120° C. In some embodiments, the reaction temperature of the condensation reaction is 50° C., 55° C., 60° C., 65° C., 70° C., 75, 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C.

[0042] In some embodiments, the molar ratio of BVT00 to n-butyraldehyde is 1.0:1.0 to 1.0:3.0. In some embodiments, the molar ratio of BVT00 to n-butyraldehyde is 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3, 1.0:2.4, 1.0:2.5, 1.0:2.6, 1.0:2.7, 1.0:2.8, 1.0:2.9 or 1.0:3.0.

[0043] In a second aspect, the present invention provides a method for preparing compound S-BVT02.

[0044] A method for preparing compound S-BVT02, comprising:

[0045]

[0046] Compound BVT02 is subjected to enzyme-catalyzed reaction to obtain compound S-BVT02;

[0047] Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl,

[0048] R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

[0049] In some embodiments, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0050] In some embodiments, R is methyl or phenyl; R 2 are independently selected from methyl or ethyl.

[0051] In some embodiments, R, R 2 It is methyl.

[0052] In some embodiments, the enzyme comprises at least one of an esterase, a lipase, and a protease.

[0053] In some preferred embodiments, the enzyme is lipase; using lipase is more conducive to improving the ee value and yield of the obtained product.

[0054] In some embodiments, the lipase comprises at least one of Lipolase 100L, Lipase D Amano, Lipolase 30T, Lipolase 100T, Lipolase EX Rhizomucor miehei lipase Palatase 20000L. In some preferred embodiments, the lipase comprises at least one of Lipolase 100L, Palatase 20000L, and Lipase D Amano.

[0055] In some embodiments, the enzyme comprises an immobilized esterase.

[0056] In some embodiments, the immobilized enzyme includes Candida Antarcticalipase-B (CALB).

[0057] In some embodiments, the reaction is carried out at a pH of 6.0-10.0. In some embodiments, the reaction is carried out at a pH of 6.2-8.2. In some preferred embodiments, the reaction is carried out at a pH of 7.0-8.5. In some embodiments, the reaction is carried out at a pH of 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0.

[0058] In some embodiments, the reaction temperature of the reaction is 30°C to 55°C. In some embodiments, the reaction temperature of the reaction is 40°C to 50°C. In some embodiments, the reaction temperature of the reaction is 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C or 55°C.

[0059] In some embodiments, the reaction is carried out in a buffer solution.

[0060] In some embodiments, the buffer solution contains at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0061] In some embodiments, the preparation method also includes a method for preparing compound BVT02, wherein the method for preparing compound BVT02 is as described in the first aspect.

[0062] In a third aspect, the present invention provides a method for preparing compound BVT03.

[0063] A method for preparing compound BVT03, comprising:

[0064]

[0065] Compound S-BVT02 reacts with an oxidant in a solvent to obtain compound BVT03;

[0066] Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl,

[0067] R 2 are independently selected from methyl, ethyl, isopropyl, benzyl or tert-butyl;

[0068] Wherein, the oxidant includes at least one of peracetic acid, meta-chloroperbenzoic acid, potassium persulfate complex salt, trifluoroacetic anhydride and urea peroxide.

[0069] In some embodiments, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0070] In some embodiments, R is methyl or phenyl; R 1 , R 2 are independently selected from methyl or ethyl.

[0071] In some embodiments, R, R 1 , R 2 It is methyl.

[0072] In some embodiments, the solvent is at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, toluene, chlorobenzene, or dimethyl sulfoxide.

[0073] In some embodiments, the molar ratio of the compound S-BVT02 to the oxidant is 1.0:1.1 to 1.0:3.0. In some embodiments, the molar ratio of the compound S-BVT02 to the oxidant is 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3, 1.0:2.4, 1.0:2.5, 1.0:2.6, 1.0:2.7, 1.0:2.8, 1.0:2.9 or 1.0:3.0.

[0074] In some embodiments, the reaction temperature is -20°C to 40°C. In some embodiments, the reaction temperature is -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0075] In some embodiments, the preparation method also includes a method for preparing compound S-BVT02, and the method for preparing compound S-BVT02 is as described in the method for preparing compound S-BVT02 described in the second aspect.

[0076] In a fourth aspect, the present invention provides a method for preparing compound BVT04.

[0077] A method for preparing compound BVT04, comprising:

[0078]

[0079] Compound BVT03 reacts in the presence of a catalyst in a solvent to obtain compound BVT04;

[0080] Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl,

[0081] R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

[0082] In some embodiments, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0083] In some embodiments, R is methyl or phenyl; R 2 Selected from methyl or ethyl.

[0084] In some embodiments, R, R 2 It is methyl.

[0085] In some embodiments, the catalyst includes at least one of trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, sulfuric acid, phosphoric acid, and an acidic cation exchange resin.

[0086] In some embodiments, the solvent of the reaction to obtain compound BVT04 includes at least one of dioxane, ethylene glycol dimethyl ether, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, and butyl acetate.

[0087] In some embodiments, the molar ratio of the compound BVT03 to the catalyst is 1.00:0.05 to 1.00:0.50. In some embodiments, the molar ratio of the compound BVT03 to the catalyst is 1.00:0.10, 1.00:0.15, 1.00:0.20, 1.00:0.25, 1.00:0.30, 1.00:0.35, 1.00:0.40, 1.00:0.45 or 1.00:0.50.

[0088] In some embodiments, the reaction temperature of the reaction to obtain compound BVT04 is 40° C. to 120° C. In some embodiments, the reaction temperature of the reaction to obtain compound BVT04 is 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85, 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C.

[0089] In some embodiments, the preparation method also includes a preparation method of compound BVT03, and the preparation method of compound BVT03 is as described in the preparation method of compound BVT03 described in the third aspect.

[0090] In a fifth aspect, the present invention provides a compound.

[0091] A compound having one of the following structures:

[0092]

[0093] Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl,

[0094] R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

[0095] In some embodiments, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.

[0096] In some embodiments, R is methyl or phenyl; R 2 Selected from methyl or ethyl.

[0097] In some embodiments, R, R 2 It is methyl.

[0098] Beneficial Effects

[0099] Compared with the prior art, any of the technical solutions of the present invention has at least one of the following technical effects:

[0100] (1) The method provided by the present invention has mild reaction conditions, simple operation, low cost, high yield, high purity, high optical purity, short reaction route, and readily available raw materials.

[0101] (2) The present invention uses enzymes to resolve compound BVT02 to obtain compound S-BVT02, which has the advantages of mild reaction conditions, simple operation, low cost, high yield, high purity, etc. Preferably, using lipase such as lipase Lipolase 100L for resolution can further help improve the yield and purity of compound S-BVT02.

[0102] (3) The present invention preferably uses an alkali metal halide such as lithium bromide as a decarboxylation agent to carry out a decarboxylation reaction on compound BVT01-A to obtain compound BVT02, which can further help improve the product yield and purity.

[0103] Terminology

[0104] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context dictates otherwise.

[0105] The term "room temperature" refers to ambient temperature, which is 15°C to 40°C or 20°C to 35°C.

[0106] The term "optional", "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur. For example, "optional surfactant" means that a surfactant may or may not be present.

[0107] "Me" means methyl.

[0108] "Et" means ethyl.

[0109] "Ac" means acetyl.

[0110] "Ph" means phenyl.

[0111] The term "comprising" and its variations, such as "including" and "comprising" should be understood as open-ended, i.e., "including but not limited to". When used to define compositions and methods, "consisting essentially of..." or its grammatical variations should mean the exclusion of other elements that have any significance to the compositions and methods of preparation, but factors that have no substantial effect on the compositions and methods of preparation are not excluded. "Consisting of..." or its grammatical variations should mean the exclusion of elements not explicitly listed. Embodiments defined by each of these transition terms are within the scope of the present invention. For example, when a formulation is described as comprising ingredients A, B, and C, a formulation consisting essentially of A, B, and C and a formulation consisting of A, B, and C are independently within the scope of the present invention.

[0112] Unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" include plural references. For example, reference to "a stabilizer" includes one or more stabilizers.

[0113] As used herein, the quantitative measurement term "about" in the context refers to ±10%, ±5% or ±1% of the value. For example, "about 70%" means 63%-77%, 66.5%-73.5% or 69.3%-70.7%. The term "about X" also includes the number of "X", for example, "about 70%" also includes 70%.

[0114] Recitation of ranges of values ​​herein are intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein.

[0115] The term "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, for example, the material can be incorporated into a pharmaceutical preparation administered to a patient without causing any significant adverse biological effect or interacting with the other components of the formulation in any harmful manner. Pharmaceutically acceptable carriers (e.g., carriers, adjuvants and / or other excipients) preferably meet the standards of toxicology and manufacturing testing and / or contain inactive ingredients in the guidelines prepared by the U.S. Food and Drug Administration. DETAILED DESCRIPTION

[0116] It will be understood by those skilled in the art that the following examples are intended to illustrate the present invention, rather than to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Unless otherwise specified, in the following embodiments, specific techniques or conditions are not clearly described, and those skilled in the art may proceed according to the commonly used techniques or conditions in the art or according to the product specification. The drugs, reagents or instruments used without indicating the manufacturer are all commercially available conventional products.

[0117] Example 1: Preparation of compound BVT01-a

[0118]

[0119] Methyl acetoacetate (23.22 g, 1.0 eq), n-butyraldehyde (15.8 g, 1.1 eq), and dipropylamine (2 g, 0.1 eq) were dissolved in 80 mL of n-hexane, and the temperature was raised to reflux (about 70°C) for reaction. The reaction was stopped when the water distilled out of the reaction no longer changed. The solvent and unreacted n-butyraldehyde were removed by distillation under reduced pressure to obtain 30.6 g of compound BVT01-a (light yellow oily liquid, GC purity: 88%, yield: 90%). An appropriate amount of the obtained compound BVT01-a was purified by silica gel column and sent to GC-MS for inspection, and the result was: 170.2.

[0120] Example 2: Preparation of compound BVT01-b

[0121]

[0122] Ethyl acetoacetate (65g, 1.0eq), n-butyraldehyde (37.8g, 1.05eq), and morpholine (4.35g, 0.1eq) were dissolved in 200mL cyclohexane, and the temperature was raised to reflux (about 70°C) for reaction. The reaction was stopped when the water distilled out of the reaction no longer changed. The solvent and unreacted n-butyraldehyde were removed by distillation under reduced pressure to obtain 84.7g of compound BVT01-b (light yellow oily liquid, GC purity: 90%, yield: 92%). An appropriate amount of the obtained compound BVT01-b was sent for GC-MS inspection, and the result was: 184.3.

[0123] Example 3: Preparation of compound BVT01-c

[0124]

[0125] Ethyl benzoyl acetate (19.2 g, 1.0 eq), n-butyraldehyde (10.8 g, 1.5 eq), and pyrrolidine (1.42 g, 0.2 eq) were dissolved in 50 mL of n-heptane, and the temperature was raised to reflux reaction (about 100°C). The reaction was stopped after the water distilled out by the reaction no longer changed, and the solvent was removed by distillation under reduced pressure to obtain 22.9 g of compound BVT01-c (light yellow oily liquid, GC purity: 92%, yield: 93%). An appropriate amount of the obtained compound BVT01-c was sent for GC-MS inspection, and the result was: 246.3.

[0126] Example 4: Preparation of compound BVT02-a

[0127]

[0128] Compound BVT01-a (17.0 g, 1.0 eq), dimethyl malonate (13.2 g, 1.0 eq) and piperidine (17.0 g, 2.0 eq) were mixed and reacted for 16 h at room temperature under stirring. After the reaction, 200 ml of DCM (dichloromethane) was added, and the liquid was separated to obtain an organic phase layer, which was washed twice with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated under reduced pressure to obtain a light yellow oily product BVT01-A1. BVT01-A1 was dissolved in 100 ml of DMSO (dimethyl sulfoxide), lithium bromide (1.0 eq) and 2 ml of water were added, and the temperature was raised to 170 ° C for 5 hours to stop the reaction. 200 ml of water was added, and then extracted with ethyl acetate to obtain an organic phase layer, which was washed once with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure to obtain 14.5 g of compound BVT02-a (light yellow oily product, GC purity: 89%, yield: 78%). An appropriate amount of the obtained compound BVT02-a was purified by silica gel column and then tested by high-resolution mass spectrometry and nuclear magnetic resonance. The results are as follows:

[0129] 1 H NMR (400MHz, CDCl3) δ3.59 (s, 3H), 2.56–2.18 (m, 5H), 2.09 (s, 3H), 1.26 (d, J = 3.4Hz, 4H), 0.86 (t, J = 6.5Hz, 3H).

[0130] HRMS: calculated value M+1=187.1329; measured value M+1=187.1332.

[0131] Example 5: Preparation of compound BVT02-b

[0132]

[0133] Compound BVT01-b (55.3 g, 1.0 eq), diethyl malonate (57.6 g, 1.2 eq) and 1,8-diazabicyclo-bicyclo (5,4,0)-7-undecene (22.8 g, 0.5 eq) were mixed and reacted for 20 h at room temperature under stirring. After the reaction, 300 ml of DCM was added, and the liquid was separated to obtain an organic phase layer, which was washed twice with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated under reduced pressure to obtain compound BVT01-A2 (light yellow oily product). Compound BVT01-A2 was dissolved in 200 ml of DMF, sodium bromide (2.5 eq) and 5 ml of water were added, and the temperature was raised to 150°C and refluxed for 6 hours to stop the reaction. 400 ml of water was added, and then extracted with ethyl acetate to obtain an organic phase layer, which was washed once with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure to obtain 50.4 g of compound BVT02-b (light yellow oily product, GC purity: 87%, yield: 84%). An appropriate amount of the obtained compound BVT02-b was purified by silica gel column and then detected by high-resolution mass spectrometry and nuclear magnetic resonance. The results are as follows:

[0134] HRMS: calculated value M+1=201.1485; measured value M+1=201.1476.

[0135] 1 H NMR (400MHz, CDCl3) δ4.08 (q, J = 7.1Hz, 2H), 2.53–2.16 (m, 5H), 2.10 (s, 3H), 1.27 (d, J = 3.4Hz, 4H), 1.21 (t, J = 7.1Hz, 3H), 0.86 (t, J = 6.5Hz, 3H).

[0136] Example 6: Preparation of compound BVT02-b

[0137]

[0138] 20g (58mmol, 1eq) of compound BVT01-A2 was dissolved in 200ml DMSO, sodium chloride (3.0eq) and 3ml water were added, the temperature was raised to 180°C for reaction for 12 hours, and the reaction was stopped. 200ml of water was added, and then extracted with ethyl acetate to obtain an organic phase layer, which was washed once with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure to obtain 9.16g of compound BVT02-b (light yellow oily product, GC purity: 83%, yield: 79%).

[0139] Example 7: Preparation of compound BVT02-c

[0140]

[0141] Compound BVT01-c (19.7 g, 1.0 eq), diethyl malonate (15.4 g, 1.2 eq) and 1,8-diazabicyclo-bicyclo (5,4,0)-7-undecene (3.6 g, 0.3 eq) were mixed and reacted at room temperature for 20 h. After the reaction, 100 ml of DCM was added, and the liquid was separated to obtain an organic phase layer, which was washed twice with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated under reduced pressure to obtain compound BVT01-A3 (light yellow oily product). Compound BVT01-A3 was dissolved in 100 ml of DMF (N,N-dimethylformamide), lithium bromide (2.5 eq) and 2 ml of water were added, and the temperature was raised to reflux reaction (about 150°C) for 6 hours to stop the reaction. 200 ml of water was added, and then extracted with ethyl acetate to obtain an organic phase layer, which was washed once with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure to obtain 17.8 g of compound BVT02-c (light yellow oily product, GC purity: 92%, yield: 85%). An appropriate amount of the obtained compound BVT02-c was taken for GC-MS and NMR testing, and the results were as follows:

[0142] 1 H NMR (400MHz, CDCl3) δ7.16–7.54(m,5H),4.11(q,J=7.0Hz,2H),2.56–2.35(m,5H),1.31(d,J=3.5Hz,4H),1.24(t,J=7.4Hz,3H),0.89(t,J=6.5Hz,3H).

[0143] GC-MS: 262.4.

[0144] Example 8: Preparation of compound S-BVT02-b (immobilized enzyme CALB)

[0145]

[0146] Compound BVT02-b (10 g, 1.0 eq) was added to a buffer solution containing sodium dihydrogen phosphate and sodium dihydrogen phosphate (pH = 7.5), and immobilized enzyme CALB (5 g, mass ratio of compound BVT02-b to immobilized enzyme CALB = 1:0.5) was added under stirring at room temperature, and the temperature was raised to 40°C for reaction for 26 hours. After the reaction was completed, the pH was adjusted to 9-10 with a 2N sodium hydroxide aqueous solution, extracted with methyl tert-butyl ether, separated, and the organic phase was evaporated under reduced pressure to remove the solvent to obtain 3.3 g of compound S-BVT02-b (light yellow oil, ee = 95.2%, yield: 33% (the theoretical yield of kinetic resolution is up to 50%)).

[0147] Example 9: Preparation of compound S-BVT02-b (lipase)

[0148]

[0149] Compound BVT02-b (10 g, 1.0 eq) was added to a buffer solution containing sodium dihydrogen phosphate and sodium dihydrogen phosphate (pH = 8.0), and lipase Lipolase 100L (2.0 g, mass ratio of compound BVT02-b to lipase Lipolase 100L = 1:0.2) was added under stirring at room temperature, and the temperature was raised to 45°C for reaction for 18 hours. After the reaction was completed, 2N sodium hydroxide aqueous solution was added to adjust the pH to 9-10, and the mixture was extracted with methyl tert-butyl ether, separated, and the organic phase was evaporated to remove the solvent under reduced pressure to obtain 4.0 g of compound S-BVT02-b (light yellow oil, ee = 98.6%, yield: 40% (the theoretical yield of kinetic resolution is up to 50%)).

[0150] Example 10: Preparation of compound BVT03-b

[0151]

[0152] Compound S-BVT02-b (50 g, 1.0 eq) was dissolved in 300 ml of dichloromethane, the system was cooled to 0°C, and m-chloroperbenzoic acid (52 g, 1.2 eq) was added. After the addition, the temperature was raised to room temperature and the reaction was continued for 4 hours. After the reaction was completed, the mixture was washed twice with saturated sodium bicarbonate and concentrated under reduced pressure to obtain 49.1 g of compound BVT03-b (oil, yield: 91%). An appropriate amount of the obtained compound BVT03-b was taken for GC-MS and NMR testing, and the results were as follows:

[0153] 1 H NMR (400MHz, CDCl3) δ4.18–4.05(m,3H),3.95(dd,J=11.0,6.5Hz,1H),2.33(qd,J=15.3,6.7H z,2H),2.26–2.18(m,1H),1.41–1.30(m,4H),1.26(dd,J=9.3,5.0Hz,6H),0.95–0.88(m,3H).

[0154] GC-MS: 216.3.

[0155] Example 11: Preparation of compound BVT04

[0156]

[0157] Compound BVT03-b (15 g, 1.0 eq) was dissolved in 100 ml of dioxane, 10 ml of trifluoroacetic acid was added, and the temperature was raised to 100 ° C for 24 hours. After the reaction, it was washed twice with saturated sodium bicarbonate and concentrated under reduced pressure to obtain 7.2 g of compound BVT04 (oil, yield: 81%, ee = 98.5%). Take an appropriate amount of the obtained compound BVT04 for GC-MS detection, and the results are as follows:

[0158] GC-MS: 128.2.

[0159] Example 12: Preparation of compound S-BVT02-a

[0160]

[0161] Compound BVT02-a (9.3 g, 0.05 mol) was added to a buffer solution containing sodium dihydrogen phosphate and sodium dihydrogen phosphate (pH = 7.0), and liquid lipase (Palatase 20000L) (5 mL, W: V = 1: 0.5) was added under stirring at room temperature, and the temperature was raised to 38°C for reaction for 26 hours. After the reaction was completed, 2N sodium hydroxide aqueous solution was added to adjust the pH to 9-10, and the mixture was extracted with methyl tert-butyl ether, separated, and the organic phase was evaporated under reduced pressure to remove the solvent to obtain 3.07 g of compound S-BVT02-a (light yellow oil, ee = 96%, yield: 33% (the theoretical yield of kinetic resolution is up to 50%)).

[0162] Example 13: Preparation of compound BVT04 (two-step continuous administration)

[0163]

[0164] Compound S-BVT02-a (8 g, 1.0 eq) was dissolved in 100 ml of ethyl acetate, cooled to 0°C, trifluoroacetic anhydride (10.8 g, 1.2 eq) and urea peroxide (6.06 g, 1.5 eq) were added, and then the temperature was raised to room temperature and the reaction was continued for 2 hours. After the reaction was completed, the mixture was washed twice with saturated sodium bicarbonate and concentrated under reduced pressure to obtain 7.6 g of compound BVT03-a (oil, yield: 88%);

[0165] The compound BVT03-a (7.6 g) obtained above was dissolved in 30 ml of toluene, 1.6 g (0.2 eq) of p-toluenesulfonic acid was added, the temperature was raised to reflux for reaction for 16 h, the temperature was lowered, and then washed with saturated sodium carbonate, and the solvent was evaporated under reduced pressure to obtain 3.76 g of compound BVT04 (oil, ee = 95%, yield 78%). An appropriate amount of the obtained compound BVT04 was taken for GC-MS detection, and the results were as follows:

[0166] GC-MS: 128.2.

[0167] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing compound BVT02, characterized in that: include: Compound BVT01 and compound A undergo Michael addition reaction in the presence of an alkaline reagent in a solvent to obtain compound BVT01-A. Compound BVT01-A, water and a decarboxylation reagent undergo decarboxylation reaction in a solvent to obtain compound BVT02, wherein: R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl; R 1 , R 2 Each is independently selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

2. The preparation method according to claim 1, wherein R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; and / or The decarboxylation reagent is at least one of lithium bromide, sodium bromide, sodium iodide and sodium chloride; and / or The alkaline agent includes an organic alkaline agent or an inorganic alkaline agent; and / or The organic alkaline reagent includes at least one of diethylamine, dipropylamine, diisopropylamine, morpholine, piperidine, pyrrolidine, and 1,8-diazabicyclo-bicyclo (5,4,0)-7-undecene; and / or The inorganic alkaline reagent includes at least one of potassium carbonate, cesium carbonate, potassium phosphate, sodium methoxide and potassium tert-butoxide; and / or The solvent of the Michael addition reaction comprises at least one of water, dichloromethane, DMF, DMSO, N-methylpyrrolidone and dioxane; and / or The molar ratio of the compound BVT01 to the compound A is 1.0:1.0 to 1.0:3.0; and / or The molar ratio of the compound BVT01 to the alkaline reagent is 1.0:0.1 to 1.0:2.0; and / or The reaction temperature of the Michael addition reaction is 10°C-40°C or 15°C-35°C; and / or The reaction temperature of the decarboxylation reaction is 60 to 180° C.; and / or The molar ratio of the compound BVT01-A to the decarboxylation agent is 1.0:1.0-1.0:3.0; and / or The solvent for the decarboxylation reaction includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

3. The preparation method according to any one of claims 1 to 2, further comprising a preparation method of BVT01, wherein the preparation method of BVT01 comprises: Compound BVT00 and n-butyraldehyde undergo condensation reaction in a solvent in the presence of an alkaline reagent to obtain compound BVT01; Optionally, the alkaline agent is a secondary amine; or optionally, the alkaline agent is at least one of diethylamine, dipropylamine, diisopropylamine, morpholine, piperidine, and pyrrolidine; and / or Optionally, the solvent for the condensation reaction includes at least one of n-hexane, cyclohexane, n-heptane, toluene, dichloromethane and chloroform; and / or Optionally, the reaction temperature of the condensation reaction is 50°C to 120°C; and / or Optionally, the molar ratio of BVT00 to n-butyraldehyde is 1.0:1.0 to 1.0:3.

0.

4. A method for preparing compound S-BVT02, comprising: Compound BVT02 is subjected to enzyme-catalyzed reaction to obtain compound S-BVT02; Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl; or, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

5. The preparation method according to claim 4, wherein the enzyme comprises at least one of esterase, lipase and protease; and / or The lipase comprises at least one of Lipolase 100L, Lipase D Amano, Lipolase 30T, Lipolase 100T, Lipolase EX, and Rhizomucor miehei lipase Palatase 20000L; and / or, the lipase comprises at least one of Lipolase 100L, Palatase 20000L, and Lipase D Amano; and / or The enzyme comprises an immobilized enzyme; and / or, The immobilized enzyme comprises Candida antarctica lipase B; and / or The reaction is carried out at a pH of 6.0-10.0 or 6.2-8.2, preferably at a pH of 7.0-8.5; and / or The reaction temperature of the reaction is 30°C to 55°C or 40°C to 50°C; and / or The reaction is carried out in a buffer solution; and / or The buffer solution comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate; and / or The preparation method also includes a method for preparing compound BVT02, wherein the method is as described in any one of claims 1-3.

6. A method for preparing compound BVT03, comprising: Compound S-BVT02 reacts with an oxidant in a solvent to obtain compound BVT03; Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl; or, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl; Wherein, the oxidant includes at least one of peracetic acid, meta-chloroperbenzoic acid, potassium persulfate complex salt, trifluoroacetic anhydride and urea peroxide.

7. The preparation method according to claim 6, wherein: The solvent is at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, toluene, chlorobenzene and dimethyl sulfoxide; and / or The molar ratio of the compound S-BVT02 to the oxidant is 1.0:1.1 to 1.0:3.0; and / or The reaction temperature of the reaction is -20 to 40°C; and / or The preparation method also includes a method for preparing compound S-BVT02, wherein the method is as described in any one of claims 4-5.

8. A method for preparing compound BVT04, comprising: Compound BVT03 is prepared according to the preparation method according to any one of claims 6 to 7, and then compound BVT03 reacts in a solvent in the presence of a catalyst to obtain compound BVT04; Where R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl; or, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl; Wherein, the catalyst includes at least one of trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, sulfuric acid, phosphoric acid, and acidic cation exchange resin.

9. The preparation method according to claim 8, wherein: The solvent of the reaction comprises at least one of dioxane, ethylene glycol dimethyl ether, toluene, chlorobenzene, ethyl acetate, isopropyl acetate and butyl acetate; and / or The molar ratio of the compound BVT03 to the catalyst is 1.00:0.05 to 1.00:0.50; and / or The reaction temperature of the reaction is 40°C to 120°C; and / or The preparation method also includes a method for preparing compound BVT03, wherein the method is as described in any one of claims 6-7.

10. A compound having one of the following structures: in, R is C1-C 10 Alkyl, C3-C 10 Cycloalkyl or C6-C 20 Aryl; or, R is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; R 2 is selected from methyl, ethyl, isopropyl, benzyl or tert-butyl.

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