Preparation method of milobalin benzenesulfonic acid intermediate compound

Abstract

The present invention discloses a method for preparing a milobalin benzenesulfonate intermediate compound. Specifically, the present invention discloses a method for preparing a compound of formula III, which comprises the following steps: in an organic solvent, in the presence of an organic base and an inorganic catalyst, a compound of formula II and a compound of formula A undergo an addition reaction to obtain a compound of formula III. The method of the present invention is a key step in the method for preparing a milobalin benzenesulfonate intermediate compound, so that the method for preparing a milobalin benzenesulfonate intermediate compound has a better yield, milder reaction conditions, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a milobarlin besylate intermediate compound. Background Art

[0002] At present, the drugs for treating neuralgia on the market include gabapentin and pregabalin, both of which have serious deficiencies in clinical treatment. Milobalin besylate is a new, selective α2δ-1 ligand, which is used to study the treatment of postherpetic neuralgia, fibromyalgia and diabetic peripheral neuropathy, and its clinical therapeutic effect is better than gabapentin and pregabalin. In the preparation process of milobalin besylate, the preparation of the key intermediate bicyclic compound is the key technology, so this application focuses on the preparation method of the bicyclic compound.

[0003] In the prior art, the following synthesis techniques of bicyclic compounds are reported in the literature:

[0004] Method 1: The method reported in document US2010 / 249229 uses dicarbonyl ester as the starting material, reacts with allyl bromide via strong base catalysis, and then reduces the carbonyl group with sodium borohydride to obtain compound 2, which is hydrolyzed to obtain compound 3, and then ring-closed to obtain compound 4, i.e., a bicyclic compound.

[0005]

[0006] The substituents are defined as follows: 1 is hydrogen or C 1 -C 6 alkyl;

[0007] The disadvantage of this route is that the first step requires the use of butyl lithium as a catalyst, which often needs to be operated at ultra-low temperatures (such as -78°C), is not easy to scale up, is highly dangerous, and has a high cost.

[0008] Method 2: The method reported in document CN103582622A, wherein compound 1 is prepared by condensation reaction of aliphatic aldehyde and secondary amine, compound 1 is reacted with allyl bromide to form an iminium salt, and then a bicyclic compound is prepared by decarboxylation and cyclization reaction.

[0009]

[0010] The substituents are defined as follows: 1 is hydrogen or C 1 -C 6 alkyl;

[0011] This route avoids the use of strong base catalysts, does not require ultra-low temperature conditions, and has a relatively mild reaction. However, secondary amines and fatty aldehydes are highly active and easily generate a variety of impurities. In addition, secondary amines can also catalyze the aldehydes themselves to undergo aldol condensation reactions under certain conditions, resulting in large losses. The yield of this step is only 74%, and the total yield is 47%, which is a relatively low yield.

[0012] Method 3: Document CN103562170A uses acetal to activate the α-carbon of the carbonyl group to enhance the activity of the reaction with allyl bromide to generate compound 2, which undergoes a condensation reaction with malonic acid and then a cyclization reaction to prepare a bicyclic compound.

[0013]

[0014] The substituents are defined as follows: 1 is hydrogen or C 1 -C 6 alkyl;

[0015] This route requires a 24-hour reaction at high temperature (120-125°C) to prepare compound 2, with a total yield of 62%. This route consumes a lot of energy during the production process and has a high synthesis cost.

[0016] It can be seen from the methods reported in the above literature that the methods for preparing bicyclic compounds currently have defects such as harsh reaction conditions, high reaction costs, and low yields. Summary of the invention

[0017] The technical problem to be solved by the present invention is to overcome the defects of the prior art such as harsh reaction conditions, high reaction cost, low yield, etc. In this regard, the present invention provides a novel preparation method of milopalline besylate intermediate compound, the total yield of the method is 70%, the yield is relatively high, the reaction does not need to be carried out under high temperature conditions of 120-125°C, nor under ultra-low temperature conditions (such as -78°C), the reaction conditions are relatively mild, the reagents used are economical and feasible, and it can be suitable for industrial production.

[0018] The present invention mainly solves the above technical problems through the following technical solutions.

[0019] The present invention provides a method for preparing a compound of formula III, which comprises the following steps: in an organic solvent, in the presence of an organic base and an inorganic catalyst, a compound of formula II and a compound of formula A undergo an addition reaction to obtain a compound of formula III;

[0020] ;

[0021] Among them, R 1 is hydrogen or C 1 -C 6 wherein X is halogen.

[0022] In one embodiment, the R 1 C 1 -C 6 An alkyl group such as a methyl group or an ethyl group, for example an ethyl group.

[0023] In one embodiment, X is fluorine, chlorine, bromine or iodine, for example bromine.

[0024] In the present invention, the organic solvent is a conventional organic solvent for this type of addition reaction in the art.

[0025] In one embodiment, the organic solvent is one or more of a nitrile solvent, an alcohol solvent and a cyclic ether solvent, for example, a cyclic ether solvent.

[0026] In one embodiment, the nitrile solvent is acetonitrile.

[0027] In one embodiment, the alcohol solvent is ethanol and / or methanol.

[0028] In one embodiment, the cyclic ether solvent is tetrahydrofuran.

[0029] In one embodiment, the mass volume ratio of the compound of formula II to the organic solvent is (0.2-0.6) g / mL, for example 0.4 g / mL.

[0030] In the present invention, the organic base is a conventional organic base for this type of addition reaction in the art.

[0031] In one embodiment, the organic base is potassium tert-butoxide and / or sodium tert-butoxide, such as potassium tert-butoxide.

[0032] In one embodiment, the molar ratio of the compound of formula II to the organic base is 1:(0.5-3.5), for example 1:1.

[0033] In the present invention, the inorganic catalyst is a conventional inorganic catalyst for this type of addition reaction in the art.

[0034] In one embodiment, the inorganic catalyst is one or more of zinc iodide, zinc chloride and potassium iodide, such as zinc iodide.

[0035] In one embodiment, the molar ratio of the compound of formula II to the inorganic catalyst is 1:(0.001-0.007), for example 1:0.004.

[0036] In one embodiment, the molar ratio of the compound of formula II to the compound of formula A is 1:(0.5-3.5), for example 1:1.

[0037] In the present invention, the reaction temperature of the addition reaction is the conventional reaction temperature of this type of addition reaction in the art.

[0038] In one embodiment, the reaction temperature of the addition reaction is -5-5°C, such as 0°C.

[0039] In the present invention, the reaction time of the addition reaction is the conventional reaction time of this type of addition reaction in the art.

[0040] In one embodiment, the reaction time of the addition reaction is 3-8 h, for example 5 h.

[0041] In the present invention, the order of adding materials for the addition reaction is the conventional order of adding materials for this type of addition reaction in the art.

[0042] In a certain embodiment, the order of adding materials for the addition reaction includes the following steps: mixing an organic base and an inorganic catalyst with a part of an organic solvent to form a first mixed solution; then mixing the first mixed solution with a solution of a compound of formula II to form a second mixed solution; then mixing the second mixed solution with a solution of a compound of formula A to carry out the addition reaction; wherein the solution of the compound of formula II is a mixed solution of the compound of formula II and a part of an organic solvent; the solution of the compound of formula A is a mixed solution of the compound of formula A and a part of an organic solvent; the amount of "part" in the part of organic solvent is generally an organic solvent that can obtain a mixed solution for easy dropwise addition; wherein the sum of the amounts of all "parts" of organic solvents is the amount of organic solvent used in the addition reaction.

[0043] In one embodiment, the organic solvent in the addition sequence of the addition reaction is tetrahydrofuran.

[0044] In a certain embodiment, the organic base in the addition sequence of the addition reaction is potassium tert-butoxide.

[0045] In one embodiment, the inorganic catalyst in the addition sequence of the addition reaction is zinc iodide.

[0046] In the present invention, the post-treatment of the addition reaction is the conventional post-treatment of this type of addition reaction in the art.

[0047] In a certain embodiment, the post-treatment of the addition reaction comprises the following steps: quenching with a quencher in the reaction system, extracting with an organic solvent, drying with a desiccant, concentrating the extract in vacuo, and then performing column chromatography.

[0048] In a certain embodiment, the quenching agent in the post-treatment of the addition reaction is water.

[0049] In one embodiment, the organic solvent in the post-treatment of the addition reaction is ethanol.

[0050] In one embodiment, the desiccant used in the post-treatment of the addition reaction is anhydrous sodium sulfate.

[0051] In one embodiment, the addition reaction satisfies the following conditions:

[0052] (1) R 1 is ethyl;

[0053] (2) The organic solvent is tetrahydrofuran;

[0054] (3) The mass volume ratio of the compound of formula II to the organic solvent is 0.4 g / mL;

[0055] (4) The organic base is potassium tert-butoxide;

[0056] (5) The molar ratio of the compound of formula II to the organic base is 1:1;

[0057] (6) The inorganic catalyst is zinc iodide;

[0058] (7) The molar ratio of the compound of formula II to the inorganic catalyst is 1:0.004;

[0059] (8) The compound of formula A is allyl bromide;

[0060] (9) The molar ratio of the compound of formula II to the compound of formula A is 1:1;

[0061] (10) The reaction temperature of the addition reaction is 0°C;

[0062] (11) The order of adding materials for the addition reaction comprises the following steps: mixing potassium tert-butoxide and zinc iodide with part of tetrahydrofuran to form a first mixed solution; then mixing the first mixed solution with a tetrahydrofuran solution of the compound of formula II to form a second mixed solution; then mixing the second mixed solution with a tetrahydrofuran solution of the compound of formula A to carry out the addition reaction; wherein the solution of the compound of formula II is a mixed solution of the compound of formula II and part of tetrahydrofuran; the solution of the compound of formula A is a mixed solution of the compound of formula A and part of tetrahydrofuran; the amount of "part" in "part of tetrahydrofuran" is generally an amount of tetrahydrofuran that can obtain a mixed solution for easy dropwise addition; wherein the sum of the amounts of all "parts" of tetrahydrofuran is the amount of tetrahydrofuran used in the addition reaction; and

[0063] (12) The post-treatment of the addition reaction comprises the following steps: adding water to the reaction system for quenching, extracting with ethanol, drying with anhydrous sodium sulfate, concentrating the extract in vacuo and then performing column chromatography.

[0064] The preparation method of the compound of formula III also includes the preparation method of the compound of formula II, and the preparation method of the compound of formula II comprises the following steps: in an organic solvent, in the presence of an organic base and an inorganic catalyst, subjecting the compound of formula I to an aldehyde enol silylation reaction with a chlorosilane compound to obtain a compound of formula II;

[0065] ;

[0066] Among them, R 1 Same as above.

[0067] In the preparation method of the compound of formula II of the present invention, the organic solvent is a conventional organic solvent for enol silylation reaction of such aldehydes in the art.

[0068] In one embodiment, in the method for preparing the compound of formula II, the organic solvent is one or more of a nitrile solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent and an amide solvent, such as a nitrile solvent.

[0069] In one embodiment, in the method for preparing the compound of formula II, the nitrile solvent is acetonitrile.

[0070] In one embodiment, the halogenated hydrocarbon solvent is dichloromethane.

[0071] In one embodiment, the aromatic hydrocarbon solvent is toluene.

[0072] In one embodiment, the amide solvent is N,N-dimethylformamide.

[0073] In one embodiment, in the method for preparing the compound of formula II, the mass volume ratio of the compound of formula I to the organic solvent is (0.05-0.2) g / mL, for example, 0.09 g / mL.

[0074] In the method for preparing the compound of formula II of the present invention, the organic base is a conventional organic base used in the enol silylation reaction of such aldehydes in the art.

[0075] In one embodiment, in the method for preparing the compound of formula II, the organic base is a tertiary amine compound.

[0076] In one embodiment, the tertiary amine compound is one or more of triethylamine, tripropylamine, tributylamine and N-methylmorpholine, such as triethylamine.

[0077] In one embodiment, in the method for preparing the compound of formula II, the molar ratio of the compound of formula I to the organic base is 1:(1-4), for example 1:2.4.

[0078] In the method for preparing the compound of formula II of the present invention, the inorganic catalyst is a conventional inorganic catalyst for enol silylation reaction of such aldehydes in the art.

[0079] In one embodiment, in the method for preparing the compound of formula II, the inorganic catalyst is an iodine metal compound.

[0080] In one embodiment, the iodine metal compound is one or more of sodium iodide, potassium iodide and lithium iodide, such as sodium iodide.

[0081] In one embodiment, the molar ratio of the compound of formula I to the iodine metal compound is 1:(0.5-2.5), for example 1:1.

[0082] In the present invention, the chlorosilane compound is a conventional chlorosilane compound used in the enol silylation reaction of aldehydes in the art.

[0083] In one embodiment, the chlorosilane compound is trimethylchlorosilane and / or tert-butyldimethylchlorosilane, such as trimethylchlorosilane.

[0084] In one embodiment, the molar ratio of the compound of formula I to the chlorosilane compound is 1:(1-4), for example 1:1.5.

[0085] In the present invention, the temperature of the enol silylation reaction of the aldehyde is the conventional reaction temperature of the enol silylation reaction of the aldehyde in the art.

[0086] In one embodiment, the temperature of the enol silylation reaction of the aldehyde is 20-100°C, such as 25°C, such as 45°C, and further such as 82°C.

[0087] In the present invention, the time for the enol silylation reaction of the aldehyde is the conventional reaction time for the enol silylation reaction of the aldehyde in the art.

[0088] In one embodiment, the enol silylation reaction time of the aldehyde is 2-7 h, such as 2-4 h.

[0089] In the present invention, the order of adding materials for the enol silylation reaction of aldehyde is the conventional order of adding materials for the enol silylation reaction of aldehyde in the art.

[0090] In a certain embodiment, the feeding sequence of the enol silylation reaction of the aldehyde comprises the following steps: mixing the compound of formula I, an organic base, an inorganic catalyst and an organic solvent to form a first mixed solution, mixing the first mixed solution with a chlorosilane compound, and performing the enol silylation reaction of the aldehyde; wherein the first mixed solution and the chlorosilane compound are mixed by dropwise addition; and the dropwise addition rate is 3-6 drops (e.g., 3-4 drops) per minute.

[0091] In one embodiment, the organic solvent in the addition sequence of the enol silylation reaction of the aldehyde is acetonitrile.

[0092] In one embodiment, the organic base in the addition sequence of the enol silylation reaction of the aldehyde is triethylamine.

[0093] In one embodiment, the inorganic catalyst in the addition sequence of the enol silylation reaction of the aldehyde is sodium iodide.

[0094] In the present invention, the post-treatment of the enol silylation reaction of the aldehyde is the conventional post-treatment of the enol silylation reaction of the aldehyde in the art.

[0095] In a certain embodiment, the post-treatment of the enol silylation reaction of the aldehyde comprises the following steps: quenching the reaction system with a quencher, extracting with an organic solvent, washing with a cleaning agent, combining the organic phases, drying with a desiccant, and purifying by distillation.

[0096] In one embodiment, the quenching agent is a mixed solution of ice pentane and ice water.

[0097] In one embodiment, the organic solvent is pentane.

[0098] In one embodiment, the cleaning agent is ice water.

[0099] In one embodiment, the desiccant is anhydrous sodium sulfate.

[0100] In one embodiment, the enol silylation reaction of the aldehyde satisfies the following conditions:

[0101] (1) R 1 is ethyl;

[0102] (2) The organic solvent is acetonitrile;

[0103] (3) The mass volume ratio of the compound of formula I to the organic solvent is 0.09 g / mL;

[0104] (4) The organic base is triethylamine;

[0105] (5) The molar ratio of the compound of formula I to the organic base is 1:2.4;

[0106] (6) The inorganic catalyst is sodium iodide;

[0107] (7) The molar ratio of the compound of formula I to the inorganic catalyst is 1:1;

[0108] (8) The chlorosilane compound is trimethylchlorosilane;

[0109] (9) The molar ratio of the compound of formula I to the chlorosilane compound is 1:1.5;

[0110] (10) The temperature of the enol silylation reaction of the aldehyde is 82°C;

[0111] (11) The adding sequence of the enol silylation reaction of the aldehyde comprises the following steps: mixing the compound of formula I, triethylamine, sodium iodide and acetonitrile to form a first mixed solution, mixing the first mixed solution with trimethylsilyl chloride, and performing the enol silylation reaction of the aldehyde; wherein the first mixed solution and trimethylsilyl chloride are mixed by dropwise addition; the dropwise addition rate is 3-4 drops per minute; and

[0112] (12) The post-treatment of the enol silylation reaction of the aldehyde comprises the following steps: quenching the reaction system with a mixed solution of ice pentane and ice water, extracting with pentane, washing with ice water, combining the organic phases, drying with anhydrous sodium sulfate, and purifying by distillation.

[0113] The present invention provides a method for preparing a compound of formula II, which comprises the following steps: in an organic solvent, in the presence of an organic base and an inorganic catalyst, subjecting a compound of formula I to an aldehyde enol silyl etherification reaction with a chlorosilane compound to obtain a compound of formula II;

[0114] .

[0115] R 1 Same as above; the conditions and parameters of the enol silylation reaction of the aldehyde are the same as above.

[0116] The present invention provides a method for preparing a compound of formula V, which comprises the following steps:

[0117] S1: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula I is subjected to an aldehyde enol silylation reaction with a chlorosilane compound to obtain a compound of formula II;

[0118] ;

[0119] S2: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula II and the compound of formula A undergo an addition reaction to obtain a compound of formula III;

[0120] ;

[0121] S3: In an organic solvent, in the presence of an organic base and a catalyst, the compound of formula III undergoes a Knoevenagel condensation reaction with malonic acid to obtain a compound of formula IV;

[0122] ;

[0123] S4: In an organic solvent, in the presence of an organic base, the compound of formula IV and an acid anhydride compound undergo a [2+2] cycloaddition reaction to obtain a compound of formula V;

[0124] ;

[0125] Among them, R 1 Same as X as above.

[0126] In step S1, the conditions and parameters of the enol silylation reaction of the aldehyde are the same as described above.

[0127] In step S2, the conditions and parameters of the addition reaction are the same as described above.

[0128] In the present invention, in step S3, the organic solvent is a conventional organic solvent for this type of Knoevenagel condensation reaction in the art.

[0129] In one embodiment, in step S3, the organic solvent is one or more of an aromatic heterocyclic solvent, a nitrile solvent and an aromatic hydrocarbon solvent, such as a nitrile solvent and / or an aromatic hydrocarbon solvent, and another example is an aromatic hydrocarbon solvent.

[0130] In one embodiment, in step S3, the aromatic heterocyclic solvent is pyridine.

[0131] In one embodiment, in step S3, the nitrile solvent is acetonitrile.

[0132] In one embodiment, in step S3, the aromatic hydrocarbon solvent is toluene.

[0133] In one embodiment, in step S3, the mass volume ratio of the compound of formula III to the organic solvent is 0.1-0.5 g / mL, for example 0.2 g / mL.

[0134] In the present invention, in step S3, the organic base is a conventional organic base for this type of Knoevenagel condensation reaction in the art.

[0135] In one embodiment, in step S3, the organic base is pyridine and / or triethylamine, such as pyridine.

[0136] In one embodiment, in step S3, the molar ratio of the compound of formula III to the organic base is 1:(1-4), for example, 1:2.3.

[0137] In the present invention, in step S3, the catalyst is a conventional catalyst for this type of Knoevenagel condensation reaction in the art.

[0138] In one embodiment, in step S3, the catalyst is morpholine and / or piperidine, such as morpholine.

[0139] In one embodiment, in step S3, the molar ratio of the compound of formula III to the catalyst is 1:(0.3-0.7), for example 1:0.58 or 1:0.56, and for example 1:0.58.

[0140] In one embodiment, in step S3, the molar ratio of the compound of formula III to the malonic acid is 1:(1-3), for example, 1:1.7.

[0141] In the present invention, in step S3, the temperature of the Knoevenagel condensation reaction is a conventional temperature for such Knoevenagel condensation reactions in the art.

[0142] In one embodiment, in step S3, the temperature of the Knoevenagel condensation reaction is 75-100°C, such as 80°C, and also such as 85-100°C.

[0143] In the present invention, in step S3, the time of the Knoevenagel condensation reaction is the conventional time of this type of Knoevenagel condensation reaction in the art.

[0144] In one embodiment, in step S3, the Knoevenagel condensation reaction time is 14-25 h, for example 18 h.

[0145] In the present invention, in step S4, the organic solvent is a conventional organic solvent for this type of [2+2] cycloaddition reaction in the art.

[0146] In one embodiment, in step S4, the organic solvent is an aprotic solvent.

[0147] In one embodiment, in step S4, the aprotic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone, such as N,N-dimethylacetamide.

[0148] In one embodiment, in step S4, the mass volume ratio of the compound of formula IV to the organic solvent is 0.2-0.5 g / mL, for example 0.3 g / mL.

[0149] In the present invention, in step S4, the organic base is a conventional organic base for this type of [2+2] cycloaddition reaction in the art.

[0150] In one embodiment, in step S4, the organic base is a tertiary amine compound.

[0151] In one embodiment, in step S4, the tertiary amine compound is one or more of triethylamine, tripropylamine, tributylamine and N-methylmorpholine, such as triethylamine.

[0152] In one embodiment, in step S4, the molar ratio of the compound of formula IV to the organic base is 1:(0.5-3), such as 1:1 or 1:1.7, and another example is 1:1.

[0153] In one embodiment, in step S4, the acid anhydride compound is one or more of acetic anhydride, propionic anhydride and butyric anhydride, such as acetic anhydride.

[0154] In one embodiment, in step S4, the molar ratio of the compound of formula IV to the acid anhydride compound is 1:(1-5), for example 1:2.

[0155] In the present invention, in step S4, the temperature of the [2+2] cycloaddition reaction is the conventional reaction temperature of this type of [2+2] cycloaddition reaction in the art.

[0156] In one embodiment, in step S4, the temperature of the [2+2] cycloaddition reaction is 90-130°C, such as 105-115°C, and also such as 100-120°C.

[0157] In the present invention, in step S4, the time of the [2+2] cycloaddition reaction is the conventional reaction time of this type of [2+2] cycloaddition reaction in the art.

[0158] In one embodiment, in step S4, the [2+2] cycloaddition reaction time is 4-10 h, such as 6.5 h, and another example is 5-10 h.

[0159] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0160] The reagents and raw materials used in the present invention are commercially available.

[0161] The positive and progressive effects of the present invention are:

[0162] The invention provides a novel preparation method of a milopalpine besylate intermediate compound. The method has a total yield of 70%, which is relatively high. The reaction does not need to be carried out under high temperature conditions of 120-125° C., nor does it need to be carried out under ultra-low temperature conditions (such as -78° C.). The reaction conditions are relatively mild, the reagents used are economical and feasible, and the method is suitable for industrial production. DETAILED DESCRIPTION

[0163] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0164] Example 1

[0165]

[0166] At room temperature, add a solution of n-butyraldehyde (4.30 g, 50 mmol), triethylamine (12.1 g, 120 mmol) and sodium iodide (7.50 g, 50 mmol) in acetonitrile (50 mL), and drip the mixed solution into a reaction bottle of chlorotrimethylsilane (8.10 g, 75 mmol) via a cannula. The mixed solution is dripped at a rate of 3-4 drops per minute, and the mixed solution is heated to 82°C for reaction for 2-4 hours, and cooled for 3 hours after the reaction is completed. Quench with ice pentane and ice water in turn, extract the water layer with pentane, wash the collected organic layer with ice water, dry with anhydrous sodium sulfate, and purify by distillation to obtain 6.48 g of enol silyl ether of butyraldehyde, with a molar yield of 90%, bp.76-82°C / 180 mm Hg;

[0167] 1 H-NMR (400 MHz, CDCl 3 ); δ6.03 (dd, J=5.9, 1.0Hz, 1H), 4.35 (dd, J=9.0, 5.9Hz, 1H), 2.79 (m, 2H), 0.95 (d, J=6.8Hz, 3H), 0.17 (s, 9H) ppm.

[0168] Example 2

[0169]

[0170] Potassium tert-butoxide (5.60 g, 50 mmol) and zinc iodide (0.07 g, 0.2 mmol) were added to THF (5 mL) to form a first mixed solution, a solution of silyl enol ether (7.21 g, 50 mmol) in THF (10 mL) was added dropwise to the first mixed solution, and the mixture was stirred for 45 minutes and then cooled to 0°C to form a second mixed solution, and then a solution of bromoallyl (6.05 g, 50 mmol) in THF (5 mL) was added to the second mixed solution to form a third mixed solution. The third mixed solution was stirred at 0°C for 5 hours, quenched with water (10 mL), extracted with ether, dried with anhydrous magnesium sulfate, and the extract was concentrated in vacuo. The product was separated by silica gel column chromatography (petroleum ether: ether = 98:2) to obtain 5.40 g of a colorless oil with a molar yield of 96.43%;

[0171] 1 H-NMR (400 MHz, CDCl 3)δ 0.93 (t, 3H, J=7.4Hz), 1.53-1.61 (m, 1H), 1.64-1.73 (m, 1H), 2.21-2.34 (m, 2H), 2.37-2. 44 (m, 1H), 5.04-5.11 (m, 2H), 5.75 (ddt, 1H, J=10.0, 17.2, 7.0Hz), 9.62 (d, 1H, J=2.0Hz).

[0172] Example 3

[0173]

[0174] Under a nitrogen atmosphere, malonic acid (93.74 g, 0.90 mol), acetonitrile (102 mL), morpholine (26 mL, 0.30 mol) and pyridine (97 mL, 1.20 mol) were added to a toluene solution (204 mL) of 2-ethylpent-4-enal (58.44 g) in sequence, and the mixture was slowly heated to about 80°C over about 1 hour. After the mixture was stirred at 80°C for 13.5 hours, malonic acid (6.24 g, 0.06 mol) was added thereto, and the mixture was further stirred at 80°C for 3 hours, and then the mixture was cooled to room temperature. Water (408 mL) was added to the reaction mixture, and concentrated hydrochloric acid (130 mL) was added to separate the organic layer. The aqueous layer was extracted with toluene (153 mL), and the extract was combined with the organic layer, followed by extraction twice with 2M NaOH aqueous solution (360 mL*1 and 90 mL*1) to allow the target compound to enter the aqueous layer. The aqueous layers were combined, and concentrated hydrochloric acid (80 mL) was added to adjust the acidity, followed by extraction with toluene twice (204 mL each time). The organic layers were combined and then washed with water (102 mL). The organic layer was concentrated under reduced pressure to obtain compound IV (80.00 g, yellow oil, molar yield 99.65%);

[0175] 1 H-NMR (400 MHz, CDCl 3 )δ 0.88 (t, 3H, J=7.4Hz), 1.32-1.42 (m, 1H), 1.5-1.6 (m, 1H), 2.12-2.25 (m, 3H), 5.00-5 .06 (m, 2H), 5.65-5.76 (m, 1H), 5.80 (d, 1H, J=15.8Hz), 6.90 (dd, 1H, J=8.4, 15.8Hz).

[0176] Example 4

[0177]

[0178] Under nitrogen atmosphere, (2E)-4-ethylhept-2,6-dienoic acid (34.0 g, purity: 90.7%) was dissolved in N,N-dimethylacetamide (100 mL) solution. Acetic anhydride (37.8 mL, 0.40 mol) and triethylamine (28 mL, 0.20 mol) were added to the mixed solution. The reaction mixture was heated and stirred at 105-115°C for 6.5 hours. The reaction mixture was cooled to room temperature, and water (200 mL) was added thereto, followed by extraction with n-hexane four times (150 mL*2 and 50 mL*2). All the extracted organic layers were combined and then washed with a saturated aqueous solution of sodium bicarbonate (50 mL) and water (50 mL) in sequence. The obtained organic layer was concentrated under reduced pressure (93-102°C, about 25 mmHg) to obtain compound V (22.06 g, colorless oil) (molar yield: 81%, total molar yield: 70%);

[0179] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.07 (t, 3H, J=7.4Hz), 2.14 (q, 2H, J=7.4Hz), 2.28-2.34 (m, 1H), 2.75-2.86 (m, 3H), 3.16-3.25 (m, 1H), 4.16-4.22 (m, 1H), 5.20-5.24 (m, 1H).

[0180] Example 5

[0181]

[0182] Under nitrogen atmosphere, malonic acid (48.12 g, 0.46 mol), morpholine (13 mL, 0.15 mol) and pyridine (50 mL, 0.62 mol) were added to an acetonitrile solution (156 mL) of 2-ethylpent-4-enal (30.00 g) (prepared in Example 2) in sequence, and the mixture was slowly heated to about 80°C over about 1 hour. After the mixture was stirred at 80°C for 13.5 hours, malonic acid (3.20 g, 0.03 mol) was added thereto, and the mixture was further stirred at 80°C for 3 hours, and then the mixture was cooled to room temperature. Water (209 mL) was added to the reaction mixture, and concentrated hydrochloric acid (67 mL) was added to separate the organic layer. The aqueous layer was extracted with toluene (80 mL), and the extract was combined with the organic layer, and then extracted twice with 2M NaOH aqueous solution (185 mL*1 and 23 mL*1) to allow the target compound to enter the aqueous layer. The aqueous layers were combined, and concentrated hydrochloric acid (80 mL) was added to adjust it to acidity, followed by extraction with toluene twice (102 mL each time). The organic layers were combined and then washed with water (50 mL). The organic layer was concentrated under reduced pressure to obtain compound IV (38.00 g, yellow oil, molar yield 94.66%);

[0183] 1 H-NMR (400 MHz, CDCl 3 )δ 0.88 (t, 3H, J=7.4Hz), 1.32-1.42 (m, 1H), 1.5-1.6 (m, 1H), 2.12-2.25 (m, 3H), 5.00-5 .06 (m, 2H), 5.65-5.76 (m, 1H), 5.80 (d, 1H, J=15.8Hz), 6.90 (dd, 1H, J=8.4, 15.8Hz).

[0184] Example 6

[0185]

[0186] Under nitrogen atmosphere, (2E)-4-ethylhept-2,6-dienoic acid (20.0 g, purity: 90.7%) was dissolved in N,N-dimethylformamide (60 mL) solution. Acetic anhydride (22.2 mL, 0.24 mol) and triethylamine (28 mL, 0.20 mol) were added to the mixed solution. The reaction mixture was heated and stirred at 105-115°C for 6.5 hours. The reaction mixture was cooled to room temperature, and water (100 mL) was added thereto, followed by extraction with n-hexane four times (80 mL*2 and 50 mL*2). All the extracted organic layers were combined and then washed with a saturated aqueous solution of sodium bicarbonate (50 mL) and water (50 mL) in sequence. The obtained organic layer was concentrated under reduced pressure (93-102°C, about 25 mmHg) to obtain compound V (14.11 g, colorless oil) (molar yield: 80%, total molar yield: 66%);

[0187] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.07 (t, 3H, J=7.4Hz), 2.14 (q, 2H, J=7.4Hz), 2.28-2.34 (m, 1H), 2.75-2.86 (m, 3H), 3.16-3.25 (m, 1H), 4.16-4.22 (m, 1H), 5.20-5.24 (m, 1H).

Claims

1. A method for preparing a compound of formula III, characterized in that: It includes the following steps: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula II and the compound of formula A undergo an addition reaction as shown below to obtain a compound of formula III; ； Wherein, R1 is hydrogen or C1-C6 alkyl, and X is halogen.

2. The method for preparing the compound of formula III according to claim 1, characterized in that: It meets one or more of the following conditions: (1) R1 is a C1-C6 alkyl group; (2) X is fluorine, chlorine, bromine or iodine; (3) The organic solvent is one or more of a nitrile solvent, an alcohol solvent and a cyclic ether solvent, such as a cyclic ether solvent; (4) The mass volume ratio of the compound of formula II to the organic solvent is (0.2-0.6) g / mL; (5) The organic base is potassium tert-butoxide and / or sodium tert-butoxide; (6) The molar ratio of the compound of formula II to the organic base is 1:(0.5-3.5); (7) The inorganic catalyst is one or more of zinc iodide, zinc chloride and potassium iodide; (8) The molar ratio of the compound of formula II to the inorganic catalyst is 1:(0.001-0.007); (9) The molar ratio of the compound of formula II to the compound of formula A is 1:(0.5-3.5); (10) The reaction temperature of the addition reaction is -5-5°C; and (11) The order of adding materials for the addition reaction comprises the following steps: mixing an organic base and an inorganic catalyst with a part of an organic solvent to form a first mixed solution; then mixing the first mixed solution with a solution of a compound of formula II to form a second mixed solution; then mixing the second mixed solution with a solution of a compound of formula A to carry out the addition reaction; wherein the solution of the compound of formula II is a mixed solution of the compound of formula II and a part of an organic solvent; and the solution of the compound of formula A is a mixed solution of the compound of formula A and a part of an organic solvent; wherein the sum of the amounts of all "parts" of organic solvents used is the amount of organic solvent used for the addition reaction.

3. The method for preparing the compound of formula III as claimed in claim 2, characterized in that: It meets one or more of the following conditions: (1) R1 is methyl or ethyl, for example ethyl; (2) X is bromine; (3) The nitrile solvent is acetonitrile; (4) The alcohol solvent is ethanol and / or methanol; (5) The cyclic ether solvent is tetrahydrofuran; (6) The mass volume ratio of the compound of formula II to the organic solvent is 0.4 g / mL; (7) The organic base is potassium tert-butoxide; (8) The molar ratio of the compound of formula II to the organic base is 1:1; (9) The inorganic catalyst is zinc iodide; (10) The molar ratio of the compound of formula II to the inorganic catalyst is 1:0.004; (11) the molar ratio of the compound of formula II to the compound of formula A is 1:1; and (12) The reaction temperature of the addition reaction is 0°C.

4. A method for preparing a compound of formula III as claimed in any one of claims 1 to 3, characterized in that: The method further comprises the following steps: in an organic solvent, in the presence of an organic base and an inorganic catalyst, subjecting the compound of formula I to an aldehyde enol silyl etherification reaction with a chlorosilane compound to obtain the compound of formula II; 。 5. The method for preparing the compound of formula III as claimed in claim 4, characterized in that: The preparation method of the compound of formula II satisfies one or more of the following conditions: (1) The organic solvent is one or more of a nitrile solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent and an amide solvent, such as a nitrile solvent; (2) The mass volume ratio of the compound of formula I to the organic solvent is (0.05-0.2) g / mL; (3) The organic base is a tertiary amine compound; (4) The molar ratio of the compound of formula I to the organic base is 1:(1-4); (5) The inorganic catalyst is an iodine metal compound; (6) The molar ratio of the compound of formula I to the iodine metal compound is 1:(0.5-2.5); (7) The chlorosilane compound is trimethylchlorosilane and / or tert-butyldimethylchlorosilane; (8) The molar ratio of the compound of formula I to the chlorosilane compound is 1:(1-4); (9) The temperature of the enol silylation reaction of the aldehyde is 20-100°C; and (10) The feeding sequence of the enol silylation reaction of the aldehyde comprises the following steps: mixing the compound of formula I, an organic base, an inorganic catalyst and an organic solvent to form a first mixed solution, and then mixing the first mixed solution with a chlorosilane compound to carry out the enol silylation reaction of the aldehyde; wherein the first mixed solution and the chlorosilane compound are mixed by dropwise addition; and the dropwise addition rate is 3-6 drops (e.g., 3-4 drops) per minute.

6. The method for preparing the compound of formula III as claimed in claim 5, characterized in that: The preparation method of the compound of formula II satisfies one or more of the following conditions: (1) The nitrile solvent is acetonitrile; (2) The halogenated hydrocarbon solvent is dichloromethane; (3) The aromatic hydrocarbon solvent is toluene; (4) The amide solvent is N,N-dimethylformamide; (5) The mass volume ratio of the compound of formula I to the organic solvent is 0.09 g / mL; (6) The tertiary amine compound is one or more of triethylamine, tripropylamine, tributylamine and N-methylmorpholine, such as triethylamine; (7) The molar ratio of the compound of formula I to the organic base is 1:2.4; (8) The iodine metal compound is one or more of sodium iodide, potassium iodide and lithium iodide, such as sodium iodide; (9) The molar ratio of the compound of formula I to the iodine metal compound is 1:1; (10) The chlorosilane compound is trimethylchlorosilane; (11) the molar ratio of the compound of formula I to the chlorosilane compound is 1:1.5; and The temperature of the enol silylation reaction of the aldehyde described in (12) is 82°C.

7. A method for preparing a compound of formula II, comprising the following steps: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula I is subjected to an aldehyde enol silyl etherification reaction with a chlorosilane compound to obtain a compound of formula II; ； The conditions and parameters of the enol silylation reaction of the aldehyde are as described in any one of claims 5-6.

8. A method for preparing a compound of formula V, comprising the following steps: S1: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula I is subjected to an aldehyde enol silyl etherification reaction with a chlorosilane compound to obtain a compound of formula II; ； S2: In an organic solvent, in the presence of an organic base and an inorganic catalyst, the compound of formula II and the compound of formula A undergo an addition reaction to obtain a compound of formula III; ； S3: In an organic solvent, in the presence of an organic base and a catalyst, the compound of formula III undergoes a Knoevenagel condensation reaction with malonic acid to obtain a compound of formula IV; ； S4: In an organic solvent, in the presence of an organic base, the compound of formula IV undergoes a [2+2] cycloaddition reaction with an acid anhydride compound to obtain a compound of formula V; ； Wherein, R1 is hydrogen or C1-C6 alkyl, and X is halogen.

9. The method for preparing the compound of formula V according to claim 8, characterized in that: It meets one or more of the following conditions: (1) In step S1, the conditions and parameters of the enol silylation reaction of the aldehyde are as described in any one of claims 5 to 6; (2) In step S2, the conditions and parameters of the addition reaction are as described in any one of claims 1 to 3; (3) In step S3, the organic solvent is one or more of an aromatic heterocyclic solvent, a nitrile solvent and an aromatic hydrocarbon solvent, such as a nitrile solvent and / or an aromatic hydrocarbon solvent, and further such as an aromatic hydrocarbon solvent; (4) In step S3, the mass volume ratio of the compound of formula III to the organic solvent is 0.1-0.5 g / mL; (5) In step S3, the organic base is pyridine and / or triethylamine; (6) In step S3, the molar ratio of the compound of formula III to the organic base is 1:(1-4); (7) In step S3, the catalyst is morpholine and / or piperidine; (8) In step S3, the molar ratio of the compound of formula III to the catalyst is 1:(0.3-0.7); (9) In step S3, the molar ratio of the compound of formula III to the malonic acid is 1:(1-3); (10) In step S3, the temperature of the Knoevenagel condensation reaction is 75-100°C; (11) In step S4, the organic solvent is an aprotic solvent; (12) In step S4, the mass volume ratio of the compound of formula IV to the organic solvent is 0.2-0.5 g / mL; (13) In step S4, the organic base is a tertiary amine compound; (14) In step S4, the molar ratio of the compound of formula IV to the organic base is 1:(0.5-3); (15) In step S4, the acid anhydride compound is one or more of acetic anhydride, propionic anhydride and butyric anhydride; (16) In step S4, the molar ratio of the compound of formula IV to the acid anhydride compound is 1:(1-5); and (17) In step S4, the temperature of the [2+2] cycloaddition reaction is 90-130°C.

10. The method for preparing the compound of formula V according to claim 9, characterized in that: It meets one or more of the following conditions: (1) In step S3, the aromatic heterocyclic solvent is pyridine; (2) In step S3, the nitrile solvent is acetonitrile; (3) In step S3, the aromatic hydrocarbon solvent is toluene; (4) In step S3, the mass volume ratio of the compound of formula III to the organic solvent is 0.2 g / mL; (5) In step S3, the organic base is pyridine; (6) In step S3, the molar ratio of the compound of formula III to the organic base is 1:2.3; (7) In step S3, the catalyst is morpholine; (8) In step S3, the molar ratio of the compound of formula III to the catalyst is 1:0.58 or 1:0.56, for example 1:0.58; (9) In step S3, the molar ratio of the compound of formula III to the malonic acid is 1:1.7; (10) In step S3, the temperature of the Knoevenagel condensation reaction is 82° C.; (11) In step S4, the aprotic solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone, for example, N,N-dimethylacetamide; (12) In step S4, the mass volume ratio of the compound of formula IV to the organic solvent is 0.3 g / mL; (13) In step S4, the tertiary amine compound is one or more of triethylamine, tripropylamine, tributylamine and N-methylmorpholine, for example, triethylamine; (14) In step S4, the molar ratio of the compound of formula IV to the organic base is 1:1 or 1:1.7, for example 1:1; (15) In step S4, the acid anhydride compound is acetic anhydride; (16) In step S4, the molar ratio of the compound of formula IV to the acid anhydride compound is 1:2; and (17) In step S4, the temperature of the [2+2] cycloaddition reaction is 100-120°C, for example 105-115°C.

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