Preparation method of melogabalin besylate key intermediate

Abstract

The invention discloses a preparation method of a melogabalin besylate key intermediate. The invention provides a preparation method of a compound IV, which comprises the following steps: step (1): in a solvent, in the presence of alkali, a compound III is subjected to a reaction under a reflux condition; and (2) in a solvent, continuously reacting the product obtained in the step (1) to obtain a compound IV. The preparation method disclosed by the invention is simple, low in cost, high in yield and high in purity, and has a good application prospect in industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing a key intermediate of melogabalin besylate. Background Art

[0002] Peripheral neuropathic pain is caused by peripheral nerve damage or dysfunction due to various reasons, typically including diabetic and post-herpetic neuralgia. Peripheral neuropathic pain caused by diabetes is the most common long-term complication of diabetes patients. Symptoms include sharp pain or hypersensitivity, numbness, loss of balance and coordination, tingling, and burning sensations, which are worse at night. Shingles is caused by a decrease in immunity to the varicella-zoster virus, which forms a latent infection in the ganglia. In neuralgia, even after the shingles are cured, the burning pain or pain that penetrates the body like electricity still exists. The disease is considered a stubborn pain that can cause muscle weakness and, in rare cases, paralysis.

[0003] Mirogabalin is a GABA (γ-aminobutyric acid) analog that acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely present in the nervous system that mediates pain transmission and processing throughout the body), thereby playing a role in treating chronic neuropathic pain. It is a new drug developed by Daiichi Sankyo Co., Ltd. in Japan to treat peripheral neuropathic pain. Its molecular formula is as follows:

[0004]

[0005] The reported synthesis methods of melogabalin benzenesulfonate all contain the key intermediate compound 3-ethylbicyclo[3.2.0]hept-3-en-6-one (Compound I), the structure of which is as follows:

[0006]

[0007] WO20010110361 reports a process for preparing compound I by using ethyl acetoacetate and 3-bromopropylene as raw materials through a four-step reaction. However, ethyl acetoacetate has two α-carbon atoms and the reaction site is not specific, which results in a low yield of the process and is not suitable for industrialization.

[0008]

[0009] WO2012169475 uses n-butyraldehyde and allyl alcohol as raw materials, and generates heptadienoic acid through acetal reaction, Claisen rearrangement and Clauwinger condensation, and then undergoes intramolecular reaction to generate the key intermediate compound I. This route uses allyl alcohol as a liquid highly toxic substance, which has high requirements for personal protection during production and is not conducive to large-scale commercial production.

[0010]

[0011] WO2012169474 reports that n-butyraldehyde and diisobutylamine are used as raw materials, condensed to form an enamine intermediate, which is then substituted with 3-bromopropylene to form a quaternary ammonium salt, which is then condensed by Krypton-Winger to form an intermediate heptadienoic acid, which is then cyclized by an intramolecular reaction to form compound I. This route avoids the use of highly toxic allyl alcohol, and diisobutylamine is relatively expensive.

[0012]

[0013] CN117945887A uses (E)-2-hexenoic acid ester as a raw material and 3-bromopropylene as a raw material to prepare heptadienoic acid through a one-pot process. According to the above-mentioned reported method, heptadienoic acid can be used to prepare compound I through a one-step reaction. However, (E)-2-hexenoic acid ester is very expensive and is not suitable for commercial production.

[0014] . Summary of the invention

[0015] The present invention aims to overcome the defects of high cost and possible use of highly toxic drugs in the preparation of key intermediates of melogabalin benzenesulfonate in the prior art. The present invention provides a method for preparing a key intermediate of melogabalin benzenesulfonate. The preparation method of the present invention is simple, low in cost, high in yield and high in purity, and has good application prospects in industrial production.

[0016] The present invention provides a method for preparing compound IV, which comprises the following steps:

[0017] Step (1): Compound III is reacted under reflux conditions in a solvent in the presence of a base;

[0018] Step (2): In a solvent, the product obtained in step (1) is further reacted to prepare compound IV;

[0019] ;

[0020] Among them, R 1 and R 2 are independently C1-C6 alkyl; or R 1 and R 2 Connected to form .

[0021] In one embodiment of the present invention, R 1 and R 2 same.

[0022] In a certain embodiment of the present invention, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; preferably methyl, ethyl or tert-butyl.

[0023] In a certain embodiment of the present invention, compound III is , , or ; preferably , or .

[0024] In one embodiment of the present invention, in step (1), the solvent is an organic solvent; preferably an alcohol solvent; for example, ethanol.

[0025] In one embodiment of the present invention, in step (1), the base is an inorganic base; preferably an alkali metal hydroxide; for example, potassium hydroxide and / or sodium hydroxide.

[0026] In one embodiment of the present invention, in step (1), the molar volume ratio of the compound III to the solvent is 1 mmol: (0.8-1.2) mL; preferably 1 mmol: 1 mL.

[0027] In one embodiment of the present invention, in step (1), the molar ratio of the compound III to the base is 1:(1-2); preferably 1:1.3.

[0028] In one embodiment of the present invention, in step (2), the solvent is a mixed solvent of an organic solvent and water; the organic solvent may be an alcohol solvent; for example, ethanol.

[0029] In one embodiment of the present invention, in step (2), the volume ratio of the organic solvent to water is 1:(0.8-1.2); for example, 1:1.

[0030] In one embodiment of the present invention, the molar volume ratio of the compound III in step (1) to the solvent in step (2) is 1 mmol:(1.8-2.2) mL; preferably 1 mmol:2 mL.

[0031] In one embodiment of the present invention, in step (2), the reaction is carried out under reflux conditions; or the reaction temperature is 15-45°C; preferably 20-30°C.

[0032] In a certain embodiment of the present invention, when compound III is , or When, in step (2), the reaction temperature is 15-45°C; preferably 20-30°C; when compound III is When, in step (2), the reaction is carried out under reflux conditions.

[0033] In one embodiment of the present invention, the disappearance of compound III is regarded as the end point of step (1).

[0034] In a certain embodiment of the present invention, the preparation method of compound IV further includes the following post-processing steps: concentration, dissolution, adjusting pH ≤ 3, separation, extraction, combining organic phases, washing and concentration; the concentration may be reduced pressure concentration; the dissolution may be methyl tert-butyl ether dissolution; the pH adjustment may be adjusted by hydrochloric acid, for example, concentrated hydrochloric acid; the extraction solvent may be methyl tert-butyl ether; the washing may be washed with 10% sodium chloride solution.

[0035] In one embodiment of the present invention, the raw materials for the preparation method of compound IV are compound III, the base, the solvent in step (1) and the solvent in step (2).

[0036] In one embodiment of the present invention, the preparation method of compound IV also includes the preparation method of compound III, and the preparation method of compound III includes the following steps: in a solvent, in the presence of a base, compound II and 3-bromopropylene undergo a substitution reaction to prepare compound III;

[0037] ;

[0038] Among them, R 1 and R 2 The definition of is as described in any embodiment of the present invention.

[0039] In a certain embodiment of the present invention, the compound II is , , or .

[0040] In one embodiment of the present invention, the solvent is an organic solvent; preferably an ether solvent; the ether solvent may be tetrahydrofuran; for example, anhydrous tetrahydrofuran.

[0041] In one embodiment of the present invention, the base is sodium hydride; for example, 60% sodium hydride.

[0042] In a certain embodiment of the present invention, the mass volume ratio of the compound II to the solvent is 1 g:(2-8) mL; preferably 1 g: 5 mL.

[0043] In a certain embodiment of the present invention, the molar ratio of the compound II to the base is 1:(1-1.2); preferably 1:1.1.

[0044] In a certain embodiment of the present invention, the molar ratio of the compound II to the 3-bromopropylene is 1:(1-1.2); preferably 1:1.05.

[0045] In one embodiment of the present invention, the base is added dropwise at ≤5°C.

[0046] In one embodiment of the present invention, the 3-bromopropylene is added dropwise at ≤5°C.

[0047] In one embodiment of the present invention, the reaction steps of the preparation method of compound III are as follows: adding a base, reacting at 0°C for 0.5-2 hours, for example, 1 hour; adding 3-bromopropylene, reacting at 0-5°C for 0.5-2 hours, for example, 1 hour; heating to 20-35°C, for example, 25°C; reacting until the reaction of compound II is complete as monitored by TLC.

[0048] In a certain embodiment of the present invention, the raw materials for the preparation method of the compound III are the compound II, the solvent, the base and the 3-bromopropylene.

[0049] The present invention provides a method for preparing compound III, and the method for preparing compound III is as described in any scheme of the present invention.

[0050] In a certain embodiment of the present invention, the preparation method of the compound III further includes the following post-treatment steps: quenching, liquid separation, extraction and concentration; the quenching can be slowly adding the reaction solution to 5-6 mol / L dilute hydrochloric acid at a temperature not higher than 10°C; the solvent for the liquid separation can be toluene; the extraction can be first washed with water and then with 5% sodium bicarbonate solution; the concentration can be pressurized concentration.

[0051] The present invention provides a method for preparing compound I, which comprises the following steps:

[0052] Step 1, step (1): in a solvent, in the presence of a base, compound III reacts under reflux conditions;

[0053] Step (2): In a solvent, the product obtained in step (1) is further reacted to prepare compound IV;

[0054] ;

[0055] The preparation method of compound IV is as described in any scheme of the present invention;

[0056] Step 2, in a solvent, compound IV is reacted with triethylamine to prepare compound V;

[0057] ;

[0058] Step 3, in a solvent, in the presence of an acid and a catalyst, compound V undergoes a cyclization reaction to prepare compound I;

[0059] .

[0060] In one embodiment of the present invention, in step 2, the solvent is an organic solvent; preferably an ether solvent and an alkane solvent; for example, methyl tert-butyl ether and n-heptane; preferably, the volume ratio of the ether solvent to the alkane solvent is 1:(8-10); for example, 1:9.38.

[0061] In a certain embodiment of the present invention, in step 2, the mass volume ratio of the compound IV to the solvent is 1 g:(8-12) mL; preferably 1 g:10.78 mL.

[0062] In a certain embodiment of the present invention, in step 2, the mass ratio of the compound IV to the triethylamine is 1:(0.6-0.9); preferably 1:0.79.

[0063] In one embodiment of the present invention, in step 2, the triethylamine is first mixed with an alkane solvent; and then reacted with compound II.

[0064] In one embodiment of the present invention, in step 2, the reaction temperature is room temperature; for example, 25°C.

[0065] In a certain embodiment of the present invention, the step 2 further comprises the following post-processing steps: cooling, filtering and concentrating; the cooling may be reduced to 0-5°C; the concentrating may be reduced pressure concentration.

[0066] In a certain embodiment of the present invention, in step 3, the solvent is an organic solvent; preferably an aprotic solvent; for example, one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; another example is N,N-dimethylacetamide.

[0067] In one embodiment of the present invention, in step 3, the catalyst is a base catalyst; the base catalyst may be a tertiary amine; for example, one or more selected from triethylamine, tripropylamine, tributylamine and N-methylmorpholine; for example, triethylamine.

[0068] In a certain embodiment of the present invention, in step 3, the acid is an acid anhydride; for example, one or more selected from acetic anhydride, propionic anhydride and butyric anhydride; for example, acetic anhydride.

[0069] In a certain embodiment of the present invention, in step 3, the mass volume ratio of the compound V to the solvent is 1 g: (1.3-1.8) mL; preferably 1 g: 1.53 mL.

[0070] In a certain embodiment of the present invention, in step 3, the molar ratio of the compound V to the catalyst is 1:(0.06-0.1); preferably 1:0.089.

[0071] In a certain embodiment of the present invention, in step 3, the molar ratio of the compound V to the acid is 1:(1.2-1.8); preferably 1:1.69.

[0072] In one embodiment of the present invention, in step 3, the reaction temperature is 100-125°C; preferably 115-117°C.

[0073] In a certain embodiment of the present invention, in step 3, the reaction time is 4-6 h, preferably 5 h.

[0074] In a certain embodiment of the present invention, the step 3 also includes the following post-processing steps: cooling, adding solvent; extraction, combining organic phases; washing, concentration and distillation; the cooling can be reduced to 20-30°C; the added solvent can be water and n-hexane; the extraction solvent can be n-hexane; the washing can be washed with 5% sodium bicarbonate solution and water; the concentration can be pressurized concentration; the distillation can be reduced pressure distillation; for example, 60-70°C, about 10 mmHg.

[0075] In a certain embodiment of the present invention, the preparation method of compound I also includes a preparation method of compound III, and the preparation method of compound III is as described in any embodiment of the present invention.

[0076] In one embodiment of the present invention, the method for preparing compound I also includes the following method for preparing compound II, wherein n-butyraldehyde and compound A react in a solvent under a catalyst to prepare compound II; wherein compound II is defined as described in any embodiment of the present invention;

[0077] ;

[0078] The compound A is a malonate or .

[0079] In a certain embodiment of the present invention, in the method for preparing compound II, the malonate is dimethyl malonate, diethyl malonate or di-tert-butyl malonate.

[0080] In one embodiment of the present invention, in the preparation method of compound II, the catalyst is an acid catalyst and a base catalyst; the acid catalyst is preferably glacial acetic acid; the base catalyst is preferably nitrogen methylmorpholine or 4-methylpiperidine; for example, nitrogen methylmorpholine.

[0081] In one embodiment of the present invention, in the method for preparing compound II, the solvent is an organic solvent; preferably an alcohol solvent; more preferably methanol or ethanol.

[0082] In one embodiment of the present invention, in the preparation method of compound II, when compound A is dimethyl malonate, the solvent is methanol; when compound A is diethyl malonate, di-tert-butyl malonate or When, the solvent is ethanol.

[0083] In one embodiment of the present invention, in the method for preparing compound II, the molar ratio of the n-butyraldehyde to the catalyst is 1:(0.2-0.4); for example, 1:0.3.

[0084] In one embodiment of the present invention, in the method for preparing compound II, the molar ratio of the n-butyraldehyde to the compound A is 1:(1-1.2); for example, 1:1.1.

[0085] In a certain embodiment of the present invention, in the method for preparing compound II, the mass volume ratio of the n-butyraldehyde to the solvent is 1:(3-6); for example, 1:5.

[0086] In a certain embodiment of the present invention, the preparation method of compound II further includes the following post-treatment steps: concentration, dissolution, hydrochloric acid (e.g., 0.5M dilute hydrochloric acid), separation, washing the organic phase and concentration; the concentration may be reduced pressure concentration; the dissolution may be methyl tert-butyl ether dissolution; the washing may be washing with 5% sodium bicarbonate and water in sequence.

[0087] The present invention also provides a compound as shown in formula III,

[0088] ;

[0089] Wherein, the compound represented by formula III is defined as described in any scheme of the present invention.

[0090] 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.

[0091] The reagents and raw materials used in the present invention are commercially available.

[0092] The positive progress effect of the present invention is that the present invention provides a method for preparing a key intermediate of melogabalin besylate. The preparation method of the present invention is simple, low in cost, high in yield and purity, and has good application prospects in industrial production. DETAILED DESCRIPTION

[0093] 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.

[0094] Example 1, preparation of compound II:

[0095]

[0096] Under nitrogen protection, add 7.2g of n-butyraldehyde (100mmol), malonic acid ester (110mol), 1.51g of nitrogen methylmorpholine (15mmol), 0.90g of glacial acetic acid (15mmol), and 36mL of anhydrous alcohol to the reaction bottle, heat and reflux to react until TLC shows that n-butyraldehyde disappears. Concentrate to dryness under reduced pressure, add 36mL of methyl tert-butyl ether and 20mL of 0.5M dilute hydrochloric acid, stir evenly and separate the liquids, wash the organic phase with 20mL of 5% sodium bicarbonate and 20mL of water in turn, and concentrate to dryness under pressure to obtain compound II.

[0097] R 1 and R 2 The methyl group: the malonate is dimethyl malonate, the anhydrous alcohol is methanol, and 18.0 g of oily liquid is obtained, with a yield of 96.8%. 1H NMR (400 MHz, CDCl3): δ ppm 7.01 (t, 1H), 4.36 (s, 3H), 4.31 (s,3H), 2.16-2.23 (m, 2H), 1.83-1.87 (m, 2H), 0.94 (t, 3H)

[0098] R 1 and R 2 The ethyl:malonic acid ester is diethyl malonate, the anhydrous alcohol is ethanol, and 21.5 g of oily liquid is obtained, with a yield of 100.0%. 1H NMR (400 MHz, CDCl3): δ ppm 7.03 (t, 1H), 4.31 (q, 2H), 4.26 (q,2H), 2.17-2.24 (m, 2H), 1.84-1.87 (m, 2H), 1.33 (t, 3H), 1.31 (t, 3H), 0.95(t, 3H)

[0099] R 1 and R 2For tert-butyl: the malonate is di-tert-butyl malonate, the anhydrous alcohol is ethanol, 26.8 g, yield 99.3%, 1H NMR (400 MHz, CDCl3): δ ppm 7.00 (t, 1H), 2.15-2.20 (m, 2H), 1.80-1.85 (m, 2H), 1.41 (s, 9H), 1.39 (s, 9H), 0.93 (t, 3H)

[0100] R 1 and R 2 Connected to form: : Anhydrous alcohol is replaced by ethanol, and malonate is replaced by , 19.5 g of a light yellow solid was obtained, with a yield of 98.5%. 1H NMR (400 MHz, CDCl3): δ ppm 7.02 (t, 1H), 2.17-2.22 (m, 2H), 1.80-1.85 (m, 2H), 1.76(s, 9H), 1.39 (s, 9H), 0.95 (t, 3H)

[0101] Example 2, preparation of compound III:

[0102]

[0103] Add 100mmol of compound II and anhydrous tetrahydrofuran (1g of compound II / 5mL of tetrahydrofuran) to the reaction bottle, cool to 0℃, control the temperature not higher than 5℃, slowly add 2.64g of NaH (110mmol, 60%), then control the temperature to 0℃ and stir for 1 hour, control the temperature not higher than 5℃ and slowly add 12.7g of 3-bromopropylene (105mmol), stir for 1 hour after addition, raise the temperature to 25℃, and keep the temperature to react until TLC shows that compound II disappears. Control the temperature not higher than 10℃ and slowly add the reaction solution to 30mL of 5-6mol / L dilute hydrochloric acid, add 100mL of toluene after addition, and separate the liquids. Wash the organic phase with 30mL of water, 30mL of 5% sodium bicarbonate solution, and concentrate under pressure to dry compound III.

[0104] R 1 and R 2Methyl: oily liquid, 20.8 g, yield 92.3%, 1H NMR (400 MHz, CDCl3): δ ppm7.65 (d, 1H), 5.64-5.75(m, 1H), 4.96-5.05(m, 2H), 4.30(s, 3H), 4.21(s, 3H),3.70-3.78(m, 1H), 2.34-2.42(m, 1H), 2.16-2.25(m, 1H), 1.45-1.58(m, 2H), 0.93(t, 3H)

[0105] R 1 and R 2 Ethyl: oily liquid, 23.6 g, yield 92.9%, 1H NMR (400 MHz, CDCl3): δ ppm7.63 (d, 1H), 5.66-5.77(m, 1H), 4.97-5.06(m, 2H), 4.26(s, 2H), 4.19(s, 2H),3.69-3.78(m, 1H), 2.33-2.42(m, 1H), 2.12-2.21(m, 1H), 1.46-1.58(m, 2H), 1.35(t, 3H), 1.32 (t, 3H), 0.92(t, 3H)

[0106] R 1 and R 2 For tert-butyl: oily liquid, 30.5 g, yield 98.4%, 1H NMR (400 MHz, CDCl3): δppm 7.64 (d, 1H), 5.65-5.77(m, 1H), 4.97-5.08(m, 2H), 3.68-3.78(m, 1H), 2.33-2.42(m, 1H), 2.12-2.21(m, 1H), 1.62-1.72(m, 1H), 1.42-1.53(m, 1H), 1.41 (s,9H), 1.39 (s, 9H), 0.93(t, 3H)

[0107] R 1 and R 2 Connected to form: : Obtained slightly yellow solid, 23.0 g, yield 98.7%, 1H NMR (400 MHz,CDCl3): δ ppm 7.63 (d, 1H), 5.66-5.77(m, 1H), 4.97-5.06(m, 2H), 3.69-3.78(m,1H), 2.33-2.42(m, 1H), 2.12-2.21(m, 1H), 1.74(s, 6H), 1.62-1.72(m, 1H), 1.42-1.53(m, 1H), 0.92(t, 3H)

[0108] Example 3, preparation of compound IV:

[0109]

[0110] Add 100 mmol of compound III, 100 mL of ethanol, and 7.28 g of sodium hydroxide (130 mmol) to the reaction vessel, raise the temperature to reflux, and keep the temperature under reflux until compound III disappears. Cool to 20-30 ° C, add 100 mL of water, and continue to keep the temperature until TLC shows that the intermediate state disappears. Concentrate under reduced pressure to about 100 mL. Add 100 mL of methyl tert-butyl ether, adjust the pH to ≤ 3 with concentrated hydrochloric acid, separate the liquids, and extract the aqueous phase with 50 mL of methyl tert-butyl ether. Combine the organic phases, wash the organic phases with 10% sodium chloride solution (50 mL*2), and concentrate under reduced pressure to obtain an oily liquid. MS (MH + ):153.

[0111] R 1 and R 2 The product was methyl, 15.0 g, with a yield of 97.7%.

[0112] R 1 and R 2 Ethyl group, 14.8 g, yield 96.1%.

[0113] R 1 and R 2 Connected to form: , 14.9 g was obtained, with a yield of 96.7%.

[0114] Example 4, preparation of compound IV:

[0115]

[0116] Add 31.0g of compound III-tBu (100mmol), 100mL of ethanol, and 7.28g of sodium hydroxide (130mmol) to the reaction container, heat to reflux, keep warm under reflux for reaction, then add 100mL of water, continue to keep warm until the reaction is completed, and concentrate under reduced pressure to about 100mL. Add 100mL of methyl tert-butyl ether, adjust pH ≤ 3 with concentrated hydrochloric acid, separate the liquids, and extract the aqueous phase with 50mL of methyl tert-butyl ether. Combine the organic phases, wash the organic phases with 10% sodium chloride solution (50mL*2), and concentrate under reduced pressure to obtain 11.8g of oily liquid with a yield of 76.6%.

[0117] Example 5, Preparation of Compound V:

[0118]

[0119] Add 15.4 g of compound II (100 mmol) and 16 mL of methyl tert-butyl ether to the reaction bottle, and add dropwise a solution of 12.1 g of triethylamine dissolved in 150 mL of n-heptane at room temperature (20-30°C). After the addition is complete, cool to 0-5°C, filter, and dry under reduced pressure to obtain 24.0 g of a white solid with a yield of 94.1%.

[0120] Example 6, Preparation of Compound V:

[0121]

[0122] Add 100mmol of compound II and anhydrous tetrahydrofuran (1g of compound II / 5mL of tetrahydrofuran) to the reaction flask, cool to 0℃, keep the temperature below 5℃ and slowly add 2.64g of NaH (110mmol, 60%), then keep the temperature at 0℃ and stir for 1 hour, keep the temperature below 5℃ and slowly drop 12.7g of 3-bromopropylene (105mmol), stir for 1 hour after addition, heat to 25℃, and keep warm until TLC shows compound II disappears. Add 70mL of ethanol and 7.28g of sodium hydroxide (130mmol) to the reaction flask, heat and distill at the same time, wait until the internal temperature rises to about 80℃, keep warm until TLC shows compound III disappears. Cool to room temperature (20-30℃), add 100mL of water, keep warm until the reaction is completed, and concentrate under reduced pressure to about 100mL. Add 100 mL of methyl tert-butyl ether, adjust pH to ≤ 3 with concentrated hydrochloric acid, separate the liquids, and extract the aqueous phase with 50 mL of methyl tert-butyl ether. Combine the organic phases, wash with 10% sodium chloride solution (50 mL*2) in turn, and dry the organic phase with anhydrous sodium sulfate. Concentrate under reduced pressure to 30-40 mL, and dropwise add a solution of 12.1 g of triethylamine dissolved in 150 mL of n-heptane. After the addition is complete, cool to 0-5 °C, filter, and dry under reduced pressure to obtain a white solid.

[0123] R 1 and R2 Methyl was obtained, 23.5 g, with a yield of 92.2%.

[0124] R 1 and R 2 Ethyl group, 23.7 g, yield 92.9%.

[0125] R 1 and R 2 Connected to form: , 21.6 g was obtained, with a yield of 84.7%.

[0126] Example 7, Preparation of Compound V:

[0127]

[0128] Add 27.0g of compound II-tBu (100mmol) and 135mL of anhydrous tetrahydrofuran to the reaction flask, cool to 0℃, control the temperature not higher than 5℃, slowly add 2.64g of NaH (110mmol, 60%), then control the temperature to 0℃ and stir for 1 hour, control the temperature not higher than 5℃ and slowly add 12.7g of 3-bromopropylene (105mmol), stir for 1 hour after addition, heat to 25℃, and keep warm until TLC shows that compound II disappears. Add 70mL of ethanol and 7.28g of sodium hydroxide (130mmol) to the reaction flask, heat and distill at the same time, wait until the internal temperature rises to about 80℃, and keep warm until TLC shows that compound III-tBu disappears. Then add 100mL of water, continue to reflux until the reaction is completed, and concentrate under reduced pressure to about 100mL. Add 100mL of methyl tert-butyl ether, adjust pH ≤ 3 with concentrated hydrochloric acid, separate the liquids, and extract the aqueous phase with 50mL of methyl tert-butyl ether. Combine the organic phases, wash the organic phases with 10% sodium chloride solution (50mL*2), and dry the organic phases with anhydrous sodium sulfate. Concentrate under reduced pressure to 30-40mL, and dropwise add a solution of 12.1g of triethylamine dissolved in 150mL of n-heptane. After the addition is complete, cool to 0-5℃, filter, and dry under reduced pressure to obtain 15.6g of white solid with a yield of 61.2%.

[0129] Example 8, Preparation of Compound I:

[0130]

[0131] Add 255g of compound V (1mol), 390mL of N,N-dimethylacetamide, 159mL of acetic anhydride, and 89.9g of triethylamine (89.0mmol) to the reaction bottle. Heat the reaction solution to 115-117°C under stirring and keep the temperature for 5 hours. Cool the reaction solution to room temperature, control the temperature not higher than 30°C, add 1090mL of water, 780mL of n-hexane, stir evenly and separate the liquids, and extract the aqueous phase with n-hexane (390mL*2). Combine the organic phases and wash them with 5% sodium bicarbonate solution (160mL) and water (160mL) once. After the organic phase is pressurized and concentrated, it is distilled under reduced pressure (60-70°C, about 10mmHg) to obtain 103g of colorless liquid compound I, with a yield of 75.7%. Purity 99.82%. 1H NMR (400 MHz, CDCl3): δ ppm 5.22(t, 1H), 2.18-4.19(m, 1H), 3.16-3.21(m, 1H), 2.80-2.81(m, 2H), 2.28-2.32(m, 1H), 2.12(q, 2H), 1.06(s, 3H).

Claims

1. A method for preparing compound IV, characterized in that: It includes the following steps: Step (1): Compound III is reacted under reflux conditions in a solvent in the presence of a base; Step (2): In a solvent, the product obtained in step (1) is further reacted to prepare compound IV; ； Among them, R 1 and R 2 are independently C1-C6 alkyl; or R 1 and R 2 Connected to form .

2. The method for preparing compound IV according to claim 1, characterized in that: R 1 and R 2 same.

3. The method for preparing compound IV according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; preferably methyl, ethyl or tert-butyl; (2) In step (1), the solvent is an organic solvent; (3) In step (1), the base is an inorganic base; (4) In step (1), the molar volume ratio of the compound III to the solvent is 1 mmol: (0.8-1.2) mL; (5) In step (1), the molar ratio of the compound III to the base is 1:(1-2); (6) In step (2), the solvent is a mixed solvent of an organic solvent and water; (7) The molar volume ratio of the compound III in step (1) to the solvent in step (2) is 1 mmol: (1.8-2.2) mL; (8) In step (2), the reaction is carried out under reflux conditions; or the reaction temperature is 15-45°C; (9) Step (1) is terminated when compound III disappears; and (10) The raw materials of the preparation method of compound IV are compound III, the base, the solvent in step (1) and the solvent in step (2).

4. The method for preparing compound IV according to claim 3, characterized in that: It meets one or more of the following conditions: (1) Compound III is , , or ; preferably , or ; (2) In step (1), the solvent is an alcohol solvent; for example, ethanol; (3) In step (1), the base is an alkali metal hydroxide; for example, potassium hydroxide and / or sodium hydroxide; (4) In step (1), the molar volume ratio of the compound III to the solvent is 1 mmol:1 mL; (5) In step (1), the molar ratio of the compound III to the base is 1:1.3; (6) In step (2), the organic solvent is an alcohol solvent; for example, ethanol; (7) In step (2), the volume ratio of the organic solvent to water is 1:(0.8-1.2); for example, 1:1; (8) The molar volume ratio of the compound III in step (1) to the solvent in step (2) is 1 mmol:2 mL; (9) In step (2), the reaction temperature is 20-30°C; and (10) When compound III is , or When, in step (2), the reaction temperature is 15-45°C; preferably 20-30°C; when compound III is When, in step (2), the reaction is carried out under reflux conditions.

5. The method for preparing compound IV according to claim 1, characterized in that: The preparation method of the compound IV also includes the preparation method of the compound III, and the preparation method of the compound III includes the following steps: in a solvent, in the presence of a base, compound II and 3-bromopropylene undergo a substitution reaction to prepare compound III; ； Among them, R 1 and R 2 The definition as described in any one of claims 1 to 4.

6. The method for preparing compound IV according to claim 5, characterized in that: It meets one or more of the following conditions; (1) The compound II is , , or ; (2) The solvent is an organic solvent; preferably an ether solvent; the ether solvent may be tetrahydrofuran; for example, anhydrous tetrahydrofuran; (3) The base is sodium hydride; for example, 60% sodium hydride; (4) The mass volume ratio of the compound II to the solvent is 1 g: (2-8) mL; preferably 1 g: 5 mL; (5) The molar ratio of the compound II to the base is 1:(1-1.2); preferably 1:1.1; (6) The molar ratio of the compound II to the 3-bromopropylene is 1:(1-1.2); preferably 1:1.05; (7) the base is added dropwise at ≤5°C; (8) adding 3-bromopropylene dropwise at ≤5°C; (9) The reaction steps of the preparation method of compound III are as follows: after adding a base, reacting at 0°C for 0.5-2 hours, for example, 1 hour; adding 3-bromopropylene, reacting at 0-5°C for 0.5-2 hours, for example, 1 hour; heating to 20-35°C, for example, 25°C; reacting until the reaction of compound II is complete as monitored by TLC; and (10) The raw materials of the preparation method of the compound III are the compound II, the solvent, the base and the 3-bromopropylene.

7. A method for preparing compound I, characterized in that: It includes the following steps, Step 1, step (1): in a solvent, in the presence of a base, compound III reacts under reflux conditions; Step (2): In a solvent, the product obtained in step (1) is further reacted to prepare compound IV; ； The preparation method of compound IV is as described in any one of claims 1 to 6; Step 2, in a solvent, compound IV is reacted with triethylamine to prepare compound V; ； Step 3, in a solvent, in the presence of an acid and a catalyst, compound V undergoes a cyclization reaction to prepare compound I; 。 8. The method for preparing compound I according to claim 7, characterized in that: It meets one or more of the following conditions; (1) In step 2, the solvent is an organic solvent; preferably an ether solvent and an alkane solvent; for example, methyl tert-butyl ether and n-heptane; preferably, the volume ratio of the ether solvent to the alkane solvent is 1:(8-10); for example, 1:9.38; (2) In step 2, the mass volume ratio of the compound IV to the solvent is 1 g: (8-12) mL; preferably 1 g: 10.78 mL; (3) In step 2, the mass ratio of the compound IV to the triethylamine is 1:(0.6-0.9); preferably 1:0.79; (4) In step 2, the triethylamine is first mixed with an alkane solvent; and then reacted with compound II; (5) In step 2, the reaction temperature is room temperature; for example, 25°C; (6) In step 3, the solvent is an organic solvent; preferably an aprotic solvent; for example, one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; another example is N,N-dimethylacetamide; (7) In step 3, the catalyst is a base catalyst; the base catalyst may be a tertiary amine; for example, one or more selected from triethylamine, tripropylamine, tributylamine and N-methylmorpholine; for example, triethylamine; (8) In step 3, the acid is an acid anhydride; for example, one or more selected from acetic anhydride, propionic anhydride and butyric anhydride; for example, acetic anhydride; (9) In step 3, the mass volume ratio of the compound V to the solvent is 1 g: (1.3-1.8) mL; preferably 1 g: 1.53 mL; (10) In step 3, the molar ratio of the compound V to the catalyst is 1:(0.06-0.1); preferably 1:0.089; (11) In step 3, the molar ratio of the compound V to the acid is 1:(1.2-1.8); preferably 1:1.69; (12) In step 3, the reaction temperature is 100-125°C; preferably 115-117°C; (13) In step 3, the reaction time is 4-6 h; preferably 5 h. (14) The method for preparing compound I also includes a method for preparing compound III, wherein the method for preparing compound III is as described in claim 5 or 6.

9. The method for preparing compound I according to claim 7, characterized in that: The preparation method of the compound I also includes the following preparation method of the compound II, in a solvent, under a catalyst condition, n-butyraldehyde and compound A react to prepare compound II; ； Wherein, the definition of compound II is as described in claim 5 or 6; The compound A is a malonate or ; Preferably, the preparation method of compound II satisfies one or more of the following conditions: (1) In the preparation method of compound II, the malonate is dimethyl malonate, diethyl malonate or di-tert-butyl malonate; (2) In the preparation method of compound II, the catalyst is an acid catalyst and a base catalyst; the acid catalyst is preferably glacial acetic acid; the base catalyst is preferably nitrogen methylmorpholine or 4-methylpiperidine; for example, nitrogen methylmorpholine; (3) In the preparation method of compound II, the solvent is an organic solvent; preferably an alcohol solvent; more preferably methanol or ethanol; more preferably; When compound A is dimethyl malonate, the solvent is methanol; when compound A is diethyl malonate, di-tert-butyl malonate or When the solvent is ethanol; (4) In the preparation method of compound II, the molar ratio of the n-butyraldehyde to the catalyst is 1:(0.2-0.4); for example, 1:0.3; (5) In the preparation method of compound II, the molar ratio of n-butyraldehyde to compound A is 1:(1-1.2); for example, 1:1.1; and (6) In the preparation method of compound II, the mass volume ratio of the n-butyraldehyde to the solvent is 1:(3-6); for example, 1:

5.

10. A compound as shown in formula III, characterized in that: ； Wherein, the compound represented by formula III is defined as any one of claims 1-4.

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