Preparation method of piperazinone and ring-expanded analogue thereof

Abstract

The invention belongs to the technical field of drug development, and particularly relates to a synthetic method of piperazinone and ring-expanded analogues thereof, for example, a synthetic method of (R)-3-methyl-4-(2, 4-dimethoxybenzyl) piperazin-2-ketone, the reaction general formula is as follows: # imgabs0 #. The synthetic method comprises the following steps: step (1), a compound shown in a formula III or a salt thereof and a compound shown in a formula IV are subjected to a reaction under the action of an acid-binding agent to obtain a compound shown in a formula III; reacting in a solvent to obtain a compound shown as a formula V; the method is simple to operate, impurities in the product are obviously reduced, the purity is up to 99% or above, post-treatment is greatly simplified, the cost is reduced, the method is more suitable for amplified industrial production, more possibilities are provided for synthesis of piperazinone and ring-expanded analogues thereof, and the method has better market value and profound practical significance.

Description

Technical Field

[0001] The invention belongs to the technical field of drug development, and specifically provides a method for synthesizing piperazinone and its ring-expanded analogs, for example, a method for synthesizing (R)-3-methyl-4-(2,4-dimethoxybenzyl)piperazine-2-one. Background Art

[0002] Piperazinone and its ring-expanded analogs are important pharmaceutical intermediates. For example, the general chemical structure of (R)-3-methyl-4-(2,4-dimethoxybenzyl)piperazin-2-one and its derivatives is shown in Formula V:

[0003]

[0004] (R)-3-Methyl-4-(2,4-dimethoxybenzyl)piperazine-2-one is one of the key intermediates of the new NK-3 antagonist drug fizonetant discovered in recent years. Developed by Astellas, fizonetant is a new NK-3 antagonist drug used to treat menopausal polycystic ovary syndrome (PCOS) and vasomotor symptoms (hot flashes) caused by uterine leiomyoma. It was approved for marketing by the U.S. Food and Drug Administration (FDA) in May 2023. It is the first NK3 receptor antagonist approved by the FDA for menopausal VMS and the world's first non-hormonal treatment for VMS with this new mechanism of action.

[0005] At present, the synthesis route of (R)-3-methyl-4-(2,4-dimethoxybenzyl)piperazine-2-one in the prior art is reported as follows:

[0006]

[0007] The first step of the synthesis route will produce impurities such as the bimolecular amine ester exchange shown in formula (2), resulting in low raw material utilization; at the same time, the second step of the reaction will produce isomeric impurities such as the formula (3), which need to be removed by recrystallization, resulting in a low yield and unsatisfactory economic benefits.

[0008]

[0009] Therefore, it is necessary to develop a method for synthesizing piperazinone and its ring-expanded analogues that is easy to operate, has a simple route, is short in time, and has high atom utilization, so as to improve efficiency and promote industrial production. Summary of the invention

[0010] In view of the above technical background, in order to solve the problems in the prior art, the present invention provides a method for preparing piperazinone and its ring-expanded analogs, which has simple process, high yield, high purity, high applicability, low cost and is green and environmentally friendly.

[0011] The present invention provides a method for synthesizing piperazinone and its ring-expanded analogs, and the general reaction formula is as follows:

[0012]

[0013] Wherein, compounds IV and V may be R or S configuration optical isomers or racemates;

[0014] n=1,2,3,4;

[0015] R 1 , R 2 Independently selected from H, C 1-3 an alkyl group, an amino protecting group, wherein the amino protecting group is selected from one of benzyl, substituted benzyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), acetyl (Ac) or benzoyl (Bz);

[0016] X is selected from one of Cl, Br, I, OTs, OMs, and OTf;

[0017] R 3 Selected from H, C 1～6 Alkyl, substituted C 1～6 One of alkyl, phenyl, and substituted phenyl;

[0018] The term "substituted phenyl" or "substituted benzyl" refers to a phenyl group substituted by 1 to 4 groups selected from the following groups: 1-4 Alkyl, C 1-4 Alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, these substituents are in any possible position on the benzyl ring;

[0019] The term "substituted C 1～6 "alkyl" refers to a C alkyl group substituted by 1 to 4 groups selected from the following groups 1～6 Alkyl: C 1-4 Alkyl, C 1-4 Alkoxy, nitro, trifluoromethyl, trifluoromethoxy, these substituents are 1～6 Any possible position on the alkyl group;

[0020] R 4 Selected from C 1 ~ 5 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or tert-pentyl.

[0021] The following steps are involved:

[0022] Step (1) reacting a compound of formula III or a salt thereof with a compound of formula IV in a solvent in the presence of an acid-binding agent to obtain a compound of formula V;

[0023] Furthermore, the acid-binding agent can be the compound of formula III itself or selected from an inorganic base, and the inorganic base is selected from a combination of one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide, preferably potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide.

[0024] Furthermore, in step (1), the molar ratio of compound IV to the acid binding agent is 1:(1-3), preferably 1:(1-2).

[0025] Furthermore, in the step (1), the molar equivalent ratio of compound III to compound IV is (1-3):1, preferably (1-2.5):1.

[0026] Furthermore, in the step (1), the mass volume ratio of the compound of formula IV to the solvent is (0.1-0.5):1 g / mL, preferably (0.1-0.2):1 g / mL.

[0027] Furthermore, the reaction temperature in step (1) is 10 to 80° C., preferably 10 to 65° C.; the reaction time is 1 to 8 hours, preferably 2 to 6 hours.

[0028] Furthermore, the solvent used in step (1) is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated alkanes, nitriles or alcohols, preferably toluene, 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, more preferably methanol, ethanol, isopropanol, dichloromethane, carbon tetrachloride, acetonitrile.

[0029] In certain embodiments, the target compound can be obtained in high purity by selective post-treatment such as filtration, concentration, washing, drying, column chromatography, etc.

[0030] In certain embodiments, after the reaction is completed, the reaction is first filtered and concentrated, then washed, separated, and concentrated, and then n-heptane is added, and the temperature is slowly lowered to 5-10° C. to precipitate a white solid, which is then filtered and dried to obtain the target compound.

[0031] In certain embodiments, after the reaction is completed, the reaction is first filtered, then concentrated to dryness, and then purified by column chromatography, and finally the target compound is concentrated to dryness.

[0032] Furthermore, the present invention also provides a method for synthesizing a non-zonetant intermediate V', and the reaction formula is as follows:

[0033]

[0034] The steps include:

[0035] Step (1) reacting a compound of formula III' or a salt thereof with a compound of formula IV' in a solvent in the presence of an acid-binding agent to obtain a compound of formula V';

[0036] Unless otherwise specified, R 2 , R 4 and X substituents are as defined above;

[0037] The preferred technical solution of the present invention, step (1) is fully cited in the present invention specification. The above-mentioned present invention provides a complete technical solution for the synthesis of piperazinone and its ring-expanded analogs.

[0038] Wherein, the compound III (including III') can be obtained by the following method or commercially available.

[0039] In certain embodiments, the preparation method of compound III (including III') is as follows:

[0040]

[0041] Step A: reacting the compound of formula I with a protective agent to obtain a compound of formula II or a compound of formula III (wherein R 1 or R 2 is H);

[0042] Step B: Reducing the compound of formula II to obtain the compound of formula III by reductive amination or substitution reaction;

[0043] Step C: The compound of formula III is reacted with a conventional deprotection reagent to obtain R 1 or R 2 The compound of formula III or a salt thereof is H.

[0044] Unless otherwise specified, R 1 and R 2 As mentioned above.

[0045] In certain embodiments, the compound of formula III is prepared by only step A, for example, reacting ethylenediamine and benzyl chloride to obtain N-benzylethylenediamine.

[0046] In certain embodiments, the preparation of the compound of formula III needs to be prepared through steps A, B, and C, for example, ethylenediamine and di-tert-butyl dicarbonyl ester are reacted to obtain N-Boc-ethylenediamine, which is then reacted with 2,4-dimethoxybenzaldehyde to obtain (2-((2,4-dimethoxybenzyl)amino)ethyl)carbamic acid tert-butyl ester, and finally Boc is removed to obtain N 1 -(2,4-Dimethoxybenzyl)ethane-1,2-diamine hydrochloride.

[0047] In certain embodiments, the protecting agent in step A is preferably an acyl chloride, an acid anhydride, a methylating agent, or a halide, wherein the halide is, for example, benzyl bromide or benzyl chloride.

[0048] In certain embodiments, the reductive amination reaction in step B refers to the reduction of the compound of formula II with the corresponding aldehyde using a reducing agent in an acid system to obtain the compound of formula III.

[0049] In certain embodiments, the acid in step B is acetic acid, etc., and the reducing agent is selected from sodium acetate borohydride and sodium cyanoborohydride.

[0050] In certain embodiments, the substitution reaction in step B refers to the reaction of the compound of formula II with the corresponding halide to obtain the compound of formula III.

[0051] In certain embodiments, the conventional deprotection reagent in step C is, for example, hydrochloric acid gas, hydrochloric acid, organic hydrochloric acid solution, trifluoroacetic acid, etc.

[0052] The present invention also provides a method for synthesizing fezonetant, and the reaction formula is as follows:

[0053]

[0054] The steps include:

[0055]

[0056] Unless otherwise specified, R 2 , R 4 and X substituents are as defined above;

[0057] Step (1) The compound of formula III' or its salt and the compound of formula IV' are reacted in a solvent under the action of an acid-binding agent to obtain a compound of formula V'

[0058] Compound; then the compound of formula V 'is acylated, imino ether formed and the imino ether is formed into triazolopiperazine to obtain fezonetant;

[0059] The steps include:

[0060] Step (1) reacting a compound of formula III' or a salt thereof with a compound of formula IV' in a solvent in the presence of an acid-binding agent to obtain a compound of formula V';

[0061] Then, fezonetant was obtained by referring to the preparation method of the prior art CN107001289 B.

[0062] The preferred technical solution of the present invention, step (1) is fully cited in the present invention specification. The above-mentioned present invention provides a method for synthesizing piperazinone and its ring-expanded analogs or a method for synthesizing a non-zonetant intermediate V'.

[0063] Beneficial technical effects of the present invention:

[0064] 1. The route for preparing the compound of formula V in the prior art is prone to produce impurities and isomer impurities of bimolecular amine ester exchange, low atom utilization and low yield. The preparation method of the present invention can avoid the appearance of related impurities, and the total yield is as high as more than 90%, and the ee value is as high as 99%, which is more than 50% higher than the yield of the route in the prior art. When compound IV is an R or S configuration optical isomer, the chirality and chiral purity of the reaction product can be greatly maintained.

[0065] 2. The present invention is simple to operate, significantly reduces impurities in the product, and the product purity is as high as 99% or more, which greatly simplifies the post-processing and reduces the cost. It is more suitable for scaled-up industrial production, provides more possibilities for the synthesis of piperazinone and its ring-expanded analogs, and has good market value and far-reaching practical significance.

[0066] 3. Currently, most similar cyclization reactions use primary amines as raw materials, and when there are substituents on N, the yield is not very ideal. The substrates and conditions selected in the present invention can be substituted by the side chain of the target product on N while also obtaining a high-purity, high-yield cyclization product.

[0067] 4. When compound IV is an optical isomer of R or S configuration, the acid binding agent used in the present invention has obvious technical advantages over the prior art sodium alcoholate. The acid binding agent used in the present invention has low equipment requirements, the reaction is easier to control, and the cost is reduced; the prior art sodium alcoholate easily leads to racemization. The acid binding agent of the present invention, for example, the acid binding agent can be the compound of formula III itself or selected from an inorganic base (such as potassium carbonate), the reaction conditions are mild, the yield is high, and the chirality and chiral purity of the reaction product can be greatly maintained. DETAILED DESCRIPTION

[0068] The beneficial effects of the present invention are now further described by the following examples. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0069] Example 1

[0070]

[0071] (1) Ethylenediamine (5.0 g, 83.2 mmol) was dissolved in 50 mL of dichloromethane, and di-tert-butyl dicarbonate (18.1 g, 82.9 mmol) was slowly added dropwise at room temperature. The mixture was stirred for 16 h at room temperature. The reaction solution was washed three times with water, and the organic phase was concentrated to dryness to obtain 13.1 g of an oily liquid compound of formula 2, with a yield of 98.3%.

[0072] (2) The compound of formula 2 (13.0 g, 81.1 mmol) was dissolved in 100 mL of methanol, and 2,4-dimethoxybenzaldehyde (13.5 g, 81.2 mmol) and acetic acid (7.3 g, 121.7 mmol) were added to the reaction solution, respectively, and stirred at room temperature for 1 h. NaBH 4 (4.3 g, 113.6 mmol), stirred at room temperature for 0.5 h, and saturated NaHCO 3 The pH was adjusted to 6-7, concentrated under reduced pressure, ethyl acetate was added, stirred, and allowed to stand for separation. Hydrochloric acid gas was introduced into the organic phase for 20 min, stirred for 2 hours, and filtered to obtain 20 g of the compound of formula 4 as a white solid.

[0073] (3) Add acetonitrile (200 mL), potassium carbonate (12.6 g, 91.2 mmol), (R)-2-toluenesulfonyloxypropionic acid methyl ester (20.96 g, 81.1 mmol) to the compound of formula 4 (20 g), and react at 40°C for 4 h. Filter under reduced pressure, concentrate the filtrate to dryness, dissolve it in ethyl acetate, wash it twice with water, concentrate the organic phase to 20 mL, add n-heptane, slowly cool it to 10°C, precipitate a white solid, filter under reduced pressure, rinse it with n-heptane, and dry it to obtain 20.8 g of the compound of formula 6, with a purity of 99.9%, ee%=99.9%, and a yield of 97.0%.

[0074] 1 H NMR: (400MHz, CDCl 3 )δ7.23-7.21(d,1H),δ6.92(s,1H),δ6.48-6.45(m,2H),δ3.82-3.79(m,7H),δ3.55-3.51(d,1H),δ 3.34-3.19(m,3H), δ2.98-2.92(m,1H), δ2.51-2.45(m,1H), δ1.50-1.48(d,3H); MS(EI):265[M+H] + .

[0075] Example 2

[0076]

[0077] Dissolve 1,3-propylenediamine (3.56 g, 48.03 mmol) in 10 mL of methanol, cool to 10°C, add ethyl bromophenylacetate (5.0 g, 20.57 mmol) and potassium carbonate (3.0 g, 20.57 mmol) in 3 ml of methanol, and the solution turns milky white after 15 minutes; add 20 mL of methanol to the reaction solution, heat to 60°C, and continue to react for 4 hours. Concentrate the reaction solution and purify by column chromatography (eluent: DCM: MeOH = 10:1), and concentrate the product solution to dryness to obtain a white solid compound of formula 9 (3.82 g, purity 99.8%, ee value 99.9%, yield 97.6%).

[0078] 1 HNMR:(400MHz,CDCl 3 ) δ7.45-7.36(m,5H), δ6.96(s,1H), δ4.66(s,1H), δ3.41-3.33(m,3H), δ3.12-3.05(m,1H), δ2.02(s,1H), δ1.86-1.81(m,2H). MS(EI):191[M+H] + .

[0079] Example 3

[0080]

[0081] (1) Methyl 2-(4-nitrophenyl)acetate (5.0 g, 25.62 mmol) was dissolved in 50 mL of chloroform, and NBS (4.56 g, 25.62 mmol) and azobisisobutyronitrile (420 mg, 2.56 mmol) were added at room temperature (10-15° C.), and the temperature was raised to 60-65° C. for 18 h under nitrogen protection. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated to dryness, dissolved in dichloromethane, and purified by column chromatography (eluent: PE:EA=30:1), and finally concentrated to dryness to obtain a light yellow solid compound of formula 11 (6.6 g, purity 99.8%, yield 94.0%).

[0082] 1 H NMR: (400MHz, CDCl 3 )δ8.30(d,J=8.7Hz,2H),7.81(d,J=8.7Hz,2H),5.49(s,1H),3.90(s,3H); MS(EI):275.9[M+H] + .

[0083] (2) Dissolve dimethylethylenediamine (2.13 g, 24.16 mmol) in 30 mL of ethanol, add compound 11 (3.0 g, 10.95 mmol) at 10-15°C, and react for 2 h. Concentrate the reaction solution to dryness, purify by column chromatography (eluent: DCM: MeOH = 20:1), and finally concentrate to dryness to obtain a light yellow solid compound 13 (2.5 g, purity 99.7%, yield 91.6%).

[0084] 1 H NMR: (400MHz, CDCl 3 )δ8.19(d,J=8.7Hz,2H),7.62(d,J=8.7Hz,2H),3.83(s,1H),3.76(d,J=4.2Hz,1H),3.2 4(d,J=1.3Hz,1H),3.08–3.01(m,1H),2.97(s,3H),2.73(d,J=3.8Hz,1H),2.18(s,3H). MS(EI):250.1[M+H] + .

[0085] Example 4

[0086]

[0087] (1) Dissolve ethylenediamine (10.4 g, 173.04 mmol) in 60 mL of acetonitrile, add potassium carbonate (43.7 g, 316.19 mmol), add benzyl chloride (20.0 g, 158.00 mmol) dropwise at a temperature of 15-20°C, raise the temperature to 45°C and keep the reaction for 20 h. Filter under reduced pressure, wash the filter cake with acetonitrile, concentrate the filtrate, dissolve it in dichloromethane, and purify it by column chromatography (eluent: DCM: MeOH = 80: 1), and finally concentrate to obtain a light yellow oily compound of formula 15 (20.6 g, purity 99.8%, yield 87.0%). 1 H NMR: (400MHz, CDCl 3 )δ7.42(dd,J=9.9,3.6Hz,5H),3.87(s,2H),3.68(s,1H),2.85(d,J=8.4Hz,3H); MS(EI):151.1[M+H] + .

[0088] (2) The compound of formula 16 (3.0 g, 11.6 mmol) was dissolved in 20 mL of methanol, potassium carbonate (1.6 g, 11.6 mmol) was added, and the compound of formula 15 (2.09 g, 13.9 mmol) was added. After nitrogen protection, the mixture was stirred at 10-15°C for 30 min, and the temperature was raised to 60°C for reaction for 6 h. The mixture was cooled to room temperature, filtered under reduced pressure, the filter cake was washed with methanol, the filtrate was concentrated to dryness, and purified by column chromatography (eluent: DCM: MeOH = 30: 1), and finally concentrated to dryness to obtain an off-white solid compound of formula 17 (2.0 g, purity 99.6%, ee value 99.8%, yield 84%).

[0089] 1 H NMR: (400MHz, CDCl 3 )δ7.46–7.34(m,5H),3.99(d,J=13.5Hz,1H),3.49(d,J=13.5Hz,1H),3.38–3.26(m, 3H),3.0–2.92(m,1H),2.57–2.49(m,1H),1.53(d,J=6.9Hz,3H); MS(EI):205.1[M+H] + .

[0090] Comparative Example 1

[0091]

[0092] (1) Ethylenediamine (179.6 g, 3.0 mol) was dissolved in 630 mL of methanol, (R)-methyl 2-toluenesulfonyloxypropionate (350 g, 1.4 mol) was slowly added dropwise at room temperature, stirred at 15°C for 1 h, 1050 mL of methanol was added, and stirred at 58°C for 1 h. The reaction solution was concentrated to dryness under reduced pressure, 1500 mL of dichloromethane was added, stirred for 0.5 h, and filtered under reduced pressure. The filter cake was rinsed with 1000 mL of dichloromethane, and the filtrate was concentrated under reduced pressure to obtain 228.0 g of a yellow oily liquid. Flash column chromatography (DCM: MeOH = 10:1) obtained 98.0 g of an off-white solid (R)-3-methyl-2-ketopiperazine, with a yield of 63.4%.

[0093] 1 H NMR: (400MHz, CDCl 3 ) δ6.85(s,1H), δ3.60-3.55(m,1H), δ3.51-3.45(m,1H), δ3.35-3.32(m,1H), δ3.20-3. 17(m,1H), δ3.08-3.01(m,1H), δ1.97(s,1H), δ1.46-1.41(d,3H); MS(EI):115[M+H]+.

[0094] (2) (R)-3-methyl-2-ketopiperazine (30.0 g, 262.8 mmol) was dissolved in 330 mL of acetonitrile, 2,4-dimethoxybenzaldehyde (43.7 g, 263.0 mmol) and sodium triacetoxyborohydride (78.0 g, 368.0 mmol) were added, and the mixture was stirred evenly. Acetic acid (23.7 g, 395.0 mmol) was added dropwise at room temperature, and stirred for 4 h. 1500 mL of saturated sodium bicarbonate solution was slowly added, and 600 mL x 2 of ethyl acetate was added. The mixture was stirred and allowed to stand for separation. The organic phases were combined, concentrated under reduced pressure, and column chromatography (DCM: MeOH = 30: 1) was performed to obtain 62.4 g of a yellow oil with a purity of 99.7% and an ee value of 85.2%. PE: EA = 4: 1 was used for recrystallization to obtain 48.4 g of an off-white solid with a purity of 99.9% and an ee value of 99.8%; the yield was 69.7%.

[0095] 1 H NMR: (400MHz, CDCl 3 )δ7.23-7.21(d,1H),δ6.92(s,1H),δ6.48-6.45(m,2H),δ3.82-3.79(m,7H),δ3.55-3.51(d,1H),δ 3.34-3.19(m,3H), δ2.98-2.92(m,1H), δ2.51-2.45(m,1H), δ1.50-1.48(d,3H); MS(EI):265[M+H] + .

Claims

1. A method for synthesizing a compound of formula V, wherein the reaction formula is as follows: The following steps are involved: in, Compounds IV and V are R or S configuration optical isomers or racemates; n＝1,2,3,4； R1, R2 are independently selected from H, C 1-3 Alkyl, amino protecting group, wherein the amino protecting group is selected from one of benzyl, substituted benzyl, benzyloxycarbonyl Cbz, tert-butyloxycarbonyl Boc, 9-fluorenylmethyloxycarbonyl Fmoc, p-toluenesulfonyl Ts, methanesulfonyl Ms, acetyl Ac or benzoyl Bz; X is selected from one of Cl, Br, I, OTs, OMs, and OTf; R3 is selected from H, C 1～6 Alkyl, substituted C 1～6 One of alkyl, phenyl, and substituted phenyl; "Substituted phenyl" or "substituted benzyl" refers to a phenyl group substituted on the benzene ring by 1 to 4 groups selected from the following groups: 1-4 Alkyl, C 1-4 Alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, these substituents are in any possible position on the benzyl ring; "Replaced C 1～6 "alkyl" refers to a C alkyl group arbitrarily substituted by 1 to 4 groups selected from the following groups 1～6 Alkyl: C 1-4 Alkyl, C 1-4 Alkoxy, nitro, trifluoromethyl, trifluoromethoxy; R4 is selected from C1-5 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or t-pentyl; The following steps are involved: Step (1): a compound of formula III or a salt thereof and a compound of formula IV are reacted in a solvent in the presence of an acid-binding agent to obtain a compound of formula V.

2. A method for synthesizing a non-zonetant intermediate V', the reaction formula is as follows: The steps include: Step (1) reacting a compound of formula III' or a salt thereof with a compound of formula IV' in a solvent in the presence of an acid-binding agent to obtain a compound of formula V'; in, The definitions of R2, R4 and X substituents are the same as those of claim 1.

3. The synthesis method according to claim 1 or 2, characterized in that The acid-binding agent in step (1) is selected from the compound of formula III or formula III' or selected from an inorganic base.

4. The synthesis method according to claim 3, characterized in that The inorganic base is selected from a combination of one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide, preferably potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide.

5. The synthesis method according to claim 1 or 2, characterized in that: In the step (1), the molar ratio of compound IV to the acid binding agent is 1:(1-3), preferably 1:(1-2).

6. The synthesis method according to claim 1 or 2, characterized in that: In the step (1), the molar equivalent ratio of compound III to compound IV is (1-3):1, preferably (1-2.5):

1.

7. The synthesis method according to claim 1 or 2, characterized in that: In the step (1), the mass volume ratio of the compound of formula IV to the solvent is (0.1-0.5):1 g / mL, preferably (0.1-0.2):1 g / mL.

8. The synthesis method according to claim 1 or 2, characterized in that: The reaction temperature in step (1) is 10 to 80° C., preferably 10 to 65° C.; the reaction time in step (1) is 1 to 8 hours, preferably 2 to 6 hours.

9. The synthesis method according to claim 1 or 2, characterized in that: The solvent used in step (1) is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated alkanes, nitriles or alcohols; preferably toluene, 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, more preferably methanol, ethanol, isopropanol, dichloromethane, carbon tetrachloride, acetonitrile.

10. A synthetic method of fezonetam, the reaction formula is as follows: The steps include: in, R2, R4 and X substituents are defined as the substituents defined in claim 1; The compound of formula III' or its salt and the compound of formula IV' are synthesized by the method as claimed in claim 2 to obtain the compound of formula V'; then the compound of formula V' is acylated, imino ether formed and triazolopiperazine formed from imino ether to obtain fezonetant.

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