Synthesis method for fezolinetant and series of intermediate compounds thereof

Abstract

The present invention provides a synthesis method for fezolinetant, comprising: using (R)-3-methylpiperazin-2-one compound 1 as a starting material, first using p-toluenesulfonyl chloride to protect amino groups, to obtain (R)-3-methyl-4-p-toluenesulfonylpiperazin-2-one compound 2, then performing an alkylation reaction to activate amides, to obtain compound 3; compound 3 producing (R)-3-methyl-5-(8-methyl-7-p-toluenesulfonyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]piperazin-3-yl)-1,2,4-thiadiazole compound 7 by means of two pathways; finally, deprotecting and salifying compound 7 to obtain compound 8, and compound 8 undergoing a condensation reaction with compound 9, to yield a final product of fezolinetant, compound 10. This route is simple in operation, provides a relatively high overall yield, obtains a product having high purity, and is suitable for scaled-up production.

Description

Synthesis method of fezolinetan and intermediate compounds in fezolinetan series TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and particularly relates to a synthesis method of fezolinetan and intermediate compounds in fezolinetan series. BACKGROUND

[0002] Fezolinetan is a NK3 receptor (Neurokinin 3 Receptor) antagonist developed by Astellas Company in the United States. The drug is used for treating patients with moderate to severe vasomotor symptoms caused by menopause. The clinical phase III experiment results prove that it can significantly relieve symptoms, provide reliable long-term treatment effect, and show good characteristics in safety and tolerability. Fezolinetan was approved for marketing in the United States and Europe in May 2023 and December 2023 respectively, and the trade names are and It has become the first non-hormone targeted drug for treating moderate to severe vasomotor symptoms caused by menopause in the world.

[0003] The chemical name of fezolinetan is (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone, and the structural formula is as follows:

[0004] PCT patent WO2014154895A1 reports a synthesis route of fezolinetan: N-PG protecting group-3-methylpiperazin-2-one is used as a starting material, and triethyl oxonium tetrafluoroborate is used to activate and ethylate the carbonyl group to obtain an intermediate 5-ethoxy-6-methyl-1-(PG protecting group)-1,2,3,6-tetrahydropyrazine; 4-methylthiadiazole-2-carboxylic acid ethyl ester is used to complete the urethane exchange reaction under the action of hydrazine hydrate to obtain 4-methylthiadiazole-2-carboxyhydrazine, and then the intermediate 5-ethoxy-6-methyl-1-(PG protecting group)-1,2,3,6-tetrahydropyrazine is subjected to a cyclization reaction to obtain 3-methyl-5-(8-methyl-7-(PG protecting group)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole. Then, after the PG protecting group is removed, condensation with 4-fluorobenzoyl chloride is carried out to obtain racemic fezolinetan, and finally chiral column separation is carried out to obtain fezolinetan product. The method needs to use chiral column separation, and the synthesis efficiency is low, and the total yield is low.

[0005] The document ACS Med. Chem. Lett. 2015, 6, 736-740 reports an improved route to nonzamantadine, using a chiral (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one instead of the racemic starting material, synthesized chiral nonzamantadine using similar synthetic conditions, avoiding chiral column resolution, but the synthesis yield of the key intermediate (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole is still low, and the route cost is still high.

[0006] In general, the two methods for synthesizing nonzamantadine have low total yield and high cost, and a method with simple process route, low cost and suitable for industrial production is still needed.

[0007] SUMMARY

[0008] In view of the deficiencies of the prior art, the purpose of the present application is to provide a method for synthesizing nonzamantadine with a short synthesis route, simple operation, high yield and high product purity, which is suitable for industrial production.

[0009] To achieve the purpose of the application, the present application provides a series of new intermediate compounds for synthesizing nonzamantadine, which adopts the following technical solution:

[0010] The nonzamantadine series intermediate compounds 2, 3, 5, 7 and 8 have the following chemical structures:

[0011] wherein R is methyl or ethyl;

[0012] HA is a common inorganic acid or organic acid, and as a preferred, the HA acid is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzene sulfonic acid, methyl sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyl tartaric acid or L-di-p-toluoyl tartaric acid.

[0013] As a preferred, the compound 8 is selected from the following structural formula compounds:

[0014] The present application relates to a method for synthesizing nonzamantadine intermediate compound 3, which adopts the following technical solution:

[0015] The method for synthesizing nonzamantadine intermediate compound 3 comprises the following steps:

[0016] (1) Compound 1 is condensed with p-toluenesulfonyl chloride under the action of an acid-binding agent to obtain intermediate compound 2;

[0017] (2) Compound 2 is subjected to alkylation under the action of an acid-binding agent to activate the amide to obtain compound 3;

[0018] As a preference, in the condensation reaction of step (1), the acid-binding agent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; and the reaction temperature is -15-60°C.

[0019] As a preference, in the alkylation reaction of step (2), the alkylating agent is trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, iodomethane, bromoethane, methyl triflate, ethyl triflate, methyl p-toluenesulfonate or ethyl p-toluenesulfonate; no acid-binding agent or an acid-binding agent selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine is added; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile or 1,4-dioxane; and the reaction temperature is -20-110°C.

[0020] The present application relates to a synthesis method of non-azaindane intermediate compound 7, which adopts the following technical scheme:

[0021] The synthesis method of non-azaindane intermediate compound 7 comprises completing ring-closing reaction of compound 3 and hydrazine compound 4 to obtain intermediate compound 7.

[0022] In the formula, R is methyl or ethyl.

[0023] As preferred, in the cyclization reaction, no catalyst is added or a catalyst selected from molecular sieve, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride etherate, p-toluenesulfonic acid pyridinium, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, potassium propionate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine is added; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP or acetonitrile; and the reaction temperature is 0-130℃.

[0024] The present application relates to another synthesis method of non-azaindole intermediate compound 7, which adopts the following technical scheme:

[0025] The present application relates to another synthesis method of non-azaindole intermediate compound 7, which adopts the following technical scheme:

[0026] (1) reacting compound 3 with hydrazine hydrate to obtain intermediate compound 5 in free base form, or salifying the free base form with a common acid to obtain the salt form of intermediate compound 5;

[0027] (2) completing the cyclization reaction of compound 5 and compound 6 to obtain intermediate compound 7;

[0028] wherein, R is methyl or ethyl; compound 5 is in free base form or salified form, and the salified acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzylsulfonic acid, methylsulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid;

[0029] LG is a leaving group selected from chlorine, hydroxyl, alkoxy OR 1 or an active ester group OCO2R 2 , R 1 is C1-C6 alkyl or benzyl, RP 2 P is C1-C6 alkyl or benzyl.

[0030] As preferred, in the reaction of step (1) and hydrazine hydrate, the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, t-amyl alcohol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile; and the reaction temperature is 0-110℃.

[0031] As preferred, in the cyclization reaction of step (2), no dehydrating agent is added or molecular sieves, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride ether, p-toluenesulfonic acid pyridine, DCC, DIC, EDCI, HATU or HBTU are added as the dehydrating agent; no acid binding agent is added or an acid binding agent selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine is added; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP or acetonitrile; and the reaction temperature is 0-130°C.

[0032] The present application relates to a synthesis method of non-azelnidipine intermediate compound 8, which adopts the following technical scheme:

[0033] The synthesis method of non-azelnidipine intermediate compound 8 comprises deprotecting compound 7 under the action of a strong acid or a strong base, and then salifying with an acid HA to obtain intermediate compound 8.

[0034] wherein HA is a common inorganic acid or an organic acid, and the acid HA is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzylsulfonic acid, methylsulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyl tartaric acid or L-di-p-toluoyl tartaric acid.

[0035] As preferred, in the deprotection reaction, a strong acid or a base is selected for deprotection, and the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid or trifluoromethanesulfonic acid or a combination of two of these acids; no solvent is added or the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile or water or a mixed solvent system formed by any two of these solvents; and the reaction temperature is 0-90°C.

[0036] When the deprotection reaction uses a base, the base is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide; the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, water or a mixed solvent system formed by any two of these solvents; the reaction temperature is 0-110°C; the salifying solvent is selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water or a mixed solvent system formed by any two of these solvents; and the salifying temperature is -20-65°C.

[0037] The present application also relates to a synthesis method of non-azelnidipine, which adopts the following technical scheme:

[0038] A synthetic method of fezolinetant, comprising condensation reaction of compound 8 with 4-fluorobenzoyl chloride compound 9 under the action of an acid binding agent to obtain the target product fezolinetant compound 10;

[0039] wherein HA is a common inorganic acid or an organic acid, and the HA acid is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzene sulfonic acid, methyl sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyl tartaric acid or L-di-p-toluoyl tartaric acid.

[0040] As preferred, in the condensation reaction, the acid binding agent is selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile or 1,4-dioxane, water or a mixed solvent system formed by any two of these solvents; the reaction temperature is -15 to 60°C.

[0041] Specifically, a synthetic method of fezolinetant, comprising taking (R)-3-methylpiperazin-2-one compound 1 as a starting material, first protecting the amino group by using p-toluenesulfonic acid chloride to obtain (R)-3-methyl-4-p-toluenesulfonylpiperazin-2-one compound 2, and then activating the amide by alkylation to obtain compound 3; compound 3 is converted into compound 7 by two methods: (R)-3-methyl-5-(8-methyl-7-p-toluenesulfonyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole, method one is to complete the cyclization reaction of compound 3 with hydrazine compound 4 to obtain 7; method two is to first obtain compound 5 after the reaction of compound 3 with hydrazine, and then complete the cyclization reaction of compound 5 with compound 6 to obtain compound 7; finally, compound 7 is deprotected and salted to obtain compound 8, and finally, compound 8 is condensed with compound 9 to obtain fezolinetant final product 10, the route is as follows:

[0042] The application relates to a synthesis method of non-azaindanes, which adopts (R)-3-methylpiperazin-2-one as a starting material, reduces the synthesis difficulty, reduces the synthesis steps, has a simple route, provides a total yield of the route, and reduces the process cost. The application improves the crystallization performance of intermediates of compounds 2, 3 and 7 by making full use of p-toluenesulfonyl protection, studies the salt formation characteristics of compound 8, and improves the purity of the final product. The route is simple to operate, has a high total yield, has high product purity, and is suitable for scale-up production. DETAILED DESCRIPTION

[0043] The following detailed description of the embodiments of the application is given on the premise of the technical scheme of the application, detailed implementation manners and specific operation processes are given, and the protection scope of the application is not limited to the following embodiments.

[0044] Example 1

[0045] A three-necked flask is added with compound 1 (11.41 g, 100 mmol), N,N-dimethylformamide (57 mL) is added and stirred to dissolve, sodium hydroxide (8.00 g, 200 mmol) is added, stirring is uniformly carried out, p-toluenesulfonyl chloride (20.97 g, 110 mmol) is added, and reaction is carried out at 20-30 DEG C for 4-6 hours. After the reaction is completed, water (114 mL) is added, stirring is carried out, liquid separation is carried out, the water phase is extracted with ethyl acetate (57 mL) once, the organic phase is combined and washed with water (57 mL) once, most of the solvent is removed by concentration, n-heptane (91 mL) is added, heating is carried out to 50-55 DEG C, slow cooling is carried out to 0-10 DEG C, and the slurry is filtered and dried to obtain the intermediate of formula 2 (25.11 g, a yield of 93.6%).

[0046] MS (ESI) [M+H] + = 269.0

[0047] 1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.40 (br, 1H), 4.43-4.49 (m, 1H), 3.83 (d, J = 13.5 Hz, 1H), 3.35-3.46 (m, 1H), 3.23-3.32 (m, 1H), 3.15-3.21 (m, 1H), 2.43 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H).

[0048] In Example 1, N,N-dimethylformamide can be replaced with N,N-dimethylacetamide, N-methylpyrrolidinone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; sodium hydroxide can be replaced with potassium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine.

[0049] Example 2

[0050] A three-necked flask was charged with compound 2 (26.83 g, 100 mmol), stirred to dissolve in tetrahydrofuran (134 mL), potassium carbonate (13.82 g, 100 mmol) was added, and after stirring to homogeneity, trimethyl oxonium tetrafluoroborate (17.75 g, 120 mmol) was added, and the reaction was allowed to proceed with warming to 20-30°C for 2-3 hours. Upon completion, the reaction was cooled to room temperature, water (268 mL) was added, and the mixture was stirred to partition into dichloromethane (134 mL) and water (134 mL). The aqueous phase was extracted with additional dichloromethane (134 mL), and the combined organic phases were washed with water (134 mL), concentrated to remove most of the solvent, and heptane (268 mL) was added. The mixture was heated to 50-55°C, and allowed to cool slowly to 0-10°C to induce precipitation. The precipitate was collected by filtration and dried to give intermediate 3a (25.64 g, 90.8% yield). MS (ESI) [M+H] + = 283.2

[0051] 1 HNMR (500 MHz, CDC13) δ 7.69 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.30 (q, J = 7.0 Hz, 1H), 3.59 (s, 3H), 3.54-3.59 (m, 1H), 3.37-3.43 (m, 1H), 3.20-3.28 (m, 1H), 3.11-3.18 (m, 1H), 2.42 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H).

[0052] In Example 2, tetrahydrofuran can be replaced with N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, DMSO, dichloromethane, 2-methyltetrahydrofuran, toluene, acetonitrile or 1,4-dioxane; potassium carbonate can be omitted or replaced with potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; and trimethyl oxonium tetrafluoroborate can be replaced with triethyl oxonium tetrafluoroborate, iodomethane, bromoethane, methyl triflate, ethyl triflate, methyl p-toluenesulfonate or ethyl p-toluenesulfonate.

[0053] Example 3

[0054] Into a three-necked flask was placed compound 2 (26.83 g, 100 mmol), toluene (134 mL) was added and stirred to dissolve, triethylamine (10.12 g, 100 mmol) was added, after stirring to homogeneity, triethylsilyl oxide tetrafluoroborate (22.80 g, 120 mmol) was added, and the reaction was allowed to proceed at 20-30 °C for 2-3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (268 mL) was added, and the mixture was stirred to separate into two phases, the aqueous phase was extracted with ethyl acetate (134 mL), the combined organic phase was washed with water (134 mL), most of the solvent was removed by concentration, n-heptane (268 mL) was added, the mixture was heated to 50-55 °C, and then slowly cooled to 0-10 °C to form a slurry, which was filtered and dried to obtain intermediate compound 3b (26.20 g, yield 88.4%).

[0055] MS (ESI) [M+H] + = 297.1

[0056] In Example 3, toluene can be replaced with tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; triethylamine can be omitted or replaced with potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, DBU, DABCO or N-methylmorpholine; and triethylsilyl oxide tetrafluoroborate can be replaced with trimethylsilyl oxide tetrafluoroborate, iodomethane, bromoethane, methyl triflate, ethyl triflate, methyl-p-toluenesulfonate or ethyl-p-toluenesulfonate.

[0057] Example 4

[0058] Into a three-necked flask was placed compound 3a (28.24 g, 100 mmol), anhydrous ethanol (141 mL) was added and stirred to dissolve, compound 4 (15.82 g, 100 mmol) was added, and the reaction was allowed to proceed at 70-75 °C for 6-8 hours. After the reaction was completed, most of the solvent was removed by concentration, the mixture was heated to 50-55 °C, water (282 mL) was slowly added, and the mixture was slowly cooled to 0-10 °C to form a slurry, which was filtered and dried to obtain intermediate compound 7 (34.87 g, yield 89.3%).

[0059] MS (ESI) [M+H] + = 391.1

[0060] 1HNMR (500 MHz, CDC13) δ 7.73 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.54 (q, J = 7.0 Hz, IH), 4.77 (dd, J = 13.5, 3.0 Hz, IH), 4.25 (dd, J = 14.5, 4.5 Hz, IH), 3.99-4.06 (m, IH), 3.51-3.60 (m, IH), 2.71 (s, 3H), 2.39 (s, 3H), 1.63 (d, J = 7.0 Hz, 3H).

[0061] In Example 4, ethanol can be replaced with methanol, isopropanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or acetonitrile.

[0062] Example 5

[0063] Into a three-necked flask was placed compound 3b (29.64 g, 100 mmol), toluene (148 mL) was added and stirred to dissolve, compound 4 (15.82 g, 100 mmol) was added, p-toluenesulfonic acid (3.44 g, 20 mmol) was added, and the mixture was stirred and heated to 105-110 °C for 6-8 hours. After the reaction was completed, the solvent was removed by concentration, the mixture was heated to 50-55 °C, n-heptane (237 mL) was slowly added, the mixture was slowly cooled to 0-10 °C and slurried, and the intermediate of formula 7 (36.00 g, yield 92.2%) was obtained by filtration and drying.

[0064] In Example 5, p-toluenesulfonic acid can be omitted or replaced with molecular sieves, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride etherate, p-toluenesulfonic acid pyridinium, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, potassium propionate, diisopropylethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; and toluene can be replaced with methanol, ethanol, isopropanol, n-butanol, t-butanol, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or acetonitrile.

[0065] Example 6

[0066] Into a three-necked flask was placed compound 3a (28.24 g, 100 mmol), ethanol (141 mL) was added and stirred to dissolve, 80% hydrazine hydrate (7.51 g, 120 mmol) was added, and the mixture was stirred and heated to 50-55 °C for 8-12 hours. After the reaction was completed, the mixture was concentrated to dryness to obtain a foamy solid, n-heptane (282 mL) was slowly added, the mixture was slurried at room temperature, the mixture was slowly cooled to 0-10 °C and slurried, and the intermediate of formula 5a (25.53 g, yield 90.4%) was obtained by filtration and drying.

[0067] MS (ESI) [M+H] + = 283.0

[0068] 1 H NMR (500 MHz, CDC13) δ 7.72 (d, J = 7.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.50-4.59 (m 1H), 3.54-3.57 (m, 2H), 3.23-3.29 (m, 1H), 3.11-3.19 (m, 1H), 2.42 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H).

[0069] In Example 6, ethanol can be replaced with methanol, isopropanol, n-butanol, t-butanol, t-amyl alcohol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

[0070] Example 7

[0071] Into a three-necked flask was added compound 3b (29.64 g, 100 mmol), isopropanol (148 mL) was added to stir and dissolve, 80% hydrazine hydrate (7.51 g, 120 mmol) was added, after stirring uniformly, heated to 55-60°C for 5-8 hours. After the reaction was completed, concentrated to substantially no distillate, methyl tert-butyl ether (282 mL) was added to dissolve, heated to 50-55°C, acetic acid (6.01 g, 100 mmol) was added, slowly cooled to 0-10°C to pulp, filtered and dried to obtain intermediate 5b (31.71 g, yield 92.6%).

[0072] MS (ESI) [M+H] + = 283.0

[0073] 1 H NMR (500 MHz, DMSO) δ 7.66 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 4.16-4.22 (m 1H), 3.42-3.47 (m, 1H), 3.14-3.25 (m, 2H), 2.98-3.04 (m, 1H), 2.39 (s, 3H), 1.92 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H).

[0074] In Example 7, isopropanol can be replaced with ethanol, methanol, n-butanol, t-butanol, t-amyl alcohol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

[0075] Example 8

[0076] A three-necked flask was charged with compound 5a (28.24 g, 100 mmol), stirred to dissolve in tetrahydrofuran (141 mL), compound 6a (14.42 g, 100 mmol) was added, DIC (15.14 g, 120 mmol) was added, stirred at 20-30 °C for 2-4 h, then heated to 60-65 °C for 6-8 h. The reaction was completed, concentrated to remove most of the solvent, ethyl acetate (282 mL) and water (141 mL) were added, the mixture was separated, the organic layer was washed with water (141 mL) once, concentrated to a small volume, heated to 50-55 °C, slowly added with n-heptane (282 mL), slowly cooled to 0-10 °C to form a slurry, filtered and dried to give intermediate compound 7 (35.92 g, yield 92.0%).

[0077] In Example 8, the dehydrating agent DIC can be replaced by molecular sieves, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride etherate, p-toluenesulfonic acid pyridinium, DCC, EDCI, HATU or HBTU; the reaction solvent tetrahydrofuran can be replaced by methanol, ethanol, isopropanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, 2-methyltetrahydrofuran, DMF, DMAC, NMP or acetonitrile.

[0078] Example 9

[0079] A three-necked flask was charged with compound 5a (28.24 g, 100 mmol), stirred to dissolve in tetrahydrofuran (141 mL), compound 6a (14.42 g, 100 mmol) was added, DIC (15.14 g, 120 mmol) was added, stirred at 20-30 °C for 2-4 h, then heated to 60-65 °C for 6-8 h. The reaction was completed, concentrated to remove most of the solvent, ethyl acetate (282 mL) and water (141 mL) were added, the mixture was separated, the organic layer was washed with water (141 mL) once, concentrated to a small volume, heated to 50-55 °C, slowly added with n-heptane (282 mL), slowly cooled to 0-10 °C to form a slurry, filtered and dried to give intermediate compound 7 (35.92 g, yield 92.0%).

[0080] In Example 9, the sodium bicarbonate can be replaced by potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent toluene can be replaced by methanol, ethanol, isopropanol, n-butanol, t-butanol, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP or acetonitrile.

[0081] Example 10

[0082] A three-necked flask was charged with compound 5b (34.24 g, 100 mmol), stirred to dissolve in isopropanol (171 mL), compound 6c (17.22 g, 100 mmol) was added, and stirred to homogeneity before heating to 70-75 °C for 14-16 h. Upon completion of the reaction, the bulk of the solvent was removed by concentration, and the residue was heated to 50-55 °C, and 5% sodium bicarbonate solution (282 mL) was added slowly. The mixture was allowed to cool to 0-10 °C and was slurried, and filtered to give intermediate compound 7 (34.68 g, 88.8% yield).

[0083] In Example 10, sodium bicarbonate can be omitted or replaced with potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; and the reaction solvent isopropanol can be replaced with methanol, ethanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP, or acetonitrile.

[0084] Example 11

[0085] A three-necked flask was charged with compound 7 (39.05 g, 100 mmol), stirred to dissolve in methanol (190 mL), 30% sodium hydroxide solution (66.67 g, 500 mmol) was added, and heated to 60-65 °C for 8-12 h. Upon completion of the reaction, the bulk of the solvent was removed by concentration, and the residue was cooled to room temperature, and water (380 mL) was added. The mixture was extracted twice with toluene (190 mL), and the combined organic phase was washed once with water (95 mL). The mixture was heated to 50-55 °C, and p-toluenesulfonic acid (17.22 g, 100 mmol) was added. The mixture was stirred for 0.5 h, and was allowed to cool to 0-5 °C and was slurried, and filtered to give intermediate compound 8a (37.46 g, 91.7% yield).

[0086] MS (ESI) [M+H] + = 237.0

[0087] 1 H NMR (500 MHz, DMSO) δ 10.05 (br, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.85 (q, J = 7.0 Hz, 1H), 4.75-4.82 (m, 1H), 4.48-4.57 (m, 1H), 3.76-3.83 (m, 1H), 3.50-3.58 (m, 1H), 2.72 (s, 3H), 2.28 (s, 3H), 1.74 (d, J = 7.0 Hz, 3H).

[0088] In Example 11, methanol can be replaced with ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents; sodium hydroxide can be replaced with lithium hydroxide or potassium hydroxide; and the salting solvent toluene can be replaced with methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents.

[0089] Example 12

[0090] A three-necked flask was charged with compound 7 (39.05 g, 100 mmol), ethanol (190 mL) was added and stirred to dissolve, 30% sodium hydroxide solution (66.67 g, 500 mmol) was added, heated to 60-65 °C and reacted for 8-12 hours. After the reaction was completed, most of the solvent was removed by concentration, cooled to room temperature, water (380 mL) was added, extracted twice with isopropyl acetate (190 mL), combined the organic phase, washed once with 95 mL of water, heated to 50-55 °C, oxalic acid (9.00 g, 100 mmol) was added, stirred for 0.5 h, slowly cooled to 0-5 °C and slurried, filtered and dried to obtain the intermediate of formula 8b (29.21 g, yield 89.5%).

[0091] MS (ESI) [M+H] + = 237.0

[0092] 1 H NMR (500 MHz, DMSO) 5.55 (br, 3H), 4.65-4.75 (m, 2H), 4.42-4.51 (m, 1H), 3.64-3.71 (m, 1H), 3.36-3.45 (m, 1H), 2.72 (s, 3H), 1.69 (d, J = 6.5 Hz, 3H).

[0093] In Example 12, ethanol can be replaced with methanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents; sodium hydroxide can be replaced with lithium hydroxide or potassium hydroxide; and the salting solvent isopropyl acetate can be replaced with toluene, methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents.

[0094] Example 13

[0095] Into a three-necked flask was added compound 7 (39.05 g, 100 mmol), methanol (190 mL) was added and stirred to dissolve, 30% sodium hydroxide solution (66.67 g, 500 mmol) was added, heated to 60-65 °C and reacted for 8-12 hours. After the reaction was completed, most of the solvent was removed by concentration, cooled to room temperature, water (380 mL) was added, extracted twice with ethyl acetate (190 mL), the organic phase was combined, washed once with water (95 mL), concentrated to remove the fraction, acetone was added, heated to 50-55 °C, D-tartaric acid (15.01 g, 100 mmol) was added, stirred for 0.5 h, slowly cooled to 0-5 °C, and filtered to obtain intermediate compound 8c (35.24 g, yield 91.2%).

[0096] MS (ESI) [M+H] + = 237.0

[0097] 1 H NMR (500 MHz, CD3OD) δ 4.69-4.75 (m, 1H), 4.50 (s, 2H), 4.33-4.43 (m, 2H), 3.50-3.57 (m, 1H), 3.21-3.31 (m, 1H), 2.72 (s, 3H), 1.68 (d, J = 7.0 Hz, 3H).

[0098] In Example 13, methanol can be replaced by ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents; sodium hydroxide can be replaced by lithium hydroxide or potassium hydroxide; the salt-forming solvent ethyl acetate can be replaced by isopropyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, MIBK, water, or a mixed solvent system formed by any two of these solvents.

[0099] Example 14

[0100] A three-necked flask was charged with compound 7 (39.05 g, 100 mmol), stirred to dissolve in tetrahydrofuran (190 mL), 98% sulfuric acid (30.02 g, 300 mmol) was added, heated to 75-80 °C for 5-8 h. The reaction was completed by concentrating to remove most of the solvent, cooled to 0-10 °C, 5% sodium hydroxide solution (380 mL) was added, extracted twice with ethyl acetate (190 mL), the organic phase was combined and washed once with water (95 mL), concentrated to no fraction flow, isopropyl alcohol (312 mL) was added, heated to 50-55 °C, L-tartaric acid (15.01 g, 100 mmol) was added, stirred for 0.5 h, slowly cooled to 0-5 °C, and filtered to dryness to give intermediate compound 8d (34.89 g, yield 90.3%). MS (ESI) [M+H] + = 237.0

[0101] 1 H NMR (500 MHz, CD3OD) δ 4.68-4.74 (m, 1H), 4.50 (s, 2H), 4.31-4.40 (m, 2H), 3.49-3.55 (m, 1H), 3.24-3.29 (m, 1H), 2.72 (s, 3H), 1.67 (d, J = 7.0 Hz, 3H).

[0102] In Example 14, the concentrated sulfuric acid can be replaced with hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, or triflic acid, or a combination of two of these acids; the tetrahydrofuran can be replaced with methanol, ethanol, isopropanol, toluene, 2-methyltetrahydrofuran, acetonitrile, water, or a mixture of any two of these solvents

[0103] Example 15

[0104] A three-necked flask was charged with compound 7 (39.05 g, 100 mmol), stirred to dissolve in tetrahydrofuran (190 mL), 98% sulfuric acid (30.02 g, 300 mmol) was added, heated to 75-80 °C for 5-8 h. The reaction was completed by concentrating to remove most of the solvent, cooled to 0-10 °C, 5% sodium hydroxide solution (380 mL) was added, extracted twice with ethyl acetate (190 mL), the organic phase was combined and washed once with water (95 mL), concentrated to no fraction flow, isopropyl alcohol (312 mL) was added, heated to 50-55 °C, L-tartaric acid (15.01 g, 100 mmol) was added, stirred for 0.5 h, slowly cooled to 0-5 °C, and filtered to dryness to give intermediate compound 8d (34.89 g, yield 90.3%). MS (ESI) [M+H]

[0105] MS (ESI) [M+H] + = 237.0

[0106] 1 H NMR (500 MHz, CD3OD) δ 8.08-8.11 (m, 4H), 7.61-7.66 (m, 2H), 7.48-7.52 (m, 4H), 5.93 (s, 2H), 4.73-4.79 (m, 1H), 4.49 (q, J = 7.0 Hz, 1H) 4.36-4.43 (m, 1H), 3.58-3.64 (m, 1H), 3.33-3.40 (m, 1H), 2.72 (s, 3H), 1.69 (d, J = 6.5 Hz, 3H).

[0107] In Example 15, methanol can be replaced by ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water or a mixed solvent system formed by any two of these solvents; sodium hydroxide can be replaced by lithium hydroxide or potassium hydroxide; the salt-forming solvent acetonitrile can be replaced by ethyl acetate, isopropyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, MIBK, water or a mixed solvent system formed by any two of these solvents.

[0108] Example 16

[0109] Into a three-necked flask was added compound 8 (39.05 g, 100 mmol), isopropanol (190 mL) was added and stirred to dissolve, 30% sodium hydroxide solution (66.67 g, 500 mmol) was added, heated to 60-65 °C and reacted for 8-12 hours. After the reaction was completed, most of the solvent was removed by concentration, cooled to room temperature, water (380 mL) was added, extracted twice with MIBK (190 mL), the organic phase was combined, washed once with 95 mL of water, heated to 50-55 °C, L-di-p-toluoyl tartaric acid (38.64 g, 100 mmol) was added, stirred for 0.5 h, slowly cooled to 0-5 °C and slurried, filtered and dried to obtain intermediate compound 8f (57.91 g, yield 93.0%).

[0110] MS (ESI) [M+H] + = 237.0

[0111] 1H NMR (500 MHz, CD3OD) δ 7.97 (d, J = 8.5 Hz, 4H), 7.31 (d, J = 8.5 Hz, 4H), 5.90 (s, 2H), 4.72-4.78 (m, 1H), 4.48 (q, J = 7.0 Hz, 1H) 4.35-4.42 (m, 1H), 3.57-3.62 (m, 1H), 3.32-3.39 (m, 1H), 2.72 (s, 3H), 2.42 (s, 6H), 1.69 (d, J = 6.5 Hz, 3H).

[0112] In Example 16, isopropyl alcohol can be replaced by methanol, ethanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water, or a mixed solvent system formed by any two of these solvents; sodium hydroxide can be replaced by lithium hydroxide or potassium hydroxide; and the salt-forming solvent MIBK can be replaced by acetonitrile, ethyl acetate, isopropyl acetate, toluene, methanol, ethanol, isopropyl alcohol, n-butanol, t-butanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, water, or a mixed solvent system formed by any two of these solvents.

[0113] Example 17

[0114] A three-necked flask was charged with compound 8a (40.85 g, 100 mmol), toluene (204 mL) was added and stirred to dissolve, triethylamine (30.36 g, 300 mmol) was added, and after stirring to homogeneity, the mixture was cooled to 0-10 °C, a solution of compound 9 (18.23 g, 115 mmol) in toluene (102 mL) was added slowly, and the mixture was warmed to 20-30 °C and reacted for 4-6 hours. After the reaction was completed, the mixture was cooled to room temperature, water (408 mL) was added, the mixture was stirred and partitioned, the aqueous phase was extracted with toluene (102 mL) once more, the combined organic phases were washed with water (102 mL) twice, most of the solvent was removed by concentration, isopropyl alcohol (123 mL) was added, the mixture was heated to 55-60 °C, water (327 mL) was added slowly, the mixture was cooled to 0-5 °C and slurried, and the product 10 (33.08 g, 92.2% yield, 99.87% purity) was filtered and dried.

[0115] In Example 17, the acid-binding agent triethylamine can be replaced by potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, diisopropylethylamine, DBU, DABCO, or N-methylmorpholine; and the reaction solvent toluene can be replaced by dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, or 1,4-dioxane, water, or a mixed solvent system formed by any two of these solvents.

[0116] Example 18

[0117] Into a three-necked flask was added compound 8b (38.64 g, 100 mmol), stirred to dissolve in tetrahydrofuran (193 mL), diisopropylethylamine (38.77 g, 300 mmol) was added, stirred to uniform, cooled to 0-10 °C, compound 9 (18.23 g, 115 mmol, dissolved in 97 mL tetrahydrofuran) was added slowly in tetrahydrofuran solution, warmed to 20-30 °C, reacted for 4-6 hours. After the reaction was completed, cooled to room temperature, added water (386 mL), stirred to separate into two phases, the aqueous phase was extracted with ethyl acetate (193 mL) twice, combined the organic phase, washed with water (97 mL) twice, concentrated to remove most of the solvent, added acetone (123 mL), heated to 38-42 °C, slowly added n-heptane (386 mL), cooled to 0-5 °C, slurried, filtered and dried to obtain fezakinumab product 10 (32.67 g, yield 91.1%, purity 99.92%).

[0118] In Example 18, the base diisopropylethylamine can be replaced by triethylamine, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, DBU, DABCO or N-methylmorpholine; the reaction solvent tetrahydrofuran can be replaced by toluene, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, 2-methyltetrahydrofuran, acetone, acetonitrile or 1,4-dioxane, water or a mixed solvent system formed by any two of these solvents.

Claims

1. Intermediates compounds 2, 3, 5, 7, 8 of the non-azaindane series characterized in that, The chemical structure is shown below: Where R is methyl or ethyl; HA is a common inorganic or organic acid, and the HA acid is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, or L-di-p-toluyltartaric acid.

2. A method of synthesizing a non-oxazinatan intermediate compound 3, characterized by, Includes the following steps: (1) condensation of compound 1 with p-toluenesulfonyl chloride in the presence of an acid binding agent to give intermediate compound 2; (2) Compound 2 is subjected to an alkylating reaction with an alkylating agent in the presence of an acid-binding agent to activate the amide to obtain Compound 3; 3. The method of claim 2, wherein the compound is 3. In step (1) the condensation reaction, the acid-binding agent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, or 1,4-dioxane; in step (2) the alkylation reaction, the alkylating agent is trimethyloxygenase. Onyx tetrafluoroborate, triethyloxonium tetrafluoroborate, iodomethane, bromoethane, methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate, methyl p-toluenesulfonate, or ethyl p-toluenesulfonate; with or without an acid-binding agent, the acid-binding agent is selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, or 1,4-dioxane.

4. A method of synthesizing a non-oxazinatan intermediate compound 7, characterized by, completing a ring-closing reaction of compound 3 and hydrazine compound 4 to obtain intermediate compound 7; Wherein, R is methyl or ethyl; Or, including: (1) reacting compound 3 with hydrazine hydrate to obtain the free base form of intermediate compound 5, or isolating it in the form of a salt by salification with a common acid; (2) completing a ring-closing reaction of compound 5 and compound 6 to obtain intermediate compound 7; Wherein, R is methyl or ethyl; compound 5 is in free base form or salt form, and the acid forming the salt is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzylsulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, and citric acid. LG is a leaving group selected from the group consisting of chlorine, hydroxyl, alkoxy OR 1 or an active ester group OCO2R 2 , R 1 is C1-C6 alkyl or benzyl, R 2 is C1-C6 alkyl or benzyl.

5. The method for synthesizing the nonzonantane intermediate compound 7 according to claim 4, characterized in that, In the cyclization reaction, no catalyst is added or the following catalysts are added: molecular sieve, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride ether, p-toluenesulfonic acid pyridinium, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, potassium propionate, diisopropylethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP, or acetonitrile. In step (1) and the reaction with hydrazine hydrate, the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or acetonitrile. The step (2) cyclization reaction, without adding dehydrating agent or adding molecular sieve, p-toluene sulfonic acid, trifluoroacetic acid, boron trifluoride ether, p-toluene sulfonic acid pyridine, DCC, DIC, EDCI, HATU or HBTU as dehydrating agent; without adding acid binding agent or adding acid binding agent selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropyl ethylamine, triethylamine, DBU, DABCO or N-methyl morpholine; reaction solvent selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, DMF, DMAC, NMP or acetonitrile.

6. A method of synthesizing a non-oxazinatan intermediate compound 8, characterized by, comprising deprotection of compound 7 under the action of a strong acid or a strong base, followed by salt formation with an acid HA to obtain intermediate compound 8; Wherein HA is a common inorganic acid or organic acid, the HA acid is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluene sulfonic acid, benzyl sulfonic acid, methyl sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethane sulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyl tartaric acid or L-di-p-toluoyl tartaric acid.

7. The method for synthesizing a nonzonantane intermediate compound 8 according to claim 6, characterized in that, As preferred, the deprotection reaction, selected with strong acid or base deprotection, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid or trifluoromethane sulfonic acid or two of these acids combination; no solvent or reaction solvent selected from methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 2-methyl tetrahydrofuran, acetonitrile or water or any two of these solvents form a mixed solvent system; the deprotection reaction selected with base, the base is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide; reaction solvent selected from methanol, ethanol, isopropanol, tetrahydrofuran, toluene, 2-methyl tetrahydrofuran, acetonitrile, water or any two of these solvents form a mixed solvent system; salt forming solvent selected from methanol, ethanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, toluene, 2-methyl tetrahydrofuran, acetonitrile, methyl t-butyl ether, ethyl acetate, isopropyl acetate, MIBK, water or any two of these solvents form a mixed solvent system.

8. A method of synthesis of non-oxaliplatin characterized in that, The compound 8 is subjected to condensation reaction with 4-fluorobenzoyl chloride compound 9 in the presence of an acid-binding agent to obtain the target product fezolinetant compound 10. Wherein HA is a common inorganic acid or organic acid, the HA acid is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluene sulfonic acid, benzyl sulfonic acid, methyl sulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethane sulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyl tartaric acid or L-di-p-toluoyl tartaric acid.

9. A process for the synthesis of a non-oxaliplatin according to claim 8, characterized in that, The condensation reaction, acid binding agent selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium t-butylate, potassium t-butylate, sodium t-butylate, diisopropyl ethylamine, triethylamine, DBU, DABCO or N-methyl morpholine; reaction solvent selected from dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, DMSO, toluene, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone, acetonitrile or 1,4-dioxane, water or any two of these solvents form a mixed solvent system.

10. A method of synthesis of non-azaindanes, characterized by, The present application relates to a novel synthesis method of nonazatinan, which comprises the following steps: (R)-3-methylpiperazin-2-one compound 1 is used as a starting material, the amino group is protected by p-toluenesulfonic acid chloride to obtain (R)-3-methyl-4-p-toluenesulfonate piperazin-2-one compound 2, and then the amide is activated by an alkylation reaction to obtain compound 3; compound 3 is used to obtain (R)-3-methyl-5-(8-methyl-7-p-toluenesulfonyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole compound 7 by two methods; method one is to complete a ring-closing reaction of compound 3 and hydrazine compound 4 to obtain 7; method two is to complete a ring-closing reaction of compound 5 obtained by reacting compound 3 with hydrazine and compound 6 to obtain compound 7; finally, compound 7 is deprotected and salified to obtain compound 8, and then compound 8 is condensed with compound 9 to obtain nonazatinan final product 10, and the route is as follows:

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