A method for the synthesis of non-oxazinatans and intermediates thereof using chiral auxiliaries

Abstract

The application relates to a method for synthesizing non-azatin and intermediates thereof by using a chiral auxiliary base, and belongs to the technical fields of medicines and chemistry. The application provides a method for synthesizing non-azatin by using a chiral auxiliary base, and the reaction is as follows: wherein R1 is selected from one of the following; X is selected from Cl and Br; the method comprises the following steps: step 3: compound 7 is reacted with compound 8 in the presence of an organic solvent, and an optional dehydrating agent is added to obtain compound 9; step 4: compound 9 is reacted in the presence of a methyl Grignard reagent and an organic solvent to obtain compound 10; step 5: compound 10 is removed from the chiral auxiliary base to obtain compound 11; and step 6: compound 11 is reacted with compound 12 in the presence of a base and an organic solvent to obtain compound 13. The application provides a preparation method for preparing non-azatin and intermediates thereof by using a chiral auxiliary base, and the method has the advantages of high chiral purity, high yield, high purity and good reproducibility.

Description

Technical Field

[0001] This invention relates to a method for synthesizing fezonatetan and its intermediates using a chiral cofactor, belonging to the fields of pharmaceutical and chemical technology. Background Technology

[0002] Fezolinetant is a selective antagonist of the neurokinin-3 (NK-3) receptor, with a structure shown in Formula 13. It is the world's first non-hormonal medication for menopausal hot flashes and vasomotor symptoms, first approved in the United States in May 2023 for the treatment of menopausal vasomotor symptoms. It is currently in Phase III clinical trials in China. Menopausal hot flashes and vasomotor symptoms are characteristic symptoms caused by decreased or fluctuating estrogen levels in postmenopausal women, leading to unstable vasomotor function, manifesting as hot flashes or excessive sweating. The incidence is high in menopausal women. The conventional treatment is hormone replacement therapy, but its side effects, such as increased venous thromboembolism and the effects of hormones themselves on the body, limit this treatment method. The use of non-hormonal drugs is becoming the main trend for the future.

[0003]

[0004] The chiral synthesis of fezolinate in existing technologies mainly involves two methods. The first method uses chiral auxiliaries for resolution, such as CN111499640A. The yields in this patent's examples range from 18% to 41%, with most between 22% and 35%, resulting in low yields and wasting more than half of the raw materials. The second method uses (R)-3-methylpiperazin-2-one as the starting material and proceeds through multiple steps to obtain fezolinate. This route uses expensive raw materials, and during the formation of the basic nucleus, piperazine one requires non-amide protecting groups to protect the secondary amine group, involving protection followed by deprotection, which affects synthesis efficiency and does not conform to atom economy. Furthermore, maintaining high chiral purity in each step is difficult, the reaction steps are lengthy, and the yield is low, making it unsuitable for industrial production. Therefore, there is an urgent need to develop a new, economical, rapid, simple, high-yield, simple route, short time consumption, high atom utilization, and high chiral purity method for synthesizing fezolinate to improve efficiency and promote industrial production.

[0005] This invention provides a novel method for preparing fezolinate and its intermediates. The method uses a chiral cofactor to cyclically synthesize chiral fezolinate intermediates by closing (R)-2-methylpiperazine ring. It has the advantages of high yield, simple operation, simple post-processing, economy, speed and short time consumption while ensuring high chiral purity. It is suitable for industrial production and therefore has good market value and far-reaching practical significance. Summary of the Invention

[0006] In view of the above technical background, the present invention provides a method for synthesizing fezonine and its intermediates using chiral cofactors. The preparation method of the present invention is simple to operate, has high atom utilization, high conversion rate, high chiral purity, short time consumption, and reduced cost, which is conducive to industrial production.

[0007] The first aspect of this invention provides a method for preparing compound 10, wherein the reaction is as follows:

[0008]

[0009] Wherein, R1 is selected from

[0010] One of them;

[0011] X is selected from Cl and Br;

[0012] Includes the following steps:

[0013] Step 3: Compound 7 and Compound 8 react in the presence of an organic solvent, optionally with the addition of a dehydrating agent, to obtain Compound 9;

[0014] Step 4: Compound 9 reacts in the presence of a methyl Grignard reagent and an organic solvent to give compound 10;

[0015] As a further improvement of the present invention, including but not limited to, the dehydrating agent in step 3 is selected from one or more of tetraethyl titanate, isopropyl titanate, n-butyl titanate, tetraisopropyl titanate, methyl titanate, titanium tetrachloride, copper sulfate, potassium hydrogen sulfate, and cesium carbonate, preferably tetraethyl titanate.

[0016] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 7 to dehydrating agent in step 3 is 1:(1-5), preferably 1:(1-3).

[0017] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 7 to compound 8 in step 3 is 1:(1-2), preferably 1:(1-1.5).

[0018] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 3 is 40-100°C, preferably 40-80°C.

[0019] As a further improvement of the present invention, including but not limited to, the reaction time of step 3 is 1 to 24 hours, preferably 1 to 12 hours.

[0020] As a further improvement of the present invention, including but not limited to, the organic solvent in step 3 is selected from one or more of chloroform, methanol, ethanol, propanol, butanol, pentanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, n-propyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, carbon tetrachloride, n-hexane, cyclohexane, acetonitrile, and dioxane, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and toluene.

[0021] As a further improvement to the present invention, including but not limited to, steps 3 and 4 can be performed in one batch.

[0022] As a further improvement of the present invention, including but not limited to, the methyl Grignard reagent in step 4 is selected from one of methyl magnesium chloride and methyl magnesium bromide.

[0023] As a further improvement of the present invention, including but not limited to, the molar ratio of the Grignard reagent in step 4 to compound 7 in step 3 is (1-3):1, preferably (1-2):1.

[0024] As a further improvement of the present invention, including but not limited to, the organic solvent in step 4 is selected from one or more of chloroform, methanol, ethanol, propanol, butanol, pentanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, n-propyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, carbon tetrachloride, n-hexane, cyclohexane, acetonitrile, and dioxane, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and toluene.

[0025] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 4 is -78 to 0°C, preferably -78 to -10°C.

[0026] As a further improvement of the present invention, including but not limited to, the reaction time of step 4 is 1 to 24 hours, preferably 1 to 12 hours.

[0027] As a further improvement of the present invention, in some embodiments, after the reaction in step 4 is complete, the reaction solution is placed in an ice-water bath, quenched by adding a saturated ammonium chloride aqueous solution, concentrated under reduced pressure, extracted and separated by adding an organic solvent, washed, dried, and concentrated to obtain compound 10.

[0028] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0029] As a further improvement of the present invention, in some embodiments, the above-mentioned compound 10 may optionally be further purified by column chromatography, with column chromatography eluent such as dichloromethane / methanol = 10:1.

[0030] A second aspect of this invention provides a method for synthesizing fezoniltan using a chiral cofactor, wherein the reaction is as follows:

[0031]

[0032] Wherein, R1 is selected from

[0033] One of them;

[0034] X is selected from Cl and Br;

[0035] Includes the following steps:

[0036] Step 3: Compound 7 and Compound 8 react in the presence of an organic solvent, optionally with the addition of a dehydrating agent, to obtain Compound 9;

[0037] Step 4: Compound 9 was reacted in the presence of a methyl Grignard reagent and an organic solvent to give compound 10;

[0038] Step 5: Compound 10 is dechiralized to obtain compound 11;

[0039] Step 6: Compound 11 and Compound 12 react in the presence of a base and an organic solvent to give Compound 13.

[0040] The preferred technical solution of the present invention, step 3 can be described in all the technical solutions of step 3 of the method for preparing compound 10 provided in the first aspect of the present invention;

[0041] The preferred technical solution of the present invention, step 4 can be described in all the technical solutions of step 4 of the method for preparing compound 10 provided in the first aspect of the present invention;

[0042] As a further improvement to the present invention, including but not limited to step 5,

[0043] Method 1: When R1 is Compound 10 was dechiralized under acidic conditions to yield compound 11;

[0044] Furthermore, the acidic reagent is selected from one or more of the following: trifluoroacetic acid (TFA), hydrochloric acid, and hydrochloric acid organic solution;

[0045] Furthermore, the hydrochloric acid organic solution is selected from one or more of the following: hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid isopropanol solution, hydrochloric acid acetone solution, hydrochloric acid ethyl acetate solution, and hydrochloric acid dioxane solution.

[0046] Method 2: When R1 is Compound 10 was dechiralized under the conditions of a metal catalyst and a hydrogen source to obtain compound 11;

[0047] Furthermore, the metal catalyst is selected from palladium on carbon, palladium hydroxide, platinum dioxide, platinum on carbon, and Raney nickel; preferably, palladium on carbon, palladium hydroxide, and Raney nickel.

[0048] Furthermore, the hydrogen source is selected from hydrogen gas or ammonium formate.

[0049] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 5 is 10-50°C, preferably 20-40°C.

[0050] As a further improvement of the present invention, including but not limited to, the reaction time of step 5 is 2 to 24 hours, preferably 1 to 20 hours.

[0051] As a further improvement of the present invention, including but not limited to, step 5 may optionally involve adding an organic solvent, wherein the organic solvent is selected from one or more of ethyl acetate, dichloromethane, carbon tetrachloride, dichloroethane, acetone, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile, diethyl ether, tetrahydrofuran, and dioxane; preferably one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, and carbon tetrachloride.

[0052] As a further improvement of the present invention, including but not limited to, the base in step 6 is selected from one or more of 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), pyridine, triethylamine, potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and 4-methylmorpholine, preferably one or more of triethylamine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), and pyridine.

[0053] As a further improvement of the present invention, including but not limited to, in step 6, the molar ratio of compound 11, compound 12 and base is 1:(1-2):(1-10), preferably 1:(1-1.5):(1-6).

[0054] As a further improvement of the present invention, including but not limited to, the organic solvent in step 6 is selected from one or more of dichloromethane, carbon tetrachloride, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and dioxane; preferably one or more of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dichloromethane.

[0055] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 6 is 0 to 50°C, preferably 10 to 40°C.

[0056] As a further improvement of the present invention, including but not limited to, the reaction time of step 6 is 1 to 24 hours, preferably 4 to 12 hours.

[0057] As a further improvement of the present invention, in some embodiments, after the reaction in step 6 is complete, the solvent is removed by vacuum evaporation, the residue is diluted with an organic solvent, washed with water and saturated brine, and the organic phase is dried, filtered, and concentrated to obtain compound 13.

[0058] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0059] As a further improvement of the present invention, in some embodiments, the above-mentioned compound 13 may optionally be further purified by pulping or recrystallization, with pulping solution such as n-hexane; and recrystallization solvent such as ethanol / water (1 / 3).

[0060] A third aspect of the present invention provides a method for preparing compound 7, wherein the reaction is as follows:

[0061]

[0062] Wherein, R1 is selected from

[0063] One of them;

[0064] X is selected from Cl and Br;

[0065] Step 1: Compound 4 and compound 5 react in an organic solvent to give compound 6;

[0066] Step 2: Compound 6 reacts with a halogenating agent to give compound 7;

[0067] As a further improvement of the present invention, including but not limited to, the organic solvent in step 1 is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, pentanol, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and dioxane; preferably one or more of methanol, ethanol, propanol, and isopropanol.

[0068] As a further improvement of the present invention, including but not limited to, in step 1, the molar ratio of compound 4 to compound 5 is 1:(1-5), preferably (1-2).

[0069] As a further improvement of the present invention, including but not limited to, in step 1, the reaction temperature is selected from 40 to 90°C, preferably 50 to 80°C.

[0070] As a further improvement of the present invention, including but not limited to, in step 1, the reaction time is selected from 2 to 24 hours, preferably 3 to 16 hours.

[0071] As a further improvement of the present invention, in some embodiments, after the reaction in step 1 is complete, the solvent is removed by vacuum evaporation, the residue is diluted with an organic solvent, washed with an alkaline solution, and the organic phase is dried, filtered, and concentrated to obtain the crude product of compound 6.

[0072] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0073] As a further improvement of the present invention, including but not limited to, the alkaline solution is selected from one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and sodium bicarbonate aqueous solution;

[0074] As a further improvement of the present invention, in some embodiments, the crude product may be further purified by pulping to obtain a pure product of compound 6, for example, by pulping a methyl tert-butyl ether / methanol (10 / 1).

[0075] As a further improvement of the present invention, including but not limited to, in step 2, the Lucas reagent is prepared by dissolving zinc chloride in hydrochloric acid.

[0076] As a further improvement of the present invention, including but not limited to, in step 2, the halogenated reagent is selected from one or more of Lucas reagent, hydrochloric acid, zinc chloride, hydrobromic acid, bromine, aluminum tribromide, N-bromosuccinimide, sodium bromide, zinc bromide, and dibromohydantoin.

[0077] As a further improvement of the present invention, including but not limited to, in step 2, a solvent may be optionally added, the solvent being selected from one or more of dichloroethane, dichloromethane, tetrahydrofuran, chloroform, and water.

[0078] As a further improvement of the present invention, including but not limited to, in step 2, the reaction temperature is selected from 10 to 110°C, preferably 20 to 110°C.

[0079] As a further improvement of the present invention, including but not limited to, in step 2, the reaction time is selected from 2 to 24 hours, preferably 4 to 18 hours.

[0080] As a further improvement of the present invention, in some embodiments, after the reaction in step 2 is complete, the reaction solution is cooled to room temperature, diluted with an organic solvent, and the pH value is adjusted to alkaline by adding an alkaline solution. The aqueous phase is then separated, extracted with an organic solvent, the organic phases are combined, dried, and concentrated to obtain compound 7.

[0081] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0082] As a further improvement of the present invention, including but not limited to, the alkaline solution is selected from one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and sodium bicarbonate aqueous solution;

[0083] As a further improvement of the present invention, in some embodiments, the above-mentioned compound 7 may optionally be further purified by column chromatography, with column chromatography eluent such as dichloromethane / methanol = 10:1.

[0084] As a further improvement of the present invention, including but not limited to, the preparation method of compound 4 may include the following steps:

[0085]

[0086] Compound 4 was synthesized in two steps using compounds 1 and 2 as raw materials. Compound 1 was first converted into an acyl chloride under conventional conditions and then reacted with compound 2 to obtain compound 3 (refer to Organic Letters, 2017, vol. 19, #23, pp. 6424-6427). Then, the acyl chloride was cyclized with an alcohol solution, and finally, compound 4 was obtained by alkylation with Meerwein reagent (refer to CN102276661A, WO2022178205A1).

[0087] In a fourth aspect, the present invention provides a compound having the following structural formula:

[0088]

[0089] Wherein, R1 is selected from

[0090] One of them;

[0091] X is selected from either Cl or Br;

[0092] As a further improvement of the present invention, including but not limited to, compounds 7, 9 and 10 are selected from the group consisting of:

[0093]

[0094] The fifth aspect of the present invention provides a method for preparing fezonine, which includes the method for preparing compound 10 provided by the first aspect above, or the method for preparing compound 7 provided by the third aspect of the present invention above, or compounds 4, 6, 7, 7A, 9, 9A, 9B, 9C, 10, 10A, 10B, and 10C of the fourth aspect above.

[0095] Beneficial technical effects of the present invention:

[0096] 1. This invention provides a novel method for preparing fezonelam and its intermediates, which has the advantages of high chiral purity, high yield, high purity and good reproducibility.

[0097] 2. The substrates used in this invention are inexpensive and readily available, eliminating the need for expensive chiral starting materials and avoiding subsequent chiral column separation. This makes it more suitable for large-scale industrial production, reducing costs, and providing high chiral purity. The overall route is simple and easy to operate.

[0098] 3. The route of this invention uses chiral cofactors, which improves the efficiency of synthesizing fenezotan and avoids the protection and deprotection steps in the original route. It is more atom-economical and conducive to industrial-scale production, thus having good market value and far-reaching practical significance.

[0099] 4. The method of this invention utilizes five novel intermediates, providing new insights into the synthesis of fenezolam. This novel series of intermediate compounds has made a significant contribution to the successful commercialization of fenezolam. This invention overcomes the shortcomings of existing technologies and provides a novel method for preparing fenezolam. Each step of this method exhibits high chiral purity, yielding a high-purity product, which is superior to currently reported methods for fenezolam. Specific implementation methods

[0100] To make the objectives, technical solutions, and advantages of this invention clearer, the following embodiments are provided to further illustrate the invention in detail. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this invention are within the scope of protection of this invention.

[0101] Unless otherwise specified, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers and are ready for use without treatment.

[0102] Example 1:

[0103]

[0104] Dehydrated glyoxylic acid (100 g, 1.35 mol) was dissolved in thionyl chloride (400 mL) and heated under reflux for 24 hours under nitrogen protection. Excess thionyl chloride was evaporated under reduced pressure, and the residue was dried under vacuum to obtain a gel. This gel was dissolved in dichloromethane (800 mL), and ethanolamine (82.5 g, 1.35 mol) was added. After stirring until homogeneous, triethylamine (300 mL, 2.16 mol) was added in portions at 10 °C. After the addition was complete, the mixture was stirred at room temperature for 16 hours. TLC showed no glyoxylic acid, indicating the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in methyl ether (300 mL). Insoluble matter was filtered off, washed with methyl ether, and the filtrate was concentrated under reduced pressure and dried to obtain crude compound 3 (158 g). No further purification was required, and the reaction could proceed directly to the next step.

[0105] Example 2:

[0106]

[0107] Methanol (300 mL) was added to a three-necked flask. Under nitrogen protection in an ice-water bath, acetyl chloride (24.29 mL, 340.4 mmol) was added. Compound 3 (100 g, 854 mmol) prepared in the previous step was added all at once. The mixture was stirred in an ice-water bath for 1 hour and then stirred at room temperature for 6 hours. After the substrate reaction was complete as detected by TLC, solid sodium carbonate (45.26 g, 427.03 mmol) was added to consume the hydrochloric acid produced. After stirring for 1 hour, the solid was filtered off, and the filtrate was distilled under reduced pressure. The residue was dissolved in dichloromethane (300 mL). The temperature was kept below 15 °C, and solid sodium carbonate (203.7 g, 1.92 mol) was added. After stirring evenly, triethyloxonium tetrafluoroborate (201.7 g, 1.35 mol) was slowly added. After stirring evenly, continue stirring at room temperature for 2 hours, add saturated brine to quench, extract, separate the organic phase, dry, filter and concentrate to obtain compound 4 (102g, yield 75%) as a yellow oil.

[0108] Example 3:

[0109]

[0110] Compound 4 (100 g, 628.2 mmol) was dissolved in anhydrous methanol (500 mL). Under nitrogen protection, compound 5 (104 g, 657.5 mmol) was added. The reaction system was heated to 60-70 °C and stirred at this temperature for 10 hours. The starting material disappeared as detected by TLC. The reaction system was then cooled to room temperature. The solvent was removed by vacuum distillation. The residue was dissolved in dichloromethane and washed twice with 1 N sodium hydroxide aqueous solution. The organic phase was dried, filtered, and concentrated under vacuum to obtain crude compound 6. The crude compound 6 was slurried using methyl tert-butyl ether / methanol (10 / 1), filtered, and the filter cake was washed with methyl tert-butyl ether / methanol (10 / 1) solvent. The cake was transferred to a tray and dried at 60 °C with forced air to obtain white solid compound 6 (126 g, yield 79.2%).

[0111] 1 H-NMR (400MHz, CDCl3): δ6.52 (s, 1H), 3.92-3.80 (m, 4H), 4.54 (s, 3H), 2.36 (s, 3H). LC-MS: 254.20[M+1] + .

[0112] Example 4:

[0113]

[0114] Zinc chloride (306 g, 2.25 mol) was dissolved in hydrochloric acid (209 mL) under ice-water bath conditions to prepare Lucas' reagent. After the system stabilized, it was heated to room temperature, and compound 6 (100 g, 395 mmol) was added. The mixture was heated to reflux under nitrogen protection for 8 hours. TLC analysis showed no residue of the starting material. The mixture was cooled to room temperature, diluted with dichloromethane, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was then separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 7A (82.4 g, purity 99%, yield 81%) as a pale yellow solid.

[0115] 1 H-NMR (400MHz, CDCl3): δ9.81 (s, 1H), 4.65 (t, J = 8.2 Hz, 2H), 3.73 (t, J = 8.2 Hz, 2H), 2.42 (s, 3H). LC-MS: 258.21[M+1] + .

[0116] Example 5:

[0117]

[0118] Compound 7A (120 g, 466 mmol) was dissolved in tetrahydrofuran (240 mL). Under nitrogen protection, compound 8A (56.5 g, 466 mmol) and tetraethyl titanate (212 g, 929.4 mmol) were added. The mixture was heated to reflux for 6 hours. TLC analysis showed no reactants remaining. The reaction system was cooled to room temperature, quenched with saturated sodium chloride, and stirred for another hour. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrates were separated, extracted, and combined. The organic phases were washed once with water and once with saturated sodium chloride, dried, and concentrated under reduced pressure to obtain compound 9A. Compound 9A was dissolved in tetrahydrofuran (600 mL). Under nitrogen protection, the temperature was controlled at -72±5℃ with dry ice and ethanol. 3M methyl magnesium chloride tetrahydrofuran solution (187mL, 561mmol) was slowly added dropwise to the reaction system. After controlling the temperature for 2 hours, the temperature was raised to room temperature and stirred for 5 hours. TLC detection showed that the substrate disappeared. The mixture was cooled in an ice-water bath and quenched with saturated ammonium chloride aqueous solution at 0-10℃. Stirring was continued for 1 hour. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, separated, washed, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 10A (130g, purity 98%, yield 82%) as a pale yellow solid.

[0119] 1 H-NMR (400MHz, CDCl3): δ4.87-5.06 (m, 1H), 3.98-4.03 (m, 2H), 3.58-3.72 (m, 2H), 2.39 (s, 3H), 1.56 (d, J = 6.8Hz, 3H), 1.26 (s, 9H).

[0120] Example 6:

[0121]

[0122] Compound 10A (130 g, 382 mmol) was dissolved in dichloromethane (300 mL). While stirring, 4 M hydrochloric acid-methanol solution (300 mL) was added. The reaction was carried out at room temperature for 3 hours. TLC analysis showed no substrate residue. The solution was concentrated under reduced pressure to obtain crude hydrochloride of compound 11. The hydrochloride of compound 11 was dissolved in DMF (200 mL). Triethylamine was added until the system became alkaline, followed by the addition of triethylamine (64 mL, 456 mmol, 1.2 eq). Under nitrogen protection, the temperature was maintained in an ice-water bath at -5 to 5 °C, and compound 12 was slowly added dropwise. (60.6 g, 382 mmol, 1 eq), after addition, the reaction was stirred at room temperature for 6 hours. TLC analysis showed no residue of the starting material. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. It was washed once with water and once with saturated brine. The organic phase was dried, filtered, and concentrated to obtain crude compound 13. The crude compound 13 was slurried with n-hexane, filtered, dried, and then recrystallized with anhydrous ethanol / water (1 / 3). The solid was dried to obtain compound 13 (126 g, purity 99.23%, chiral purity ee value 99.68%, yield 92.1%) as an off-white solid.

[0123] 1 H-NMR (400MHz, CDCl3): δ7.51-7.42(m,2H),7.17(d,J=8.5Hz,2H),5.84-5.43(m,1H),4.8 7-4.43(m,1H),4.01-3.92(m,2H),3.54-3.57(m,1H),2.36(s,3H),1.70(d,J=6.9Hz,3H). LC-MS: 359.29[M+1] + .

[0124] Example 7:

[0125]

[0126] Compound 7A (100 g, 388 mmol) was dissolved in tetrahydrofuran (500 mL), and compound 8B (47 g, 388 mmol, 1 eq) was added. After heating under reflux for 2 hours, the mixture was cooled and kept at -72 ± 5 °C using a dry ice ethanol bath. 3 M methyl magnesium chloride tetrahydrofuran solution (130 mL, 390 mmol) was slowly added. After the addition was complete, the temperature was controlled for 1 hour, then raised to room temperature and stirred for 2 hours. Samples were taken for testing. If less than 1% of the raw material remained, the reaction was stopped. The reaction solution was placed in an ice-water bath, quenched with saturated ammonium chloride, concentrated under reduced pressure, extracted with ethyl acetate, washed, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 10B (100.4 g, purity 97%, yield 76%) as a pale yellow solid.

[0127] Example 8:

[0128]

[0129] Compound 10B (100.4 g, 294.9 mmol) was dissolved in methanol (300 mL), and 5% palladium on carbon (10 g) was added. Hydrogen was added to 2-3 MPa, and the reaction was carried out at room temperature for 16 hours. Samples were taken for analysis; the remaining starting material was less than 2%. The mixture was filtered through diatomaceous earth to remove the palladium on carbon. The filtrate was concentrated and dried to obtain crude compound 11, which was then directly dissolved in DMF (200 mL). Triethylamine (49 mL, 349 mmol) was added, and under nitrogen protection and temperature control in an ice-water bath, compound 12 (46.6 g, 2...) was slowly added dropwise. 94 mmol), after the addition was complete, the mixture was stirred at room temperature for 5 hours. TLC analysis showed that almost no starting material remained. The solvent was removed by vacuum distillation, and the residue was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with n-hexane, filtered, dried the filter cake, and recrystallized from anhydrous ethanol / water (1 / 3). The solid was dried to give compound 13 (95.8 g, purity 95.38%, chiral purity ee value 97.48%, yield 90.6%) as an off-white solid.

[0130] LC-MS: 359.28 [M+1] + .

[0131] Example 9:

[0132]

[0133] Compound 7A (100 g, 388 mmol) was dissolved in tetrahydrofuran (500 mL), and compound 8C (53.2 g, 388 mmol) was added. After heating under reflux for 2 hours, the mixture was cooled and the temperature was controlled using a dry ice-ethanol bath. 3M methyl magnesium chloride tetrahydrofuran solution (260 mL, 780 mmol) was slowly added. After the addition was complete, the temperature was controlled for 1 hour, then raised to room temperature and stirred for 2 hours. Samples were taken for testing. If less than 1% of the raw material remained, the reaction was stopped. The reaction solution was placed in an ice-water bath, quenched with saturated ammonium chloride aqueous solution, concentrated under reduced pressure, extracted with ethyl acetate, and separated. The organic phase was washed, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 10C (98.2 g, purity 97.21%, yield 71%) as a pale yellow solid.

[0134] Example 10:

[0135]

[0136] Compound 10C (98.2 g, 275 mmol) was dissolved in methanol (300 mL), and 5% palladium on carbon (9.8 g) was added. Hydrogen was added to 2-3 MPa, and the reaction was carried out at room temperature for 16 hours. Samples were taken for analysis; the remaining starting material was less than 2%. The mixture was filtered through diatomaceous earth to remove the palladium on carbon. The filtrate was concentrated and dried to obtain compound 11, which was then directly dissolved in DMF (200 mL). Triethylamine (46 mL, 327.7 mmol) was added, and under nitrogen protection and with temperature controlled in an ice-water bath, compound 12 (43.6 g) was slowly added dropwise. 275 mmol), after addition, the reaction was stirred at room temperature for 5 hours. TLC analysis showed almost no residue of the starting material. The solvent was removed by vacuum distillation. The residue was diluted with ethyl acetate, washed once with water and once with saturated brine, dried, filtered, and concentrated. The residue was slurried with n-hexane, filtered, and the filter cake was dried and recrystallized from anhydrous ethanol / water (1 / 3). The resulting solid was dried to give compound 13 (89.7 g, purity 98.33%, chiral purity ee value 98.01%, yield 91%) as an off-white solid. LC-MS: 359.30 [M+1] + .

[0137] The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing compound 10, the reaction being as follows: ###0001### Compound 10 wherein R1 is selected from ###0002### wherein X is selected from Cl, Br; One of them; characterized in comprising the following steps: Step 3: compound 7 reacts with compound 8 in the presence of an organic solvent, and a dehydration reagent is added to obtain compound 9; Step 4: compound 9 reacts in the presence of methyl Grignard reagent and an organic solvent to obtain compound 10.

2. A method for preparing nonazatinan, the reaction being as follows: ###0003### Compound 10 wherein R1 is selected from ###0004### X is selected from Cl, Br; wherein, characterized in comprising the following steps: One of them; Step 3: compound 7 reacts with compound 8 in the presence of an organic solvent, and a dehydration reagent is added to obtain compound 9; Step 4: compound 9 reacts in the presence of methyl Grignard reagent and an organic solvent to obtain compound 10; Step 5: compound 10 removes chiral auxiliary to obtain compound 11; Step 6: compound 11 reacts with compound 12 in the presence of a base and an organic solvent to obtain compound 13. wherein the compound of formula 7 is prepared by the following method, the reaction being as follows: ###0005### Compound 7 wherein R1 is selected from ###0006### X is selected from Cl, Br; 3. The method according to claim 1 or 2, characterized in that, Step 1: compound 4 reacts with compound 5 in an organic solvent to obtain compound 6; Step 2: compound 6 reacts with a halogenated reagent to obtain compound 7. One of them; The preparation method meets one or more of the following conditions: (1) the dehydration reagent in the step 3 is selected from one or more of tetraethyl titanate, isopropyl titanate, n-butyl titanate, tetraisopropyl titanate, methyl titanate, titanium tetrachloride, copper sulfate, potassium bisulfate, cesium carbonate; (2) the molar ratio of compound 7 to the dehydration reagent in the step 3 is 1:(1-5); 4. The production method according to claim 1 or 2, characterized by, (3) the molar ratio of compound 7 to compound 8 in the step 3 is 1:(1-2); (4) the reaction temperature of the step 3 is 40-100℃; (5) the reaction time of the step 3 is 1-24 hours; (6) the organic solvent in the step 3 is selected from one or more of chloroform, methanol, ethanol, propanol, butanol, pentanol, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, isopropyl ether, n-propyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, carbon tetrachloride, n-hexane, cyclohexane, acetonitrile, dioxane; (7) the step 3 and the step 4 can be carried out in one pot; (8) the methyl Grignard reagent in the step 4 is selected from one of methyl magnesium chloride and methyl magnesium bromide; (9) the molar ratio of the Grignard reagent to compound 7 in the step 3 is (1-3):1; (10) the organic solvent in the step 4 is selected from one or more of chloroform, methanol, ethanol, propanol, butanol, pentanol, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, isopropyl ether, n-propyl ether, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, carbon tetrachloride, n-hexane, cyclohexane, acetonitrile, dioxane; (11) the reaction temperature of the step 4 is -78-0℃; (12) the reaction time of the step 4 is 1-24 hours; ​ ​ ​ (13) after the reaction of step 4 is completed, the reaction solution is placed in an ice water bath, saturated ammonium chloride aqueous solution is added for quenching, concentrated under reduced pressure, extracted with an organic solvent, washed, dried, and concentrated to obtain compound 10, which is further purified by column chromatography.

5. The preparation method according to claim 4, characterized in that, The preparation method meets one or more of the following conditions: (1) the dehydrating agent in step 3 is tetraethyl titanate; (2) the molar ratio of compound 7 to the dehydrating agent in step 3 is 1:(1-3); (3) the molar ratio of compound 7 to compound 8 in step 3 is 1:(1-1.5); (4) the reaction temperature in step 3 is 40-80°C; (5) the reaction time in step 3 is 1-12 hours; (6) the organic solvent in step 3 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and toluene; (7) the molar ratio of the Grignard reagent to compound 7 in step 4 is (1-2):1; (8) the organic solvent in step 4 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, and toluene; (9) the reaction temperature in step 4 is -78 to -10°C; (10) the reaction time in step 4 is 1-12 hours.

6. The production method according to claim 2, wherein The preparation method meets one or more of the following conditions: (1) in step 5, Method 1 : When R1is compound 10 is removed under acidic conditions to give compound 11; Method 2: When R1is compound 10 under conditions of a metal catalyst and a hydrogen source to give compound 11; (2) the reaction temperature in step 5 is 10-50°C; (3) the reaction time in step 5 is 2-24 hours; (4) an organic solvent is added in step 5, and the organic solvent is selected from one or more of ethyl acetate, dichloromethane, carbon tetrachloride, dichloroethane, acetone, methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, acetonitrile, diethyl ether, tetrahydrofuran, and dioxane; (5) the base in step 6 is selected from one or more of 4-dimethylaminopyridine, N,N-diisopropylethylamine, pyridine, triethylamine, potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and 4-methylmorpholine; (6) in step 6, the molar ratio of compound 11, compound 12, and the base is 1:(1-2):(1-10); (7) the organic solvent in step 6 is selected from one or more of dichloromethane, carbon tetrachloride, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and dioxane; (8) the reaction temperature in step 6 is 0-50°C; (9) the reaction time in step 6 is 1-24 hours; (10) after the reaction in step 6 is completed, the solvent is evaporated under reduced pressure, the residue is diluted with an organic solvent, washed with water and saturated brine, and the organic phase is dried, filtered, and concentrated to obtain compound 13, which is further purified by beating or recrystallization.

7. The production method according to claim 6, characterized by, The preparation method meets one or more of the following conditions: (1) the reaction temperature in step 5 is 20-40°C; (2) the reaction time in step 5 is 1-20 hours; (3) the organic solvent in step 5 is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, and carbon tetrachloride; (4) the base in step 6 is selected from one or more of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, pyridine; (5) in step 6, the molar ratio of compound 11, compound 12 and base is 1: (1-1.5): (1-6); (6) the organic solvent in step 6 is selected from one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane; (7) the reaction temperature in step 6 is 10-40℃; (8) the reaction time in step 6 is 4-12 hours.

8. The preparation method according to claim 6, characterized in that, The preparation method meets one or more of the following conditions: (1) the acidic reagent is selected from one or more of trifluoroacetic acid, hydrochloric acid, hydrochloric acid organic solution; (2) the metal catalyst is selected from one of palladium on carbon, palladium hydroxide, platinum dioxide, platinum carbon, Raney nickel; (3) the hydrogen source is selected from one of hydrogen gas, ammonium formate.

9. The preparation method according to claim 8, characterized in that, (1) the hydrochloric acid organic solution is selected from one or more of hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid isopropanol solution, hydrochloric acid acetone solution, hydrochloric acid ethyl acetate solution, hydrochloric acid dioxane solution; (2) the metal catalyst is selected from one of palladium on carbon, palladium hydroxide, Raney nickel.

10. The method of claim 3, wherein, The preparation method meets one or more of the following conditions: (1) the organic solvent in step 1 is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, pentanol, toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane; (2) in step 1, the molar ratio of compound 4 and compound 5 is 1: (1-5); (3) in step 1, the reaction temperature is selected from 40-90℃; (4) in step 1, the reaction time is selected from 2-24 hours; (5) after the reaction in step 1 is complete, the solvent is evaporated under reduced pressure, the residue is diluted with an organic solvent, washed with a basic solution, and the organic phase is dried, filtered, and concentrated to obtain a crude compound 6, which is further beaten to obtain a pure compound 6; (6) in step 2, the halogenating reagent is selected from one or more of Lucas reagent, hydrochloric acid, zinc chloride, hydrobromic acid, bromine, aluminum tribromide, N-bromosuccinimide, sodium bromide, zinc bromide, dibromohydantoin; (7) in step 2, a solvent is added, and the solvent is selected from one or more of dichloroethane, dichloromethane, tetrahydrofuran, chloroform, water; (8) in step 2, the reaction temperature is selected from 10-110℃; (9) in step 2, the reaction time is selected from 2-24 hours; (10) after the reaction in step 2 is complete, the reaction solution is cooled to room temperature, diluted with an organic solvent, and adjusted to alkaline pH after adding a basic solution, then separated, the aqueous phase is extracted with an organic solvent, the combined organic phase is dried, concentrated to obtain compound 7, which is further purified by column chromatography.

11. The method of claim 10, wherein, The preparation method meets one or more of the following conditions: (1) the organic solvent in step 1 is selected from one or more of methanol, ethanol, propanol, isopropanol; (2) in the step 1, the molar ratio of compound 4 to compound 5 is (1-2); (3) in the step 1, the reaction temperature is 50-80℃; (4) in the step 1, the reaction time is 3-16 hours; (5) in the step 2, the reaction temperature is 20-110℃; (6) in the step 2, the reaction time is 4-18 hours.

12. A compound having the structure: wherein R1 is selected from one of the group consisting of X is selected from the group consisting of Cl, Br.

13. The compound of claim 12, wherein the compound 9, the compound 10 is selected from

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