Fisurazan intermediate and preparation method thereof

Abstract

The invention provides a fisurazan intermediate and a preparation method thereof. Specifically, the invention provides a preparation method of a compound as shown in a formula XVI, and the preparation method comprises the following step: in the presence of a solvent, a compound as shown in a formula XV and DMF-DMA are subjected to a ring closing reaction to generate the compound as shown in the formula XVI. The preparation method provided by the invention meets one or more of the following advantages: (1) reaction steps are short; (2) the yield is high; (3) the production cost is low; and (4) the method is suitable for commercial amplification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a fexuprazan intermediate and a preparation method thereof. Background Art

[0002] Fexuprazan, with the chemical name 1-{5-(2,4-difluorophenyl)-1-[(3-fluorophenyl)sulfonyl]-4-methoxy-1H-pyrrol-3-yl}-N-methylmethanamine, has the molecular formula C 19 H 17 F 3 N 2 O 3 S, with a molecular weight of 410.4, is a novel potassium ion competitive acid blocker produced by Daejoon Pharmaceutical in South Korea. It is a new generation of proton pump inhibitor that can reversibly block the proton pump secreting gastric acid. Its molecular formula is as follows:

[0003]

[0004] WO2017164575 discloses a method for preparing fexuprazan. The preparation process includes a total of four reaction steps. However, the yield in the preparation process of this patent is relatively low. The total yield of the last four steps is 51.4%, and dangerous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting reagents (such as pyridinium chlorochromate) are used, which is not suitable for large-scale industrial production. Its preparation route is as follows:

[0005]

[0006] WO2020060213 does not change the route based on WO2017164575, but only optimizes the process, removes dangerous reagents (such as sodium hydride, diisobutylaluminum hydride, etc.) and environmentally polluting reagents (such as pyridinium chlorochromate), and improves the yield. This route can adapt to commercial production, but generally there is no essential change, and the production operation is complex. This patent also reports a new route for preparing compound VII. This route has shorter steps, but uses expensive and dangerous TMS-diazomethane, which is not conducive to commercial cost control.

[0007] Summary of the Invention

[0008] In order to overcome the defects of the above-mentioned route with high cost and complex operation, the present invention provides a preparation method of a key intermediate of fexuprazan with short reaction steps, low cost and high yield.

[0009] The present invention mainly solves the above technical problems through the following technical solutions.

[0010] The present invention provides a method for preparing a compound represented by Formula XVI, which comprises the following steps: in the presence of a solvent, a compound represented by Formula XV and DMF-DMA undergo a ring-closing reaction to form a compound represented by Formula XVI;

[0011]

[0012] In the ring-closing reaction, the solvent used in the present application is a conventional solvent for this type of reaction in the art, such as an ether solvent, for example, methyl tert-butyl ether.

[0013] In some embodiments, in the ring-closing reaction, the molar ratio of the compound represented by Formula XV to DMF-DMA is 1:2 - 1:4, preferably 1:3.

[0014] In some embodiments, in the ring-closing reaction, the molar to volume ratio of the compound represented by Formula XV to the solvent is 0.1 - 0.3 mol / L, preferably 0.2 mol / L.

[0015] In some embodiments, in the ring-closing reaction, the reaction temperature is 45 - 65 °C, preferably 55 °C.

[0016] In some embodiments, in the ring-closing reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the reaction end point is when the compound of Formula XV disappears, and the reaction time is generally 14 - 18 hours, for example, 16 hours.

[0017] In some embodiments, the ring-closing reaction further includes the following post-treatment steps: after the reaction ends, adjust the pH to 6 - 7 with hydrochloric acid, separate the layers, concentrate, add a volume of n-heptane 9 - 10 times the volume of the solution dropwise, and filter.

[0018] In some embodiments, in the ring-closing reaction, the reaction materials of the ring-closing reaction are composed of the compound represented by Formula XV, DMF-DMA and the solvent.

[0019] In some embodiments, the method for preparing the compound represented by Formula XVI further includes the following steps:

[0020] In the presence of a solvent, a catalyst and an organic strong acid, a compound represented by Formula XIV and 3-fluorobenzenesulfonamide undergo a Hinsberg reaction to form the compound represented by Formula XV

[0021]

[0022] In some embodiments, in the Hinsberg reaction, the solvent is a cyclic ether solvent, for example, 2-methyltetrahydrofuran.

[0023] In some embodiments, in the Hinsberg reaction, the molar to volume ratio of the compound represented by Formula XIV and the solvent is 0.7 - 0.9 mol / L, for example, 0.79 mol / L.

[0024] In the Hinsberg reaction, the catalyst can be a conventional catalyst for this type of reaction in the art, such as tetraethyl titanate.

[0025] In the Hinsberg reaction, the organic strong acid can be a conventional organic strong acid for this type of reaction in the art, such as p-toluenesulfonic acid, for example, p-toluenesulfonic acid monohydrate.

[0026] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV and the catalyst is 1:1.5 - 1:2.5, for example, 1:1.8.

[0027] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV and the organic strong acid is 18:1 - 25:1, for example, 22:1.

[0028] In some embodiments, in the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV and 3-fluorobenzenesulfonamide is 1:1 - 1.3:1, for example, 1.1:1.

[0029] In some embodiments, in the Hinsberg reaction, the reaction temperature is 70 - 100 °C, for example, 80 - 90 °C.

[0030] In some embodiments, in the Hinsberg reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the reaction end point is when the compound of Formula XIV disappears, and the reaction time is generally 14 - 18 hours, for example, 16 hours.

[0031] In some embodiments, in the Hinsberg reaction, the reaction materials of the Hinsberg reaction are composed of the compound represented by Formula XIV, the solvent, the catalyst, the organic strong acid and 3-fluorobenzenesulfonamide.

[0032] In some embodiments, the Hinsberg reaction includes the following post-treatment steps: after the reaction is completed, the temperature is controlled to room temperature, water is added to quench the reaction, liquid separation is carried out, concentration is performed, n-heptane with a volume 5 - 7 times that of the solution volume is added dropwise, and filtration is carried out.

[0033] In some embodiments, the preparation of the compound represented by Formula XVI further includes the following steps:

[0034] In the presence of a solvent, a catalyst, and a Lewis acid, the compound shown in Formula XIII reacts with an acyl chloride reagent and m-difluorobenzene to undergo an acylation reaction to produce the compound shown in Formula XIV;

[0035]

[0036] In the acylation reaction, the solvent is a conventional solvent for this type of reaction in the art, such as a chloroalkane solvent, preferably dichloromethane.

[0037] In the acylation reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as DMF.

[0038] In the acylation reaction, the Lewis acid is a conventional Lewis acid for this type of reaction in the art, such as aluminum trichloride, preferably anhydrous aluminum trichloride.

[0039] In the acylation reaction, the acyl chloride reagent is a conventional acyl chloride reagent for this type of reaction in the art, such as oxalyl chloride and / or thionyl chloride, preferably oxalyl chloride.

[0040] In some embodiments, in the acylation reaction, the molar ratio of the compound shown in Formula XIII to the acyl chloride reagent is 1:1 - 1:1.5, for example 1:1.2.

[0041] In some embodiments, in the acylation reaction, the molar ratio of the compound shown in Formula XIII to the catalyst is 1:0.08 - 1:0.15, preferably 1:0.13.

[0042] In some embodiments, in the acylation reaction, the molar ratio of the compound shown in Formula XIII to the m-difluorobenzene is 1:10 - 1:15, for example 1:12.

[0043] In some embodiments, in the acylation reaction, the molar ratio of the compound shown in Formula XIII to the Lewis acid is 1:1 - 1:1.2, for example 1:1.1.

[0044] In some embodiments, in the acylation reaction, the reaction temperature is 50 - 70 °C, for example 55 - 65 °C.

[0045] In some embodiments, in the acylation reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC, or NMR), and the reaction time is generally 16 - 24 hours, preferably 20 hours.

[0046] In some embodiments, in the acylation reaction, the reaction materials for the acylation reaction consist of the solvent, the catalyst, the Lewis acid, the compound shown in Formula XIII, the acyl chloride reagent, and the m-difluorobenzene.

[0047] In some embodiments, the acylation reaction comprises the following steps: in the presence of a solvent and a catalyst, the acyl chloride reagent is added dropwise to the solution of the compound shown in Formula XIII while controlling the temperature, stirred at room temperature, concentrated, the solvent and the m-difluorobenzene are added, and the m-difluorobenzene solution of the Lewis acid is added dropwise at the reaction temperature for reaction.

[0048] In some embodiments, the acylation reaction further comprises the following post-treatment steps: after the reaction is completed, the reaction solution is added dropwise to water while controlling the temperature not exceeding 10°C, and liquid separation is carried out at 20 - 30°C.

[0049] In some embodiments, the preparation of the compound shown in Formula XVI further comprises the following steps:

[0050] In the presence of a base, lithium bromide, and a solvent, the compound shown in Formula XII undergoes a substitution reaction with dimethyl sulfate and diisopropylethylamine to form the compound shown in Formula XIII;

[0051]

[0052] In the substitution reaction, the base is a conventional base for this type of reaction in the art, an alkali metal carbonate, preferably potassium carbonate.

[0053] In the substitution reaction, the solvent is a conventional solvent for this type of reaction in the art, such as a cyclic ether solvent and / or water, for example, tetrahydrofuran and / or water.

[0054] In some embodiments, in the substitution reaction, the molar ratio of the compound shown in Formula XII to the base is 1:1.5 - 1:2.5, for example, 1:2.

[0055] In some embodiments, in the substitution reaction, the molar ratio of the compound shown in Formula XII to dimethyl sulfate is 1:1 - 1:1.5, for example, 1:1.2.

[0056] In some embodiments, in the substitution reaction, the molar ratio of the compound shown in Formula XII to lithium bromide is 1:2 - 1:3, for example, 1:2.5.

[0057] In some embodiments, in the substitution reaction, the molar ratio of the compound shown in Formula XII to diisopropylethylamine is 1:3 - 1:5, for example, 1:4.

[0058] In some embodiments, in the substitution reaction, the temperature of the reaction is 25 - 50 °C, for example 30 - 40 °C.

[0059] In some embodiments, in the substitution reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the end point of the reaction is when the compound of formula XII disappears, and the reaction time is generally 3 - 6 hours, for example 4 - 5 hours.

[0060] In some embodiments, in the substitution reaction, the reaction materials of the substitution reaction are composed of the solvent, the base, dimethyl sulfate, lithium bromide, diisopropylethylamine, and the compound as shown in formula XII.

[0061] In some embodiments, the substitution reaction comprises the following steps: in the presence of a base and a cyclic ether solvent, the compound as shown in formula XII and dimethyl sulfate react at 30 - 40 °C for 12 - 20 hours, cool to 5 - 15 °C, add water, stir and add lithium bromide and diisopropylethylamine, and keep the temperature for reaction for 4 - 5 hours.

[0062] In some embodiments, the substitution reaction further comprises the following post-treatment steps: after the reaction is completed, adjust the pH to 4 - 5, and extract with dichloromethane.

[0063] The present invention also provides a method for preparing a compound as shown in formula XVII, which is characterized in that it comprises the following steps:

[0064] In the presence of a solvent, dichlorodiphenylmethane, DIPEA and a catalyst, the compound as shown in formula XVI and methylamine hydrochloride undergo an amidation reaction to form the compound as shown in formula XVII;

[0065]

[0066] In the amidation reaction, the solvent is a conventional solvent for this type of reaction in the art, such as a chloroalkane solvent, for example dichloromethane.

[0067] In the amidation reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as stannous chloride.

[0068] In some embodiments, in the amidation reaction, the molar ratio of the compound as shown in formula XVI to dichlorodiphenylmethane is 1:1 - 1:1.4, for example 1:1.2.

[0069] In some embodiments, in the amidation reaction, the molar ratio of the compound as shown in formula XVI to stannous chloride is 25:1 - 100:1, for example 50:1.

[0070] In some embodiments, in the amidation reaction, the molar ratio of the compound represented by Formula XVI to DIPEA is 1:2.5 - 3.5, such as 1:2.5.

[0071] In some embodiments, in the amidation reaction, the molar ratio of the compound represented by Formula XVI to methylamine hydrochloride is 1:1 - 1:1.4, such as 1:1.2.

[0072] In some embodiments, in the amidation reaction, the reaction temperature is 15 - 35 °C, such as 20 - 30 °C.

[0073] In some embodiments, in the amidation reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR), and the reaction time is generally 1 - 5 hours, such as 2 - 4 hours.

[0074] In some embodiments, in the amidation reaction, the reaction materials of the amidation reaction are composed of the solvent, the compound represented by Formula XVI, the catalyst, dichlorodiphenylmethane, stannous chloride, DIPEA and methylamine hydrochloride.

[0075] In some embodiments, the amidation reaction comprises the following steps: in the presence of the catalyst and the solvent, the compound represented by Formula XVI and stannous chloride are stirred at 20 - 30 °C for 1 - 2 hours, and then DIPEA and methylamine hydrochloride are added for reaction.

[0076] In some embodiments, the amidation reaction further comprises the following post-treatment steps: after the reaction is completed, water is added to quench the reaction, the pH is adjusted to 4 - 5, liquid separation is carried out, and n-heptane in an amount 4.5 - 5 times the volume of the solution is added dropwise at 20 - 30 °C, and then filtration is carried out.

[0077] In some embodiments, the amidation reaction further comprises the following steps: preparing the compound represented by Formula XVI by any of the previous methods.

[0078] The present invention also provides a method for preparing a compound represented by Formula I, which is characterized by comprising the following steps:

[0079] (S1) Preparing the compound represented by Formula XVII by any of the previous methods;

[0080] (S2) In the presence of an acid and a solvent, the compound represented by Formula XVII and a reducing agent undergo a reduction reaction to generate the compound represented by Formula I;

[0081]

[0082] In the reduction reaction, the acid is a conventional acid for this type of reaction in the art, such as an organic acid, for example, trifluoroacetic acid.

[0083] In the reduction reaction, the solvent is a conventional solvent for this type of reaction in the art, such as a cyclic ether solvent, for example, tetrahydrofuran.

[0084] In the reduction reaction, the reducing agent is a conventional reducing agent for this type of reaction in the art, such as aluminum hydroxide and / or sodium borohydride, for example, sodium borohydride.

[0085] In some embodiments, in the reduction reaction, the molar ratio of the compound of formula XVIII to the reducing agent is 1:3 - 1:5, for example, 1:4.2.

[0086] In some embodiments, in the reduction reaction, the molar ratio of the compound of formula XVIII to the acid is 1:3.5 - 1:5.5, for example, 1:4.7.

[0087] In some embodiments, in the reduction reaction, the reaction temperature is 25 - 45 °C. For example, 30 - 40 °C.

[0088] In some embodiments, in the reduction reaction, the progress of the reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). Generally, the reaction end point is when the compound of formula XVII disappears, and the reaction time is generally 6 - 9 hours, for example, 7 - 8 hours.

[0089] In some embodiments, in the reduction reaction, the reaction materials of the reduction reaction are composed of the solvent, the compound as shown in formula XVII, the acid and the reducing agent.

[0090] In some embodiments, the reduction reaction includes the following steps: in the presence of the solvent and the compound as shown in formula XVII, the reducing agent is added while controlling the temperature not higher than 30 °C. After addition, the acid is added while controlling the temperature at 30 - 35 °C, and the reaction is carried out at 30 - 40 °C.

[0091] In some embodiments, the reduction reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is added to water while controlling the temperature not higher than 15 °C, the pH is adjusted to 6.5 - 7.5, liquid separation is carried out, extraction is carried out with ethyl acetate, the water content is removed until the water content is not higher than 0.5%, and n-heptane with a volume 2.6 - 4 times that of the solution volume is added dropwise while controlling the temperature at 20 °C - 30 °C, and then filtration is carried out.

[0092] The present invention also provides the following compounds;

[0093]

[0094] On the basis of not violating the common knowledge in this field, the above preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0095] The reagents and raw materials used in the present invention are all commercially available.

[0096] The positive and progressive effects of the present invention are as follows: providing a preparation method of non-surazam with short steps, low cost and high yield. Detailed implementation manners

[0097] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions indicated in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0098] Example 1

[0099]

[0100] 20.4 g of compound XII (0.1 mol), 27.6 g of potassium carbonate (0.2 mol), 15.1 g of dimethyl sulfate (0.12 mol), and 102 mL of tetrahydrofuran were added to a reaction flask, and the temperature was controlled at 30 - 40 °C for reaction for 16 hours. TLC showed that the raw materials had completely reacted. The reaction mixture was cooled to 5 - 15 °C, 100 mL of water was added, 21.7 g of lithium bromide (0.25 mol) and 51.6 g of diisopropylethylamine (0.4 mol) were added with stirring, and the temperature was kept for 4 - 5 hours. TLC showed that the reaction was complete. The pH was adjusted to 4 - 5 with 1N dilute hydrochloric acid, and it was concentrated under reduced pressure to about 100 - 110 mL. The residue was extracted with dichloromethane (100 mL * 3). The combined organic phase was washed successively with 100 mL of 1N dilute hydrochloric acid and 100 mL of 10% sodium chloride solution. The organic phase was concentrated to dryness under reduced pressure to obtain 19.6 g, with a yield of 96.1%, MS(M - H) - : 203.3. 1 HNMR(400 MHz, MeOD) δ ppm: 4.09 (s, 3H), 3.50 (d, 1H), 3.00 (dd, 1H), 2.93 (dd, 1H), 1.41 (s, 9H).

[0101] Example 2

[0102]

[0103] Add compound XIII to the reaction flask. Add 20.4 g of compound XIII (0.1 mol), 0.5 mL of DMF, and 102 mL of dichloromethane to R1. Dropwise add 15.2 g of oxalyl chloride (0.12 mol) under an ice-water bath. After the addition is complete, remove the ice-water bath and stir at room temperature for 4 hours. TLC shows that the raw materials have completely reacted. Concentrate under reduced pressure to dryness, add 102 mL of dichloromethane, concentrate under reduced pressure to dryness again, and then add 40 mL of m-difluorobenzene and stir until evenly mixed to obtain Solution 1. Add 14.7 g of anhydrous aluminum trichloride and 82 mL of m-difluorobenzene to the reaction flask, and dropwise add Solution 1 to the reaction flask while controlling the temperature not to exceed 60 °C. Keep the temperature at 55 - 65 °C and react for 16 hours. After the reaction is complete, control the temperature not to exceed 10 °C, and slowly add the reaction solution dropwise to 102 mL of water. After the addition, raise the temperature to 20 - 30 °C, separate the layers, and wash the organic phase with 102 mL of 1N dilute hydrochloric acid, 102 mL of water, 102 mL of 5% sodium bicarbonate, and 102 mL of water. Concentrate the organic phase under reduced pressure to dryness to obtain 22.4 g, with a yield of 74.7%. 1 H-NMR(400MHz, CDCl 3 ) δ ppm: 7.26 - 7.30 (m, 1H), 6.85 - 6.92 (m, 2H), 4.12 (s, 3H), 3.58 (d, 1H), 3.01 (dd, 1H), 2.92 (dd, 1H), 1.39 (s, 9H).

[0104] Example 3

[0105]

[0106] Add 33.0 g of compound XIV (0.11 mol), 17.5 g of 3-fluorobenzenesulfonamide (0.1 mol), 45.6 g of tetraethyl titanate (0.2 mol), 0.95 g of p-toluenesulfonic acid monohydrate (5 mmol), and 140 mL of 2-methyltetrahydrofuran to the reaction flask, and react at 80 - 90 °C for 16 hours. TLC shows that the raw materials have completely reacted. Cool to room temperature, add 35 mL of water, stir for 1 - 2 hours, filter, wash the filter cake with 35 mL of methyltetrahydrofuran, and separate the layers. Concentrate the organic phase under reduced pressure to 40 - 50 mL, and dropwise add 280 mL of n-heptane at room temperature. After the addition, keep stirring at the same temperature for 2 - 3 hours, filter, wash the filter cake with 70 mL of n-heptane, and dry in vacuo at 40 - 50 °C to obtain 34.2 g, with a yield of 74.8%. MS(M+H) + : 457.9. 1HNMR (400 MHz, MeOD) δ ppm: 7.46 - 7.41 (m, 1H), 7.26 - 7.30 (m, 1H), 7.26 (d, 1H), 7.15 - 7.09 (m, 2H), 6.85 - 6.92 (m, 2H), 3.98 (s, 3H), 2.98 (d, 1H), 2.87 (d, 1H), 1.40 (s, 9H).

[0107] Example 4

[0108]

[0109] 45.7 g of compound XV (0.1 mol), 35.7 g of DMF-DMA (0.3 mol), and 500 mL of methyl tert-butyl ether were added to a reaction kettle, and the temperature was raised to reflux (∼55 °C), and the reaction was maintained under reflux for 16 hours. TLC showed that the reaction was complete. The temperature was lowered to 5 - 15 °C, and 200 mL of water was added. The pH was adjusted to 6 - 7 with 1 mol / L hydrochloric acid, and the mixture was stirred at a constant temperature for 1 - 2 hours, and then separated. The organic phase was washed with 200 mL of 10% sodium chloride solution. The organic phase was concentrated under reduced pressure to about 90 - 100 mL, the temperature was lowered to 20 - 30 °C, and 900 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 0 - 5 °C and stirred for 2 - 3 hours, filtered, and dried in vacuo at 40 - 50 °C to obtain 38.4 g, with a yield of 82.2%. MS (M + H) + : 467.9. 1 HNMR (400 MHz, MeOD) δ ppm: 7.99 (s, 1H), 7.44 - 7.39 (m, 1H), 7.31 (t, 1H), 7.24 (d, 1H), 7.17 - 7.10 (m, 2H), 6.92 (t, 1H), 6.78 (t, 1H), 2.80 (s, 3H), 1.38 (s, 9H).

[0110] Example 5

[0111]

[0112] Add 46.7 g of compound XVI (0.1 mol), 28.3 g of dichlorodiphenylmethane (0.12 mol), 0.38 g of stannous chloride (2 mmol), and 467 mL of dichloromethane to a reaction flask, and stir at 20 - 30 °C for 1 - 2 hours. Add 38.4 g of DIPEA (0.3 mol) and 8.1 g of methylamine hydrochloride (0.12 mol) to the reaction solution, and react for 1 - 2 hours after addition. Add 93 mL of water to the reaction solution, and adjust the pH to 4 - 5 with 1N dilute hydrochloric acid, then separate the layers. Add 93 mL of water to the organic phase, and adjust the pH to 4 - 5 with 1N dilute hydrochloric acid, then separate the layers. Wash the organic phase with 93 mL of 5% sodium bicarbonate and 93 mL of water respectively, and concentrate to 90 - 100 mL. While controlling the temperature at 20 - 30 °C, add 467 mL of n - heptane dropwise, keep warm and stir for 3 - 4 hours, filter, wash the filter cake with 93 mL of n - heptane, and dry in vacuo at 40 - 50 °C to obtain 39.7 g, with a yield of 93.4% and a purity of 99.01%, MS(M + H) + : 425.8. 1 HNMR(400 MHz, MeOD) δ ppm: 7.92(s, 1H), 7.42 - 7.39(m, 1H), 7.33(t, 1H), 7.22(d, 1H), 7.19 - 7.11(m, 2H), 6.97(t, 1H), 6.75(t, 1H), 3.89(s, 3H), 2.80(s, 3H).

[0113] Example 6

[0114]

[0115] Add 100 g of compound XVII (0.236 mol) and 500 mL of tetrahydrofuran to the reaction kettle. While controlling the temperature not higher than 30 °C, add 37.1 g of sodium borohydride (0.981 mol). After addition, add trifluoroacetic acid (125 g, 1.10 mol) while controlling the temperature at 30 - 35 °C. After addition, react at 30 - 40 °C for 7 - 8 hours. TLC shows that the raw materials have completely reacted. Cool the reaction solution to 5 - 15 °C. While controlling the temperature not higher than 15 °C, add the reaction solution to 500 mL of water, stir for 4 - 5 hours while controlling the temperature not higher than 15 °C, adjust the pH to about 7, and separate the layers. Extract the aqueous phase with 500 mL of ethyl acetate. Combine the organic phases, wash with 10% NaCl solution (200 mL * 2), and concentrate the organic phase under reduced pressure to 200 - 300 mL. Add 500 mL of ethyl acetate and stir for 10 - 20 minutes, filter, concentrate the filtrate under reduced pressure to 200 - 300 mL, and detect that the water content is not higher than 0.5%. While controlling the temperature at 20 - 30 °C, add 800 mL of n-heptane dropwise with stirring, keep warm and stir for 2 - 3 hours, filter, wash the filter cake with 200 mL of ethyl acetate / n-heptane (V:V = 1:4) solution, and dry to obtain 86.5 g of compound I, with a yield of 89.5% and a purity of 99.63%. MS(M+H) + : 410.9. 1 HNMR(400 MHz, MeOD) δ ppm: 7.70 (s, 1H), 7.60 - 7.54 (m, 1H), 7.47 (t, 1H), 7.31 (d, 1H), 7.21 - 7.16 (m, 2H), 7.04 - 6.95 (m, 2H), 4.08 (d, 2H), 3.47 (s, 3H), 2.72 (s, 3H).

Claims

1. A method for preparing a compound represented by Formula XVI, characterized in that, it comprises the following steps: In the presence of a solvent, the compound represented by Formula XV and DMF-DMA undergo a ring-closing reaction to form the compound represented by Formula XVI; 2. The preparation method according to claim 1, characterized in that, it satisfies one or more of the following conditions (1) In the ring-closing reaction, the solvent is an ether solvent, such as methyl tert-butyl ether; (2) In the ring-closing reaction, the molar ratio of the compound represented by Formula XV to DMF-DMA is 1:2 - 1:4, preferably 1:3; (3) In the ring-closing reaction, the molar-to-volume ratio of the compound represented by Formula XV to the solvent is 0.1 - 0.3 mol / L, preferably 0.2 mol / L; (4) In the ring-closing reaction, the reaction temperature is 45 - 65 °C, preferably 55 °C; (5) In the ring-closing reaction, the reaction time is 14 - 18 hours, such as 16 hours; (6) The ring-closing reaction further comprises the following post-treatment steps. After the reaction is completed, the pH is adjusted to 6 - 7 with hydrochloric acid, liquid separation is carried out, concentration is performed, n-heptane in an amount 9 - 10 times the volume of the dropped solution is added dropwise, and filtration is carried out; (7) In the ring-closing reaction, the reaction materials of the ring-closing reaction are composed of the compound represented by Formula XV, DMF-DMA and the solvent.

3. The preparation method according to claim 1, characterized in that, the method for preparing the compound represented by Formula XVI further comprises the following steps: In the presence of a solvent, a catalyst and an organic strong acid, the compound represented by Formula XIV and 3-fluorobenzenesulfonamide undergo a Hinsberg reaction to form the compound represented by Formula XV; 4. The preparation method according to claim 3, characterized in that, it satisfies one or more of the following conditions; (1) In the Hinsberg reaction, the solvent is a cyclic ether solvent, such as 2-methyltetrahydrofuran; (2) In the Hinsberg reaction, the molar-to-volume ratio of the compound represented by Formula XIV to the solvent is 0.7 - 0.9 mol / L, such as 0.79 mol / L; (3) In the Hinsberg reaction, the catalyst is tetraethyl titanate; (4) In the Hinsberg reaction, the organic strong acid is p-toluenesulfonic acid, such as p-toluenesulfonic acid monohydrate; (5) In the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV to the catalyst is 1:1.5 - 1:2.5, such as 1:1.8; (6) In the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV to the organic strong acid is 18:1 - 25:1, such as 22:1; (7) In the Hinsberg reaction, the molar ratio of the compound represented by Formula XIV to 3-fluorobenzenesulfonamide is 1:1 - 1.3:1, such as 1.1:1; (8) In the Hinsberg reaction, the reaction temperature is 70 - 100 °C, such as 80 - 90 °C; (9) In the Hinsberg reaction, the reaction time is 14 - 18 hours, such as 16 hours; (10) In the Hinsberg reaction, the reaction materials of the Hinsberg reaction are composed of the compound shown in Formula XIV, the solvent, the catalyst, the organic strong acid, and 3-fluorobenzenesulfonamide; (11) The Hinsberg reaction includes the following post-treatment steps: after the reaction is completed, the temperature is controlled to room temperature, water is added for quenching, liquid separation is carried out, concentration is performed, n-heptane with a volume 5-7 times that of the solution is added dropwise, and filtration is carried out.

5. The preparation method according to claim 1, characterized in that, the preparation of the compound shown in Formula XVI further includes the following steps: In the presence of a solvent, a catalyst, and a Lewis acid, the compound shown in Formula XIII reacts with an acyl chloride reagent and m-difluorobenzene to undergo an acylation reaction to form the compound shown in Formula XIV; 6. The preparation method according to claim 5, characterized in that, it satisfies one or more of the following conditions; (1) In the acylation reaction, the solvent is a chloroalkane solvent, preferably dichloromethane; (2) In the acylation reaction, the catalyst is DMF; (3) In the acylation reaction, the Lewis acid is aluminum trichloride, preferably anhydrous aluminum trichloride; (4) In the acylation reaction, the acyl chloride reagent is oxalyl chloride and / or thionyl chloride, preferably oxalyl chloride; (5) In the acylation reaction, the molar ratio of the compound shown in Formula XIII to the acyl chloride reagent is 1:1 - 1:1.5, for example 1:1.2; (6) In the acylation reaction, the molar ratio of the compound shown in Formula XIII to the catalyst is 1:0.08 - 1:0.15, preferably 1:0.13; (7) In the acylation reaction, the molar ratio of the compound shown in Formula XIII to m-difluorobenzene is 1:10 - 1:15, for example 1:12; (8) In the acylation reaction, the molar ratio of the compound shown in Formula XIII to the Lewis acid is 1:1 - 1:1.2, for example 1:1.1; (9) In the acylation reaction, the reaction temperature is 50 - 70 °C, for example 55 - 65 °C; (10) In the acylation reaction, the reaction time is 16 - 24 hours, preferably 20 hours; (11) In the acylation reaction, the reaction materials of the acylation reaction are composed of the solvent, the catalyst, the Lewis acid, the compound shown in Formula XIII, the acyl chloride reagent, and m-difluorobenzene; (12) The acylation reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is added dropwise to water while controlling the temperature not exceeding 10 °C, and liquid separation is carried out at 20 - 30 °C; Preferably, the acylation reaction includes the following steps: in the presence of a solvent and a catalyst, the acyl chloride reagent is added dropwise to the solution of the compound shown in Formula XIII while controlling the temperature, stirred at room temperature, concentrated, the solvent and m-difluorobenzene are added, and a solution of the Lewis acid in m-difluorobenzene is added dropwise at the reaction temperature for reaction.

7. The preparation method according to claim 1, characterized in that, the preparation of the compound shown in Formula XVI further includes the following steps: In the presence of a base, lithium bromide and a solvent, the compound shown in Formula XII undergoes a substitution reaction with dimethyl sulfate and diisopropylethylamine to form the compound shown in Formula XIII; 8. The preparation method according to claim 7, characterized in that, it satisfies one or more of the following conditions; (1) In the substitution reaction, the base is an alkali metal carbonate, preferably potassium carbonate; (2) In the substitution reaction, the solvent is a cyclic ether solvent and / or water, such as tetrahydrofuran and / or water; (3) In the substitution reaction, the molar ratio of the compound shown in Formula XII to the base is 1:1.5 - 1:2.5, such as 1:2; (4) In the substitution reaction, the molar ratio of the compound shown in Formula XII to dimethyl sulfate is 1:1 - 1:1.5, such as 1:1.2; (5) In the substitution reaction, the molar ratio of the compound shown in Formula XII to lithium bromide is 1:2 - 1:3, such as 1:2.5; (6) In the substitution reaction, the molar ratio of the compound shown in Formula XII to diisopropylethylamine is 1:3 - 1:5, such as 1:4; (7) In the substitution reaction, the reaction temperature is 25 - 50 °C, such as 30 - 40 °C; (8) In the substitution reaction, the reaction time is 3 - 6 hours, such as 4 - 5 hours; (9) In the substitution reaction, the reaction materials of the substitution reaction are composed of the solvent, the base, dimethyl sulfate, lithium bromide, diisopropylethylamine and the compound shown in Formula XII; (10) The substitution reaction further includes the following post-treatment steps: after the reaction is completed, adjust the pH to 4 - 5 and extract with dichloromethane; Preferably, the substitution reaction includes the following steps: in the presence of a base and a cyclic ether solvent, the compound shown in Formula XII and dimethyl sulfate react at 30 - 40 °C for 12 - 20 hours, cool to 5 - 15 °C, add water, stir and add lithium bromide and diisopropylethylamine, and keep the temperature for reaction for 4 - 5 hours.

9. A preparation method of a compound shown in Formula XVII, characterized in that, it includes the following steps: In the presence of a solvent, dichlorodiphenylmethane, DIPEA and a catalyst, the compound shown in Formula XVI undergoes an amidation reaction with methylamine hydrochloride to form the compound shown in Formula XVII; 10. The preparation method according to claim 9, characterized in that, it satisfies one or more of the following conditions (1) In the amidation reaction, the solvent is a chloroalkane solvent, such as dichloromethane; (2) In the amidation reaction, the catalyst is stannous chloride; (3) In the amidation reaction, the molar ratio of the compound shown in Formula XVI to dichlorodiphenylmethane is 1:1 - 1:1.4, such as 1:1.2; (4) In the amidation reaction, the molar ratio of the compound shown in Formula XVI to stannous chloride is 25:1 - 100:1, such as 50:1; (5) In the amidation reaction, the molar ratio of the compound represented by Formula XVI to DIPEA is 1:2.5 - 3.5, such as 1:2.5; (6) In the amidation reaction, the molar ratio of the compound represented by Formula XVI to methylamine hydrochloride is 1:1 - 1:1.4, such as 1:1.2; (7) In the amidation reaction, the reaction temperature is 15 - 35 °C, such as 20 - 30 °C; (8) In the amidation reaction, the reaction time is 1 - 5 hours, such as 2 - 4 hours; (9) In the amidation reaction, the reaction materials of the amidation reaction are composed of the solvent, the compound represented by Formula XVI, the catalyst, dichlorodiphenylmethane, stannous chloride, DIPEA, and methylamine hydrochloride; (10) The amidation reaction further includes the following post-treatment steps: after the reaction is completed, add water to quench, adjust the pH to 4 - 5, separate the liquid, and dropwise add n-heptane 4.5 - 5 times the volume of the solvent at a temperature controlled at 20 - 30 °C, and then filter; Preferably, the amidation reaction includes the following steps: in the presence of the catalyst and the solvent, the compound represented by Formula XVI and stannous chloride are stirred at 20 - 30 °C for 1 - 2 hours, then add DIPEA and methylamine hydrochloride and react; Preferably, the amidation reaction further includes the following step: prepare the compound represented by Formula XVI by the preparation method of the compound represented by Formula XVI as described in any one of claims 1 - 8.

11. A preparation method of a compound represented by Formula I, characterized in that, it includes the following steps: (S1) Prepare the compound represented by Formula XVII by the preparation method of the compound represented by Formula XVII as described in any one of claims 9 - 10; (S2) In the presence of an acid and a solvent, the compound represented by Formula XVII and a reducing agent undergo a reduction reaction to generate a compound represented by Formula I; 12. The preparation method according to claim 11, characterized in that, it satisfies one or more of the following conditions; (1) In the reduction reaction, the acid is an organic acid, such as trifluoroacetic acid; (2) In the reduction reaction, the solvent is a cyclic ether solvent, such as tetrahydrofuran; (3) In the reduction reaction, the reducing agent is aluminum hydroxide and / or sodium borohydride, such as sodium borohydride; (4) In the reduction reaction, the molar ratio of the compound represented by Formula XVIII to the reducing agent is 1:3 - 1:5, such as 1:4.2; (5) In the reduction reaction, the molar ratio of the compound represented by Formula XVIII to the acid is 1:3.5 - 1:5.5, such as 1:4.7; (6) In the reduction reaction, the reaction temperature is 25 - 45 °C, such as 30 - 40 °C; (7) In some embodiments, in the reduction reaction, the reaction time is 6 - 9 hours, such as 7 - 8 hours; (8) In the reduction reaction, the reaction materials of the reduction reaction are composed of the solvent, the compound represented by Formula XVII, the acid, and the reducing agent; (9) The reduction reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is added to water while controlling the temperature not higher than 15°C, the pH is adjusted to 6.5 - 7.5, liquid separation is carried out, extraction is performed with ethyl acetate, water is removed until the water content is not higher than 0.5%, n-heptane in an amount 2.6 - 4 times the volume of the solution is added dropwise while controlling the temperature at 20°C - 30°C, and filtration is carried out; Preferably, the reduction reaction includes the following steps: in the presence of the solvent and the compound shown in Formula XVII, the reducing agent is added while controlling the temperature not higher than 30°C. After addition is complete, the acid is added while controlling the temperature at 30 - 35°C, and the reaction is carried out at 30 - 40°C.

13. Compounds shown in Formula XIII, Formula XIV, Formula XV and Formula XVI;

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