Preparation method for 1,5-dihydro-2,4-benzodiazepine-3-one derivative, intermediate therefor, and preparation method for intermediate

Abstract

Disclosed is a preparation method for a 1,5-dihydro-2,4-benzodiazepine-3-one derivative. According to the preparation method, required raw materials are cheap and easily available; the use of a flammable and explosive reagent namely borane, a difficult-to-handle and highly-toxic reagent namely triphosgene, and a precious metal namely palladium is avoided; the operation is simple and convenient, production costs are reduced; and the preparation method is more suitable for industrial preparation and use, and has higher yield than that of the prior art. Additionally, further disclosed are an intermediate as shown in formula III or a salt thereof for preparing the derivative, and a preparation method for the intermediate or salt.

Description

Preparation method of 1,5-dihydro-2,4-benzodiazepine-3-one derivatives and intermediates thereof and preparation method thereof Preparation method of 1,5-dihydro-2,4-benzodiazepine-3-one derivatives and intermediates thereof and preparation method thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2023110957579, filed on August 29, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a 1,5-dihydro-2,4-benzodiazepine -3-ketone derivatives, and intermediates and their preparation methods. Background Art

[0003] Patent application WO2021218863A1 discloses a series of 1,5-dihydro-2,4-benzodiazepines -3-keto derivatives, which act on 5-HT2A and 5-HT2C receptors, have better selectivity for 5-HT2A than pemoserine, and have good antipsychotic activity, as well as smaller sedative side effects, motor exacerbation side effects and smaller cardiac toxicity. These derivatives can be used to treat schizophrenia or Parkinson's disease, dementia-related behavioral disorders and psychosis.

[0004] So far, only patent application WO2021218863A1 discloses the synthesis of 1,5-dihydro-2,4-benzodiazepine -3-ketone derivatives. The synthetic route is as follows:

[0005] The above-mentioned route has a low yield and requires the use of the highly toxic reagent triphosgene and the flammable and explosive reagent borane, as well as the use of the precious metal palladium, which is costly and unsuitable for industrial preparation.

[0006] Therefore, it is necessary to find a preparation method with easy-to-obtain raw materials, simple and convenient operation, low toxicity, low cost, environmental friendliness, high yield, and suitability for industrial preparation.

[0007] Summary of the Invention

[0008] The present invention aims to provide a method for preparing 1,5-dihydro-2,4-benzodiazepine with cheap and easy-to-obtain raw materials, simple and convenient operation, low toxicity, low cost, environmental friendliness, high yield, and suitable for industrial preparation. The present invention also provides a method for preparing 1,5-dihydro-2,4-benzodiazepine -3-ketone derivative intermediates and preparation methods thereof.

[0009] The present invention provides a 1,5-dihydro-2,4-benzodiazepine shown in formula I A method for preparing a -3-ketone derivative, which uses a cyano-substituted bromobenzyl derivative as a starting material and is prepared successively from a compound of formula III and a compound of formula II; in particular, the preparation method comprises step (2): a cyclization reaction of the compound of formula II with a catalyst in the presence of a base compound and an organic solvent to obtain a compound of formula I;

[0010] wherein R1 is selected from H and halogen;

[0011] R2 is selected from C1-C8 alkyl, C3-C8 cycloalkyl and

[0012] R3 and R4 are each independently selected from a C1-C8 alkyl group;

[0013] Wherein, the catalyst in step (2) is selected from one or more of carbonate compounds and chloroformate compounds, preferably selected from one or more of di(p-nitrobenzene) carbonate, phenyl chloroformate, diphenyl carbonate and 4-nitrophenol chloromethyl ester, and more preferably di(p-nitrobenzene) carbonate.

[0014] In one embodiment, R1 is selected from halogen, preferably F.

[0015] In one embodiment, R2 is selected from C1-C5 alkyl, C3-C6 cycloalkyl and Preferably selected from C3-C6 cycloalkyl and More preferably, it is selected from cyclopropyl.

[0016] In one embodiment, R1 is F; and R2 is cyclopropyl.

[0017] In one embodiment, the 1,5-dihydro-2,4-benzodiazepine shown in Formula I The method for preparing a -3-ketone derivative further comprises the step (1): using a compound of formula II or a salt thereof as a raw material, in an organic solvent, in the presence of a reducing agent and a base, and performing an amination reaction with N-methyl-4-piperidone to prepare a compound of formula II;

[0018] wherein R1, R2, R3, and R4 are as described above.

[0019] In one embodiment, the base in step (1) is selected from one or more of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.

[0020] In one embodiment, the reducing agent in step (1) is selected from one or more borohydride reagents and acyloxy borohydride compounds, preferably one or more sodium triacetoxyborohydride and sodium cyanoborohydride, and more preferably sodium triacetoxyborohydride.

[0021] In one embodiment, the organic solvent in step (2) is selected from amide solvents, preferably one or more selected from N,N-dimethylformamide (DMF), N-methylpyrrolidone and N,N-dimethylacetamide, preferably N,N-dimethylformamide (DMF).

[0022] In one embodiment, the base compound in step (2) is selected from one or more of potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and potassium tert-butoxide, preferably potassium carbonate.

[0023] In one embodiment, the temperature when the reducing agent is added in step (1) is 0 to 20°C, preferably by dropwise addition. In one embodiment, the temperature when the reducing agent is added dropwise in step (1) is 0 to 5°C. In one embodiment, the temperature when the reducing agent is added dropwise in step (1) is 5 to 15°C. In one embodiment, the temperature when the reducing agent is added dropwise in step (1) is 15 to 20°C.

[0024] In one embodiment, the reaction temperature in step (1) is controlled to be 0-20°C. In one embodiment, the reaction temperature in step (1) is 0-5°C. In one embodiment, the reaction temperature in step (1) is 5-15°C. In one embodiment, the reaction temperature in step (1) is 15-20°C.

[0025] In one embodiment, in the post-treatment step in step (1), the pH is adjusted to 4-8, preferably 5-6, and more preferably 6.

[0026] In one embodiment, the molar ratio of compound II to the catalyst in step (2) is 1.00:0.90 to 1.00:1.00, preferably 1.00:0.97.

[0027] In one embodiment, the temperature when the catalyst is added dropwise in step (2) is -5 to 30°C. In one embodiment, the temperature when the catalyst is added dropwise in step (2) is -5 to 15°C. In one embodiment, the temperature when the catalyst is added dropwise in step (2) is -5 to 5°C. In one embodiment, the temperature when the catalyst is added dropwise in step (2) is 15 to 30°C.

[0028] In one embodiment, after the dropwise addition in step (2) is completed, heating reaction is carried out, and the reaction temperature is 120-140°C, preferably 125-135°C.

[0029] The present invention also provides an intermediate or a salt thereof as shown in Formula II,

[0030] wherein R1 is selected from H and halogen;

[0031] R2 is selected from H, C1-C8 alkyl, C3-C8 cycloalkyl and

[0032] R3 and R4 are independently selected from H and C1-C8 alkyl.

[0033] In one embodiment, R1 is selected from halogen, preferably F.

[0034] In one embodiment, R2 is selected from C1-C5 alkyl, C3-C6 cycloalkyl and Preferably selected from C3-C6 cycloalkyl and More preferably, it is a cyclopropyl group.

[0035] In a specific embodiment, the compound of formula II is as shown in formula II-1,

[0036] The present invention also provides an intermediate or a salt thereof as shown in Formula III,

[0037] wherein R1 is selected from H and halogen;

[0038] R2 is selected from H, C1-C8 alkyl, C3-C8 cycloalkyl and

[0039] R3 and R4 are independently selected from H and C1-C8 alkyl.

[0040] In one embodiment, R1 is selected from halogen, preferably F.

[0041] In one embodiment, R2 is selected from C1-C5 alkyl, C3-C6 cycloalkyl and Preferably selected from C3-C6 cycloalkyl and More preferably, it is a cyclopropyl group.

[0042] In a specific embodiment, the compound of formula III is as shown in formula III-1, More preferred is its trifluoroacetate.

[0043] Accordingly, the present invention also provides a method for preparing the intermediate of formula III, comprising the following steps: (3) reacting a cyano-substituted bromobenzyl derivative and bis(tert-butyloxycarbonyl)amine as raw materials in the presence of a base and an organic solvent to obtain a compound of formula VI;

[0044] (4) subjecting the compound of formula VI to a hydrogenation reduction reaction in the presence of Raney nickel and an organic solvent under a H2 atmosphere to obtain a compound of formula V;

[0045] (5) Reductive amination of the compound of formula V with the compound of formula IV in an organic solvent in the presence of a borohydride reagent to obtain a compound of formula III or a salt thereof;

[0046] wherein R1 and R2 are as described above.

[0047] Accordingly, the present invention also provides a method for preparing 1,5-dihydro-2,4-benzodiazepine as shown in formula I. The method for preparing a -3-ketone derivative is characterized by further comprising adopting the above method to use formula VII as a raw material to prepare an intermediate represented by formula III or a salt thereof.

[0048] In one embodiment, the salt of the intermediate compound of formula III is preferably a trifluoroacetate salt.

[0049] In one embodiment, the base in step (3) is selected from one or more of sodium carbonate, cesium carbonate, potassium carbonate and potassium tert-butoxide, preferably cesium carbonate.

[0050] In one embodiment, the borohydride reagent in step (5) is selected from one or more of sodium triacetoxyborohydride and sodium cyanoborohydride, preferably sodium triacetoxyborohydride.

[0051] In one embodiment, the molar ratio of the compound of formula V to the compound of formula IV in step (5) is 1.00:0.80 to 1.00:0.95. In one embodiment, the molar ratio of the compound of formula V to the compound of formula IV in step (5) is 1.00:0.80 to 1.00:0.85. In one embodiment, the molar ratio of the compound of formula V to the compound of formula IV in step (5) is 1.00:0.84.

[0052] In one embodiment, the temperature when the compound of formula IV is added in step (5) is -10 to 20°C, preferably by dropwise addition. In one embodiment, the temperature when the compound of formula IV is added dropwise in step (5) is -10 to 10°C. In one embodiment, the temperature when the compound of formula IV is added dropwise in step (5) is -10 to -5°C. In one embodiment, the temperature when the compound of formula IV is added dropwise in step (5) is 5 to 10°C. In a preferred embodiment, the temperature when the compound of formula IV is added dropwise in step (5) is -5 to 5°C.

[0053] In one embodiment, after the compound of formula IV is added dropwise in step (5), the reaction temperature is controlled to be 0 to 20°C. In one embodiment, after the compound of formula IV is added dropwise in step (5), the reaction temperature is controlled to be 0 to 5°C. In one embodiment, after the compound of formula IV is added dropwise in step (5), the reaction temperature is controlled to be 15 to 20°C. In one embodiment, after the compound of formula IV is added dropwise in step (5), the reaction temperature is controlled to be 5 to 10°C. In one embodiment, after the compound of formula IV is added dropwise in step (5), the reaction temperature is controlled to be 5 to 15°C.

[0054] In one embodiment, the reaction time of step (5) is controlled to be 1 to 4 hours, preferably 2 hours.

[0055] In one embodiment, step (4) employs hydrogenation at normal pressure.

[0056] There is no particular limitation on the organic solvent used in step (1), step (3), step (4) or step (5), as long as it can dissolve the reactants and is sufficient to cause an effective reaction. For example, the organic solvent can be selected from one or more of alcohols, ethers, ketones, nitriles, halogenated hydrocarbons, and amide organic compounds, preferably selected from one or more of methanol, ethanol, butanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide (DMF), more preferably selected from one or more of methanol, dichloromethane, acetonitrile, and DMF. DETAILED DESCRIPTION

[0057] Unless otherwise indicated or there is an obvious conflict in the context, all scientific and technical terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0058] General Terms and Definitions

[0059] Unless otherwise indicated, as used herein, for example, in a compound of formula I, the point of attachment of the substituent may be from any suitable position of the substituent.

[0060] In addition, it should be noted that, unless otherwise expressly stated, the description method used in the present invention of "respectively and independently" should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0061] The term "room temperature" refers to a temperature from 0°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C ​​to 25°C.

[0062] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0063] Beneficial technical effects of the present invention

[0064] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0065] 1. The required raw materials are cheap and easy to obtain;

[0066] 2. Avoid using flammable and explosive reagents, and the operation is simple and convenient;

[0067] 3. Avoid using the highly toxic reagent triphosgene which is difficult to operate;

[0068] 4. Avoid the use of precious metal palladium to reduce production costs;

[0069] 5. The reaction is more suitable for scale-up and industrial preparation;

[0070] 6. The yield is higher than that of the prior art.

[0071] Example

[0072] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0073] DETAILED DESCRIPTION

[0074] The present invention relates to an N-(2-(aminomethyl)benzyl)-1-phenylmethylamine intermediate as shown in formula III and a preparation method thereof, and the use of these intermediates to prepare 1,5-dihydro-2,4-benzodiazepine as shown in formula I. The following method is to use 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropyloxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine Taking the preparation of -3-ketone as an example, the scheme of the present invention is described in detail.

[0075] In a specific embodiment of the present invention: the following route is used for synthesis:

[0076] Example 1

[0077] 1.1 Preparation of Intermediate VI-1

[0078] 1.1.1 Add 2.10 kg (9.81 mol) of 2-cyano-5-fluorobenzyl bromide, 2.20 kg (10.14 mol) of bis(tert-butyloxycarbonyl)amine, 6.40 kg (19.65 mol) of cesium carbonate, and 19.74 kg of acetonitrile to a 50 L glass reaction tank and heat under reflux for 2 hours.

[0079] The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure; drinking water and ethyl acetate were added to extract the liquid; the organic phase was washed with 20% sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product; the crude product was recrystallized from isopropanol to obtain 2.95 kg of white solid, namely intermediate VI-1, with a yield of 85.81%. 1 H NMR(500MHz, DMSO-d6)δ7.99-7.96(m,1H),7.38(t,J=8.5Hz,1H),7.09(d,J=9.6Hz,1H),4.91(s,2H),1.40(s,18H).MS:([M+Na] + ):373.

[0080] 1.2 Preparation of intermediate V-1

[0081] 1.2.1 Weigh 0.12 kg of Raney nickel into a 3 L four-necked glass reaction flask. Then add 0.54 kg of methanol and 0.54 kg of ammonia methanol solution. Add 0.35 kg of Intermediate VI-1, start stirring, replace the hydrogen atmosphere, and react at room temperature for 22 hours. Filter the reaction mixture through celite, wash the filter cake with methanol, and concentrate the filtrate under reduced pressure to obtain Intermediate V-1.

[0082] 1.3 Preparation of Intermediate III-1

[0083] Method 1.3.1 Add 350.0 g of intermediate V-1 and dichloromethane to a 5 L glass reaction flask, start stirring, cool to 20°C, add 418.6 g of sodium triacetoxyborohydride, and dissolve 152.2 g of 4-cyclopropyloxybenzaldehyde in dichloromethane and add dropwise to the reaction flask. After the addition is complete, react at 20°C for 2 hours.

[0084] After the reaction is complete, water is added to quench the reaction, the mixture is stirred, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; the organic phase is washed with sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily product; dichloromethane is added to the yellow oily product, stirred, the reaction solution is cooled to 10°C, trifluoroacetic acid is added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 20 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dichloromethane and water are added to the residue, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; additional dichloromethane and water are added, stirred, filtered, the filter cake is washed with dichloromethane, and then the filter cake is slurried with dichloromethane to obtain 206.1g of a white solid, namely intermediate III-1, with a yield of 50.36%.

[0085] Alternative Method 1.3.2: Add 350.0 g of intermediate V-1 and dichloromethane to a 5 L glass reaction flask, start stirring, cool to 20°C, add 124.1 g of sodium cyanoborohydride, and dissolve 144.2 g of 4-cyclopropyloxybenzaldehyde in dichloromethane and add dropwise to the reaction flask. After the addition is complete, react at 20°C for 2 hours.

[0086] After the reaction is complete, water is added to quench the reaction, the mixture is stirred, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; the organic phase is washed with sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily product; dichloromethane is added to the yellow oily product, stirred, the reaction solution is cooled to 10°C, trifluoroacetic acid is added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 20 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dichloromethane and water are added to the residue, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; additional dichloromethane and water are added, stirred, filtered, the filter cake is washed with dichloromethane, and then the filter cake is slurried with dichloromethane to obtain 254.7g of a white solid, namely intermediate III-1, with a yield of 60.23%.

[0087] Alternative method 1.3.3: Add 350.0 g of intermediate V-1 and dichloromethane to a 5 L glass reaction flask, start stirring, cool to 0°C, add 418.6 g of sodium triacetoxyborohydride, and dissolve 136.1 g of 4-cyclopropyloxybenzaldehyde in dichloromethane and add dropwise to the reaction flask. After the addition is complete, react at 15°C for 2 hours.

[0088] After the reaction is complete, water is added to quench the reaction, the mixture is stirred, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; the organic phase is washed with sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily product; dichloromethane is added to the yellow oily product, stirred, the reaction solution is cooled to 10°C, trifluoroacetic acid is added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 20 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dichloromethane and water are added to the residue, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; additional dichloromethane and water are added, stirred, filtered, the filter cake is washed with dichloromethane, and then the filter cake is slurried with dichloromethane to obtain 330.1g of a white solid, namely intermediate III-1, with a yield of 80.65%.

[0089] Alternative Method 1.3.4: Add 350.0 g of intermediate V-1 and dichloromethane to a 5 L glass reaction flask, start stirring, cool to -10°C, add 418.6 g of sodium triacetoxyborohydride, and dissolve 136.1 g of 4-cyclopropyloxybenzaldehyde in dichloromethane and add dropwise to the reaction flask. After the addition is complete, react at 10°C for 4 hours.

[0090] After the reaction is complete, water is added to quench the reaction, the mixture is stirred, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; the organic phase is washed with sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily product; dichloromethane is added to the yellow oily product, stirred, the reaction solution is cooled to 10°C, trifluoroacetic acid is added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 20 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dichloromethane and water are added to the residue, the mixture is allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; additional dichloromethane and water are added, stirred, filtered, the filter cake is washed with dichloromethane, and then the filter cake is slurried with dichloromethane to obtain 313.4g of a white solid, namely intermediate III-1, with a yield of 76.57%.

[0091] Alternative method 1.3.5: Add 2.80 kg of intermediate V-1 and 29.68 kg of dichloromethane to a 50 L glass reaction tank, start stirring, cool to 5°C, add 3.36 kg of sodium triacetoxyborohydride, dissolve 1.09 kg of 4-cyclopropyloxybenzaldehyde (VI-1) in dichloromethane and add dropwise to the reaction tank. After the addition is complete, react at 10°C for 2 hours.

[0092] After the reaction is complete, water is added to quench the reaction, stirred, allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; the organic phase is washed with sodium hydroxide solution, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily product; dichloromethane is added to the yellow oily product, stirred, the reaction solution is cooled to 10°C, 12.74 kg of trifluoroacetic acid is added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 20 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dichloromethane and water are added to the residue, allowed to stand for separation, the aqueous phase is extracted with dichloromethane, and the organic phases are combined; additional dichloromethane and water are added, stirred, filtered, the filter cake is washed with dichloromethane, and then the filter cake is slurried with dichloromethane to obtain 2.58 kg of white solid, namely intermediate III-1, with a yield of 77.91%.

[0093] 1 H NMR (500MHz, DMSO-d6) δ9.34(s,1H),8.43(s,3H),7.63(dd,J=8.7,5.9Hz,1H),7.45(d,J=8.2Hz,2H),7.41(dd,J=10.1,2.7Hz,1H),7.35-7. 30(m,1H),7.09(d,J=8.4Hz,2H),4.26(s,2H),4.22(s,2H),4.19(s,2H ),3.88-3.84(m,1H),0.82-0.77(m,2H),0.65-0.62(m,2H).MS:([M+H] + ):301.

[0094] 1.4 Preparation of Intermediate II-1

[0095] Method 1.4.1: Add 2.50 kg of intermediate III-1 and 9.20 kg of dichloromethane to a 50 L reaction tank, add sodium hydroxide solution, stir, and allow to stand for separation. Extract the aqueous phase with dichloromethane, combine the organic phases, wash with sodium chloride solution, and dry over anhydrous sodium sulfate. Lower the reaction temperature to 5-15°C, then add 2.55 kg of sodium triacetoxyborohydride and stir. Slowly add 0.70 kg of N-methyl-4-piperidone dissolved in dichloromethane dropwise to the reaction tank. After the addition is complete, react at room temperature for 2 hours.

[0096] After the reaction is completed, water is added to quench the reaction, concentrated hydrochloric acid is added dropwise, the pH of the reaction solution is adjusted to about 6, stirred, allowed to stand for separation, the aqueous phase is collected, the organic phase is extracted with water, the aqueous phases are combined, and the collected aqueous phases are washed with dichloromethane; dichloromethane is added to the aqueous phase, and sodium hydroxide solution is gradually added thereto, stirred, allowed to stand for separation, the aqueous phase is extracted with dichloromethane, the organic phases are combined, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filter cake is washed with dichloromethane, and the filtrate is concentrated under reduced pressure to obtain 1.77 kg of an oily liquid, namely intermediate II-1, with a yield of 73.80%.

[0097] Alternative method 1.4.2: Mix 375.0 g of intermediate III-1 with 1000 mL of dichloromethane, add 1000 mL of potassium hydroxide solution, stir for 30 minutes, extract and separate the liquids, collect the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, wash the organic phase twice with saturated sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, pour the organic phase into a 5000 mL four-necked glass reaction flask, lower the reaction system temperature to 5-15°C in an ice-water bath, add 114.0 g of sodium cyanoborohydride, dissolve 107.5 g of N-methyl-4-piperidone in dichloromethane, and slowly add dropwise to the reaction system. After the addition is complete, react at room temperature for 2 hours.

[0098] After the reaction was completed, water was added to quench the reaction, concentrated hydrochloric acid was added dropwise, the pH of the reaction solution was adjusted to about 6, stirred, allowed to stand for separation, the aqueous phase was collected, the organic phase was extracted with water, the aqueous phases were combined, and the collected aqueous phases were washed with dichloromethane; dichloromethane was added to the aqueous phase, and sodium hydroxide solution was gradually added thereto, stirred, allowed to stand for separation, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain 252.0 g of an oily liquid with a yield of 70.1%.

[0099] 1 H NMR (500MHz, DMSO-d6) δ7.32(dd,J=8.5,6.2Hz,1H),7.24(dd,J=8.4,1.7Hz,2H),7.16(dd,J=10.3,2.7Hz,1H),7.01-6. 96(m,3H),3.81-3.77(m,1H),3.69(s,2H),3.65(s,2H),3.62(s,2H),2.65(d,J=10.9Hz,2H),2.33-2.28(m,1H),2.11(s, 3H),1.83(t,J=11.3Hz,2H),1.72(d,J=12.3Hz,2H),1.30-1.13(m,2H),0.78-0.74(m,2H),0.64-0.60(m,2H).MS:([M+H] + ):398.

[0100] 1.5 Preparation of Compound I-1

[0101] Method 1.5.1: Add 200.0 g of intermediate II-1 and 1 L of N-methylpyrrolidone to a 5 L reaction flask. Start stirring and protect with nitrogen. At 25°C, dissolve 153.0 g of di(p-nitrobenzene) carbonate in N-methylpyrrolidone and add the solution dropwise to the reaction flask. After the addition is complete, add anhydrous potassium carbonate and react at 130°C for 2 hours.

[0102] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 105.8 g of an oily liquid, i.e., compound I-1, with a yield of 49.68%.

[0103] Alternative method 1.5.2: Add 200.0 g of intermediate II-1 and 1 L of N,N-dimethylacetamide to a 5 L reaction flask, start stirring, protect with nitrogen, and cool the reaction liquid to 15°C. Dissolve 145.4 g of di(p-nitrobenzene) carbonate in N,N-dimethylacetamide and add the solution dropwise to the reaction flask. After the addition is complete, add anhydrous potassium carbonate and react at 130°C for 2 hours.

[0104] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 149.7 g of an oily liquid, i.e., compound I-1, with a yield of 70.26%.

[0105] Alternative method 1.5.3: Add 200.0 g of intermediate II-1 and 1 L of N,N-dimethylacetamide to a 5 L reaction flask, start stirring, protect with nitrogen, and cool the reaction liquid to 5°C. Dissolve 145.0 g of di(p-nitrobenzene) carbonate in N,N-dimethylformamide and add the solution dropwise to the reaction flask. After the addition is complete, add anhydrous potassium carbonate and react at 130°C for 2 hours.

[0106] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 156.7 g of an oily liquid, i.e., compound I-1, with a yield of 73.55%.

[0107] Alternative method 1.5.4: Add 200.0 g of intermediate II-1 and 1 L of N,N-dimethylformamide to a 5 L reaction flask, start stirring, protect with nitrogen, and cool the reaction liquid to -5°C. Dissolve 137.7 g of di(p-nitrobenzene) carbonate in N,N-dimethylformamide and add the solution dropwise to the reaction flask. After the addition is complete, add anhydrous potassium carbonate and react at 130°C for 2 hours.

[0108] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 139.3 g of an oily liquid, i.e., compound I-1, with a yield of 65.38%.

[0109] Alternative method 1.5.5: Add 1.74 kg of intermediate II-1 and 4.11 kg of N,N-dimethylformamide to a 20 L reaction flask, start stirring, protect with nitrogen, lower the reaction liquid temperature to 5°C, dissolve 1.30 kg of di(p-nitrobenzene) carbonate in N,N-dimethylformamide, and add dropwise to the reaction flask; after the addition is complete, add 1.20 kg of anhydrous potassium carbonate and react at 130°C for 2 hours.

[0110] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; the organic phase, water and 0.50 kg of phosphoric acid were added to a 50 L reaction tank, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; the collected aqueous phase, ethyl acetate and sodium hydroxide solution were added to a 50 L reaction tank, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.43 kg of an oily liquid, i.e., compound I-1, with a yield of 77.14%.

[0111] Alternative method 1.5.6: Add 200.0 g of intermediate II-1 and 1 L of N,N-dimethylformamide to a 5 L reaction flask. Start stirring, protect with nitrogen, and cool the reaction solution to -5°C. Dissolve 91.3 g of 4-nitrophenol chloromethyl ester in N,N-dimethylformamide and add the solution dropwise to the reaction flask. After the addition is complete, add anhydrous potassium carbonate and react at 130°C for 2 hours.

[0112] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 102.6 g of an oily liquid, i.e., compound I-1, with a yield of 48.15%.

[0113] Alternative method 1.5.7: Add 200.0 g of intermediate II-1 and 1 L of N,N-dimethylformamide to a 5 L reaction flask, start stirring, protect with nitrogen, and cool the reaction liquid to 15°C. Dissolve 145.4 g of di(p-nitrobenzene) carbonate in N,N-dimethylacetamide and add the solution dropwise to the reaction flask. After the addition is complete, add cesium carbonate and react at 130°C for 2 hours.

[0114] The reaction solution was cooled, water and ethyl acetate were added, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with sodium hydroxide solution, and then washed with hydrochloric acid solution; water and phosphoric acid were added to the organic phase, stirred, allowed to stand for separation, the organic phase was extracted with water, and the aqueous phases were combined; ethyl acetate and sodium hydroxide solution were added to the collected aqueous phase, stirred, allowed to stand for separation, the aqueous phase was extracted with ethyl acetate again, stirred, allowed to stand for separation, and the organic phases were combined; finally, the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 142.0 g of an oily liquid, i.e., compound I-1, with a yield of 66.64%.

[0115] 1 H NMR(400MHz,DMSO-d6)δ7.30-7.19(m,3H),7.11(dd,J=8.4,5.7Hz,1H),7.05-6.94(m,3 H),4.36(d,J=7.1Hz,4H),4.29(s,2H),3.96(tt,J=11.4,4.0Hz,1H),3.80(tt,J=6.0,3 .0Hz,1H),2.86-2.78(m,2H),2.16(s,3H),1.95-1.85(m,2H),1.89-1.75(m,2H),1.45( dd,J=11.0,3.9Hz,2H),0.81-0.67(m,2H),0.67-0.59(m,2H); LCMS(ES,m / z):424[M+H] + .

[0116] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the scope of protection of the present invention. Any equivalent changes or modifications made based on the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A 1,5-dihydro-2,4-benzodiazepine shown in formula I -3-ketone derivative preparation method, characterized in that, The method comprises the step (2): a compound of formula II is subjected to a cyclization reaction with a catalyst in the presence of a base compound and an organic solvent to obtain a compound of formula I; Wherein, R1 is selected from H and halogen; R2 is selected from C1-C8 alkyl, C3-C8 cycloalkyl and R3 and R4 are independently selected from C1-C8 alkyl; The catalyst in step (2) is selected from one or more of carbonate compounds and chloroformate compounds, preferably selected from one or more of di(p-nitrobenzene) carbonate, phenyl chloroformate, diphenyl carbonate, and 4-nitrophenol chloromethyl ester, and more preferably di(p-nitrobenzene) carbonate.

2. 1,5-dihydro-2,4-benzodiazepine shown in formula I according to claim 1 -3-ketone derivative preparation method, characterized in that, The method further comprises the step (1): using the compound of formula III or its salt as a raw material, in an organic solvent, in the presence of a reducing agent and a base, to carry out an amination reaction with N-methyl-4-piperidone to prepare a compound of formula II; Wherein, R1, R2, R3, and R4 are as described in claim 1.

3. 1,5-dihydro-2,4-benzodiazepine shown in formula I according to claim 1 or 2 -3-ketone derivative preparation method, characterized in that, In step (1), the base is selected from one or more of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the reducing agent is selected from one or more of borohydride agents and acyloxy borohydride compounds, preferably selected from one or more of sodium triacetoxyborohydride and sodium cyanoborohydride, more preferably sodium triacetoxyborohydride; The organic solvent in step (2) is selected from amide solvents, preferably one or more selected from N,N-dimethylformamide (DMF), N-methylpyrrolidone and N,N-dimethylacetamide, preferably N,N-dimethylformamide (DMF); the alkaline compound is selected from one or more selected from potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide and potassium tert-butoxide, preferably potassium carbonate.

4. 1,5-dihydro-2,4-benzodiazepine according to any one of the formulas I in claim 1-3 -3-ketone derivative preparation method, characterized in that, The reaction temperature in step (1) is 0 to 20°C, preferably 5 to 15°C; In step (2), the molar ratio of the compound of formula II to the catalyst is 1.00:0.90 to 1.00:1.00, preferably 1.00:0.97; When the catalyst is added dropwise in step (2), the temperature of the reaction solution is -5 to 30°C, preferably -5 to 5°C; After the dropwise addition in step (2) is completed, heating reaction is carried out, and the reaction temperature is 120-140°C, preferably 125-135°C.

5. 1,5-dihydro-2,4-benzodiazepine according to any one of the formulas I in claim 1-4 -3-ketone derivative preparation method, characterized in that, One or more of the following conditions are met: (1) R1 is selected from halogen, preferably F; (2) R2 is selected from C1-C5 alkyl, C3-C6 cycloalkyl and Preferably selected from C3-C6 cycloalkyl and It is further preferably selected from cyclopropyl.

6. 1,5-dihydro-2,4-benzodiazepine shown in formula I according to claim 5 -3-ketone derivative preparation method, characterized in that, R1 is F; R2 is cyclopropyl.

7. An intermediate or a salt thereof as shown in formula II or III, in, R1 is selected from H and halogen; R2 is selected from C1-C8 alkyl, C3-C8 cycloalkyl and R3 and R4 are independently selected from C1-C8 alkyl; Preferred are compounds represented by formula II-1 and formula III-1 The compound of formula III is further preferably the trifluoroacetate salt of the compound of formula III-1.

8. A method for preparing the intermediate represented by formula III or its salt as claimed in claim 7, characterized in that: The following steps are involved: (3) using a cyano-substituted bromobenzyl derivative and bis(tert-butyloxycarbonyl)amine as raw materials, reacting in the presence of a base and an organic solvent to obtain a compound of formula VI; (4) subjecting the compound of formula VI to a hydrogenation reduction reaction in the presence of Raney nickel and an organic solvent under a H2 atmosphere to obtain a compound of formula V; (5) Reductive amination of the compound of formula V with the compound of formula IV in an organic solvent in the presence of a borohydride reagent to obtain a compound of formula III or a salt thereof; Wherein, R1 and R2 are as described in claim 8.

9. 1,5-dihydro-2,4-benzodiazepine according to any one of the formulas I in claim 2-4. -3-ketone derivative preparation method, characterized in that, The method further comprises adopting the method according to claim 9, using formula VII as a raw material to prepare the intermediate represented by formula III or a salt thereof.

10. The preparation method according to claim 8 or 9, characterized in that: The salt of the compound of formula III is preferably trifluoroacetate; The base in step (3) is selected from one or more of sodium carbonate, cesium carbonate, potassium tert-butoxide and potassium hydroxide, preferably cesium carbonate; The borohydride reagent in step (5) is selected from one or more of sodium triacetoxyborohydride and sodium cyanoborohydride, preferably sodium triacetoxyborohydride; In step (5), the molar ratio of the compound of formula V to the compound of formula IV is 1.00:0.80 to 1.00:0.95, preferably 1.00:0.84; When the compound of formula IV is added dropwise in step (5), the temperature is -10 to 20°C, preferably -10 to 10°C, and more preferably -5 to 5°C; After the compound of formula IV is added dropwise in step (5), the reaction temperature is 0 to 20°C, preferably 5 to 15°C.

11. The preparation method according to claim 8 or 9, characterized in that: Step (4) adopts hydrogenation at normal pressure.

Images