Preparation method of gepirone and its intermediates

Abstract

This application relates to a preparation method of grapiprant and its intermediates. The preparation method of grapiprant in this application comprises the following steps: nitrating the compound of Formula I to obtain the compound of Formula II; reacting the compound of Formula II with the compound of Formula III to obtain the compound of Formula IV; reducing the nitro group in the compound of Formula IV to obtain the compound of Formula V; cyclizing the amino functional group and the aminopyridine functional group of the compound of Formula V to obtain the compound of Formula VI; brominating the compound of Formula VI to obtain the compound of Formula VII; reducing the carbonyl group in the compound of Formula VII to obtain the compound of Formula VIII; reacting the compound of Formula VIII with an organic amine or an organic amine salt and performing hydrolysis under acidic conditions to obtain the compound of Formula IX; and reacting the compound of Formula IX with the compound of Formula X to obtain grapiprant of Formula XI. This method significantly reduces the cost, is safe and easy to implement, and improves the total yield and purity of the target product grapiprant.

Description

Technical Field

[0001] The present application relates to a preparation method of veterinary drugs, and particularly to a preparation method of grapiprant and its intermediates. Background Art

[0002] Grapiprant is an animal-specific drug approved for marketing in May 2016, which is used to treat pain and joint swelling caused by osteoarthritis in dogs. Currently, the license holder is Elanco Animal Health, and its sales volume has increased rapidly, from less than $20 million in 2018 to approximately $100 million in 2020. Its market performance is significantly better than other analgesic drugs such as rofecoxib and meloxicam.

[0003] Grapiprant does not reduce the production of prostaglandins by blocking cyclooxygenase, but reduces pain and inflammation by blocking the activities of certain prostaglandins. Compared with currently sold painkillers, the probability of side effects is relatively low. Grapiprant is easily absorbed from the gastrointestinal tract after oral administration, and the absorption is rapid. Eating will affect drug absorption. The blood drug concentration reaches the peak in 1 hour under fasting conditions and 2.5 hours when eating. After repeated dosing, there is no accumulation in the body. The plasma protein binding rate of grapiprant in vivo is 95%, the apparent volume of distribution is 0.79 L / kg, about 70% of the administered dose is excreted as the drug prototype through feces, about 20% of the administered dose is excreted through urine, and the elimination half-life is about 5 hours.

[0004] The chemical structure of grapiprant (C 26 H 29 N 5 O 3 S, CAS: 415903-37-6) is shown as follows:

[0005]

[0006] Chinese Patent Application CN101967146A discloses a class of aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents. The application introduces the preparation method of grapiprant in the specification, which is specifically as follows:

[0007]

[0008] Among them, this method uses 4-(2-hydroxyethyl)aniline to react with 4-chloro-2,6-dimethyl-3-nitropyridine at 150 °C to obtain intermediate 1-1. Subsequently, the nitro group is reduced with 10% Pd-C to obtain intermediate 1-2, which then reacts with propionic anhydride to form a ring and an ester simultaneously to obtain intermediate 1-3. Hydrolysis gives intermediate 1-4, which reacts with thionyl chloride at 80 °C to obtain intermediate 1-5, and reacts with sodium azide at 100 °C to obtain intermediate 1-6. It is reduced again with 10% Pd-C to obtain intermediate 1-7, and then reacts with p-toluenesulfonyl isocyanate at room temperature to obtain the target product grapiprant. The total yield of this method is only 17.8%, and the overall route design is too long, which is not conducive to process control. Moreover, in this method, two steps use expensive noble metal catalysts (10% Pd-C) for reduction. In addition, sodium azide is used in this method to introduce the azide group, which poses serious safety hazards, making the feasibility of large-scale industrialization relatively low.

[0009] Chinese Patent Application CN101137656A discloses a crystal form of an imidazole derivative and discloses a preparation method of grapiprant in the specification, which is specifically as follows:

[0010]

[0011] This method uses 4-(2-aminoethyl)aniline as the raw material, which is protected by benzyl chloroformate to obtain intermediate 2-1. It then couples with 4-chloro-2,6-dimethyl-3-nitropyridine at 80 °C to obtain intermediate 2-2. The nitro group is reduced with 10% Pd-C to obtain intermediate 2-3. Propionic anhydride is added to cyclize at 80 °C to form an imidazole ring, obtaining intermediate 2-4. The protecting group is removed with 10% Pd-C continuously to obtain intermediate 2-5, and then it reacts with p-toluenesulfonyl isocyanate to obtain the target product grapiprant. The total yield of this method is 53.1%, but the selectivity in the preparation process of intermediate 2-1 cannot be well controlled, and a double amide bond by-product may be formed in the ring-forming step of intermediate 2-4. Moreover, this method uses expensive noble metal catalysis of 10% Pd-C for reduction, and the raw material 4-(2-aminoethyl)aniline is also relatively expensive, which is not conducive to cost control. In addition, when the nitro group is reduced with 10% Pd-C in the preparation process of intermediate 2-3, the protecting group will be removed simultaneously, and obvious impurities will be generated in the subsequent ring-forming step with propionic anhydride, which is not conducive to product quality control.

[0012] US Patent Application US20210079000A1 discloses a preparation method of grapiprant, which is specifically as follows:

[0013]

[0014] This method is similar to the method disclosed in Chinese Patent Application CN101137656A. It utilizes the aminolysis of esters to prepare the target compound. The key intermediate is still the same as that in the above patent application, and no method adjustment is seen. Moreover, compared with the above patent application that uses p-toluenesulfonyl isocyanate, this method adds reaction steps. When the amino group reacts with the ester group, catalysts such as HOBt and CDI need to be added, resulting in a relatively large increase in cost.

[0015] Chinese Patent Application CN101967146A also introduces a possible method for synthesizing similar compounds, which is specifically as follows:

[0016]

[0017] The main problem of this method is that the reduction of the cyano group requires the use of precious metal catalysts, and the raw materials used are expensive, which is not conducive to industrialization. Summary of the Invention

[0018] In view of the above problems of the prior art, one aspect of the present application provides a method for preparing grapiprant. This method has a novel synthetic route and corresponding novel intermediates. The main raw materials used have a simple structure and are cheap and easily available, reducing or even avoiding the dependence on high-cost reagents such as precious metal catalysts, having significant cost advantages, and the entire route process is simple to operate, each reaction is mild and safe, without special reaction conditions, and is suitable for industrialization.

[0019] To achieve the above object, the present application provides a method for preparing grapiprant, including the following steps:

[0020] Step (1) Nitrate the compound of formula I to obtain the compound of formula II

[0021]

[0022] Step (2) React the compound of formula II with the compound of formula III to obtain the compound of formula IV

[0023]

[0024] Step (3) Reduce the nitro group in the compound of formula IV to obtain the compound of formula V

[0025]

[0026] Step (4) Cyclize the amino functional group and the aminopyridine functional group of the compound of formula V to obtain the compound of formula VI

[0027]

[0028] Step (5) Brominate the compound of formula VI to obtain the compound of formula VII

[0029]

[0030] Step (6) reduces the carbonyl group in the compound of formula VII to obtain the compound of formula VIII.

[0031]

[0032] Step (7) reacts the compound of formula VIII with an organic amine or an organic amine salt and performs hydrolysis under acidic conditions to obtain the compound of formula IX.

[0033] and

[0034] Step (8) reacts the compound of formula IX with the compound of formula X to obtain the compound of formula XI, grapiprant:

[0035]

[0036] In some embodiments, nitration is carried out using nitric acid in step (1). In some embodiments, step (1) is carried out in the presence of sulfuric acid. In some embodiments, step (1) is carried out under temperature control. In some embodiments, step (1) is carried out at a temperature not exceeding room temperature, preferably not exceeding 20 °C.

[0037] Generally, step (2) is carried out in an organic solvent. The organic solvent can be selected from one or more of dimethylformamide, toluene, 2-methyltetrahydrofuran. In some embodiments, in step (2), the compound of formula II is first reacted with phosphorus oxychloride before reacting with the compound of formula III.

[0038] Generally, step (3) is carried out in an organic solvent. The organic solvent can be selected from ethanol, methanol. In some embodiments, the reaction in step (3) does not involve a noble metal catalyst. In some embodiments, the reaction in step (3) is carried out in the presence of ethanol, ammonium chloride and zinc.

[0039] Generally, step (4) is carried out in a solvent. In some embodiments, the reaction in step (4) is carried out in a weak base environment. In some embodiments, the reagent for the cyclization reaction of step (4) with the compound of formula V to form the compound of formula VI is propionaldehyde, propionic anhydride or triethyl orthopropionate, preferably propionaldehyde. In some embodiments, step (4) is carried out under heating conditions, preferably at 50 °C.

[0040] Generally, step (5) is carried out in an organic solvent. The organic solvent can be selected from one or more of ethyl acetate, diethyl ether, and chloroform. In some embodiments, step (5) is brominated using cuprous bromide or liquid bromine, preferably cuprous bromide.

[0041] Generally, step (6) is carried out in an organic solvent. The organic solvent can be selected from 2-methyltetrahydrofuran, toluene, and methanol. In some embodiments, there is no noble metal catalyst in the reaction of step (6). In some embodiments, the reaction of step (6) uses sodium cyanoborohydride to reduce the carbonyl group in the compound of formula VII.

[0042] Generally, step (7) is carried out in an organic solvent. In some embodiments, the organic amine or organic amine salt in step (7) is potassium phthalimide, succinimide, or hexamethylenetetramine, preferably potassium phthalimide.

[0043] Generally, step (8) is carried out in an organic solvent. The organic solvent can be selected from dichloromethane or chloroform.

[0044] Another aspect of the present application provides a method for preparing a gepirone intermediate, including: nitrating the compound of formula I in step (1) to obtain the compound of formula II

[0045]

[0046] reacting the compound of formula II with the compound of formula III in step (2) to obtain the compound of formula IV

[0047]

[0048] reducing the nitro group in the compound of formula IV in step (3) to obtain the compound of formula V

[0049]

[0050] cyclizing the amino functional group and the aminopyridine functional group of the compound of formula V in step (4) to obtain the compound of formula VI

[0051]

[0052] brominating the compound of formula VI in step (5) to obtain the compound of formula VII

[0053]

[0054] reducing the carbonyl group in the compound of formula VII in step (6) to obtain the compound of formula VIII

[0055]

[0056] Step (7) reacts the compound of Formula VIII with an organic amine or an organic amine salt and performs hydrolysis under acidic conditions to obtain the compound of Formula IX as an intermediate for gepirone.

[0057]

[0058] Through the design of a novel synthetic route and novel intermediates, the method for preparing gepirone of the present application can use starting materials and reaction reagents that are simple in structure, inexpensive, and easily available, and reduce or even avoid the use of expensive reagents such as noble metal catalysts. Therefore, it has a significant cost advantage compared to the prior art; and the entire route process is simple to operate, has no special process parameter requirements, the reaction process is mild and safe, the novel intermediates have stable properties, are easy to scale up, and realize industrialization. In addition, through the design of a novel synthetic route, the method for preparing gepirone of the present application unexpectedly reduces the generation of by-products and improves the total yield and purity of the target product gepirone.

[0059] These and other aspects of the present application will be more clearly understood in the description of the following embodiments. Description of the Drawings

[0060] The following drawings of the present application are provided only to more intuitively embody the present application. They are exemplary and are not intended to limit the scope of the present application.

[0061] Figure 1 Shows the mass spectrum of Intermediate 7 (2-(4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethylamine) prepared according to a method embodiment of the present application.

[0062] Figure 2 Shows the mass spectrum of the target product gepirone prepared according to a method embodiment of the present application.

[0063] Figure 3 Shows the 1H nuclear magnetic resonance spectrum of the target product gepirone prepared according to a method embodiment of the present application.

[0064] Figure 4 Shows a schematic flow chart of a method embodiment of the present application. Detailed Description of the Embodiments

[0065] To make this application easier to understand, the following further elaborates on this application in combination with specific embodiments (implementation schemes). Unless otherwise specified, the experimental methods described in this application are all conventional methods; unless otherwise specified, the materials described can all be obtained from commercial channels. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. In case of inconsistency, the meaning described in this specification or the meaning derived from the content recorded in this specification shall prevail. Additionally, the terms used herein are only for the purpose of describing the implementation modes of this application and are not intended to limit this application.

[0066] The term "one embodiment" or "one scheme" used in this specification means that the specific features, steps or characteristics described in connection with that embodiment or scheme are included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in a scheme" that appear throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. In addition, in one or more embodiments or schemes, the various specific features, steps or characteristics can be combined in any appropriate manner, as will be apparent to those of ordinary skill in the art from this application.

[0067] Although the numerical ranges and parameters used to define the broader scope of this application are approximate values, the relevant values in the specific embodiments have been presented as precisely as possible herein. However, any numerical value inherently inevitably contains standard deviations caused by individual testing methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Or, the term "about" represents that the actual value falls within the acceptable standard error of the average value, depending on the consideration of those skilled in the art. Except for experimental examples, or unless otherwise clearly stated, it can be understood that all ranges, quantities, numerical values and percentages (such as those used to describe material usage, time duration, temperature, operating conditions, quantity ratios and others similar) used herein are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this application are all approximate values and can be changed as needed. At least these numerical parameters should be understood as the values obtained by indicating the significant digits and applying the general rounding method.

[0068] The preparation method of grapiprant of the present application has a novel synthetic route and corresponding novel intermediates. The intermediates 2-6 disclosed in the present application were searched in Reaxys, and no relevant reports were found. The intermediates involved in the present application have stable chemical properties, so they can be prepared by different entities, that is, the preparation method of grapiprant of the present application can involve different manufacturers, and each manufacturer may only prepare one or some of the intermediates disclosed in the present application. The preparation schemes of each intermediate involved in the preparation method of grapiprant of the present application will be listed separately in the form of examples below. It should be understood that those skilled in the art can select different preparation schemes according to needs for different intermediates to form the preparation method of grapiprant of the present application or the preparation method of its intermediates. The present application is not limited to the specific preparation schemes described here, and various obvious changes, re-adjustments and substitutions can be made by those skilled in the art to form the preparation method of grapiprant of the present application or the preparation method of its intermediates without departing from the protection scope of the present application.

[0069] Preparation of Intermediate 1 (Compound of Formula II, 2,6-dimethyl-3-nitro-4-hydroxypyridine) by Nitration

[0070] Scheme 1.1: Immerse the reaction vessel in an ice-water bath. Gradually add 30 g (243 mmol) of 2,6-dimethyl-4-hydroxypyridine to 100 ml of sulfuric acid, and then slowly add 20 ml of nitric acid, controlling the temperature of the reaction solution not to exceed 20 °C during the addition; remove the ice-water bath and let it rise to room temperature for reaction; pour the reaction solution into ice cubes to quench the reaction; add concentrated NaOH solution to adjust the pH to neutral; extract with dichloromethane, dry the organic phase and concentrate it under reduced pressure to dryness to obtain 38.0 g of Intermediate 1, with a yield of 92.9% and m / z (mass-to-charge ratio) of 169.

[0071] Preparation of Intermediate 2 (Compound of Formula IV, 2,6-dimethyl-3-nitro-4-(4-acetylphenyl)-aminopyridine)

[0072] Scheme 2.1: Add 17 g of Intermediate 1 to 200 ml of 2-methyltetrahydrofuran, add 6.3 ml (2 eq) of phosphorus oxychloride, and react at room temperature for 30 minutes; treat with saturated sodium bicarbonate solution, dry and concentrate the organic phase to near dryness; add 200 ml of 2-methyltetrahydrofuran and 16.4 g (1.2 eq) of p-acetylaniline; heat up to 70-75 °C and react for 1 hour; adjust the pH value to 2-3 with hydrochloric acid; wash with saturated sodium chloride and saturated sodium bicarbonate solutions in sequence, and evaporate the organic phase to dryness to obtain 27.3 g of Intermediate 2, with a yield of 94.8%; m / z is 286.

[0073] Scheme 2.2: Add 10 g of Intermediate 1 to 100 ml of 2-methyltetrahydrofuran, add 9.6 g (1.2 eq) of p-acetylaniline, heat up to 70 - 75 °C and react for 4 hours; adjust the pH value to 2 - 3 with hydrochloric acid; wash with saturated sodium chloride and saturated sodium bicarbonate solutions in sequence, evaporate the organic phase to dryness, and separate by column chromatography, where the ratio of the eluent dichloromethane∶methanol is 5∶1, thus obtaining 7.2 g of Intermediate 2 with a yield of 42.4%.

[0074] Scheme 2.3: Add 1.0 g of Intermediate 1 to 10 ml of 2-methyltetrahydrofuran, add 1.0 g (1.2 eq) of p-acetylaniline and 0.2 g of the catalyst Raney Ni, heat up to 70 - 75 °C and react for 16 h; extract with saturated sodium bicarbonate solution, evaporate the organic phase to dryness, and separate by column chromatography, where the ratio of the eluent dichloromethane∶methanol is 5∶1, thus obtaining 1.25 g of Intermediate 2 with a yield of 74%.

[0075] Scheme 2.1 is more preferred because the overall yield is high after extraction without purification and directly re-feeding, no additional catalyst is needed to improve the reaction conversion rate, and no column chromatography is required to purify the unreacted substances.

[0076] Reductive preparation of Intermediate 3 (Compound of Formula V, 2,6-dimethyl-3-amino-4-(4-acetylphenyl)aminopyridine)

[0077] Scheme 3.1: Add 8 g of Intermediate 2 to 200 ml of 95% ethanol, add 10 g of ammonium chloride and 50 g of zinc powder, then add 50 ml of water, heat under reflux for 4 hours; filter with diatomaceous earth, extract the filtrate, and evaporate the organic phase under reduced pressure, thus obtaining 7.0 g of Intermediate 3 with a yield of 97.8% and m / z of 256.

[0078] Scheme 3.2: Add 2 g of Intermediate 2 to 10 ml of methanol, add 0.2 g of 10% Pd - C, and react at room temperature for 1 hour under H 2 atmosphere; filter and evaporate to dryness, thus obtaining 7.3 g of Intermediate 3 with a yield of 100%.

[0079] Scheme 3.1 is more preferred because it does not use precious metal catalysts and hydrogen, has lower costs and the reaction is safe.

[0080] Cyclization to prepare Intermediate 4 (Compound of Formula VI, 2-ethyl-4,6-dimethyl-1-(4-acetyl)phenyl-1H-imidazo[4,5-c]pyridine)

[0081] Scheme 4.1: Add 5 g of intermediate 3 to 100 ml of 2-methyltetrahydrofuran, add 50 ml of propionaldehyde, heat up to 50 °C and reflux for 8 hours; directly evaporate to dryness to obtain 5.6 g of intermediate 4, with a yield of 98% and m / z of 294.

[0082] Scheme 4.2: Add 5 g of intermediate 3 to 100 ml of 2-methyltetrahydrofuran, add 2 ml of triethylamine and 5.0 ml (2 eq) of propionic anhydride, heat up to reflux for 4 hours; add saturated sodium bicarbonate solution to quench the reaction, separate the layers, dry and evaporate the organic phase; purify by column chromatography, where the ratio of the eluent dichloromethane:methanol is 4:3, and visualize with iodine fuming to obtain 4.7 g of intermediate 4, with a yield of 82%.

[0083] Scheme 4.3: Add 5 g of intermediate 3 to 100 ml of 2-methyltetrahydrofuran, add 2 ml of triethylamine and 5.8 ml (1.5 eq) of triethyl orthopropionate, heat up to reflux for 3 hours; add 5% hydrochloric acid aqueous solution and stir for extraction, separate the layers, dry and evaporate the organic phase; purify by column chromatography, where the ratio of the eluent dichloromethane:methanol is 4:3, and visualize with iodine fuming to obtain 5.2 g of intermediate 4, with a yield of 91.2%.

[0084] The reactants of Scheme 4.1 are convenient to use, the reaction process is easy to control, and it is easy to realize industrialization, so it is more preferred. In addition, using propionaldehyde or triethyl orthopropionate to participate in the formation of the imidazole ring can obtain intermediate 4 with a high yield and purity, and reduce the generation of side reactions.

[0085] Preparation of intermediate 5 by bromination (Compound of formula VII, 2-ethyl-4,6-dimethyl-1-(4-bromoacetyl)phenyl-1H-imidazo[4,5-c]pyridine)

[0086] Scheme 5.1: Add 12 g of cuprous bromide to 100 ml of ethyl acetate, heat up to reflux, and dropwise add 150 ml of a chloroform solution containing 5 g of intermediate 4 thereto, and keep refluxing for 12 hours; filter and evaporate to dryness to obtain 6.5 g of intermediate 5, with a yield of 95%.

[0087] Scheme 5.2: Add 1 g of intermediate 4 to 10 ml of diethyl ether, add a catalytic amount of aluminum chloride (AlCl 3 )), dropwise add 0.18 ml (1 eq) of liquid bromine at 0 °C, and maintain the low temperature reaction for 2 hours; add 20 ml of saturated sodium bicarbonate solution to quench the reaction, separate the layers, and evaporate the organic phase; purify by column chromatography, where the ratio of the eluent dichloromethane:methanol is 2:1, to obtain 1.07 g of intermediate 5, with a yield of 85%.

[0088] The reaction process of Scheme 5.1 is mild, with fewer by-products and no benzene ring bromine substitution by-products that may be produced in Scheme 5.2, which is conducive to quality control and is thus more preferred.

[0089] Reductive preparation of intermediate 6 (compound of formula VIII, 2-ethyl-4,6-dimethyl-1-(4-bromoethyl)phenyl-1H-imidazo[4,5-c]pyridine)

[0090] Scheme 6.1: Add 6.5 g of intermediate 5 obtained in Scheme 5.1 to 100 ml of 2-methyltetrahydrofuran, add 5.3 g (5 eq) of sodium cyanoborohydride under an ice bath, remove the ice bath, and allow the reaction to proceed at room temperature for 12 hours; treat the reaction solution with 10% hydrochloric acid aqueous solution, separate the layers, wash with saturated sodium chloride solution, and evaporate the organic phase under reduced pressure; purify by slurrying with isopropanol to obtain 5.3 g of intermediate 6 with a yield of 91.7%.

[0091] Scheme 6.2: Dissolve 1 g of intermediate 5 in 10 ml of toluene, add zinc amalgam and hydrochloric acid, and reflux for 4 hours; filter, wash with saturated sodium chloride solution, and evaporate the organic phase under reduced pressure; purify by slurrying with isopropanol to obtain 0.78 g of intermediate 6 with a yield of 81.3%.

[0092] Scheme 6.3: Dissolve 1 g of intermediate 5 in 10 ml of methanol, add 0.2 g of 10% Pd-C and 0.4 g of ammonium formate, and react under H 2 at a pressure of 0.6 MPa for 16 hours; filter, wash with saturated sodium chloride solution, and evaporate the organic phase under reduced pressure; purify by slurrying with isopropanol to obtain 0.72 g of intermediate 6 with a yield of 75.1%.

[0093] The reaction process of Scheme 6.1 is mild and the reactants are safe, so it is more preferred.

[0094] Preparation of intermediate 7 (compound of formula IX, 2-(4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethylamine)

[0095] Scheme 7.1: Add 10 g of intermediate 6 to 100 ml of 2-methyltetrahydrofuran, stir and add 5.55 g (1.05 eq) of potassium phthalimide, stir and reflux for 4 hours; add 10% hydrochloric acid and continue stirring for 0.5 hour, add 100 ml × 3 of saturated sodium bicarbonate solution for extraction, and evaporate the organic phase; dissolve in 100 ml of methanol, add 5 ml of concentrated hydrochloric acid, cool in an ice-water bath and stir for 2 hours, filter to obtain 7.25 g of intermediate 7 with a yield of 88.02% and m / z of 295. The mass spectrum of the obtained intermediate 7 is shown in Figure 1 .

[0096] Scheme 7.2: Add 10 g of intermediate 6 to 100 ml of 2-methyltetrahydrofuran, add 20 ml of 10% sodium hydroxide solution, add 4.45 g (1.6 eq) of succinimide under stirring, heat up to reflux for 4 h; add 10% hydrochloric acid under ice bath and continue stirring for 0.5 h, separate the layers, wash with saturated sodium bicarbonate solution, and evaporate the organic phase to dryness; dissolve with 100 ml of methanol, add 5 ml of concentrated hydrochloric acid, cool down to room temperature in an ice-water bath and stir for 2 h, filter by suction to obtain 6.85 g of intermediate 7, with a yield of 83.1%.

[0097] Scheme 7.3: Add 1 g of intermediate 6 to 10 ml of chloroform, add 0.78 g (2 eq) of hexamethylenetetramine under stirring, heat up to react for 2 h; add 10 ml of ethanol and 2 ml of concentrated hydrochloric acid, stir for 30 min; add 20 ml of water for extraction, evaporate the organic phase to dryness, and then triturate with methanol, filter by suction to obtain 0.52 g of intermediate 7, with a yield of 63.1%.

[0098] From the above results, it is found that all three schemes can be achieved, but judging from the yield results, Scheme 7.1 is preferred.

[0099] Preparation of the target product (Compound XI, grapiprant)

[0100] Scheme 8.1: Add 25 g of intermediate 7 to 500 ml of dichloromethane, cool down in an ice bath, add 18.5 g (1.1 eq) of p-toluenesulfonyl isocyanate, stir at room temperature for 2 h; add saturated sodium chloride solution to separate the layers, evaporate the organic phase to dryness; purify by triturating with 50 ml of acetone to obtain 38.5 g of the target product grapiprant, with a yield of 92.2%, m / z is 491. The mass spectrum of the obtained target product grapiprant is shown in Figure 2 .

[0101] The nuclear magnetic resonance spectrum of the obtained target product 1 HNMR(CD 4 O) peaks are 7.92 - 7.85 (2H, m), 7.54–7.47 (m, 2H), 7.39 (t, J = 4.0 Hz, 2H), 7.36–7.29 (m, 2H), 6.88 (s, 1H), 3.67 (q, J = 6.6 Hz, 2H), 3.06 (q, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.92 (q, J = 7.5 Hz, 2H), 2.65 (s, 3H), 2.51 (s, 3H), 1.45–1.36 (m, 3H); The nuclear magnetic resonance spectrum is shown in Figure 3 .

[0102] Scheme 8.2: Add 1.2 g of p-toluenesulfonamide to 10 ml of chloroform. Under ice bath, add 0.91 g (1.2 eq) of ethyl chloroacetate and 0.2 ml of triethylamine, and then heat to reflux for 4 h; add 10 ml of 10% sodium hydroxide solution, extract and separate the layers. Wash the organic phase twice with saturated sodium chloride solution, dry it, add 2 g of intermediate 7, and stir and reflux for 5 h; add water to separate the layers, and after treatment and purification, 2.23 g of the target product, grapiprant, is obtained, with a yield of 66.7%.

[0103] It is found from the above results that both schemes can be realized, but Scheme 8.1 has simpler operation and higher reaction yield, so Scheme 8.1 is preferred.

[0104] In one embodiment, using 2,6-dimethyl-4-hydroxypyridine as the starting material, and respectively adopting Schemes 1.1, 2.1, 3.1, 4.1, 5.1, 6.1, 7.1 and 8.1 as the process steps to synthesize grapiprant, the total yield is 59.67%. For the schematic diagram of the reaction process of this example, see Figure 4 . Compared with the total yields of 17% (CN101967146A) and 53.1% (CN101137656A) disclosed in the prior art, the total yield of this embodiment is significantly improved. In this embodiment, the use of noble metal catalysts is completely avoided during the reaction, and the estimated cost is about 12,000 yuan / kg. Compared with the estimated cost of about 50,000 yuan / kg for preparing grapiprant according to CN101137656A, it has a significant cost advantage. The reaction process of this embodiment is mild and controllable. In particular, a bromo substituent is directly introduced at the α-position of the phenylacetyl group, and then an amino group is formed, avoiding the risks that may be caused by introducing an azide group as in the prior art. There are no special reaction conditions in the entire synthesis route of this embodiment, which is suitable for large-scale industrialization and is easy to implement.

[0105] In one embodiment, using 2,6-dimethyl-3-nitro-4-hydroxypyridine and p-acetylaniline as the starting materials, and respectively adopting Schemes 2.1, 3.1, 4.1, 5.1, 6.1, 7.1 and 8.1 as the process steps to synthesize grapiprant, the total yield is 64.23%. Compared with the total yields of 17% (CN101967146A) and 53.1% (CN101137656A) disclosed in the prior art, the total yield of this embodiment is significantly improved. In this embodiment, the use of noble metal catalysts is completely avoided during the reaction, which has a cost advantage. The use of p-acetylaniline for coupling in this embodiment avoids the protection and deprotection operations of amino groups, hydroxyl groups, etc., and shortens the synthesis route.

[0106] In one embodiment, 2,6-dimethyl-4-hydroxypyridine is used as the starting material, and Schemes 1.1, 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1 are respectively adopted as process steps to synthesize the key intermediate of grapiprant, 2-(4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethanamine. The key intermediate obtained in this embodiment has stable chemical properties and can be used for the synthesis of grapiprant.

[0107] In one embodiment, 2,6-dimethyl-3-nitro-4-hydroxypyridine and p-acetylaniline are used as the starting materials, and Schemes 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1 are respectively adopted as process steps to synthesize the key intermediate of grapiprant, 2-(4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl)ethanamine. The key intermediate obtained in this embodiment has stable chemical properties and can be used for the synthesis of grapiprant.

[0108] Although the present application has been described in more detail through the above embodiments, the present application is not limited to the above embodiments. Without departing from the concept of the present application, more other equivalent embodiments can be included, all of which fall within the protection scope of the present application.

Claims

1. A preparation method of grapiprant, characterized in that, it comprises the following steps: Step (1): Nitrate the compound of Formula I to obtain the compound of Formula II Step (2): React the compound of Formula II with the compound of Formula III to obtain the compound of Formula IV Step (3): Reduce the nitro group in the compound of Formula IV to obtain the compound of Formula V Step (4): Cyclize the amino functional group and the aminopyridine functional group of the compound of Formula V to obtain the compound of Formula VI Step (5): Brominate the compound of Formula VI to obtain the compound of Formula VII Step (6): Reduce the carbonyl group in the compound of Formula VII to obtain the compound of Formula VIII Step (7): React the compound of Formula VIII with an organic amine or an organic amine salt and carry out hydrolysis under acidic conditions to obtain the compound of Formula IX and Step (8): React the compound of Formula IX with the compound of Formula X to obtain grapiprant of Formula XI:

2. The preparation method according to claim 1, characterized in that, in step (1), nitration is carried out using nitric acid.

3. The preparation method according to claim 1, characterized in that, step (1) is carried out in the presence of sulfuric acid.

4. The preparation method according to claim 1, characterized in that, step (1) is carried out under temperature control.

5. The preparation method according to claim 1, characterized in that, the reaction in step (2) is carried out in the presence of an organic solvent.

6. The preparation method according to claim 1, characterized in that, the reaction in step (2) is carried out in an environment of phosphorus oxychloride.

7. The preparation method according to claim 1, characterized in that, in step (2), before the compound of Formula II reacts with the compound of Formula III, it first reacts with phosphorus oxychloride.

8. The preparation method according to claim 1, characterized in that, the reaction in step (3) does not have a noble metal catalyst.

9. The preparation method according to claim 1, characterized in that, the reaction in step (3) is carried out in the presence of ethanol, ammonium chloride and zinc.

10. The preparation method according to claim 1, characterized in that, step (4) is carried out in a weak base environment.

11. The preparation method according to claim 1, characterized in that, the reagent that cyclizes with the compound of Formula V to form the compound of Formula VI in step (4) is propionaldehyde, propionic anhydride or triethyl orthopropionate.

12. The preparation method according to claim 11, characterized in that, the reagent that cyclizes with the compound of Formula V to form the compound of Formula VI in step (4) is propionaldehyde.

13. The preparation method according to claim 1, characterized in that, in step (5), bromination is carried out using cuprous bromide or liquid bromine.

14. The preparation method according to claim 1, characterized in that, the reaction in step (6) does not have a noble metal catalyst.

15. The preparation method according to claim 1, characterized in that, in step (6), the reaction uses sodium cyanoborohydride to reduce the carbonyl group in the compound of Formula VII.

16. The preparation method according to claim 1, It is characterized in that the organic amine or organic amine salt in the step (7) is potassium phthalimide, succinimide or hexamethylenetetramine.

17. The preparation method according to claim 16, it is characterized in that the organic amine or organic amine salt in the step (7) is potassium phthalimide.

18. A preparation method of a gepirone intermediate, it is characterized in that it includes the following steps: Step (1) Nitrate the compound of formula I to obtain the compound of formula II Step (2) React the compound of formula II with the compound of formula III to obtain the compound of formula IV Step (3) Reduce the nitro group in the compound of formula IV to obtain the compound of formula V Step (4) Cyclize the amino functional group and the aminopyridine functional group of the compound of formula V to obtain the compound of formula VI Step (5) Brominate the compound of formula VI to obtain the compound of formula VII Step (6) Reduce the carbonyl group in the compound of formula VII to obtain the compound of formula VIII and Step (7) React the compound of formula VIII with an organic amine or organic amine salt and carry out hydrolysis under acidic conditions to obtain the compound of formula IX as a gepirone intermediate

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