CN116478155A - A kind of preparation method of Grapiron and its intermediate - Google Patents

Abstract

The present application relates to the preparation method of grapiprant and its intermediates. The preparation method of grapirum of the present 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; reacting an organic amine or an organic amine salt, and hydrolyzing it under acidic conditions to obtain a compound of formula IX; and reacting a compound of formula IX with a compound of formula X to obtain a compound of formula XI, grapiramate. The cost of the method is significantly reduced, the method is safe and easy to implement, and the total yield and purity of the target product grapirom are improved.

Description

A kind of preparation method of Grapirun and its intermediate

technical field

The present application relates to a preparation method of veterinary medicine, in particular to a preparation method of Grapirant and its intermediate.

Background technique

Grapiprant is an animal-specific drug that was approved for marketing in May 2016. It is used to treat pain and joint swelling caused by osteoarthritis in dogs. The current licensee is Lilan Animal Health. Its sales have grown rapidly, from less than US$20 million in 2018 to about US$100 million in 2020. The market performance is significantly better than other analgesic drugs such as firocoxib and meloxicam.

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

The chemical structure of Grapirone (C ₂₆ H ₂₉ N ₅ O ₃ S, CAS: 415903-37-6) is shown below:

Chinese patent application CN101967146A discloses a class of aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents. This application has introduced the preparation method of Grapiron in specification sheet, specifically as follows:

.

The method uses 4-(2-hydroxyethyl)aniline to react with 4-chloro-2,6-dimethyl-3-nitropyridine at 150°C to obtain intermediate product 1-1, and then uses 10% Pd-C to reduce the nitro group to obtain intermediate product 1-2, and then reacts with propionic anhydride to form ring and ester to obtain intermediate product 1-3, hydrolyzes to obtain intermediate product 1-4, reacts with thionyl chloride at 80°C to obtain intermediate product 1-5, and reacts with sodium azide at 100°C The intermediate product 1-6 was obtained by the reaction, and the intermediate product 1-7 was obtained by reduction with 10% Pd-C again, and then reacted 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. And there are two steps in this method to use the noble metal catalyst (10%Pd-C) reduction of higher cost. In addition, sodium azide is used to introduce azide groups in this method, which has serious safety hazards, making the feasibility of scale-up industrialization low.

Chinese patent application CN101137656A discloses a crystal form of imidazole derivatives, and discloses a preparation method of Grapiron in the description, as follows:

.

The method uses 4-(2-aminoethyl)aniline as a raw material, which is protected by benzyl chloroformate to obtain an intermediate product 2-1, which is then coupled with 4-chloro-2,6-dimethyl-3-nitropyridine at 80°C to obtain an intermediate product 2-2, and the nitro group is reduced with 10% Pd-C to obtain an intermediate product 2-3, and propionic anhydride is added to form an imidazole ring at 80°C to obtain an intermediate product 2-4. 5. Reaction with p-toluenesulfonyl isocyanate to obtain the target product, grapiprant. The overall yield of this method is 53.1%, but the selectivity in the preparation process of intermediate product 2-1 cannot be well controlled, and the ring-forming step of intermediate product 2-4 may form a double amide bond by-product. Moreover, in this method, expensive noble metals are used to catalyze the reduction of 10% Pd—C, and the raw material 4-(2-aminoethyl)aniline is also relatively expensive, which is not conducive to cost control. In addition, in the preparation process of intermediate 2-3, when the nitro group is reduced with 10% Pd-C, the protecting group will be removed at the same time, and the next step of ring formation with propionic anhydride will produce obvious impurities, which is not conducive to product quality control.

U.S. patent application US20210079000A1 discloses a preparation method of grapirene, as follows:

.

This method is similar to the method disclosed in the Chinese patent application CN101137656A, and utilizes the aminolysis of the ester to prepare the target product. The key intermediate is still consistent with the above patent application, and no method adjustment has been seen. Moreover, compared with the above-mentioned patent application using p-methylsulfonamide isocyanate, this method increases the reaction steps, and the reaction between the amino group and the ester group needs to be carried out by adding catalysts such as HOBt and CDI, and the cost increases a lot.

Chinese patent application CN101967146A also introduces possible methods for synthesizing similar compounds, specifically as follows:

The main problem of this method is that the reduction of the cyano group requires the use of a noble metal catalyst, and the raw materials used are expensive, which is not conducive to industrialization.

Contents of the invention

In view of the above-mentioned problems in the prior art, one aspect of the present application provides a preparation method of grapirom. This method has a novel synthetic route and corresponding novel intermediates. The main raw materials are simple in structure, cheap and easy to obtain, and reduce or even avoid dependence on expensive reagents such as noble metal catalysts. The method has significant cost advantages, and the entire route process is simple to operate, each reaction is mild and safe, and does not require special reaction conditions, which is suitable for industrialization.

In order to achieve the above-mentioned purpose, the application provides the preparation method of the Grapiron comprising the following steps:

Step (1) nitration formula I compound, to obtain formula II compound

Step (2) reacts the compound of formula II with the compound of formula III to obtain the compound of formula IV

Step (3) reducing the nitro group in the compound of formula IV to obtain the compound of formula V

Step (4) cyclization of the amino functional group and the aminopyridine functional group of the compound of formula V to obtain the compound of formula VI

Step (5) bromination of the compound of formula VI to obtain the compound of formula VII

Step (6) reducing the carbonyl group in the compound of formula VII to obtain the compound of formula VIII

Step (7) reacting the compound of formula VIII with an organic amine or an organic amine salt, and hydrolyzing it under acidic conditions to obtain a compound of formula IX

as well as

Step (8) reacts the compound of the formula IX with the compound of the formula X to obtain the compound of the formula XI, Grapirant:

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

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

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

Usually, step (4) is carried out in a solvent. In some embodiments, the reaction in step (4) is carried out under a weak base environment. In some embodiments, the step (4) reacts with the formula V to generate the compound of the formula VI through a ring closure reaction, which is propionaldehyde, propionic anhydride or triethyl orthopropionate, preferably propionaldehyde. In some embodiments, step (4) is performed at elevated temperature, preferably at 50°C.

Usually, step (5) is carried out in an organic solvent. The organic solvent may be selected from one or more of ethyl acetate, diethyl ether, and chloroform. In some embodiments, step (5) uses cuprous bromide or liquid bromine for bromination, preferably cuprous bromide.

Usually, step (6) is carried out in an organic solvent. The organic solvent can be selected from 2-methyltetrahydrofuran, toluene, methanol. In some embodiments, the reaction of step (6) does not have a noble metal catalyst. In some embodiments, the reaction of step (6) uses sodium cyanoborohydride to reduce the carbonyl group in the compound of formula VII.

Usually, step (7) is carried out in an organic solvent. In some embodiments, the organic amine or organic amine salt described in step (7) is potassium phthalamide, succinimide or urotropine, preferably potassium phthalamide.

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

Another aspect of the application provides a method for preparing a grapirom intermediate, comprising: step (1) nitrating the compound of formula I to obtain the compound of formula II

Step (2) reacts the compound of formula II with the compound of formula III to obtain the compound of formula IV

Step (3) reducing the nitro group in the compound of formula IV to obtain the compound of formula V

Step (4) cyclization of the amino functional group and the aminopyridine functional group of the compound of formula V to obtain the compound of formula VI

Step (5) bromination of the compound of formula VI to obtain the compound of formula VII

Step (6) reducing the carbonyl group in the compound of formula VII to obtain the compound of formula VIII

Step (7) reacting the compound of the formula VIII with an organic amine or an organic amine salt, and hydrolyzing it under acidic conditions to obtain the compound of the formula IX as an intermediate of grapiramate

Through the novel synthetic route and the design of novel intermediates, the preparation method of grapiron of the present application can adopt simple, cheap and easy-to-obtain starting materials and reaction reagents, and reduce or even avoid the use of high-priced reagents such as noble metal catalysts. Therefore, compared with the prior art, it has a significant advantage in cost; and the whole route process is simple to operate, without special process parameter requirements, the reaction process is mild and safe, and the novel intermediates are stable in properties, easy to expand, and realize industrialization. In addition, through the design of a novel synthetic route, the preparation method of grapirom unexpectedly reduces the generation of by-products and improves the overall yield and purity of the target product grapirom.

These and other aspects of the present application will be more clearly understood in the following description of various embodiments.

Description of drawings

The accompanying drawings of the present application will be provided below, and these drawings are only for embodying the present application in a more intuitive form, they are exemplary, and are not intended to limit the scope of the present application.

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.

Fig. 2 shows the mass spectrum of the target product grapirene prepared according to a method embodiment of the present application.

Fig. 3 shows the H NMR spectrum of the target product grapirene prepared according to a method embodiment of the present application.

Fig. 4 shows a schematic flowchart of a method embodiment of the present application.

Detailed ways

In order to make the present application easier to understand, the present application will be further described below in conjunction with specific examples (embodiments). The experimental methods described in this application, unless otherwise specified, are conventional methods; the materials described, unless otherwise specified, can be obtained from commercial sources. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. In case of any inconsistency, the meaning stated in this manual or the meaning derived from the content recorded in this manual shall prevail. In addition, the terms used herein are only for the purpose of describing the embodiments of the present application, and are not intended to limit the present application.

The word "one embodiment" or "an aspect" used in this specification means that a specific feature, step or characteristic described in conjunction with the embodiment or aspect is included in at least one embodiment of the present invention. Therefore, the appearances of the terms "in one embodiment" or "in an aspect" in various places in this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. Furthermore, the specific features, steps or characteristics may be combined in any suitable manner as would be apparent to one of ordinary skill in the art from the present application in one or more implementations or aspects.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the application are approximations, the relative numerical values set forth in the specific examples are reported here as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by 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 used herein (for example, to describe the amount of materials used, the length of time, temperature, operating conditions, ratios of quantities, and the like) are modified by "about". Therefore, unless otherwise indicated to the contrary, the numerical parameters disclosed in the present application are approximate values and may be changed according to requirements. At least these numerical parameters should be understood as the value obtained by applying the normal rounding method to the indicated effective digits.

The preparation method of grapirun of the present application has a novel synthetic route and corresponding novel intermediates. The intermediates 2-6 disclosed in this application have been retrieved by Reaxys, but no relevant reports have been found. The intermediates involved in this application are stable in chemical properties, so they can be prepared by different subjects, that is, the preparation method of grapiron in this application may involve different manufacturers, and each manufacturer may only prepare one or some intermediates disclosed in this application. The preparation schemes of the various intermediates involved in the preparation method of grapirun of the present application will be respectively listed below in the form of examples. It should be understood that those skilled in the art can select different preparation schemes for different intermediates according to needs, so as to form the preparation method of grapiron or the preparation method of its intermediates of the present application. The application is not limited to the specific preparation scheme described here, and various obvious changes, readjustments and substitutions can be made by those skilled in the art to form the preparation method of grapiron of the application or the preparation method of its intermediate, without departing from the scope of protection of the application.

Preparation of intermediate 1 by nitration (compound of formula II, 2,6-dimethyl-3-nitro-4-hydroxypyridine)

Scheme 1.1: Add 30 g (243 mmol) of 2,6-dimethyl-4-hydroxypyridine to 100 ml of sulfuric acid in batches in an ice-water bath in the reaction vessel, and then slowly add 20 ml of nitric acid to control the temperature of the reaction solution not to exceed 20°C during the addition process; remove the ice-water bath and let it rise to room temperature to react naturally; pour the reaction solution into ice cubes to quench the reaction; add concentrated NaOH solution to adjust the pH to neutral; 38.0 g of intermediate 1 was obtained with a yield of 92.9% and an m/z (mass-to-charge ratio) of 169.

Preparation of intermediate 2 (compound of formula IV, 2,6-dimethyl-3-nitro-4-(4-acetylphenyl)-aminopyridine)

Scheme 2.1: Add 17g of intermediate 1 to 200ml of 2-methyltetrahydrofuran, add 6.3ml (2eq) of phosphorus oxychloride, and react at room temperature for 30 minutes; add saturated sodium bicarbonate solution for treatment, dry and concentrate the organic phase to near dryness; add 200ml of 2-methyltetrahydrofuran and 16.4g (1.2eq) of p-acetylaniline; heat up to 70-75°C for 1 hour; 2-3; add saturated sodium chloride and saturated sodium bicarbonate solution to wash 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.

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; add hydrochloric acid to adjust the pH value to 2-3; add saturated sodium chloride and saturated sodium bicarbonate solution to wash in sequence, evaporate the organic phase to dryness, and separate by column chromatography. 2. The yield is 42.4%.

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 catalyst Raney Ni, heat up to 70-75 ° C for 16 h; add saturated sodium bicarbonate solution for extraction, evaporate the organic phase to dryness, and separate by column chromatography. The rate is 74%.

Scheme 2.1 directly feeds again without purification after extraction, the overall yield is high, no catalyst is needed to increase the reaction conversion rate, and column chromatography is not required to purify unreacted substances, so it is more preferred.

Preparation of intermediate 3 by reduction (compound of formula V, 2,6-dimethyl-3-amino-4-(4-acetylphenyl)-aminopyridine)

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

Scheme 3.2: Add 2g of intermediate 2 to 10ml of methanol, add 0.2g of 10% Pd-C, and react at room temperature under _H2 atmosphere for 1 hour; filter and evaporate to dryness to obtain 7.3g of intermediate 3 with a yield of 100%.

Scheme 3.1 is more preferred because it does not use noble metal catalysts and hydrogen, and has lower cost and safe reaction.

Preparation of intermediate 4 by cyclization (compound of formula VI, 2-ethyl-4,6-dimethyl-1-(4-acetyl)phenyl-1H-imidazo[4,5-c]pyridine)

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

Scheme 4.2: 5g of intermediate 3 was added to 100ml of 2-methyltetrahydrofuran, 2ml of triethylamine, 5.0ml (2eq) of propionic anhydride were added, and the temperature was raised to reflux for 4 hours; saturated sodium bicarbonate solution was added to quench the reaction, the layers were separated, the organic phase was dried, and evaporated to dryness; column chromatography purification, wherein the ratio of developing agent dichloromethane:methanol was 4:3, iodine smoked to develop color, and obtained 4.7g of intermediate 4, and the yield was 82%.

Scheme 4.3: Add 5 g of intermediate 3 to 100 ml of 2-methyltetrahydrofuran, add 2 ml of triethylamine, 5.8 ml (1.5 eq) of triethyl orthopropionate, heat and reflux for 3 hours; add 5% aqueous hydrochloric acid to stir and extract, separate layers, dry the organic phase, and evaporate to dryness; column chromatography purification, wherein the ratio of developing agent dichloromethane: methanol is 4: 3, and iodine fumigates the color to obtain 5.2 g of intermediate 4. The yield is 91.2%.

The reactant of scheme 4.1 is convenient to use, easy to control the reaction process, and easy to realize industrialization, so it is more preferred. In addition, the use of propionaldehyde or triethyl orthopropionate to participate in the formation of the imidazole ring can obtain intermediate 4 with higher yield and purity, reducing the occurrence of side reactions.

Bromination of intermediate 5 (compound of formula VII, 2-ethyl-4,6-dimethyl-1-(4-bromoacetyl)phenyl-1H-imidazo[4,5-c]pyridine)

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

Scheme 5.2: Add 1 g of intermediate 4 to 10 ml of ether, add a catalytic amount of aluminum chloride (AlCl ₃ ), add 0.18 ml (1 eq) of liquid bromine dropwise 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 layers, and evaporate the organic phase to dryness; column chromatography purification, wherein the ratio of developing agent dichloromethane:methanol is 2:1, and 1.07 g of intermediate 5 is obtained, with a yield of 85%.

Scheme 5.1 has a mild reaction process, fewer by-products, and no by-products substituted by benzene ring bromine that may be produced in Scheme 5.2, which is beneficial to quality control, and thus is more preferred.

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

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 ice bath, remove the ice bath, and naturally rise to room temperature for 12 hours of reaction; add 10% hydrochloric acid aqueous solution to treat the reaction solution, separate layers, wash with saturated sodium chloride solution, and evaporate the organic phase to dryness under reduced pressure; beat and purify with isopropanol to obtain 5.3 g of intermediate 6, and the yield is 91.5%. 7%.

Scheme 6.2: Dissolve 1 g of intermediate 5 in 10 ml of toluene, add zinc amalgam and hydrochloric acid, and heat to reflux for 4 hours; filter, wash with saturated sodium chloride solution, and evaporate the organic phase to dryness under reduced pressure; purify with isopropanol to obtain 60.78 g of the intermediate, with a yield of 81.3%.

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

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

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)

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

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 and reflux for 4 h; add 10% hydrochloric acid under ice bath and continue stirring for 0.5 hour, separate 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, and The temperature was lowered in a water bath and stirred for 2 hours, and filtered with suction to obtain 6.85 g of intermediate 7 with a yield of 83.1%.

Scheme 7.3: Add 1 g of intermediate 6 to 10 ml of chloroform, add 0.78 g (2 eq) of urotropine while stirring, and heat up for 2 hours; add 10 ml of ethanol and 2 ml of concentrated hydrochloric acid, and stir for 30 minutes; add 20 ml of water for extraction, evaporate the organic phase to dryness, beat with methanol, and suction filter to obtain 0.52 g of intermediate 7, with a yield of 63.1%.

From the above results, it is found that all three schemes can be realized, but judging from the yield results, scheme 7.1 is preferred.

Preparation of target product (compound of formula XI, Grapirin)

Scheme 8.1: 25g of intermediate 7 was added to 500ml of dichloromethane, cooled in an ice bath, 18.5g (1.1eq) of p-toluenesulfonyl isocyanate was added, and the reaction was stirred at room temperature for 2 hours; saturated sodium chloride solution was added for layering, and the organic phase was evaporated to dryness; 50ml of acetone was used for beating and purification to obtain 38.5g of the target product grapirene. The yield was 92.2%, and the m/z was 491. See Figure 2 for the mass spectrum.

The nuclear magnetic resonance spectrum of gained target product¹HNMR (CD₄O) peaks at 7.92-7.85(2H,m), 7.54–7.47(m,2H), 7.39(t,J=4.0Hz,2H), 7.36–7.29(m,2H), 6.88(s,1H), 3.67(q,J=6.6Hz,2H), 3.06(q,J=7.0Hz,2H), 3.01 (s,3H), 2.92(q,J=7.5Hz,2H), 2.65(s,3H), 2.51(s,3H), 1.45–1.36(m,3H); the NMR spectrum is shown in Figure 3.

Scheme 8.2: Add 1.2 g of p-toluenesulfonamide to 10 ml of chloroform, add 0.91 g (1.2 eq) of ethyl chloroacetate and 0.2 ml of triethylamine under an ice bath, heat up and reflux for 4 hours; add 10 ml of 10% sodium hydroxide solution, extract and separate the layers, wash the organic phase twice with saturated sodium chloride solution, dry, add 2 g of intermediate 7, stir and reflux for 5 hours; Obtained 2.23 g of the target product, grapirene, with a yield of 66.7%.

From the above results, it is found that both schemes can be realized, but scheme 8.1 is simple to operate and has a higher reaction yield, so scheme 8.1 is preferred.

In one embodiment, starting from 2,6-dimethyl-4-hydroxypyridine, schemes 1.1, 2.1, 3.1, 4.1, 5.1, 6.1, 7.1, and 8.1 were used as process steps to synthesize grapiramate with an overall yield of 59.67%. The schematic diagram of the reaction process of this embodiment is shown in Figure 4. Compared with the total yields of 17% (CN101967146A) and 53.1% (CN101137656A) disclosed in the prior art, this embodiment significantly improves the total yield. This embodiment completely avoids the use of noble metal catalysts in the reaction, and the estimated cost is about 12,000 yuan/kg, which has a significant cost advantage compared to the estimated cost of about 50,000 yuan/kg for the preparation of grapirom according to CN101137656A. The reaction process of this embodiment is mild and controllable, especially the bromine substituent is introduced directly at the alpha position of the phenylacetyl group to form an amine group, which avoids the risks that may be caused by the introduction of an azido group as in the prior art. There are no special reaction conditions in the whole synthetic route of this embodiment, which is suitable for expanding industrialization and is easy to implement.

In one embodiment, 2,6-dimethyl-3-nitro-4-hydroxypyridine and p-acetylaniline are used as starting materials, and schemes 2.1, 3.1, 4.1, 5.1, 6.1, 7.1 and 8.1 are used as process steps to synthesize grapirom with a total yield of 64.23%. Compared with the total yields of 17% (CN101967146A) and 53.1% (CN101137656A) disclosed in the prior art, this embodiment significantly improves the total yield. This embodiment completely avoids the use of noble metal catalysts in the reaction, which has a cost advantage. In this embodiment, the coupling of p-acetylaniline avoids the protection and deprotection operations of amino groups, hydroxyl groups, etc., and shortens the synthesis route.

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

In one embodiment, 2,6-dimethyl-3-nitro-4-hydroxypyridine and p-acetylaniline are used as starting materials, and schemes 2.1, 3.1, 4.1, 5.1, 6.1, and 7.1 are used as process steps to synthesize the key intermediate 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 synthesizing grapirom.

Although the present application has been described in detail through the above embodiments, the present application is not limited to the above embodiments, and may include more other equivalent embodiments without departing from the concept of the present application, all of which belong to the protection category of the present application.

Claims (10)

1. A method for preparing grapiprant, comprising the steps of:

step (1) nitration of the compound of formula I to give a compound of formula II

Step (2) reacting the compound of formula II with a compound of formula III to obtain a compound of formula IV

Step (3) reducing the nitro group in the compound of formula IV to give a compound of formula V

Step (4) cyclizing the amino and aminopyridine functionalities of the compound of formula V to give a compound of formula VI

Step (5) brominating the compound of formula VI to obtain a compound of formula VII

Step (6) reducing the carbonyl group in the compound of formula VII to give a compound of formula VIII

Step (7) reacting the compound of formula VIII with an organic amine or organic amine salt and hydrolyzing under acidic conditions to obtain a compound of formula IX

and

Step (8) reacting the compound of formula IX with a compound of formula X to obtain the compound glaepin of formula XI:

2. the preparation method according to claim 1, wherein the step (1) is performed by using nitric acid, preferably the step (1) is performed in the presence of sulfuric acid, further preferably the step (1) is performed under temperature-controlled conditions.

3. The preparation method according to claim 1, wherein the reaction of step (2) is performed in the presence of an organic solvent, preferably the reaction of step (2) is performed in an environment of phosphorus oxychloride.

4. The process according to claim 1, wherein in step (2), the compound of formula II is reacted with phosphorus oxychloride before reacting with the compound of formula III.

5. The process according to claim 1, wherein the reaction of step (3) is in the absence of a noble metal catalyst, preferably the reaction of step (3) is carried out in the presence of ethanol, ammonium chloride and zinc.

6. The process according to claim 1, wherein step (4) is carried out in a weak alkaline environment, preferably the reagent which is cyclized with formula V in step (4) to form the compound of formula VI is propanal, propionic anhydride or triethyl orthopropionate, preferably propanal.

7. The method of claim 1, wherein step (5) is performed using cuprous bromide or liquid bromine.

8. The process of claim 1, wherein the reaction of step (6) is in the absence of a noble metal catalyst, and further wherein the reaction of step (6) reduces the carbonyl group in the compound of formula VII using sodium cyanoborohydride.

9. The process according to claim 1, wherein the organic amine or organic amine salt in step (7) is potassium phthalamide, succinimide or urotropine, preferably potassium phthalamide.

10. A method for preparing a grapiprant intermediate, which is characterized by comprising the following steps:

step (1) nitration of the compound of formula I to give a compound of formula II

Step (2) reacting the compound of formula II with a compound of formula III to obtain a compound of formula IV

Step (3) reducing the nitro group in the compound of formula IV to give a compound of formula V

Step (4) cyclizing the amino and aminopyridine functionalities of the compound of formula V to give a compound of formula VI

Step (5) brominating the compound of formula VI to obtain a compound of formula VII

Step (6) reducing the carbonyl group in the compound of formula VII to give a compound of formula VIII

and

Step (7) reacting the compound of formula VIII with an organic amine or organic amine salt and hydrolyzing under acidic conditions to obtain the compound of formula IX as an intermediate for grapiprant