Synthesis method of agometinib

Abstract

The invention belongs to the technical field of raw material medicine preparation, and relates to a synthesis method of agometinib. The invention relates to a method for synthesizing non-gogotinib, which comprises the following steps of: carrying out boron esterification reaction on p-bromobenzaldehyde (compound 1) serving as a starting raw material and bis (pinacolato) diboron (compound 2) under the catalysis of palladium to obtain an intermediate 3, carrying out Suzuki coupling reaction on the intermediate 3 and 2-amino-6-bromopyridine (compound 4) to obtain an intermediate 5, and carrying out reaction on the intermediate 5 and thiomorpholine-1, 3, 5, 6-tetramethyl-4-piperidine (compound 4) to obtain the non-gogotinib. The preparation method comprises the following steps: reacting 1, 1-dioxide (compound 6) to generate an intermediate 7, condensing the intermediate 7 with cyclopropylformyl chloride (compound 8) and potassium thiocyanate (compound 9) to obtain an intermediate 10, and cyclizing the intermediate 10 with hydroxylamine hydrochloride (compound 11) to obtain the final product Figotinib. The synthesis method provided by the invention solves the problems of difficult acquisition of initial raw materials, harsh reaction conditions, tedious process route and the like of the synthesis method for preparing Filgotinib in the prior art, and has the advantages of short synthesis route, easy acquisition of materials used in the reaction, and simple reaction operation.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug preparation and relates to a synthesis method of filgotinib. Background Art

[0002] Filgotinib is a JAK (Janus kinase) inhibitor used to treat rheumatoid arthritis. It can be used as a monotherapy or in combination with drugs such as methotrexate. Developed by Galapagos NV and Gilead Science, in December 2020, Filgotinib was approved in Japan, the United Kingdom, the European Union and other places for the treatment of adult patients with moderate to severe rheumatoid arthritis who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.

[0003] Filgotinib's Chinese reference translation: Filgotinib

[0004] Product name: Jyseleca

[0005] Chemical name: N-(5-{4-[(1,1-dioxidothiomorpholino)methyl]phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamideCAS number: 1206161-97-8;

[0006] Relative molecular mass: 425.5;

[0007] Molecular formula: C 21 H 23 N 5 O 3 S;

[0008] Structural formula:

[0009]

[0010] Existing synthesis methods of Filgotinib:

[0011] Method 1 is a synthetic process route disclosed in international patent WO 2010149769 A1, using 2-amino-6-bromopyridine (2) as a starting material, condensing with ethoxycarbonyl isothiocyanate to obtain 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea (3), and then cyclizing with hydroxylamine hydrochloride to obtain 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (4), acylation reaction of 4 with cyclopropylcarbonyl chloride to obtain N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (5), and 5 with p-hydroxymethyl Phenylboronic acid is subjected to Suzuki coupling to obtain N-{5-[4-(hydroxymethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (6). Intermediate 6 is subjected to bromination reaction to obtain N-{5-[4-(bromomethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (7). Finally, 7 is subjected to substitution reaction with thiomorpholine-1,1-dioxide to obtain the final product Filgotinib (1). The specific reaction is as follows.

[0012]

[0013] Reagent and conditions: a.CH 2 Cl 2 ,rt; b.NH 2 OH·HCl,DIPEA,C 2 H 5 OH,CH 3 OH, reflux; c. ①Et 3 N,CH 3 CN,rt; ②NH 3 ,CH 3 OH, rt; d.Pd(dppf)Cl 2 ,K 2 CO 3 ,Dioxane,H 2 O,N 2 ,90℃;e.PBr 3 ,CHCl 3 ,rt;f.DIPEA,CH 2 Cl 2 ,CH 3 OH,N 2 ,rt;

[0014] This route has a wide range of raw materials, but it belongs to a linear synthesis strategy with many reaction steps, low overall yield, and overly complicated post-processing operations. In addition, phosphorus tribromide is used in the reaction, which will produce a large amount of phosphorus-containing waste, causing certain harm to the environment. Chloroform is used as a solvent in the route, which is highly toxic and not conducive to industrial promotion.

[0015] Method 2 is a 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide compound as a JAK inhibitor of CN102482273A. This route uses 2-amino-6-bromopyridine (2) as a starting material, condenses with ethoxycarbonyl isothiocyanate to obtain 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea (3), 3 is cyclized with hydroxylamine hydrochloride to obtain 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (4), and 4 is acylated with cyclopropylcarbonyl chloride to obtain N -(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (5); using p-bromomethylphenylboronic acid ester (8) as a raw material, a substitution reaction is carried out with thiomorpholine-1,1-dioxide to obtain an intermediate 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiomorpholine-1,1-dioxide (9); intermediate 9 is subjected to Suzuki coupling reaction with 5 to obtain the final product Filgotinib (1). The specific reaction is as follows.

[0016]

[0017] Reagent and conditions: a.CH 2 Cl 2 ,rt; b.NH 2 OH·HCl,DIPEA,C 2 H 5 OH,CH 3 OH, reflux; c. ①Et 3 N,CH 3 CN,rt; ②NH 3 ,CH 3 OH, rt; d.DIPEA, CH 2 Cl 2 ,CH 3 OH,N 2 ,rt; e.Pd(dppf)Cl 2 ,K 2 CO 3 ,Dioxane,H 2 O,N 2 ,90℃.

[0018] Compared with method 1, this method shortens the reaction route by adopting a convergent synthesis strategy, greatly reduces waste generation, and has a higher synthesis efficiency. However, the raw material p-bromomethylphenyl borate (8) is expensive and unstable in nature, which has a certain adverse effect on industrial production. Therefore, it is still not an ideal synthesis route.

[0019] Method three is a method for synthesizing Filgotinib disclosed in patent CN 104987333 A. The method uses 2-amino-6-chloropyridine (10) as a starting material, is protected by di-tert-butyl dicarbonate, and is hydrolyzed in a sodium hydroxide solution to obtain (6-hydroxypyridin-2-yl)carbamic acid tert-butyl ester (11). 11 is esterified with trifluoromethylsulfonic anhydride to obtain 2-tert-butyloxycarbonylamino-6-pyridyl trifluoromethanesulfonate (12). 12 is subjected to a Suzuki coupling reaction with intermediate 9, and then deprotected with trifluoroacetic acid to obtain 4-[4-(6-aminopyridin-2-yl)benzyl]thiomorpholine-1 ,1-dioxide (13), 13 is condensed with ethoxycarbonyl isothiocyanate to obtain 1-{4-[4-(6-aminopyridin-2-yl)benzyl]thiomorpholine-1,1-dioxide}-3-(ethoxycarbonyl)thiourea (14), 14 is cyclized with hydroxylamine hydrochloride to obtain 4-{4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl}thiomorpholine 1,1-dioxide (15), 15 is acylated with cyclopropylcarbonyl chloride to obtain the final product Filgotinib (1), the specific reaction is as follows.

[0020]

[0021] Reagent and conditions:a.①(Boc) 2 O,CH 2 Cl 2 ,60℃; ②NaOH,TBAC,Dioxane,H 2 O,95℃; b.Tf 2 O,Et 3 N, 0℃; c.①Pd(PPh 3 ) 2 Cl 2 ,K 2 CO 3 ,LiCl,Toluene,H 2 O,N 2 ,110℃;②TFA,rt;d.ClCH 2 CH 2 Cl,rt; e.NH 2 OH·HCl,DIPEA,CH 3 OH, 60℃; f.Et3 N,CHCl 3 ,(Et) 2 N, 70℃.

[0022] This method is still a linear synthesis route, which is exactly opposite to the connection order of method one. Its disadvantage is that the reaction route is longer, the cost of raw material 9 is high and its nature is unstable, repeated protection and deprotection steps are required in the route, each step of the reaction contains more by-products, the use of lithium chloride in Suzuki coupling is not safe enough, and chloroform and other highly toxic solvents are also used in the route. Therefore, it is not suitable for industrial promotion.

[0023] Method 4 is a method for synthesizing the JAK1 inhibitor Filgotinib in patent CN 110204542 A. The method uses 2-amino-6-bromopyridine (2) as a starting material, and undergoes a Suzuki coupling reaction with p-methylphenylboronic acid to obtain 6-(4-methylphenyl)-2-aminopyridine (16). 16 is condensed with ethoxycarbonyl isothiocyanate to obtain [6-(4-methylphenyl)pyridin-2-ylthiocarbamoyl]ethyl carbamate (17). 17 is cyclized with hydroxylamine hydrochloride to obtain 5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridine -2-amine (18), and then acylated with cyclopropylcarbonyl chloride to obtain N-(5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (19), 19 was brominated to obtain N-{5-[4-(bromomethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (7), and finally 7 was substituted with thiomorpholine-1,1-dioxide to obtain the final product Filgotinib (1). The specific reaction is as follows.

[0024]

[0025] Reagent and conditions:a.Pd(dppf)Cl 2 ,AcOK,Dioxane,H 2 O,N 2 ,reflux;b.AcOEt,50℃;c.NH 2 OH·HCl,DIPEA,C 2 H 5 OH, reflux; dK 2 CO 3 ,DMF,80℃;e.NBS,AIBN,CCl 4 ,reflux;fK 2 CO 3 ,DMF,80℃.

[0026] This method line is the same as the synthesis strategy of method 1, which is linear. The reaction steps are too long. Carbon tetrachloride and DMF are used as solvents in the route, which are relatively toxic. In addition, the bromination reaction has many side reactions, which easily produce more impurities and affect the purity of the final product. In addition, more three wastes are produced, the total yield is low, the raw material price is high, and the route process is difficult to scale up, so it cannot meet the needs of industrial production.

[0027] Method 5 is a new method for preparing Filgotinib in U.S. Patent US2020062744 A1, which uses 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (20) as a starting material, condenses with ethoxycarbonyl isothiocyanate to obtain 1-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine]-3-(ethoxycarbonyl)thiourea (21), and 21 is cyclized with hydroxylamine hydrochloride to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine 22 is acylated with cyclopropylcarbonyl chloride to obtain N-{5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (23), which is then subjected to Suzuki coupling reaction with 4-(4-bromobenzyl)thiomorpholine-1,1-dioxide to obtain the final product Filgotinib (1). The specific reaction is as follows.

[0028]

[0029] Reagent and conditions: a.CH 2 Cl 2 rt.; b.NH 2 OH·HCl,DIPEA,C 2 H 5 OH,CH 3 OH, reflux; c. ①Et 3 N,CH 3 CN, rt.; ②NH 3 ,CH 3 OH, rt.; d.Pd(dppf)Cl 2 ,K 2 CO 3 ,Dioxane,H 2 O,N 2 ,140℃.

[0030] This is a convergent route that shortens the reaction route and greatly reduces waste generation. However, the starting raw materials are inconvenient to source, the borate ester is unstable, and each subsequent step of the reaction retains the borate ester group, which easily produces more impurities and affects the purity of the final product. In addition, column chromatography purification is used multiple times in the route, and the overall reaction yield is low, making it unsuitable for industrial production.

[0031] By analyzing the above five synthesis methods, we found that the five reaction routes all use Suzuki coupling reaction for the construction of carbon-carbon bonds between aromatic rings. Methods 1 and 4 involve bromination reactions, which are prone to produce more impurities. Each step of the reaction in method 5 retains boric ester, and the reaction is difficult to control. The repeated protection and deprotection in method 3 increases the reaction steps and reduces the reaction yield, which is not suitable for industrial production. Method 2 has a higher synthesis efficiency, but the price of p-bromomethylphenyl borate (8) in the raw material is high and the properties are unstable. In view of this, the present invention is committed to developing a new synthesis route with cheap and easy-to-obtain reagents, short synthesis steps, simple operation, high yield, and cost advantages. Summary of the invention

[0032] The present invention aims to solve the problems of the prior art synthesis method for preparing Filgotinib, such as the difficulty in obtaining starting materials, harsh reaction conditions, and complicated process routes, and provides a synthesis method for Filgotinib.

[0033] To achieve the above purpose, the present invention adopts the following technical solution:

[0034] A synthesis method of filgotinib comprises the following steps: using p-bromobenzaldehyde (compound 1) as a starting material, subjecting the starting material to a boroesterification reaction with diboronic acid pinacol ester (compound 2) under palladium catalysis to obtain an intermediate 3; subjecting the intermediate 3 to a Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 4) to obtain an intermediate 5; reacting the intermediate 5 with thiomorpholine-1,1-dioxide (compound 6) to generate an intermediate 7; condensing the intermediate 7 with cyclopropylcarbonyl chloride (compound 8) and potassium thiocyanate (compound 9) to obtain an intermediate 10; and cyclizing the intermediate 10 with hydroxylamine hydrochloride (compound 11) to obtain a final product, filgotinib.

[0035] Further,

[0036] (1) p-Bromobenzaldehyde (Compound 1) and diboronic acid pinacol ester (Compound 2) undergo boroesterification reaction in the presence of a catalyst and a base to obtain intermediate 3:

[0037]

[0038] (2) In the presence of a base and a catalyst, the intermediate 3 obtained above was subjected to a Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 4) at 100°C to obtain intermediate 5:

[0039]

[0040] (3) Intermediate 5 is subjected to a reductive amination reaction with thiomorpholine-1,1-dioxide (compound 6) in the presence of a reducing agent to obtain intermediate 7:

[0041]

[0042] (4) Cyclopropylcarbonyl chloride (Compound 8) and potassium thiocyanate (Compound 9) are first subjected to a synthesis reaction and then subjected to a condensation reaction with Intermediate 7 to obtain Intermediate 10:

[0043]

[0044] (5) Under the action of a base, the intermediate 10 undergoes a cyclization reaction with hydroxylamine hydrochloride (compound 11) to obtain the product Filgotinib:

[0045]

[0046] In the step (1), compound 1, compound 2, base and catalyst are mixed in a molar ratio of 1:1-2:1-3:0.01-0.05, and reacted under nitrogen protection at 90° C. in the presence of a solvent to obtain an intermediate compound 3; the solvent is one or more of 1,4-dioxane, toluene, DMF, ethanol, and methanol; the catalyst is Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 ; The base is potassium acetate.

[0047] In the step (2), the compound 4, the intermediate 3, the base and the catalyst are mixed in a molar ratio of 1:1.0-1.5:2-3:0.01-0.05, and reacted under nitrogen protection at 100° C. in the presence of a solvent to obtain an intermediate 5; the solvent is 1,4-dioxane, DMSO, DMF or a mixture of toluene and water; the catalyst is Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 , the base is cesium carbonate.

[0048] In the step (3), the intermediate 5 and the compound 6 are mixed, dissolved in a solvent, and reacted for 30 minutes, a catalytic amount of an acid is added to the system and stirred for 30 minutes, and then a reducing agent is added to the reaction solution in batches, and the reaction is carried out at room temperature for 17 hours to obtain the intermediate 7; wherein the molar ratio of the intermediate 5, the compound 6 and the reducing agent is 1:1.1:2; the solvent is tetrahydrofuran, methanol, ethanol or acetonitrile; the catalyst is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; the reducing agent is sodium triacetoxyborohydride; and the acid is acetic acid or propionic acid.

[0049] In the step (4), compound 9 is dissolved in a solvent, and compound 8 is added thereto after dissolution, and the reaction is carried out at room temperature for 1 hour. After the reaction is completed, intermediate 7 is added and the reaction is carried out at 40° C. to obtain intermediate 10; wherein the molar ratio of intermediate 7, compound 8 and compound 9 is 1:1:1;

[0050] The solvent is acetone, acetonitrile, 1,4-dioxane, toluene or tetrahydrofuran.

[0051] In the step (5), compound 11 and the base are dissolved in a solvent, and after dissolution, intermediate 10 is added thereto, and the reaction is carried out at 60° C. to obtain the product Filgotinib; wherein the molar ratio of intermediate 10, compound 11 and base is 1:6:3; the solvent is methanol, ethanol, ethylene glycol, toluene, 1,4-dioxane or tetrahydrofuran; and the base is triethylamine and / or N,N-diisopropylethylamine.

[0052] The advantages of the present invention are:

[0053] The present invention uses p-bromobenzaldehyde as a starting material, and obtains the final product Filgotinib through boroesterification, Suzuki coupling, condensation, and cyclization. The original route is shortened during the synthesis process, and the reaction conditions are mild, the yield is high, the reaction type is mature, and the raw material source is wide and the price is low, which greatly reduces the cost. The synthesis method of the present invention solves the problems of the synthetic method of preparing Filgotinib in the prior art, such as the difficulty in obtaining the starting raw materials, the harsh reaction conditions, and the complicated process route. The synthetic route of the present invention is short, the materials used in the reaction are easy to obtain, and the reaction operation is simple. DETAILED DESCRIPTION

[0054] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0055] Example 1

[0056] Preparation of intermediate 3:

[0057]

[0058] Compound 1 (20 g, 108.1 mmol) and compound 2 (46.66 g, 183.77 mmol) were dissolved in 1,4-dioxane (300 mL), and then Pd(dppf)Cl was added under nitrogen protection. 2 (3.95 g, 5.41 mmol), potassium acetate (31.82 g, 324.3 mmol), react at 90 ° C for 2 h, after the reaction, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (15 mL), concentrated under reduced pressure, the remaining residue was diluted with water (50 mL), extracted with ethyl acetate 3 times (50 mL × 3), the organic layers were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, the desiccant was filtered and concentrated under reduced pressure to obtain a white solid intermediate 3 (23.5 g, yield 93.6%).

[0059] Example 2

[0060] Preparation of intermediate 3:

[0061] Compound 1 (20 g, 108.1 mmol) and compound 2 (46.66 g, 183.77 mmol) were dissolved in 1,4-dioxane (300 mL), and then Pd(PPh 3 ) 4 (6.25 g, 5.41 mmol), potassium acetate (31.82 g, 324.3 mmol), react at 90 ° C for 2 h, after the reaction, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (15 mL), concentrated under reduced pressure, the remaining residue was diluted with water (50 mL), extracted with ethyl acetate 3 times (50 mL × 3), the organic layers were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, the desiccant was filtered and concentrated under reduced pressure to obtain a white solid intermediate 3 (22.0 g, yield 87.6%).

[0062] Example 3

[0063] Preparation of intermediate 5:

[0064]

[0065] The intermediate 3 (22.8 g, 98.26 mmol) obtained in Example 1 and compound 4 (10 g, 57.8 mmol) were dissolved in 1,4-dioxane-water (v / v=4:1, 150 mL), and then cesium carbonate (56.49 g, 173.4 mmol) and Pd(dppf)Cl were added under nitrogen protection. 2(2.11 g, 2.8 mmol), react at 100 °C for 2.5 h, cool to room temperature, and concentrate under reduced pressure. The remaining residue was diluted with water (50 mL), extracted with ethyl acetate 3 times (30 mL × 3), the organic layers were combined, washed with water, dried over anhydrous sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain a light yellow solid intermediate 5 (10.4 g, yield 91.2%).

[0066] Example 4

[0067] Preparation of intermediate 5:

[0068] The intermediate 3 (22.8 g, 98.26 mmol) obtained in Example 1 and compound 4 (10 g, 57.8 mmol) were dissolved in DMF-water (v / v=4:1, 150 mL), and then cesium carbonate (56.49 g, 173.4 mmol), Pd(dppf)Cl 2 (2.11 g, 2.8 mmol), react at 100 °C for 2.5 h, cool to room temperature, and concentrate under reduced pressure. The remaining residue was diluted with water (50 mL), extracted with ethyl acetate 3 times (30 mL × 3), the organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered the desiccant, and concentrated under reduced pressure to obtain a light yellow solid intermediate 5 (9.4 g, yield 82.5%).

[0069] Example 5

[0070] Preparation of intermediate 5:

[0071] The intermediate 3 (22.8 g, 98.26 mmol) obtained in Example 1 and compound 4 (10 g, 57.8 mmol) were dissolved in toluene-water (v / v=4:1, 150 mL), and then cesium carbonate (56.49 g, 173.4 mmol) and Pd(dppf)Cl were added under nitrogen protection. 2 (2.11 g, 2.8 mmol), react at 100 °C for 2.5 h, cool to room temperature, and concentrate under reduced pressure. The remaining residue was diluted with water (50 mL), extracted with ethyl acetate 3 times (30 mL × 3), the organic layers were combined, washed with water, dried over anhydrous sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain a light yellow solid intermediate 5 (9.6 g, yield 84.4%).

[0072] Example 6

[0073] Preparation of intermediate 7:

[0074]

[0075] The intermediate 5 (8 g, 40.36 mmol) obtained in Example 3 and compound 6 (5.99 g, 44.40 mmol) were dissolved in THF (80 mL). After reacting for 30 min, a catalytic amount of acetic acid was added. After stirring for 30 min, sodium triacetoxyborohydride (17.1 g, 80.72 mmol) was added three times within 1 h at room temperature. The reaction was continued for 17 h, and water was added to quench the reaction. The mixture was extracted with dichloromethane 3 times (30 mL×3). The organic phases were combined, washed with water, and concentrated under reduced pressure to obtain a white solid intermediate 7 (10.8 g, yield 84.5%).

[0076] Example 7

[0077] Preparation of intermediate 7:

[0078] The intermediate 5 (8 g, 40.36 mmol) obtained in Example 3 and compound 6 (5.99 g, 44.40 mmol) were dissolved in acetonitrile (80 mL). After reacting for 30 min, a catalytic amount of acetic acid was added. After stirring for 30 min, sodium triacetoxyborohydride (17.1 g, 80.72 mmol) was added three times within 1 h at room temperature. The reaction was continued for 17 h, and water was added to quench the reaction. The mixture was extracted with dichloromethane 3 times (30 mL×3). The organic phases were combined, washed with water, and concentrated under reduced pressure to obtain a white solid intermediate 7 (9.6 g, yield 75.3%).

[0079] Example 8

[0080] Preparation of intermediate 7:

[0081] The intermediate 5 (8 g, 40.36 mmol) obtained in Example 3 and compound 6 (5.99 g, 44.40 mmol) were dissolved in THF (80 mL). After reacting for 30 min, a catalytic amount of acetic acid was added. After stirring for 30 min, sodium borohydride (3.1 g, 80.72 mmol) was added three times within 1 h at room temperature. The reaction was continued for 17 h, and water was added to quench the reaction. The mixture was extracted with dichloromethane 3 times (30 mL×3). The organic phases were combined, washed with water, and concentrated under reduced pressure to obtain a white solid intermediate 7 (3.0 g, yield 25.7%).

[0082] Example 9

[0083] Preparation of intermediate 10:

[0084]

[0085] Compound 9 (1.53 g, 15.8 mmol) was dissolved in acetone (50 mL), and compound 8 (1.65 g, 15.8 mmol) was slowly added dropwise at room temperature with stirring. The reaction was continued for 1 h. Intermediate 7 (5 g, 15.8 mmol) obtained in Example 6 was slowly added to the reaction system, and the reaction was continued at 60°C for 4 h. The reaction was cooled to room temperature, water was added to the reactant, filtered, the filter cake was washed with water, and dried to obtain a light yellow solid intermediate 10 (6.09 g, yield 86.7%).

[0086] Example 10

[0087] Preparation of intermediate 10:

[0088] Compound 9 (1.53 g, 15.8 mmol) was dissolved in 1,4-dioxane (50 mL), and compound 8 (1.65 g, 15.8 mmol) was slowly added dropwise at room temperature with stirring. The reaction was continued for 1 h. Intermediate 7 (5 g, 15.8 mmol) obtained in Example 6 was slowly added to the reaction system, and the reaction was continued at 60°C for 4 h. The reaction was cooled to room temperature, water was added to the reactant, filtered, the filter cake was washed with water, and dried to obtain a light yellow solid intermediate 10 (4.61 g, yield 65.7%).

[0089] Embodiment 11

[0090] Preparation of intermediate 10:

[0091] Compound 9 (1.53 g, 15.8 mmol) was dissolved in acetonitrile (50 mL), and compound 8 (1.65 g, 15.8 mmol) was slowly added dropwise at room temperature with stirring. The reaction was continued for 1 h. Intermediate 7 (5 g, 15.8 mmol) obtained in Example 6 was slowly added to the reaction system, and the reaction was continued at 60°C for 4 h. The reaction was cooled to room temperature, water was added to the reactant, filtered, the filter cake was washed with water, and dried to obtain a light yellow solid intermediate 10 (5.28 g, yield 75.1%).

[0092] Example 12

[0093] Preparation of the final product Filgotinib:

[0094]

[0095] Compound 11 (4.69 g, 67.5 mmol), triethylamine (3.42 g, 33.75 mmol), and methanol (50 mL) were stirred at room temperature for 1 h to completely dissolve. Intermediate 10 (5 g, 11.25 mmol) obtained in Example 9 was slowly added thereto, and ethylene glycol (20 mL) was added, and the reaction was continued at 60°C for 3 h, cooled to room temperature, and water was added to the reactant, and dichloromethane was extracted 3 times, the organic phases were combined, washed with water, and the organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a light yellow oil, which was purified by slurrying with ethyl acetate and filtered to obtain a white solid final product (3.76 g, yield 78.6%).

[0096] Example 13

[0097] Preparation of the final product Filgotinib:

[0098] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropylethylamine (3.36 g, 33.75 mmol), and methanol (50 mL) were stirred at room temperature for 1 h to completely dissolve. Intermediate 10 (5 g, 11.25 mmol) obtained in Example 9 was slowly added thereto, and ethylene glycol (20 mL) was added. The reaction was continued at 60°C for 3 h, cooled to room temperature, and water was added to the reactant. The mixture was extracted with dichloromethane 3 times, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a light yellow oily substance, which was purified by slurrying with ethyl acetate and filtered to obtain a white solid final product (3.12 g, yield 65.3%).

[0099] Embodiment 14

[0100] Preparation of the final product Filgotinib:

[0101] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropylethylamine (3.36 g, 33.75 mmol), and ethanol (50 mL) were stirred at room temperature for 1 h to completely dissolve. Intermediate 10 (5 g, 11.25 mmol) obtained in Example 9 was slowly added thereto, and ethylene glycol (20 mL) was added. The reaction was continued at 60°C for 3 h, cooled to room temperature, water was added to the reactant, and dichloromethane was extracted 3 times. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a light yellow oil, which was purified by slurrying with ethyl acetate and filtered to obtain a white solid final product (3.64 g, yield 76%).

[0102] Embodiment 15

[0103] Preparation of the final product Filgotinib:

[0104] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropylethylamine (3.36 g, 33.75 mmol), and 1,4-dioxane (50 mL) were stirred at room temperature for 1 h to completely dissolve. Intermediate 10 (5 g, 11.25 mmol) obtained in Example 9 was slowly added thereto, and ethylene glycol (20 mL) was added. The reaction was continued at 60°C for 3 h, cooled to room temperature, water was added to the reactant, and dichloromethane was extracted 3 times. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a light yellow oil, which was purified by slurrying with ethyl acetate and filtered to obtain a white solid final product (2.96 g, yield 61.9%).

[0105] Example 16

[0106] Preparation of the final product Filgotinib:

[0107] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropylethylamine (3.36 g, 33.75 mmol), and ethylene glycol (50 mL) were stirred at room temperature for 1 h to completely dissolve. Intermediate 10 (5 g, 11.25 mmol) obtained in Example 9 was slowly added thereto, and ethylene glycol (20 mL) was added, and the reaction was continued at 60°C for 3 h, cooled to room temperature, and water was added to the reactant, and dichloromethane was extracted 3 times, the organic phases were combined, washed with water, and the organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a light yellow oil, which was purified by slurrying with ethyl acetate and filtered to obtain a white solid final product (3.55 g, yield 74.3%).

[0108] The structure of the product Filgotinib obtained in the above example was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1 H-NMR (600 MHz, DMSO-d 6 )δ11.05(s,1H),7.99(d,J=8.2Hz,2H),7.75-7.65(m,2H),7.52(d,J=8.2Hz,2H),7.29(dd,J=6.7, 1.8Hz,1H),3.78(s,2H),3.22-3.09(m,4H),2.98-2.89(m,4H),2.03(br,s,1H),0.88-0.78(m,4H).

[0109] 13C-NMR(151MHz,DMSO)δ171.80,158.58,150.86,140.22,139.90,131.36,130.80,129.47,129.20,113.99,59.69,50.73,50.69,14.36,8.19.

[0110] ESI-HRMS(m / z):448.1434[M+Na] + 。

Claims

1. A method for synthesizing filgotinib, characterized in that: p-Bromobenzaldehyde (compound 1) is used as the starting material, and is subjected to a boroesterification reaction with diboronic acid pinacol ester (compound 2) under palladium catalysis to obtain intermediate 3, intermediate 3 is subjected to a Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 4) to obtain intermediate 5, intermediate 5 is reacted with thiomorpholine-1,1-dioxide (compound 6) to generate intermediate 7, intermediate 7 is condensed with cyclopropylcarbonyl chloride (compound 8) and potassium thiocyanate (compound 9) to obtain intermediate 10, and intermediate 10 is cyclized with hydroxylamine hydrochloride (compound 11) to obtain the final product Filgotinib.

2. The method for synthesizing filgotinib according to claim 1, characterized in that: (1) p-Bromobenzaldehyde (Compound 1) and diboronic acid pinacol ester (Compound 2) undergo boroesterification reaction in the presence of a catalyst and a base to obtain intermediate 3: (2) In the presence of a base and a catalyst, the intermediate 3 obtained above was subjected to a Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 4) at 100° C. to obtain intermediate 5: (3) Intermediate 5 is subjected to a reductive amination reaction with thiomorpholine-1,1-dioxide (compound 6) in the presence of a reducing agent to obtain intermediate 7: (4) Cyclopropylcarbonyl chloride (Compound 8) and potassium thiocyanate (Compound 9) are first subjected to a synthesis reaction and then subjected to a condensation reaction with Intermediate 7 to obtain Intermediate 10: (5) Under the action of a base, the intermediate 10 undergoes a cyclization reaction with hydroxylamine hydrochloride (compound 11) to obtain the product Filgotinib:

3. The method for synthesizing filgotinib according to claim 2, characterized in that: In the step (1), compound 1, compound 2, base and catalyst are mixed in a molar ratio of 1:1-2:1-3:0.01-0.05, and reacted under nitrogen protection at 90° C. in the presence of a solvent to obtain an intermediate compound 3; the solvent is one or more of 1,4-dioxane, toluene, DMF, ethanol, and methanol; the catalyst is Pd(dppf)Cl2, Pd(PPh3)4; and the base is potassium acetate.

4. The method for synthesizing filgotinib according to claim 2, characterized in that: The compound 4, the intermediate 3, the base and the catalyst in the step (2) are mixed in a molar ratio of 1:1.0-1.5:2-3:0.01-0.05, and reacted under nitrogen protection at 100° C. in the presence of a solvent to obtain an intermediate 5; the solvent is 1,4-dioxane, DMSO, DMF or a mixture of toluene and water; the catalyst is Pd(dppf)Cl2, Pd(PPh3)4, and the base is cesium carbonate.

5. The method for synthesizing filgotinib according to claim 2, characterized in that: In the step (3), the intermediate 5 and the compound 6 are mixed, dissolved in a solvent, and reacted for 30 minutes, a catalytic amount of acid is added to the system and stirred for 30 minutes, and then a reducing agent is added to the reaction solution in batches, and the reaction is carried out at room temperature for 17 hours to obtain the intermediate 7; wherein the molar ratio of the intermediate 5, the compound 6 and the reducing agent is 1:1.1:2; the solvent is tetrahydrofuran, methanol, ethanol or acetonitrile; the catalyst is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; and the reducing agent is sodium triacetoxyborohydride.

6. The method for synthesizing filgotinib according to claim 5, characterized in that: The acid is acetic acid or propionic acid.

7. The method for synthesizing filgotinib according to claim 2, characterized in that: In the step (4), compound 9 is dissolved in a solvent, and compound 8 is added thereto after dissolution, and the reaction is carried out at room temperature for 1 hour. After the reaction is completed, intermediate 7 is added and the reaction is carried out at 40° C. to obtain intermediate 10; wherein the molar ratio of intermediate 7, compound 8 and compound 9 is 1:1:1; The solvent is acetone, acetonitrile, 1,4-dioxane, toluene or tetrahydrofuran.

8. The method for synthesizing filgotinib according to claim 2, characterized in that: In the step (5), compound 11 and the base are dissolved in a solvent, and after dissolution, intermediate 10 is added thereto, and the reaction is carried out at 60° C. to obtain the product Filgotinib; wherein the molar ratio of intermediate 10, compound 11 and base is 1:6:3; the solvent is methanol, ethanol, ethylene glycol, toluene, 1,4-dioxane or tetrahydrofuran; and the base is triethylamine and / or N,N-diisopropylethylamine.

Images