A method for the synthesis of filgotinib

Abstract

The application belongs to the technical field of bulk drug preparation and relates to a synthesis method of Filgotinib. The synthesis method of Filgotinib takes bromobenzaldehyde (compound 1) as a starting material, and boron esterification reaction is carried out under the catalysis of palladium to obtain intermediate 3. Intermediate 3 is subjected to 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. Intermediate 10 is subjected to cyclization with hydroxylamine hydrochloride (compound 11) to obtain the final product Filgotinib. The synthesis method solves the problems of the prior art, such as difficulty in obtaining starting materials, harsh reaction conditions and complicated process route, and has the advantages of a short synthesis route, easy availability of materials used in the reaction and simple reaction operation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of bulk drug preparation, and relates to a synthetic method of filgotinib. BACKGROUND

[0002] Filgotinib is a JAK (Janus kinase) inhibitor for treating rheumatoid arthritis. It can be used as a single drug treatment or in combination with methotrexate and other drugs. It is developed by Galapagos NV and Gilead Science Company. In December 2020, Filgotinib was approved in Japan, the United Kingdom, the European Union and other places for treating adult patients with moderate to severe rheumatoid arthritis and insufficient response or intolerance to one or more disease-modifying antirheumatic drugs.

[0003] The Chinese reference translation name of Filgotinib is: Filgotinib

[0004] Trade name: Jyseleca

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

[0006] Relative molecular mass: 425.5;

[0007] Molecular formula: C 21 H 23 N5O3S;

[0008] Structural formula:

[0009]

[0010] The existing synthetic method of Filgotinib is:

[0011] The first method is the synthetic process route disclosed in international patent WO 2010149769 A1. 2-amino-6-bromopyridine (2) is used as the starting material, condensed with ethoxycarbonylisothiocyanate to obtain 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea (3), then cyclized with hydroxylamine hydrochloride to obtain 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (4), acylated with cyclopropylcarbonyl chloride to obtain N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (5), and then subjected to Suzuki coupling with p-hydroxymethylphenylboronic acid to obtain N-{5-[4-(hydroxymethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (6), and then subjected to bromination to obtain N-{5-[4-(bromomethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}cyclopropylcarboxamide (7), and finally subjected to substitution reaction with thiomorpholine-1,1-dioxide to obtain the final product Filgotinib (1). The specific reactions are as follows.

[0012]

[0013] Reagent and conditions: a. CH2Cl2, r.t.; b. NH2OH·HCl, DIPEA, C2H5OH, CH3OH, reflux; c. ① Et3N, CH3CN, r.t.; ② NH3, CH3OH, r.t.; d. Pd(dppf)Cl2, K2CO3, Dioxane, H2O, N2, 90℃; e. PBr3, CHCl3, r.t.; f. DIPEA, CH2Cl2, CH3OH, N2, r.t.

[0014] This route has a wide source of raw materials, but belongs to the straight-line synthesis strategy, has many reaction steps, low total yield, and the operation of post-treatment is too cumbersome. 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 the solvent in the route, which is highly toxic and is not conducive to industrialization.

[0015] The second method is a 5-phenyl-[1,2,4]triazolo[1,5-A]pyridine-2-carboxamide compound as a JAK inhibitor in CN102482273A, which takes 2-amino-6-bromopyridine (2) as a starting material, and condenses with ethoxycarbonylisothiocyanate to obtain 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea (3), and 3 is cyclized with hydroxylamine hydrochloride to obtain 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-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); p-bromomethylphenylboronic acid ester (8) is used as a raw material, and substitution reaction is carried out with thiomorpholine-1,1-dioxide to obtain intermediate 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiomorpholine-1,1-dioxide (9), and Suzuki coupling reaction is carried out between intermediate 9 and 5 to obtain the final product Filgotinib (1), and the specific reaction is as follows.

[0016]

[0017] Reagent and conditions: a. CH2Cl2, r.t.; b. NH2OH·HCl, DIPEA, C2H5OH, CH3OH, reflux; c. ① Et3N, CH3CN, r.t.; ② NH3, CH3OH, r.t.; d. DIPEA, CH2Cl2, CH3OH, N2, r.t.; e. Pd(dppf)Cl2, K2CO3, Dioxane, H2O, N2, 90℃.

[0018] Compared with method one, although the convergent synthesis strategy shortens the reaction route, greatly reduces the generation of waste, and has high synthesis efficiency, the p-bromomethylphenylboronic acid ester (8) in the raw material is high in price and unstable in nature, which has certain adverse effects on industrial production, and is still not an ideal synthesis route.

[0019] Method three is a synthesis method of Filgotinib in patent CN 104987333 A. The method takes 2-amino-6-chloropyridine (10) as a starting material, protects it by di-tert-butyl dicarbonate, hydrolyzes it in sodium hydroxide solution to obtain tert-butyl (6-hydroxypyridin-2-yl) carbamate (11), esterifies 11 with trifluoromethyl sulfonic anhydride to obtain 2-tert-butoxycarbonylamino-6-pyridyl triflate (12), performs Suzuki coupling reaction on 12 with intermediate 9, and then deprotects it with trifluoroacetic acid to obtain 4-[4-(6-aminopyridin-2-yl)benzyl]thiomorpholine-1,1-dioxide (13), condenses 13 with ethoxycarbonyl isothiocyanate to obtain 1-{4-[4-(6-aminopyridin-2-yl)benzyl]thiomorpholine-1,1-dioxide}-3-(ethoxycarbonyl) thiourea (14), performs cyclization on 14 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), and performs acylation reaction on 15 with cyclopropylcarbonyl chloride to obtain the final product Filgotinib (1). The specific reactions are as follows.

[0020]

[0021] Reagent and conditions: a. ① (Boc)2O, CH2Cl2, 60℃; ② NaOH, TBAC, Dioxane, H2O, 95℃; b. Tf2O, Et3N, 0℃; c. ① Pd(PPh3)2Cl2, K2CO3, LiCl, Toluene, H2O, N2, 110℃; ② TFA, r.t.; d. ClCH2CH2Cl, r.t.; e. NH2OH·HCl, DIPEA, CH3OH, 60℃; f. Et3N, CHCl3, (Et)2N, 70℃.

[0022] This method is also a straight-line synthesis route, and the connection order is just the opposite of method one. The disadvantage is that the reaction route is longer, the cost of raw material 9 is high and the property is unstable, repeated protection and deprotection steps are needed in the route, each reaction contains more by-products, lithium chloride is not safe enough when performing Suzuki coupling, and chloroform and other solvents with high toxicity are also used in the route, so it is also not suitable for industrialization promotion.

[0023] Method four is a synthesis method of a JAK1 inhibitor Filgotinib in patent CN 110204542 A. The method takes 2-amino-6-bromopyridine (2) as a starting material, and performs Suzuki coupling reaction with p-tolylboronic acid to obtain 6-(4-methylphenyl)-2-aminopyridine (16). 16 is condensed with ethoxycarbonylisothiocyanate to obtain [6-(4-methylphenyl)pyridin-2-ylthio carbamoyl] ethyl carbamate (17). 17 is cyclized with hydroxylamine hydrochloride to obtain 5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (18). Then acylation reaction is performed with cyclopropylcarbonyl chloride to obtain N-(5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarbamide (19). Bromination reaction is performed on 19 to obtain N-{5-[4-(bromomethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl} cyclopropylcarbamide (7). Finally, substitution reaction is performed on 7 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)Cl2, AcOK, Dioxane, H2O, N2, reflux; b. AcOEt, 50℃; c. NH2OH·HCl, DIPEA, C2H5OH, reflux; d. K2CO3, DMF, 80℃; e. NBS, AIBN, CCl4, reflux; f. K2CO3, DMF, 80℃.

[0026] The method line is linear like the synthesis strategy of method one, the reaction steps are too long, carbon tetrachloride and DMF are used as solvents in the route, which are toxic, and the byproduct reaction of bromination is more, which is easy to produce more impurities, affecting the purity of the final product. In addition, more three wastes are produced, the total yield is low, the price of raw materials is high, the route process amplification is difficult, and therefore it cannot meet the needs of industrial production.

[0027] Method five is a new method for preparing Filgotinib in US2020062744 A1, which takes 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (20) as the starting material, condenses with ethoxycarbonylisothiocyanate to obtain 1-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine]-3-(ethoxycarbonyl)thiourea (21), 21 cyclizes with hydroxylamine hydrochloride to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (22), 22 acylates 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), and then performs 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. CH2Cl2 rt.; b. NH2OH·HCl, DIPEA, C2H5OH, CH3OH, reflux; c. ① Et3N, CH3CN, rt.; ② NH3, CH3OH, rt.; d. Pd(dppf)Cl2, K2CO3, Dioxane, H2O, N2, 140℃.

[0030] This is a convergent route, which shortens the reaction route and greatly reduces waste generation, but the source of the starting material is not convenient, the borate ester is unstable, and each subsequent reaction retains the borate ester group, which is easy to produce more impurities, affecting the purity of the final product, and column chromatography is used multiple times in the route, the total reaction yield is low, and it is not suitable for industrial production.

[0031] By analyzing the above five synthesis methods, we find that the five reaction routes all use Suzuki coupling reaction for the construction of carbon-carbon bond between aromatic rings, method one and method four involve bromination reaction, which is easy to produce more impurities. Each step of method five retains boronic ester, and the reaction is not easy to control. In method three, repeated protection and deprotection increase the reaction steps, reduce the reaction yield, and are not suitable for industrial production. Method two has high synthesis efficiency, but the raw material p-bromomethylphenyl boronic acid ester (8) is high in price and unstable in nature. Therefore, the present application is dedicated to developing a new synthesis route which is cheap and easy to obtain, short in synthesis steps, simple in operation, high in yield and has cost advantage. SUMMARY

[0032] The present application aims to solve the problems of the prior art in preparing Filgotinib, such as difficult to obtain starting materials, harsh reaction conditions, and complicated process route, and provides a synthesis method of Filgotinib.

[0033] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0034] A synthesis method of Filgotinib, p-bromobenzaldehyde (compound 1) is used as a starting material, and boron esterification reaction is carried out under the catalysis of palladium to obtain intermediate 3, Suzuki coupling reaction is carried out between intermediate 3 and 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 ring closure is carried out between intermediate 10 and hydroxylamine hydrochloride (compound 11) to obtain the final product Filgotinib.

[0035] Further,

[0036] (1) p-bromobenzaldehyde (compound 1) and pinacol diboron (compound 2) are subjected to boron esterification reaction under the action of a catalyst and a base to obtain intermediate 3:

[0037]

[0038] (2) under the action of a base and a catalyst, intermediate 3 obtained above is subjected to Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 4) at 100 degrees to obtain intermediate 5:

[0039]

[0040] (3) intermediate 5 is subjected to reductive amination reaction with thiomorpholine-1,1-dioxide (compound 6) under the action 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) intermediate 10 is subjected to a ring and reaction with hydroxylamine hydrochloride (compound 11) under the action of a base to obtain product Filgotinib:

[0045]

[0046] In step (1), compound 1, compound 2, a base and a catalyst are mixed in a molar ratio of 1:1-2:1-3:0.01-0.05, and are subjected to a reaction under the protection of nitrogen and at 90°C in the presence of a solvent to obtain intermediate compound 3 after the reaction; the solvent is one or more of 1,4-dioxane, toluene, DMF, ethanol and methanol; the catalyst is Pd(dppf)Cl2 or Pd(PPh3)4; and the base is potassium acetate.

[0047] In step (2), compound 4, intermediate 3, a base and a catalyst are mixed in a molar ratio of 1:1.0-1.5:2-3:0.01-0.05, and are subjected to a reaction under the protection of nitrogen and at 100°C in the presence of a solvent to obtain intermediate 5 after the reaction; the solvent is a mixture of 1,4-dioxane, DMSO, DMF or toluene and water; the catalyst is Pd(dppf)Cl2 or Pd(PPh3)4; and the base is cesium carbonate.

[0048] In step (3), intermediate 5 is mixed with compound 6, is dissolved in a solvent and is reacted for 30 min, a catalytic amount of acid is added to the system and is stirred for 30 min, and then a reducing agent is added to the reaction liquid in batches, and is reacted at room temperature for 17 h to obtain intermediate 7 after the reaction; the molar ratio of intermediate 5, 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 step (4), compound 9 is dissolved in a solvent, compound 8 is added thereto after the dissolution, and is reacted at room temperature for 1 h, and then intermediate 7 is added after the reaction, and is reacted at 40°C to obtain intermediate 10; 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] The compound 11 in the step (5) is dissolved with a base in a solvent, after dissolution, the intermediate 10 is added thereto, and reaction is carried out at 60 DEG C, to obtain the product Filgotinib; wherein, the molar ratio of the intermediate 10, the compound 11 and the 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-diisopropyl ethylamine.

[0052] The present application has the advantages of:

[0053] The present application takes p-bromobenzaldehyde as a starting material, and obtains the end product Filgotinib through boron esterification, Suzuki coupling, condensation and cyclization. The synthesis process shortens the original route, and has the advantages of mild reaction conditions, high yield, mature reaction type, wide source of raw materials and low price, thereby greatly reducing the cost. The synthesis method of the present application solves the problems of the prior art, such as difficulty in obtaining starting materials, harsh reaction conditions and complicated process route. The synthesis route of the present application is short, the materials used in the reaction are easy to obtain, and the reaction operation is simple. DETAILED DESCRIPTION

[0054] The embodiments of the present application are described in detail below. The embodiments are implemented on the premise of the technical scheme of the present application, and detailed implementation modes and specific operation processes are given. However, the protection scope of the present application is not limited to the following embodiments.

[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), then Pd(dppf)Cl2(3.95 g, 5.41 mmol) and potassium acetate (31.82 g, 324.3 mmol) were added under nitrogen protection, and reaction was carried out at 90 DEG C for 2 h. After reaction, the system was cooled to room temperature, diatomite was filtered, washed with dichloromethane (15 mL), concentrated under reduced pressure, the remaining residue was diluted with water (50 mL), extracted with ethyl acetate for 3 times (50 mL x 3), the organic layers were combined, washed with water (50 mL), dried with anhydrous sodium sulfate, filtered and dried, and then concentrated under reduced pressure to obtain 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), compound 2 (46.66 g, 183.77 mmol) were dissolved in 1,4-dioxane (300 mL), then Pd(PPh3)4(6.25 g, 5.41 mmol), potassium acetate (31.82 g, 324.3 mmol) were added under nitrogen protection, and the reaction was carried out at 90 °C for 2 h. After the reaction, the system was cooled to room temperature, filtered with diatomite, washed with dichloromethane (15 mL), concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate for 3 times (50 mL x 3), combined the organic layers, washed with water (50 mL), dried with anhydrous sodium sulfate, filtered and dried, and concentrated under reduced pressure to obtain white solid intermediate 3 (22.0 g, yield 87.6%).

[0062] Example 3

[0063] Preparation of intermediate 5:

[0064]

[0065] Intermediate 3 (22.8 g, 98.26 mmol) obtained from Example 1, compound 4 (10 g, 57.8 mmol) were dissolved in 1,4-dioxane-water (v / v = 4:1, 150 mL), then cesium carbonate (56.49 g, 173.4 mmol), Pd(dppf)Cl2(2.11 g, 2.8 mmol) were added under nitrogen protection, and the reaction was carried out at 100 °C for 2.5 h. After cooling to room temperature, it was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate for 3 times (30 mL x 3), combined the organic layers, washed with water, dried with anhydrous sodium sulfate, filtered and dried, and concentrated under reduced pressure to obtain yellowish solid intermediate 5 (10.4 g, yield 91.2%).

[0066] Example 4

[0067] Preparation of intermediate 5:

[0068] Intermediate 3 (22.8 g, 98.26 mmol) obtained from Example 1, compound 4 (10 g, 57.8 mmol) were dissolved in 1,4-dioxane-water (v / v = 4:1, 150 mL), then cesium carbonate (56.49 g, 173.4 mmol), Pd(dppf)Cl2(2.11 g, 2.8 mmol) were added under nitrogen protection, and the reaction was carried out at 100 °C for 2.5 h. After cooling to room temperature, it was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate for 3 times (30 mL x 3), combined the organic layers, washed with water, dried with anhydrous sodium sulfate, filtered and dried, and concentrated under reduced pressure to obtain yellowish solid intermediate 5 (10.4 g, yield 91.2%).

[0069] Example 5

[0070] Preparation of intermediate 5:

[0071] Intermediate 3 (22.8 g, 98.26 mmol) obtained from example 1, compound 4 (10 g, 57.8 mmol) were dissolved in toluene-water (v / v = 4:1, 150 mL), then cesium carbonate (56.49 g, 173.4 mmol), Pd(dppf)Cl2(2.11 g, 2.8 mmol) were added under nitrogen protection, and the reaction was carried out at 100°C for 2.5 h. After cooling to room temperature, the remaining residue was diluted with water (50 mL), extracted with ethyl acetate three times (30 mL x 3), the organic layers were combined, washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure after filtering the drying agent. A light yellow solid intermediate 5 (9.6 g, yield 84.4%) was obtained.

[0072] Example 6

[0073] Preparation of intermediate 7:

[0074]

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

[0076] Example 7

[0077] Preparation of intermediate 7:

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

[0079] Example 8

[0080] Preparation of intermediate 7:

[0081] Intermediate 5 obtained from example 3 (8 g, 40.36 mmol), compound 6 (5.99 g, 44.40 mmol) were dissolved in THF (80 mL), after 30 min catalytic amount of acetic acid was added, after 30 min of stirring, sodium borohydride (3.1 g, 80.72 mmol) was added in three portions in 1 h at room temperature, the reaction was continued for 17 h, the reaction was quenched with water, extracted with dichloromethane three times (30 mL x 3), the organic phases were combined, washed with water, concentrated under reduced pressure to obtain intermediate 7 as a white solid (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), compound 8 (1.65 g, 15.8 mmol) was added slowly dropwise under stirring at room temperature, after the dropwise addition was completed, the reaction was continued for 1 h. Intermediate 7 obtained from example 6 (5 g, 15.8 mmol) was added slowly to the reaction system, the reaction was continued for 4 h at 60 °C, the reaction was cooled to room temperature, water was added to the reaction, the filter cake was washed with water, dried to obtain intermediate 10 as a light yellow solid (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), compound 8 (1.65 g, 15.8 mmol) was added slowly dropwise under stirring at room temperature, after the dropwise addition was completed, the reaction was continued for 1 h. Intermediate 7 obtained from example 6 (5 g, 15.8 mmol) was added slowly to the reaction system, the reaction was continued for 4 h at 60 °C, the reaction was cooled to room temperature, water was added to the reaction, the filter cake was washed with water, dried to obtain intermediate 10 as a light yellow solid (4.61 g, yield 65.7%).

[0089] Example 11

[0090] Preparation of intermediate 10:

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

[0092] Example 12

[0093] Preparation of the end product Filgotinib:

[0094]

[0095] Compound 11 (4.69 g, 67.5 mmol), triethylamine (3.42 g, 33.75 mmol), methanol (50 mL) were stirred at room temperature for 1 h to make it completely dissolved. Intermediate 10 (5 g, 11.25 mmol) obtained from Example 9 was added slowly to it and glycol (20 mL) was added. The reaction was allowed to proceed for 3 h at 60 °C. The reaction mixture was cooled to room temperature and water was added to the reaction mixture. The organic layer was extracted with dichloromethane three times. The organic layer was combined and washed with water. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to obtain a light yellow oil. The product was purified by slurry in ethyl acetate and filtered to obtain the end product (3.76 g, 78.6% yield) as a white solid.

[0096] Example 13

[0097] Preparation of the end product Filgotinib:

[0098] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropylethylamine (3.36 g, 33.75 mmol), methanol (50 mL) were stirred at room temperature for 1 h to make it completely dissolved. Intermediate 10 (5 g, 11.25 mmol) obtained from Example 9 was added slowly to it and glycol (20 mL) was added. The reaction was allowed to proceed for 3 h at 60 °C. The reaction mixture was cooled to room temperature and water was added to the reaction mixture. The organic layer was extracted with dichloromethane three times. The organic layer was combined and washed with water. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to obtain a light yellow oil. The product was purified by slurry in ethyl acetate and filtered to obtain the end product (3.12 g, 65.3% yield) as a white solid.

[0099] Example 14

[0100] Preparation of the end product Filgotinib:

[0101] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropyl ethylamine (3.36 g, 33.75 mmol), 1,4-dioxane (50 mL) were stirred at room temperature for 1 h to make it completely dissolved. Intermediate 10 obtained from example 9 (5 g, 11.25 mmol) was slowly added to it, added ethylene glycol (20 mL) and continued the reaction at 60 °C for 3 h, cooled to room temperature, added water to the reaction, extracted with dichloromethane 3 times, combined the organic phase, washed with water, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure after removing the drying agent, obtained a light yellow oil, purified by slurry with ethyl acetate, filtered, obtained the final product as a white solid (2.96 g, 61.9% yield).

[0102] Example 15

[0103] Preparation of end product Filgotinib:

[0104] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropyl ethylamine (3.36 g, 33.75 mmol), 1,4-dioxane (50 mL) were stirred at room temperature for 1 h to make it completely dissolved. Intermediate 10 obtained from example 9 (5 g, 11.25 mmol) was slowly added to it, added ethylene glycol (20 mL) and continued the reaction at 60 °C for 3 h, cooled to room temperature, added water to the reaction, extracted with dichloromethane 3 times, combined the organic phase, washed with water, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure after removing the drying agent, obtained a light yellow oil, purified by slurry with ethyl acetate, filtered, obtained the final product as a white solid (2.96 g, 61.9% yield).

[0105] Example 16

[0106] Preparation of end product Filgotinib:

[0107] Compound 11 (4.69 g, 67.5 mmol), N,N-diisopropyl ethylamine (3.36 g, 33.75 mmol), 1,4-dioxane (50 mL) were stirred at room temperature for 1 h to make it completely dissolved. Intermediate 10 obtained from example 9 (5 g, 11.25 mmol) was slowly added to it, added ethylene glycol (20 mL) and continued the reaction at 60 °C for 3 h, cooled to room temperature, added water to the reaction, extracted with dichloromethane 3 times, combined the organic phase, washed with water, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure after removing the drying agent, obtained a light yellow oil, purified by slurry with ethyl acetate, filtered, obtained the final product as a white solid (2.96 g, 61.9% yield).

[0108] The product Filgotinib obtained in the above examples was confirmed for structure by mass spectrometry and nuclear magnetic resonance, and the results were as follows: 1H-NMR (600 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.75-7.65 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.29 (dd, J = 6.7, 1.8 Hz, 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] 13 C-NMR (151 MHz, DMSO) δ 171.80, 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: (1) p-Bromobenzaldehyde (Compound 1) and diboronic acid pinacol ester (Compound 2) undergo boroesterification reaction in the presence of palladium catalyst and 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 undergoes 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 condensed with intermediate 7 to obtain intermediate 10: ； (5) Under the action of a base, intermediate 10 undergoes a cyclization reaction with hydroxylamine hydrochloride (compound 11) to obtain the product filgotinib: 。 2. The method for synthesizing filgotinib according to claim 1, wherein: In the step (1), compound 1, compound 2, a base and a 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 or Pd(PPh3)4; and the base is potassium acetate.

3. The method for synthesizing filgotinib according to claim 1, wherein: 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 at 100° C. in the presence of a solvent under nitrogen protection to obtain the intermediate 5; the solvent is 1,4-dioxane, DMSO, DMF or a mixture of toluene and water; the catalyst is Pd(dppf)Cl2 or Pd(PPh3)4, and the base is cesium carbonate.

4. The method for synthesizing filgotinib according to claim 1, wherein: In the step (3), intermediate 5 and 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. Then, a reducing agent is added to the reaction solution in batches and reacted at room temperature for 17 hours to obtain intermediate 7. The molar ratio of intermediate 5, compound 6, and reducing agent is 1:1.1:

2. The solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile. The reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride.

5. The method for synthesizing filgotinib according to claim 4, wherein: The acid is acetic acid or propionic acid.

6. The method for synthesizing filgotinib according to claim 1, wherein: In step (4), compound 9 is dissolved in a solvent, and compound 8 is added thereto after dissolution, and the mixture is reacted at room temperature for 1 hour. After the reaction, intermediate 7 is added thereto, and the mixture is reacted 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.

7. The method for synthesizing filgotinib according to claim 1, wherein: 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