WO2023082839A1 - Filgotinib preparation method - Google Patents

Abstract

Disclosed in the present invention is a Filgotinib preparation method. The preparation method of the present invention comprises the following step: reacting a compound A (N-(5-Bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide) and a compound B (4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]thiomorpholine-1,1-dioxide) in a mixed solvent of an alcohol-based solvent and water in the presence of a palladium-based catalyst and alkali. The preparation method of the present invention has the advantages of being environmentally friendly, low in cost, easy to operate, high in product purity, low in impurity content, and conducive to industrialization and the like.

Description

A kind of preparation method of Filgotinib technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of Filgotinib.

Background technique

Filgotinib is a JAK1 inhibitor with the chemical name N-[5-[4-[(1,1-dioxo-4-thiomorpholinyl)methyl]phenyl][1,2,4]tri Azolo[1,5-A]pyridin-2-yl]cyclopropanecarboxamide, its chemical structural formula is:

Filgotinib is a novel once-daily oral JAK kinase inhibitor that preferentially inhibits JAK1. Approved by the European Commission and the Japanese Ministry of Health, Labor and Welfare,

(filgotinib maleate 200mg and 100mg tablets) was launched in the European Union and Japan in November 2020 for the treatment of rheumatoid arthritis (RA). In addition, the new indication application of the oral JAK1 inhibitor Jyseleca (filgotinib, 200mg) has been accepted by the European Medicines Agency (EMA) and has started review. The drug is intended for the treatment of: insufficient response to conventional therapy or biological therapy, loss of response or intolerant adult patients with moderate to severe ulcerative colitis (UC).

Filgotinib was first disclosed in the patent application publication number CN102105471A, and reported the following two synthetic routes:

route 2

Route 2 uses highly toxic phosphorus tribromide, which is not suitable for industrial production.

Route 1 uses the Suzuki reaction for the synthesis of Filgotinib. The catalyst causes higher Pd residues, and the solubility of Filgotinib is poor, making product purification difficult. In the patent application publication number CN102105471A, the target product is obtained by column chromatography, which is not suitable for industrial production. In the patent application publication number CN102482273A, the post-treatment method of route 1 is improved: compound B is added to the 1,4-dioxane/water (4/1) solution of compound A, and K ₂ CO is added to the solution ₃ (2eq.) and Pd(dppf) _Cl2 (0.03eq.). The resulting mixture was heated in a 90 °C oil bath for 16 hrs under _N2 atmosphere. After the reaction was completed, the Pd-removing reagent "1,2-di(diphenylphosphine)ethane" was added, and the reaction mixture was cooled and filtered. The filter cake was resuspended in acetone, stirred and washed, filtered, rinsed with acetone, and dried. And the obtained solid was suspended in water, added aqueous HCl, stirred at room temperature, and the resulting solution was filtered through celite. Then, NaOH aqueous solution was added to the filtrate, and the resulting suspension was stirred at room temperature, filtered with suction, and rinsed with water to obtain a crude product. Finally, the crude product was dissolved in THF/H ₂ O mixture, treated with Pd-removing reagent at 50°C, the suspension was filtered, concentrated to remove the organic solvent, water and methanol were added to the resulting slurry, stirred at room temperature, filtered, Dried to obtain Filgotinib.

The above-mentioned post-treatment process is cumbersome to operate, the reaction solvent 1,4-dioxane used is highly toxic, and the amount of catalyst used is relatively high. Moreover, due to the poor solubility of Filgotinib hydrochloride, the experimental operation is not easy to repeat. The by-product "impurity 1" produced by the reaction is not easy to be removed in the above process. In addition, because THF is prone to produce peroxide during storage, during the above-mentioned Pd removal operation, "impurity 2" is easy to be produced. The above two Impurities can affect the product purity of Filgotinib.

Therefore, there is an urgent need in this field to develop a process for preparing Filgotinib that is environmentally friendly, lower in cost, easier to operate, better in quality control, and suitable for scale-up production.

Contents of the invention

The technical problem to be solved by the present invention is to propose a preparation method of Filgotinib in view of the problems of unfriendly environment, cumbersome handling and low product purity in the preparation of Filgotinib in the prior art. The preparation method of the present invention has the advantages of environmental friendliness, low cost, simple and convenient operation, high product purity and favorable industrialization.

The invention provides a kind of preparation method of Filgotinib, it comprises the steps:

In a mixed solvent of alcohol solvent and water, in the presence of a palladium catalyst and a base, compound A and compound B are subjected to the following reaction to obtain Filgotinib;

The alcoholic solvent can be a conventional alcoholic solvent for this type of reaction in the art, preferably a C ₁ -C ₅ alcoholic solvent, more preferably one or more of methanol, ethanol and isopropanol.

In the mixed solvent, the volume ratio of the alcohol solvent to water can be conventional in the field, preferably 1:1-20:1, for example, 4:1 or 10:1.

The amount of the mixed solvent can be the usual amount used in this field for this type of reaction, and the volume molar ratio of the mixed solvent to the compound A is preferably 2.0-4.0 L/mol, for example, 2.78 L/mol.

The palladium catalyst can be a conventional palladium catalyst for this type of reaction in the art, preferably one or more of PddppfCl ₂ , Pd(PPh ₃ ) ₂ Cl ₂ and Pd(OAc) ₂ . The amount of the palladium catalyst can be the usual amount used in this field for this type of reaction, and the molar ratio of palladium catalyst to compound A is preferably 0.01-0.03.

The base may be a conventional base used in this type of reaction in the art, preferably an alkali metal carbonate and/or an alkali metal bicarbonate. The alkali metal is preferably one or more of sodium, potassium and cesium. The alkali metal carbonate is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The bicarbonate of alkali metal is preferably sodium bicarbonate and/or potassium bicarbonate.

The amount of the base used may be the conventional amount used in the field for this type of reaction, and the molar ratio of the base to the compound A is preferably 1.0-1.5, for example, 1.22.

The amount of compound B used may be the conventional amount used in this field for this type of reaction, and the molar ratio of compound B to compound A is preferably 0.9-1.2, for example, 1.03.

The reaction is preferably carried out in an atmosphere of protective gas. The protective gas is preferably nitrogen and/or argon.

The reaction temperature of the reaction is preferably 60-100°C, for example, 70-80°C.

The progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of compound A is generally used as the end point of the reaction. The reaction time may be 10-24 hours.

After the reaction is finished, preferably, post-processing is also included, and the post-processing preferably includes the following steps:

(1) after the reaction finishes, cool down, suction filter, obtain filter cake;

(2) At 65-80° C., after dissolving the filter cake in a mixed solvent of acetonitrile and water, mix it with a palladium-removing reagent, and filter with suction to obtain a filtrate; The volume molar ratio is preferably 15.0-20.0 L/mol, for example, 17.8 L/mol; in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile and water is preferably 2.0-8.0, for example, 7.0;

(3) Concentrate the filtrate to volume A, and suction filter at 0-10° C. to obtain the final product; the volume molar ratio of volume A to compound A is 6.0-13.0 L/mol (for example, 8.3-11.1 L /mol).

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The positive progress effect of the present invention is:

1. The preparation method of the present invention adopts the alcohol solvent with lower toxicity as the reaction solvent, the raw material conversion is complete, and the impurities generated are less;

2. Through nitrogen replacement, the formation of "impurity 1" can be effectively reduced, which is conducive to improving product purity;

3. The amount of catalyst used is less, which reduces the residual amount of Pd in the crude product, which is beneficial to reduce the residual amount of Pd in the product;

4. Using acetonitrile as a solvent in the Pd removal process can avoid the formation of "impurity 2" and help improve product purity;

5. The post-treatment process is simple and easy to operate, and the product yield is high.

Description of drawings

Figure 1 is the ¹ H NMR chart of Filgotinib prepared in Example 1.

Fig. 2 is the HPLC graph of the Filgotinib prepared in Example 1.

Detailed ways

The present invention will be explained in more detail below in conjunction with the examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention, and the spirit and scope of the present invention are not limited thereto. Percentages and parts are by weight unless otherwise indicated.

Pd residue detection method: Microwave digestion instrument with a power of 800W, climbed to 190°C in 30mins, and maintained the temperature for 40mins. Digested the sample, diluted the sample after digestion, and used an inductively coupled plasma mass spectrometer (ICP-MS) to detect Pd in the sample. content determination.

Example 1:

Compound A (75.0g, 0.27mol), Compound B (98.4g, 0.28mol), NaHCO ₃ (27.7g, 0.33mol), Pd(dppf)Cl ₂ (2.0g, 2.7mmol), ethanol (600mL) and Water (150 mL) was added into the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80° C. for 15-20 hrs, followed by HPLC until the reaction was complete.

The temperature of the reaction solution was lowered to 15-30° C., and stirred for 2-3 hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

Add the crude Filgotinib above to a reaction flask, add acetonitrile (4200mL) and water (600mL), heat to 65-80°C under stirring to obtain a clear solution, add palladium-removing reagent, keep stirring at 60-70°C, suction filter, filter cake Rinse with acetonitrile (75mL×2), concentrate to 2250mL-3000mL, drop to 0-10°C and stir for 1-2hrs. After suction filtration, the filter cake was rinsed with acetonitrile (150 mL×2) to obtain 98.5 g of a white solid with an HPLC purity of 99.7% and a yield of 86.8%. The content of impurity 1 is 0.14%, the content of impurity 2 is 0.05%, and the content of Pd is 2ppm, wherein the content of impurity 1 and impurity 2 is its actual weight percent in the compound measured by external standard method, and the following examples mention The content of impurity 1 and impurity 2 is determined in the same way.

The mass spectral data of Filgotinib obtained in this example are: ¹ H NMR (300 MHz, DMSO-d6): δ=11.03 (1H, s, NH), 7.99 (2H, d, 2ArH), 7.71～7.67 (2H, m ,2ArH),7.52(2H,d,2ArH),7.29(1H,dd,ArH),3.77(2H,s,CH ₂ ),3.15～3.3.13(4H,m,4CH),2.93～2.95(4H , m, 4CH), 2.03 (1H, br, CH), 0.81 (4H, d, 2CH ₂ ).

Example 2

Compound A (7.50g, 27mmol), Compound B (9.84g, 28mmol), K ₂ CO ₃ (4.55g, 33mmol), Pd(dppf)Cl ₂ (0.2g, 0.27mmol), isopropanol (60mL) and water (6 mL) were added to the reaction flask, and after nitrogen replacement, the temperature was raised to 80-90° C. to react for 10-15 hrs, followed by HPLC until the reaction was complete.

The temperature of the reaction solution was lowered to 15-30° C., and stirred for 2-3 hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

Add the crude Filgotinib above to a reaction flask, add acetonitrile (420mL) and water (60mL), heat to 65-80°C under stirring to obtain a clear solution, add palladium-removing reagent, keep stirring at 60-70°C, suction filter, filter cake Rinse with acetonitrile (7.5mL×2), concentrate to 225mL-300mL, drop to 0-10°C and stir for 1-2hrs. Suction filtration, the filter cake was rinsed with acetonitrile (15mL×2) to obtain 102.2g of white solid, the HPLC purity was 99.8%, the yield was 88.8%, the content of impurity 1 was 0.15%, the content of impurity 2 was 0.06%, and the content of Pd is 3ppm.

Example 3

Compound A (75.0g, 0.27mol), Compound B (98.4g, 0.28mol), NaHCO ₃ (27.7g, 0.33mol), Pd(dppf)Cl ₂ (6.0g, 8.1mmol), ethanol (600mL) and Water (150 mL) was added to the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80° C. for 15-20 hrs, followed by HPLC until the reaction was complete.

The temperature of the reaction solution was lowered to 15-30° C., and stirred for 2-3 hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

Add the crude Filgotinib above to a reaction flask, add acetonitrile (4200mL) and water (600mL), heat to 65-80°C under stirring to obtain a clear solution, add palladium-removing reagent, keep stirring at 60-70°C, suction filter, filter cake Rinse with acetonitrile (75mL×2), concentrate to 2250mL-3000mL, drop to 0-10°C and stir for 1-2hrs. Suction filtration, the filter cake was rinsed with acetonitrile (150mL×2) to obtain 96.0g of white solid, the HPLC purity was 99.7%, the yield was 84.6%, the content of impurity 1 was 0.17%, the content of impurity 2 was 0.07%, and the content of Pd is 25ppm.

Example 4

Compound A (75.0g, 0.27mol), Compound B (98.4g, 0.28mol), NaHCO ₃ (27.7g, 0.33mol), Pd(dppf)Cl ₂ (2.0g, 2.7mmol), ethanol (600mL) and Water (150 mL) was added into the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80° C. for 15-20 hrs, followed by HPLC until the reaction was complete.

The temperature of the reaction solution was lowered to 15-30° C., and stirred for 2-3 hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

Add the crude Filgotinib above to a reaction flask, add acetonitrile (3000mL) and water (600mL), heat to 65-80°C under stirring to obtain a clear solution, add palladium-removing reagent, keep stirring at 60-70°C, suction filter, filter cake Rinse with acetonitrile (75mL×2), concentrate to 2250mL-3000mL, drop to 0-10°C and stir for 1-2hrs. Suction filtration, the filter cake was rinsed with acetonitrile (150mL × 2) to obtain 98.5g of white solid, the HPLC purity was 99.7%, the yield was 86.8%, the content of impurity 1 was 0.17%, the content of impurity 2 was 0.06%, and the content of Pd is 18ppm.

Example 5

Compound A (75.0g, 0.27mol), Compound B (98.4g, 0.28mol), NaHCO ₃ (27.7g, 0.33mol), Pd(dppf)Cl ₂ (2.0g, 2.7mmol), ethanol (600mL) and Water (150 mL) was added into the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80° C. for 15-20 hrs, followed by HPLC until the reaction was complete.

The temperature of the reaction solution was lowered to 15-30° C., and stirred for 2-3 hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

Add the crude Filgotinib above to the reaction flask, add acetonitrile (4800mL) and water (600mL), heat to 65-80°C under stirring to obtain a clear solution, add palladium removal reagent, keep stirring at 60-70°C, suction filter, filter cake Rinse with acetonitrile (75mL×2), concentrate to 2250mL-3000mL, drop to 0-10°C and stir for 1-2hrs. Suction filtration, the filter cake was rinsed with acetonitrile (150mL×2) to obtain 98.5g of white solid, the HPLC purity was 99.7%, the yield was 86.8%, the content of impurity 1 was 0.17%, the content of impurity 2 was 0.06%, and the content of Pd is 26ppm.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (9)

1. A kind of preparation method of Filgotinib, it is characterized in that, it comprises the steps: in the mixed solvent of alcoholic solvent and water, in the presence of palladium catalyst and alkali, compound A and compound B are carried out the following reaction namely Filgotinib is available;

   
2. The preparation method according to claim 1, characterized in that, the alcohol solvent is a C ₁ -C ₅ alcohol solvent;

   And/or, the volume ratio of the alcohol solvent to water is 1:1-20:1;

   And/or, the volume molar ratio of the mixed solvent to compound A is 2.0-4.0 L/mol.
3. The preparation method according to claim 2, wherein the alcoholic solvent is one or more of methanol, ethanol and isopropanol.
4. The preparation method according to claim 1, wherein the palladium catalyst is one or more of PddppfCl ₂ , Pd(PPh ₃ ) ₂ Cl ₂ and Pd(OAc) ₂ ;

   And/or, the molar ratio of the palladium catalyst to compound A is 0.01-0.03.
5. The preparation method according to claim 1, wherein the alkali is alkali metal carbonate and/or alkali metal bicarbonate;

   And/or, the molar ratio of the base to compound A is 1.0-1.5.
6. preparation method as claimed in claim 5, is characterized in that,

   The alkali metal is one or more of sodium, potassium and cesium;

   And/or, the alkali metal carbonate is one or more of sodium carbonate, potassium carbonate and cesium carbonate;

   And/or, the alkali metal bicarbonate is sodium bicarbonate and/or potassium bicarbonate.
7. The preparation method according to claim 1, wherein the molar ratio of compound B to compound A is 0.9 to 1.2;

   And/or, described reaction is carried out in the atmosphere of protective gas;

   The reaction temperature of the reaction is preferably 60-100°C.
8. The preparation method according to claim 1, characterized in that, after the reaction, the reaction also includes post-processing, and the post-processing includes the following steps:

   (1) after the reaction finishes, cool down, suction filter, obtain filter cake;

   (2) at 65-80°C, after dissolving the filter cake in a mixed solvent of acetonitrile and water, mix it with a palladium-removing reagent, and filter with suction to obtain a filtrate; and

   (3) Concentrate the filtrate to volume A, and suction filter at 0-10° C. to obtain the final product; the volume molar ratio of volume A to compound A is 6.0-13.0 L/mol.
9. The preparation method according to claim 8, characterized in that the volume molar ratio of the mixed solvent of acetonitrile and water to compound A is 15.0-20.0 L/mol;

   And/or, in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile and water is 2.0-8.0.

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