Preparation method of pircetinib

Abstract

The invention discloses a preparation method of pircetinib. The pircetinib is prepared through the steps of condensation, coupling, hydrolysis and the like. Compared with a method in the prior art, the method has the advantages that the reaction temperature is low, the operation method is simple, the purity and the yield of the product are improved, and the industrial practicability is obvious; and the use of a highly toxic catalyst tributylamine is avoided, so that the method is green and environment-friendly and is beneficial to large-scale production.

Description

Technical Field

[0001] The invention relates to a method for preparing piricitinib, and belongs to the technical field of chemical drug synthesis. Background Art

[0002] Piricetinib, molecular formula C 18 H 22 N4O2, CAS No. 944118-01-8, the structure of piricitinib is shown in the figure below, the structure of the compound of formula V is shown:

[0003]

[0004] Picitinib is a JAK3 inhibitor indicated for the treatment of patients with rheumatoid arthritis who have an inadequate response to conventional therapies, including the prevention of structural joint damage.

[0005] JAK-3 kinase (Janus kinase 3), as a member of the tyrosine protein kinase family, is mainly expressed in immune cells and transmits signals through tyrosine phosphorylation after being activated by interleukins. The regulation of JAK-3 activity plays a key role in the treatment of various diseases. At present, there have been many related studies on inhibitors of this kinase, and several JAK-3 kinase inhibitors have entered clinical studies, showing good JAK-3 selectivity and inhibitory activity. Currently, there are 2 JAK3 inhibitors approved for marketing worldwide. In addition to piricitinib, the other is Pfizer's tofacitinib, which is a JAK1 / 2 / 3 inhibitor.

[0006] At present, the synthesis route reported in patent WO2007077949A1 and literature (Bioorganic & Medicinal Chemistry (2018), 26 (18), 4971-4983) is as follows:

[0007]

[0008] Among them, aminoadamantanol and pyridopyrrole ring need to undergo coupling reaction at a high temperature of 200°C to obtain pisitinib, and large-scale industrial equipment is difficult to achieve a high temperature of 200°C during the preparation process; the coupling reaction also uses highly toxic tri-n-butylamine as a catalyst for the reaction, which is highly corrosive, irritating and flammable, and tri-n-butylamine is very easy to leak at a high temperature of 200°C, which can easily cause poisoning of operators and cause serious environmental pollution; further, the product and its related intermediates are difficult to purify during the preparation process, resulting in poor reaction selectivity, low yield and low purity. In summary, the existing technology is difficult to be suitable for industrialization. Summary of the invention

[0009] In order to solve the above problems in the prior art, the present invention provides a method for preparing piricitinib. The method uses an alkali metal carbonate as a catalyst, avoids using highly toxic tri-n-butylamine as a catalyst, and changes the temperature of the preparation reaction, so that the reaction does not need to be carried out at a high temperature.

[0010] The preparation method disclosed by the invention has mild reaction conditions, low requirements on operating equipment, simple and convenient operation method, improves the purity and yield of the product, and has obvious industrial practicality; and avoids the use of highly toxic catalysts, is green and environmentally friendly, and is conducive to large-scale production.

[0011] The technical solution of the present invention is:

[0012] A method for preparing piricitinib, using 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (compound of formula I) as a starting material, and obtaining piricitinib through condensation reaction, coupling reaction, and hydrolysis reaction. The invention discloses a method for preparing piricitinib, comprising the following steps:

[0013] (1) dissolving the compound of formula I in an organic solvent, adding an acyl chloride in the presence of an acid binding agent, and condensing to obtain a compound of formula II;

[0014] (2) dissolving the compound of formula II in an organic solvent, adding the compound of formula III and carrying out a coupling reaction with an alkali metal carbonate as a catalyst to obtain a compound of formula IV;

[0015] (3) dissolving the compound of formula IV in an organic solvent and hydrolyzing it in the presence of an alkaline solution and a peroxide solution to obtain a compound of formula V, wherein the compound of formula V is piricitinib;

[0016] The reaction scheme described above is as follows:

[0017]

[0018] in,

[0019] The compound of formula I is 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile;

[0020] R is selected from -C(O)R 2 、-S(O)2R 2 ;

[0021] R 2 Selected from C1-C6 alkyl, substituted or unsubstituted phenyl.

[0022] Wherein, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, methanol, ethanol, and isopropanol; the acyl chloride is selected from one of benzenesulfonyl chloride and p-toluenesulfonyl chloride; the acid binding agent is selected from one of potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine; the alkali metal carbonate is selected from one of potassium carbonate, sodium carbonate, and calcium carbonate; the alkaline solution is selected from one of sodium hydroxide aqueous solution and potassium hydroxide aqueous solution; the peroxide solution is selected from one of hydrogen peroxide aqueous solution and urea hydrogen peroxide aqueous solution.

[0023] Further, the organic solvent is selected from one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; the acyl chloride is selected from one of benzenesulfonyl chloride and p-toluenesulfonyl chloride; the acid-binding agent is selected from one of potassium carbonate and diisopropylethylamine; the alkali metal carbonate is potassium carbonate; the alkaline solution is a sodium hydroxide aqueous solution; and the peroxide solution is a hydrogen peroxide aqueous solution. Further, the acid-binding agent is potassium carbonate.

[0024] Specifically, in the step (1), the compound of formula I is added to N,N-dimethylformamide or dichloromethane to dissolve, an acid binding agent and an acyl chloride are added, the temperature is raised to 20-30° C., the temperature is controlled and stirred for 2-3 hours, water is added, the temperature is controlled at 20-40° C., the mixture is stirred for 2-3 hours, the mixture is filtered and dried to obtain a compound of formula II.

[0025] Specifically, the step (2) is to add the compound of formula II into N-methylpyrrolidone to dissolve it, add the compound of formula III, heat it to 80-130° C. and stir it for 3-10 hours in the presence of an alkali metal carbonate, add water, crystallize it for 1-4 hours, then cool it to 20-30° C. and stir it for 1-4 hours, filter it, and dry it to obtain the compound of formula IV.

[0026] Specifically, the step (2) can also be: adding the compound of formula II to N,N-dimethylacetamide to dissolve, adding the compound of formula III, and continuously stirring in the presence of an alkali metal carbonate, heating to 80-130° C. and stirring for 3-10 hours, adding water, and continuing to stir for 20-30 minutes, then cooling the system to 20-30° C., continuing to stir for 1-2 hours, filtering, and drying to obtain the compound of formula IV.

[0027] Furthermore, in step (2), the temperature of the heating reaction is selected from 80 to 100° C., and further, the temperature of the heating reaction is selected from 80 to 90° C.; wherein the reactants in the reaction, such as the compound of formula II and the compound of formula III, can react completely to produce the compound of formula IV, and the impurities produced in the reaction of step (2) are small.

[0028] Furthermore, in step (2), the molar ratio of compound of formula II: compound of formula III: alkali metal carbonate is 1:1:(1-5), preferably 1:1:(1-3).

[0029] Specifically, in step (3), the compound of formula IV is added to dimethyl sulfoxide to dissolve, and then a 20-40% aqueous sodium hydroxide solution and a 20-30% aqueous hydrogen peroxide solution are added, the temperature is controlled at 20-50° C. and stirred for 4-10 hours, water is added for crystallization, and stirring is continued for 30-60 minutes, and then the system is temperature controlled at 10-30° C., stirred for 1-2 hours, filtered, and dried to obtain a compound of formula V, i.e., piricitinib.

[0030] Furthermore, in step (3), 2 to 8 equivalents of 20 to 40% aqueous sodium hydroxide solution and 2 to 8 equivalents of 20 to 30% aqueous hydrogen peroxide solution are added, preferably 2 to 6 equivalents of 20 to 40% aqueous sodium hydroxide solution and 2 to 6 equivalents of 20 to 30% aqueous hydrogen peroxide solution.

[0031] Furthermore, in steps (1)-(3), the adding of water is the addition of 100-400 ml of purified water; the filtering includes normal pressure filtration or reduced pressure filtration; and the drying is vacuum drying.

[0032] Furthermore, the amount of the organic solvent used in each of steps (1) to (3) is independently 100 to 400 ml.

[0033] The present invention is a method for preparing pilitinib, comprising the following specific steps:

[0034] (1) Add the compound of formula I to N,N-dimethylformamide and dissolve it. After adding the acid binding agent, control the temperature at 0-10°C and stir for 20-30 minutes. After adding the acid chloride, raise the temperature to 20-30°C and control the temperature and stir for 2-3 hours. Add purified water, control the temperature at 20-40°C and stir for 2-3 hours, filter and dry to obtain the compound of formula II.

[0035] (2) Add the compound of formula II obtained in step (1) into N-methylpyrrolidone to dissolve, add the compound of formula III, raise the temperature to 80-130° C. in the presence of an alkali metal carbonate, stir for 3-10 hours, add water to crystallize, then cool to 20-30° C., stir for 1-4 hours, filter, and dry to obtain a compound of formula IV.

[0036] (3) Add the compound of formula IV obtained in step (2) into dimethyl sulfoxide to dissolve, then add 2 to 6 equivalents of 20 to 40% aqueous sodium hydroxide solution and 2 to 6 equivalents of 20 to 30% aqueous hydrogen peroxide solution, control the temperature at 20 to 50° C. and stir for 4 to 10 hours, add water to crystallize, continue stirring for 30 to 60 minutes, then control the temperature at 10 to 30° C. and stir for 1 to 2 hours, filter and dry to obtain a compound of formula V.

[0037] Beneficial Effects

[0038] Compared with the prior art, the present invention has the following outstanding advantages and positive effects:

[0039] 1. The reaction temperature in the preparation process is significantly reduced, which is much lower than 200°C disclosed in the prior art. The reaction conditions are mild, the operation is simple, and industrialization is easy to achieve.

[0040] 2. In step (2), the use of highly toxic compounds as catalysts to catalyze the reaction is avoided. Instead, alkali metal carbonates are used as catalysts in the reaction, which reduces the toxicity of the reaction, improves operational safety, is friendly to humans and the environment, and is more environmentally friendly.

[0041] 3. The preparation method disclosed in the present invention not only avoids the use of highly toxic compounds as catalysts, but also greatly improves the purity and yield of the intermediates produced in the preparation and simplifies the post-processing operation.

[0042] 4. The preparation process produces fewer impurities and by-products, less waste, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 It is the high performance liquid chromatography (HPLC) spectrum of the compound of formula CTS obtained in the present invention, and the abscissa represents time in minutes. DETAILED DESCRIPTION

[0044] The present invention will be further described below with reference to the embodiments, but is not limited thereto.

[0045] Example 1

[0046] The specific reaction route is as follows:

[0047]

[0048] Steps:

[0049] (1) Add 35.5 g (0.20 mol) of the compound of formula I to 284 ml of N,N-dimethylformamide, stir and dissolve, add 55.2 g (0.40 mol) of potassium carbonate, stir for 20 to 30 minutes, control the temperature at 0 to 10° C., then add 41.9 g (0.22 mol) of p-toluenesulfonyl chloride in batches, then raise the temperature to 25° C., control the temperature at 25° C. and stir for 3 hours. After the reaction is complete, add 284 ml of purified water, control the temperature at 30° C., stir for 3 hours, filter and dry to obtain 64.6 g of the compound of formula II-A, with a purity of 98.6% and a yield of 97.4%;

[0050] 1 HNMR (400MHz, DMSO-d6): δ (ppm): 8.860 (s, 1H), 8.226 ~ 8.215 (d, J = 4.4, 1H), 8.047 ~ 8.016 (d ,J=12.4Hz,2H),7.467~7.447(d,J=8.0Hz,2H),7.033~7.023(d,J=4.0Hz,1H),2.359(S,3H)

[0051] (2) 60.0 g (0.18 mol) of the compound of formula II-A was added to 300 ml of N-methylpyrrolidone and stirred to dissolve. Then, 30.2 g (0.18 mol) of the compound of formula III and 37.4 g (0.27 mol) of potassium carbonate were added under stirring. After the addition was completed, the temperature was raised to 90° C. and the mixture was stirred for 6 hours. Then, 300 ml of water was added dropwise to the reaction solution to crystallize. After the addition was completed, the system was stirred at 70° C. for 30 minutes. Then, the system was cooled to 25° C. and stirred for 1.5 hours. The stirred system was filtered and the filter cake was dried under vacuum to obtain 74.6 g of the compound of formula CTS with a purity of 98.7% and a yield of 89.2%. The HPLC spectrum of the compound of formula CTS is shown in FIG. Figure 1 As shown;

[0052] 1 HNMR (400MHz, DMSO-d6): δ (ppm): 8.242 (s, 1H), 7.978 ~ 7.957 (d, J = 8.4Hz, 2H), 7.741~7.730(d,J=4.4Hz,1H),7.446~7.425(d,J=8.4Hz,2H),7.116~7.106(d, J=4.0Hz,1H),4.518(bs,1H),4.248~4.233(m,1H),2.334(s,3H),2.176(m,2H) ,2.032(m,1H),1.884~1.802(m,4H),1.653~1.624(m,4H),1.389~1.356(m,2H).

[0053] (3) 69.4 g (0.15 mol) of the compound of formula CTS was added to 350 ml of dimethyl sulfoxide and stirred to dissolve. Then, 100.0 g of a 30% aqueous sodium hydroxide solution and 70 ml of a 30% aqueous hydrogen peroxide solution were added, and the mixture was heated to 30° C. with stirring. The temperature was controlled and stirred for 5 hours. After the reaction was completed, 350 ml of water was added to the reaction system for crystallization. The mixture was stirred for 1 hour, and the temperature of the mixture was cooled to 15° C. and stirred for 1 hour. The stirred mixture was filtered and the filter cake was dried under vacuum to obtain 41.6 g of the compound of formula V, i.e., piricitinib, with a purity of 99.2% and a yield of 84.9%.

[0054] 1 HNMR (400MHz, DMSO-d6): δ (ppm): 11.438 (s, 1H), 10.101 ~ 10.081 (d, J = 8.0Hz, 1H), 8.369 (s, 1H), 7.742 (bs, 1H), 7.137 ~ 7.123 (m, 2H), 6.410 ~ 6 .397(m,1H),4.503(s,1H),4.144~4.123(m,1H),2.147(m,2H),2.052( m,1H),1.859~1.829(m,4H),1.702~1.626(m,4H),1.428~1.396(m,2H).

[0055] Example 2

[0056] Reaction route:

[0057]

[0058] Steps:

[0059] (1) 35.5 g (0.20 mol) of the compound of formula I was added to 284 ml of dichloromethane, stirred and dissolved, 38.8 g (0.30 mol) of diisopropylethylamine was added, the resulting solution was cooled to 5° C., and then 38.8 g (0.22 mol) of benzenesulfonyl chloride was added in batches, and then the temperature was raised to 25° C. and stirred at 25° C. for 2 hours. After the reaction was completed, 284 ml of saturated sodium carbonate aqueous solution was added to the reaction solution and stirred for 30 minutes. After standing, the reaction mixture was separated and the dichloromethane phase was concentrated under reduced pressure to obtain 60.6 g of the compound of formula II-B with a purity of 98.4% and a yield of 95.3%;

[0060] (2) 47.7 g (0.15 mol) of the compound of formula II-B was added to 238 ml of N,N-dimethylacetamide and stirred to dissolve. Then, 25.1 g (0.15 mol) of the compound of formula III and 32.0 g (0.23 mol) of potassium carbonate were added under stirring. After the addition was completed, the temperature was raised to 80° C. and the mixture was stirred for 10 hours. After the reaction was completed, 238 ml of water was added dropwise to the reaction solution for crystallization. After the addition was completed, the system was stirred at 70° C. for 30 minutes. Then, the system was cooled to 20-30° C. and stirred for 1.5 hours. The stirred system was filtered and the filter cake was dried under vacuum to obtain 54.7 g of the compound of formula IV-B with a purity of 98.9% and a yield of 81.3%.

[0061] (3) 44.8 g (0.10 mol) of the compound of formula IV-B was added to 224 ml of dimethyl sulfoxide and stirred to dissolve. Then, 70.0 g of a 30% aqueous sodium hydroxide solution and 40 ml of a 30% aqueous hydrogen peroxide solution were added, the temperature was raised to 40° C. with stirring, and the temperature was controlled and stirred for 6 hours. After the reaction was completed, 224 ml of water was added to the reaction system for crystallization. The stirring was continued for 1 hour, and then the mixed system was cooled to 15° C. and stirred for 1 hour. The stirred system was filtered and the filter cake was dried under vacuum to obtain 27.6 g of the compound of formula V with a purity of 99.3% and a yield of 84.5%.

Claims

1. A method for preparing piricitinib, characterized in that: The following steps are involved: (1) dissolving the compound of formula I in an organic solvent, adding an acyl chloride in the presence of an acid binding agent, and condensing to obtain a compound of formula II; (2) dissolving the compound of formula II in an organic solvent, adding the compound of formula III, and performing a coupling reaction with an alkali metal carbonate as a catalyst to obtain a compound of formula IV; (3) dissolving the compound of formula IV in an organic solvent and hydrolyzing it in the presence of an alkaline solution and a peroxide solution to obtain a compound of formula V; in, The compound of formula I is 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; The compound of formula V is piricitinib; R-select-C(O)R 2 , -S(O)2R 2 ; R 2 Selected from C1-C6 alkyl, substituted or unsubstituted phenyl.

2. A method for preparing piricitinib according to claim 1, characterized in that: The organic solvent is selected from one or a combination of two or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, methanol, ethanol, and isopropanol; the acyl chloride is selected from one of benzenesulfonyl chloride and p-toluenesulfonyl chloride; the acid binding agent is selected from one of potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine; the alkali metal carbonate is selected from one of potassium carbonate, sodium carbonate, and calcium carbonate; the alkaline solution is selected from one of sodium hydroxide aqueous solution and potassium hydroxide aqueous solution; the peroxide solution is selected from one of hydrogen peroxide aqueous solution and urea hydrogen peroxide aqueous solution.

3. A method for preparing piricitinib according to claim 2, characterized in that: The organic solvent is selected from one or a combination of two or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; the acid binding agent is selected from one of potassium carbonate and diisopropylethylamine; the alkali metal carbonate is potassium carbonate; the alkaline solution is a sodium hydroxide aqueous solution; and the peroxide solution is a hydrogen peroxide aqueous solution.

4. The method for preparing piricitinib according to claim 1, characterized in that: The following steps are involved: (1) Add the compound of formula I into N,N-dimethylformamide to dissolve, add an acid binding agent and an acyl chloride, heat to 20-30°C, control the temperature and stir for 2-3 hours, add water, control the temperature to 20-40°C and stir for 2-3 hours, filter and dry to obtain a compound of formula II.

5. The method for preparing piricitinib according to claim 1, characterized in that: The following steps are involved: (2) Add the compound of formula II to N-methylpyrrolidone to dissolve, add the compound of formula III, raise the temperature to 80-130° C. in the presence of an alkali metal carbonate, stir for 3-10 hours, add water to crystallize, then cool to 20-30° C., stir for 1-4 hours, filter, and dry to obtain the compound of formula IV.

6. The method for preparing piricitinib according to claim 1, characterized in that: The following steps are involved: (3) Add the compound of formula IV into dimethyl sulfoxide to dissolve, then add 20-40% sodium hydroxide aqueous solution and 20-30% hydrogen peroxide aqueous solution, control the temperature at 20-50° C. and stir for 4-10 hours, add water to crystallize, stir for 30-60 minutes, control the temperature of the system at 10-30° C., continue stirring for 1-2 hours, filter and dry to obtain the compound of formula V.

7. A method for preparing piricitinib according to claim 5, characterized in that: The temperature is raised to 80-100° C. and stirred for 6-8 hours.

8. A method for preparing piricitinib according to claim 6, characterized in that: Add 2 to 8 equivalents of 20 to 40% aqueous sodium hydroxide solution and 2 to 8 equivalents of 20 to 30% aqueous hydrogen peroxide solution.

Images