CN110878097B - Preparation method of feigninib - Google Patents
Preparation method of feigninib Download PDFInfo
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- CN110878097B CN110878097B CN201911197230.0A CN201911197230A CN110878097B CN 110878097 B CN110878097 B CN 110878097B CN 201911197230 A CN201911197230 A CN 201911197230A CN 110878097 B CN110878097 B CN 110878097B
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Abstract
The preparation method of the phenanthroline britinib comprises the steps of directly carrying out suzuki coupling on compounds shown in formula 1 and 4-formylphenylboronic acid, then reacting with cyclopropyl formyl chloride to obtain a compound shown in formula 4, and then carrying out reductive amination reaction and hydrolysis on the compound and thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a phenanthroline britinib product 9; or the compound formula 1 is coupled with cyclopropyl formyl chloride, reacts with 4-formyl phenylboronic acid and then reacts with thiomorpholine 1, 1-dioxide for reductive amination to obtain a phenanthrene gatinib product 9. The method widens the range of the substrate, improves the route efficiency, reduces the process cost, reduces the generation of by-products by improving the crystallization performance of the intermediate, and is beneficial to improving the purity of the final finished product; the route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a selective inhibitor feigninib for treating rheumatoid arthritis JAK 1.
Background
Rheumatoid arthritis is a chronic inflammatory autoimmune disease. As the immune system attacks the synovium in the joint itself, inflammation and thickening of the synovium results, eventually leading to damage of the cartilage and bone in the joint. Rheumatoid arthritis may affect the functions of a plurality of joints of a patient, affects the lives of about 2370 thousands of people all over the world, and currently, specific medicines are still lacking. Fei Getinib (Filgotinib) is a JAK1 selective inhibitor, is used for treating autoimmune diseases and related inflammations, is discovered by Galapagos in Belgian and is studied in cooperation with Everovi, and then is successfully developed by combining a Gilidd catcher after the Everovi is withdrawn midway, so that the Fei Getinib (Filgotinib) has a good effect on treating various inflammatory diseases, particularly in multiple phase III clinical tests for treating rheumatoid arthritis. Currently, Jilidard has submitted a new drug application to the FDA, and once approved, the market prospect is wide.
The chemical name of the Feitetinib is as follows: n- [5- [4- [ (1, 1-dioxo-4-thiomorpholinyl) methyl ] phenyl ] [1,2,4] triazolo [1,5-a ] pyridin-2-yl ] cyclopropylcarboxamide, having the following structural formula:
US patent US20100331319 reports the synthetic route of feigninib, using 6-bromopyridine-2-amine to react with ethyl isothiocyanatecarboxylate, then cyclizing under the action of hydroxylamine hydrochloride to obtain 5-bromo- [1,2,4] triazolo [1,5-a ] pyridine-2-amine, further reacting with cyclopropyl formyl chloride to obtain an amide intermediate, coupling with Suzuki, bromination, and finally reacting with thiomorpholine 1, 1-dioxide to obtain the feigninib product, the route is shown below:
the method for synthesizing the feigninib has the advantages that the price of the starting raw material 6-bromo-2-aminopyridine is high, the steps of the route are too long, the side reactions of the bromination reaction are more, impurities are easily generated, the purity of the final product is influenced, the generation of three wastes is more, the total yield is low, the cost of the route is higher, and the process amplification is difficult.
The patent also mentions that phenanthritinib is prepared by a reductive amination method, but the reduction reaction requires the use of expensive sodium cyanoborohydride, is relatively expensive and has certain dangers in scale-up production, as follows:
in addition, the aldehyde intermediate is synthesized by the suzuki reaction using 5-bromo- [1,2,4] triazolo [1,5-a ] pyridin-2-amine and 4-formylphenylboronic acid, which is reported in Journal of Medicinal Chemistry 2014 57, 9323, and the coupling yield is only 74%, but the process is difficult to scale up by using 140 ℃ microwave reaction conditions:
in addition, another preparation method is reported in the patent, but the preparation method is optimized on the basis of a substrate and a linear reaction, the starting materials are expensive overall, the Suzuki coupling reaction is used in the last step, the palladium residue of the phenanthratinib is difficult to control, and an expensive palladium removing reagent is required. The route is as follows:
generally speaking, the methods for synthesizing the feigninib for the process production still have certain limitations, the route cost is high, the competitiveness is lacked, and the method which is simple in process route, low in cost and suitable for industrial production still needs to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for preparing feigninib, which has the advantages of simple preparation process route and low cost and is suitable for industrial production.
The invention relates to a preparation method of feigninib, which comprises two methods:
the method comprises the following steps:
the preparation method of the feigninib comprises the following steps:
(1) carrying out condensation reaction on the compound shown in the formula 3 and cyclopropyl formyl chloride to obtain an intermediate compound shown in the formula 4;
(2) carrying out reductive amination reaction on a compound shown in a formula 4 and a compound shown in a formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a compound shown in a formula 6;
(3) deprotecting the compound shown in formula 6 under the action of alkali to obtain a final product, namely a phenanthrene grittide compound shown in formula 9;
preferably, the base in step (1) is selected from diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; DMAP is selected without adding a catalyst or as the catalyst; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane; the reaction temperature is-15 to 55 ℃.
Preferably, the compound of formula 5 in the reductive amination in step (2) is thiomorpholine 1, 1-dioxide or its hydrochloride; no or no base is added, and the base is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the additive is selected from acetic acid, n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid, trifluoroacetic acid or boron trifluoride diethyl etherate; the reducing agent is selected from sodium borohydride, sodium borohydride acetate, triethylsilane, triisopropylsilane or tetramethyldisiloxane; the reaction solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene; the reaction temperature is-15 to 110 ℃.
Preferably, in the deprotection reaction in the step (3), the base is selected from ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide or potassium carbonate; the reaction solvent is selected from dichloromethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol, acetonitrile or water; the reaction temperature is-20 to 90 ℃.
The second method comprises the following steps:
the preparation method of the feigninib comprises the following steps:
(1) reacting 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound formula 1 with cyclopropyl formyl chloride to obtain a phenanthroline tinib intermediate compound formula 7;
(2) directly carrying out suzuki coupling on a compound shown in a formula 7 and a 4-formylphenylboronic acid compound shown in a formula 2 to obtain an intermediate compound shown in a formula 8;
(3) carrying out reductive amination reaction on a compound shown in a formula 8 and a compound shown in a formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a product, namely phenanthroline 9;
preferably, the base of step (1) is selected from diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane; the reaction temperature is-15 to 55 ℃.
Preferably, the coupling reaction catalyst in step (2) can be selected from palladium bis (triphenylphosphine) dichloride, bis (di-tert-butylphenyl) phosphine palladium dichloride, bis ((4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine palladium dichloride, chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) palladium or Pd (dppf) Cl2(ii) a The base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the reaction temperature is 20-130 ℃.
Preferably, the compound of formula 5 in the reductive amination in step (3) is thiomorpholine 1, 1-dioxide or its hydrochloride; no base is added or the base is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the additive is selected from acetic acid, n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid, trifluoroacetic acid or boron trifluoride diethyl etherate; the reducing agent is selected from sodium borohydride, sodium borohydride acetate, triethylsilane, triisopropylsilane or tetramethyldisiloxane; the reaction solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene; the reaction temperature is-15 to 110 ℃.
Another object of the present invention is to provide a feigninib intermediate compound formula 3 and a preparation method thereof:
the structural formula of the phenanthratinib intermediate compound shown in formula 3 is as follows:
a preparation method of a feigninib intermediate compound shown as formula 3 comprises the step of carrying out Suzuki coupling reaction on 5-halogenated- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound shown as formula 1 and a 4-formylphenylboronic acid compound shown as formula 2 under the action of a catalyst to obtain an intermediate compound shown as formula 3:
preferably, the coupling reaction catalyst may be selected from palladium bis (triphenylphosphine) dichloride, bis (di-tert-butylphenyl) phosphine palladium dichloride, bis ((4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine palladium dichloride, chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) palladium or Pd (dppf) Cl2(ii) a The base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the reaction temperature is 20-130 ℃.
More specifically;
the invention relates to a preparation method of feigninib, which comprises the following steps:
(1) directly carrying out suzuki coupling on 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound shown in formula 1 and 4-formylphenylboronic acid compound shown in formula 2 to obtain an intermediate compound shown in formula 3;
(2) reacting the compound shown in the formula 3 with two-molecule cyclopropyl formyl chloride to obtain a phenanthrene gatinib intermediate compound shown in the formula 4;
(3) carrying out reductive amination reaction on an intermediate compound shown in the formula 4 and a compound shown in the formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain an intermediate compound shown in the formula 6, and then directly obtaining a phenanthroline product compound shown in the formula 9 through hydrolysis;
or;
(1) reacting 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound formula 1 with one molecule of cyclopropyl formyl chloride to obtain a phenanthrene gatinib intermediate compound formula 7;
(2) directly carrying out suzuki coupling on a compound shown in a formula 7 and a 4-formylphenylboronic acid compound shown in a formula 2 to obtain an intermediate compound shown in a formula 8;
(3) carrying out reductive amination reaction on the intermediate compound shown in the formula 8 and a compound shown in the formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a phenanthroline product compound shown in the formula 9;
the route is as follows:
in the preparation method of the fei getinib, the 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound formula 1 with relatively low price is taken as a starting material, and is directly coupled with 4-formyl phenylboronic acid 2 to obtain an intermediate 3 or 8 after being derived directly or through cyclopropyl propionyl chloride, so that the mild condition and the high reaction yield are achieved. In the subsequent steps, reductive amination reaction conditions of aldehyde and the thiomorpholine dioxide or hydrochloride thereof are optimized, and the reaction yield is improved. We find that the intermediate compounds of formulas 4 and 6 not only have good crystallization performance, but also are beneficial to reducing reaction sites after the bicyclic propionyl protects amino, can effectively reduce the generation of byproducts, and are beneficial to improving the purity of a final product.
The method widens the range of the substrate, improves the route efficiency, reduces the process cost, has simple operation and mild reaction conditions, has higher total yield and higher purity of the obtained product, and is suitable for large-scale production.
The specific implementation mode is as follows:
the following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
A three-neck flask is added with a compound of formula 1(16.86g,100mmol), 4-formylphenylboronic acid (16.49g,110mmol), chlorine (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) palladium (360mg,0.5mmol) and N, N-dimethylacetamide (85mL), stirred and dissolved, added with potassium carbonate (27.64g, 200mmol) and 17mL of deionized water, vacuum-switched with nitrogen for 3 times, heated to 95-100 ℃ and reacted for 6-8 hours. After completion of the reaction, the reaction mixture was filtered through celite, and water (255mL) was added to the filtrate to precipitate a solid, which was then slurried, filtered and dried to obtain compound formula 3(21.87g, 91.8%).
MS(ESI)m/z＝239.1[M+H]+，1H NMR(400MHz,CDCl3)δ10.14(s,1H),8.13(d,J＝8.0Hz,2H),8.07(d,J＝8.1Hz,2H),7.51(m,2H),7.00(d,J＝6.8Hz,1H),4.68(s,2H).
As the chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) palladium used in example 1, ditriphenylphosphine palladium dichloride, bis (di-t-butylphenyl) phosphine palladium dichloride, ((4- (N, N-dimethylamino) phenyl) di-t-butylphosphine palladium dichloride or Pd (dppf) Cl was used2Replacing; the potassium carbonate can be replaced by triethylamine, diisopropylethylamine, sodium carbonate or potassium phosphate; the N, N-dimethylacetamide may be replaced by N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene.
Example 2
Adding a compound of formula 3(23.82g, 100mmol), triethylamine (20.24g,200mmol), DMAP (244mg,2mmol) and dichloromethane (119mL) into a reaction bottle, stirring to dissolve, cooling to 0-5 ℃, slowly dropping cyclopropanecarbonyl chloride (23.00g,220mmol), slowly raising the temperature to 25-30 ℃ after dropping, reacting for 8-12 hours, slowly adding 10% ammonium chloride solution to quench reaction (238mL), separating, adding dichloromethane (119mL) into a water phase to extract for 1 time, combining organic phases, washing for 1 time (60mL), concentrating until the organic phases are dry, adding petroleum ether (238mL), slowly cooling to crystallize, filtering, collecting a solid, and drying to obtain an intermediate compound of formula 4(34.86g, 93.1%).
MS(ESI)m/z＝375.2[M+H]+，1H NMR(400MHz,CDCl3)δ10.34(s,1H),8.36(d,J＝8.3Hz,2H),8.29(d,J＝8.3Hz,2H),8.05(m,1H),7.94(dd,J＝8.9,7.3Hz,1H),7.50(m,1H),2.32(td,J＝7.9,3.9Hz,2H),1.44(m,4H),1.16(m,4H).
In example 2, the triethylamine can be replaced by diisopropylethylamine, DBU, DABCO or N-methylmorpholine; the dichloromethane can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane; the catalyst DMAP may also be omitted from the reaction.
Example 3
Adding a compound of formula 4(37.44g,100mmol) and thiomorpholine 1, 1-dioxide 5a (16.70g,110mmol) into a three-neck flask, adding tetrahydrofuran (187mL), stirring for 1-2 hours, adding acetic acid (6.01g,100mmol), stirring for 30 minutes, cooling to 0-5 ℃, adding sodium borohydride acetate (25.43g,120mmol) in batches, stirring for 1 hour at room temperature, slowly heating to room temperature, and reacting for 12-18 hours. Part of the solvent was removed by evaporation, water (374mL) was added slowly and stirred, ethyl acetate (187mL) was added and extracted 2 times, the combined organic phases were washed 1 time with water (93mL), concentrated to dryness and petroleum ether (187mL) was added, crystallized under slow cooling, filtered and the solid collected to dryness to give intermediate 6(42.25g, 85.6%).
MS(ESI)m/z＝494.2[M+H]+，1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.1Hz,2H),7.76(d,J＝8.9Hz,1H),7.67(t,J＝8.1Hz,1H),7.50(d,J＝8.0Hz,2H),7.19(d,J＝7.1Hz,1H),3.74(s,2H),3.09(m,8H),2.09(m,2H),1.19(dd,J＝7.3,3.5Hz,4H),0.92(m,4H).
In example 3, compound 5a can be replaced by thiomorpholine 1, 1-dioxide hydrochloride and the corresponding base selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the acetic acid can be replaced by n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid, trifluoroacetic acid or boron trifluoride diethyl etherate, and the acetic acid can be omitted; sodium borohydride acetate can be replaced by sodium borohydride, triethylsilane, triisopropylsilane or tetramethyldisiloxane; the tetrahydrofuran can be replaced by ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene.
Example 4
Adding a compound of formula 1(16.86g,100mmol), diisopropylethylamine (19.39g,150mmol) and dichloromethane (84mL) into a reaction bottle, stirring to dissolve, cooling to 0-5 ℃, slowly dropping cyclopropane carbonyl chloride (11.50g,110mmol), slowly raising the temperature to 25-30 ℃ after dropping, and reacting for 4-6 hours. After the reaction was completed, the reaction was quenched by slowly adding 10% aqueous ammonia solution (169mL), the reaction solution was separated, the aqueous phase was extracted 2 times by adding dichloromethane (84mL), the combined organic phases were washed 1 time with water (84mL), concentrated to dryness and added with petroleum ether (168mL), crystallized by slow cooling, filtered, and the solid was collected and dried to obtain intermediate compound formula 7(22.34g, 94.4%).
MS(ESI)m/z＝237.1[M+H]+
In example 4, diisopropylethylamine can be replaced by triethylamine, DBU, DABCO or N-methylmorpholine; the dichloromethane can be replaced by N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane;
example 5
Adding a compound shown in formula 7(23.67g,100mmol), 4-formylphenylboronic acid (16.49g,110mmol), palladium (211mg,0.3mmol) and 1, 4-dioxane (237mL) into a three-neck flask, stirring to dissolve, adding potassium phosphate (31.84g, 150mmol) and 24mL of deionized water, switching nitrogen gas for 3 times in vacuum, heating to 95-100 ℃, and reacting for 6-8 hours. After completion of the reaction, the reaction mixture was filtered through celite, and water (237mL) was added to the filtrate to precipitate a solid, which was then slurried, filtered and dried to obtain compound formula 8(27.44g, 89.6%).
MS(ESI)m/z＝307.2[M+H]+。
Dichlorotriphenylphosphine Palladium dichloride in example 5 Chlorophos (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) Palladium, bis (di-t-butylphenyl) phosphine Palladium dichloride, ((4- (N, N-dimethylamino) phenyl) di-t-butylphosphine Palladium dichloride or Pd (dppf) Cl2Replacing; potassium phosphate can be replaced by triethylamine, diisopropylethylamine, sodium carbonate or potassium carbonate; the 1, 4-dioxane can be replaced by N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylacetamide, acetonitrile or toluene.
Example 6
Adding compound 6(49.36g,100mmol) and ethanol (247mL) into a three-neck flask, uniformly stirring, adding 25% ammonia water (34.06g,500mmol), reacting at room temperature for 6-8 hours, concentrating after the reaction is finished to remove part of solvent, adding 5% diluted hydrochloric acid to adjust the pH value to 6-7, slowly cooling to 0-5 ℃, pulping, filtering, and recrystallizing a crude product with ethanol and water to obtain a feignenib product 9(40.13g, 94.3%, purity 99.86%).
In example 6, the aqueous ammonia may be replaced by lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide or potassium carbonate; (ii) a The reaction solvent ethanol can be replaced by dichloromethane, 1, 4-dioxane, toluene, acetone, methanol, isopropanol, acetonitrile or water.
Example 7
A three-necked flask was charged with compound 8(30.63g,100mmol) and thiomorpholine 1, 1-dioxide hydrochloride 5b (18.88g,110mmol), acetonitrile (153mL) was added, triethylamine (12.14g,120mmol) was added, and after stirring for 1 to 2 hours, trifluoroacetic acid (22.80g,200mmol) was added, and after stirring for 30 minutes, triethylsilane (23.26g,200mmol) was added dropwise, and after stirring for 30 minutes at room temperature, the temperature was slowly raised to reflux reaction for 8 to 10 hours. And (3) after the reaction is finished, removing part of the solvent by spinning, slowly adding water (306mL), stirring, adding ethyl acetate (153mL) for extraction for 2 times, combining organic phases, washing for 1 time (77mL) by water, concentrating until the organic phases are dry, adding ethanol (153mL) and water (306mL), heating to 55-60 ℃, slowly cooling for crystallization, filtering, and collecting and drying solid to obtain the feigninib product 9(37.66g, 88.5% and 99.74% in purity).
In example 7 the hydrochloride salt of thiomorpholine 1, 1-dioxide may be replaced by thiomorpholine 1, 1-dioxide; triethylamine is not added or can be replaced by diisopropylethylamine or N-methylmorpholine; the trifluoroacetic acid can be replaced by acetic acid, n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid or boron trifluoride diethyl etherate; the triethylsilane can be replaced by sodium borohydride, sodium borohydride acetate, triisopropylsilane or tetramethyldisiloxane; the acetonitrile solvent can be replaced by ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene.
Claims (7)
1. The preparation method of the feigninib is characterized by comprising the following steps:
(1) carrying out condensation reaction on the compound shown in the formula 3 and cyclopropyl formyl chloride to obtain an intermediate compound shown in the formula 4;
(2) carrying out reductive amination reaction on a compound shown in a formula 4 and a compound shown in a formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a compound shown in a formula 6;
(3) deprotecting the compound shown in formula 6 under the action of alkali to obtain a final product, namely a phenanthrene grittide compound shown in formula 9;
2. the process for preparing feigninib according to claim 1, wherein the base used in step (1) is selected from diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; DMAP is selected without adding a catalyst or as the catalyst; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane; the compound shown in the formula 5 in the step (2) is thiomorpholine 1, 1-dioxide or hydrochloride thereof; the base is not added or is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; no additive or additive selected from acetic acid, n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid, trifluoroacetic acid or boron trifluoride diethyl etherate; adopting a reducing agent selected from sodium borohydride, sodium borohydride acetate, triethylsilane, triisopropylsilane or tetramethyldisiloxane; the reaction solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene; the alkali in the step (3) is selected from ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide or potassium carbonate; the reaction solvent is selected from dichloromethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol, acetonitrile or water.
3. The preparation method of the feigninib is characterized by comprising the following steps:
(1) reacting 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound formula 1 with cyclopropyl formyl chloride to obtain a phenanthroline tinib intermediate compound formula 7;
(2) directly carrying out suzuki coupling on a compound shown in a formula 7 and a 4-formylphenylboronic acid compound shown in a formula 2 to obtain an intermediate compound shown in a formula 8;
(3) carrying out reductive amination reaction on a compound shown in a formula 8 and a compound shown in a formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain a product, namely phenanthroline 9;
the base adopted in the step (1) is selected from diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile or 1, 4-dioxane; the catalyst adopted in the coupling reaction in the step (2) is selected from palladium bis (triphenylphosphine) dichloride, bis (di-tert-butylphenyl) phosphine palladium dichloride, bis ((4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine palladium dichloride and chlorine (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1 '-biphenyl) (2' -ammonia)1,1' -Biphenyl-3-yl) Palladium or Pd (dppf) Cl2(ii) a The base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the compound shown in formula 5 in the reductive amination reaction in the step (3) is thiomorpholine 1, 1-dioxide or hydrochloride thereof; the base is not added or is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the additive is selected from acetic acid, n-propionic acid, n-butyric acid, pivalic acid, isooctanoic acid, trifluoroacetic acid or boron trifluoride diethyl etherate; the reducing agent is selected from triethylsilane, triisopropylsilane or tetramethyldisiloxane; the reaction solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane or toluene.
4. The structural formula of the phenanthratinib intermediate compound shown in formula 3 is as follows:
5. the preparation method of the feigninib intermediate compound shown in formula 3 is characterized by comprising the step of carrying out Suzuki coupling reaction on 5-halogenated- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound shown in formula 1 and 4-formylphenylboronic acid compound shown in formula 2 under the action of a catalyst to obtain an intermediate compound shown in formula 3;
6. the method for preparing the phenanthroline intermediate compound shown in the formula 3 in the claim 5, wherein the catalyst used in the coupling reaction is selected from the group consisting of palladium bis (triphenylphosphine) dichloride, bis (di-tert-butylphenyl) phosphine palladium dichloride and bis ((4- (N, N-dimethylamino)Phenyl) di-tert-butylphosphine palladium dichloride, chloro (2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-3-yl) palladium or Pd (dppf) Cl2(ii) a The base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene.
7. The preparation method of the feigninib is characterized by comprising the following steps:
(1) directly carrying out suzuki coupling on 5-chloro- [1,2,4] triazolo [1,5-a ] pyridine-2-amine compound shown in formula 1 and 4-formylphenylboronic acid compound shown in formula 2 to obtain an intermediate compound shown in formula 3;
(2) reacting the compound shown in the formula 3 with two-molecule cyclopropyl formyl chloride to obtain a phenanthrene gatinib intermediate compound shown in the formula 4;
(3) carrying out reductive amination reaction on an intermediate compound shown in the formula 4 and a compound shown in the formula 5, namely thiomorpholine 1, 1-dioxide or hydrochloride thereof to obtain an intermediate compound shown in the formula 6, and then directly obtaining a phenanthroline product compound shown in the formula 9 through hydrolysis;
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| CN102482273A (en) * | 2009-06-26 | 2012-05-30 | 加拉帕戈斯股份有限公司 | 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors |
| WO2017133423A1 (en) * | 2016-02-02 | 2017-08-10 | 深圳市塔吉瑞生物医药有限公司 | Substituted picolinamide compound and use thereof |
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| CN102482273A (en) * | 2009-06-26 | 2012-05-30 | 加拉帕戈斯股份有限公司 | 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors |
| WO2017133423A1 (en) * | 2016-02-02 | 2017-08-10 | 深圳市塔吉瑞生物医药有限公司 | Substituted picolinamide compound and use thereof |
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| Christel J. Menet et al..Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634.《Journal of Medicinal Chemistry》.2014,第57卷 * |
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