CN111217819B - Synthetic method of sepiatinib - Google Patents
Synthetic method of sepiatinib Download PDFInfo
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- CN111217819B CN111217819B CN201811422977.7A CN201811422977A CN111217819B CN 111217819 B CN111217819 B CN 111217819B CN 201811422977 A CN201811422977 A CN 201811422977A CN 111217819 B CN111217819 B CN 111217819B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a synthetic method of Upactinib, which is characterized in that a compound 1 is used as an initial raw material, a compound formula 4 is obtained through chlorination, coupling, hydrolysis and hydrogenation salification, and then a midbody compound 6 is obtained through derivatization and halogenation by using Maillard acid. Next, we utilized 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ]]The pyrazine compound 7 is used as a raw material, and an intermediate compound 9 is obtained through ammonolysis reaction and amino protection. The chemical formula 10 is obtained by the butt-joint reaction of the compound 6 and the compound 9, and the key parent nucleus 11 of the lapatinib is obtained by utilizing trifluoroacetic anhydride to form a ring. And finally, the docking reaction of trifluoroethylamine is optimized, and the product of the Upactinib is obtained by two methods. These improvements greatly improve the route efficiency, reduce the process steps of using noble metal catalysts, reduce the process cost, and greatly reduce the generation of secondary products, which is beneficial to improving the purity of the final finished product. The route is as follows:
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a synthetic method for preparing lapatinib.
Background
In the early 2018, the once daily oral JAK1 selective inhibitor, uppatinib (ABT-494), developed by ebervine (AbbVie) usa, for the treatment of severe atopic dermatitis in adults, received FDA breakthrough therapy approval. Atopic dermatitis, also called allergic dermatitis or allergic eczema, has common symptoms including itching, redness, and chapped skin. The inflammation area is often drained of clear liquid, the liquid is concentrated along with the longer inflammation time, the initial attack is often seen in infants, about 20% of asthma children can simultaneously suffer from the disease, the atopic dermatitis symptom can last from years to tens of years, and the pathogenesis is still unknown at present. The current treatment options for atopic dermatitis patients are extremely limited and addressing the needs of these patients is crucial to both the medical and pharmaceutical communities. Ebervib indicates that empferitinib will be pushed as soon as possible into phase III clinical studies in atopic dermatitis treatment and, if successful, will have great market prospects.
The chemical name of the empatinib is as follows: (3S,4R) -3-ethyl-4- (3H-pyrazolo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) -N- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide, the structural formula is as follows:
US patent US2017129902 reports a synthetic method of uppatinib, which is characterized in that the raw material for synthesizing the key chiral acid intermediate (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-carboxylic acid is expensive, the synthetic steps are long, and two times of palladium catalytic hydrogenation is needed; in addition, the chiral resolution yield is low, the enantiomer of the chiral resolution yield cannot be utilized, and the synthesis cost is high; according to another key intermediate of the ipatinib, namely tert-butyl (5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine-2-yl) carbonate, in the synthesis steps of the patent route, multi-step reactions need to be catalyzed by palladium, and the current market price is high; in the subsequent reaction, sodium hydride is required for the butt-joint reaction of two key intermediates, a lawson reagent which is expensive in price and has stink and sulfur is required for the cyclization reaction, the process amplification has certain difficulty and the total yield is low; the CBZ removal and Ts protection group use strong acid and alkali conditions, side reactions are more, so that the final finished product is difficult to purify, and the reaction route is as follows:
PCT patent WO2017066775A discloses an improved synthetic method of lapatinib, optimizes the synthetic route of lapatinib key chiral acid intermediate (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formic acid, and converts the butted fragment into ethyl (5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] -pyrrole]Pyrazin-2-yl) carbonate, and optimizes the cyclization process, reduces experimental steps and improves route yield. But the key chiral acid intermediate and ethyl (5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] are synthesized]Pyrazin-2-yl) carbonates use relatively high-value reagents such as ethylboric acid, palladium acetate and Pd (dppf) Cl2CatalysisAgents, etc., the synthesis cost is still high, and the route is shown as follows:
therefore, a route with simpler steps, simple process amplification operation, lower process cost and higher yield needs to be searched for producing the Upactinib.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a new synthetic method of Upactinib and a key intermediate thereof, and the method has the advantages of simple process route, low cost and suitability for industrial production.
In order to realize the purpose of the invention, the invention firstly provides an Upacitorib key intermediate compound shown as formula 9 and a synthetic method thereof, wherein the compound shown as formula 9 has the following structural formula:
wherein R is2Is methyl or 4-tolyl.
A method for synthesizing a key intermediate compound of uppatinib, formula 9, comprising the steps of:
(1) carrying out ammonolysis on the compound shown in the formula 7 by using ammonia water under the catalysis of copper to obtain an intermediate compound shown in a formula 8;
(2) protecting hydroxyl of the compound shown in the formula 8 with sulfonyl in an alkaline system to obtain an intermediate compound shown in the formula 9;
wherein R is2Is methyl or 4-tolyl.
Preferably, the copper catalyst in step 1 is selected from cuprous iodide, cuprous bromide, cuprous oxide, cupric bromide or cupric chloride, etc.; the ligand is not added or is selected from acetylacetone, L-proline, TMEDA or 2- (methylamino) ethanol, etc.; the added alkali is selected from sodium carbonate, potassium carbonate or cesium carbonate, etc.; the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1, 4-dioxane or toluene; the reaction temperature is 50-140 ℃.
Preferably, the sulfonyl protection reaction adopts methylsulfonyl chloride or p-toluenesulfonyl chloride as a sulfonylation reagent; the base is selected from triethylamine, diisopropylethylamine, DMAP or pyridine, etc.; the reaction solvent is selected from dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene. The reaction temperature is-10 to 50 ℃.
The invention also provides a synthetic method of the Upacitorib key intermediate compound 6, which adopts the following technical scheme:
a method for synthesizing a key intermediate compound of uppatinib, formula 6, comprising the steps of:
(1) chloridizing a 1- ((benzyloxy) carbonyl) -4-oxo-pyrroline-3-carboxylate compound shown in a formula 1 under the action of triethylamine and phosphorus oxychloride to obtain a compound shown in a formula 2;
(2) carrying out coupling reaction on the compound shown in the formula 2 and an ethyl Grignard reagent under the catalysis of nickel, and hydrolyzing the compound shown in the formula 2 under the action of sodium hydroxide to obtain an intermediate compound shown in the formula 3;
(3) carrying out hydrogenation reaction on a compound shown in a formula 3 under the catalysis of chiral ruthenium, and salifying the compound with chiral 1-phenylethylamine to obtain an intermediate compound shown in a formula 4;
(4) separating the compound shown in the formula 4 under the action of hydrochloric acid, reacting the separated compound with thionyl chloride or oxalyl chloride to obtain an acyl chloride compound, and then performing condensation reaction with wheat straw acid to obtain an intermediate 5;
(5) carrying out halogenation reaction on the compound shown in the formula 5 in an acid system and carrying out acidolysis and decarboxylation by a one-pot method to obtain an intermediate 6;
wherein X represents bromine or chlorine.
Preferably, the coupling reaction ethyl grignard reagent is selected from ethyl magnesium bromide or ethyl magnesium chloride; the catalyst is selected from nickel salt such as bis triphenylphosphine nickel dichloride, nickel dichloride or nickel acetate; the selected reaction solvent is benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane, etc.; the reaction temperature is-20 to 110 ℃;
preferably, in the hydrogenation reaction in the step 3, the ruthenium catalyst is [ Ru (C) ]6H6)Cl2]2The ligand is S-Sunphos; the added alkali is selected from triethylamine, diisopropylethylamine, DBU, DABCO and the like; the reaction solvent is selected from methanol, ethanol or isopropanol, etc.; the hydrogen pressure is 0.2-6.0 Mpa; the reaction temperature is 0-90 ℃; s-1-phenylethylamine or R-1-phenylethylamine is selected for salt formation; the salifying solvent is selected from methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, toluene or methyl tertiary butyl ether and a mixed solvent of the methanol, the ethanol, the isopropanol, the acetonitrile, the ethyl acetate, the isopropyl acetate and the toluene; the salifying temperature is-20 to 90 ℃.
Preferably, the alkali for condensation reaction with wheat straw acid is selected from triethylamine, diisopropylethylamine, DBU, N-methylmorpholine, DMAP and the like; the condensation reaction solution is selected from dichloromethane, 1, 2-dichloroethane, acetonitrile, toluene or tetrahydrofuran; the reaction temperature is-20 to 90 ℃;
preferably, in the halogenation reaction in the step 5, the halogenating agent is selected from chlorosuccinimide, sulfonyl chloride, liquid bromine, bromosuccinimide, dibromohydantoin, or the like; no additive is added or acetic anhydride or trifluoroacetic anhydride is selected as an additive; the solution is selected from acetic acid, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixed solvent; the decarboxylated acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid, etc.; the reaction temperature is-20 to 90 ℃;
the invention also aims to provide a synthesis method of the Upacatinib key mother nucleus compound shown in formula 11, which adopts the following technical scheme:
a method for synthesizing a key parent nucleus compound of uppatinib as shown in formula 11, comprising the following steps:
(1) carrying out condensation reaction on a compound shown in a formula 6 and a compound shown in a formula 9 under proper conditions to obtain an intermediate compound shown in a formula 10;
(2) cyclizing the compound shown in the formula 10 under the action of trifluoroacetic anhydride and organic base, and deprotecting under the action of inorganic base to obtain an intermediate compound shown in the formula 11;
preferably, the base used in the condensation reaction is potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU, DABCO or the like; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or acetone, etc. The reaction temperature is generally-10 to 110 ℃.
Preferably, in the cyclization reaction in the step 2, the base is selected from triethylamine, diisopropylethylamine, pyridine or 2, 6-dimethylpyridine, etc.; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, etc.; the deprotection base is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide and the like; the reaction temperature is-20 to 110 ℃;
the fourth purpose of the invention is to provide two synthetic methods of the lapatinib, which adopt the following technical scheme:
method 1
The synthetic method of the lapatinib comprises the following steps:
(1) carrying out urethane exchange reaction on the compound formula 11 and trifluoroethylamine under the action of an additive and alkali to obtain an Upactinib compound 12;
preferably, the urethane exchange reaction additive is selected from trifluoromethanesulfonic anhydride, boron trifluoride diethyl etherate or trimethylaluminum, etc.; the base is selected from triethylamine, diisopropylethylamine, pyridine, 2-chloropyridine or 2, 6-dichloropyridine; the reaction solvent is selected from dichloromethane, 1, 2-dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene. The reaction temperature is-10 to 110 ℃.
Method two
The synthetic method of the lapatinib comprises the following steps:
(1) protecting compound formula 11 with Boc anhydride under the action of base to obtain compound formula 13
(2) Hydrogenating the compound 13 under the catalytic action of palladium carbon to remove CBZ protection to obtain a compound formula 14;
(3) carrying out condensation reaction on a compound shown in a formula 14 and trifluoroethylamine under the reaction of carbonyl diimidazole to obtain a compound shown in a formula 15;
(4) heating the compound 15 in butanol to remove Boc protection to obtain an Upactinib product 12;
preferably, the condensation reaction base in step (3) is selected from potassium carbonate, sodium carbonate, cesium carbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU, DABCO or the like; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene and the like; the reaction temperature is-10 to 110 ℃.
In the second method, the compound of formula 13, the compound of formula 14 and the compound of formula 15 are novel compounds.
The invention relates to a synthetic method of Upacitinib, which is characterized in that a compound 1- ((benzyloxy) carbonyl) -4-oxopyrroline-3-carboxylic ester 1 is used as an initial raw material, chlorination is carried out under the action of phosphorus oxychloride, then the product is coupled with an ethyl Grignard reagent under the action of a nickel catalyst, and hydrolysis is carried out to obtain an intermediate 1- ((benzyloxy) carbonyl) -4-ethyl-2, 5-dihydro-1H-pyrrole-3-formic acid compound 3. Then, the compound 3 is hydrogenated under the action of a chiral ruthenium catalyst, and is salified and purified by chiral amine to obtain an amine salt compound 4 of a key chiral acid intermediate (3R,4S) -1- ((benzyloxy) carbonyl) -4-ethylpyrrolidine-3-formic acid, and then, the derivative is carried out by using Maillard acid and is halogenated to obtain an intermediate 6. Then, 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine is used as a raw material, an intermediate 8 is obtained through copper-catalyzed ammonolysis reaction, and an intermediate 9 is obtained through amino protection. The intermediate 6 and the intermediate 9 are optimized to carry out butt-joint reaction to obtain a chemical formula 10, and then trifluoroacetic anhydride is utilized to carry out cyclization to obtain the key parent nucleus 11 of the lapatinib. Finally, we optimized the docking reaction of trifluoroethylamine and obtained the product of uppertinib with both methods. These improvements greatly improve the route efficiency, reduce the process steps of using noble metal catalysts, reduce the process cost, and greatly reduce the generation of secondary products, which 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. The route is as follows:
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
Transferring 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine 7(35.22g,100mmol) into a sealed reaction bottle, adding ethylene glycol (105mL), copper oxide (398mg,5.0mmol), L-proline (1.15g,10.0mmol), potassium carbonate (27.64g,200mmol), ammonia water (25%, 105g), sealing, heating in an oil bath to an internal temperature of 110-120 ℃ for reaction for 36-48 hours, cooling to room temperature after the reaction is finished, adding 15% saline (140mL), adding isopropyl acetate (175mL) for extraction for 3 times, combining organic phases, washing with saturated saline for 2 times (105mL), drying with sodium sulfate, concentrating to remove most of the solvent, adding petroleum ether (215mL), pulping, filtering, and drying to obtain compound 8(25.37g, 88%).
The cupric oxide can be replaced by cuprous iodide, cuprous bromide, cuprous oxide, cupric bromide or cupric chloride; the solvent ethylene glycol can be replaced by methanol, ethanol, isopropanol, N-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1, 4-dioxane or toluene; l-proline can be replaced by acetylacetone, TMEDA or 2- (methylamino) ethanol, or L-proline can be omitted;
example 2
Adding a compound shown in the formula 8(28.83g,100mmol) and dichloromethane (144mL) into a three-neck flask, adding triethylamine (20.24g,200mmol), uniformly stirring, cooling to 0-5 ℃, dropwise adding methylsulfonyl chloride (12.60g,110mmol), and heating to room temperature for reacting for 6-8 hours after dropwise adding. After the reaction, saturated ammonium chloride solution (144mL) was added, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (144mL), the combined organic phases were washed 1 time with saturated brine (144mL), dried over sodium sulfate, concentrated, slurried with petroleum ether (144mL), filtered, and dried to give compound of formula 9a (33.34g, 91%).
MS(ESI)m/z=367.0[M+H]+,1H NMR(400MHz,DMSO-d6)δ11.14(br,1H),8.22(d,J=16.4Hz,2H),8.01(s,2H),7.40(s,2H),6.96(s,1H),3.44(s,3H),2.30(s,3H)。
The triethylamine can be replaced by diisopropylethylamine, DMAP or pyridine; the solvent dichloromethane can be replaced by acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; methanesulfonyl chloride may be replaced with p-toluenesulfonyl chloride.
Example 3
Adding the compound shown in the formula 8(28.83g,100mmol) and dichloromethane (144mL) into a three-neck flask, adding diisopropylethylamine (25.85g,200mmol), stirring uniformly, cooling to 0-5 ℃, dropwise adding p-toluenesulfonyl chloride (20.97g,110mmol), and heating to room temperature for reacting for 6-8 hours. After the reaction, saturated ammonium chloride solution (144mL) was added, the organic phase was separated, the aqueous phase was extracted 3 times with ethyl acetate (144mL), the combined organic phases were washed 1 time with saturated brine (144mL), dried over sodium sulfate, concentrated, slurried with petroleum ether (144mL), filtered, and dried to give compound of formula 9b (41.60g, 94%).
MS(ESI)m/z=443.1[M+H]+,1H NMR(400MHz,DMSO-d6)δ11.45(br,1H),8.20(d,J=4.0Hz,1H),8.17(s,1H),7.96(d,J=8.4Hz,2H),7.86(d,J=8.0Hz,2H),7.40(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),6.85(d,J=4.0Hz,1H),2.31(s,3H),2.30(s,3H)。
The diisopropylethylamine can be replaced by triethylamine, DMAP or pyridine; the solvent dichloromethane can be replaced by acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; p-toluenesulfonyl chloride may be replaced by methanesulfonyl chloride.
Example 4
Adding 1a (29.13g,100mmol) and acetonitrile (145mL) into a three-neck flask, stirring to dissolve, adding triethylamine (20.24g,200mmol), slowly adding phosphorus oxychloride (23.00g,150mmol), stirring uniformly, and heating to 45-55 ℃ for reaction for 10-16 hours. After the reaction, part of acetonitrile was removed by rotation, water (291mL) was added, dichloromethane was added to extract for 2 times, the organic phase was combined and washed with saturated sodium bicarbonate solution (145mL) for 1 time, brine (145mL) for 1 time, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 2a, which was directly used for the next reaction.
Example 5
A three-neck flask was charged with 2a (crude from the previous step, 100mmol) and catalyst NiCl2(PPh3)2(1.31g,2mmol) and tetrahydrofuran (150mL), stirring for dissolving, cooling to-10-0 ℃, switching nitrogen in vacuum for 3 times, slowly dropping ethyl magnesium chloride solution (2.0M,55mL) into a reaction bottle under the protection of nitrogen, stirring for 30 minutes at-10-0 ℃ after dropping, and slowly heating to 25-30 ℃ for reaction for 4-6 hours. After the reaction is finished, 1mol/L diluted hydrochloric acid (200mL) is added to quench the reactionExtracting the water phase with ethyl acetate (150mL) for 2 times, combining the organic phases, washing with saturated salt water for 1 time (150mL), concentrating, adding methanol (150mL), stirring for dissolving, slowly dropping sodium hydroxide solution (10%, 75mL) into a reaction bottle, and slowly heating to 45-55 ℃ for reaction for 4-6 hours after dropping. After completion of the reaction, a part of methanol was removed by evaporation, and 0.5mol/L diluted hydrochloric acid (200mL) was added dropwise to precipitate a large amount of solid, which was then filtered and dried to obtain Compound 3(20.10g, yield in two steps: 73%).
Here NiCl2(PPh3)2The bis (triphenylphosphine) nickel dichloride can be replaced by nickel dichloride or nickel acetate; the tetrahydrofuran can be replaced by benzene, toluene, 2-methyltetrahydrofuran or 1, 4-dioxane; ethyl magnesium bromide can be replaced by ethyl magnesium chloride.
Example 6
The hydrogenation vessel was charged with 3(27.53,100mmol), triethylamine (12.14g,120mmol) and methanol (138mL), dissolved by stirring, sparged with nitrogen 3 times and then rapidly charged with [ Ru (C)6H6)Cl2]2(25.0mg,0.05mmol) and S-Sunphos (66.7mg,0.10mmol), after the addition, the hydrogen is switched for three times, and then the mixture is pressurized to 3.6-4.0 Mpa and heated to 45-55 ℃ for reaction for 24-36 hours. Filtering with diatomite after the reaction is finished, removing part of methanol by spinning, dropping 1.0mol/L sodium hydroxide solution (138mL), adding methyl tertiary butyl ether for extraction (138mL), discarding the organic phase, adding methyl tertiary butyl ether (138mL) into the water phase for extraction for 2 times, combining the organic phases, washing with saturated common salt water (138mL) for 1 time, drying with anhydrous sodium sulfate, heating to 40-50 ℃ after filtering, adding a methanol (27mL) solution of S-1-phenylethylamine (11.51g,95mmol), adding a small amount of seed crystals, slowly cooling to 0-10 ℃, precipitating a large amount of solid, filtering, collecting the solid, and drying to obtain the product 4a (36.26g, yield 91%).
1H NMR(400MHz,DMSO-d6)δ7.46-7.50(m,2H),7.28-7.43(m,8H),5.00-5.09(m,2H),4.34-4.39(m,1H),3.26-3.54(m,3H),3.13-3.20(m,1H),2.75-2.82(m,1H),1.48(d,J=6.8Hz,3H),1.14-1.26(m,1H),1.01-1.12(m,2H),0.87-0.92(m,3H)。
The reaction solvent methanol can be replaced by ethanol or isopropanol; the base triethylamine can be replaced by diisopropylethylamine, DBU or DABCO; the S-1-phenylethylamine can be replaced by R-1-phenylethylamine; the salifying solvent methyl tertiary butyl ether can be replaced by methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate or toluene.
Example 7
The hydrogenation vessel was charged with 3(27.53,100mmol), triethylamine (12.14g,120mmol) and methanol (138mL), dissolved by stirring, sparged with nitrogen 3 times and then rapidly charged with [ Ru (C)6H6)Cl2]2(25.0mg,0.05mmol) and S-Sunphos (66.7mg,0.10mmol), after the addition, the hydrogen is switched for three times, and then the mixture is pressurized to 3.6-4.0 Mpa and heated to 45-55 ℃ for reaction for 24-36 hours. Filtering with diatomite after the reaction is finished, removing part of methanol by spinning, dropping 1.0mol/L sodium hydroxide solution (138mL), adding methyl tertiary butyl ether for extraction (138mL), discarding the organic phase, adding methyl tertiary butyl ether (138mL) into the water phase for extraction for 2 times, combining the organic phases, washing with saturated common salt water (138mL) for 1 time, drying with anhydrous sodium sulfate, heating to 40-50 ℃ after filtering, adding a methanol (27mL) solution of R-1-phenylethylamine (11.51g,95mmol), adding a small amount of seed crystals, slowly cooling to 0-10 ℃, precipitating a large amount of solid, filtering, collecting the solid, and drying to obtain a product 4b (35.07g, yield 88%).
1H NMR(400MHz,DMSO-d6)δ7.45-7.51(m,2H),7.25-7.45(m,8H),4.98-5.10(m,2H),4.33-4.40(m,1H),3.25-3.55(m,3H),3.15-3.21(m,1H),2.73-2.81(m,1H),1.49(d,J=6.8Hz,3H),1.12-1.25(m,1H),1.02-1.13(m,2H),0.88-0.93(m,3H)。
The reaction solution methanol can be replaced by ethanol or isopropanol; the base triethylamine can be replaced by diisopropylethylamine, DBU or DABCO; r-1-phenylethylamine can be replaced by S-1-phenylethylamine; the salifying solvent methyl tertiary butyl ether can be replaced by methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate or toluene.
Example 8
Adding 4a (39.85g and 100mmol) and ethyl acetate (200mL) into a three-neck flask, slowly stirring 1M dilute hydrochloric acid (200mL and 200mmol), stirring for liquid separation, washing with organic phase saturated saline (100mL) for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating, adding dichloromethane (200mL) for dissolution, dropwise adding thionyl chloride (17.85g and 150mmol), stirring uniformly, and heating to reflux for reaction for 4-6 hours. After the reaction is finished, removing part of dichloromethane by spinning, adding dichloromethane (100mL) for 2 times, adding tetrahydrofuran (50mL) for dissolving, adding tetrahydrofuran (150mL) into another reaction bottle, adding triethylamine (30.36g,300mmol), adding Meldrum's acid (15.85g,110mmol), stirring for 15-20 minutes, slowly adding the prepared acyl chloride solution, heating to room temperature after the addition is finished, stirring for 1 hour, adding saturated ammonium chloride solution (200mL) to quench the reaction after the reaction is finished, adding ethyl acetate (200mL) for 2 times of extraction, combining organic phase saturated sodium bicarbonate solution (100mL) for 1 time, washing with saline (100mL) for 1 time, drying with anhydrous sodium sulfate, filtering and concentrating to obtain a crude compound 5, and directly feeding the crude compound to the next reaction.
The triethylamine base can be replaced by diisopropylethylamine, DBU, N-methylmorpholine or DMAP; the condensation solvent dichloromethane can be replaced by 1, 2-dichloroethane, acetonitrile, toluene or tetrahydrofuran.
Example 9
5(100mmol, obtained from example 8) and acetic acid (121mL) are added into a three-neck flask, cooled to 0-5 ℃, stirred to dissolve, then acetic anhydride (30.63g,300mmol) is added, sulfonyl chloride (16.20g,120mmol) is slowly added, stirred uniformly and heated to 80-90 ℃ for reaction for 4-6 hours. After the reaction is finished, part of acetic acid is removed, 2M dilute hydrochloric acid (402mL) is added, the mixture is stirred at room temperature for 2-3 hours, ethyl acetate (201mL) is added for extraction for 2 times after the reaction is finished, organic phase saturated sodium bicarbonate solution (201mL) is combined and washed for 1 time, brine (201mL) is washed for 1 time, anhydrous sodium sulfate is dried, filtration and concentration are carried out, petroleum ether is added for pulping, and compound 6a (25.09g, two steps are 81%) is filtered.
The halogenating agent sulfonyl chloride here can be replaced by chlorosuccinimide; the additive acetic anhydride can be replaced by trifluoroacetic anhydride or not; the solvent acetic acid can be replaced by dichloromethane, acetonitrile, toluene or tetrahydrofuran; the hydrochloric acid can be replaced by sulfuric acid or phosphoric acid.
Example 10
5(100mmol, obtained in example 8) and acetic acid (121mL) were added to a three-necked flask, cooled to 0-5 ℃, stirred to dissolve, acetic anhydride (30.63g,300mmol) was added, liquid bromine (17.58g,110mmol) was slowly added, and after stirring, the mixture was reacted at room temperature for 4-6 hours. After the reaction is finished, part of acetic acid is removed, 2M dilute sulfuric acid (402mL) is added, the mixture is stirred at room temperature for 2-3 hours, ethyl acetate (201mL) is added for extraction for 2 times after the reaction is finished, organic phase saturated sodium bicarbonate solution (201mL) is combined and washed for 1 time, brine (201mL) is washed for 1 time, anhydrous sodium sulfate is dried, filtration and concentration are carried out, petroleum ether is added for pulping, and compound 6b (29.39g, 83%) is filtered.
Here, the halogenating reagent liquid bromine can be replaced by bromosuccinimide or dibromohydantoin; the additive acetic anhydride can be replaced by trifluoroacetic anhydride or not; the solvent acetic acid can be replaced by dichloromethane, acetonitrile, toluene or tetrahydrofuran; the hydrochloric acid can be replaced by sulfuric acid or phosphoric acid.
Example 11
Adding the compound 9a (36.64g,100mmol) into a three-neck flask, adding N, N-dimethylformamide (111mL), stirring and dissolving, cooling to 0-5 ℃ in an ice bath, adding cesium carbonate (48.88g,150mmol), stirring for 5-10 minutes, adding the compound 6a (32.53g,105mmol), and heating to room temperature for reaction for 6-8 hours. After the reaction, water (250mL) was added and the mixture was slurried, filtered and dried to give Compound 10a (57.58g, 90% yield).
MS(ESI)m/z=640.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.25-8.29(m,1H),8.01(d,J=8.4Hz,2H),7.28-7.66(m,7H),6.72-6.83(m,1H),4.81-5.10(m,3H),3.21-3.55(m,8H),2.98-3.11(m,1H),2.36(s,3H),0.73-1.27(m,6H)。
The cesium carbonate can be replaced by potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the solvent N, N-dimethylformamide may be replaced by N, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or acetone.
Example 12
Adding the compound 9b (35.42g,100mmol) into a three-neck flask, adding N, N-dimethylformamide (105mL), stirring and dissolving, cooling to 0-5 ℃ in an ice bath, adding potassium carbonate (20.73g,150mmol), stirring for 5-10 minutes, adding the compound 6b (32.53g,105mmol), and heating to room temperature for reaction for 6-8 hours. After the reaction, water (354mL) was added and the mixture was slurried, filtered and dried to give Compound 10b (65.86g, 92% yield).
MS(ESI)m/z=716.3[M+H]+,1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.25-8.30(m,1H),8.03(d,J=8.4Hz,2H),7.66(dd,J=8.0,2.4Hz,2H),7.45(d,J=8.4Hz,2H),7.28-7.40(m,7H),6.77(dd,J=21.2,4.0Hz,1H),4.84-5.13(m,3H),3.34-3.55(m,5H),3.02-3.12(m,1H),2.36(s,6H),1.14-1.26(m,2H),0.94-1.08(m,1H),0.73-0.92(m,3H)。
The potassium carbonate can be sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent N, N-dimethylformamide may be replaced by N, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or acetone.
Example 13
Adding the compound 10a (63.97g,100mmol) into a three-neck flask, adding tetrahydrofuran (320mL), stirring for dissolving, adding pyridine (23.73g,300mmol), cooling to 0-5 ℃ in an ice bath, slowly dropping trifluoroacetic anhydride (84.01g,400mmol), heating to 55-60 ℃ and reacting for 6-8 hours. After the reaction is finished, cooling to room temperature, adding 10% sodium hydroxide solution (160mL), stirring at room temperature for 2-3 hours, removing part of solvent after the reaction is finished, adding isopropyl acetate (160mL) for extraction for 3 times, combining organic phase saturated saline solution (160mL) for washing for 2 times, concentrating, adding mixed solvent of isopropanol and petroleum ether for pulping, filtering and drying to obtain the compound 11(35.05g, yield 90%).
The pyridine can be replaced by triethylamine, diisopropylethylamine or 2, 6-dimethylpyridine; the tetrahydrofuran may be replaced by dichloromethane, toluene, acetonitrile, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.
Example 14
Adding the compound 10b (71.58g,100mmol) into a three-neck flask, adding tetrahydrofuran (360mL), stirring for dissolving, adding 2, 6-lutidine (32.15g,300mmol), cooling to 0-5 ℃ in an ice bath, slowly and dropwise adding trifluoroacetic anhydride (84.01g,400mmol), and heating to 55-60 ℃ for reacting for 6-8 hours. After the reaction is finished, cooling to room temperature, adding 10% sodium hydroxide solution (180mL), stirring at room temperature for 2-3 hours, removing part of solvent after the reaction is finished, adding isopropyl acetate (180mL) for extraction for 3 times, combining organic phases, washing with saturated saline solution (180mL) for 2 times, concentrating, adding a mixed solvent of isopropanol and petroleum ether for pulping, filtering and drying to obtain the compound 11(36.61g, yield 94%).
The base 2, 6-lutidine can be replaced by triethylamine, diisopropylethylamine or pyridine; the tetrahydrofuran may be replaced by dichloromethane, toluene, acetonitrile, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.
Example 15
Compound 11(38.95g,100mmol) and 2, 6-dichloropyridine (44.40g,300mmol) are added into a three-neck flask, dichloromethane (195mL) is added and stirred to dissolve, cooling is carried out in an ice bath to 0-5 ℃, trifluoromethanesulfonic anhydride (42.32g,150mmol) is added under the protection of nitrogen, and the reaction is carried out at room temperature for 1-2 hours. Adding trifluoroethylamine (29.72g,300mmol), reacting at room temperature for 4-6 hours, adding saturated ammonium chloride (390mL) to quench the reaction after the reaction is finished, stirring for 1-2 hours, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate (195mL), combining organic phases, washing for 1 time by using 10% potassium dihydrogen phosphate solution (195mL), concentrating to a small volume, adding n-heptane, pulping, filtering, and drying to obtain the product Upactinib (33.47g, yield 88%).
The 2, 6-dichloropyridine may be replaced by triethylamine, diisopropylethylamine, pyridine or 2-chloropyridine; the dichloromethane can be replaced by 1, 2-dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the trifluoromethanesulfonic anhydride may be replaced with boron trifluoride diethyl etherate or trimethylaluminum.
Example 16
Compound 11(38.95g,100mmol) was charged into a three-necked flask, dichloromethane (195mL) was added thereto and the mixture was dissolved with stirring, DMAP (18.33g,150mmol) was added thereto, and the mixture was reacted at room temperature for 6 to 8 hours. After the reaction, 5% potassium dihydrogen phosphate solution (195mL) is added, stirring and liquid separation are carried out, the water phase is extracted for 2 times by dichloromethane (195mL), organic phase saturated saline solution (195mL) is combined for washing for 1 time, and the mixture is concentrated to obtain 13 crude products which are directly put into the next step for reaction.
Example 17
A hydrogenation flask was charged with compound 13(100mmol, obtained in example 16), dissolved in methanol (245mL), charged with 5% palladium on carbon (0.98g), and the mixture was subjected to three times of hydrogen switching under vacuum, pressurized to 0.10 to 0.15MPa, and reacted at an internal temperature of 50 to 55 ℃ for 16 to 24 hours. After the reaction was completed, the palladium on carbon was filtered off from cooled celite, part of the methanol was concentrated and removed, n-heptane (245mL) was slowly added for beating, filtration and washing with a small amount of n-heptane were carried out to collect a solid and dry to obtain compound 14(31.98g, 90% yield in two steps).
MS(ESI)m/z=356.2[M+H]+,1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.59(s,1H),7.80-7.95(m,1H),7.24-7.35(m,1H),4.49-4.65(m,1H),3.55-3.80(m,3H),3.01-3.21(m,1H),2.58-2.76(m,1H),1.52-1.79(m,9H),0.87-1.18(m,2H),0.67(t,J=7.3Hz,3H)。
Example 18
Carbonyl diimidazole (22.70g,140mmol) was added to a three-necked flask, N-dimethylformamide (150mL) was added and dissolved with stirring, potassium carbonate (27.64g,200mmol) was added, trifluoroethylamine (14.86g,150mmol) was slowly added dropwise, 14(35.54g,100mmol) was added after stirring for 20 to 30 minutes, and the mixture was reacted at room temperature for 6 to 8 hours. After the reaction, water (356mL) was added, ethyl acetate (356mL) was stirred for liquid separation, the aqueous phase was extracted with ethyl acetate (178mL) 1 time, the organic phases were combined, washed with saturated brine (178mL) 2 times, dried over sodium sulfate, concentrated to remove most of the solvent, added with petroleum ether (356mL), recrystallized by heating, slurried, filtered and dried to give intermediate 15(44.68g, 93% yield) as a white solid.
MS(ESI)m/z=481.2[M+H]+,1HNMR(400MHz,DMSO-d6)δ8.52(s,1H),7.32-7.48(m,2H),7.01-6.87(m,2H),4.31(q,J=6.4Hz,1H),3.58-3.93(m,5H),3.15-3.32(m,1H),2.47-2.61(m,1H),1.50-1.75(m,9H),1.00-1.13(m,1H),0.49-0.85(m,4H)。
The potassium carbonate can be replaced by sodium carbonate, cesium carbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent N, N-dimethylformamide may be replaced by acetonitrile, N-dimethylacetamide, N-methylpyrrolidone or toluene.
Example 19
The compound 15(48.05g,100mmol) was added to a three-necked flask, n-butanol (240mL) was added thereto, and the mixture was slowly heated to 85 to 90 ℃ to react for 4 to 6 hours. And (3) after the reaction is finished, removing part of n-butanol, adding n-heptane, pulping, filtering and drying to obtain the product of the empatinib (36.13g, yield 95%).
Claims (5)
1. The synthetic method of the lapatinib is characterized by comprising the following steps of:
(1) carrying out condensation reaction on a compound shown in a formula 6 and a compound shown in a formula 9 under alkaline conditions to obtain an intermediate compound shown in a formula 10;
(2) cyclizing the compound shown in the formula 10 under the action of trifluoroacetic anhydride and organic base, and deprotecting under the action of inorganic base to obtain an intermediate compound shown in the formula 11;
(3) protecting the compound shown in the formula 11 with Boc anhydride under the action of alkali to obtain a compound shown in the formula 13;
(4) hydrogenating the compound formula 13 under the catalytic action of palladium carbon to remove Cbz protection to obtain a compound formula 14;
(5) under the alkaline condition, carrying out condensation reaction on a compound shown in a formula 14 and trifluoroethylamine under the reaction of carbonyl diimidazole to obtain a compound shown in a formula 15;
(6) heating the compound shown in the formula 15 in butanol to remove Boc protection to obtain an Upacatinib compound shown in the formula 12;
the synthesis method of the compound shown in the formula 9 comprises the following steps:
(a) carrying out ammonolysis on the compound shown in the formula 7 by using ammonia water under the catalysis of copper to obtain an intermediate compound shown in a formula 8;
(b) protecting amino group of the compound shown in the formula 8 with sulfonyl in an alkaline system to obtain an intermediate compound shown in the formula 9;
wherein R is2Is methyl or 4-tolyl;
the synthesis method of the compound shown in the formula 6 comprises the following steps:
(a') chlorinating a 1- ((benzyloxy) carbonyl) -4-oxopyrroline-3-carboxylate compound of formula 1 under the action of triethylamine and phosphorus oxychloride to obtain a compound of formula 2;
(b') carrying out coupling reaction on the compound shown in the formula 2 and an ethyl Grignard reagent under the catalysis of nickel, and then hydrolyzing the compound shown in the formula 2 through the action of sodium hydroxide to obtain an intermediate compound shown in the formula 3;
(c') carrying out hydrogenation reaction on the compound shown in the formula 3 under the catalysis of chiral ruthenium, and salifying the compound with chiral 1-phenylethylamine to obtain an intermediate compound shown in the formula 4;
(d') separating the compound shown in the formula 4 under the action of hydrochloric acid, reacting the separated compound with thionyl chloride or oxalyl chloride to obtain an acyl chloride compound, and then performing condensation reaction with wheat straw acid to obtain an intermediate 5;
(e') carrying out halogenation reaction on the compound shown in the formula 5 in an acid system and carrying out acidolysis and decarboxylation by a one-pot method to obtain an intermediate 6;
wherein R represents a methyl group, an ethyl group or a tert-butyl group; x represents bromine or chlorine.
2. The method for synthesizing upatinib according to claim 1, characterized in that the condensation reaction base of step (5) is selected from potassium carbonate, sodium carbonate, cesium carbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene.
3. The synthetic method of uppatinib according to claim 1, characterized in that the copper catalyst in step (a) is selected from cuprous iodide, cuprous bromide, cuprous oxide, cupric bromide or cupric chloride; the ligand is not added or is selected from acetylacetone, L-proline, TMEDA or 2- (methylamino) ethanol; the added alkali is selected from sodium carbonate, potassium carbonate or cesium carbonate; the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1, 4-dioxane or toluene; the sulfonyl protection reaction in the step (b) adopts methylsulfonyl chloride or p-toluenesulfonyl chloride as a sulfonylation reagent; the base is selected from triethylamine, diisopropylethylamine, DMAP or pyridine; the reaction solvent is selected from dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene.
4. The method for synthesizing uppatinib according to claim 1, wherein the ethyl grignard reagent in the coupling reaction of step (b') is selected from ethyl magnesium bromide or ethyl magnesium chloride; the nickel catalyst is selected from bis triphenylphosphine nickel dichloride, nickel dichloride or nickel acetate; the selected reaction solvent is benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or 1, 4-dioxane; in the hydrogenation reaction in the step (C'), the ruthenium catalyst is [ Ru (C) ]6H6)Cl2]2The ligand is S-Sunphos; the added alkali is selected from triethylamine, diisopropylethylamine, DBU or DABCO; the reaction solvent is selected from methanol, ethanol or isopropanol; the hydrogen pressure is 0.2-6.0 Mpa; the reaction temperature is 0-90 ℃; s-1-phenylethylamine or R-1-phenylethylamine is selected for salt formation in the step (c'); the salifying solvent is selected from methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, toluene or methyl tertiary butyl ether and a mixed solvent of the methanol, the ethanol, the isopropanol, the acetonitrile, the ethyl acetate, the isopropyl acetate and the toluene; the condensation reaction base with wheat straw acid in the step (d') is selected from triethylamine, diisopropylethylamine, DBU, N-methylmorpholine or DMAP; the condensation solvent is selected from dichloromethane1, 2-dichloroethane, acetonitrile, toluene or tetrahydrofuran; the reaction temperature is-20 to 90 ℃; in the halogenation reaction in the step (e'), the halogenating agent is selected from chlorosuccinimide, sulfonyl chloride, liquid bromine, bromosuccinimide or dibromohydantoin; no additive is added or acetic anhydride or trifluoroacetic anhydride is selected as an additive; the solvent is selected from acetic acid, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixture; the decarboxylated acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
5. The method for synthesizing sepitinib according to claim 1, characterized in that the base in the condensation reaction in step (1) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent used is selected from N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or acetone; in the cyclization reaction in the step (2), the base is selected from triethylamine, diisopropylethylamine, pyridine or 2, 6-dimethylpyridine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the deprotection base is selected from sodium hydroxide, lithium hydroxide or potassium hydroxide.
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