WO2022242278A1

WO2022242278A1 - Preparation methods for upadacitinib and intermediate thereof

Info

Publication number: WO2022242278A1
Application number: PCT/CN2022/080533
Authority: WO
Inventors: 阮晶; 严恭超; 阮晓娜; 张薇; 张鑫鑫
Original assignee: 上海鼎雅药物化学科技有限公司
Priority date: 2021-05-16
Filing date: 2022-03-13
Publication date: 2022-11-24
Also published as: CN115417802A

Abstract

A method for synthesizing an intermediate of upadacitinib, comprising: (1) compound formula 1 undergoes an epoxidation reaction, an addition reaction, and a protection reaction to obtain compound formula 4; compound formula 4 reacts with an acetyl reagent to obtain compound formula 5; and then compound formula 5 reacts with a bromination reagent to obtain compound formula 6. A reaction formula is as follows: formula (1), wherein G is the protecting group of a nitrogen atom or a trifluoroethylformamide group, and R is the protecting group of a hydroxyl group.

Description

Preparation method of upadatinib and its intermediate

technical field

The invention relates to the field of drug synthesis, in particular to a preparation method of an upadatinib intermediate, and furthermore to a preparation method of upadatinib.

Background technique

The chemical name of upatinib is (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:

It is a novel target JAK1 inhibitor, which is used to treat atopic dermatitis.

Currently, U.S. patents US2017129902A1 and WO20170667751A1 report the synthetic route of upatinib from the original research company AbbVie. It is not difficult to see from the above patent application that the construction of the chiral key intermediate I is one of the cores of the synthetic route of upatinib.

There are also many reports on the preparation methods of the chiral key intermediate I, such as patent documents CN 111217819 A, WO 2020202183 Al, WO2020043033A2, etc. The preparation methods of the chiral key intermediate I disclosed in the above patent documents are obtained by chemical resolution. pure intermediate

The intermediate is further converted into the chiral key intermediate I.

Chinese patent CN 109369659 B reports a synthetic route that does not require chemical resolution to prepare the chiral key intermediate I. In this route, the carbonyl intermediate A-1 is used as the starting material, which is reacted with a Grignard reagent to obtain the hydroxyl intermediate A-2. Then dehydration by sulfuric acid and alkali hydrolysis to obtain intermediate A-4. Then directly obtain the chiral carboxylic acid intermediate A-5 through hydrogenation with a chiral Ru metal catalyst, and then obtain the target intermediate I through chlorination, diazotization, and bromination, and the reaction formula is as follows:

This route uses a diazonium compound as a reaction material, which has great potential safety hazards. The chiral Ru metal catalyst used is expensive and costly, which is not conducive to industrial scale-up production.

In view of this, the present invention is proposed.

Contents of the invention

One of the objectives of the present invention is to provide a new preparation method of upadatinib intermediates, so as to solve the problems of high preparation cost and potential safety hazards in the existing preparation methods of upadatinib intermediates.

In order to achieve the above object, the first aspect of the present invention provides a method for preparing a new upadatinib intermediate compound formula 6, the preparation method comprising the following steps:

(1) compound formula 1 obtains compound formula 2 through epoxidation reaction;

(2) Compound formula 2 and organometallic reagents undergo an addition reaction to prepare compound formula 3;

(3) compound formula 3 is prepared compound formula 4 through protection reaction;

(4) compound formula 4 reacts with acetyl reagent to prepare compound formula 5;

(5) Compound formula 5 is reacted with brominating reagent to prepare compound formula 6;

The process route is as follows:

Wherein G is a protecting group for a nitrogen atom or a trifluoroethyl formamide group, and R is a protecting group for a hydroxyl group.

Preferably, the oxidant commonly used in the epoxidation reaction in step (1) is an organic peroxyacid, and the organic peroxyacid is m-chloroperoxybenzoic acid, peracetic acid, peroxyformic acid, peroxytrifluoroacetic acid, dimethyl Base copper peroxide, any one of dimethyldioxirane; commonly used solvents are inert solvents, including but not limited to halogenated hydrocarbons, benzene, toluene, xylene, nitrobenzene, acetonitrile, ether One or more of the group.

Preferably, in step (2), the organometallic reagent is any one of Grignard reagents, organolithium reagents, organoaluminum reagents, organotitanium reagents, organomanganese reagents, organozinc reagents, organotin reagents, organosamarium reagents, solvent One or more of toluene, dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane; the preferred Grignard reagent of the organometallic reagent includes But not limited to ethylmagnesium bromide and ethylmagnesium chloride; the molar ratio of compound formula 2 to Grignard reagent is 1:1-1.5; the reaction temperature is 0-90°C.

Preferably, in step (3), the solvent is one or more of N, N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1,2-dioxane, acetone; the base is One or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, sodium hydride, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine ; The molar ratio of the compound formula 3 to the base is 1:1-3; the reaction temperature is -78-80°C.

Preferably, in step (4), the acetyl reagent is vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-vinyloxyethanol, vinyloxytrimethylsilane One or more; the solvent is one or more of toluene, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, acetonitrile; the base is N,N- Diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine, 1,8-diazabicycloundec Carb-7-ene or 1,4-diazabicyclo[2.2.2]octane, preferably N,N-diisopropylethylamine; the amount of base added is 1-3 of compound formula 4 double equivalent; the catalyst is tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tris(dibenzylideneacetone)dipalladium , the amount of catalyst added is 0.5%-1% equivalent of compound formula 4; ligands can also be added according to the reaction type, and the ligands are 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine) Phenylphosphino)propane, 1,1-bis(diphenylphosphino)ferrocene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, the amount of ligand added is 1% of the catalyst- 2% equivalent.

Preferably, in the step (5), the bromination reagent is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; the solvent is ethyl acetate, methylene chloride, acetonitrile, Toluene or tetrahydrofuran or their mixed solvents.

As for the protecting group of nitrogen atom, various types of protecting groups known in the art can be selected, and the protecting group of nitrogen atom includes but not limited to alkoxycarbonyl, acyl and alkyl. Preferably, the protecting groups for the nitrogen atom include but are not limited to benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, o-phenylene Diformyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl. For the purposes of the present application, preferred protecting groups are benzyl, benzyloxycarbonyl, allyloxycarbonyl.

Regarding the hydroxyl protecting group, various types of protecting groups known in the art can be selected, and the hydroxyl protecting group includes but not limited to alkyl, alkoxyalkyl, acyl, silicon ether. Preferably, hydroxyl protecting groups include, but are not limited to, methyl, methoxymethyl, tetrahydrofuranyl, benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl , Triisopropylsilyl, Benzoyl, Trifluoromethanesulfonyl.

The second aspect of the present invention also provides an upadatinib intermediate compound formula 6, which is prepared by the above synthesis process.

The third aspect of the present invention also provides a new method for preparing the key core compound formula 8 of upatinib, the preparation method comprising the following steps: carrying out the condensation reaction of the above-mentioned compound formula 6 and compound a under suitable conditions Obtain intermediate compound formula 7; Compound formula 7 obtains intermediate compound formula 8 through ring-forming reaction under the action of trifluoroacetic anhydride and organic base; Wherein the structural formula of compound a, compound formula 7, compound formula 8 is as follows:

wherein G is a nitrogen atom protecting group or a trifluoroethyl formamide group.

Preferably, the base selected for the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N,N-diisopropylethylamine, triethylamine, pyridine, 4-Dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or 1,4-diazabicyclo[2.2.2]octane, or benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinyl; In addition, the amount of base added is 3 times the equivalent of compound formula 6; the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, Acetonitrile, 1,4-dioxane or tetrahydrofuran; the reaction temperature is -20°C to 110°C.

Preferably, the base of the cyclization reaction is selected from triethylamine, N,N-diisopropylethylamine, pyridine or 2,6-lutidine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, Tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is -20℃～110℃.

The fourth aspect of the present invention also provides upatinib key core compound formula 8, which is prepared by the aforementioned synthesis process.

The fifth aspect of the present invention also provides a new preparation method of upapatib, adopting the following technical scheme:

The above compound formula 8 is subjected to deprotection reaction to obtain compound formula 9, compound formula 9 undergoes condensation reaction with trifluoroethylamine in the presence of carbonyldiimidazole to obtain chemical compound formula 10, and chemical compound formula 10 is subjected to deprotection reaction to obtain upapatidine Ni, wherein G is the protecting group of nitrogen atom in compound formula 8, compound formula 9, the structural formula of compound formula 10 is as follows:

Preferably, the compound formula 9 is prepared by reacting the compound formula 8 under the action of a deamination protection reagent, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and acetic acid Ethyl ester or _H2 /Pd-C.

Preferably, the base of the condensation reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundec-7-ene or 1,4-diazabicyclo[2.2.2]octane; the reaction solvent is selected from acetonitrile, N,N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is -10°C to 110°C.

Preferably, upatinib is prepared by reacting compound formula 10 under the action of a deamination protection reagent, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and Ethyl acetate or _H2 /Pd-C.

The sixth aspect of the present invention also provides a second new method for preparing upatinib, which adopts the following technical scheme:

The above-mentioned compound formula 8 is prepared through a deprotection reaction to upatinib, wherein the structural formula of the compound formula 8 is as follows:

Preferably, compound formula 8 is reacted under the action of a deamination protection reagent to prepare upatinib, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and Ethyl acetate or _H2 /Pd-C.

The seventh aspect of the present invention also provides upadatinib, which is prepared by any one of the aforementioned synthesis processes.

Applying the technical scheme of the present invention, the trans-hydroxyl compound is generated through an asymmetric epoxidation reaction, and after being catalyzed by palladium, the acetyl group attacks from the back to generate a cis-type product, no chiral resolution is required, and a chiral compound is synthesized directionally, avoiding The use of expensive raw materials reduces the preparation cost of upadatinib and its intermediates, and facilitates industrialization.

Detailed ways

It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below in conjunction with examples.

As described in the background technology, the existing preparation methods of upadatinib intermediates have the problems of high preparation cost and potential safety hazards. In order to solve the above-mentioned technical problems, the application provides a preparation method of a new upadatinib intermediate compound formula 6, which preparation method comprises the following steps:

(1) compound formula 1 obtains compound formula 2 through epoxidation reaction;

The process route is as follows:

The compound formula 1 can be obtained through purchase, or can be synthesized by referring to the prior art.

The third aspect of the present invention also provides a new preparation method of upadatinib key core compound formula 8, the preparation method is as follows:

The specific preparation method includes the following steps: use the compound formula 6 synthesized above to undergo condensation reaction with compound a under suitable conditions to obtain the intermediate compound formula 7; the compound formula 7 undergoes ring formation under the action of trifluoroacetic anhydride and an organic base The reaction gives an intermediate compound of formula 8, wherein G is a protecting group for a nitrogen atom or a trifluoroethylformamide group.

The fifth aspect of the present invention also provides a new preparation method of upapatib, the preparation method is as follows:

The specific preparation method includes the following steps: the compound formula 8 is deprotected to obtain the compound formula 9, the compound formula 9 is condensed with trifluoroethylamine in the presence of carbonyldiimidazole to obtain the chemical compound formula 10, and the chemical compound formula 10 is obtained by The deprotection reaction prepares upatinib, wherein G is the protecting group of the nitrogen atom.

Preferably, upatinib is prepared by reacting compound formula 10 under the action of a deamination protection reagent, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and Ethyl acetate or _H2 /Pd-C, base.

The sixth aspect of the present invention also provides a second new preparation method of upatinib, the preparation method is as follows:

The specific preparation method includes the following steps: the above compound formula 8 is subjected to a deprotection reaction to prepare upatinib, wherein G is trifluoroethylformamide.

Preferably, compound formula 8 is reacted under the action of a deamination protection reagent to prepare upatinib, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and Ethyl acetate or _H2 /Pd-C, base.

It should be noted that in this application, DIPEA refers to N,N-diisopropylethylamine, and DMSO refers to thionyl chloride.

Example 1

40.6g of compound formula 1 (0.2mol) was dissolved in 600mL of dichloromethane, the reaction temperature was controlled at 0°C, and 41.6g of m-chloroperoxybenzoic acid (0.24mol, 1.2eq) was added in batches. After the addition was complete, the temperature was raised After the reaction was complete at room temperature, the reaction liquid was concentrated to about 100 mL, then cooled to 0°C and filtered, the filter cake was washed with dichloromethane at 0°C, and the filtrate was concentrated to obtain 40.4 g of the product with a yield of 92.2%.

Mass spectral data of compound 2: [M+H] ⁺ 220.0.

Example 2

32.9g compound formula 2 (0.15mol) is dissolved in the tetrahydrofuran (400ml) solution of CuBr (3.0g), at-78 ℃, adds ethylmagnesium chloride under nitrogen protection [from ethylchloride (50 grams) and magnesium ( 9.2 g) was prepared]. After the addition, the temperature was raised to room temperature, and the stirring was continued for 2 hours. The reaction was complete, and the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with 1N HCl, water, saturated NaHCO ₃ , concentrated, and the concentrate was purified by silica gel chromatography to obtain 33.7 g of compound formula 3 with a yield of 90.1%.

Mass spectral data of compound 3: [M+H] ⁺ 251.1.

Example 3

29.9g of compound formula 3 (0.12mol) was dissolved in 300mL of dichloromethane, the temperature was cooled to 0°C, and 39.5g of trifluoromethanesulfonic anhydride (0.14mol) was added in batches. After the addition, the reaction was complete at room temperature, and saturated chlorine was added The sodium chloride solution was washed 3 times (100 mL/time), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 41.1 g of the product with a yield of 89.9%.

Mass spectral data of compound 4: [M+H] ⁺ 382.1.

Example 4

In a nitrogen atmosphere, add 38.1g of compound 4 (0.1mol), 1% equivalent of palladium acetate, 2% equivalent of 1,3-bis(diphenylphosphine)propane, 2 equivalents of DIPEA, 1.2 equivalents in a 500mL reaction vessel Tributyl (1-ethoxyethylene) tin, 200mL DMSO, stirred and reacted at 100°C for 3 hours, detected that the reaction was complete, cooled to room temperature, added 6N hydrochloric acid to the reaction solution to adjust the pH to 5-6, stirred at room temperature for 1 hours, water and ethyl acetate were added for extraction, the organic phase was dried and concentrated, and purified to obtain 23.4 g of compound formula 5 with a yield of 85.0%.

Mass spectral data of compound 5: [M+H] ⁺ 276.2.

Example 5

Add 27.5g of compound formula 5 (0.1mol) into a 500mL three-necked flask, dissolve it in 300mL of ethyl acetate and chloroform (1:1 volume ratio), add 16.0g of copper bromide (0.11mol), and control the temperature at 50-60°C. React for 5 to 6 hours, spot the plate to detect the reaction is complete, filter and concentrate, then dissolve with ethyl acetate, wash the organic phase with ammonium chloride aqueous solution until the water phase is colorless, dry and concentrate the organic phase to obtain 28.3 g of the product, the yield is 79.9% .

Mass spectral data of compound 6: [M+H] ⁺ 354.1.

Example 6

Add 39.5g of compound a (0.102mol) to a 500mL three-necked flask, add 180mL of N,N-dimethylacetamide, protect with nitrogen, cool down to 5°C in an ice-water bath, add 8.96g (0.112mol) of NaH, React for 30 minutes, lower the temperature to -15°C, add 39.1g of N,N-dimethylacetamide solution 180mL of compound formula 6 (0.110mol) dropwise, control the dropping temperature at -20～-10°C, and add in about 45 minutes After completion of the dropwise addition, react for 1 hour to detect that the reaction is complete, add 17.03g of acetic acid, stir at room temperature for 0.5 hours, heat up to 10-20°C, add 600mL of water, add 360mL of isopropyl acetate, stir, separate liquid, water phase Extract once with 180mL isopropyl acetate, combine organic phase, organic phase wash twice with 180mL 4% sodium bicarbonate solution, wash once with 180mL water, purify, vacuum-dry to obtain 42.1g compound formula 7, yield 62.6%.

The NMR data of compound 7 are as follows: ¹ H-NMR (400MHz, d-DMSO) δ8.76(s,1H),8.22-8.17(m,1H),8.02-7.95(m,2H),7.43-7.41(m, 2H),7.32-7.27(m,5H),6.81-6.67(m,1H),5.08-5.05(m,2H),4.76(s,2H),3.65-3.57(m,1H),3.50-3.44( m,3H),3.20-3.17(m,1H),2.42-2.38(m,1H),2.36(s,3H),1.42-1.29(m,10H),1.27-1.25(m,1H),0.90- 0.86 (m,3H).

Example 7

Add 10g of compound formula 7 (15.1mmol), 100mL of acetonitrile, 13.0g (61.9mmol) of trifluoroacetic anhydride into a 250mL three-necked flask, heat up to 70-80°C, the reaction is complete, cool to room temperature, add 500mL of water, add 150mL of ethyl acetate The esters were separated, the aqueous phase was extracted twice with ethyl acetate, the organic phase was washed with 100 mL of saturated brine, the organic phase was concentrated, and purified by column to obtain 5.0 g of compound 8 with a yield of 61.0%.

Mass spectral data of compound 8: [M+H] ⁺ 544.1.

Example 8

10g of compound 8 (18.4mmol), 150mL of methanol, 2.0g of Pd/C were added to a 500mL three-neck flask, hydrogen was replaced three times, and the reaction was performed at room temperature. It was detected that the reaction was complete, filtered, and concentrated to obtain 5.3g of compound 9 with a yield of 95.0%.

The NMR data of compound 9 are as follows: ¹ H-NMR (400MHz, d-DMSO) δ9.91(s,1H),8.78(s,1H),8.05-7.99(m,3H),7.91(s,1H),7.46 -7.43(m,3H),4.46-4.43(m,1H),3.70-3.62(m,3H),3.17-3.13(m,1H),2.60-2.57(m,1H),2.33(s,3H) ,0.92-0.87(m,2H),0.60-0.56(m,3H).

Mass spectral data of compound 9: [M+H] ⁺ 410.2.

Example 9

Add carbonyldiimidazole (22.70g, 140mmol) into the three-necked flask, add N,N-dimethylformamide (150mL) and stir to dissolve, add potassium carbonate (27.64g, 200mmol), cool to 0°C, slowly add trifluoro Ethylamine (14.86g, 150mmol), stirred at room temperature for 30 minutes after the dropwise addition, added compound 9 (35.54g, 100mmol), the reaction was complete at room temperature, the reaction solution was added to 1L of water, then added 500mL of ethyl acetate, stirred and separated , the aqueous phase was extracted twice with 300mL ethyl acetate, the organic phases were combined, washed twice with 300mL saturated brine, dried over sodium sulfate, the organic phase was concentrated to about 150mL, petroleum ether was added dropwise under stirring until crystals were precipitated, slowly Cool down to 0°C, continue stirring and crystallizing at 0°C for 2 hours, filter, wash the filter cake with petroleum ether and ethyl acetate at a volume ratio of 2:1 at 0°C, and dry to obtain white solid intermediate 10, 44.68g, yield 93%.

The NMR data of compound 10 are as follows: ¹ H-NMR (400MHz, d-DMSO) δ8.79(s,1H),8.09-8.4(m,2H),8.00-7.96(m,1H),7.61(s,1H) ,7.47-7.43(m,3H),6.97-6.92(m,1H),4.35-4.30(m,1H),3.88-3.67(m,5H),3.28-3.23(m,1H),2.52-2.47( m, 1H), 2.33(s, 3H), 1.05-0.98(m, 1H), 0.82-0.79(m, 1H), 0.63-0.59(m, 3H).

Example 10

Add 3g of compound 10 (5.61mmol), 15mL DMSO, and 1.5 equivalents of potassium tert-butoxide into a 250mL three-neck flask, react until complete at room temperature, add 50mL of water, extract 3 times with 50mL of ethyl acetate, combine the organic phases, and wash with 50mL of saturated saline Once, the organic phase was concentrated and purified by column to obtain 1.86 g of upadatinib, with a yield of 87.3%.

Example 11

Add 6.9g raw material S1 (0.1mol), 9.91g trifluoroethylamine (0.1mol), 21.2g sodium carbonate (0.2mol), 150mL tetrahydrofuran into the three-necked flask, add 17.84g carbonyldiimidazole (0.11mol) in batches, and Stir until the reaction is complete, add the reaction solution to 100 mL of water, then add 100 mL of ethyl acetate, stir and separate the layers, wash the organic phase twice with 50 mL of saturated brine, dry over sodium sulfate, concentrate, and purify by column chromatography to obtain 17.49 g of intermediate Body 1, yield 90.1%.

Mass spectral data of compound 1: [M+H] ⁺ 195.1.

Example 12

Dissolve 38.8g of compound formula 1 (0.2mol) in 600mL of dichloromethane, control the reaction temperature at 0°C, add 41.6g of m-chloroperoxybenzoic acid (0.24mol, 1.2eq) in batches, after the addition is complete, heat up After the reaction was complete at room temperature, the reaction solution was concentrated to about 100 mL, then cooled to 0°C and filtered. The filter cake was washed with dichloromethane at 0°C, and the filtrate was concentrated to obtain 38.6 g of the product with a yield of 91.8%.

Mass spectral data of compound 2: [M+Na] ⁺ 233.1.

Example 13

31.5g compound formula 2 (0.15mol) is dissolved in the tetrahydrofuran (400ml) solution of CuBr (3.0g), at-78 ℃, adds ethylmagnesium chloride under nitrogen protection [from ethylchloride (50 grams) and magnesium ( 9.2 g) was prepared]. After the addition, the temperature was raised to room temperature, and the stirring was continued for 1 hour. The reaction was complete, and the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with 1N HCl, water, saturated NaHCO ₃ , concentrated, and the concentrate was purified by silica gel chromatography to obtain 32.8 g of compound formula 3 with a yield of 91.1%.

Mass spectral data of compound 3: [M+H] ⁺ 241.1.

Example 14

28.8g of compound formula 3 (0.12mol) was dissolved in 300mL of dichloromethane, the temperature was cooled to 0°C, and 39.5g of trifluoromethanesulfonic anhydride (0.14mol) was added in batches. After the addition, the reaction was complete at 40°C and cooled to At room temperature, add 100 mL of saturated sodium chloride solution to wash 3 times, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 40.2 g of the product with a yield of 90.0%.

Mass spectral data of compound 4: [M+18] ⁺ 390.0.

Example 15

In a 500mL reaction vessel, add 37.2g of compound 4 (0.1mol), 1% equivalent of palladium acetate, 2% equivalent of 1,3-bis(diphenylphosphine)propane, 2 equivalents of DIPEA, 1.2 equivalents of tributyl (1-Ethoxyethylene) tin, 200mL DMSO, nitrogen replacement 3 times, heated to 100°C and stirred until the reaction was complete, cooled to room temperature, added 6N hydrochloric acid to the reaction solution to adjust the pH to 5-6, stirred at room temperature for 1 hour, added Extract with water and ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify to obtain 22.2 g of compound formula 5 with a yield of 83.6%.

Mass spectral data of compound 5: [M+H] ⁺ 267.0.

Example 16

Add 26.6g of compound formula 5 (0.1mol) into a 500mL three-necked flask, dissolve it in 300mL of ethyl acetate and chloroform (1:1 volume ratio), add 16.0g of copper bromide (0.11mol), and control the temperature at 50-60°C. React for 5-6 hours, check the reaction is complete by pointing the plate, filter and concentrate, then dissolve with dichloromethane, wash the organic phase with ammonium chloride aqueous solution until the water phase is colorless, dry and concentrate the organic phase to obtain 28.3 g of the product, the yield is 82.1% .

Mass spectral data of compound 6: [M+H] ⁺ 345.1.

Example 17

Add 39.5g of compound a (0.102mol) to a 500mL three-necked flask, add 180mL of N,N-dimethylacetamide, protect with nitrogen, cool down to 5°C in an ice-water bath, add 8.96g (0.112mol) of NaH, React for 30 minutes, lower the temperature to -15°C, add 38.0g of N,N-dimethylacetamide solution 180mL of compound formula 6 (0.110mol) dropwise, control the dropping temperature at -20～-10°C, and add in about 45 minutes After completion of the dropwise addition, react for 1 hour to detect that the reaction is complete, add 17.03g of acetic acid, stir at room temperature for 0.5 hours, raise the temperature to 10-20°C, add 600mL of water, add 360mL of dichloromethane, stir, separate liquid, and use it for the water phase 180mL dichloromethane was extracted once, the organic phase was combined, and the organic phase was washed twice with 180mL 4% sodium bicarbonate solution, washed once with 180mL saturated brine, dried, concentrated, and purified by column chromatography to obtain 44.7g of compound formula 7, Yield 67.2%.

Mass spectral data of compound 6: [M+H] ⁺ 653.4.

Example 18

Add 3.3g of compound formula 7 (5mmol), 50mL of acetonitrile, 3.2g (15mmol) of trifluoroacetic anhydride into a 100mL three-necked flask, heat up to 70-80°C, the reaction is complete, cool to room temperature, add 150mL of water, and add 80mL of ethyl acetate , layered, the aqueous phase was extracted twice with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was concentrated, and purified by column to obtain 1.9 g of compound 8 with a yield of 72.0%.

Mass spectral data of compound 8: [M+H] ⁺ 535.1.

The NMR data of compound 8 are as follows: ¹ H-NMR (400MHz, d-DMSO) δ8.78(s,1H),8.07-8.39(m,2H),8.01-7.96(m,1H),7.61(s,1H) ,7.47-7.44(m,3H),6.96-6.92(m,1H),4.34-4.29(m,1H),3.89-3.65(m,5H),3.28-3.24(m,1H),2.51-2.47( m, 1H), 2.34(s, 3H), 1.03-0.98(m, 1H), 0.82-0.79(m, 1H), 0.63-0.60(m, 3H).

Example 19

Add 6g of compound 8 (11.22mmol), 20mL DMSO, and 1.5 equivalents of potassium tert-butoxide to a 500mL three-neck flask, react until complete at room temperature, add 80mL of water, extract 3 times with 50mL of ethyl acetate, combine the organic phases, and wash with 50mL of saturated saline Once, the organic phase was concentrated and purified by column to obtain 3.82 g of upadatinib, with a yield of 89.4%.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

A kind of preparation method of new upadatinib intermediate compound formula 6, this preparation method comprises the following steps:

(1) compound formula 1 obtains compound formula 2 through epoxidation reaction;

(2) Compound formula 2 and organometallic reagents undergo an addition reaction to prepare compound formula 3;

(3) compound formula 3 is prepared compound formula 4 through protection reaction;

(4) compound formula 4 reacts with acetyl reagent to prepare compound formula 5;

(5) Compound formula 5 is reacted with brominating reagent to prepare compound formula 6;

The process route is as follows:

Wherein G is the protecting group of nitrogen atom or trifluoroethyl formamide group, R is the hydroxyl protecting group, and the protecting group of described nitrogen atom includes but not limited to alkoxycarbonyl class, acyl class and alkyl class; The protection of nitrogen atom Groups include but are not limited to benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl Acyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl; preferred protecting groups are benzyl, benzyloxycarbonyl, allyloxy Carbon group; the hydroxyl protecting group includes but not limited to alkyl, alkoxyalkyl, acyl, silicon ether; preferably, the hydroxyl protecting group includes but not limited to methyl, methoxymethyl, tetrahydrofuran benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl, triisopropylsilyl, benzoyl, trifluoromethanesulfonyl.
method according to claim 1, is characterized in that, in the described step (1), the commonly used oxidizing agent of epoxidation reaction is organic peroxyacid, and described organic peroxyacid is m-chloroperoxybenzoic acid, peracetic acid, Any one of peroxyformic acid, peroxytrifluoroacetic acid, dimethyl copper peroxide, and dimethyldioxirane; commonly used solvents are inert solvents, including but not limited to halogenated hydrocarbons, benzene, toluene, One or more of the group consisting of xylene, nitrobenzene, acetonitrile and ether.
The method according to claim 1, wherein the organometallic reagents in the step (2) are Grignard reagents, organolithium reagents, organoaluminum reagents, organotitanium reagents, organomanganese reagents, organozinc reagents, organotin reagents Any one of reagents and organic samarium reagents, and the solvent is one or more of toluene, dichloromethane, chloroform, tetrahydrofuran, 1,2-dichloroethane, and 1,4-dioxane; The organometallic reagent is preferably a Grignard reagent, including but not limited to ethylmagnesium bromide and ethylmagnesium chloride; the molar ratio of compound formula 2 to the Grignard reagent is 1:1-1.5; the reaction temperature is 0-90°C.
The method according to claim 1, characterized in that, in the step (3), the solvent is N,N-dimethylformamide, acetonitrile, toluene, methylene chloride, tetrahydrofuran, 1,2-dioxane , one or more of acetone; the base is imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, sodium hydride, potassium carbonate, N,N-diisopropylethylamine, carbonic acid One or more of sodium and triethylamine; the molar ratio of compound formula 3 to base is 1:1-3; the reaction temperature is -78-80°C.
The method according to claim 1, characterized in that, in the step (4), the acetyl reagent is vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-ethylene oxide One or more of base ethanol, vinyloxytrimethylsilane; the solvent is toluene, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, acetonitrile One or more; bases are N,N-diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine , 1,8-diazabicycloundec-7-ene or 1,4-diazabicyclo[2.2.2]octane, preferably N,N-diisopropylethylamine; the described The amount of base added is 1-3 times the equivalent of compound formula 4; the catalyst is tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, acetic acid Palladium, three (dibenzylidene acetone) dipalladium, the addition amount of catalyst is 0.5%-1% equivalent of compound formula 4; Can also add ligand according to reaction type, and ligand is 1,2-bis (diphenyl Phosphine)ethane, 1,3-bis(diphenylphosphino)propane, 1,1-bis(diphenylphosphino)ferrocene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine , the amount of ligand added is the equivalent of 1%-2% of the catalyst.
method according to claim 1, is characterized in that, in described step (5), bromination reagent is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; The solvent is ethyl acetate, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixed solvents.
A preparation method of a new upatinib key core compound formula 8, characterized in that it comprises the following steps: compound formula 6 obtained by the preparation method described in claims 1-6 and compound a under suitable conditions Carry out condensation reaction to obtain intermediate compound formula 7; Compound formula 7 obtains intermediate compound formula 8 through ring-forming reaction under the action of trifluoroacetic anhydride and organic base; Wherein the structural formula of compound a, compound formula 7, compound formula 8 is as follows :

wherein G is a nitrogen atom protecting group or a trifluoroethyl formamide group.
The method according to claim 7, wherein the alkali selected for the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N,N-diisopropyl ethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or 1,4-diazabicyclo[2.2.2]octane , or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate; in addition, the amount of base added is 3 times the equivalent of compound formula 6; the reaction solvent is N,N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, 1,4-dioxane or tetrahydrofuran; the reaction temperature is -20°C to 110°C.
The method according to claim 7, characterized in that, the base of the ring-forming reaction is selected from triethylamine, N,N-diisopropylethylamine, pyridine or 2,6-lutidine; reaction solvent Selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is -20°C ~110°C.
A new preparation method of upatinib, characterized in that the compound formula 8 obtained by the preparation method according to claims 7 to 9 is subjected to a deprotection reaction to obtain the compound formula 9, and the compound formula 9 is present under the condition of carbonyl diimidazole Condensation reaction with trifluoroethylamine to obtain chemical compound formula 10, chemical compound formula 10 is deprotected to obtain upatinib, wherein G is the protecting group of nitrogen atom, compound formula 9, the structural formula of compound formula 10 is as follows Show:
The method according to claim 10, wherein the compound formula 8 is reacted to obtain the compound formula 9 under the action of a deamination protection reagent, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and Trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 /Pd-C.
The method according to claim 10, wherein the alkali of the condensation reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, triethylamine, diisopropylethylamine , pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or 1,4-diazabicyclo[2.2.2]octane; the reaction solvent is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is -10℃～110℃.
The method according to claim 10, characterized in that, the compound formula 10 is reacted to prepare upatinib under the action of a deamination protection reagent, and the deamination protection reagent is hydrobromic acid, acetic acid, dichloromethane With trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, H 2 /Pd-C or alkali.
A new method for preparing upatinib, characterized in that the compound formula 8 obtained by the preparation method according to claims 7 to 9 is subjected to a deprotection reaction to prepare upatinib, wherein the compound formula 8 The structural formula is as follows:
The compound formula 8 is reacted under the action of a deamination protection reagent to prepare upatinib, and the deamination protection reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate Esters, H2 /Pd-C or bases.