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CN115417802A - Preparation method of sepiatinib and intermediate thereof - Google Patents

Preparation method of sepiatinib and intermediate thereof Download PDF

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CN115417802A
CN115417802A CN202110531186.3A CN202110531186A CN115417802A CN 115417802 A CN115417802 A CN 115417802A CN 202110531186 A CN202110531186 A CN 202110531186A CN 115417802 A CN115417802 A CN 115417802A
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acid
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阮晶
严恭超
阮晓娜
张薇
张鑫鑫
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Shanghai Dingya Pharmaceutical Chemicals Co ltd
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    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract

The invention provides a new synthetic method of an Upaginib intermediate. The synthesis method comprises the following steps: (1) The compound formula 1 is subjected to epoxidation reaction, addition reaction and protection reaction to prepare a compound formula 4; reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in a formula 5; then reacting with a brominating reagent to obtain a compound shown as a formula 6; the reaction formula is shown as follows:

Description

乌帕替尼及其中间体的制备方法Preparation method of upadatinib and its intermediate

技术领域technical field

本发明涉及药物合成领域,具体而言,涉及一种乌帕替尼中间体的制备方法,此外还涉及乌帕替尼的制备方法。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.

背景技术Background technique

乌帕替尼化学名称为(3S,4R)-3-乙基-4-(3H-吡唑并[1,2-a]吡咯并[2,3-e]吡嗪-8-基)-N-(2,2,2-三氟乙基)吡咯烷-1-甲酰胺,结构式如下: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:

Figure 607408DEST_PATH_IMAGE001
Figure 607408DEST_PATH_IMAGE001

其是一种新型靶点JAK1抑制剂,被用于治疗特应性皮炎。It is a novel target JAK1 inhibitor, which is used to treat atopic dermatitis.

目前,美国专利US2017129902A1和WO20170667751A1报道了原研公司艾伯维的乌帕替尼合成路线。从上述专利申请中不难看出,手性关键中间体I的构建是乌帕替尼合成路线的核心之一。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.

Figure 351373DEST_PATH_IMAGE002
Figure 351373DEST_PATH_IMAGE002

而对手性关键中间体I的制备方法也有诸多报道,如专利文献CN 111217819 A、WO2020202183 Al、WO2020043033A2等, 上述专利文献公开的手性关键中间体I的制备方法均是经化学拆分得到光学纯中间体

Figure 463685DEST_PATH_IMAGE003
,再由该中间体进一步转化为手性关键中间体I。There are also many reports on the preparation method of the chiral key intermediate I, such as patent documents CN 111217819 A, WO2020202183 Al, WO2020043033A2, etc. The preparation methods of the chiral key intermediate I disclosed in the above patent documents are obtained by chemical resolution. intermediate
Figure 463685DEST_PATH_IMAGE003
, and then further transformed into chiral key intermediate I by this intermediate.

中国专利CN 109369659 B报道了不需要经过化学拆分制备手性关键中间体I的合成路线。该路线以羰基中间体A-1为起始原料,与格氏试剂反应得到羟基中间体A-2。而后经硫酸脱水、碱水解得到中间体A-4。再经手性Ru金属催化剂氢化直接得到手性羧酸中间体A-5,再经氯代、重氮化、溴代得到目标中间体I,反应式如下:Chinese patent CN 109369659 B reports a synthetic route for preparing chiral key intermediate I without chemical resolution. 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:

Figure 798852DEST_PATH_IMAGE004
Figure 798852DEST_PATH_IMAGE004

该路线使用了重氮化合物作为反应物料,存在较大的安全隐患,使用的手性Ru金属催化剂价格昂贵,成本高,不利于进行工业化放大生产。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.

鉴于此,特提出本发明。In view of this, the present invention is proposed.

发明内容Contents of the invention

本发明的目的之一在于提供一种新的乌帕替尼中间体的制备方法,以解决现有的乌帕替尼中间体的制备方法存在制备成本高、有安全隐患的问题。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.

为了实现上述目的,本发明第一方面提供了一种新的乌帕替尼中间体化合物式6的制备方法,该制备方法包括下列步骤: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)化合物式1经环氧化反应制得化合物式2;(1) compound formula 1 is prepared by epoxidation reaction to compound formula 2;

(2)化合物式2与有机金属试剂发生加成反应制得化合物式3;(2) Addition reaction of compound formula 2 with an organometallic reagent to prepare compound formula 3;

(3)化合物式3经保护反应制得化合物式4;(3) compound formula 4 is prepared by protection reaction of compound formula 3;

(4)化合物式4与乙酰基试剂反应制得化合物式5;(4) compound formula 4 is reacted with an acetyl reagent to prepare compound formula 5;

(5)化合物式5与溴化试剂反应制得化合物式6;(5) compound formula 5 is reacted with a brominating reagent to prepare compound formula 6;

工艺路线如下所示:The process route is as follows:

Figure 996615DEST_PATH_IMAGE005
Figure 996615DEST_PATH_IMAGE005

其中G为氮原子的保护基或三氟乙基甲酰胺基,R为羟基保护基。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.

优选地,步骤(1)中环氧化反应常用的氧化剂为有机过氧酸,所述的有机过氧酸为间氯过氧苯甲酸,过氧乙酸,过氧甲酸,过氧三氟乙酸,二甲基过氧化铜,二甲基双环氧乙烷中的任意一种;常用的溶剂为惰性溶剂,包括但不限于卤代烃、苯、甲苯、二甲苯、硝基苯、乙腈、乙醚组成的组中的一种或多种。Preferably, the oxidizing agent 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.

优选地,步骤(2)中有机金属试剂为格氏试剂、有机锂试剂、有机铝试剂、有机钛试剂、有机锰试剂、有机锌试剂、有机锡试剂、有机钐试剂中的任意一种,溶剂为甲苯、二氯甲烷、三氯甲烷、四氢呋喃,1,2-二氯乙烷、1,4-二氧六环中的一种或多种;所述的有机金属试剂优选格氏试剂,包括但不限于乙基溴化镁,乙基氯化镁;化合物式2与格氏试剂摩尔比为1:1~1.5;反应温度为0~90℃。Preferably, the organometallic reagent in step (2) is any one of Grignard reagents, organolithium reagents, organoaluminum reagents, organotitanium reagents, organomanganese reagents, organozinc reagents, organotin reagents, organosamarium reagents, and the 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.

优选地,步骤(3)中溶剂为N,N-二甲基甲酰胺、乙腈、甲苯、二氯甲烷、四氢呋喃、1,2-二氧六环、丙酮中的一种或多种;碱为咪唑、吡啶、四丁基氟化铵,2,6-二甲基吡啶,氢化钠、碳酸钾,N,N-二异丙基乙胺,碳酸钠、三乙胺中的一种或多种;化合物式3与碱的摩尔比为1:1~3;反应温度为-78~80℃。Preferably, the solvent in step (3) is one or more of N,N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1,2-dioxane, and 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.

优选地,步骤(4)中乙酰基试剂为乙烯基正丁醚、乙酸酐、三丁基(1-乙氧基乙烯)锡、2-乙烯氧基乙醇、乙烯氧基三甲基硅烷中的一种或多种;溶剂为甲苯、N,N-二甲基甲酰胺、二甲基亚砜、1,4-二氧六环、乙腈中的一种或多种;碱为N,N-二异丙基乙胺、三乙胺、吡啶、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基,4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷,优选N,N-二异丙基乙胺;所述的碱的加入量为化合物式4的1-3倍当量;催化剂为四(三苯基膦)钯,[1,1'-双(二苯基膦基)二茂铁]二氯化钯,醋酸钯,三(二亚苄基丙酮)二钯,催化剂的加入量为化合物式4的0.5%-1%当量;根据反应类型还可以加入配体,配体为1,2-双(二苯基膦)乙烷,1,3-双(二苯基膦)丙烷,1,1-双(二苯基膦)二茂铁,1,1’-联萘-2,2’-双二苯膦,配体的加入量为催化剂的1%-2%的当量。Preferably, the acetyl reagent in step (4) 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; catalysts are 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 type of reaction, and the ligands are 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine) phenylphosphine) propane, 1,1-bis(diphenylphosphino)ferrocene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, the amount of ligand added is 1% of the catalyst- 2% equivalent.

优选地,步骤(5)中溴化试剂为三溴吡啶嗡盐,液溴、溴代丁二酰亚胺、二溴海因或溴化铜;溶剂为乙酸乙酯、二氯甲烷、乙腈、甲苯或四氢呋喃或它们的混合溶剂。Preferably, the bromination reagent in step (5) is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, Toluene or tetrahydrofuran or their mixed solvents.

关于氮原子的保护基,可以选择本领域已知的各种类型的保护基团,氮原子的保护基包括但不限于烷氧羰基类,酰基类和烷基类。优选地,氮原子的保护基包括但不限于苄氧基羰基,叔丁氧羰基,芴甲氧羰基,烯丙氧羰基,三甲基硅乙氧羰基,甲氧羰基,乙氧羰基,邻苯二甲酰基,对甲苯磺酰基,三氟乙酰基,三苯甲基,2,4-二甲氧基苄基,对甲氧基苄基,苄基。作为本申请用途,优选的保护基为苄基、苄氧基羰基、烯丙氧基碳基。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.

关于羟基保护基,可以选择本领域已知的各种类型的保护基团,羟基保护基包括但不限于烷基、烷氧基烷基、酰基类、硅醚。优选地,羟基保护基包括但不限于甲基、甲氧基甲基、四氢呋喃基、苄基、对甲氧基苄基、三苯甲基、乙酰基、新戊酰基、三甲基甲硅烷基、三异丙基甲硅烷基、苯甲酰基、三氟甲磺酰基。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.

本发明的第二方面还提供了乌帕替尼中间体化合物式6,该乌帕替尼中间体化合物式6由上述合成工艺制备得到。The second aspect of the present invention also provides an upadatinib intermediate compound formula 6, which is prepared by the above synthesis process.

本发明的第三方面还提供了一种新的乌帕替尼关键母核化合物式8的制备方法,其制备方法包括下列步骤:将上述化合物式6与化合物a在合适的条件下进行缩合反应得到中间体化合物式7;化合物式7在三氟醋酐和有机碱作用下经成环反应得到中间体化合物式8;其中化合物a,化合物式7、化合物式8的结构式如下所示: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:

Figure 42806DEST_PATH_IMAGE006
Figure 9625DEST_PATH_IMAGE007
Figure 781272DEST_PATH_IMAGE008
Figure 42806DEST_PATH_IMAGE006
,
Figure 9625DEST_PATH_IMAGE007
,
Figure 781272DEST_PATH_IMAGE008

其中G为氮原子的保护基或三氟乙基甲酰胺基。wherein G is a nitrogen atom protecting group or a trifluoroethyl formamide group.

优选地,所述缩合反应选用的碱为碳酸钠、磷酸钾、碳酸钾、碳酸铯、叔丁醇钾、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷,或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基;此外碱的加入量为化合物式6的3倍当量;反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯、乙腈、1,4-二氧六环或四氢呋喃;反应温度为-20℃~110℃。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~110°C.

优选地,所述成环反应的碱选自三乙胺、N,N-二异丙基乙胺、吡啶或2,6-二甲基吡啶;反应溶剂选自二氯甲烷、甲苯、乙腈、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮;反应温度为-20℃~110℃。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℃.

本发明的第四方面还提供了乌帕替尼关键母核化合物式8,该乌帕替尼关键母核化合物式8由前述合成工艺制备得到。The fourth aspect of the present invention also provides upatinib key core compound formula 8, which is prepared by the aforementioned synthesis process.

本发明的第五方面还提供了一种新的乌帕替的制备方法,采用如下技术方案:The fifth aspect of the present invention also provides a new preparation method of upapatib, adopting the following technical scheme:

上述化合物式8经脱保护反应得到化合物式9,化合物式9在羰基二咪唑存在条件下与三氟乙胺发生缩合反应得到化学物式10,化学物式10经脱保护反应制得乌帕替尼,其中化合物式8中G为氮原子的保护基,化合物式9,化合物式10的结构式如下所示: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:

Figure 200752DEST_PATH_IMAGE009
Figure 552099DEST_PATH_IMAGE010
Figure 200752DEST_PATH_IMAGE009
,
Figure 552099DEST_PATH_IMAGE010
.

优选地,将化合物式8在脱氨基保护试剂作用下反应制得化合物式9,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-C。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.

优选地,缩合反应的碱选自碳酸钾、碳酸钠、碳酸铯、磷酸二氢钾、磷酸二氢钠、三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷;反应溶剂选自乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或甲苯;反应温度为-10℃~110℃。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~110°C.

优选地,将化合物式10在脱氨基保护试剂作用下反应制得乌帕替尼,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-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.

本发明的第六方面还提供了第二种新的乌帕替尼的制备方法,采用如下技术方案:The sixth aspect of the present invention also provides a second new method for preparing upatinib, which adopts the following technical scheme:

将上述化合物式8经脱保护反应制得乌帕替尼,其中所述化合物式8的结构式如下所示:

Figure 373424DEST_PATH_IMAGE011
。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:
Figure 373424DEST_PATH_IMAGE011
.

优选地,将化合物式8在脱氨基保护试剂作用下反应制得乌帕替尼,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-C。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.

本发明的第七方面还提供了乌帕替尼,该乌帕替尼由前述任一项合成工艺制备得到。The seventh aspect of the present invention also provides upadatinib, which is prepared by any one of the aforementioned synthesis processes.

应用本发明的技术方案,通过不对称的环氧化反应生成反式羟基化合物,在经钯催化,乙酰基从背面进攻生成顺式产物,不需要手性拆分,定向合成手性化合物,避免昂贵原材料的使用,降低乌帕替尼及其中间体的制备成本,便于工业化推广。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.

具体实施方式Detailed ways

需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。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.

正如背景技术中所描述的,现有的乌帕替尼中间体的制备方法存在制备成本高、有安全隐患的问题。为了解决上述技术问题,本申请提供了一种新的乌帕替尼中间体化合物式6的制备方法,该制备方法包括下列步骤: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)化合物式1经环氧化反应制得化合物式2;(1) compound formula 1 is prepared by epoxidation reaction to compound formula 2;

(2)化合物式2与有机金属试剂发生加成反应制得化合物式3;(2) Addition reaction of compound formula 2 with an organometallic reagent to prepare compound formula 3;

(3)化合物式3经保护反应制得化合物式4;(3) compound formula 4 is prepared by protection reaction of compound formula 3;

(4)化合物式4与乙酰基试剂反应制得化合物式5;(4) compound formula 4 is reacted with an acetyl reagent to prepare compound formula 5;

(5)化合物式5与溴化试剂反应制得化合物式6;(5) compound formula 5 is reacted with a brominating reagent to prepare compound formula 6;

工艺路线如下所示:The process route is as follows:

Figure 315972DEST_PATH_IMAGE005
Figure 315972DEST_PATH_IMAGE005

其中G为氮原子的保护基或三氟乙基甲酰胺基,R为羟基保护基。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.

优选地,步骤(1)中环氧化反应常用的氧化剂为有机过氧酸,所述的有机过氧酸为间氯过氧苯甲酸,过氧乙酸,过氧甲酸,过氧三氟乙酸,二甲基过氧化铜,二甲基双环氧乙烷中的任意一种;常用的溶剂为惰性溶剂,包括但不限于卤代烃、苯、甲苯、二甲苯、硝基苯、乙腈、乙醚组成的组中的一种或多种。Preferably, the oxidizing agent 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.

优选地,步骤(2)中有机金属试剂为格氏试剂、有机锂试剂、有机铝试剂、有机钛试剂、有机锰试剂、有机锌试剂、有机锡试剂、有机钐试剂中的任意一种,溶剂为甲苯、二氯甲烷、三氯甲烷、四氢呋喃,1,2-二氯乙烷、1,4-二氧六环中的一种或多种;所述的有机金属试剂优选格氏试剂,包括但不限于乙基溴化镁,乙基氯化镁;化合物式2与格氏试剂摩尔比为1:1~1.5;反应温度为0~90℃。Preferably, the organometallic reagent in step (2) is any one of Grignard reagents, organolithium reagents, organoaluminum reagents, organotitanium reagents, organomanganese reagents, organozinc reagents, organotin reagents, organosamarium reagents, and the 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.

优选地,步骤(3)中溶剂为N,N-二甲基甲酰胺、乙腈、甲苯、二氯甲烷、四氢呋喃、1,2-二氧六环、丙酮中的一种或多种;碱为咪唑、吡啶、四丁基氟化铵,2,6-二甲基吡啶,氢化钠、碳酸钾,N,N-二异丙基乙胺,碳酸钠、三乙胺中的一种或多种;化合物式3与碱的摩尔比为1:1~3;反应温度为-78~80℃。Preferably, the solvent in step (3) is one or more of N,N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1,2-dioxane, and 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.

优选地,步骤(4)中乙酰基试剂为乙烯基正丁醚、乙酸酐、三丁基(1-乙氧基乙烯)锡、2-乙烯氧基乙醇、乙烯氧基三甲基硅烷中的一种或多种;溶剂为甲苯、N,N-二甲基甲酰胺、二甲基亚砜、1,4-二氧六环、乙腈中的一种或多种;碱为N,N-二异丙基乙胺、三乙胺、吡啶、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基,4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷,优选N,N-二异丙基乙胺;所述的碱的加入量为化合物式4的1-3倍当量;催化剂为四(三苯基膦)钯,[1,1'-双(二苯基膦基)二茂铁]二氯化钯,醋酸钯,三(二亚苄基丙酮)二钯,催化剂的加入量为化合物式4的0.5%-1%当量;根据反应类型还可以加入配体,配体为1,2-双(二苯基膦)乙烷,1,3-双(二苯基膦)丙烷,1,1-双(二苯基膦)二茂铁,1,1’-联萘-2,2’-双二苯膦,配体的加入量为催化剂的1%-2%的当量。Preferably, the acetyl reagent in step (4) 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; catalysts are 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 type of reaction, and the ligands are 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine) phenylphosphine) propane, 1,1-bis(diphenylphosphino)ferrocene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, the amount of ligand added is 1% of the catalyst- 2% equivalent.

优选地,步骤(5)中溴化试剂为三溴吡啶嗡盐,液溴、溴代丁二酰亚胺、二溴海因或溴化铜;溶剂为乙酸乙酯、二氯甲烷、乙腈、甲苯或四氢呋喃或它们的混合溶剂。Preferably, the bromination reagent in step (5) is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, Toluene or tetrahydrofuran or their mixed solvents.

关于氮原子的保护基,可以选择本领域已知的各种类型的保护基团,氮原子的保护基包括但不限于烷氧羰基类,酰基类和烷基类。优选地,氮原子的保护基包括但不限于苄氧基羰基,叔丁氧羰基,芴甲氧羰基,烯丙氧羰基,三甲基硅乙氧羰基,甲氧羰基,乙氧羰基,邻苯二甲酰基,对甲苯磺酰基,三氟乙酰基,三苯甲基,2,4-二甲氧基苄基,对甲氧基苄基,苄基。作为本申请用途,优选的保护基为苄基、苄氧基羰基、烯丙氧基碳基。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.

关于羟基保护基,可以选择本领域已知的各种类型的保护基团,羟基保护基包括但不限于烷基、烷氧基烷基、酰基类、硅醚。优选地,羟基保护基包括但不限于甲基、甲氧基甲基、四氢呋喃基、苄基、对甲氧基苄基、三苯甲基、乙酰基、新戊酰基、三甲基甲硅烷基、三异丙基甲硅烷基、苯甲酰基、三氟甲磺酰基。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.

化合物式1可以通过购买得到,或者可以参照现有技术合成得到。The compound formula 1 can be obtained through purchase, or can be synthesized by referring to the prior art.

本发明的第二方面还提供了乌帕替尼中间体化合物式6,该乌帕替尼中间体化合物式6由上述合成工艺制备得到。The second aspect of the present invention also provides an upadatinib intermediate compound formula 6, which is prepared by the above synthesis process.

本发明的第三方面还提供了一种新的乌帕替尼关键母核化合物式8的制备方法,该制备方法如下: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:

Figure 222749DEST_PATH_IMAGE012
Figure 222749DEST_PATH_IMAGE012
.

具体的制备方法包括下列步骤:利用上述合成得到的化合物式6与化合物a在合适的条件下进行缩合反应得到中间体化合物式7;化合物式7在三氟醋酐和有机碱作用下经成环反应得到中间体化合物式8,其中G为氮原子的保护基或三氟乙基甲酰胺基。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.

优选地,所述缩合反应选用的碱为碳酸钠、磷酸钾、碳酸钾、碳酸铯、叔丁醇钾、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷,或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基;此外碱的加入量为化合物式6的3倍当量;反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯、乙腈、1,4-二氧六环或四氢呋喃;反应温度为-20℃~110℃。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~110°C.

优选地,所述成环反应的碱选自三乙胺、N,N-二异丙基乙胺、吡啶或2,6-二甲基吡啶;反应溶剂选自二氯甲烷、甲苯、乙腈、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮;反应温度为-20℃~110℃。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℃.

本发明的第四方面还提供了乌帕替尼关键母核化合物式8,该乌帕替尼关键母核化合物式8由前述合成工艺制备得到。The fourth aspect of the present invention also provides upatinib key core compound formula 8, which is prepared by the aforementioned synthesis process.

本发明的第五方面还提供了一种新的乌帕替的制备方法,该制备方法如下:The fifth aspect of the present invention also provides a new preparation method of upapatib, the preparation method is as follows:

Figure 112207DEST_PATH_IMAGE013
Figure 112207DEST_PATH_IMAGE013
.

具体的制备方法包括下列步骤:上述化合物式8经脱保护反应得到化合物式9,化合物式9在羰基二咪唑存在条件下与三氟乙胺发生缩合反应得到化学物式10,化学物式10经脱保护反应制得乌帕替尼,其中G为氮原子的保护基。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.

优选地,将化合物式8在脱氨基保护试剂作用下反应制得化合物式9,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-C。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.

优选地,缩合反应的碱选自碳酸钾、碳酸钠、碳酸铯、磷酸二氢钾、磷酸二氢钠、三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或1,4-二氮杂二环[2.2.2]辛烷;反应溶剂选自乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或甲苯;反应温度为-10℃~110℃。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~110°C.

优选地,将化合物式10在脱氨基保护试剂作用下反应制得乌帕替尼,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-C,碱。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.

本发明的第六方面还提供了第二种新的乌帕替尼的制备方法,该制备方法如下:The sixth aspect of the present invention also provides a second new preparation method of upatinib, the preparation method is as follows:

Figure 584777DEST_PATH_IMAGE014
Figure 584777DEST_PATH_IMAGE014
.

具体的制备方法包括下列步骤:将上述化合物式8经脱保护反应制得乌帕替尼,其中G为三氟乙基甲酰胺基。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.

优选地,将化合物式8在脱氨基保护试剂作用下反应制得乌帕替尼,所述的脱氨基保护试剂为氢溴酸与乙酸、二氯甲烷与三氟乙酸、盐酸与甲醇、盐酸与乙酸乙酯或H2/Pd-C,碱。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.

本发明的第七方面还提供了乌帕替尼,该乌帕替尼由前述任一项合成工艺制备得到。The seventh aspect of the present invention also provides upadatinib, which is prepared by any one of the aforementioned synthesis processes.

应用本发明的技术方案,通过不对称的环氧化反应生成反式羟基化合物,在经钯催化,乙酰基从背面进攻生成顺式产物,不需要手性拆分,定向合成手性化合物,避免昂贵原材料的使用,降低乌帕替尼及其中间体的制备成本,便于工业化推广。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.

需要说明的是本申请中DIPEA 是指N,N-二异丙基乙胺,DMSO是指氯化亚砜。It should be noted that in this application, DIPEA refers to N,N-diisopropylethylamine, and DMSO refers to thionyl chloride.

实施例1Example 1

Figure 167068DEST_PATH_IMAGE015
Figure 167068DEST_PATH_IMAGE015

将40.6g化合物式1 (0.2mol)溶解在600mL二氯甲烷中,反应温度控制在0℃,分批加入41.6g的间氯过氧苯甲酸 (0.24mol,1.2eq),加入完毕后,升温至室温反应完全,将反应液浓缩至约100mL,再冷却至0℃过滤,滤饼用0℃的二氯甲烷洗涤,浓缩滤液,得到产物40.4g,收率92.2%。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 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 40.4 g of the product with a yield of 92.2%.

化合物2的质谱数据:[M+H]+ 220.0。Mass spectral data of compound 2: [M+H] + 220.0.

实施例2Example 2

Figure 71394DEST_PATH_IMAGE016
Figure 71394DEST_PATH_IMAGE016

将32.9g化合物式2 (0.15mol)溶解在CuBr(3.0g)的四氢呋喃(400ml)溶液中,在-78℃,氮气保护下加入乙基氯化镁[由乙基氯化物(50克)和镁(9.2克)制得]。加入完毕后,升温至室温,继续搅拌2小时,反应完全,反应液用乙酸乙酯和水萃取。将有机层用1N HCl,水,饱和NaHCO3洗涤,浓缩,将浓缩物通过硅胶色谱法纯化,得到化合物式3产物33.7g,收率90.1%。32.9g compound formula 2 (0.15mol) is dissolved in the tetrahydrofuran (400ml) solution of CuBr (3.0g), at-78 ℃, adds ethyl magnesium chloride [by ethyl chloride (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%.

化合物3的质谱数据:[M+H]+ 251.1。Mass spectral data of compound 3: [M+H] + 251.1.

实施例3Example 3

Figure 295702DEST_PATH_IMAGE017
Figure 295702DEST_PATH_IMAGE017

29.9g化合物式3(0.12mol)溶解在300mL二氯甲烷中,温度冷却至0℃,分批加入39.5g三氟甲磺酸酐(0.14mol),加入完后,室温反应至完全,加入饱和氯化钠溶液洗涤3次(100mL/次),用无水硫酸钠干燥,过滤,浓缩得到产物41.1g,收率89.9%。Dissolve 29.9g of compound formula 3 (0.12mol) in 300mL of dichloromethane, cool the temperature to 0°C, add 39.5g of trifluoromethanesulfonic anhydride (0.14mol) in batches, after adding, react at room temperature until complete, add saturated chlorine 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%.

化合物4的质谱数据:[M+H]+ 382.1。Mass spectral data of compound 4: [M+H] + 382.1.

实施例4Example 4

Figure 826040DEST_PATH_IMAGE018
Figure 826040DEST_PATH_IMAGE018

氮气氛围中,在500mL反应容器中加入38.1g化合物4 (0.1mol),1%当量的醋酸钯,2%当量的1,3-双(二苯基膦)丙烷,2当量的DIPEA,1.2当量的三丁基(1-乙氧基乙烯)锡,200mL DMSO,在100℃搅拌反应3小时,检测反应完全,冷却至室温,向反应液中加入6N 盐酸调pH至5~6,室温搅拌1小时,加入水和乙酸乙酯萃取,有机相干燥浓缩,纯化得23.4g化合物式5,收率85.0%。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%.

化合物5的质谱数据:[M+H]+ 276.2。Mass spectral data of compound 5: [M+H] + 276.2.

实施例5Example 5

Figure 264719DEST_PATH_IMAGE019
Figure 264719DEST_PATH_IMAGE019

500mL三口烧瓶中加入27.5g 化合物式5(0.1mol),用300mL乙酸乙酯和氯仿(1:1体积比)溶解,加入16.0g溴化铜(0.11mol),温度控制在50~60℃,反应5~6小时,点板检测反应完全,过滤浓缩,再用乙酸乙酯溶解,用氯化铵水溶液洗涤有机相至水相无色,有机相干燥浓缩纯化得到产物28.3g,收率79.9%。Add 27.5g of compound formula 5 (0.1mol) into a 500mL three-necked flask, dissolve it with 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% .

化合物6的质谱数据:[M+H]+ 354.1。Mass spectral data of compound 6: [M+H] + 354.1.

实施例6Example 6

Figure 146087DEST_PATH_IMAGE020
Figure 146087DEST_PATH_IMAGE020

500mL三口瓶中加入39.5g 化合物a(0.102mol),加入N,N-二甲基乙酰胺180mL,氮气保护,冰水浴降温至5℃,加入NaH 8.96g(0.112mol),在0~10℃反应30分钟,降温至-15℃,滴加39.1g的化合物式6(0.110mol)的N,N-二甲基乙酰胺溶液180mL,控制滴加温度-20~-10℃,约45分钟加完,滴加完毕后,反应1小时,检测反应完全,加入17.03g乙酸,室温搅拌0.5小时,升温至10~20℃,加入600mL水,加入360mL乙酸异丙酯,搅拌,分液,水相用180mL乙酸异丙酯萃取一次,合并有机相,有机相用180mL 4%的碳酸氢钠溶液洗涤两次,用180mL水洗涤一次,纯化,真空干燥得到42.1g化合物式7,收率62.6%。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, at 0~10°C React for 30 minutes, cool down to -15°C, add 39.1g of compound formula 6 (0.110mol) in 180mL of N,N-dimethylacetamide solution 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 the organic phases, wash the organic phase twice with 180mL 4% sodium bicarbonate solution, wash once with 180mL water, purify, and dry in vacuo to obtain 42.1g of compound formula 7 with a yield of 62.6%.

化合物7核磁数据如下:1H-NMR(400MHz,d-DMSO) δ 8.76(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)。The NMR data of compound 7 are as follows: 1 H-NMR(400MHz,d-DMSO) δ 8.76(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).

实施例7Example 7

Figure 642927DEST_PATH_IMAGE021
Figure 642927DEST_PATH_IMAGE021

250mL三口瓶中加入10g化合物式7(15.1mmol), 100mL乙腈,13.0g (61.9mmol)三氟乙酸酐,升温至70~80℃,反应完全,冷却至室温,加入500mL水,加入150 mL乙酸乙酯,分层,水相用乙酸乙酯萃取2次,有机相用100mL饱和食盐水洗涤,浓缩有机相,过柱纯化得到5.0g 化合物8,收率61.0%。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, and add 150 mL of acetic acid Ethyl ester was 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%.

化合物8的质谱数据:[M+H]+ 544.1。Mass spectral data of compound 8: [M+H] + 544.1.

实施例8Example 8

Figure 824510DEST_PATH_IMAGE022
Figure 824510DEST_PATH_IMAGE022

500mL三口瓶中加入10g 化合物8(18.4 mmol), 150mL甲醇,加入2.0g Pd/C,置换氢气三次,室温反应,检测反应完全,过滤,浓缩,得到5.3g化合物9,收率95.0%。Add 10g of compound 8 (18.4 mmol), 150mL of methanol into a 500mL three-neck flask, add 2.0g of Pd/C, replace hydrogen three times, react at room temperature, check that the reaction is complete, filter, and concentrate to obtain 5.3g of compound 9 with a yield of 95.0%.

化合物9核磁数据如下:1H-NMR(400MHz,d-DMSO) δ 9.91(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)。The NMR data of compound 9 are as follows: 1 H-NMR (400MHz, d-DMSO) δ 9.91(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).

化合物9的质谱数据:[M+H]+410.2。Mass spectral data of compound 9: [M+H] + 410.2.

实施例9Example 9

Figure 483024DEST_PATH_IMAGE023
Figure 483024DEST_PATH_IMAGE023

三口烧瓶中加入羰基二咪唑(22.70g,140mmol), 加入N,N-二甲基甲酰胺(150mL)搅拌溶解,加入碳酸钾(27.64g,200mmol),冷却至0℃,缓慢滴加三氟乙胺(14.86g,150mmol),滴加完毕后室温搅拌30分钟,加入化合物9(35.54g,100mmol),室温反应完全,将反应液加入到1L水,再加入500mL乙酸乙酯,搅拌分层,水相再用300mL乙酸乙酯萃取2次,合并有机相,用300mL饱和食盐水洗2次,硫酸钠干燥,有机相浓缩至约150mL,搅拌条件下滴加石油醚至有晶体析出时,缓慢降温至0℃,在0℃继续搅拌析晶2小时,过滤,滤饼用0℃的体积比2:1的石油醚和乙酸乙酯洗涤,干燥得白色固体中间体10, 44.68g,收率93%。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), after the dropwise addition, stir at room temperature for 30 minutes, add compound 9 (35.54g, 100mmol), the reaction is complete at room temperature, add the reaction solution to 1L of water, then add 500mL of ethyl acetate, stir and separate , 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%.

化合物10核磁数据如下:1H-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)。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).

实施例10Example 10

Figure 287907DEST_PATH_IMAGE024
Figure 287907DEST_PATH_IMAGE024

250mL 三口瓶中加入3g 化合物10 (5.61mmol),15mL DMSO,1.5当量的叔丁醇钾,室温反应至完全,加入50mL水,50mL乙酸乙酯萃取3次,合并有机相,50mL饱和食盐水洗涤一次,有机相浓缩,过柱纯化得到1.86g乌帕替尼,收率87.3%。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 brine Once, the organic phase was concentrated and purified by column to obtain 1.86g of upadatinib, with a yield of 87.3%.

实施例11Example 11

Figure 854018DEST_PATH_IMAGE025
Figure 854018DEST_PATH_IMAGE025

三口烧瓶中加入6.9g原料S1(0.1mol),9.91g三氟乙胺(0.1mol),21.2g碳酸钠(0.2mol),150mL四氢呋喃,分批加入17.84g羰基二咪唑(0.11mol),室温搅拌至反应完全,将反应液加入到100mL水,再加入100mL乙酸乙酯,搅拌分层,有机相用50mL饱和食盐水洗2次,硫酸钠干燥,浓缩,用柱层析纯化,得17.49g中间体1,收率90.1%。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%.

化合物1的质谱数据:[M+H]+195.1。Mass spectral data of compound 1: [M+H] + 195.1.

实施例12Example 12

Figure 624528DEST_PATH_IMAGE026
Figure 624528DEST_PATH_IMAGE026

将38.8g化合物式1 (0.2mol)溶解在600mL二氯甲烷中,反应温度控制在0℃,分批加入41.6g的间氯过氧苯甲酸 (0.24mol,1.2eq),加入完毕后,升温至室温反应完全,将反应液浓缩至约100mL,再冷却至0℃过滤,滤饼用0℃的二氯甲烷洗涤,浓缩滤液,得到产物38.6g,收率91.8%。38.8g 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 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%.

化合物2的质谱数据:[M+Na]+233.1。Mass spectral data of compound 2: [M+Na] + 233.1.

实施例13Example 13

Figure 453943DEST_PATH_IMAGE027
Figure 453943DEST_PATH_IMAGE027

将31.5g化合物式2 (0.15mol)溶解在CuBr(3.0g)的四氢呋喃(400ml)溶液中,在-78℃,氮气保护下加入乙基氯化镁[由乙基氯化物(50克)和镁(9.2克)制得]。加入完毕后,升温至室温,继续搅拌1小时,反应完全,反应液用乙酸乙酯和水萃取。将有机层用1N HCl,水,饱和NaHCO3洗涤,浓缩,将浓缩物通过硅胶色谱法纯化,得到化合物式3产物32.8g,收率91.1%。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 ethyl chloride (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%.

化合物3的质谱数据:[M+H]+ 241.1。Mass spectral data of compound 3: [M+H] + 241.1.

实施例14Example 14

Figure 841062DEST_PATH_IMAGE028
Figure 841062DEST_PATH_IMAGE028

28.8g化合物式3(0.12mol)溶解在300mL二氯甲烷中,温度冷却至0℃,分批加入39.5g三氟甲磺酸酐(0.14mol),加入完后,40℃反应至完全,冷却至室温,加入100mL饱和氯化钠溶液洗涤3次,用无水硫酸钠干燥,过滤,浓缩得到产物40.2g,收率90.0%。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 over anhydrous sodium sulfate, filter, and concentrate to obtain 40.2 g of the product, with a yield of 90.0%.

化合物4的质谱数据:[M+18]+ 390.0。Mass spectral data of compound 4: [M+18] + 390.0.

实施例15Example 15

Figure 679705DEST_PATH_IMAGE029
Figure 679705DEST_PATH_IMAGE029

在500mL反应容器中加入37.2g化合物4 (0.1mol),1%当量的醋酸钯,2%当量的1,3-双(二苯基膦)丙烷,2当量的DIPEA,1.2当量的三丁基(1-乙氧基乙烯)锡,200mL DMSO,氮气置换3次,加热至100℃搅拌至反应完全,冷却至室温,向反应液中加入6N 盐酸调pH至5~6,室温搅拌1小时,加入水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,浓缩,纯化得22.2g化合物式5,收率83.6%。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, Water and ethyl acetate were added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 22.2 g of compound formula 5 with a yield of 83.6%.

化合物5的质谱数据:[M+H]+ 267.0。Mass spectral data of compound 5: [M+H] + 267.0.

实施例16Example 16

Figure 39143DEST_PATH_IMAGE030
Figure 39143DEST_PATH_IMAGE030

500mL三口烧瓶中加入26.6g 化合物式5(0.1mol),用300mL乙酸乙酯和氯仿(1:1体积比)溶解,加入16.0g溴化铜(0.11mol),温度控制在50~60℃,反应5~6小时,点板检测反应完全,过滤浓缩,再用二氯甲烷溶解,用氯化铵水溶液洗涤有机相至水相无色,有机相干燥浓缩纯化得到产物28.3g,收率82.1%。Add 26.6g of compound formula 5 (0.1mol) into a 500mL three-necked flask, dissolve it with 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, spot plate detection reaction is complete, 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 28.3g of the product, the yield is 82.1% .

化合物6的质谱数据:[M+H]+ 345.1。Mass spectral data of compound 6: [M+H] + 345.1.

实施例17Example 17

Figure 836197DEST_PATH_IMAGE031
Figure 836197DEST_PATH_IMAGE031

500mL三口瓶中加入39.5g 化合物a(0.102mol),加入N,N-二甲基乙酰胺180mL,氮气保护,冰水浴降温至5℃,加入NaH 8.96g(0.112mol),在0~10℃反应30分钟,降温至-15℃,滴加38.0g的化合物式6(0.110mol)的N,N-二甲基乙酰胺溶液180mL,控制滴加温度-20~-10℃,约45分钟加完,滴加完毕后,反应1小时,检测反应完全,加入17.03g乙酸,室温搅拌0.5小时,升温至10~20℃,加入600mL水,加入360mL二氯甲烷,搅拌,分液,水相用180mL二氯甲烷萃取一次,合并有机相,有机相用180mL 4%的碳酸氢钠溶液洗涤两次,用180mL饱和食盐水洗涤一次,干燥,浓缩,用柱层析纯化,得到44.7g化合物式7,收率67.2%。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, at 0~10°C React for 30 minutes, cool down to -15°C, add 38.0g of compound formula 6 (0.110mol) in 180mL of N,N-dimethylacetamide solution 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, check 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, use for water phase Extract once with 180mL dichloromethane, combine the organic phases, wash the organic phase twice with 180mL 4% sodium bicarbonate solution, wash once with 180mL saturated brine, dry, concentrate, and purify by column chromatography to obtain 44.7g of compound formula 7 , yield 67.2%.

化合物6的质谱数据:[M+H]+ 653.4。Mass spectral data of compound 6: [M+H] + 653.4.

实施例18Example 18

Figure 350093DEST_PATH_IMAGE032
Figure 350093DEST_PATH_IMAGE032

100mL三口瓶中加入3.3g化合物式7(5mmol), 50mL乙腈,3.2g (15mmol)三氟乙酸酐,升温至70~80℃,反应完全,冷却至室温,加入150mL水,加入80 mL乙酸乙酯,分层,水相用乙酸乙酯萃取2次,有机相用饱和食盐水洗涤,浓缩有机相,过柱纯化得到1.9g 化合物8,收率72.0%。Add 3.3g of compound formula 7 (5mmol), 50mL of acetonitrile, 3.2g (15mmol) of trifluoroacetic anhydride into a 100mL three-neck flask, heat up to 70~80°C, the reaction is complete, cool to room temperature, add 150mL of water, add 80 mL of ethyl acetate Esters were separated, 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%.

化合物8的质谱数据:[M+H]+ 535.1。Mass spectral data of compound 8: [M+H] + 535.1.

化合物8核磁数据如下:1H-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)。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).

实施例19Example 19

Figure 992427DEST_PATH_IMAGE033
Figure 992427DEST_PATH_IMAGE033

500mL 三口瓶中加入6g 化合物8 (11.22mmol),20mL DMSO,1.5当量的叔丁醇钾,室温反应至完全,加入80mL水,50mL乙酸乙酯萃取3次,合并有机相,50mL饱和食盐水洗涤一次,有机相浓缩,过柱纯化得到3.82g乌帕替尼,收率89.4%。Add 6g of compound 8 (11.22mmol), 20mL DMSO, and 1.5 equivalents of potassium tert-butoxide into 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 brine Once, the organic phase was concentrated and purified by column to obtain 3.82g of upadatinib, with a yield of 89.4%.

以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。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 (14)

1. A process for the preparation of a novel oupatinib intermediate compound of formula 6, comprising the steps of:
(1) The compound formula 1 is subjected to epoxidation reaction to prepare a compound formula 2;
(2) The compound formula 2 and an organic metal reagent are subjected to addition reaction to prepare a compound formula 3;
(3) The compound shown in the formula 3 is subjected to protection reaction to obtain a compound shown in the formula 4;
(4) Reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in the formula 5;
(5) Reacting the compound shown in the formula 5 with a brominating reagent to obtain a compound shown in the formula 6;
the process route is as follows:
Figure 251090DEST_PATH_IMAGE001
wherein G is a protecting group of nitrogen atom or trifluoroethyl carboxamide group, R is a protecting group of hydroxyl group, the protecting group of nitrogen atom includes but is not limited to alkoxycarbonyl group, acyl group and alkyl group; protecting groups for nitrogen atoms include, but are not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl; preferred protecting groups are benzyl, benzyloxycarbonyl, allyloxycarbonyl; the hydroxyl protecting group includes, but is not limited to, alkyl, alkoxyalkyl, acyl, silyl ether; preferably, the hydroxyl protecting group includes, but is not limited to, methyl, methoxymethyl, tetrahydrofuranyl, benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl, triisopropylsilyl, benzoyl, trifluoromethanesulfonyl.
2. The method according to claim 1, wherein the common oxidant for epoxidation in step (1) is organic peroxy acid, and the organic peroxy acid is any one of m-chloroperoxybenzoic acid, peroxyacetic acid, peroxyformic acid, peroxytrifluoroacetic acid, dimethyl copper peroxide, dimethyl dioxirane; commonly used solvents are inert solvents including, but not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, xylene, nitrobenzene, acetonitrile, diethyl ether.
3. The method according to claim 1, wherein in the step (2), the organometallic reagent is any one of a Grignard reagent, an organolithium reagent, an organoaluminum reagent, an organotitanium reagent, an organomagnesium reagent, an organozinc reagent, an organotin reagent, and an organosamarium reagent, and the solvent is one or more of toluene, dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane, and 1, 4-dioxane; the organometallic reagent is preferably a grignard reagent, including but not limited to ethylmagnesium bromide, ethylmagnesium chloride; the molar ratio of the compound shown in formula 2 to the Grignard reagent is 1 to 1.5; the reaction temperature is 0 to 90 ℃.
4. The method according to claim 1, wherein the solvent in step (3) is one or more of N, N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1, 2-dioxane, and acetone; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, sodium hydride, potassium carbonate, N, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the compound of formula 3 to the base is 1 to 3; the reaction temperature is-78 to 80 ℃.
5. The method according to claim 1, wherein the acetyl reagent in the step (4) is one or more of vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-vinyloxyethanol, vinyloxytrimethylsilane; the solvent is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile; the base is N, N-diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably N, N-diisopropylethylamine; the addition amount of the base is 1-3 times of the equivalent of the compound shown in the formula 4; the catalyst is tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate and tris (dibenzylideneacetone) dipalladium, and the addition amount of the catalyst is 0.5-1% equivalent of the compound shown in the formula 4; according to the reaction type, a ligand can be added, wherein the ligand is 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1-bis (diphenylphosphino) ferrocene, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, and the addition amount of the ligand is 1% -2% of the equivalent of the catalyst.
6. The method according to claim 1, wherein the brominating agent in the step (5) is pyridinium tribromide, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixture.
7. A novel preparation method of a key mother nucleus compound of Upacatinib shown in formula 8 is characterized by comprising the following steps: carrying out condensation reaction on a compound shown in formula 6 obtained by the preparation method of claims 1-6 and a compound a under a proper condition to obtain an intermediate compound shown in formula 7; the compound shown in the formula 7 is subjected to cyclization reaction under the action of trifluoroacetic anhydride and organic base to obtain an intermediate compound shown in the formula 8; wherein the structural formulas of the compound a, the compound formula 7 and the compound formula 8 are shown as follows:
Figure 732887DEST_PATH_IMAGE002
Figure 615392DEST_PATH_IMAGE003
Figure 499035DEST_PATH_IMAGE004
wherein G is a protecting group for a nitrogen atom or a trifluoroethylcarboxamido group.
8. The method according to claim 7, wherein the base used in the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecene-7-ene or 1, 4-diazabicyclo [2.2.2] octane, or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate; further, the base is added in an amount of 3 times equivalent to that of the compound of formula 6; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran; the reaction temperature is-20 ℃ to 110 ℃.
9. The process according to claim 7, wherein the base of the cyclization reaction is selected from triethylamine, N-diisopropylethylamine, pyridine or 2, 6-lutidine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is-20 ℃ to 110 ℃.
10. A novel preparation method of Upatinib is characterized in that a compound formula 8 obtained by the preparation method of claims 7 to 9 is subjected to deprotection reaction to obtain a compound formula 9, the compound formula 9 is subjected to condensation reaction with trifluoroethylamine in the presence of carbonyldiimidazole to obtain a chemical formula 10, the chemical formula 10 is subjected to deprotection reaction to obtain Upatinib, wherein G is a protecting group of a nitrogen atom, the compound formula 9 is shown in the specification, and the structural formula of the compound formula 10 is shown as follows:
Figure 441583DEST_PATH_IMAGE005
Figure 912141DEST_PATH_IMAGE006
11. the process of claim 10, wherein the compound of formula 8 is reacted with a deaminating protecting agent selected from the group consisting of hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H to form the compound of formula 9 2 /Pd-C。
12. The process according to claim 10, wherein 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-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is-10 ℃ to 110 ℃.
13. The process of claim 10, wherein the compound of formula 10 is reacted with a deaminating protecting agent selected from the group consisting of hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H 2 Pd-C or a base.
14. A novel preparation method of Upaltinib, which is characterized in that the Upaltinib is prepared by carrying out deprotection reaction on a compound formula 8 obtained by the preparation method of claims 7 to 9, wherein the structural formula of the compound formula 8 is shown as follows:
Figure 332758DEST_PATH_IMAGE007
the compound formula 8 is reacted under the action of a deamination protective reagent to prepare the lapatinib, wherein the deamination protective reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H 2 Pd-C or a base.
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