WO2015188686A1 - Method for preparing ceritinib and intermediate thereof - Google Patents

Method for preparing ceritinib and intermediate thereof Download PDF

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WO2015188686A1
WO2015188686A1 PCT/CN2015/079455 CN2015079455W WO2015188686A1 WO 2015188686 A1 WO2015188686 A1 WO 2015188686A1 CN 2015079455 W CN2015079455 W CN 2015079455W WO 2015188686 A1 WO2015188686 A1 WO 2015188686A1
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isopropoxy
methyl
palladium
piperidin
reaction
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PCT/CN2015/079455
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French (fr)
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许学农
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苏州明锐医药科技有限公司
哲人药业南京有限公司
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Publication of WO2015188686A1 publication Critical patent/WO2015188686A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of Ceritinib and its intermediates.
  • Ceritinib (formerly LDK378) is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed by Novartis, which was approved by the FDA for use in April 2014. Treatment with patients with metastatic NSCLC who have progressed or are intolerant after treatment with izozinib (Crizotinib) under the trade name Zykadia. Since the drug has not been officially listed in China and does not have a standard Chinese translation, the applicant hereby transliterates it as “serinibini”. Ceritinib is the second FDA-approved ALK inhibitor following crizotinib and is the second drug to be marketed via the four-pass special channel following Ibrutinib.
  • ALK anaplastic lymphoma enzyme
  • Serui erlotinib (Ceritinib, VIII), the chemical name 5-Chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4-yl) - phenyl)] - N 4- [2-(Isopropylsulfonyl)-phenyl]-pyrimidine-2,4-diamine.
  • one of the objects of the present invention is to provide an intermediate required to prepare serritinib, 2-isopropoxy-5-methyl-4-(in accordance with the synthesis concept of green chemistry).
  • Piperidin-4-yl)halobenzene (I) and a preparation method thereof the preparation method is simple in process, mild in condition and less in side reaction, and is suitable for industrialization amplification.
  • the preparation of the intermediate comprises the following steps: using 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) as a raw material, Catalytic hydrogenation to give 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III), compound (III) is obtained by Sandmeyer reaction to obtain the 2-iso Propoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I).
  • the halogen in the 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) is fluorine, chlorine, bromine or iodine, preferably bromine or iodine.
  • the catalyst for the catalytic hydrogenation reaction is palladium carbon, Raney nickel, ruthenium, rhodium, platinum, palladium chloride, rhodium chloride, ruthenium chloride, platinum chloride, aluminum oxide, palladium oxide, ruthenium oxide, platinum oxide, oxidation.
  • the halogenating agent of the Sandmeyer reaction is a potassium halide, a sodium halide, a cuprous halide, a copper halide or a trimethylhalosilane, preferably a copper halide or a trimethylhalosilane, more preferably copper bromide or trimethyliodide. Silane.
  • the second object of the present invention is to provide an application of the above-described seratinib intermediate (I) as a raw material in preparing serritinib (VIII), which has the same simple process, mild conditions and less side reactions. Suitable for industrial amplification requirements.
  • serritinib is known in English as Ceritinib, and its chemical name is 5-chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]- N 4 - [2- (isopropylsulfonyl) - phenyl] - pyrimidine-2,4-diamine, the following chemical structure:
  • the preparation method of the above serritinib comprises the following steps: 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) and 4-nitro-5-chloro- Substitution reaction of pyrimidine-2-amine (IV) (1) to 4-nitro 5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-benzene yl)] - pyrimidin-2-amine (V); intermediate (V) by reduction reaction of 5-chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4 Base)-phenyl)]-pyrimidine-2,4-diamine (VI); substitution reaction of intermediate (VI) with 2-bromo-(isopropylsulfonyl)benzene (VII) (2) generation of seri Tini (VIII).
  • the catalysts for the substitution reactions (a) and (ii) are copper, cuprous iodide, brominated ketone, cuprous chloride, palladium, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, and Chlorobis(triphenylphosphine)palladium, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride or (bisbenzylideneacetone)dipalladium, preferably cuprous iodide, tetra ( Triphenylphosphine) palladium or (bisbenzylideneacetone) dipalladium.
  • the basic cocatalysts of the substitution reactions (a) and (ii) are potassium t-butoxide, sodium t-butoxide, sodium amide, sodium bis(trimethylsilyl)amide, sodium hydride, potassium hydroxide, sodium hydroxide or Potassium carbonate, preferably potassium t-butoxide or sodium bis(trimethylsilyl)amide.
  • the solvent for the substitution reactions (a) and (ii) is xylene, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably dimethyl Sulfoxide or N,N-dimethylformamide.
  • the temperature of the substitution reactions (1) and (2) is 50-150 °C.
  • the reducing agent for the reduction reaction is iron powder, tin powder, zinc powder, aluminum powder, hydrazine hydrate, insurance powder, hydrazine hydrate, stannous chloride, sodium sulfide or hydrogen, preferably iron powder, zinc powder or hydrogen.
  • the catalyst used is palladium carbon, platinum carbon, palladium hydroxide carbon or Raney nickel, preferably palladium carbon or platinum carbon.
  • the preparation method of the serritinib and the intermediate thereof according to the invention has the advantages of simple process, mild conditions and reduced side reaction, and is suitable for industrial amplification.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • reaction was carried out for 8 hours at ° C, and the reaction was terminated by TLC. Cool and filter to remove insolubles.
  • the mixture was dissolved in methylene chloride, washed successively with saturated aqueous sodium hydrogen carbonate solution, brine and purified water, and dried over anhydrous sodium sulfate.

Abstract

Provided is an intermediate 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)halogeno-benzene (I) which can be used for preparing ceritinib and a preparation method thereof. The preparation method comprises the following steps: carrying out catalytic hydrogenation on the raw material 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) to obtain 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)aniline (III); and carrying out a Sandmeyer reaction on the compound (III) to obtain the intermediate (I). Also provided is a method for preparing ceritinib. The intermediate (I) which is used as the raw material is sequentially subjected to substitution, reduction and substitution reactions to obtain the ceritinib (VIII). The preparation method has the advantages of a simple technique, mild conditions and fewer side reactions, and is suitable for industrial amplification.

Description

塞瑞替尼及其中间体的制备方法Preparation method of seratinib and intermediate thereof 技术领域Technical field
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种塞瑞替尼(Ceritinib)及其中间体的制备方法。The invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of Ceritinib and its intermediates.
背景技术Background technique
塞瑞替尼(Ceritinib，原名LDK378)是由诺华制药(Novartis)研发的一种间变性淋巴瘤酶(ALK)酪氨酸激酶抑制剂，该药于2014年4月被FDA批准用于经克唑替尼(Crizotinib)治疗后已有疾病进展或不能耐受的转移性NSCLC患者的治疗，商品名为Zykadia。因该药物在我国未正式上市，还不具有标准的中文译名，故本申请人在此将其音译为“塞瑞替尼”。塞瑞替尼(Ceritinib)是继克唑替尼(Crizotinib)之后FDA批准的第二个ALK抑制剂，也是继伊鲁替尼(Ibrutinib)后第二个经四重特批通道上市的药物。Ceritinib (formerly LDK378) is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed by Novartis, which was approved by the FDA for use in April 2014. Treatment with patients with metastatic NSCLC who have progressed or are intolerant after treatment with izozinib (Crizotinib) under the trade name Zykadia. Since the drug has not been officially listed in China and does not have a standard Chinese translation, the applicant hereby transliterates it as “serinibini”. Ceritinib is the second FDA-approved ALK inhibitor following crizotinib and is the second drug to be marketed via the four-pass special channel following Ibrutinib.
塞瑞替尼(Ceritinib，VIII)，化学名为5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-N4-[2-(异丙基磺酰基)-苯基]-嘧啶-2，4-二胺。Serui erlotinib (Ceritinib, VIII), the chemical name 5-Chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4-yl) - phenyl)] - N 4- [2-(Isopropylsulfonyl)-phenyl]-pyrimidine-2,4-diamine.
Figure PCTCN2015079455-appb-000001
Figure PCTCN2015079455-appb-000001
原研的世界专利WO2008/073687、文献“Journal of Medicinal Chemistry(2013)，56(14)，5675-5690”和“Archives of Pharmacia Research(2013)，Published online：16 October 2013”等先后报道了塞瑞替尼及其类似物的制备方法。该方法是以2，4，5-三氯嘧啶(IX)为起始原料，首先与2-(异丙基磺酰基)苯胺(X)发生4-位亲核取代反应生成中间体2，5-二氯-N-[2-(异丙基磺酰 基)苯基]嘧啶-4-胺(XI)，该化合物再与另一中间体4-(4-氨基-5-异丙氧基-2-甲基-苯基)哌啶-1-甲酸叔丁酯(XII)发生2-位亲核取代反应，所得化合物脱除N-保护基，可制得塞瑞替尼(VIII)。考察该方法，由于起始原料2，4，5-三氯嘧啶(IX)中的三个氯原子在发生亲核取代反应时，选择性差异有限，存在多个竞争反应，使副反应增加。实际操作过程中，为了减少副反应，不得不对原料(XII)中的哌啶环进行仲胺的Boc保护，从而增加反应步骤；同时，由于副反应的存在，使大多数反应的后处理不得不通过柱层析来纯化分离，操作繁琐，总收率降低，不适合工业化放大的要求。The original world patent WO2008/073687, the literature "Journal of Medicinal Chemistry (2013), 56 (14), 5675-5690" and "Archives of Pharmacia Research (2013), Published online: 16 October 2013" have reported Seri A method for preparing fentan and its analogs. The method uses 2,4,5-trichloropyrimidine (IX) as a starting material, and firstly undergoes 4-position nucleophilic substitution reaction with 2-(isopropylsulfonyl)aniline (X) to form intermediate 2,5. -dichloro-N-[2-(isopropylsulfonyl) Phenyl]pyrimidin-4-amine (XI), this compound is further combined with another intermediate 4-(4-amino-5-isopropoxy-2-methyl-phenyl)piperidine-1-carboxylic acid The tert-butyl ester (XII) undergoes a 2-position nucleophilic substitution reaction, and the obtained compound is subjected to removal of the N-protecting group to obtain serritinib (VIII). Investigating this method, since the three chlorine atoms in the starting material 2,4,5-trichloropyrimidine (IX) undergo a nucleophilic substitution reaction, the selectivity difference is limited, and there are a plurality of competing reactions, which increase the side reaction. In the actual operation, in order to reduce the side reaction, the piperidine ring in the starting material (XII) has to be subjected to Boc protection of the secondary amine, thereby increasing the reaction step; meanwhile, due to the presence of the side reaction, the post-treatment of most reactions has to be Purification and separation by column chromatography, the operation is cumbersome, the total yield is reduced, and it is not suitable for industrial amplification.
Figure PCTCN2015079455-appb-000002
Figure PCTCN2015079455-appb-000002
所以，寻求一种由经典单元反应组成、副反应少、收率高的塞瑞替尼及其中间体的合成路线及制备方法，对于塞瑞替尼的工业化生产具有较现实的意义。Therefore, the search for a synthetic route and preparation method of serritinib and its intermediates consisting of classical unit reaction, low side reaction and high yield have practical significance for the industrial production of serritinib.
发明内容Summary of the invention
为了克服现有技术中的缺陷，本发明的目的之一在于按照绿色化学的合成理念，提供一种制备塞瑞替尼所需中间体2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)及该中间体的制备方法，该制备方法工艺简洁、条件温和且副反应少，适合工业化放大的要求。In order to overcome the deficiencies in the prior art, one of the objects of the present invention is to provide an intermediate required to prepare serritinib, 2-isopropoxy-5-methyl-4-(in accordance with the synthesis concept of green chemistry). Piperidin-4-yl)halobenzene (I) and a preparation method thereof, the preparation method is simple in process, mild in condition and less in side reaction, and is suitable for industrialization amplification.
为了实现上述目的，本发明所提供的主要技术方案如下：一种塞瑞替尼中间体，其化学名称为2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)，化学式如式(I)所示：In order to achieve the above object, the main technical solution provided by the present invention is as follows: a serritinib intermediate having the chemical name of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) Halogenated benzene (I), the chemical formula is as shown in formula (I):
Figure PCTCN2015079455-appb-000003
Figure PCTCN2015079455-appb-000003
该中间体的制备包括如下步骤：以4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶(II)为原料，经 催化氢化反应得到2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺(III)，化合物(III)经桑德迈尔(Sandmeyer)反应得到所述2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)。The preparation of the intermediate comprises the following steps: using 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) as a raw material, Catalytic hydrogenation to give 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III), compound (III) is obtained by Sandmeyer reaction to obtain the 2-iso Propoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I).
Figure PCTCN2015079455-appb-000004
Figure PCTCN2015079455-appb-000004
所述2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)中的卤素为氟、氯、溴或碘，优选溴或碘。The halogen in the 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) is fluorine, chlorine, bromine or iodine, preferably bromine or iodine.
所述催化氢化反应的催化剂为钯炭、雷尼镍、铑、钌、铂、氯化钯、氯化钌、氯化铑、氯化铂、氧化铝、氧化钯、氧化钌、氧化铂、氧化铝或二氧化钛，优选钯炭或雷尼镍。The catalyst for the catalytic hydrogenation reaction is palladium carbon, Raney nickel, ruthenium, rhodium, platinum, palladium chloride, rhodium chloride, ruthenium chloride, platinum chloride, aluminum oxide, palladium oxide, ruthenium oxide, platinum oxide, oxidation. Aluminum or titanium dioxide, preferably palladium carbon or Raney nickel.
所述桑德迈尔反应的卤化剂为卤化钾、卤化钠、卤化亚铜、卤化铜或三甲基卤硅烷，优选卤化铜或三甲基卤硅烷，更优选溴化铜或三甲基碘硅烷。The halogenating agent of the Sandmeyer reaction is a potassium halide, a sodium halide, a cuprous halide, a copper halide or a trimethylhalosilane, preferably a copper halide or a trimethylhalosilane, more preferably copper bromide or trimethyliodide. Silane.
另外，本发明目的之二在于提供一种上述塞瑞替尼中间体(I)为原料在制备塞瑞替尼(VIII)中的应用，该制备应用同样工艺简洁、条件温和且副反应少，适合工业化放大的要求。In addition, the second object of the present invention is to provide an application of the above-described seratinib intermediate (I) as a raw material in preparing serritinib (VIII), which has the same simple process, mild conditions and less side reactions. Suitable for industrial amplification requirements.
上述塞瑞替尼的英文名为Ceritinib，化学名为5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-N4-[2-(异丙基磺酰基)-苯基]-嘧啶-2，4-二胺，化学结构式如下：The above-mentioned serritinib is known in English as Ceritinib, and its chemical name is 5-chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]- N 4 - [2- (isopropylsulfonyl) - phenyl] - pyrimidine-2,4-diamine, the following chemical structure:
Figure PCTCN2015079455-appb-000005
Figure PCTCN2015079455-appb-000005
上述塞瑞替尼的制备方法包括如下步骤：2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)与4-硝基-5-氯-嘧啶-2-胺(IV)发生取代反应(一)生成4-硝基5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺(V)；中间体(V)经还原反应生成5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺(VI)；中间体(VI)与2-溴-(异丙基磺酰基)苯(VII)发生取代反应(二)生成塞瑞替尼(VIII)。 The preparation method of the above serritinib comprises the following steps: 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) and 4-nitro-5-chloro- Substitution reaction of pyrimidine-2-amine (IV) (1) to 4-nitro 5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-benzene yl)] - pyrimidin-2-amine (V); intermediate (V) by reduction reaction of 5-chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4 Base)-phenyl)]-pyrimidine-2,4-diamine (VI); substitution reaction of intermediate (VI) with 2-bromo-(isopropylsulfonyl)benzene (VII) (2) generation of seri Tini (VIII).
Figure PCTCN2015079455-appb-000006
Figure PCTCN2015079455-appb-000006
所述取代反应(一)和(二)的催化剂为铜、碘化亚铜、溴化亚酮、氯化亚铜、钯、氯化钯、醋酸钯、四(三苯基膦)钯、二氯双(三苯基膦)钯、(1，1′-双(二苯基膦)二茂铁)二氯化钯或(双亚苄基丙酮)二钯，优选碘化亚铜、四(三苯基膦)钯或(双亚苄基丙酮)二钯。The catalysts for the substitution reactions (a) and (ii) are copper, cuprous iodide, brominated ketone, cuprous chloride, palladium, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, and Chlorobis(triphenylphosphine)palladium, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride or (bisbenzylideneacetone)dipalladium, preferably cuprous iodide, tetra ( Triphenylphosphine) palladium or (bisbenzylideneacetone) dipalladium.
所述取代反应(一)和(二)的碱性助催化剂为叔丁醇钾、叔丁醇钠、氨基钠、双(三甲硅基)氨基钠、氢化钠、氢氧化钾、氢氧化钠或碳酸钾，优选叔丁醇钾或双(三甲硅基)氨基钠。The basic cocatalysts of the substitution reactions (a) and (ii) are potassium t-butoxide, sodium t-butoxide, sodium amide, sodium bis(trimethylsilyl)amide, sodium hydride, potassium hydroxide, sodium hydroxide or Potassium carbonate, preferably potassium t-butoxide or sodium bis(trimethylsilyl)amide.
所述取代反应(一)和(二)的溶剂为二甲苯、二氧六环、二甲亚砜、N，N-二甲基甲酰胺或N，N-二甲基乙酰胺，优选二甲亚砜或N，N-二甲基甲酰胺。The solvent for the substitution reactions (a) and (ii) is xylene, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably dimethyl Sulfoxide or N,N-dimethylformamide.
所述取代反应(一)和(二)的温度为50-150℃。The temperature of the substitution reactions (1) and (2) is 50-150 °C.
所述还原反应的还原剂为铁粉、锡粉、锌粉、铝粉、水合肼、保险粉、水合肼、氯化亚锡、硫化钠或氢气，优选铁粉、锌粉或氢气。The reducing agent for the reduction reaction is iron powder, tin powder, zinc powder, aluminum powder, hydrazine hydrate, insurance powder, hydrazine hydrate, stannous chloride, sodium sulfide or hydrogen, preferably iron powder, zinc powder or hydrogen.
所述还原反应的还原剂为氢气时，使用的催化剂为钯炭、铂炭、氢氧化钯炭或雷尼镍，优选钯炭或铂炭。When the reducing agent for the reduction reaction is hydrogen, the catalyst used is palladium carbon, platinum carbon, palladium hydroxide carbon or Raney nickel, preferably palladium carbon or platinum carbon.
相比于现有技术，本发明所涉及的塞瑞替尼及其中间体的制备方法，其优点是工艺简洁、条件温和和副反应减少，适合工业化放大的要求。Compared with the prior art, the preparation method of the serritinib and the intermediate thereof according to the invention has the advantages of simple process, mild conditions and reduced side reaction, and is suitable for industrial amplification.
具体实施方式detailed description
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶(II)、4-硝基-5-氯-嘧啶-2-胺(IV)和2-溴-(异丙基磺酰基)苯(VII) 的制备分别参见世界专利WO2008073687、文献Angewandte Chemie，International Edition，46(14)，2478-2484；2007及文献Organometallics，30(5)，1130-1138；2011对相同化合物的制备方法。The technical solution of the present invention will be further described in detail below in conjunction with several preferred embodiments. Wherein 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II), 4-nitro-5-chloro-pyrimidin-2-amine (IV) and 2-bromo- (isopropylsulfonyl)benzene (VII) For the preparation of the same compound, see, for example, World Patent WO2008073687, Document Angewandte Chemie, International Edition, 46(14), 2478-2484; 2007 and the literature Organometallics, 30(5), 1130-1138;
实施例一：Embodiment 1:
于氢化反应釜中加入4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶(II)(2.72g，10mmol)和10％钯炭(0.27g，10％w/w)、25mL饱和氯化氢异丙醇溶液和100mL异丙醇，按照氢化反应操作程序，通入氢气，保持50-60℃，8-10Kg/cm2压力，搅拌反应16小时，至不再消耗氢气。冷却，过滤回收钯炭，减压浓缩回收溶剂，残余物用二氯甲烷溶解和饱和碳酸氢钠洗涤，分出有机相，减压浓缩，所得粗品经乙酸乙酯和正己烷(1∶1)重结晶，得到类白色固体2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺(III)2.27g，收率91.5％，EI-MS m/z：249[M+H]+。Add 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) (2.72 g, 10 mmol) and 10% palladium on carbon (0.27 g, 10% w) to a hydrogenation kettle. /w), 25mL of saturated hydrogen chloride isopropanol solution and 100mL of isopropanol, according to the hydrogenation reaction procedure, pass hydrogen, keep 50-60 ° C, 8-10Kg / cm 2 pressure, stir the reaction for 16 hours, no longer consumed hydrogen. After cooling, the palladium on charcoal was collected by filtration, and the solvent was evaporated. The residue was evaporated. mjjjjjjjjjjj Recrystallization gave 2.27 g of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenylamine (III) as an off-white solid, yield 91.5%, EI-MS m/z: 249 [ M+H] + .
实施例二：Embodiment 2:
于氢化反应釜中加入4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶(II)(2.72g，10mmol)、雷尼镍(0.54g)、0.1mL浓硫酸和120mL异丙醇，按照氢化反应操作程序，通入氢气，保持40-50℃，5-8Kg/cm2压力，搅拌反应22小时，至不再消耗氢气。冷却，过滤回收催化剂，减压浓缩回收溶剂，残余物用二氯甲烷溶解和饱和碳酸氢钠洗涤，分出有机相，减压浓缩，所得粗品经乙酸乙酯和正己烷(1∶1)重结晶，得到类白色固体2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺(III)2.21g，收率89.1％，EI-MS m/z：249[M+H]+。Add 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) (2.72 g, 10 mmol), Raney nickel (0.54 g), 0.1 mL thick to the hydrogenation reactor. Sulfuric acid and 120 mL of isopropanol were introduced into the hydrogen gas according to the hydrogenation reaction procedure, maintained at 40-50 ° C, and a pressure of 5-8 Kg/cm 2 , and the reaction was stirred for 22 hours until hydrogen gas was no longer consumed. The mixture was cooled, and the title compound was evaporated. Crystallization gave 2.21 g of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenylamine (III) as an off-white solid, yield: 89.1%, EI-MS m/z: 249 [M +H] + .
实施例三：Embodiment 3:
于三口瓶中加入2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺(III)(2.48g，10mmol)、40％氢溴酸溶液5mL和水20mL，保持0-5℃下，滴加亚硝酸钠(1.38g，20mmol)的20mL水溶液，滴毕继续反应2小时。加入溴化亚铜(1.57g，11mmol)，升温至50-60℃，反应2小时，冷却，过 滤除去固体物，母液用二氯甲烷萃取3次，合并有机相，依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压回收溶剂，所得油状物为2-异丙氧基-5-甲基-4-(哌啶-4-基)溴苯(I)2.58g，收率83.0％，EI-MS m/z：312[M+H]+。Add 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III) (2.48 g, 10 mmol), 40% hydrobromic acid solution 5 mL and water 20 mL to a three-necked flask. A 20 mL aqueous solution of sodium nitrite (1.38 g, 20 mmol) was added dropwise at 0 to 5 ° C, and the reaction was continued for 2 hours. Add copper bromide (1.57 g, 11 mmol), warm to 50-60 ° C, react for 2 hours, cool, remove the solids by filtration, and extract the mother liquor three times with dichloromethane, then combine the organic phase, and then use saturated sodium hydrogen carbonate solution The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. Yield: 83.0%, EI-MS m/z: 312 [M+H] + .
实施例四：Embodiment 4:
冰浴下于三口瓶中加入亚硝酸钠(2.07g，30mmol)、三甲基碘硅烷(6g，30mmol)、四丁基氯化铵(0.16g，1.5mmol)和二氯甲烷50mL，搅拌下加入2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺(III)(2.48g，10mmol)，0℃反应1小时后，升至室温继续反应16小时。过滤除去不溶物，母液用依次用饱和碳酸氢钠溶液、饱和食盐水和纯水洗涤，无水硫酸钠干燥，减压回收溶剂，所得油状物为2-异丙氧基-5-甲基-4-(哌啶-4-基)碘苯(I)3.03g，收率84.4％，EI-MS m/z：360[M+H]+。Sodium nitrite (2.07 g, 30 mmol), trimethylsilyl iodide (6 g, 30 mmol), tetrabutylammonium chloride (0.16 g, 1.5 mmol) and 50 mL of dichloromethane were added to a three-necked flask under ice-cooling. 2-Isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III) (2.48 g, 10 mmol) was added, and the mixture was reacted at 0 ° C for 1 hour, and the reaction was continued to room temperature for 16 hours. The insoluble material was removed by filtration, and the mother liquid was washed with saturated sodium hydrogen carbonate solution, saturated brine and purified water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-isopropoxy-5-methyl- 4-(piperidin-4-yl)iodobenzene (I) 3.03 g, yield 84.4%, EI-MS m/z: 360[M+H] + .
实施例五：Embodiment 5:
氮气氛下于三口反应瓶中加入2-异丙氧基-5-甲基-4-(哌啶-4-基)溴苯(I)(3.42g，11mmol)、(双亚苄基丙酮)二钯(0.58g，1mmol)、叔丁醇钾(1.2g，11mmol)和二甲亚砜25mL，室温搅拌下，滴加4-硝基-5-氯-嘧啶-2-胺(IV)(1.73g，10mmol)的二甲亚砜溶液25mL，升温至90℃反应2小时，继续升温至120℃，反应8小时，TLC检测反应结束。冷却，加入5％的氨水25mL，搅拌30分钟。过滤除去不溶物，用二氯甲烷萃取母液三次，水洗1次，无水硫酸钠干燥。减压回收溶剂，残余物用乙醇重结晶，得淡黄色固体4-硝基-5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺(V)3.16g，收率为78.0％，EI-MS m/z：406[M+H]+。2-Isopropoxy-5-methyl-4-(piperidin-4-yl)bromobenzene (I) (3.42 g, 11 mmol), (bisbenzylideneacetone) was added to a three-neck reaction flask under a nitrogen atmosphere. Di-palladium (0.58g, 1mmol), potassium t-butoxide (1.2g, 11mmol) and dimethyl sulfoxide 25mL, 4-nitro-5-chloro-pyrimidin-2-amine (IV) was added dropwise with stirring at room temperature ( 1.73 g, 10 mmol) of a dimethyl sulfoxide solution (25 mL) was heated to 90 ° C for 2 hours, and the temperature was further raised to 120 ° C for 8 hours, and the reaction was terminated by TLC. After cooling, 25 mL of 5% ammonia water was added and stirred for 30 minutes. The insoluble material was removed by filtration, and the mother liquid was extracted three times with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure and the residue was crystallised from crystals to crystals crystals of crystal -Phenyl)]-pyrimidin-2-amine (V) 3.16 g, yield 78.0%, EI-MS m/z: 406[M+H] + .
实施例六：Example 6:
氮气氛下于三口反应瓶中加入2-异丙氧基-5-甲基-4-(哌啶-4-基)碘苯(I)(2.15g，6mmol)、碘化亚铜(0.19g，1mmol)、双(三甲硅基)氨基钠(1.1g，6mmol)和N，N-二甲基甲酰胺25mL，室 温搅拌下，滴加4-硝基-5-氯-嘧啶-2-胺(IV)(0.87g，5mmol)的N，N-二甲基甲酰胺溶液25mL，升温至85℃反应1小时，继续升温至130℃，反应15小时，TLC检测反应结束。冷却，加入5％的氨水10mL，搅拌30分钟。过滤除去不溶物，用二氯甲烷萃取母液三次，水洗，无水硫酸钠干燥。减压回收溶剂，残余物用乙醇重结晶，得淡黄色固体4-硝基-5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺(V)1.5g，收率为74.1％，EI-MS m/z：406[M+H]+。2-Isopropoxy-5-methyl-4-(piperidin-4-yl)iodobenzene (I) (2.15 g, 6 mmol) and cuprous iodide (0.19 g) were added to a three-neck reaction flask under a nitrogen atmosphere. , 1 mmol), sodium bis(trimethylsilyl)amide (1.1 g, 6 mmol) and N,N-dimethylformamide 25 mL, 4-nitro-5-chloro-pyrimidin-2-amine was added dropwise with stirring at room temperature (IV) (0.87 g, 5 mmol) of N,N-dimethylformamide solution (25 mL), the mixture was heated to 85 ° C for 1 hour, and the temperature was further increased to 130 ° C for 15 hours. The reaction was terminated by TLC. After cooling, 10 mL of 5% ammonia water was added and stirred for 30 minutes. The insoluble material was removed by filtration, and the mother liquid was extracted three times with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure and the residue was crystallised from crystals to crystals crystals of crystal -Phenyl)]-pyrimidin-2-amine (V) 1.5 g, yield 74.1%, EI-MS m/z: 406 [M+H] + .
实施例七：Example 7:
于三口反应瓶中加入4-硝基-5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺(V)(4.05g，10mmol)和异丙醇50mL，分批加入铁粉(1.68g，30mmol)和醋酸(2.4g，40mmol)，升温至65-70℃反应5小时，TLC检测反应结束。冷却，过滤除去不溶物，母液减压除去大部分异丙醇。用二氯甲烷萃取三次，合并有机相，依次用饱和碳酸氢钠溶液、饱和食盐水及纯水洗涤，无水硫酸钠干燥。减压回收溶剂，残余物用乙醇重结晶，得类白色固体5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺(VI)3.3g，收率为88.0％，EI-MS m/z：376[M+H]+。Add 4-nitro-5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]-pyrimidine-2- to a three-neck reaction flask Amine (V) (4.05 g, 10 mmol) and isopropanol 50 mL, iron powder (1.68 g, 30 mmol) and acetic acid (2.4 g, 40 mmol) were added in portions, and the mixture was heated to 65-70 ° C for 5 hours, and the reaction was terminated by TLC. . After cooling, the insolubles were removed by filtration, and the mother liquor was removed under reduced pressure to remove most of the isopropanol. The organic layer was combined and washed with a saturated aqueous sodium hydrogen carbonate solution, brine and purified water and dried over anhydrous sodium sulfate. Recovery of the solvent under reduced pressure, the residue was recrystallized from ethanol to give white solid 5-Chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4-yl) - phenyl) ]-Pyridine-2,4-diamine (VI) 3.3 g, yield 88.0%, EI-MS m/z: 376[M+H] + .
实施例八：Example 8:
于氢化反应器中加入4-硝基-5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺(V)(4.05g，10mmol)、10％钯炭(0.4g，10％w/w)和异丙醇100mL，按照氢化反应操作程序，通入氢气，保持40-50℃，5-8Kg/cm2压力，搅拌反应10小时，至不再消耗氢气。冷却，过滤回收钯炭，减压浓缩回收溶剂，残余物用二氯甲烷溶解和饱和碳酸氢钠洗涤，分出有机相，减压浓缩，所得粗品经乙醇重结晶，得类白色固体5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺(VI)3.7g，收率为91.4％，EI-MS m/z：376[M+H]+。Add 4-nitro-5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]-pyrimidine-2- to the hydrogenation reactor Amine (V) (4.05 g, 10 mmol), 10% palladium on carbon (0.4 g, 10% w/w) and 100 mL of isopropanol, hydrogen was introduced according to the hydrogenation reaction procedure, maintaining 40-50 ° C, 5-8 Kg At a pressure of /cm 2 , the reaction was stirred for 10 hours until no more hydrogen was consumed. The mixture was cooled, and the palladium charcoal was collected by filtration. The residue was purified by chromatography. -N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]-pyrimidine-2,4-diamine (VI) 3.7 g, yield 91.4%, EI-MS m/z: 376 [M+H] + .
实施例九： Example 9:
氮气氛下于三口反应瓶中加入5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺(VI)(3.75g，10mmol)、四(三苯基膦)钯(1.16g，1mmol)、叔丁醇钾(1.2g，11mmol)和二甲亚砜25mL，室温搅拌下，滴加2-溴-(异丙基磺酰基)苯(VII)(2.87g，11mmol)的二甲亚砜溶液25mL，升温至40-50℃反应10小时，TLC检测反应结束。冷却，过滤除去不溶物。加入二氯甲烷溶解，依次用饱和碳酸氢钠溶液、饱和食盐水及纯水洗涤，无水硫酸钠干燥。减压回收溶剂，残余物用乙腈重结晶，得类白色固体塞瑞替尼(VIII)4.22g，收率为75.8％，EI-MS m/z：558[M+H]+。5-Chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]-pyrimidine-2,4 was added to a three-neck reaction flask under a nitrogen atmosphere. - Diamine (VI) (3.75 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol), potassium t-butoxide (1.2 g, 11 mmol) and dimethyl sulfoxide 25 mL, stirred at room temperature 25 mL of a solution of 2-bromo-(isopropylsulfonyl)benzene (VII) (2.87 g, 11 mmol) in dimethyl sulfoxide was added, and the mixture was heated to 40-50 ° C for 10 hours, and the reaction was terminated by TLC. Cool and filter to remove insolubles. The mixture was dissolved in methylene chloride, washed successively with saturated aqueous sodium hydrogen carbonate solution, brine and purified water, and dried over anhydrous sodium sulfate. Recovery of the solvent under reduced pressure, the residue was recrystallized from acetonitrile to give an off-white solid Serui erlotinib (VIII) 4.22g, yield 75.8%, EI-MS m / z: 558 [M + H] +.
实施例十：Example 10:
氮气氛下于三口反应瓶中加入5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺(VI)(3.75g，10mmol)、(双亚苄基丙酮)二钯(0.58g，1mmol)、双(三甲硅基)氨基钠(2.0g，11mmol)和N，N-二甲基甲酰胺25mL，室温搅拌下，滴加2-溴-(异丙基磺酰基)苯(VII)(2.87g，11mmol)的N，N-二甲基甲酰胺溶液25mL，升温至40-50℃反应8小时，TLC检测反应结束。冷却，过滤除去不溶物。加入二氯甲烷溶解，依次用饱和碳酸氢钠溶液、饱和食盐水及纯水洗涤，无水硫酸钠干燥。减压回收溶剂，残余物用乙腈重结晶，得类白色固体塞瑞替尼(VIII)4.50g，收率为80.8％，EI-MS m/z：558[M+H]+，1H NMR(CDCl3)δ1.34(m，6H)，1.39(m，6H)，1.67-1.90(m，4H)，2.12(m，1H)，2.35(s，3H)，2.68-2.78(m，4H)，2.79(m，1H)，3.34(m，1H)，4.01(brs，2H)，4.08(m，1H)，6.07-6.28(m，2H)，6.74-7.02(m，3H)，7.69(m，1H)，7.92(s，1H)。5-Chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]-pyrimidine-2,4 was added to a three-neck reaction flask under a nitrogen atmosphere. -Diamine (VI) (3.75 g, 10 mmol), (bisbenzylideneacetone) dipalladium (0.58 g, 1 mmol), sodium bis(trimethylsilyl)amide (2.0 g, 11 mmol) and N,N-dimethyl 25 mL of carbamide, 25 mL of N-N-dimethylformamide solution of 2-bromo-(isopropylsulfonyl)benzene (VII) (2.87 g, 11 mmol) was added dropwise with stirring at room temperature, and the temperature was raised to 40-50. The reaction was carried out for 8 hours at ° C, and the reaction was terminated by TLC. Cool and filter to remove insolubles. The mixture was dissolved in methylene chloride, washed successively with saturated aqueous sodium hydrogen carbonate solution, brine and purified water, and dried over anhydrous sodium sulfate. Recovery of the solvent under reduced pressure, the residue was recrystallized from acetonitrile to give an off-white solid Serui erlotinib (VIII) 4.50g, yield 80.8%, EI-MS m / z: 558 [M + H] +, 1 H NMR (CDCl 3 ) δ 1.34 (m, 6H), 1.39 (m, 6H), 1.67-1.90 (m, 4H), 2.12 (m, 1H), 2.35 (s, 3H), 2.68-2.78 (m, 4H) ), 2.79 (m, 1H), 3.34 (m, 1H), 4.01 (brs, 2H), 4.08 (m, 1H), 6.07-6.28 (m, 2H), 6.74-7.02 (m, 3H), 7.69 ( m, 1H), 7.92 (s, 1H).
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。 It should be noted that the above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the contents of the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. . Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (9)

  1. 一种塞瑞替尼中间体，其特征在于其化学名称为：2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯，化学结构式如式(I)所示：A seratinib intermediate characterized by the chemical name of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene having a chemical formula of formula (I) Shown as follows:
    Figure PCTCN2015079455-appb-100001
    Figure PCTCN2015079455-appb-100001
    其中的卤素X为氟、氯、溴或碘。The halogen X therein is fluorine, chlorine, bromine or iodine.
  2. 根据权利要求1所述塞瑞替尼中间体的制备方法，其特征在于其制备包括如下步骤：以4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶为原料，经催化氢化反应得到化合物2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺，2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺经桑德迈尔反应得到所述2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯(I)。The method for preparing a seratinib intermediate according to claim 1, wherein the preparation comprises the step of: 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine The starting material is subjected to catalytic hydrogenation to give the compound 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline, 2-isopropoxy-5-methyl-4-(piperidine- The 4-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) is obtained via a Sandmeyer reaction of 4-yl)aniline.
  3. 根据权利要求2所述塞瑞替尼中间体的制备方法，其特征在于：所述催化氢化反应的催化剂为钯炭、雷尼镍、铑、钌、铂、氯化钯、氯化钌、氯化铑、氯化铂、氧化铝、氧化钯、氧化钌、氧化铂、氧化铝或二氧化钛。The method for preparing a seratinib intermediate according to claim 2, wherein the catalyst for the catalytic hydrogenation reaction is palladium carbon, Raney nickel, ruthenium, rhodium, platinum, palladium chloride, rhodium chloride or chlorine. Antimony, platinum chloride, aluminum oxide, palladium oxide, cerium oxide, platinum oxide, aluminum oxide or titanium dioxide.
  4. 根据权利要求2所述塞瑞替尼中间体的制备方法，其特征在于：所述桑德迈尔反应的卤化剂为卤化钾、卤化钠、卤化亚铜、卤化铜或三甲基卤硅烷。The method for preparing a siridineib intermediate according to claim 2, wherein the halogenating agent of the Sandmeyer reaction is potassium halide, sodium halide, cuprous halide, copper halide or trimethylhalosilane.
  5. 一种以权利要求1至4任一项所述塞瑞替尼中间体来制备塞瑞替尼的方法，A method for preparing serritinib by using the siridineib intermediate according to any one of claims 1 to 4,
    Figure PCTCN2015079455-appb-100002
    Figure PCTCN2015079455-appb-100002
    其特征在于其制备方法包括如下步骤：2-异丙氧基-5-甲基-4-(哌啶-4-基)卤代苯与4-硝基-5-氯-嘧啶-2-胺在催化剂和碱性助催化剂作用下发生取代反应(一)生成4-硝基-5-氯-N-[2-异丙 氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺；所述4-硝基-5-氯-N-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2-胺在还原剂作用下发生还原反应生成5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺；所述5-氯-N2-[2-异丙氧基-5-甲基-4-(哌啶-4-基)-苯基)]-嘧啶-2，4-二胺与2-溴-(异丙基磺酰基)苯在催化剂和碱性助催化剂作用下发生取代反应(二)生成塞瑞替尼(VIII)。It is characterized in that the preparation method comprises the following steps: 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene and 4-nitro-5-chloro-pyrimidin-2-amine Substitution reaction occurs under the action of catalyst and basic cocatalyst (1) to form 4-nitro-5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl) -phenyl)]-pyrimidin-2-amine; the 4-nitro-5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-benzene Reduction of 5-chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-benzene by the reaction of a reducing agent ,]-pyrimidine-2,4-diamine; the 5-chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)] - Pyrimidine-2,4-diamine and 2-bromo-(isopropylsulfonyl)benzene undergo a substitution reaction under the action of a catalyst and a basic cocatalyst (2) to form seratinib (VIII).
  6. 根据权利要求5所述塞瑞替尼的制备方法，其特征在于：所述取代反应(一)和(二)的催化剂为铜、碘化亚铜、溴化亚酮、氯化亚铜、钯、氯化钯、醋酸钯、四(三苯基膦)钯、二氯双(三苯基膦)钯、(1，1′-双(二苯基膦)二茂铁)二氯化钯或(双亚苄基丙酮)二钯。The method for preparing seratinib according to claim 5, wherein the catalysts for the substitution reactions (1) and (ii) are copper, cuprous iodide, brominated ketone, cuprous chloride, palladium. , palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride or (bisbenzylideneacetone) dipalladium.
  7. 根据权利要求5所述塞瑞替尼的制备方法，其特征在于：所述取代反应(一)和(二)的碱性助催化剂为叔丁醇钾、叔丁醇钠、氨基钠、双(三甲硅基)氨基钠、氢化钠、氢氧化钾、氢氧化钠或碳酸钾。The method for preparing seratinib according to claim 5, wherein the basic cocatalysts of the substitution reactions (1) and (ii) are potassium t-butoxide, sodium t-butoxide, sodium amide, and bis ( Trimethylsilyl)sodium amide, sodium hydride, potassium hydroxide, sodium hydroxide or potassium carbonate.
  8. 根据权利要求6所述塞瑞替尼的制备方法，其特征在于：所述取代反应(一)和(二)的溶剂为二甲苯、二氧六环、二甲亚砜、N，N-二甲基甲酰胺或N，N-二甲基乙酰胺；取代反应(一)和(二)的温度为50-150℃。The method for preparing seratinib according to claim 6, wherein the solvent of the substitution reaction (1) and (2) is xylene, dioxane, dimethyl sulfoxide, N, N-di Methylformamide or N,N-dimethylacetamide; the temperature of the substitution reactions (a) and (ii) is 50-150 °C.
  9. 根据权利要求6所述塞瑞替尼的制备方法，其特征在于：所述还原反应的还原剂为铁粉、锡粉、锌粉、铝粉、水合肼、保险粉、水合肼、氯化亚锡、硫化钠或氢气；其中，当还原剂为氢气时，使用的催化剂为钯炭、铂炭、氢氧化钯炭或雷尼镍。 The method for preparing seratinib according to claim 6, wherein the reducing agent of the reduction reaction is iron powder, tin powder, zinc powder, aluminum powder, hydrazine hydrate, insurance powder, hydrazine hydrate, and chlorinated Tin, sodium sulfide or hydrogen; wherein, when the reducing agent is hydrogen, the catalyst used is palladium carbon, platinum carbon, palladium hydroxide carbon or Raney nickel.
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