WO2023174062A1 - Method for preparing nilutamide and intermediate thereof - Google Patents

Method for preparing nilutamide and intermediate thereof Download PDF

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WO2023174062A1
WO2023174062A1 PCT/CN2023/079243 CN2023079243W WO2023174062A1 WO 2023174062 A1 WO2023174062 A1 WO 2023174062A1 CN 2023079243 W CN2023079243 W CN 2023079243W WO 2023174062 A1 WO2023174062 A1 WO 2023174062A1
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formula
add
nilutamide
reaction
compound
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PCT/CN2023/079243
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French (fr)
Chinese (zh)
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孟祥国
胡霞敏
邵雷
吴锴
李晨烨
王露依
郁思杰
王怡菁
常仁俊
史雨豪
曾婉婧
尹子欣
宋英玮
李临雾
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上海健康医学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention belongs to the technical field of chemical drug synthesis, specifically relates to androgen receptor antagonists, and particularly relates to a preparation method of nilutamide of formula (IV).
  • Nilutamide is a first-generation non-steroidal androgen receptor antagonist developed and launched by the French company Roussel-Uclaf. It can bind to androgen receptors without androgenic effects, thus blocking the interaction between androgens and these receptors. Combined, it plays an anti-androgen effect, and its in vitro anti-AR activity IC 50 value is 412nM. It has essentially no effect on estrogen, progesterone, salt or glucocorticoid receptors, thus reducing the side effects of anti-other hormones. The structure is stable in the body, binds to the receptor for a long time, has a long acting time, and does not produce androgenic side effects. It was approved by the U.S.
  • This method requires the use of the highly toxic gas phosgene to prepare 3-trifluoromethyl-4-cyanophenyl isocyanate (intermediate 2); the raw material 2-amino-2-cyanopropane is not readily available on the market, and preparation It also requires the use of highly toxic cyanide; hydrochloric acid is required during the hydrolysis process Disadvantages such as heating and greater corrosion to equipment.
  • This method involves the use of strong acid, which can easily cause corrosion to production equipment; the introduced iodine atoms need to be removed during the coupling reaction, and the molecular utilization rate is low; the last step uses a heavy metal catalyst used in the Ullmann coupling reaction, which is easy to dissolve in the raw materials Residues in medicines make it difficult to control the quality of raw materials.
  • This method involves the use of two strong acids, sulfuric acid and nitric acid, which can easily cause corrosion to production equipment; the iodine atoms introduced in the first step need to be removed during the coupling reaction, and the molecular utilization rate is low; the nitration reaction produces isomers, It is easy to introduce impurities and difficult to purify; the last step uses Ullmann coupling reaction, and the heavy metal catalyst used in the reaction is easy to Residues in raw materials make it difficult to control the quality of raw materials and lead to serious environmental pollution problems.
  • the purpose of the present invention is to provide a preparation method of nilutamide of formula (IV) and its intermediates, which is used to overcome the high cost and environmental problems of the method for preparing nilutamide in the prior art.
  • Defects include large pollution, unstable intermediates, cumbersome operations and serious equipment corrosion.
  • the obtained crude product can be further purified by recrystallization or column chromatography to obtain the compound of formula (III) or formula (IV);
  • reaction temperature of steps (1) to (3) is 25-160°C, and the reaction route is as follows:
  • the above-mentioned PG group can be tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc); more preferably, the PG group is Boc and Cbz;
  • the amide condensation reagent used to prepare intermediate III is 1,1-carbonyldiimidazole (CDI);
  • the alkaline reagents in the reaction step are 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et 3 N), N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), sodium methoxide (MeONa), sodium ethoxide (EtONa), sodium tert-butoxide (t-BuONa), potassium carbonate (K 2 CO 3 ), one or a mixture of sodium carbonate (Na 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 );
  • Preferred alkaline reagents DIPEA in step 1 and DBU in step 3; or DIPEA in step 1 and Cs 2 CO 3 in step 3 ;
  • the organic solvents are toluene (Tol), tetrahydrofuran (THF), ethyl acetate (EA), isopropyl acetate (IPAc), methyl ethyl ketone (MEK), dioxane (1,4-dioxane) , Pyridine (Pyridine), acetone (Acetone), acetonitrile (ACN), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP) One or a mixture of them, preferably EA, ACN, THF or DMF;
  • the reaction temperature depends on the boiling point of the selected reaction solvent, which can be between 55°C and 120°C.
  • the reaction progress is monitored according to thin layer chromatography.
  • the compound of formula (III) is completely converted into the compound of formula (IV) to stop the reaction.
  • the compound of formula (III) can be isolated and obtained when the reaction is not completely converted into the compound of formula (IV).
  • the compound of formula (III) is prepared through a condensation reaction.
  • the ring closing reaction of formula (III) directly occurs without purification, and the target compound of formula (III) is prepared by a one-pot method.
  • the reaction conditions are mild, the operation is simple, the yield is high, and it is suitable for industrial production of nilutamide and nilutamide derivatives.
  • Compounds of formula (IV) can also be prepared from compounds of formula (III). Under the action of alkali reagents and nitrogen-containing heterocycles, a ring-closing reaction occurs in an organic solvent at a temperature of 25°C-160°C to generate the formula ( IV) Compound, the obtained crude product is purified by recrystallization or column chromatography to obtain the compound of formula (IV).
  • the alkaline reagent described in the second aspect is one or a mixture of DBU, Et 3 N, DIPEA, DABCO, MeONa, EtONa, t-BuONa, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , preferably DBU or Cs 2 CO 3 ;
  • the nitrogen-containing heterocycle is imidazole, pyrazole, 1,2,3-triazole or 1,2,4-triazole;
  • the organic solvent described in the second aspect is one or a mixture of Tol, THF, EA, IPAc, MEK, 1,4-dioxane, Pyridine, Acetone, ACN, DMF, DMAc, NMP, preferably EA, ACN, THF or DMF.
  • the reaction temperature is controlled between 25°C and 160°C, depending on the boiling point of the reaction solvent.
  • the PG is an amino protecting group, preferably a tert-butoxycarbonyl group.
  • the third aspect of the invention discloses an intermediate for synthesizing nilutamide, which is characterized in that the chemical formula is formula (III), and the PG is tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or Fluorenylmethoxycarbonyl (Fmoc); preferably Boc,
  • reaction steps are short, the operation is simple, the yield is high, the reaction conditions are mild, and the reagents used are cheap and easy to obtain. It is suitable for both small-scale laboratory preparation and industrial large-scale production. Adopting the above route provides a new method for the preparation of nilutamide, which is of great significance for the development of drugs containing this type of structure.
  • the TLC described in the examples is thin layer chromatography.
  • the HPLC is high performance liquid chromatography.
  • citric acid aqueous solution 34g of citric acid dissolved in 52ml of water
  • let stand for liquid separation concentrate the organic phase to obtain the weight of the crude product, obtain compound IV through recrystallization, and dry to obtain 8.01g of reddish-brown solid, yield 51.5%, mp148. 3-149.2°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Disclosed is a method for preparing nilutamide and an intermediate thereof. The method comprises the following steps: at a temperature of 25 °C to 160 °C, using 4-nitro-3-trifluoromethylaniline represented by formula (I) and a compound represented by formula (II) with an amino protecting group PG as raw materials to conduct a condensation reaction and a ring-closing reaction to generate a compound represented by formula (III) and subjecting the compound represented by formula (III) to a direct ring closure without purification to generate nilutamide (formula IV); or subjecting the compound represented by formula (III) to a ring closure to prepare nilutamide. The present invention features short reaction steps, simple operation, high yield, and moderate reaction conditions, and uses cheap and readily available reagents, thus being suitable for both small-scale laboratory preparation and large-scale industrial production. Using the route described above, a new method for constructing a hydantoin ring is provided for the preparation of nilutamide, which is of great significance for the development of drugs comprising this structure.

Description

一种尼鲁米特及其中间体的制备方法A kind of preparation method of nilutamide and its intermediates 技术领域Technical field
本发明属于化学药物合成技术领域，具体地涉及雄激素受体拮抗剂，尤其涉及一种式(Ⅳ)的尼鲁米特的制备方法。The present invention belongs to the technical field of chemical drug synthesis, specifically relates to androgen receptor antagonists, and particularly relates to a preparation method of nilutamide of formula (IV).
背景技术Background technique
尼鲁米特是由法国Roussel-Uclaf公司研制、推出的第一代非甾体雄激素受体拮抗剂，能与雄激素受体结合而无雄激素作用，从而阻断雄激素与这些受体结合，起到抗雄激素作用，其体外抗AR活性IC50值为412nM。对雌性激素、孕激素、盐或糖皮质激素受体基本无作用，因此减少了抗其他激素的副作用。在体内结构稳定，与受体结合持久，作用时间长，不产生雄激素的副作用。1999年4月30日经美国食品药品管理局(FDA)批准用于前列腺癌，商品名为NILANDRON，化学式为5,5-二甲基-3-[4-硝基-3-(三氟甲基)苯基]-2,4-咪唑烷二酮，该药为口服制剂。尼鲁米特(nilutamide，RU 23908)，结构式如下：
Nilutamide is a first-generation non-steroidal androgen receptor antagonist developed and launched by the French company Roussel-Uclaf. It can bind to androgen receptors without androgenic effects, thus blocking the interaction between androgens and these receptors. Combined, it plays an anti-androgen effect, and its in vitro anti-AR activity IC 50 value is 412nM. It has essentially no effect on estrogen, progesterone, salt or glucocorticoid receptors, thus reducing the side effects of anti-other hormones. The structure is stable in the body, binds to the receptor for a long time, has a long acting time, and does not produce androgenic side effects. It was approved by the U.S. Food and Drug Administration (FDA) for prostate cancer on April 30, 1999. The trade name is NILANDRON, and its chemical formula is 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl base)phenyl]-2,4-imidazolidinedione, this medicine is an oral preparation. Nilutamide (RU 23908), the structural formula is as follows:
式IV(Nilutamide,RU 23908)Formula IV(Nilutamide,RU 23908)
报道的尼鲁米特合成路线主要有以下两种：There are two main reported synthetic routes for nilutamide:
1)法国Roussel-Uclaf公司报道的专利(FR7533084A)方法，用4-硝基-3-三氟甲基苯胺1为原料和光气反应生成异氰酸酯中间体2，再与2-氨基-2-氰基丙烷反应关环得中间体3，最后经水解得到式IV化合物尼鲁米特。见路线1：1) The patent (FR7533084A) method reported by Roussel-Uclaf Company in France uses 4-nitro-3-trifluoromethylaniline 1 as raw material and reacts with phosgene to generate isocyanate intermediate 2, which is then reacted with 2-amino-2-cyano Propane reacts with ring closure to obtain intermediate 3, and finally undergoes hydrolysis to obtain nilutamide, a compound of formula IV. See Route 1:
路线1.
Route 1.
该方法中需要用到剧毒物气体光气制得3-三氟甲基-4-氰基苯基异氰酸酯(中间体2)；原料2-氨基-2-氰基丙烷市售不易得，制备又需用到剧毒物氰化物；水解过程中需要有盐酸 加热，对设备腐蚀较大等缺点。This method requires the use of the highly toxic gas phosgene to prepare 3-trifluoromethyl-4-cyanophenyl isocyanate (intermediate 2); the raw material 2-amino-2-cyanopropane is not readily available on the market, and preparation It also requires the use of highly toxic cyanide; hydrochloric acid is required during the hydrolysis process Disadvantages such as heating and greater corrosion to equipment.
2)李倩等报道(中国医药工业杂志，2001,35(8)：455-456)了用化合物1为原料，在硫酸中进行重氮化碘代反应制得相应的碘苯化合物4，在氧化亚铜催化下与5,5-二甲基乙内酰脲在DMF中反应制得尼鲁米特，见路线2：2) Li Qian et al. reported (Chinese Pharmaceutical Industry Journal, 2001, 35(8): 455-456) that compound 1 was used as raw material and the corresponding iodobenzene compound 4 was prepared by diazotization iodo reaction in sulfuric acid. Nilumidate is prepared by reacting with 5,5-dimethylhydantoin in DMF under the catalysis of cuprous oxide, see route 2:
路线2.
Route 2.
该方法涉及到强酸的使用，容易对生产设备造成腐蚀；引入的碘原子在偶联反应中需要脱去，分子利用率较低；最后一步使用了Ullmann偶联反应中使用的重金属催化剂容易在原料药中残留，原料药质量难以控制。This method involves the use of strong acid, which can easily cause corrosion to production equipment; the introduced iodine atoms need to be removed during the coupling reaction, and the molecular utilization rate is low; the last step uses a heavy metal catalyst used in the Ullmann coupling reaction, which is easy to dissolve in the raw materials Residues in medicines make it difficult to control the quality of raw materials.
3)陶晓红等报道(化工生产与技术，2014,21(05)：9-11+7)了以间三氟甲基苯胺5为起始原料，在酸性条件下，与亚硝酸钠和碘化钠发生重氮化碘代反应制得相应的碘代化合物6，化合物6经过硝化反应得到中间体4，在氧化亚铜催化下与5,5-二甲基乙内酰脲在DMF中发生偶联反应制得尼鲁米特，三步反应收率为35％。见路线3：3) Tao Xiaohong et al. reported (Chemical Production and Technology, 2014, 21(05): 9-11+7) that m-trifluoromethylaniline 5 was used as the starting material, and under acidic conditions, it was mixed with sodium nitrite and iodide. The corresponding iodo compound 6 is obtained by the diazotization iodo reaction of sodium. Compound 6 undergoes nitration reaction to obtain intermediate 4, which is coupled with 5,5-dimethylhydantoin in DMF under the catalysis of cuprous oxide. Nilumid was prepared through a combined reaction, and the yield of the three-step reaction was 35%. See Route 3:
路线3.
Route 3.
该方法涉及到硫酸、硝酸两种强酸的使用，容易对生产设备造成腐蚀；第一步反应引入的碘原子在偶联反应中需要脱去，分子利用率较低；硝化反应产生异构体，容易引入杂质，纯化困难；最后一步使用了Ullmann偶联反应，反应中所使用的重金属催化剂容易在 原料药中残留，原料药质量难以控制，并导致严重的环境污染问题。This method involves the use of two strong acids, sulfuric acid and nitric acid, which can easily cause corrosion to production equipment; the iodine atoms introduced in the first step need to be removed during the coupling reaction, and the molecular utilization rate is low; the nitration reaction produces isomers, It is easy to introduce impurities and difficult to purify; the last step uses Ullmann coupling reaction, and the heavy metal catalyst used in the reaction is easy to Residues in raw materials make it difficult to control the quality of raw materials and lead to serious environmental pollution problems.
鉴于上述情况，仍需进一步改进获得适用于工业化生产尼鲁米特的新方法。In view of the above situation, further improvements are still needed to obtain new methods suitable for industrial production of nilutamide.
发明内容Contents of the invention
鉴于上述现有技术的缺点，本发明的目的是提供一种式(Ⅳ)尼鲁米特及其中间体的制备方法，用于克服现有技术中制备尼鲁米特的方法成本高，环境污染大，中间体不稳定，操作繁琐和设备腐蚀严重等缺陷。In view of the shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a preparation method of nilutamide of formula (IV) and its intermediates, which is used to overcome the high cost and environmental problems of the method for preparing nilutamide in the prior art. Defects include large pollution, unstable intermediates, cumbersome operations and serious equipment corrosion.
本发明的第一个方面公开的技术方案：The technical solution disclosed in the first aspect of the present invention:
一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：A preparation method of nilutamide of formula (IV), which is characterized in that:
(1)以式(Ⅱ)化合物为原料，在有机溶剂中，加入碱试剂、酰胺缩合试剂，搅拌加热反应；(1) Use the compound of formula (II) as raw material, add alkali reagent and amide condensation reagent to the organic solvent, stir and heat for reaction;
(2)继续加入式(I)化合物和有机溶剂并反应；(2) Continue to add the compound of formula (I) and the organic solvent and react;
(3)加入碱试剂，继续加热反应，得到式(Ⅳ)化合物；(3) Add an alkali reagent and continue the heating reaction to obtain the compound of formula (IV);
所得粗品还可以进一步通过重结晶或柱层析的方式纯化制得式(Ⅲ)或式(Ⅳ)化合物；The obtained crude product can be further purified by recrystallization or column chromatography to obtain the compound of formula (III) or formula (IV);
步骤(1)至(3)的反应温度为25-160℃，反应路线如下：
The reaction temperature of steps (1) to (3) is 25-160°C, and the reaction route is as follows:
优选地，上述的PG基团可以为叔丁氧羰基(Boc)、苄氧羰基(Cbz)或芴甲氧羰基(Fmoc)；更为优选地，所述PG基团为Boc和Cbz；Preferably, the above-mentioned PG group can be tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc); more preferably, the PG group is Boc and Cbz;
就化合物II而言，PG基团为叔丁氧羰基(Boc)时为化合物II-a；PG基团为苄氧羰基(Cbz)时为化合物II-b；PG基团为芴甲氧羰基(Fmoc)时为化合物II-c。As for compound II, when the PG group is tert-butoxycarbonyl (Boc), it is compound II-a; when the PG group is benzyloxycarbonyl (Cbz), it is compound II-b; when the PG group is fluorenylmethoxycarbonyl ( Fmoc) is compound II-c.
就化合物III而言，PG基团为叔丁氧羰基(Boc)时为化合物III-a；PG基团为苄氧羰基(Cbz)时为化合物III-b；PG基团为芴甲氧羰基(Fmoc)时为化合物III-c。As for compound III, when the PG group is tert-butoxycarbonyl (Boc), it is compound III-a; when the PG group is benzyloxycarbonyl (Cbz), it is compound III-b; when the PG group is fluorenylmethoxycarbonyl ( Fmoc) is compound III-c.
优选地，制备中间体III所使用的酰胺缩合试剂为1,1-羰基二咪唑(CDI)；Preferably, the amide condensation reagent used to prepare intermediate III is 1,1-carbonyldiimidazole (CDI);
所述反应步骤中碱试剂为1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺(Et3N)、 N,N-二异丙基乙胺(DIPEA)、三乙烯二胺(DABCO)、甲醇钠(MeONa)、乙醇钠(EtONa)、叔丁醇钠(t-BuONa)、碳酸钾(K2CO3)、碳酸钠(Na2CO3)和碳酸铯(Cs2CO3)中的一种或混合；The alkaline reagents in the reaction step are 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et 3 N), N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), sodium methoxide (MeONa), sodium ethoxide (EtONa), sodium tert-butoxide (t-BuONa), potassium carbonate (K 2 CO 3 ), one or a mixture of sodium carbonate (Na 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 );
优选碱试剂：步骤1为DIPEA，步骤3为DBU；或步骤1为DIPEA，步骤3为Cs2CO3；Preferred alkaline reagents: DIPEA in step 1 and DBU in step 3; or DIPEA in step 1 and Cs 2 CO 3 in step 3 ;
所述有机溶剂为甲苯(Tol)、四氢呋喃(THF)、乙酸乙酯(EA)、醋酸异丙酯(IPAc)、甲基乙基酮(MEK)、二氧六环(1,4-dioxane)、吡啶(Pyridine)、丙酮(Acetone)、乙腈(ACN)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAc)、N-甲基吡咯烷酮(NMP)中的一种或混合，优选EA、ACN、THF或DMF；The organic solvents are toluene (Tol), tetrahydrofuran (THF), ethyl acetate (EA), isopropyl acetate (IPAc), methyl ethyl ketone (MEK), dioxane (1,4-dioxane) , Pyridine (Pyridine), acetone (Acetone), acetonitrile (ACN), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP) One or a mixture of them, preferably EA, ACN, THF or DMF;
反应温度依据所选择的反应溶剂的沸点，可以在55℃-120℃下反应；根据薄层色谱法监控反应进程，式(III)化合物完全转化为式(Ⅳ)化合物停止反应。式(III)化合物可以在反应未完全转化为式(Ⅳ)化合物时进行分离得到。The reaction temperature depends on the boiling point of the selected reaction solvent, which can be between 55°C and 120°C. The reaction progress is monitored according to thin layer chromatography. The compound of formula (III) is completely converted into the compound of formula (IV) to stop the reaction. The compound of formula (III) can be isolated and obtained when the reaction is not completely converted into the compound of formula (IV).
根据上述条件，以式(I)和式(II)为起始原料，经过缩合反应制得式(III)化合物，式(III)不经过纯化直接发生关环反应，一锅法制得目标化合物式(IV)，该反应条件温和，操作简单，收率较高，适用于工业化生产尼鲁米特及尼鲁米特的衍生物。According to the above conditions, using formula (I) and formula (II) as starting materials, the compound of formula (III) is prepared through a condensation reaction. The ring closing reaction of formula (III) directly occurs without purification, and the target compound of formula (III) is prepared by a one-pot method. (IV), the reaction conditions are mild, the operation is simple, the yield is high, and it is suitable for industrial production of nilutamide and nilutamide derivatives.
本发明的第二个方面公开的技术方案:The technical solution disclosed in the second aspect of the present invention:
式(IV)化合物也可以式(Ⅲ)化合物为原料制得，在碱试剂和含氮杂环的作用下，有机溶剂中，于25℃-160℃温度下，发生关环反应，生成式(Ⅳ)化合物，所得粗品通过重结晶或柱层析纯化制得式(Ⅳ)化合物。
Compounds of formula (IV) can also be prepared from compounds of formula (III). Under the action of alkali reagents and nitrogen-containing heterocycles, a ring-closing reaction occurs in an organic solvent at a temperature of 25°C-160°C to generate the formula ( Ⅳ) Compound, the obtained crude product is purified by recrystallization or column chromatography to obtain the compound of formula (Ⅳ).
第二个方面所述的碱试剂为DBU、Et3N、DIPEA、DABCO、MeONa、EtONa、t-BuONa、K2CO3、Na2CO3、Cs2CO3中的一种或混合，优选DBU或Cs2CO3；The alkaline reagent described in the second aspect is one or a mixture of DBU, Et 3 N, DIPEA, DABCO, MeONa, EtONa, t-BuONa, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , preferably DBU or Cs 2 CO 3 ;
所述含氮杂环为咪唑、吡唑、1,2,3-三氮唑或1,2,4-三氮唑；The nitrogen-containing heterocycle is imidazole, pyrazole, 1,2,3-triazole or 1,2,4-triazole;
第二个方面所述的有机溶剂为Tol、THF、EA、IPAc、MEK、1,4-dioxane、Pyridine、Acetone、ACN、DMF、DMAc、NMP中的一种或混合，优选EA、ACN、THF或DMF。The organic solvent described in the second aspect is one or a mixture of Tol, THF, EA, IPAc, MEK, 1,4-dioxane, Pyridine, Acetone, ACN, DMF, DMAc, NMP, preferably EA, ACN, THF or DMF.
反应温度控制在25℃至160℃之间，根据反应溶剂的沸点来决定。 The reaction temperature is controlled between 25°C and 160°C, depending on the boiling point of the reaction solvent.
作为优选方案的式(Ⅲ)化合物，所述PG为氨基保护基团，优选为叔丁氧羰基。As a preferred embodiment of the compound of formula (III), the PG is an amino protecting group, preferably a tert-butoxycarbonyl group.
本发明的第三个方面公开了一种合成尼鲁米特的中间体，其特征在于，化学式为式(III)，所述PG为叔丁氧羰基(Boc)、苄氧羰基(Cbz)或芴甲氧羰基(Fmoc)；优选Boc,
The third aspect of the invention discloses an intermediate for synthesizing nilutamide, which is characterized in that the chemical formula is formula (III), and the PG is tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or Fluorenylmethoxycarbonyl (Fmoc); preferably Boc,
与现有技术相比，本发明的有益效果：Compared with the existing technology, the beneficial effects of the present invention are:
反应步骤短、操作简单、产率较高、反应条件温和、所用试剂廉价易得，既适合于实验室小规模制备，也适合于工业大规模生产。采用上述路线，为尼鲁米特的制备提供了一个新的方法，对开发含此类结构药物具有重要意义。The reaction steps are short, the operation is simple, the yield is high, the reaction conditions are mild, and the reagents used are cheap and easy to obtain. It is suitable for both small-scale laboratory preparation and industrial large-scale production. Adopting the above route provides a new method for the preparation of nilutamide, which is of great significance for the development of drugs containing this type of structure.
具体实施方式Detailed ways
以下通过实施例以进一步阐明本发明；应当指出，对于本技术领域的普通技术人员，在不脱离本发明构思的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本发明所用的原料、仪器设备和试剂均有商品化的产品可供选择，并可从市场上购买得到。The following examples are used to further illustrate the present invention; it should be noted that those skilled in the art can also make several improvements and modifications without departing from the concept of the present invention, and these improvements and modifications should also be regarded as the present invention. protection scope of the invention. The raw materials, instruments, equipment and reagents used in the present invention are commercially available and can be purchased from the market.
实施例中所述TLC为薄层色谱。The TLC described in the examples is thin layer chromatography.
所述HPLC为高效液相色谱。The HPLC is high performance liquid chromatography.
实施例1Example 1
氮气保护下，向250ml三颈瓶中加入化合物Ⅱ-a(10.0g，0.049mol)，加入溶剂无水THF(3V,30ml)，加入1,1-羰基二咪唑CDI(8.8g，0.054mol)，加入DIPEA(7.6g，0.059mol)并控制温度在60℃，搅拌至固体完全溶解。反应0.5小时后，加入化合物Ⅰ(10.6g，0.052mol)的THF溶液1.5ml，反应0.5小时，加入DBU(9.0g，0.059mol)。继续加热搅拌65h，TLC，停止反应。加入柠檬酸水溶液(柠檬酸34g溶于52ml水中)，静置分液，有机相浓缩得粗品重量，经重结晶得到化合物Ⅳ，烘干得到红褐色的固体8.01克，收率51.5％，m.p.148.3-149.2℃。1H-NMR(400M，DMSO-d6)：δ(ppm)8.793(s，1H)，8.293-8.272(d，1H，J＝8.4Hz)，8.168-8.163(d，1H，J＝2.0Hz)，8.045-8.018(dd，1H，J＝8.8，2.4Hz)，1.390(s， 6H)；13C-NMR(400M，DMSO-d6)：δ(ppm)176.311，153.565，137.071，131.682，126.963，125.820，123.721，122.523-122.186，121.003，58.561，25.121；[M-H]＝316.0。Under nitrogen protection, add compound II-a (10.0g, 0.049mol) to a 250ml three-neck flask, add the solvent anhydrous THF (3V, 30ml), and add 1,1-carbonyldiimidazole CDI (8.8g, 0.054mol) , add DIPEA (7.6g, 0.059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After reacting for 0.5 hours, 1.5 ml of a THF solution of compound I (10.6g, 0.052mol) was added, the reaction was continued for 0.5 hours, and DBU (9.0g, 0.059mol) was added. Continue heating and stirring for 65h, TLC, stop the reaction. Add citric acid aqueous solution (34g of citric acid dissolved in 52ml of water), let stand for liquid separation, concentrate the organic phase to obtain the weight of the crude product, obtain compound IV through recrystallization, and dry to obtain 8.01g of reddish-brown solid, yield 51.5%, mp148. 3-149.2℃. 1 H-NMR (400M, DMSO-d6): δ (ppm) 8.793 (s, 1H), 8.293-8.272 (d, 1H, J = 8.4Hz), 8.168-8.163 (d, 1H, J = 2.0Hz) , 8.045-8.018 (dd, 1H, J=8.8, 2.4Hz), 1.390 (s, 6H); 13 C-NMR (400M, DMSO-d6): δ (ppm) 176.311, 153.565, 137.071, 131.682, 126.963, 125.820, 123.721, 122.523-122.186, 121.003, 58.561, 25.12 1;[MH]=316.0.
实施例2Example 2
氮气保护下，向250ml三颈瓶中加入化合物Ⅱ-a(10.0g，0.049mol)，加入溶剂无水EA(3.0V，30ml)，加入1,1-羰基二咪唑CDI(8.8g，0.054mol)，加入DIPEA(7.6g，0.059mol)并控制温度在60℃，搅拌至固体完全溶解。反应0.5小时后，加入化合物Ⅰ(10.6g，0.052mol)的EA溶液1.5ml，反应0.5小时，加入DBU(9.0g，0.059mol)。继续加热搅拌65h，TLC，停止反应。加入柠檬酸水溶液(柠檬酸34g溶于52ml水中)，静置分液，有机相浓缩得粗品重量，经重结晶得到化合物Ⅳ，烘干得到类白色的固体9.02克，收率58.0％，m.p.154.7-155.1℃。Under nitrogen protection, add compound II-a (10.0g, 0.049mol) to a 250ml three-neck flask, add the solvent anhydrous EA (3.0V, 30ml), and add 1,1-carbonyldiimidazole CDI (8.8g, 0.054mol) ), add DIPEA (7.6g, 0.059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After reacting for 0.5 hours, 1.5 ml of EA solution of compound I (10.6g, 0.052mol) was added, the reaction was continued for 0.5 hours, and DBU (9.0g, 0.059mol) was added. Continue heating and stirring for 65h, TLC, stop the reaction. Add aqueous citric acid solution (34g of citric acid dissolved in 52ml of water), let stand for liquid separation, concentrate the organic phase to obtain the weight of the crude product, obtain compound IV through recrystallization, and dry to obtain 9.02g of off-white solid, yield 58.0%, m.p. 154.7 -155.1℃.
实施例3Example 3
氮气保护下，向250ml三颈瓶中加入化合物Ⅱ-a(10.0g，0.049mol)，加入溶剂无水乙腈(3.0V，30ml)，加入1,1-羰基二咪唑CDI(8.8g，0.054mol)，加入DIPEA(7.6g，0.059mol)并控制温度在60℃，搅拌至固体完全溶解。反应0.5小时后，加入化合物Ⅰ(10.6g，0.052mol)的ACN溶液1.5ml，反应0.5小时，加入DBU(9.0g，0.059mol)。继续加热搅拌65h，TLC，停止反应。加入柠檬酸水溶液(柠檬酸34g溶于52ml水中)，静置分液，有机相浓缩得粗品重量，经重结晶得到化合物Ⅳ，烘干得到红褐色的固体12.10克，收率77.9％，m.p.154.6-155.0℃。Under nitrogen protection, add compound II-a (10.0g, 0.049mol) to a 250ml three-neck flask, add the solvent anhydrous acetonitrile (3.0V, 30ml), and add 1,1-carbonyldiimidazole CDI (8.8g, 0.054mol) ), add DIPEA (7.6g, 0.059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After reacting for 0.5 hours, 1.5 ml of ACN solution of compound I (10.6g, 0.052mol) was added, the reaction was continued for 0.5 hours, and DBU (9.0g, 0.059mol) was added. Continue heating and stirring for 65h, TLC, stop the reaction. Add aqueous citric acid solution (34g of citric acid dissolved in 52ml of water), let stand for liquid separation, concentrate the organic phase to obtain the weight of the crude product, obtain compound IV through recrystallization, and dry to obtain 12.10g of reddish-brown solid, yield 77.9%, m.p. 154.6 -155.0℃.
实施例4Example 4
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌65h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.65g，收率为41.9％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.65g) with a yield of 41.9%.
实施例5Example 5
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g， 0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱TEA(0.60g，0.0059mol)。继续加热搅拌65h，停止反应。取样，HPLC，转化率小于1.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059 mol) and control the temperature at 60°C, stir until the solid is completely dissolved. After reacting for 1 hour, add alkali TEA (0.60g, 0.0059mol) into the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Sampling, HPLC, conversion less than 1.0%.
实施例6Example 6
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DIPEA(0.76g，0.0059mol)。继续加热搅拌65h，停止反应。取样，HPLC，转化率为1.3％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DIPEA (0.76g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Sampling, HPLC, conversion rate 1.3%.
实施例7Example 7
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DaBCO(0.66g，0.0059mol)。继续加热搅拌65h，停止反应。取样，HPLC，转化率小于1.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DaBCO (0.66g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Sampling, HPLC, conversion less than 1.0%.
实施例8Example 8
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱MeONa(0.0.32g，0.0059mol)。继续加热搅拌65h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.14g，收率为9.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base MeONa (0.0.32g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography. The amount of light yellow solid is 0.14g, and the yield is 9.0%.
实施例9Example 9
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱EtONa(0.40g，0.0059mol)。继续加热搅拌65h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.12g，收率为7.4％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base EtONa (0.40g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography. The amount of light yellow solid is 0.12g, with a yield of 7.4%.
实施例10Example 10
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a (1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱(CH3)3CONa(0.57g，0.0059mol)。继续加热搅拌65h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.40g，收率为25.8％。Under nitrogen protection, add compound Ⅰ (1.06g, 0.0052mol) and compound Ⅱ-a into a 20ml parallel reactor test tube. (1.00g, 0.0049mol), add EA (4.5ml), add CDI (0.88g, 0.0054mol), add DIPEA (0.76g, 0.0059mol) and control the temperature at 60°C, stir until the solid is completely dissolved. After 1 hour of reaction, base (CH 3 ) 3 CONa (0.57g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.40g) with a yield of 25.8%.
实施例11Example 11
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱Cs2CO3(1.92g，0.0059mol)。继续加热搅拌65h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.92g，收率为58.4％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base Cs 2 CO 3 (1.92g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.92g) with a yield of 58.4%.
实施例12Example 12
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱NaOH(0.24g，0.0059mol)。继续加热搅拌65h，停止反应。取样，HPLC，转化率小于1.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, alkali NaOH (0.24g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 65h to stop the reaction. Sampling, HPLC, conversion less than 1.0%.
实施例13Example 13
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入Toluene(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.29g，收率为18.7％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add Toluene (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.29g) with a yield of 18.7%.
实施例14Example 14
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入THF(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入 碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.34g，收率为21.9％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add THF (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After reacting for 1 hour, add Base DBU (0.90g, 0.0059mol). Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.34g) with a yield of 21.9%.
实施例15Example 15
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.20g，收率为12.9％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add EA (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.20 g) with a yield of 12.9%.
实施例16Example 16
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入MEK(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.38g，收率为24.5％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add MEK (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.38g) with a yield of 24.5%.
实施例17Example 17
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入Dioxane(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。取样，HPLC，转化率为62.2％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add Dioxane (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Sampling, HPLC, conversion rate was 62.2%.
实施例18Example 18
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入Pyridine(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为 0.20g，收率为12.9％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add Pyridine (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid. 0.20g, yield 12.9%.
实施例19Example 19
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入Acetone(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.10g，收率为6.5％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add Acetone (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.10 g) with a yield of 6.5%.
实施例20Example 20
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入ACN(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。将试管中溶液浓缩干，得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.14g，收率为9.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add ACN (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Concentrate the solution in the test tube to dryness to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography. The amount of light yellow solid is 0.14g, and the yield is 9.0%.
实施例21Example 21
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入DMF(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.28g，收率为18.1％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add DMF (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography. The pale yellow solid is 0.28g, and the yield is 18.1%.
实施例22Example 22
氮气保护下，向20ml平行反应仪试管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入NMP(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌75h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱 层析得化合物Ⅳ，淡黄色固体为0.12g，收率为7.7％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 20ml parallel reactor test tube, add NMP (4.5ml), and add CDI (0.88g, 0.0054mol) , add DIPEA (0.76g, 0.0059mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the parallel reaction tube. Continue heating and stirring for 75h to stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV was obtained by chromatography. The light yellow solid was 0.12g, and the yield was 7.7%.
实施例23Example 23
氮气保护下，向10ml史莱克管中加入化合物Ⅲ-a(1.0g，0.0026mol)，加入EA(4.0ml)，加入DBU(0.9g，0.0059mol)。搅拌加热至60℃，反应45h，停止反应。将史莱克管中溶液浓缩干，得粗品，向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.07g，收率为7.6％。Under nitrogen protection, add compound III-a (1.0g, 0.0026mol), EA (4.0ml), and DBU (0.9g, 0.0059mol) into a 10ml Shrek tube. Stir and heat to 60°C, react for 45 hours, and then stop the reaction. Concentrate the solution in the Shrek tube to dryness to obtain a crude product, add EA to the crude product, wait until it is completely dissolved, and perform column chromatography to obtain 0.07g of compound IV as a light yellow solid, with a yield of 7.6%.
实施例24Example 24
氮气保护下，向10ml史莱克管中加入化合物Ⅲ-a(1.0g，0.0026mol)和咪唑(0.5g，0.0078mol)，加入EA(4.0ml)，加入DBU(0.9g，0.0059mol)。搅拌加热至60℃，反应45h，停止反应。将史莱克管中溶液浓缩干，得粗品，向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.19g，收率为20.7％。Under nitrogen protection, add compound III-a (1.0g, 0.0026mol) and imidazole (0.5g, 0.0078mol) into a 10ml Shrek tube, add EA (4.0ml), and add DBU (0.9g, 0.0059mol). Stir and heat to 60°C, react for 45 hours, and then stop the reaction. Concentrate the solution in the Shrek tube to dryness to obtain a crude product, add EA to the crude product, wait until it is completely dissolved, and then perform column chromatography to obtain 0.19g of compound IV as a light yellow solid, with a yield of 20.7%.
实施例25Example 25
氮气保护下，向10ml史莱克管中加入化合物Ⅲ-a(1.0g，0.0026mol)和吡唑(0.5g，0.0073mol)，加入EA(4.0ml)，加入DBU(0.9g，0.0059mol)。搅拌加热至60℃，反应48h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.51g，收率为32.9％。Under nitrogen protection, add compound III-a (1.0g, 0.0026mol) and pyrazole (0.5g, 0.0073mol) into a 10ml Shrek tube, add EA (4.0ml), and add DBU (0.9g, 0.0059mol). Stir and heat to 60°C, react for 48 hours, and then stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product, wait until it is completely dissolved, and obtain 0.51g of compound IV as a light yellow solid by column chromatography, with a yield of 32.9%.
实施例26Example 26
氮气保护下，向10ml史莱克管中加入化合物Ⅲ-a(1.0g，0.0026mol)和1，2，3-三氮唑(0.5g，0.0072mol)，加入EA(4.0ml)，加入DBU(0.9g，0.0059mol)。搅拌加热至60℃，反应48h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.56g，收率为36.1％。Under nitrogen protection, add compound III-a (1.0g, 0.0026mol) and 1,2,3-triazole (0.5g, 0.0072mol) into a 10ml Shrek tube, add EA (4.0ml), add DBU ( 0.9g, 0.0059mol). Stir and heat to 60°C, react for 48 hours, and then stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product, wait until it is completely dissolved, and obtain 0.56g of compound IV as a light yellow solid by column chromatography, with a yield of 36.1%.
实施例27Example 27
氮气保护下，向10ml史莱克管中加入化合物Ⅲ-a(1.0g，0.0026mol)和1，2，4三氮唑(0.5g，0.0072mol)，加入EA(4.0ml)，加入DBU(0.9g，0.0059mol)。搅拌加热至60℃，反应48h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.54g，收率为34.8％。 Under nitrogen protection, add compound III-a (1.0g, 0.0026mol) and 1,2,4 triazole (0.5g, 0.0072mol) into a 10ml Shrek tube, add EA (4.0ml), and add DBU (0.9 g, 0.0059mol). Stir and heat to 60°C, react for 48 hours, and then stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product, wait until it is completely dissolved, and obtain 0.54g of compound IV as a light yellow solid by column chromatography, with a yield of 34.8%.
实施例28Example 28
氮气保护下，向25ml史莱克管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入DMF(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在115℃，搅拌至固体完全溶解。反应1h后，在史莱克管中加入碱DBU(0.90g，0.0059mol)。继续加热搅拌10h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.93g，收率为60.0％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 25ml Shrek tube, add DMF (4.5ml), add CDI (0.88g, 0.0054mol), Add DIPEA (0.76g, 0.0059mol), control the temperature at 115°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.90g, 0.0059mol) was added to the Shrek tube. Continue heating and stirring for 10 hours to stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.93g) with a yield of 60.0%.
实施例29Example 29
氮气保护下，向25ml史莱克管中加入化合物Ⅰ(0.91g，0.0044mol)和化合物Ⅱ-b(1.00g，0.0042mol)，加入EA(4.5ml)，加入CDI(0.75g，0.0046mol)，加入DIPEA(0.65g，0.0050mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.76g，0.0050mol)。继续加热搅拌47h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.60g，收率为38.7％。Under nitrogen protection, add compound I (0.91g, 0.0044mol) and compound II-b (1.00g, 0.0042mol) into a 25ml Shrek tube, add EA (4.5ml), add CDI (0.75g, 0.0046mol), Add DIPEA (0.65g, 0.0050mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.76g, 0.0050mol) was added to the parallel reaction tube. Continue heating and stirring for 47h to stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.60g) with a yield of 38.7%.
实施例30Example 30
氮气保护下，向25ml史莱克管中加入化合物Ⅰ(0.68g，0.0033mol)和化合物Ⅱ-c(1.00g，0.0031mol)，加入EA(4.5ml)，加入CDI(0.55g，0.0034mol)，加入DIPEA(0.48g，0.0037mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在平行反应试管中加入碱DBU(0.56g，0.0037mol)。继续加热搅拌47h，停止反应。加入柠檬酸水溶液(柠檬酸3.4g溶于5.2ml水中)，静置分液，有机相浓缩得粗品重量。向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ，淡黄色固体为0.38g，收率为24.5％。Under nitrogen protection, add compound I (0.68g, 0.0033mol) and compound II-c (1.00g, 0.0031mol) into a 25ml Shrek tube, add EA (4.5ml), add CDI (0.55g, 0.0034mol), Add DIPEA (0.48g, 0.0037mol), control the temperature at 60°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (0.56g, 0.0037mol) was added to the parallel reaction tube. Continue heating and stirring for 47h to stop the reaction. Add citric acid aqueous solution (3.4g of citric acid dissolved in 5.2ml of water), let stand for liquid separation, and concentrate the organic phase to obtain the weight of the crude product. Add EA to the crude product and wait until it is completely dissolved. Compound IV is obtained by column chromatography as a light yellow solid (0.38g) with a yield of 24.5%.
实施例31Example 31
氮气保护下，向25ml史莱克管中加入化合物Ⅰ(1.06g，0.0052mol)和化合物Ⅱ-a(1.00g，0.0049mol)，加入EA(4.5ml)，加入CDI(0.88g，0.0054mol)，加入DIPEA(0.76g，0.0059mol)并控制温度在115℃，搅拌至固体完全溶解。反应1h后，在史莱克管中加入碱DBU(2.24g，0.0147mol)。继续加热搅拌48h，停止反应。将史莱克管中溶液浓缩干，得粗品，向粗品中加入EA，待完全溶清，柱层析得化合物Ⅳ淡黄色固体0.12g，收率为7.4％。Under nitrogen protection, add compound I (1.06g, 0.0052mol) and compound II-a (1.00g, 0.0049mol) into a 25ml Shrek tube, add EA (4.5ml), add CDI (0.88g, 0.0054mol), Add DIPEA (0.76g, 0.0059mol), control the temperature at 115°C, and stir until the solid is completely dissolved. After 1 hour of reaction, the base DBU (2.24g, 0.0147mol) was added to the Shrek tube. Continue heating and stirring for 48h to stop the reaction. Concentrate the solution in the Shrek tube to dryness to obtain a crude product, add EA to the crude product, wait until it is completely dissolved, and perform column chromatography to obtain 0.12g of compound IV as a light yellow solid, with a yield of 7.4%.
实施例32 Example 32
氮气保护下，向250ml三颈瓶中加入化合物Ⅰ(10.6g，0.052mol)和化合物Ⅱ-a(10.0g，0.049mol)，加入EA(45ml)，加入CDI(8.8g，0.054mol)，加入DIPEA(7.6g，0.059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在三颈瓶中加入碱Cs2CO3(19.2g，0.059mol)。继续加热搅拌92h，TLC，停止反应。抽滤，除去Cs2CO3，加入柠檬酸水溶液(柠檬酸10g溶于16ml水中)，静置分液，有机相浓缩得粗品重量，经重结晶得到化合物Ⅳ，烘干得到固体7.01克，收率45.2％。Under nitrogen protection, add compound I (10.6g, 0.052mol) and compound II-a (10.0g, 0.049mol) into a 250ml three-neck flask, add EA (45ml), add CDI (8.8g, 0.054mol), add DIPEA (7.6g, 0.059mol) and control the temperature at 60°C, stir until the solid is completely dissolved. After reacting for 1 hour, the base Cs 2 CO 3 (19.2g, 0.059mol) was added to the three-necked flask. Continue heating and stirring for 92h, TLC, stop the reaction. Filtrate with suction to remove Cs 2 CO 3 , add citric acid aqueous solution (10g of citric acid dissolved in 16ml of water), let stand for liquid separation, concentrate the organic phase to obtain the weight of the crude product, obtain compound IV through recrystallization, dry to obtain 7.01 g of solid, and collect The rate is 45.2%.
实施例33Example 33
氮气保护下，向250ml三颈瓶中加入化合物Ⅰ(10.6g，0.052mol)和化合物Ⅱ-a(10.0g，0.049mol)，加入DMF(45ml)，加入CDI(8.8g，0.054mol)，加入DIPEA(7.6g，0.059mol)并控制温度在60℃，搅拌至固体完全溶解。反应1h后，在三颈瓶中加入碱DBU(9.0g，0.059mol)。继续加热搅拌3h，TLC，停止反应。加入柠檬酸水溶液(柠檬酸34g溶于52ml水中)，有大量固体析出，抽滤，得粗品重量，经重结晶得到化合物Ⅲ，烘干得到固体14.2克，收率74.1％，m.p.186.2-189.5℃。1H-NMR(400M，DMSO-d6)：δ(ppm)10.304(s，1H)，8.329(s，1H)，8.147(s，2H)，7.193(s，1H)，1.311(m，15H)；13C-NMR(400M，DMSO-d6)：δ(ppm)161.850，144.995，141.529，128.094，124.039，123.409，123.079，121.326，118.393-118.274，78.956，57.065，28.584，25.148；[M-H]-＝390.1。Under nitrogen protection, add compound I (10.6g, 0.052mol) and compound II-a (10.0g, 0.049mol) into a 250ml three-neck flask, add DMF (45ml), add CDI (8.8g, 0.054mol), add DIPEA (7.6g, 0.059mol) and control the temperature at 60°C, stir until the solid is completely dissolved. After reacting for 1 hour, the base DBU (9.0g, 0.059mol) was added to the three-necked flask. Continue heating and stirring for 3 h, perform TLC, and stop the reaction. Add citric acid aqueous solution (34g of citric acid dissolved in 52ml of water), and a large amount of solid will precipitate. Filter with suction to obtain the weight of the crude product. Compound III is obtained by recrystallization, and dried to obtain 14.2g of solid. Yield: 74.1%, mp186.2-189.5 ℃. 1 H-NMR (400M, DMSO-d6): δ (ppm) 10.304 (s, 1H), 8.329 (s, 1H), 8.147 (s, 2H), 7.193 (s, 1H), 1.311 (m, 15H) ; 13 C-NMR (400M, DMSO-d6): δ (ppm) 161.850, 144.995, 141.529, 128.094, 124.039, 123.409, 123.079, 121.326, 118.393-118.274, 78.956, 57.065, 2 8.584, 25.148; [MH] - = 390.1.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。 The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, etc. may be made without departing from the spirit and principles of the present invention. All simplifications should be equivalent substitutions, and are all included in the protection scope of the present invention.

Claims (16)

  1. 一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：A preparation method of nilutamide of formula (IV), which is characterized in that:
    (1)以式(Ⅱ)化合物为原料，在有机溶剂中，加入碱试剂、酰胺缩合试剂，搅拌加热反应；(1) Use the compound of formula (II) as raw material, add alkali reagent and amide condensation reagent to the organic solvent, stir and heat for reaction;
    (2)继续加入式(I)化合物和有机溶剂并反应；(2) Continue to add the compound of formula (I) and the organic solvent and react;
    (3)加入碱试剂，继续加热反应，得到式(Ⅳ)化合物；(3) Add an alkali reagent and continue the heating reaction to obtain the compound of formula (IV);
    步骤(1)至(3)的反应温度为25-160℃，反应路线如下：
    The reaction temperature of steps (1) to (3) is 25-160°C, and the reaction route is as follows:
  2. 根据权利要求1所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述反应步骤中酰胺缩合试剂为1,1-羰基二咪唑。The preparation method of nilutamide of formula (IV) according to claim 1, characterized in that: in the reaction step, the amide condensation reagent is 1,1-carbonyldiimidazole.
  3. 根据权利要求1所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述碱试剂为1,8-二氮杂双环[5.4.0]十一碳-7-烯、三乙胺、N,N-二异丙基乙胺、三乙烯二胺、甲醇钠、乙醇钠、叔丁醇钠和碳酸铯中的一种或多种。The preparation method of nilutamide of formula (IV) according to claim 1, characterized in that: the alkaline reagent is 1,8-diazabicyclo[5.4.0]undec-7- One or more of ene, triethylamine, N,N-diisopropylethylamine, triethylenediamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and cesium carbonate.
  4. 根据权利要求1所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述步骤(1)中的碱试剂为N,N-二异丙基乙胺，步骤(3)中的碱试剂为1,8-二氮杂双环[5.4.0]十一碳-7-烯的混合；或步骤(1)为N,N-二异丙基乙胺，步骤(3)为碳酸铯。The preparation method of nilutamide of formula (IV) according to claim 1, characterized in that: the alkaline reagent in step (1) is N,N-diisopropylethylamine, and the step ( The alkaline reagent in 3) is a mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene; or step (1) is N,N-diisopropylethylamine, and step (3) ) is cesium carbonate.
  5. 根据权利要求1所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述有机溶剂为甲苯、四氢呋喃、乙酸乙酯、醋酸异丙酯、甲基乙基酮、二氧六环、吡啶、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮中的一种或多种。The preparation method of nilutamide of formula (IV) according to claim 1, characterized in that: the organic solvent is toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl ethyl ketone, One or more of dioxane, pyridine, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
  6. 根据权利要求1所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述有机溶剂为乙酸乙酯、乙腈、四氢呋喃或N,N-二甲基甲酰胺。The preparation method of nilutamide of formula (IV) according to claim 1, wherein the organic solvent is ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide.
  7. 根据权利要求1中所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于，所述PG基团为叔丁氧羰基、苄氧羰基或芴甲氧羰基。The method for preparing nilutamide of formula (IV) according to claim 1, wherein the PG group is a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a fluorenylmethoxycarbonyl group.
  8. 根据权利要求1中所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于，所述PG基团为叔丁氧羰基或苄氧羰基。The method for preparing nilutamide of formula (IV) according to claim 1, wherein the PG group is a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
  9. 根据权利要求1中所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于，所述PG为叔丁氧羰基。 The method for preparing nilutamide of formula (IV) according to claim 1, wherein the PG is tert-butoxycarbonyl.
  10. 一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：以式(Ⅲ)化合物为原料，在碱试剂和含氮杂环的作用下，有机溶剂中，于25℃-160℃下，发生关环反应，生成式(Ⅳ)化合物，
    A preparation method of nilutamide of formula (IV), which is characterized in that: using the compound of formula (III) as raw material, under the action of alkali reagent and nitrogen-containing heterocycle, in an organic solvent, at 25°C-160°C Under the condition, a ring-closing reaction occurs to generate the compound of formula (IV),
  11. 根据权利要求10所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述碱试剂为DBU、Et3N、DIPEA、DABCO、MeONa、EtONa、t-BuONa和Cs2CO3中的一种或多种。The preparation method of nilutamide of formula (IV) according to claim 10, characterized in that: the alkaline reagent is DBU, Et 3 N, DIPEA, DABCO, MeONa, EtONa, t-BuONa and Cs One or more of 2 CO 3 .
  12. 根据权利要求10所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述碱试剂为DBU或Cs2CO3。The preparation method of nilutamide of formula (IV) according to claim 10, characterized in that: the alkaline reagent is DBU or Cs 2 CO 3 .
  13. 根据权利要求10所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述含氮杂环为咪唑、吡唑、1,2,3-三氮唑或1,2,4-三氮唑。The preparation method of nilutamide of formula (IV) according to claim 10, characterized in that: the nitrogen-containing heterocycle is imidazole, pyrazole, 1,2,3-triazole or 1, 2,4-Triazole.
  14. 根据权利要求10所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述反应步骤中有机溶剂为Tol、THF、EA、IPAc、MEK、1,4-dioxane、Pyridine、Acetone、ACN、DMF、DMAc、NMP中的一种或多种。The preparation method of nilutamide of formula (IV) according to claim 10, characterized in that: in the reaction step, the organic solvent is Tol, THF, EA, IPAc, MEK, 1,4-dioxane, One or more of Pyridine, Acetone, ACN, DMF, DMAc, and NMP.
  15. 根据权利要求10所述的一种式(Ⅳ)的尼鲁米特的制备方法，其特征在于：所述反应步骤中有机溶剂为EA、ACN或THF。The method for preparing nilutamide of formula (IV) according to claim 10, wherein the organic solvent in the reaction step is EA, ACN or THF.
  16. 一种合成尼鲁米特的中间体，其特征在于：化学式为式(III)，所述PG为叔丁氧羰基、苄氧羰基或芴甲氧羰基，
    An intermediate for synthesizing nilutamide, characterized in that: the chemical formula is formula (III), and the PG is tert-butoxycarbonyl, benzyloxycarbonyl or fluorenylmethoxycarbonyl,
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MAJI SAMIR KUMAR, HALDER D., VELMURUGAN D., RAJAKANNAN V., BANERJEE ARINDAM: "A unique example of a pseudo-peptide containing noncoded amino acids self-assembling into a supramolecular β-sheet-like structure in crystals", LETTERS IN PEPTIDE SCIENCE, ESCOM SCIENCE PUBLISHERS, NL, vol. 8, no. 2, 1 March 2001 (2001-03-01), NL , pages 61 - 67, XP093091786, ISSN: 0929-5666, DOI: 10.1007/BF02443606 *

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