WO2015096604A1 - 一种米拉贝隆有关物质或其盐、其制备方法和用途 - Google Patents

一种米拉贝隆有关物质或其盐、其制备方法和用途 Download PDF

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WO2015096604A1
WO2015096604A1 PCT/CN2014/092998 CN2014092998W WO2015096604A1 WO 2015096604 A1 WO2015096604 A1 WO 2015096604A1 CN 2014092998 W CN2014092998 W CN 2014092998W WO 2015096604 A1 WO2015096604 A1 WO 2015096604A1
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formula
compound
solvent
acid
salt
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French (fr)
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张福利
章磊
焦慧荣
谭支敏
徐兰霞
徐建国
裘鹏程
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国药集团国瑞药业有限公司
上海医药工业研究院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals

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  • the present invention relates to a mirablon related substance or a salt thereof, a process for the preparation thereof and use thereof.
  • Patent WO2003037881 reports that the synthesis method of Mirabelon is as follows: D-mandelic acid and p-nitrophenylethylamine are used as starting materials, and a compound represented by Formula 9 is obtained by amide condensation, and then reduced by borane. The compound of the formula 10 is further subjected to catalytic hydrogenation reduction to obtain a compound of the formula 11 and finally condensed with the compound of the formula 7 to obtain a milazide.
  • the specific synthetic route is as follows:
  • the technical problem to be solved by the present invention is to overcome the technical problems of the prior generation of impurities in the synthesis of Mirabelon, which cannot be effectively identified and quality control, and to provide a related substance of Mirabelon or a salt thereof, a preparation method thereof and use.
  • the mirablon related substance of the present invention is a necessitary product of the quality control of mirablon, and can effectively identify impurities generated in the synthesis of mirablon, thereby controlling the quality of the drug of mirablon.
  • mirablon contains a dehydroxyl impurity
  • its properties are very similar to those of Mirabelon, and conventional purification methods such as recrystallization. It is difficult to divert it, and the presence of this impurity has a great influence on the quality of Mirabelon, so effective control and removal of the dehydroxylated impurities is the key to the quality control of Mirabelon.
  • the inventors have found through extensive experiments that the quality control of Mirabelon must be based on the dehydroxylation impurity reference material in the establishment of the analytical method. Therefore, the dehydroxylation impurity is a necessity for the quality control of Mirabelon.
  • the presence of impurities may cause serious side reactions, and there is an urgent need in the art to efficiently identify impurities generated in the synthesis of Mirabelon.
  • the present invention finally solves the above technical problems by the following technical solutions.
  • the present invention provides a mirablon related substance or a salt thereof as shown in Formula I;
  • the salt of the mirabyl related substance as shown in Formula I is a salt of a compound of the formula I and an acid.
  • the acid may be a conventional inorganic or organic acid in the art.
  • the inorganic acid is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, carbonic acid, nitric acid or phosphoric acid.
  • the organic acid is preferably formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid or Glutamate.
  • the present invention also provides a method for preparing a mirablon related substance or a salt thereof as shown in Formula I, which comprises the steps of: in a solvent, a compound represented by Formula 6 under the action of a condensing agent
  • the compound represented by Formula 7 or an active ester thereof is subjected to a condensation reaction as shown below to obtain a mirablon-related substance represented by Formula I; or, a solvent a condensation reaction of a salt of a compound of the formula 6 with a compound of the formula 7 or an active ester thereof under the action of a condensing agent to obtain a mirablon-related substance as shown in Formula I or a salt thereof;
  • the active ester of the compound of formula 7 is an ester of a compound of formula 7 with 1-hydroxybenzotriazole or 1-hydroxy-7-azobenzotriazole;
  • the solvent is preferably water and/or an organic solvent.
  • the organic solvent is preferably one or more of an amide solvent, a ketone solvent, and a sulfoxide solvent.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide.
  • the ketone solvent is preferably N-methylpyrrolidone.
  • the sulfoxide-based solvent is preferably dimethyl sulfoxide.
  • the condensing agent is preferably dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethyl carbon
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC diimine hydrochloride
  • CDI carbonyl diimidazole
  • DPPA diphenylphosphoryl azide
  • DEPC diethylphosphoryl cyan
  • the molar ratio of the condensing agent to the compound of the formula 6 or a salt thereof is preferably from 1:1 to 2:1.
  • the volume of the solvent and the compound of the formula 6 or a salt thereof is preferably from 10 mL/g to 40 mL/g.
  • the temperature of the condensation reaction is preferably from 0 ° C to 60 ° C, more preferably from 25 ° C to 35 ° C.
  • the progress of the condensation reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound shown in Formula 6 or a salt thereof disappears as the end point of the reaction, the condensation reaction
  • the time is preferably from 0.5 to 2 hours.
  • the solvent is preferably water.
  • the preparation method of the mirablon related substance as shown in Formula I may further comprise the following steps: in the organic solvent, under the action of the reducing agent, the compound as shown in Formula 5 is subjected to the following Reversal shown A compound of the formula 6 is obtained by a reduction reaction of a salt of the compound of the formula 5 in an organic solvent under the action of a reducing agent to obtain a salt of the compound of the formula 6 ;
  • the method and conditions of the reduction reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following conditions:
  • the organic solvent is preferably an ether solvent, an aromatic hydrocarbon solvent, or a halogen.
  • a hydrocarbon solvent preferably one or more of a hydrocarbon solvent, an amide solvent, an ester solvent, a sulfoxide solvent, and an alcohol solvent.
  • the ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyltetrahydrofuran.
  • the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene.
  • the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1,2-dichloroethane.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide.
  • the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, and isoamyl acetate.
  • the sulfoxide-based solvent is preferably dimethyl sulfoxide.
  • the alcohol solvent is preferably methanol, ethanol or isopropanol.
  • the reducing agent is preferably a metal reducing agent or a hydrogen source.
  • the metal reducing agent is preferably one or more of iron, zinc and tin.
  • the molar ratio of the metal reducing agent to the compound of the formula 5 or a salt thereof is preferably from 5:1 to 15:1.
  • the hydrogen source is preferably hydrogen.
  • the catalyst is preferably one or more of palladium-carbon, palladium hydroxide-carbon and Raney nickel, more preferably 10% by mass of palladium carbon and/or 10% by mass.
  • Raney nickel the mass fraction is 10% palladium carbon, the percentage refers to the mass of palladium as a percentage of the total mass of palladium carbon; the mass fraction is 10% of Raney nickel, said Percentage refers to the mass of nickel as a percentage of the total mass of Raney nickel.
  • the mass of the catalyst is preferably from 2% to 50%, more preferably from 5% to 20% by mass of the compound of Formula 5 or a salt thereof.
  • the pressure of the catalytic hydrogenation reduction reaction is preferably from 1 atm to 5 atm, more preferably from 1 atm to 2 atm.
  • the volume ratio of the organic solvent to the compound of the formula 5 or a salt thereof is preferably from 5 mL/g to 20 mL/g.
  • the temperature of the reduction reaction is from 0 ° C to 60 ° C, more preferably from 25 ° C to 35 ° C.
  • the process of the reduction reaction can be The monitoring is carried out by a conventional test method (such as TLC, HPLC or NMR) in the art, and is generally the end point of the reaction when the compound represented by Formula 5 or a salt thereof disappears, and the reaction time is preferably 6-18. hour.
  • the organic solvent is preferably an alcohol solvent.
  • the method for preparing a mirablon related substance as shown in Formula I which may further comprise the following steps: in the organic solvent, the compound represented by Formula 4 is subjected to the action of a reducing agent as follows a reduction reaction to obtain a compound as shown in Formula 5;
  • the method and conditions of the reduction reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following conditions: in the organic solvent, under the action of a reducing agent, a compound of the formula 4 After mixing with a solvent, the reduction reaction shown below was carried out to obtain a compound represented by Formula 5.
  • the organic solvent is preferably one or more of an ether solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, and a nitrile solvent.
  • the ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, 2-methyltetrahydrofuran and dimethyl sulfide, more preferably tetrahydrofuran.
  • the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene.
  • the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1,2-dichloroethane.
  • the nitrile solvent is preferably acetonitrile.
  • the reducing agent is preferably one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium aluminum hydride, borane-tetrahydrofuran solution and borane-dimethyl sulfide solution, Preferably, it is a borane-tetrahydrofuran solution.
  • the solubilizing agent is preferably 1,3-dimethyl-2-imidazolidinone (DMI).
  • the molar ratio of the reducing agent to the compound of the formula 4 is preferably from 2:1 to 4:1.
  • the volume of the pro-solvent and the compound of the formula 4 is preferably from 1 mL/g to 6 mL/g.
  • the volume ratio of the organic solvent to the compound of the formula 4 is preferably from 2 mL/g to 10 mL/g.
  • the temperature of the reduction reaction is preferably from 25 ° C to 100 ° C, more preferably from 50 ° C to 80 ° C.
  • the progress of the reduction reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the compound shown in Formula 4 disappears as the end point of the reaction, and the time of the reduction reaction is compared. The best place is 4-8 hours.
  • the preparation method of the compound represented by Formula 5 may further comprise the steps of: mixing a compound represented by Formula 5 with an acid in an alcohol solvent to carry out a salt formation reaction a salt of a compound as shown in Formula 5;
  • the alcohol solvent is preferably methanol, ethanol or isopropanol.
  • the hydrochloric acid may be a commercially available hydrochloric acid reagent conventionally used in the art, preferably 10% to 37% by mass of hydrochloric acid, and the mass percentage means the mass of hydrogen chloride as a percentage of the total mass of the hydrochloric acid reagent.
  • the method for preparing a mirablon related substance as shown in Formula I which may further comprise the following steps: in an organic solvent, in the presence of a basic substance, a condensing agent and an acylating activator, a compound represented by Formula 2 and a compound represented by Formula 3 or a salt thereof are subjected to a condensation reaction as shown below to obtain a compound represented by Formula 4;
  • the method and conditions of the condensation reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following conditions:
  • the organic solvent is preferably an ether solvent, an aromatic hydrocarbon solvent, or a halogen.
  • a hydrocarbon-based solvent preferably an amide solvent, an ester solvent, a ketone solvent, a nitrile solvent, and a sulfoxide solvent; preferably an amide solvent and/or a sulfoxide solvent.
  • the ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane and 2-methyltetrahydrofuran.
  • the aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene.
  • the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1,2-dichloroethane.
  • the amide solvent is preferably N,N-dimethylformamide and/or N,N-dimethylacetamide; more preferably N,N-dimethylformamide.
  • the ester solvent is preferably one or more of ethyl acetate, isopropyl acetate and isoamyl acetate.
  • the ketone solvent is preferably one or more of acetone, 2-butanone, methyl isobutyl ketone and N-methylpyrrolidone.
  • the nitrile solvent is preferably acetonitrile.
  • the sulfoxide-based solvent is preferably dimethyl sulfoxide.
  • the condensing agent is preferably dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) and diethylphosphoryl cyanide (DEPC) One or more of them; more preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • CDI carbonyldiimidazole
  • DPPA diphenylphosphoryl azide
  • DEPC diethylphosphoryl cyanide
  • the acylation activator is preferably 4-N,N-lutidine (DMAP) and/or 1-hydroxybenzotriazole (HOBt), more preferably 1-hydroxybenzotriazole Oxazole (HOBt).
  • the basic substance is preferably an inorganic base and/or an organic base.
  • the inorganic base is preferably one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide, sodium ethoxide and potassium t-butoxide.
  • the organic base is preferably one or more of triethylamine, pyridine, quinoline and diisopropylethylamine; more preferably triethylamine.
  • the molar ratio of the basic substance to the compound represented by Formula 2 is preferably from 1:1 to 1.5:1.
  • the molar ratio of the condensing agent to the compound of the formula 2 is preferably from 1:1 to 1.5:1.
  • the molar ratio of the acylating activator to the compound of formula 2 is preferably from 1:1 to 1.5:1.
  • the volume ratio of the organic solvent to the compound of the formula 2 is preferably from 3 mL/g to 10 mL/g.
  • the temperature of the condensation reaction is preferably from 0 ° C to 60 ° C, more preferably from 25 ° C to 35 ° C.
  • the progress of the condensation reaction can be monitored by conventional test methods in the art (such as TLC, HPLC or NMR), generally when the compound shown in Formula 2 disappears as the end of the reaction, and the time of the condensation reaction is higher. The best place is 12 to 24 hours.
  • the compound of the formula I or a salt thereof, preferably, the synthetic route thereof is as follows:
  • the invention also provides the use of a compound of formula I as hereinbefore described, wherein the compound is used as a reference substance for the quality control of mirablon or for the identification of impurities in Mirabelon. .
  • the content thereof is less than 0.05%, and the percentage means that the compound represented by the formula I accounts for The percentage of the compound shown by I and the total mass of Mirabelon.
  • the present invention also provides a method for quality control or impurity identification of mirablon comprising the steps of: using the compound of formula I according to claim 1 or 2 as a quality control or impurity of mirablon Identification of related substances.
  • the preparation method and conditions of the salt of the mirablon-related substance as shown in Formula I can also be prepared according to the conventional methods and conditions for salt formation in the art.
  • the reagents and starting materials used in the present invention are commercially available.
  • the room temperature means an ambient temperature of 10 ° C to 35 ° C.
  • the mirablon related substance of the present invention is a necessity for the quality control of mirablon, and can effectively identify impurities generated in the synthesis of mirablon and quantitatively control related substances.
  • Figure 1 is a comparative HPLC chromatogram of the crude product of Mirabelon prepared in Example 13 and the compound of Formula I prepared in Example 7.
  • Figure 2 is an HPLC chromatogram of the Mirabelon product prepared in Example 13.
  • the 1 H-NMR spectrum was analyzed using a Bruker-400 nuclear magnetic resonance apparatus, the internal standard was tetramethylsilane, and the chemical shift was expressed in ⁇ (ppm).
  • Mass spectrometry was performed on an Agilent 6210 liquid chromatography-time of flight mass spectrometer.
  • the mirablon product in the following examples refers to a Mirabelon product obtained by recrystallization purification.
  • the compound of formula I (0.5 g, 1.3 mmol) and methanol (2.5 mL) prepared in Example 7 were sequentially added to the reverse In a vial, a solution of succinic acid (0.16 g, 1.3 mmol) in methanol (2.5 mL) was added dropwise to the reaction mixture, stirred at room temperature overnight and filtered to give the succinate of the compound of formula I (0.61 g, 92.42%).
  • the compound of the formula I (0.5 g, 1.3 mmol) and methanol (2.5 mL) prepared in Example 7 were sequentially added to a reaction flask, and then a solution of fumaric acid (0.15 g, 1.3 mmol) in methanol (2.5 mL) It was added dropwise to the reaction mixture, stirred at room temperature overnight, and filtered to give the compound of the compound of formula I (0.58 g, 89.23%).
  • the compound of the formula I (0.5 g, 1.3 mmol) and methanol (2.5 mL) prepared in Example 7 were sequentially added to a reaction flask, and then a solution of tartaric acid (0.20 g, 1.3 mmol) in methanol (2.5 mL) was added dropwise. It was added to the reaction mixture, stirred at room temperature overnight, and filtered to give a tart salt of the compound of formula I (0.65 g, 92.86%).
  • the preparation method of the Mirabelon is referred to the preparation method of Mirabelon in the patent application of WO2003037881 in the background art, and the specific operation is as follows:
  • a compound of the formula (5.0 g, 17.08 mmol), a compound of the formula 7 (2.7 g, 17.07 mmol), water (75 mL), concentrated hydrochloric acid (1.66 g, 17.07 mmol), EDC (3.60 g) , 18.78 mmol) was added to the reaction flask in turn, and stirred at room temperature for 1 h. Then, a 1.5 M sodium hydroxide solution (25 mL) was added dropwise to the reaction mixture to precipitate a white solid. Filtration and drying in vacuo gave a crude product of milabamide (6.45 g, 95.26%).
  • Figure 1 and Table 1 show the HPLC chromatograms of the crude milabene prepared in Example 13 and the compound of Formula I prepared in Example 7, and their retention times, peak heights, peak areas, relative Information such as area.
  • Fig. 1, 1 indicates information such as retention time, peak height, peak area, and relative area of the crude Mirabelon prepared in Example 13.
  • 2 represents information on retention time, peak height, peak area, relative area, and the like of the compound of Formula I obtained in Example 7.
  • 3 shows that the crude Mirabelon prepared in Example 13 was mixed with the compound of Formula I obtained in Example 7, and the retention time, peak height, peak area, and relative area of each component in the mixture were as follows.
  • . 1, 2, 3, and 4 in Table 1 correspond to retention time, peak height, peak area, and relative area of each component in the crude Mirabelon.
  • Fig. 2 indicates a blank control. 2 shows information such as retention time, peak height, peak area, and relative area of the HPLC spectrum of the Mirabelon product obtained in Example 13. In Table 2, 1 and 2 correspond to the retention time, peak height, peak area, and relative area of each component in the Mirabelon product.
  • the mirablon related substance of the present invention can effectively identify impurities generated in the synthesis of mirablon, thereby controlling the quality of the drug of mirablon.
  • the milavirenol product produced in the present invention has an HPLC purity of greater than 99.95% and an impurity (such as the compound of formula I) content of less than 0.05%.

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Abstract

本发明公开了一种如式I所示的米拉贝隆有关物质或其盐、其制备方法和用途。本发明公开的米拉贝隆有关物质或其盐的制备方法，包含下列步骤：溶剂中，在缩合剂的作用下，将如式6所示的化合物与如式7所示的化合物或其活性酯进行如下所示的缩合反应，制得如式I所示的米拉贝隆有关物质；或者，溶剂中，在缩合剂的作用下，将如式6所示的化合物的盐与如式7所示的化合物或其活性酯进行缩合反应，制得如式I所示的米拉贝隆有关物质的盐。本发明的米拉贝隆有关物质能够有效鉴定米拉贝隆合成中产生的杂质，从而控制米拉贝隆的药品质量。

Description

一种米拉贝隆有关物质或其盐、其制备方法和用途
本申请要求申请日为2013年12月27日的中国专利申请CN201310743091.3的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种米拉贝隆有关物质或其盐、其制备方法和用途。
背景技术
米拉贝隆，化学名(R)-2-(2-氨基噻唑-4-基)-N-(4-{2-[(2-羟基-2-苯基乙基)氨基]乙基}苯基)乙酰胺，分子式C21H24N4O2S，分子量396.51，CAS登记号223673-61-8，是日本安斯泰来(Astellas)制药有限公司开发的口服有效的新型选择性β3肾上腺素能受体激动剂，于2011年首次在日本上市，2012年6月经FDA批准用于治疗成年人膀胱过度活动症(OAB)，其结构如下所示：
Figure PCTCN2014092998-appb-000001
专利WO2003037881报道米拉贝隆的合成方法为：以D-扁桃酸和对硝基苯乙胺为起始原料，经酰胺缩合制得如式9所示的化合物，然后经硼烷还原制得如式10所示的化合物，再经催化氢化还原制得如式11所示的化合物，最后与如式7所示的化合物缩合制得米拉贝隆，具体合成路线如下所示：
Figure PCTCN2014092998-appb-000002
发明内容
本发明所要解决的技术问题是克服现有的米拉贝隆合成中产生杂质，不能有效鉴定和质量控制的技术问题，而提供了一种米拉贝隆有关物质或其盐、其制备方法和用途。本发明的米拉贝隆有关物质是米拉贝隆质量控制的必需品，能够有效鉴定米拉贝隆合成中产生的杂质，从而控制米拉贝隆的药品质量。
发明人在重复专利WO2003037881中的工艺路线合成的米拉贝隆的过程中，发现米拉贝隆中会含有一种脱羟基杂质，其性质与米拉贝隆十分相近，重结晶等常规纯化方法难以将其除尽，该杂质的存在对米拉贝隆的质量影响很大，故有效地控制和除去该脱羟基杂质是米拉贝隆质量控制的关键。发明人经大量的实验发现，米拉贝隆的质量控制在分析方法的建立上必须使用脱羟基杂质对照品进行定位，因而脱羟基杂质是米拉贝隆质量控制的必需品。此外，杂质的存在还有可能引起严重的副反应，因而本领域迫切需要有效鉴定米拉贝隆合成中产生的杂质。
本发明最终通过以下技术方案解决上述技术问题的。
本发明提供了一种如式I所示的米拉贝隆有关物质或其盐；
Figure PCTCN2014092998-appb-000003
所述的如式I所示的米拉贝隆有关物质的盐为如式I所示的化合物与酸形成的盐。所述的酸可为本领域常规的无机酸或有机酸。所述的无机酸较佳地为盐酸、氢溴酸、氢碘酸、硫酸、碳酸、硝酸或磷酸。所述的有机酸较佳地为甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、苦味酸、甲磺酸、乙磺酸或谷氨酸。
本发明还提供了一种如式I所示的米拉贝隆有关物质或其盐的制备方法，其包括下列步骤：溶剂中，在缩合剂的作用下，将如式6所示的化合物与如式7所示的化合物或其活性酯进行如下所示的缩合反应，制得如式I所示的米拉贝隆有关物质；或者，溶剂 中，在缩合剂的作用下，将如式6所示的化合物的盐与如式7所示的化合物或其活性酯进行缩合反应，制得如式I所示的米拉贝隆有关物质或其盐；其中，如式7所示的化合物的活性酯为如式7所示的化合物与1-羟基苯并三氮唑或1-羟基-7-偶氮苯并三氮唑形成的酯；
Figure PCTCN2014092998-appb-000004
其中，所述的缩合反应的方法和条件可为本领域此类反应常规的方法和条件，本发明特别优选下列条件：所述的溶剂较佳地为水和/或有机溶剂。所述的有机溶剂较佳地为酰胺类溶剂、酮类溶剂和亚砜类溶剂中的一种或多种。所述的酰胺类溶剂较佳地为N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。所述的酮类溶剂较佳地为N-甲基吡咯烷酮。所述的亚砜类溶剂较佳地为二甲基亚砜。
所述的缩合剂较佳地为二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、羰基二咪唑(CDI)、二苯基磷酰叠氮(DPPA)和二乙基磷酰氰化物(DEPC)中的一种或多种，更佳地为1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDC)。
所述的缩合剂与如式6所示的化合物或其盐的摩尔比较佳地为1:1～2:1。所述的溶剂与如式6所示的化合物或其盐的体积质量比较佳地为10mL/g～40mL/g。所述的缩合反应的温度较佳地为0℃～60℃，更佳地为25℃～35℃。所述的缩合反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC或NMR)进行监控，一般以如式6所示的化合物或其盐消失时为反应终点，所述的缩合反应的时间较佳地为0.5～2小时。
当如式6所示的化合物以盐的形式进行反应时，所述的溶剂较佳地为水。
其中，所述的如式I所示的米拉贝隆有关物质的制备方法，其还可进一步包含下列步骤：有机溶剂中，在还原剂的作用下，将如式5所示的化合物进行如下所示的还原反 应，制得如式6所示的化合物；或者，有机溶剂中，在还原剂的作用下，将如式5所示的化合物的盐进行还原反应，制得如式6所示的化合物的盐；
Figure PCTCN2014092998-appb-000005
其中，所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件，本发明特别优选下列条件：所述的有机溶剂较佳地为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂、酰胺类溶剂、酯类溶剂、亚砜类溶剂和醇类溶剂中的一种或多种。所述的醚类溶剂较佳地为四氢呋喃、乙醚、乙二醇二甲醚、二噁烷和2-甲基四氢呋喃中的一种或多种。所述的芳香烃类溶剂较佳地为苯、甲苯和二甲苯中的一种或多种。所述的卤代烃类溶剂较佳地为二氯甲烷、三氯甲烷和1,2-二氯乙烷中的一种或多种。所述的酰胺类溶剂较佳地为N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺。所述的酯类溶剂选自乙酸乙酯、乙酸异丙酯和乙酸异戊酯中的一种或多种。所述的亚砜类溶剂较佳地为二甲基亚砜。所述的醇类溶剂较佳地为甲醇、乙醇或异丙醇。
所述的还原剂较佳地为金属类还原剂或者氢源。所述的金属类还原剂较佳地为铁、锌和锡中的一种或多种。所述的金属类还原剂与如式5所示化合物或其盐的摩尔比较佳地为5:1～15:1。所述的氢源较佳地为氢气。
当所述的还原剂为氢源时，较佳地在反应体系中加入催化剂，进行催化氢化还原反应。所述的催化剂较佳地为钯-碳、氢氧化钯-碳和雷尼镍中的一种或多种，更佳地为质量分数为10％的钯碳和/或质量分数为10％的雷尼镍，所述的质量分数为10％钯碳中，所述的百分比是指钯的质量占钯碳总质量的百分比；所述的质量分数为10％的雷尼镍中，所述的百分比是指镍的质量占雷尼镍总质量的百分比。所述的催化剂的质量较佳地为如式5所示的化合物或其盐质量的2％～50％，更佳地为5％～20％。所述的催化氢化还原反应的压力较佳地为1atm～5atm，更佳地为1atm～2atm。
所述的有机溶剂与如式5所示的化合物或其盐的体积质量比较佳地为5mL/g～20mL/g。所述的还原反应的温度为0℃～60℃，更佳地为25℃～35℃。所述的还原反应的进程可以 采用本领域中的常规测试方法(如TLC、HPLC或NMR)进行监控，一般以如式5所示的化合物或其盐消失时为反应终点，所述的反应的时间较佳地为6～18小时。
当如式5所示的化合物以盐的形式进行反应时，所述的有机溶剂优选醇类溶剂。
所述的如式I所示的米拉贝隆有关物质的制备方法，其还可进一步包含下列步骤：有机溶剂中，在还原剂的作用下，将如式4所示的化合物进行如下所示的还原反应，制得如式5所示的化合物；
Figure PCTCN2014092998-appb-000006
其中，所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件，本发明特别优选下列条件：有机溶剂中，在还原剂的作用下，将如式4所示的化合物与促溶剂混合后进行如下所示的还原反应，制得如式5所示的化合物。
其中，所述的有机溶剂较佳地为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂和腈类溶剂中的一种或多种。所述的醚类溶剂较佳地为四氢呋喃、乙醚、乙二醇二甲醚、二噁烷、2-甲基四氢呋喃和二甲硫醚中的一种或多种，更佳地为四氢呋喃。所述的芳香烃类溶剂较佳地为苯、甲苯和二甲苯中的一种或多种。所述的卤代烃类溶剂较佳地为二氯甲烷、三氯甲烷和1,2-二氯乙烷中的一种或多种。所述的腈类溶剂较佳地为乙腈。
所述的还原剂较佳地为硼氢化钠、硼氢化钾、氰基硼氢化钠、氢化铝锂、硼烷-四氢呋喃溶液和硼烷-二甲硫醚溶液中的一种或多种，更佳地为硼烷-四氢呋喃溶液。所述的促溶剂较佳地为1,3-二甲基-2-咪唑啉酮(DMI)。
所述的还原剂与如式4所示的化合物的摩尔比较佳地为2:1～4:1。所述的促溶剂与如式4所示的化合物的体积质量比较佳地为1mL/g～6mL/g。所述的有机溶剂与如式4所示的化合物的体积质量比较佳地为2mL/g～10mL/g。所述的还原反应的温度较佳地为25℃～100℃，更佳地为50℃～80℃。所述的还原反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC或NMR)进行监控，一般以如式4所示的化合物消失时为反应终点，所述的还原反应的时间较佳地为4～8小时。
在所述的如式5所示的化合物的制备方法中，较佳地，其还可进一步包含下列步骤：在醇类溶剂中，将如式5所示的化合物与酸混合，进行成盐反应，制得如式5所示的化合物的盐；
Figure PCTCN2014092998-appb-000007
其中，所述的醇类溶剂较佳地为甲醇、乙醇或异丙醇。其所述的盐酸可以为本领域中常规市售盐酸试剂，优选质量百分比为10％～37％的盐酸，所述的质量百分比是指氯化氢的质量占盐酸试剂总质量的百分比。
所述的如式I所示的米拉贝隆有关物质的制备方法，其还可进一步包含下列步骤：有机溶剂中，在碱性物质、缩合剂与酰化活化剂存在的条件下，将如式2所示的化合物与如式3所示的化合物或其盐进行如下所示的缩合反应，制得如式4所示的化合物；
Figure PCTCN2014092998-appb-000008
其中，所述的缩合反应的方法和条件可为本领域此类反应常规的方法和条件，本发明特别优选下列条件：所述的有机溶剂较佳地为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂、酰胺类溶剂、酯类溶剂、酮类溶剂、腈类溶剂和亚砜类溶剂中的一种或多种；较佳地为酰胺类溶剂和/或亚砜类溶剂。所述的醚类溶剂较佳地为四氢呋喃、乙醚、乙二醇二甲醚、二噁烷和2-甲基四氢呋喃中的一种或多种。所述的芳香烃类溶剂较佳地为苯、甲苯和二甲苯中的一种或多种。所述的卤代烃类溶剂较佳地为二氯甲烷、三氯甲烷和1,2-二氯乙烷中的一种或多种。所述的酰胺类溶剂较佳地为N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；更佳地为N,N-二甲基甲酰胺。所述的酯类溶剂较佳地为乙酸乙酯、乙酸异丙酯和乙酸异戊酯中的一种或多种。所述的酮类溶剂较佳地为丙酮、2-丁酮、甲基异丁基酮和N-甲基吡咯烷酮中的一种或多种。所述的腈类溶剂较佳地为乙腈。所述的亚砜类溶剂较佳地为二甲基亚砜。
所述缩合剂较佳地为二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3- 二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、羰基二咪唑(CDI)、二苯基磷酰叠氮(DPPA)和二乙基磷酰氰化物(DEPC)中的一种或多种；更佳地为1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDC)。
所述的酰化活化剂较佳地为4-N,N-二甲基吡啶(DMAP)和/或1-羟基苯并三氮唑(HOBt)，更佳地为1-羟基苯并三氮唑(HOBt)。
所述的碱性物质较佳地为无机碱和/或有机碱。所述的无机碱较佳地为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氨基钠、氢化钠、甲醇钠、乙醇钠和叔丁醇钾中的一种或多种。所述的有机碱较佳地为三乙胺、吡啶、喹啉和二异丙基乙基胺中的一种或多种；更佳地为三乙胺。
所述的碱性物质与如式2所示的化合物的摩尔比较佳地为1:1～1.5:1。所述的缩合剂与如式2所示的化合物的摩尔比较佳地为1:1～1.5:1。所述的酰化活化剂的与如式2所示的化合物的摩尔比较佳地为1:1～1.5:1。所述的有机溶剂与如式2所示的化合物的体积质量比较佳地为3mL/g～10mL/g。所述的缩合反应的温度较佳地为0℃～60℃，更佳地为25℃～35℃。所述的缩合反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC或NMR)进行监控，一般以如式2所示的化合物消失时为反应终点，所述的缩合反应的时间较佳地为12～24小时。
本发明中，所述的如式I所示的化合物或其盐，较佳地，其合成路线如下所示：
Figure PCTCN2014092998-appb-000009
本发明还提供了一种如前所述的如式I所示的化合物的用途，其中，该化合物用作米拉贝隆质量控制的有关物质对照品，或用于米拉贝隆的杂质鉴定。
其中，当所述的如式I所示的化合物用作米拉贝隆质量控制的有关物质对照品时，其含量小于0.05％，所述的百分比是指如式I所示的化合物占如式Ⅰ所示的化合物与米拉贝隆总质量的百分比。
本发明还提供了一种米拉贝隆的质量控制或杂质鉴定的方法，其包括以下步骤：用权利要求1或2所述的如式I所示的化合物作米拉贝隆质量控制或杂质鉴定的有关物质对照品。
本发明中，所述的如式I所示的米拉贝隆有关物质的盐的制备方法和条件还可按照本领域成盐反应的常规方法和条件制备。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明中，所述的室温是指环境温度，为10℃～35℃。
本发明的积极进步效果在于：
本发明的米拉贝隆有关物质是米拉贝隆质量控制的必需品，能够有效鉴定米拉贝隆合成中产生的杂质，并对有关物质进行定量控制。
附图说明
图1是实施例13制得的米拉贝隆粗品与实施例7制得的如式I所示的化合物对照HPLC谱图。
图2是实施例13制得的米拉贝隆产品的HPLC谱图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下列实施例中，1H-NMR谱使用Bruker-400核磁共振仪，内标是四甲基硅烷，化学 位移以δ(ppm)表示。质谱用Agilent 6210液相色谱-飞行时间质谱联用仪。
下述实施例中的米拉贝隆产品是指经重结晶纯化后得到的米拉贝隆产品。
实施例1 N-(4-硝基苯基乙基)-2-苯乙酰胺的制备(如式4所示的化合物)
将如式2所示的化合物(10.0g,0.073mol)和如式3所示的化合物(14.88g,0.073mol)加至DMF(50mL)中，依次将三乙胺(7.43g,0.073mol)、1-羟基苯并三唑(9.93g,0.073mol)、1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)(14.78g,0.077mol)加至上述反应液中，室温搅拌18h。加入水、二氯甲烷萃取。有机层干燥，过滤，减压浓缩。甲苯重结晶得白色固体(17.33g,82.99％)。
mp 130.2～131.0℃。
ESI-MS(m/z):285[M+H]+,307[M+Na]+。
1H NMR(400MHz,DMSO-d6)δ:2.84～2.88(t,2H,NO2PhCH2),3.29(s,2H,COCH2),3.34～3.39(m,2H,NCH2),7.19～7.28(m,5H,Ph-H),7.42～7.44(d,2H,硝基苯间位H),8.04(s,1H,重水交换信号消失,CONH),8.09～8.11(d,2H,硝基苯邻位H)。
实施例2 N-(4-硝基苯基乙基)-2-苯乙胺盐酸盐的制备(如式5所示的化合物的盐酸盐)
将如式4所示的化合物(5.0g,17.59mmol)、无水THF(15mL)、1,3-二甲基-2-咪唑啉酮(15ml)加至三口烧瓶中，氮气保护，冷至-20℃后逐滴加入1M BH3-THF溶液(38.69mL,38.69mmol)，滴毕，65℃搅拌5h。将反应液冷却至-15℃，滴加甲醇(2.5mL)和浓盐酸(3.3mL)。滴毕，65℃搅拌1h，减压浓缩，向残渣中加入20％碳酸钾溶液(50mL)，乙酸乙酯(3×25mL)萃取，有机层用饱和食盐水洗涤，干燥，过滤，减压浓缩。残渣用异丙醇(50mL)溶解，再加浓盐酸(1.45mL)结晶化，过滤，滤饼用异丙醇洗涤，真空干燥，得淡黄色固体(4.75g,88.04％)。
mp 230.6～231.2℃。ESI-MS(m/z):271[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:3.02～3.32(m,8H,4CH2),7.23～7.36(m,5H,Ph-H),7.58～7.60(d,2H,硝基苯间位H),8.19～8.21(d,2H,硝基苯邻位H),9.55(br s,2H,NH2 +Cl－)。
实施例3 4-[2-(苯基乙基氨基)乙基]苯胺盐酸盐的制备(如式6所示的化合物的盐酸 盐)
将如式5所示的化合物的盐酸盐(3.5g,11.41mmol)、质量百分比为10％Pd/C(0.35g)加入甲醇中，通入氢气，搅拌12h后过滤反应液，滤液减压浓缩，残渣用甲醇(10mL)溶解，滴加异丙醚(70mL)结晶化，过滤，滤饼用异丙醚洗涤，真空干燥，得白色固体(2.9g,91.83％)。
mp 186℃(分解)。ESI-MS(m/z):241[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:2.80～3.16(m,8H,4CH2),4.99(br s,2H,NH2),6.53～6.55(d,2H,苯胺邻位H),6.90～6.92(d,2H,苯胺间位H),7.24～7.36(m,5H,Ph-H),9.22(br s,2H,NH2 +Cl－)。
实施例4 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺盐酸盐的制备(如式I所示化合物的盐酸盐)
将如式6所示的化合物的盐酸盐(5.0g,18.1mmol)、如式7所示的化合物(2.86g,18.1mmol)、水(100mL)、浓盐酸(1.76g,18.1mmol)、EDC(3.81g,19.87mmol)依次加至反应瓶中，室温搅拌1h。然后向反应液中滴加1.0M氢氧化钠溶液(20.0mL)，有白色固体析出。过滤，真空干燥，得淡黄色固体(6.06g,80.48％)。
mp 239.4～239.8℃。ESI-MS(m/z):381[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:2.94～3.18(m,8H,4CH2),3.48(s,2H,COCH2),6.31(s,1H,SCH),6.86(br s,2H,NH2),7.18～7.59(m,9H,Ph-H),9.24(br s,2H,NH2 +Cl－),10.12(s,1H,重水交换信号消失,NHCO)。
13C NMR(100MHz,DMSO-d6)δ:168.69,168.41,146.26,138.47,137.79,132.28,129.28,129.08,129.07,127.18,119.77,103.09,48.26,48.19,40.19,32.01,31.45.
实施例5 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺盐酸盐的制备(如式I所示化合物的盐酸盐)
将如式6所示的化合物的盐酸盐(1.0g,3.6mmol)、如式7所示的化合物(0.57g,3.6mmol)、水(20mL)、浓盐酸(0.35g,3.6mmol)、EDC(1.39g,7.2mmol)依次加至反应瓶中，60℃搅拌30min。冷至室温，然后向反应液中滴加1.0M氢氧化钠溶液(4.0mL)， 有白色固体析出。过滤，真空干燥，得淡黄色固体(1.13g,75.01％)。
实施例6 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺盐酸盐的制备(如式I所示化合物的盐酸盐)
将如式7所示的化合物(1.0g,6.3mmol)、水(30mL)、浓盐酸(0.61g,6.3mmol)、EDC(1.21g,6.3mmol)、HOBt(0.85g，6.3mmol)依次加至反应瓶中，0～5℃搅拌4h。然后将如式6所示化合物的盐酸盐(1.75g，6.3mmol)加入反应液中，继续搅拌2h。反应毕，向反应液中滴加1.0M氢氧化钠溶液(6.5mL)，有白色固体析出。过滤，真空干燥，得淡黄色固体(2.06g,78.26％)。
实施例7 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺的制备(如式I所示的化合物)
将实施例4制得的式I化合物的盐酸盐(6.0g,14.4mmol)、水(180mL)依次加至反应瓶中，然后向反应液中逐滴加入1.0M氢氧化钠溶液(15.0mL)，有白色固体析出，过滤，真空干燥，得白色固体(4.68g，85.39％)。
实施例8 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺氢溴酸盐的制备(如式I所示化合物的氢溴酸盐)
将实施例7制备的式I所示的化合物(0.5g,1.3mmol)、甲醇(5mL)依次加至反应瓶中，然后向反应液中逐滴加入48％氢溴酸水溶液(0.22g,1.3mmol)，室温搅拌过夜，过滤，得式I所示化合物的氢溴酸盐(0.51g,84.11％)。
实施例9 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺硫酸盐的制备(如式I所示化合物的硫酸盐)
将实施例7制备的式I所示的化合物(0.5g,1.3mmol)、甲醇(5mL)依次加至反应瓶中，然后向反应液中逐滴加入浓硫酸(0.13g,1.3mmol)，室温搅拌过夜，过滤，得式I所示化合物的硫酸盐(0.49g,77.92％)。
实施例10 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺琥珀酸盐的制备(如式I所示化合物的琥珀酸盐)
将实施例7制备的如式I所示化合物(0.5g,1.3mmol)、甲醇(2.5mL)依次加至反 应瓶中，然后将琥珀酸(0.16g,1.3mmol)的甲醇(2.5mL)溶液逐滴加至反应液中，室温搅拌过夜，过滤，得式I所示化合物的琥珀酸盐(0.61g,92.42％)。
实施例11 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺富马酸盐的制备(如式I所示化合物的富马酸盐)
将实施例7制备的式所示I化合物(0.5g,1.3mmol)、甲醇(2.5mL)依次加至反应瓶中，然后将富马酸(0.15g,1.3mmol)的甲醇(2.5mL)溶液逐滴加至反应液中，室温搅拌过夜，过滤，得式I所示化合物的富马酸盐(0.58g,89.23％)。
实施例12 2-(2-氨基噻唑-4-基)-N-{4-[2-(苯基乙基氨基)乙基]苯基}乙酰胺酒石酸盐的制备(如式I所示化合物的酒石酸盐)
将实施例7制备的式I所示化合物(0.5g,1.3mmol)、甲醇(2.5mL)依次加至反应瓶中，然后将酒石酸(0.20g,1.3mmol)的甲醇(2.5mL)溶液逐滴加至反应液中，室温搅拌过夜，过滤，得式I所示化合物的酒石酸盐(0.65g,92.86％)。
实施例13(R)-2-(2-氨基噻唑-4-基)-N-(4-{2-[(2-羟基-2-苯基乙基)氨基]乙基}苯基)乙酰胺(米拉贝隆)的制备及纯化
HPLC测试的具体条件如下：
色谱柱Waters X-Bridge C18柱(4.6mm×150mm,3.5μm)；流动相0.1％三氟乙酸水溶液(A)-0.1％三氟乙酸乙腈溶液(B)，梯度洗脱：0→10min，A︰B＝90︰10；10→25min，A︰B＝90︰10→30︰70；25→32min，A︰B＝30︰70→90︰10；流速1ml/min；检测波长210nm；柱温30℃)。
该米拉贝隆的制备方法参照背景技术中专利号为WO2003037881的专利申请中米拉贝隆的制备方法，具体操作如下：
将如式11所示的化合物(5.0g,17.08mmol)、如式7所示的化合物(2.7g,17.07mmol)、水(75mL)、浓盐酸(1.66g,17.07mmol)、EDC(3.60g,18.78mmol)依次加至反应瓶中，室温搅拌1h。然后向反应液中滴加1.5M氢氧化钠溶液(25mL)，有白色固体析出。过滤，真空干燥，得米拉贝隆粗品(6.45g,95.26％)。
取米拉贝隆粗品3.0g，向其中加入乙酸乙酯30mL及纯化水1.5mL，于80℃搅拌 溶解，待溶液溶清后缓慢降温，并于55℃保温搅拌1h，有白色固体析出，然后缓慢降至室温，过滤，真空干燥，得白色米拉贝隆产品2.41g，HPLC纯度99.96％。
mp 138.7～139.4℃。ESI-MS(m/z):397[M+H]+,419[M+Na]+。
1H NMR(400MHz,DMSO-d6)δ:1.60(1H,s),2.61-2.68(4H,m),2.70-2.79(2H,m),3.46(2H,s),4.59-4.62(1H,t),5.14(1H,br),6.30(1H,s),6.84(2H,s),7.11-7.13(2H,d),7.20-7.24(1H,m),7.28-7.34(4H,m),7.48-7.50(2H,d),9.93(1H,s).
图1和表1所表示的为实施例13制得的米拉贝隆粗品与实施例7制得的如式I所示的化合物对照HPLC谱图及其保留时间、峰高、峰面积、相对面积等信息。
图1中，1表示实施例13中制得的米拉贝隆粗品的保留时间、峰高、峰面积、相对面积等信息。2表示实施例7中制得的如式I所示的化合物的保留时间、峰高、峰面积、相对面积等信息。3表示将实施例13制得的米拉贝隆粗品与实施例7制得的如式I所示的化合物混合，该混合物中各组分的保留时间、峰高、峰面积、相对面积等信息。表1中的1、2、3、4对应米拉贝隆粗品中各组分的保留时间、峰高、峰面积、相对面积等信息。
图2和表2所表示的为实施例13制得的米拉贝隆产品的HPLC谱图的保留时间、峰高、峰面积、相对面积等信息。
图2中，1表示空白对照。2表示实施例13制得的米拉贝隆产品的HPLC谱图的保留时间、峰高、峰面积、相对面积等信息。表2中，1和2对应米拉贝隆产品中各组分的保留时间、峰高、峰面积、相对面积等信息。
表1
Figure PCTCN2014092998-appb-000010
Figure PCTCN2014092998-appb-000011
表2
Figure PCTCN2014092998-appb-000012
由表1和表2的数据可以看出，本发明的米拉贝隆有关物质能够有效鉴定米拉贝隆合成中产生的杂质，从而控制米拉贝隆的药品质量。本发明中制得的米拉贝隆产品HPLC纯度大于99.95％，杂质(如式I所示的化合物)含量小于0.05％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (12)

  1. 一种如式I所示的米拉贝隆有关物质或其盐；
    Figure PCTCN2014092998-appb-100001
  2. 如权利要求1所述的米拉贝隆有关物质或其盐，其特征在于，所述的如式Ⅰ所示的米拉贝隆有关物质的盐为如式Ⅰ所示的化合物与酸形成的盐，所述的酸为无机酸或有机酸；所述的无机酸为盐酸、氢溴酸、氢碘酸、硫酸、硝酸或磷酸；所述的有机酸为甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸或谷氨酸。
  3. 一种如权利要求1或2所述的如式I所示的米拉贝隆有关物质或其盐的制备方法，其特征在于，其包括下列步骤：溶剂中，在缩合剂的作用下，将如式6所示的化合物与如式7所示的化合物或其活性酯进行如下所示的缩合反应，制得如式I所示的米拉贝隆有关物质；或者，溶剂中，在缩合剂的作用下，将如式6所示的化合物的盐与如式7所示的化合物或其活性酯进行缩合反应，制得如式I所示的米拉贝隆有关物质的盐；其中，如式7所示的化合物的活性酯为如式7所示的化合物与1-羟基苯并三氮唑或1-羟基-7-偶氮苯并三氮唑形成的酯；
    Figure PCTCN2014092998-appb-100002
  4. 如权利要求3所述的制备方法，其特征在于，所述的溶剂为水和/或有机溶剂；所述的缩合剂为二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐、羰基二咪唑、二苯基磷酰叠氮和二乙基磷酰氰化物中的一种或多种；所述 的缩合剂与如式6所示的化合物的摩尔比为1:1～2:1；所述的溶剂与如式6所示的化合物的体积质量比为10mL/g～40mL/g；所述的反应的温度为0℃～60℃；当如式6所示的化合物以盐酸盐的形式进行反应时，所述的溶剂为水。
  5. 如权利要求3或4所述的制备方法，其特征在于，其还包含下列步骤：有机溶剂中，在还原剂的作用下，将如式5所示的化合物进行如下所示的还原反应，制得如式6所示的化合物；或者，有机溶剂中，在还原剂的作用下，将如式5所示的化合物的盐进行还原反应，制得如式6所示的化合物的盐；
    Figure PCTCN2014092998-appb-100003
  6. 如权利要求3-5中至少一项所述的制备方法，其特征在于，所述的有机溶剂为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂、酰胺类溶剂、酯类溶剂、亚砜类溶剂和醇类溶剂中的一种或多种；所述的还原剂为金属类还原剂或者氢源；所述的金属类还原剂与如式5所示化合物或其盐的摩尔比为5:1～15:1；所述的氢源为氢气；当所述的还原剂为氢源时，在反应体系中加入催化剂，进行催化氢化还原反应；所述的催化剂为钯-碳、氢氧化钯-碳和雷尼镍中的一种或多种；所述的催化剂为如式5所示的化合物或其盐的2％～50％；所述的催化氢化还原反应的压力为1atm～5atm；所述的有机溶剂与如式5所示的化合物或其盐的体积质量比为5mL/g～20mL/g；所述的还原反应的温度为0℃～60℃；当如式5所示的化合物以盐的形式进行反应时，所述的有机溶剂为醇类溶剂。
  7. 如权利要求3-6中至少一项所述的制备方法，其特征在于，其还包含下列步骤：有机溶剂中，在还原剂的作用下，将如式4所示的化合物进行如下所示的还原反应，制得如式5所示的化合物；
    Figure PCTCN2014092998-appb-100004
  8. 如权利要求3-7中至少一项所述的制备方法，其特征在于，其包含下列步骤：有 机溶剂中，在还原剂的作用下，将如式4所示的化合物与促溶剂混合后，进行还原反应，制得如式5所示的化合物；所述的有机溶剂为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂和腈类溶剂中的一种或多种；所述的还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠、氢化铝锂、硼烷-四氢呋喃溶液和硼烷-二甲硫醚溶液中的一种或多种；所述的促溶剂为1,3-二甲基-2-咪唑啉酮；所述的还原剂与如式4所示的化合物的摩尔比为2:1～4:1；所述的促溶剂与如式4所示的化合物的体积质量比为1mL/g～6mL/g；所述的有机溶剂与如式4所示的化合物的体积质量比为2mL/g～10mL/g；所述的反应的温度为25℃～100℃。
  9. 如权利要求3-8中至少一项所述的制备方法，其特征在于，其还包含下列步骤：有机溶剂中，在碱性物质、缩合剂与酰化活化剂存在的条件下，将如式2所示的化合物与如式3所示的化合物进行如下所示的缩合反应，制得如式4所示的化合物；
    Figure PCTCN2014092998-appb-100005
  10. 如权利要求3-9中至少一项所述的制备方法，其特征在于，所述的有机溶剂为醚类溶剂、芳香烃类溶剂、卤代烃类溶剂、酰胺类溶剂、酯类溶剂、酮类溶剂、腈类溶剂和亚砜类溶剂中的一种或多种；所述缩合剂为二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐、羰基二咪唑、二苯基磷酰叠氮和二乙基磷酰氰化物中的一种或多种；所述的酰化活化剂为4-N,N-二甲基吡啶和/或1-羟基苯并三氮唑；所述的碱性物质为无机碱和/或有机碱；所述的碱性物质与如式2所示的化合物的摩尔比为1:1～1.5:1；所述的缩合剂与如式2所示的化合物的摩尔比为1:1～1.5:1；所述的酰化活化剂的与如式2所示的化合物的摩尔比为1:1～1.5:1；所述的反应的温度为0℃～60℃。
  11. 一种如权利要求1或2所述的如式I所示的化合物的用途，其中，该化合物用作米拉贝隆质量控制的有关物质对照品，或用于米拉贝隆的杂质鉴定。
  12. 一种米拉贝隆的质量控制或杂质鉴定的方法，其特征在于包括以下步骤：用权利要求1或2所述的如式I所示的化合物作米拉贝隆质量控制或杂质鉴定的有关物质对照品。
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