WO2018227553A1 - 盐酸罗匹尼罗的纯化方法 - Google Patents

盐酸罗匹尼罗的纯化方法 Download PDF

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WO2018227553A1
WO2018227553A1 PCT/CN2017/088651 CN2017088651W WO2018227553A1 WO 2018227553 A1 WO2018227553 A1 WO 2018227553A1 CN 2017088651 W CN2017088651 W CN 2017088651W WO 2018227553 A1 WO2018227553 A1 WO 2018227553A1
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ropinirole hydrochloride
organic solvent
hydrochloride
stirring
ropinirole
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PCT/CN2017/088651
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English (en)
French (fr)
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涂国良
徐中明
周涛
黄文锋
张士文
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浙江华海立诚药业有限公司
浙江华海药业股份有限公司
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Application filed by 浙江华海立诚药业有限公司, 浙江华海药业股份有限公司 filed Critical 浙江华海立诚药业有限公司
Priority to CN201780090511.9A priority Critical patent/CN110621660B/zh
Priority to US16/623,085 priority patent/US10961194B2/en
Priority to EP17913313.7A priority patent/EP3640240B1/en
Priority to PCT/CN2017/088651 priority patent/WO2018227553A1/zh
Publication of WO2018227553A1 publication Critical patent/WO2018227553A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention relates to a method for purifying ropinirole hydrochloride, and in particular to a method for purifying ropinirole hydrochloride impurity A monopropyl ropinirole.
  • the structure (I) of impurity A is:
  • Ropinirole hydrochloride was developed by GlaxoSmithKline (GSK) and the US Food and Drug Administration (FDA) approved the first generic version of Ropinirole hydrochloride.
  • Ropinirole hydrochloride is used to treat moderate to severe restless leg syndrome (Restless Legs Syndrome, RLS).
  • RLS Restless Legs Syndrome
  • the FDA has approved ropinirole hydrochloride for the treatment of Parkinson's disease. Because the use of ropinirole hydrochloride for the treatment of Parkinson's disease is patented, the ropinirole hydrochloride generic drug can only be approved for the treatment of the restless leg syndrome. Once the original patent for the use of ropinirole hydrochloride in Parkinson's disease is expired, the generic drug manufacturer may seek permission to obtain Parkinson's disease.
  • the structural formula of ropinirole hydrochloride is as shown in the following formula (II):
  • the patent US4452808 uses 2-methyl-3-nitro-benzoic acid as a raw material, hydrogenation by borane, addition of thionyl chloride to obtain acid chloride, nitrilation, and hydrolysis to obtain 2-methyl-3-nitrate.
  • Patent US2007032540 uses 4-indene as raw material to obtain nitrostyrene compound by nitromethane reaction, and then undergoes hydrogenation reduction, addition and reduction with propionic acid. Finally, the oxidation of ropinirole hydrochloride is obtained. Finally, the patent US0156505 is prepared by using o-bromoethylbenzaldehyde as a raw material, substituted with nitromethane to obtain a nitrostyrene compound, and then subjected to cyclization, oxidation, hydrolysis, etc. to obtain hydrochloric acid. Ropinillo
  • the structure of the impurity A is similar to that of the ropinirole hydrochloride product, it is difficult to achieve separation by conventional means. Commonly used methods such as solvent washing, beating, recrystallization, etc. are difficult to remove the impurity A, and also affect the yield of ropinirole hydrochloride product. There is therefore a need for a simple, inexpensive, and efficient purification process to remove this impurity A.
  • the inventors have developed a method for purifying ropinirole hydrochloride 4-2-di-n-propylamine ethyl-1,3-dihydro-2H-indol-2-one hydrochloride, which is simple, inexpensive and The impurity A (structural formula I) is effectively removed.
  • the present invention provides ropinirole hydrochloride 4-2-di-n-propylamine ethyl-1,3-dihydro-2H-indol-2-one hydrochloride represented by the formula (II).
  • a purification method comprising the following steps:
  • -R represents a C 1 -C 6 alkyl group or a C 6 -C 10 aromatic group
  • -L represents a halogen-X, or an acyloxy group
  • the halogen may be fluorine, chlorine, bromine or iodine
  • step (1) after stirring and adding a base at room temperature, for example, it may be stirred for 20 minutes or more, and then left to stand for stratification.
  • the volume of the organic solvent in milliliters may be 2 to 20 times, preferably 5 to 15 times, more preferably 8 to 12 times the mass of ropinirole hydrochloride.
  • the volume of water in milliliters may be 5 to 20 times the mass of ropinirole hydrochloride in grams.
  • the molar amount of the base in the step (1) is 1.5 to 25 times, preferably 5 to 15 times, the molar amount of ropinirole hydrochloride.
  • the organic solvent in the step (1) may be dichloromethane, n-hexane, cyclohexane, ethyl acetate, isopropyl acetate, toluene, xylene or methyl tert-butyl ether.
  • the base in the step (1) may be selected from the group consisting of sodium carbonate, potassium hydroxide, Sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, triethylamine or diisopropylamine.
  • an acid halide or an acid anhydride is added to the organic layer, and the mixture is stirred for, for example, 10 minutes, and concentrated.
  • the molar amount of the acid halide or acid anhydride may be from 1 to 5 times the molar amount of the ropinirole hydrochloride A.
  • the impurity-removing reagent acid halide or acid anhydride may be selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, acetic anhydride or benzoic anhydride; and the like; preferably acetyl chloride, benzoyl chloride or acetic anhydride.
  • the molar amount of the acid halide or acid anhydride is 1 to 5 times the molar amount of the ropinirole hydrochloride A.
  • the liquid can be cooled, mashed and dried to obtain ropinirole hydrochloride.
  • a certain amount of an organic solvent is added to the obtained oil.
  • the volume of the solvent in milliliters may be the weight of the ropinirole hydrochloride in grams. 20 times.
  • the temperature of the reaction solution is controlled to be 15 ⁇ 5° C., and a certain amount of concentrated hydrochloric acid is slowly added.
  • the amount of concentrated hydrochloric acid may be 2 to 10 times, preferably 2 to 5 times, the molar amount of ropinirole hydrochloride. Stirring is continued for example for 30 minutes.
  • the liquid can be cooled to 5 ⁇ 5 ° C and stirring is continued for 40 minutes, filtered and dried to obtain ropinirole hydrochloride.
  • concentration of concentrated hydrochloric acid used was 37%, and the amount thereof was calculated as the amount of HCl in concentrated hydrochloric acid.
  • the organic solvent of the step (4) may be methanol, ethanol, isopropanol or n-butanol.
  • Nitrogen protection is strictly required in all the above steps.
  • the impurity A in ropinirole hydrochloride can be effectively removed, and ropinirole hydrochloride can be obtained in a good yield and purity, thereby controlling the impurity A to make the product purity reach the pharmaceutical standard.
  • Nitrogen protection is required for all processes and will not be repeated later.
  • acetyl chloride was added in an amount of 2 times the molar amount of ropinirole hydrochloride A, stirred for 10 minutes, and concentrated to dryness to give an oil.
  • HPLC analysis method of related substances of ropinirole hydrochloride is as follows:
  • Mobile phase A 2.84 g Na 2 HPO 4 was dissolved in 1000 ml of water and adjusted to pH 11.0 with 1 mol/L NaOH.
  • acetic anhydride was added in an amount of 2 times the molar amount of ropinirole hydrochloride A, stirred for 10 minutes, and concentrated to dryness to give an oil.
  • propionyl chloride was added in an amount of 2 times the molar amount of ropinirole hydrochloride A, stirred for 10 minutes, and concentrated to dryness to give an oil.
  • benzoyl chloride was added in an amount of 2 times the molar amount of ropinirole hydrochloride A, stirred for 10 minutes, and concentrated to dryness to give an oil.
  • the following table is a comparison table after purification of ropinirole hydrochloride with different impurity A (monopropyl ropinirole) content.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

提供一种盐酸罗匹尼罗4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法。该方法包括：将含有杂质A单丙基罗匹尼罗的盐酸罗匹尼罗加入水中，并加入有机溶剂，室温下搅拌溶清加入碱，搅拌后静置分层，除去水层，任选地用无水硫酸镁干燥有机层并过滤，向有机层加入酰氯或酸酐，搅拌后，浓缩有机层至干，向得到的油状物中加入有机溶剂，加入浓盐酸搅拌后得到盐酸罗匹尼罗。所述方法能够有效地除去盐酸罗匹尼罗中的杂质A，能够以较好的收率和纯度获得盐酸罗匹尼罗，从而控制杂质A使产品纯度达到药用标准。

Description

盐酸罗匹尼罗的纯化方法 技术领域
本发明涉及盐酸罗匹尼罗的纯化方法，特别地，涉及去除盐酸罗匹尼罗杂质A单丙基罗匹尼罗的纯化方法。杂质A的结构(I)为：
Figure PCTCN2017088651-appb-000001
背景技术
盐酸罗匹尼罗由GlaxoSmithKline(GSK)开发，美国食品药品管理局(FDA)批准第一个盐酸罗匹尼罗(Ropinirole hydrochloride)仿制药。
盐酸罗匹尼罗用于治疗中度到重度的多动腿综合征(Restless Legs Syndrome，RLS)。除此之外，FDA还曾批准盐酸罗匹尼罗用于治疗帕金森氏症。因为盐酸罗匹尼罗治疗帕金森氏症的用途受到了专利保护，所以盐酸罗匹尼罗仿制药仅能获准治疗多动腿综合征。一旦原研药厂的盐酸罗匹尼罗治疗帕金森氏症的用途专利期满后，仿制药生产商才可能寻求获准该药治疗帕金森氏症的可能。盐酸罗匹尼罗的结构式为如以下式(II)所示：
Figure PCTCN2017088651-appb-000002
目前专利或者非专利文献已报道的制备盐酸罗匹尼罗的方法主要有五种，其分别以2-甲基-3-硝基-苯甲酸为原料(US4452808)、以3-溴乙基苯胺为原料(WO1994/015918)、以异苯并二氢吡喃为原料(EP0300614、US4997954)、以4-吲哚甲醛为原料(US2007032540)、以邻溴乙基苯甲醛为 原料(US0156505)合成盐酸罗匹尼罗。
具体而言，专利US4452808以2-甲基-3-硝基-苯甲酸为原料，利用硼烷氢化反应，加氯化亚砜制得酰氯、腈化、水解得到2-甲基-3-硝基-苯乙酸，然后再制得酰胺，加氢还原、缩合、氧化水解，最后加氢还原，成盐得到盐酸罗匹尼罗；专利WO1994/015918以3-溴乙基苯胺为原料，经过成环、氧化、取代、还原得到盐酸罗匹尼罗；而专利EP0300614、US4997954以异苯并二氢吡喃为原料，经过溴化开环，在强碱作用下制得硝基苯乙烯化合物，再经过闭环、还原、取代反应得到盐酸罗匹尼罗；专利US2007032540以4-吲哚甲醛为原料，经过硝基甲烷反应得到硝基苯乙烯化合物，再经过加氢还原、与丙酸加成、还原，最后氧化得到盐酸罗匹尼罗；最后，专利US0156505以邻溴乙基苯甲醛为原料，经取代、与硝基甲烷反应得到硝基苯乙烯化合物，再经过环化、氧化、水解等得到盐酸罗匹尼罗。
但是上述文献都未提及一个重要的生产问题，即在盐酸罗匹尼罗生产的一步中间体中，因氧化过强产生副产物单丙基杂质，在最后一道工序时，该杂质转变为盐酸罗匹尼罗杂质A，即单丙基罗匹尼罗，该杂质在诸多合成路线中都会产生。特别要提出的是，在专利US4452808中，该杂质A是合成盐酸罗匹尼罗的中间体中含有的副产物，经过氢化还原再成盐得到含有杂质A的盐酸罗匹尼罗。由于该杂质A结构与盐酸罗匹尼罗产品相似，很难用常规手段实现分离。常用的溶剂洗涤、打浆、重结晶等方法很难去除杂质A，同时还会影响盐酸罗匹尼罗产品的收率。因此需要一种简便、廉价以及有效的纯化工艺来除去该杂质A。
发明内容
发明人研发了一种盐酸罗匹尼罗4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法，能够简便、廉价以及有效地除去杂质A(结构式I)。
具体而言，本发明提供了结构式(II)所示的盐酸罗匹尼罗4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法，其包括如下步骤：
Figure PCTCN2017088651-appb-000003
其中，-R代表C1-C6的烷基或C6-C10的芳香族基团；-L代表卤素-X，或酰氧基
Figure PCTCN2017088651-appb-000004
其中卤素可以为氟、氯、溴或碘；
(1)将含有结构式(I)所示的杂质A单丙基罗匹尼罗的盐酸罗匹尼罗与水和有机溶剂混合，室温下搅拌溶清加入碱，搅拌后静置分层，除去水层；其中所述有机溶剂为非质子溶剂；所述碱为碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐，或者为由C1-C6烷基单取代或多取代的胺；
(2)将得到的有机层用无水硫酸镁干燥，过滤；或有机层不加无水硫酸镁，直接进行下步操作；
(3)向有机层中加入结构式(IV)的酰卤或酸酐，搅拌并浓缩；
(4)浓缩至干后，向得到的油状物中加入有机溶剂，加入浓盐酸搅拌后，得到盐酸罗匹尼罗；其中所述有机溶剂为醇。
上述步骤(1)中，室温下搅拌溶清加入碱之后，例如可搅拌20分钟以上，然后静置分层。其中有机溶剂的以毫升计的体积用量可为盐酸罗匹尼罗以克计的质量的2～20倍，优选为5～15倍，更优选为8～12倍。水的以毫升计的体积用量可为盐酸罗匹尼罗以克计的质量的5～20倍。步骤(1)中碱的摩尔用量为盐酸罗匹尼罗摩尔用量的1.5～25倍，优选为5～15倍。此外，步骤(1)中的有机溶剂可为二氯甲烷、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、甲苯、二甲苯或甲基叔丁基醚。步骤(1)中的碱可以选自碳酸钠、氢氧化钾、 氢氧化钠、碳酸钾、碳酸氢钠、三乙胺或二异丙基胺。
步骤(3)中，向有机层中加入酰卤或酸酐，可搅拌例如10分钟，浓缩。酰卤或酸酐的摩尔用量可为盐酸罗匹尼罗杂质A摩尔量的1～5倍。除杂试剂酰卤或酸酐可选自乙酰氯、丙酰氯、苯甲酰氯、乙酸酐或苯甲酸酐等；优选为乙酰氯、苯甲酰氯或乙酸酐。酰卤或酸酐的摩尔用量为盐酸罗匹尼罗杂质A摩尔量的1～5倍。
步骤(4)中，加入浓盐酸搅拌后，可将料液冷却、甩滤并烘干得到盐酸罗匹尼罗。步骤(4)中，可将有机层浓缩至干后，向得到的油状物中加入一定量的有机溶剂，溶剂以毫升计的体积用量可为盐酸罗匹尼罗以克计的重量的2～20倍。控制反应液温度为15±5℃，缓慢加入一定量的浓盐酸，浓盐酸的用量可为盐酸罗匹尼罗摩尔用量的2～10倍，优选2～5倍。继续搅拌例如30分钟。可将料液冷却至5±5℃并继续搅拌40分钟，甩滤并烘干得到盐酸罗匹尼罗。其中，所使用浓盐酸的质量浓度为37％，其用量以浓盐酸中的HCl的量来计算。其中步骤(4)的有机溶剂可为甲醇、乙醇、异丙醇或正丁醇。
以上各步骤中均需要严格做好氮气保护。
本发明通过上述方法，能够有效除去盐酸罗匹尼罗中的杂质A，能够以较好的收率和纯度获得盐酸罗匹尼罗，从而控制杂质A使产品纯度达到药用标准。
具体实施方式
以下的实施例在于详细说明本发明，而非限制本发明。
所有过程均需做好氮气保护，后面不再反复说明。
实施例1
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗，结构式II)(8.9g，0.03摩尔)、二氯甲烷90ml、纯化水135ml于250ml烧瓶中搅拌，同时缓慢加入氢氧化钠(6g，0.15摩尔)。加毕后继续搅拌20分钟，静置分层。去掉水层，用3g无水硫酸镁干燥有机层，搅拌30分钟，过滤并 分离有机层。
向有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的乙酰氯，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇，控制反应液温度15±5℃，缓慢加入9.0g浓盐酸(质量浓度为37％)，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率90％。HPLC检测纯度为99.89％，杂质A含量为未检出(N.D)。
盐酸罗匹尼罗有关物质的HPLC分析方法如下：
仪器：高效液相色谱仪配备紫外检测器
色谱柱：Waters XterraTM RP18250×4.6mm，5μm
流动相A：2.84g Na2HPO4溶于1000ml水中，用1摩尔/L的NaOH调pH11.0
流动相B：乙腈
稀释液：流动相A：流动相B＝70：30(％V/V)
色谱柱温：25℃        检测波长：250nm
流速：1.0ml/分钟      运行时间：35分钟
进样量：20μL
梯度表：
Figure PCTCN2017088651-appb-000005
Figure PCTCN2017088651-appb-000006
称取50mg盐酸罗匹尼罗标准品，精密称定于100ml容量瓶中，用稀释液溶解并稀释至刻度，混匀(盐酸罗匹尼罗浓度500μg/ml)。
实施例2
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗，结构式II)(8.9g，0.03摩尔)、正己烷90ml、纯化水135ml于250ml烧瓶中搅拌，同时缓慢加入8.4g氢氧化钾。加毕后继续搅拌20分钟，静置分层，去掉水层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的乙酸酐，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml乙醇，控制反应液温度15±5℃，缓慢加入9.0g浓盐酸，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率88％。HPLC检测纯度为99.91％，杂质A含量0.02％。
实施例3
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼结构式II)(8.9g，0.03摩尔)、乙酸乙酯90ml、纯化水135ml于250ml烧瓶中搅拌，同时缓慢加入15.9g碳酸钠。加毕后继续搅拌20分钟，静置分层。去掉水层，用3g无水硫酸镁干燥有机层，搅拌30分钟，过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的丙酰氯，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml甲醇，控制反应液温度15±5℃，缓慢加入9.0g浓盐酸，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率85％。HPLC检测纯度为99.88％，杂质A含量0.01％。
实施例4
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗，结构式II)(8.9g，0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌，同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟，静置分层。去掉水层，用3g无水硫酸镁干燥有机层，搅拌30分钟，过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的苯甲酰氯，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇，控制反应液温度15±5℃，缓慢加入9.0g浓盐酸，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率90％。HPLC检测纯度为99.94％，杂质A含量为未检出(N.D)。
实施例5
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗，结构式II)(8.9g，0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌，同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟，静置分层。去掉水层，用3g无水硫酸镁干燥有机层，搅拌30分钟，过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量1倍的苯甲酰氯，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇，控制反应液温度15±5℃，缓慢加入12.0g浓盐酸，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率90％。HPLC检测纯度为99.93％，杂质A含量为0.03％。
实施例6
取4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗，结构式II)(8.9g，0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌， 同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟，静置分层。去掉水层，用3g无水硫酸镁干燥有机层，搅拌30分钟，过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量5倍的苯甲酰氯，搅拌10分钟，浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇，控制反应液温度15±5℃，缓慢加入6.0g浓盐酸，加入完毕后，继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h，甩滤至干。
烘干得到盐酸罗匹尼罗粗品，收率91％。HPLC检测纯度为99.95％，杂质A含量为0.01％。
下表是用不同杂质A(单丙基罗匹尼罗)含量的盐酸罗匹尼罗纯化后的对照表。
Figure PCTCN2017088651-appb-000007

Claims (10)

  1. 一种结构式(II)所示的盐酸罗匹尼罗4-2-二正丙基胺乙基-1，3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法，其特征在于，包括如下步骤：
    Figure PCTCN2017088651-appb-100001
    其中，-R代表C1-C6的烷基或C6-C10的芳香族基团；
    -L代表卤素-X，或酰氧基
    Figure PCTCN2017088651-appb-100002
    (1)将含有结构式(I)所示的杂质A单丙基罗匹尼罗的盐酸罗匹尼罗与水和有机溶剂混合，室温下搅拌溶清加入碱，搅拌后静置分层，除去水层；其中所述有机溶剂为非质子溶剂；所述碱为碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐，或者为由C1-C6烷基单取代或多取代的胺；
    (2)将得到的有机层用无水硫酸镁干燥，过滤；或有机层不加无水硫酸镁，直接进行下步操作；
    (3)向有机层中加入结构式(IV)的酰卤或酸酐，搅拌并浓缩；
    (4)浓缩至干后，向得到的油状物中加入有机溶剂，加入浓盐酸搅拌后，得到盐酸罗匹尼罗；其中所述有机溶剂为醇。
  2. 根据权利要求1所述的方法，其特征在于，步骤(1)中有机溶剂以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的2～20倍，水的以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的5～20倍。
  3. 根据权利要求1所述的方法，其特征在于，步骤(1)中碱的摩尔用量为盐酸罗匹尼罗摩尔用量的1.5～25倍。
  4. 根据权利要求1所述的方法，其特征在于，步骤(1)中的有机溶剂为二氯甲烷、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、甲苯、二甲苯或甲基叔丁基醚。
  5. 根据权利要求1所述的方法，其特征在于，步骤(1)中所述的碱选自碳酸钠、氢氧化钾、氢氧化钠、碳酸钾、碳酸氢钠、三乙胺或二异丙基胺。
  6. 根据权利要求1-5任一项所述的方法，其特征在于，步骤(3)中的酰卤或酸酐选自乙酰氯、丙酰氯、苯甲酰氯、乙酸酐或苯甲酸酐，其摩尔用量为杂质A摩尔量的1～5倍。
  7. 根据权利要求6所述的方法，其中所述酰卤或酸酐选自乙酰氯、苯甲酰氯或乙酸酐。
  8. 根据权利要求1-5任一项所述的方法，其特征在于，步骤(4)中有机溶剂以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的2～20倍。
  9. 根据权利要求1-5任一项所述的方法，其特征在于，步骤(4)中浓盐酸的摩尔用量为盐酸罗匹尼罗摩尔量的2～10倍。
  10. 根据权利要求1-5任一项所述的方法，其特征在于，步骤(4)中的有机溶剂为甲醇、乙醇、异丙醇或正丁醇。
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