CN114524748A - 一种罗沙司他新中间体和罗沙司他的新制备方法 - Google Patents
一种罗沙司他新中间体和罗沙司他的新制备方法 Download PDFInfo
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- 239000002904 solvent Substances 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 28
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
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- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
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- 230000003907 kidney function Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
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- JENBPOJAZCPSEW-UHFFFAOYSA-N methyl 2-bromo-4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1Br JENBPOJAZCPSEW-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
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- 230000001105 regulatory effect Effects 0.000 description 1
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- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种罗沙司他新中间体和罗沙司他的新制备方法。所述罗沙司他新中间体式(Ⅲ)由式(Ⅱ)经过氧化制备,利用罗沙司他新中间体式(Ⅲ)经过酰胺化、环化制得罗沙司他。本发明合成路线反应步骤短、工艺简单、反应条件温和、产品制得产品纯度和收率都较高,更适用于工业化生产。
Description
技术领域
本发明属于医药中间体合成技术领域,具体涉及一种用于治疗肾性贫血药物罗沙司他新中间体和罗沙司他的新制备方法。
背景技术
肾性贫血(CKD)是一种长期的进展性疾病,其特征为肾功能的丧失,最终导致终末期肾病。而贫血是CKD患者的常见并发症。治疗慢性肾病的相关性贫血的主要药物有红细胞生成刺激剂(ESAs)以及重组促红细胞生成素(EPO)。但ESAs存在增加心血管不良反应的风险,而通过调控体内缺氧诱导因子(HIF)的表达来控制EPO的含量,可以提高血液中血红蛋白的形成,提高体内血细胞的含量。因此,口服HIF抑制剂的治疗手段更具潜力。目前突出的HIF抑制剂有罗沙司他,达普司他和伐度司他等。
罗沙司他(Roxadustat),化学名为N-[(4-羟基-1-甲基-7-苯氧基-3-异喹啉)羰基]甘氨酸,如式(Ⅰ),它是由珐博进(FibroGen)公司研发的一种抑制缺氧诱导因子脯氨酰羟化酶(HIF-PH)活性的小分子抑制剂,能稳定HIF-2,同时诱导EPO的表达,在临床上用于治疗贫血。2018年12月17日,国家药品监督管理局批准1类新药罗沙司他胶囊(商品名:爱瑞卓)上市,罗沙司他的结构式如下所示:
关于罗沙司他的合成路线主要有一下几条:
路线一
该路线为原研FibroGen公司报道的一条罗沙司他的合成路线(CN2004254215A1),该方法核心步骤是异喹啉环的构建和甲基化反应。其中异喹啉环的构建采用Gabriel-Colam重排反应。异喹啉环的甲基化反应需要用到金属锂试剂且反应温度为超低温-78℃。该路线涉及到使用金属钠、丁基锂等高活性等试剂,在工业化生产中使用有较大的安全风险,且路线中多个中间体的纯化需要使用到柱层析分离,分离成本高且在工业化生产中难以实现。工艺中需要达到-78℃和200℃的极端温度,生产过程中对设备要求较高且能耗较大。
路线二
合成路线二是原研公司对其合成路线进行的再次优化和改进(CN103435546B)。该路线以2-溴苯酞为起始原料,依次经苯酚醚化,二氯亚砜开环氯化、取代氨基酸对接、环合、羟基烷基化、酰化、钯碳脱保护得到罗沙司他。该路线步骤多,甲基的进入较复杂且经过多次基团的保护和脱保护,特别是使用钯碳催化脱保护需要用到特殊加压设备,对设备要求较高。
路线三
合成路线三是苏州明锐医药科技有限公司公开的一条新颖路线(CN104892509),该路线以酪氨酸为起始物料,依次经过酯化,苯基醚化,乙醛环合、碱催化脱氢,双氧水催化羟基化、最后经酰胺化得到罗沙司他。该方法相比原研路线有所缩短,但是醚化反应易与氨基发生副反应导致产品难以纯化,同时双氧水羟基化反应收率低,因此该工艺还需要针对原料药的质量控制和工业化生产进行优化。
路线四
合成路线四是欧洲专利EP3305769A1报道的路线,该路线以2-溴-4-氟苯甲酸甲酯为起始原料,依次经醚化、噁唑啉化、钯催化偶联反应,酸催化环合、酰胺化缩合反应制得罗沙司他。该路线步骤较短,但是起始物料价格较高,必要时还需要前延路线。偶联反应所用到贵重金属钯作为催化剂价格较高,且改步骤收率较低,致使整条工艺路线的成本较高。工艺中使用到了异氰基乙酸乙酯为剧毒物质,在生产过程中对于操作人员和环境不太友好。综上所述,现有技术存在的弊端为反应操作复杂,收率极低,生产周期长。环保和安全生产压力大,成本大大提升,工艺存在重大缺陷,不适合工业化生产。罗沙司他的制备技术领域,需要开发一种更加简单、成熟、具有成本优势的工艺路线。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种罗沙司他新中间体和罗沙司他的新制备方法。所述罗沙司他新中间体式(Ⅲ)由式(Ⅱ)经过氧化制备,利用罗沙司他新中间体式(Ⅲ)经过酰胺化、环化制得罗沙司他。本发明合成路线反应步骤短、工艺简单、反应条件温和、产品制得产品纯度和收率都较高,更适用于工业化生产。
一种罗沙司他新中间体,结构式为式(Ⅲ)所示
式中R为C1~C4烷基。
一种上述所述的罗沙司他新中间体的制备方法,步骤方法包括:将式(Ⅱ)所示化合物加入溶剂A中,在加入氧化剂进行氧化反应,反应结束后,减压浓缩除去溶剂,在加入萃取溶剂进行萃取,后过滤。滤液中加入药用炭,升温回流脱色。过滤,减压浓缩,得到式(Ⅲ)化合物
进一步,上述所述氧化剂为高锰酸钾、氧化铈、硫酸铈、三氟甲烷磺酸铈、溴酸钾、溴酸钡、叔丁基过氧化氢,优选溴酸钾;所述溶剂A为丙酮、二氧六环、醋酸、水、乙腈、叔丁醇,优选二氧六环;所述萃取溶剂为萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯。
一种通过所述的一种罗沙司他新中间体制备罗沙司他的方法,步骤方法包括:
(1)将式(Ⅲ)化合物、甘氨酸、有机碱、催化剂溶于溶剂B中,升温至回流。待翻译完全减压浓缩,脱去大部分溶剂。加入水和萃取溶剂,用氢氧化钠溶液调节水相pH=8~10,静置分去有机相。在水相中再加入萃取溶剂用盐酸调水相pH=3~5,静置分去水相,有机相用无水硫酸钠干燥,过滤,浓缩得到式(Ⅳ)化合物。
(2)将式(Ⅳ)所示化合物加入溶剂C中,加如酸性试剂后升温至回流反应,反应结束后,浓缩除去溶剂,加水和萃取溶剂H萃取,用氢氧化钠溶液调节水相至pH=8~10,静置分去有机相,取水相加入萃取溶剂后用盐酸溶液调节水相pH=3~5,分取水相,取有机相用无水硫酸钠干燥。再加入药用炭升温至回流脱色,过滤,浓缩,得到目标化合物罗沙司他,即式(Ⅰ)化合物。
进一步,所述步骤(1)中溶剂B为乙腈、四氢呋喃、1,4-二氧六环、N’N-二甲基甲酰胺、二甲基亚砜,优选四氢呋喃;催化剂为4-二甲氨基吡啶(DMAP);有机碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、三乙醇胺,优选1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺;甘氨酸与化合物(Ⅲ)物质量的比为1.0~3.0:1,优选1.2:1;萃取溶剂为萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯,优选二氯甲烷。
进一步,所述步骤(2)中的溶剂C为甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、四氢呋喃、乙腈、2-甲基四氢呋喃、4,6-二氧六环,优选为乙醇;酸性试剂为盐酸、硫酸、磷酸、三氟乙酸,优选盐酸;所用的酸与式(Ⅳ)所示化合物的物质量比为0.5~1.5:1,优选1.0~1.2:1;萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯,优选乙酸乙酯。
通过采用上述技术,与现有技术相比,本发明的有益效果体现在:
(1)工艺简单,操作简便,反应条件温和;
(2)所制备产品纯度和收率较高;
(3)适用于工业化操作。
具体实施方式
通过下述具体实施例来说明本发明的技术方案,但本发明的保护范围不限于此。
本发明实施例中制备罗沙司他的典型合成步骤如下面的合成方案所示:
式中,R为C1-C4的烷基。
实施例1
2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸甲酯(Ⅲ-a)的制备
将2-乙酰氨基-3-(4-苯氧基苯基)丙酸甲酯(Ⅱ-a)20.0g(0.063mol)溶于200ml丙酮中,搅拌下降温至-78℃。依次加入高锰酸钾30.1g(3.0e.q.)、三氯化铁25.5g(2.5e.q.),保温反应2小时。然后缓慢升温至室温继续搅拌12小时。反应液用100ml二氯甲烷稀释后过滤,滤饼用100ml二氯甲烷淋洗,合并二氯甲烷相,用无水硫酸镁干燥,再用活性炭脱色后过滤浓缩,得到类白色固体2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸甲酯(Ⅲ-a)18.7g,收率:89.5%。
1H NMR(400MHz DMSO):δ=1.920(s,3H);3.662(s,3H);5.932(d,1H);7.064(d,2H);7.173(d,2H);7.188(d,1H);7.426(t,2H);8.657(s,1H)。
实施例2
2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸乙酯(Ⅲ-b)的制备
将溴酸钾10.2g、二氧化铈3.2g溶于100ml二氧六环溶液中室温搅拌五分钟,加入2-乙酰氨基-3-(4-苯氧基苯基)丙酸乙酯(Ⅱ-b)20.0g(0.061mol)后升温至95℃,保温反应1小时。降温至室温,过滤反应液,加入二氯甲烷和水萃取。分取二氯甲烷相,用饱和食盐水洗涤,分取二氯甲烷相,用无水硫酸钠干燥,过滤,浓缩,得到淡黄色固体2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸乙酯(Ⅲ-b)19.0g,收率:91.1%。
1H NMR(400MHz DMSO):δ=1.236(t,3H);1.928(s,3H);4.219(q,2H);5.934(d,1H);7.066(d,2H);7.176(d,2H);7.188(d,1H);7.429(t,2H);8.652(s,1H)。
实施例3
2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸异丙酯(Ⅲ-c)的制备
将2-乙酰氨基-3-(4-苯氧基苯基)丙酸异丙酯(Ⅱ-c)20.0g(0.059mol)溶于100ml叔丁醇中,搅拌下叔丁基过氧化氢15.9g,升温至回流(85℃),反应结束后减压蒸去叔丁醇,得到黄色油状物。在加入200ml溶解,用饱和食盐水洗涤两次(100ml×2),分取二氯甲烷相,用无水硫酸镁干燥后,加压浓缩得到淡黄色固体2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸异丙酯(Ⅲ-c)18.5g,收率:88.2%。
1H NMR(400MHz DMSO):δ=1.20(d,6H);1.945(s,3H);4.944(m,1H);5.947(d,1H);7.074(d,2H);7.183(d,2H);7.192(d,1H);7.431(t,2H);8.660(s,1H)。
实施例4
N-(2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酰基)甘氨酸(式Ⅳ)的制备
将2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸甲酯15.0g(式Ⅲ-a)、甘氨酸4.13g、4-二甲氨基吡啶0.75g(DMAP)加入乙腈75ml中溶解。加入1,8-二氮杂双环[5.4.0]十一碳-7-烯7.0g(DBU)后搅拌升温至80℃。当原料反应完全后,蒸去大部分溶剂,反应体系中加入水60ml、乙酸乙酯60ml萃取,用氢氧化钠溶液调节pH=8~10,分取水相。水相中再加入乙酸乙酯90ml,溶液用盐酸调pH=3~5,分取有机相,用无水硫酸钠干燥,过滤,减压浓缩,得到N-(2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酰基)甘氨酸(Ⅳ)12.9g,收率:76.0%。
1H NMR(400MHz DMSO):δ=1.196(d,6H);1.924(s,3H);4.935(m,1H);5.937(d,1H);7.065(d,2H);7.177(d,2H);7.189(d,1H);7.420(t,2H);8.652(s,1H)。
实施例5
N-(2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酰基)甘氨酸(Ⅳ)的制备
将2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酸乙酯15g(Ⅲ-a)、甘氨酸4.0g、4-二甲氨基吡啶0.75g(DMAP)加入四氢呋喃90ml中溶解。加入三乙胺4.4g后搅拌升温至66℃。当原料反应蒸去大部分溶剂,反应体系中加入水60ml、二氯甲烷60ml萃取,用氢氧化钠溶液调节pH=8~10,分取水相。水相中再加入二氯甲烷90ml,溶液用盐酸调pH=3~5,分取有机相,用无水硫酸钠干燥,过滤,减压浓缩,得到N-(2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酰基)甘氨酸(Ⅳ)12.3g,收率:75.7%。
实施例6
罗沙司他(Ⅰ)的制备
将N-(2-乙酰氨基-3-氧代-3-(4-苯氧基苯基)丙酰基)甘氨酸10.0g(Ⅵ)溶于50ml乙醇中,加入5ml浓盐酸升温至回流。反应结束后减压浓缩溶剂,后加入50ml水和50ml乙酸乙酯,并搅拌用30%氢氧化钠调节pH=8~10,静置,分取水相。在水相中加入100ml乙酸乙酯,溶液用浓盐酸调节pH=3~5,静置,分取有机相,用无水硫酸钠干燥,有机相中加入1g活性炭,升温至回流脱色。降温至室温,减压浓缩,得到类白色罗沙司他(Ⅰ)8.7g固体,收率:91.4%。罗沙司他分子式为C19H16N2O5,LC-MS测得的分子离子峰m/z为353.1,[M+H]+与理论值一致。
Claims (6)
3.根据权利要求2所述的罗沙司他新中间体的制备方法,其特征在于所述氧化剂为高锰酸钾、氧化铈、硫酸铈、三氟甲烷磺酸铈、溴酸钾、溴酸钡、叔丁基过氧化氢,优选溴酸钾;所述溶剂A为丙酮、二氧六环、醋酸、水、乙腈、叔丁醇,优选二氧六环;所述萃取溶剂为萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯。
4.一种通过权利要求1所述的一种罗沙司他新中间体制备罗沙司他的方法,其特征在于,所述步骤包括:
(1)将式(Ⅲ)化合物、甘氨酸、有机碱、催化剂溶于溶剂B中,升温至回流;待翻译完全减压浓缩,脱去大部分溶剂,加入水和萃取溶剂,用氢氧化钠溶液调节水相pH=8~10,静置分去有机相,在水相中再加入萃取溶剂用盐酸调水相pH=3~5,静置分去水相,有机相用无水硫酸钠干燥,过滤,浓缩得到式(Ⅳ)化合物;
(2)将式(Ⅳ)所示化合物加入溶剂C中,加如酸性试剂后升温至回流反应,反应结束后,浓缩除去溶剂,加水和萃取溶剂H萃取,用氢氧化钠溶液调节水相至pH=8~10,静置分去有机相,取水相加入萃取溶剂后用盐酸溶液调节水相pH=3~5,分取水相,取有机相用无水硫酸钠干燥,再加入药用炭升温至回流脱色,过滤,浓缩,得到目标化合物罗沙司他,即式(Ⅰ)化合物
5.根据权利要求4所述的罗沙司他制备方法,其特征在于,所述步骤(1)中溶剂B为乙腈、四氢呋喃、1,4-二氧六环、N’N-二甲基甲酰胺、二甲基亚砜,优选四氢呋喃;催化剂为4-二甲氨基吡啶(DMAP);有机碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、三乙醇胺,优选1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、三乙胺;甘氨酸与化合物(Ⅲ)物质量的比为1.0~3.0:1,优选1.2:1;萃取溶剂为萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯,优选二氯甲烷。
6.据权利要求4所述的罗沙司他制备方法,其特征在于,所述步骤(2)中的溶剂C为甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、四氢呋喃、乙腈、2-甲基四氢呋喃、4,6-二氧六环,优选为乙醇;酸性试剂为盐酸、硫酸、磷酸、三氟乙酸,优选盐酸;所用的酸与式(Ⅳ)所示化合物的物质量比为0.5~1.5:1,优选1.0~1.2:1;萃取溶剂为乙酸异丙酯、乙酸乙酯、乙酸甲酯、二氯甲烷、三氯甲烷、四氯化碳、甲基叔丁基醚、甲苯,优选乙酸乙酯。
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