CN117402044A - 一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法 - Google Patents
一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法 Download PDFInfo
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 21
- -1 olefin compound Chemical class 0.000 claims abstract description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 14
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 10
- HVCFCNAITDHQFX-UHFFFAOYSA-N 1-cyclopropylethanone Chemical compound CC(=O)C1CC1 HVCFCNAITDHQFX-UHFFFAOYSA-N 0.000 claims abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract description 7
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- 229910052751 metal Inorganic materials 0.000 claims abstract description 4
- 239000002184 metal Substances 0.000 claims abstract description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 3
- 230000008569 process Effects 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- LRWCURGZPQWMRG-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one Chemical compound C=1C=C(Cl)C=CC=1C(=O)C(C)C1CC1 LRWCURGZPQWMRG-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 238000010586 diagram Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000460 chlorine Substances 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 3
- RZHHQZSPUHYKPY-UHFFFAOYSA-N [Mg]CC1=CC=C(Cl)C=C1 Chemical compound [Mg]CC1=CC=C(Cl)C=C1 RZHHQZSPUHYKPY-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- 230000008030 elimination Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 7
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- 238000006243 chemical reaction Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- UFNOUKDBUJZYDE-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C=CC(Cl)=CC=1)C(C)C1CC1 UFNOUKDBUJZYDE-UHFFFAOYSA-N 0.000 description 3
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- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- GVNSCNGKEXNKBU-UHFFFAOYSA-M magnesium;1-chloro-4-methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=C(Cl)C=C1 GVNSCNGKEXNKBU-UHFFFAOYSA-M 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
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- 241001443610 Aschersonia Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000221300 Puccinia Species 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
- C07C45/43—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis of >CX2 groups, X being halogen
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
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- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
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- C07—ORGANIC CHEMISTRY
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- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/2632—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions involving an organo-magnesium compound, e.g. Grignard synthesis
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
- C07C17/354—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction by hydrogenation
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Abstract
本发明涉及一种1‑(4‑氯苯基)‑2‑环丙基‑1‑丙酮的合成方法,其制备方法包括如下:Step 1:以对氯氯苄金属试剂和环丙基甲基酮为主要原料,经加成消除反应得到烯烃化合物;Step 2:烯烃化合物经加氢还原得到式(Ⅱ);Step 3:式(Ⅱ)经卤代得到二卤化物;Step 4:二卤化物酸性条件下水解得到目标产物一种1‑(4‑氯苯基)‑2‑环丙基‑1‑丙酮(Ⅰ),酸性条件下水解的酸选自盐酸,硫酸,磷酸、乙酸、三氟乙酸等的一种或几种,优选盐酸,盐酸浓度10‑30%,盐酸浓度优选10‑15%。本发明采用对氯氯苄镁试剂和环丙基甲基酮经加成消除得到烯烃化合物,然后常压加氢还原,氯气氯代后,酸性水解得到目标产物,该合成方法原料廉价易得,收率高,原料成本低。
Description
技术领域
本发明涉及有机合成技术领域,特别是涉及一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法。
背景技术
1-(4-氯苯基)-2-环丙基-1-丙酮是杀菌剂环丙唑醇的重要中间体,其分子结构如下所示:
环丙唑醇属于三唑类杀菌剂。具有内吸性强与持效期长等特效,对白粉菌属、核腔菌属、喙孢属、柄锈菌属和壳针孢属菌引起的病害具有良好的治疗效果,具有良好的市场前景。1-(4-氯苯基)-2-环丙基-1-丙酮是环丙唑醇的重要中间体,该中间体已有多种合成路径的相关报道。与本发明相关的合成方法有:
专利CN101857576报道的合成方法是4-氯苄基氯化镁与环丙基甲基酮加成得到醇,然后在氧氯化磷条件下脱水得到烯烃化合物,然后硼氢化上硼再氧化得到苄醇,得到的苄醇再经Dess-Martin高碘化物氧化得到1-(4-氯苯基)-2-环丙基-1-丙酮。该方法的缺点是需要使用强腐蚀性的氧氯化磷和价格昂贵的硼氢化钠,原料成本非常高。
专利CN109715595报道的合成方法以4-氯苄基氯化镁与环丙基甲基酮加成得到醇,苄位自由基反应卤代得到卤代醇,然后卤代醇在碱性条件下关环得到环氧化物,最后在路易斯酸的条件下开环转化为1-(4-氯苯基)-2-环丙基-1-丙酮。该方法的缺点是收率太低,合成过程中需要柱层析分离纯化,不适合工业化放大生产,同样导致原料成本高。
专利CN113121322报道的合成方法以4-氯苄基氯化镁与环丙基甲基酮先加成后消除得到烯基化物,烯基化物50%双氧水环氧化,酸性条件下重排得到1-(4-氯苯基)-2-环丙基-1-丙酮。该方法使用50%双氧水存在一定的安全风险,需要找到一条更安全更环保的合成工艺路线来解决1-(4-氯苯基)-2-环丙基-1-丙酮的生产。
专利CN116396155报道的合成方法以对氯卤化苄金属试剂和环丙基甲基酮加成消除得到烯烃化合物,再经卤素加成得到式(II)化合物,在碱性条件如甲醇钠等条件下消除、水解,重排得到目标产物。
该合成方法原料成本还是偏高,需要进一步优化改进。
因此,寻求一种工艺简单流畅、成本低,安全又环保,合适工业化放大生产的1-(4-氯苯基)-2-环丙基-1-丙酮合成工艺,一直是本领域研究的重点。
发明内容
本发明提供了一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,解决了上述背景技术所提出的问题,在现有技术的基础上,提供一种1-(4-氯苯基)-2-环丙基-1-丙酮合成工艺方法,该工艺方法原料廉价易得,收率高,工艺更安全,适合工业化放大生产。相比其它专利报道的合成方法,该合成方法体现出较高的安全性,原料成本低,适合工业化放大生产。
本发明解决上述技术问题的方案如下:一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其制备方法包括如下:
Step 1:以对氯氯苄金属试剂和环丙基甲基酮为主要原料,经加成消除反应得到烯烃化合物;
Step 2:烯烃化合物经加氢还原得到式(Ⅱ);
Step 3:式(Ⅱ)经卤代得到二卤化物;
Step 4:二卤化物酸性条件下水解得到目标产物一种1-(4-氯苯基)-2-环丙基-1-丙酮(Ⅰ),酸性条件下水解的酸选自盐酸,硫酸,磷酸、乙酸、三氟乙酸等的一种或几种,优选盐酸,盐酸浓度10-30%,盐酸浓度优选10-15%,合成工艺路线图如下:
所述工艺路线中M为Mg或Zn;X为Cl或Br或I,优选Cl或Br。
在上述技术方案的基础上,本发明还可以做如下改进。
进一步,Step 2中加氢还原的加氢压力为常压下加氢。
进一步,Step 2中加氢还原反应温度为0-20℃,优选10-15℃。
进一步,Step 4中水解温度为50-80℃,优选60-65℃。
本发明的有益效果是:本发明提供了一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,具有以下优点:
1、采用对氯氯苄镁试剂和环丙基甲基酮经加成消除得到烯烃化合物,然后常压加氢还原,氯气氯代后,酸性水解得到目标产物,该合成方法原料廉价易得,收率高,原料成本低。
2、本发明合成反应条件温和,工艺更安全,适合工业化放大生产。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例详细说明如后。本发明的具体实施方式由以下实施例详细给出。
具体实施方式
以下对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。在下列段落中以举例方式更具体地描述本发明。根据下面说明和权利要求书,本发明的优点和特征将更清楚。
需要说明的是,当组件被称为“固定于”另一个组件,它可以直接在另一个组件上或者也可以存在居中的组件。当一个组件被认为是“连接”另一个组件,它可以是直接连接到另一个组件或者可能同时存在居中组件。当一个组件被认为是“设置于”另一个组件,它可以是直接设置在另一个组件上或者可能同时存在居中组件。本文所使用的术语“垂直的”、“水平的”、“左”、“右”以及类似的表述只是为了说明的目的。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
实施例1:
本发明提供了一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其制备方法包括如下:
Step 1:将20.0g烯基化合物溶于60.0g甲醇中,加入催化剂雷尼镍0.2g;
Step 2:常压下加氢,温度控制在10-15℃,反应结束,过滤回收催化剂,反应液脱溶后得到式(Ⅱ)化合物20.3g,纯度98.6%,收率99%;
GCMS(EI)m/z 194.1;
Step 3:将上述式(Ⅱ)化合物10.0g溶于30.0g二氯乙烷中,控制温度20-25℃,光照条件下,通入氯气反应6小时;
Step 4:加入10%盐酸50g,60-65℃保温3小时,反应结束,静置分相,有机相经水洗,浓缩回收溶剂,剩余物经减压蒸馏得到1-(4-氯苯基)-2-环丙基-1-丙酮9.9g,纯度98.3%,收率93%;
GCMS(EI)m/z 208.1;
1HNMR(400MHz,CDCl3)δ7.85(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),2.78-2.68(m,1H),1.26(d,J=8.0Hz,3H),1.11-0.99(m,1H),0.52-0.45(m,1H),0.23-0.10(m,2H)。
实施例2:
本发明提供了一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其制备方法包括如下:
Step 1:将20.0g烯基化合物(参考专利CN113121322合成方法制备)溶于60.0g甲醇中,加入催化剂雷尼镍0.2g;
Step 2:常压下加氢,温度控制在10-15℃,反应结束,过滤回收催化剂,反应液脱溶后得到式(Ⅱ)化合物20.3g,纯度98.6%,收率99%;
GCMS(EI)m/z 194.1;
Step 3:将上述式(Ⅱ)化合物10.0g溶于30.0g二氯乙烷中,控制温度20-25℃,光照条件下,滴加溴素反应6小时;
Step 4:加入10%盐酸50g,60-65℃保温3小时,反应结束,静置分相,有机相经水洗,浓缩回收溶剂,剩余物经减压蒸馏得到1-(4-氯苯基)-2-环丙基-1-丙酮9.4g,纯度98.1%,收率88%。
以上所述,仅为本发明的较佳实施例而已,并非对本发明作任何形式上的限制;凡本行业的普通技术人员均可按和以上所述而顺畅地实施本发明;但是,凡熟悉本专业的技术人员在不脱离本发明技术方案范围内,利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化,均为本发明的等效实施例;同时,凡依据本发明的实质技术对以上实施例所作的任何等同变化的更动、修饰与演变等,均仍属于本发明的技术方案的保护范围之内。
Claims (4)
1.一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其制备方法包括如下:
Step 1:以对氯氯苄金属试剂和环丙基甲基酮为主要原料,经加成消除反应得到烯烃化合物;
Step 2:烯烃化合物经加氢还原得到式(Ⅱ);
Step 3:式(Ⅱ)经卤代得到二卤化物;
Step 4:二卤化物酸性条件下水解得到目标产物一种1-(4-氯苯基)-2-环丙基-1-丙酮(Ⅰ),酸性条件下水解的酸选自盐酸,硫酸,磷酸、乙酸、三氟乙酸等的一种或几种,优选盐酸,盐酸浓度10-30%,盐酸浓度优选10-15%,合成工艺路线图如下:
所述工艺路线中M为Mg或Zn;X为Cl或Br或I,优选Cl或Br。
2.根据权利要求1所述一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其特征在于,Step 2中加氢还原的加氢压力为常压下加氢。
3.根据权利要求1所述一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其特征在于,Step 2中加氢还原反应温度为0-20℃,优选10-15℃。
4.根据权利要求1所述一种1-(4-氯苯基)-2-环丙基-1-丙酮的合成方法,其特征在于,Step 4中水解温度为50-80℃,优选60-65℃。
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