WO2019029491A1 - 一种(r)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法 - Google Patents

一种(r)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法 Download PDF

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WO2019029491A1
WO2019029491A1 PCT/CN2018/099020 CN2018099020W WO2019029491A1 WO 2019029491 A1 WO2019029491 A1 WO 2019029491A1 CN 2018099020 W CN2018099020 W CN 2018099020W WO 2019029491 A1 WO2019029491 A1 WO 2019029491A1
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reaction
chloro
propionate
methylphenoxy
mol
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PCT/CN2018/099020
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French (fr)
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朱月泉
龚兴宇
卢江
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科顺防水科技股份有限公司
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Priority to DE112018004066.6T priority Critical patent/DE112018004066T5/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of organic synthesis, and more particularly to a process for preparing an octyl (R)-2-(4-chloro-2-methylphenoxy)propionate root-blocking agent.
  • phenoxycarboxylic acid compounds are a class of plant growth regulators similar to phthalic acid. These plant growth regulators have good herbicidal effects at high doses and are a good class.
  • Chemical herbicide These herbicides have the advantages of low price, fast weeding speed, wide herbicidal spectrum and no residue, which occupy an important position in the whole chemical weeding.
  • 2,4-D, 2-methyl-4-chlorophenoxyacetic acid (MCPA) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were at the end of the Second World War. Commercialized as a better herbicide.
  • the herbicidal effect of 2-methyl-4-chloropropionic acid (MCPP) is similar to 2,4-D, which is effective in controlling mites, swine fever and sputum. Mix with other herbicides to expand the herbicide spectrum.
  • (R) octyl 2-(4-chloro-2-methylphenoxy)propionate as a derivative of MCPP has a certain inhibition on the growth of the main roots of evergreen shrubs and roots of roots with more developed roots at a suitable dose. The effect is to cultivate the growth of the lateral roots, which can be applied to the roofing technique.
  • the general synthesis method of phenoxycarboxylates is carried out by direct esterification of phenoxycarboxylic acid with alcohol, but for some high-grade long-chain alcohols, it is difficult to pass the direct esterification due to the influence of activity and steric hindrance. The yield gives the final target product.
  • the synthesis of chiral compounds is rare, so finding new, simple, environmentally friendly, and high-yield methods for the synthesis of such compounds is both a challenge and an opportunity.
  • the invention uses chiral L-lactate as raw material, and finally synthesizes the chiral phenoxycarboxylate derivative (R)-2-(4-chloro-) by sulfonation, etherification and transesterification in a higher yield. Octyl 2-methylphenoxy)propionate.
  • the present invention provides a method for preparing a (R)-2-(4-chloro-2-methylphenoxy)propionic acid octyl ester root-blocking agent in order to overcome at least one of the disadvantages described in the prior art.
  • the preparation method has mild reaction conditions, low cost, and simple process operation, thereby solving the problem that the compound is imported and the source is scarce to some extent.
  • the present invention adopts the following technical solutions:
  • a method for preparing an octyl (R)-2-(4-chloro-2-methylphenoxy)propionate root-blocking agent comprising the following steps:
  • the invention adopts chiral L-lactyl ethyl ester as raw material, first sulfonation reaction with p-toluenesulfonyl chloride, and then etherification reaction with 4-chloro-o-cresol, and finally transesterification with n-octanol to obtain target product hand
  • the yield of (R)-2-(4-chloro-2-methylphenoxy)propionic acid octyl ester prepared by the method is high, and the optical activity loss of the reactant is small during the preparation process, and the finally obtained optically active product is obtained.
  • the content of (R)-2-(4-chloro-2-methylphenoxy)propionic acid octyl ester is high.
  • the preparation method provided by the invention has simple process operation, mild reaction condition, low cost and less pollution to the environment.
  • the sulfonation reaction is carried out under the action of an acid binding agent.
  • the acid binding agent is an amine base; more preferably, the acid binding agent is a fatty amine compound; most preferably, the acid binding agent is triethylamine.
  • the molar ratio of the L-lactate ethyl ester, the p-toluenesulfonyl chloride to the acid binding agent is 1:1.0:1.0 to 1:1.0:1.5; more preferably, the L-lactate ethyl ester, p-toluenesulfonic acid
  • the molar ratio of the acid chloride to the acid binding agent is 1:1.0:1.0 to 1:1.0:1.3; most preferably, the molar ratio of the L-lactate ethyl ester to the p-toluenesulfonyl chloride to the acid binding agent is 1:1.0:1.2.
  • the reaction temperature of the sulfonation reaction is 20 ° C to 50 ° C; more preferably, the reaction temperature of the sulfonation reaction is 25 ° C to 40 ° C; most preferably, the reaction temperature of the sulfonation reaction is 28 ° C ⁇ 35 ° C.
  • the sulfonation reaction is carried out in a solvent of toluene or dichloromethane, preferably toluene as a solvent for the sulfonation reaction, and after the reaction, water is directly added to the system to separate the organic phase.
  • the etherification reaction is carried out under the promotion of a base.
  • the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, potassium t-butoxide or DBU (1,8-diazabicycloundecyl-7-- One or more of the alkenes; more preferably, the base is one of lithium hydroxide, sodium hydroxide or potassium hydroxide; most preferably, the base is sodium hydroxide.
  • the molar ratio of the ethyl (S)-2-p-toluenesulfonyl propionate to 4-chloro-o-cresol to the base is 1:1.0:1.0 to 1:1.5:1.5; more preferably, the The molar ratio of (S)-2-p-toluenesulfonyl propionate ethyl ester, 4-chloro-o-cresol to base is 1:1.05:1.05 to 1:1.3:1.3; most preferably, the (S)-2 The molar ratio of ethyl p-toluenesulfonate, 4-chloro-o-cresol to base was 1:1.2:1.2.
  • the etherification reaction is carried out in a solvent, which is DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NMP (N One or more of -methylpyrrolidone), DMSO (dimethyl sulfoxide), DCM (dichloromethane) or 1,4-dioxane; more preferably, the solvent is DMF, NMP or DMSO One; most preferably, the solvent is DMF.
  • a solvent which is DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), NMP (N One or more of -methylpyrrolidone), DMSO (dimethyl sulfoxide), DCM (dichloromethane) or 1,4-dioxane; more preferably, the solvent is DMF, NMP or DMSO One; most preferably, the solvent is DMF.
  • the reaction temperature of the etherification reaction is from 20 ° C to 60 ° C; more preferably, the reaction temperature of the etherification reaction is from 25 ° C to 40 ° C; most preferably, the etherification reaction The reaction temperature is from 28 ° C to 32 ° C.
  • the reaction time of the etherification reaction is 5 to 48 h; more preferably, the reaction time of the etherification reaction is 5 to 36 h; most preferably, the reaction time of the etherification reaction is 5 ⁇ 12h.
  • step S2 after the etherification reaction, petroleum ether is preferably used as the extraction solvent, and extracted 2 to 4 times, more preferably 3 times.
  • the transesterification reaction is carried out under the action of a catalyst.
  • the catalyst is trifluorosulfonic acid, methanesulfonic acid, potassium hydroxide, sodium hydroxide, sodium methoxide, DBU (1,8-diazabicycloundec-7-ene), T-12 One or more of (dibutyltin dilaurate) or T-9 (stannous octoate); more preferably, the catalyst is T-12 (dibutyltin dilaurate) or T-9 (stannous octoate) One; in view of the extremely unstable chemical nature of T-9, which is more difficult to handle than T-12, most preferably, the catalyst is T-12 (dibutyltin dilaurate).
  • the catalyst is used in an amount of from 0.5% to 20% by mole; more preferably, the catalyst is used in an amount of from 0.5% to 10% by mole; most preferably, the catalyst is used in an amount of 1% by
  • the molar ratio of the ethyl (R)-2-(4-chloro-2-methylphenoxy)propionate to n-octanol is 1:1.0 to 1:2.0; more preferably The molar ratio of ethyl (R)-2-(4-chloro-2-methylphenoxy)propionate to n-octanol is from 1:1.0 to 1:1.8; most preferably, the (R) The molar ratio of ethyl 2-(4-chloro-2-methylphenoxy)propanoate to n-octanol was 1:1.5.
  • the reaction temperature of the transesterification reaction is from 60 ° C to 140 ° C; more preferably, the reaction temperature of the transesterification reaction is from 90 ° C to 130 ° C; most preferably, the transesterification reaction The reaction temperature was 120 °C.
  • the reaction time of the transesterification reaction is 5 to 50 h; more preferably, the reaction time of the transesterification reaction is 8 to 18 h; most preferably, the reaction time of the transesterification reaction is 12 to 15h.
  • the present invention Compared with the prior art, the present invention has the following beneficial effects: the present invention uses a chiral L-lactate as a raw material, and finally synthesizes a chiral phenoxycarboxylate in a higher yield by sulfonation, etherification and transesterification.
  • the reaction conditions are mild during the preparation process, the process is simple and the cost is low, and the problem that the compound depends on imports and the source is scarce is solved to some extent.
  • the resulting product has a small loss of optical activity, maintaining the excellent chemical properties of the chiral compound.
  • a method for preparing an octyl (R)-2-(4-chloro-2-methylphenoxy)propionate root-blocking agent comprising the following steps:
  • the temperature of the reaction system is lowered to room temperature, a large amount of water is added and stirred for half an hour, the dichloromethane is extracted twice, the organic phase is combined, and the organic phase is washed back 5-6 times with water, The aqueous solution was dried over sodium sulfate, filtered, and evaporated.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 175 mL of toluene were stirred at room temperature to dissolve all the solids and uniformly mixed, and 0.275 mol of pyridine was added dropwise thereto, and the mixture was dropped in 0.5 h.
  • the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate,
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. Ethyl lactate 29.5g (0.25mol), p-toluenesulfonyl chloride 47.8g (0.25mol) and 175mL toluene, stir at room temperature to dissolve all the solids and mix well, start adding dropwise 0.275mol of 4-dimethylaminopyridine, within 0.5h Dropped. The mechanical stirring reaction was continued at 28 ° C to 35 ° C, and the progress of the reaction was monitored by TLC.
  • p-toluenesulfonyl chloride 47.8g (0.25mol
  • 175mL toluene stir at room temperature to dissolve all the solids and mix well
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 175 mL of toluene were stirred at room temperature to dissolve all the solids and uniformly mixed, and N,N-dimethylaniline 0.275 mol, 0.5 was started to be added dropwise. Drop in h.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 175 mL of toluene were stirred at room temperature to dissolve all the solids and uniformly mixed, and triethylamine 38.5 mL (0.275 mol) was added dropwise, 0.5 h. Drop inside.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. Ethyl lactate 29.5g (0.25mol), p-toluenesulfonyl chloride 47.8g (0.25mol) and 175mL of toluene, stir at room temperature to dissolve all the solids and mix well, start adding 35mL (0.25mol) of triethylamine, within 0.5h Dropped. The mechanical stirring reaction was continued at 28 ° C to 35 ° C, and the progress of the reaction was monitored by TLC.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 175 mL of toluene were stirred at room temperature to dissolve all the solids and uniformly mixed, and dropwise addition of 45.5 mL (0.325 mol) of triethylamine was started, 0.5 h. Drop inside.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 175 mL of toluene were stirred at room temperature to dissolve all the solids and uniformly mixed. Triethylamine 52.5 mL (0.375 mol) was added dropwise, 0.5 h. Drop inside.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. Ethyl lactate 29.5g (0.25mol), p-toluenesulfonyl chloride 47.8g (0.25mol) and 175mL of toluene, stirred at room temperature to dissolve all the solids and mix well, began to add 32mL (0.3mol) of triethylamine, within 0.5h Dropped. The mechanical stirring reaction was continued at 42 ° C to 48 ° C, and the progress of the reaction was monitored by TLC.
  • Example 1 The difference between this example and Example 1 is that the specific step of synthesizing S1.(S)-2-p-toluenesulfonylpropionate is to add L- to a 500 mL three-neck round bottom flask equipped with a mechanical stirring device. 29.5 g (0.25 mol) of ethyl lactate, 47.8 g (0.25 mol) of p-toluenesulfonyl chloride and 180 mL of dichloromethane were stirred at room temperature to dissolve all the solids and uniformly mixed, and dropwise addition of 42.0 mL (0.3 mol) of triethylamine was started. Drop in 0.5h.
  • the specific step of the reaction process of the step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol) and NaOH 5.2 g in a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. (0.13 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol) and LiOH 0.13 mol into a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. With 100 mL of DMF, stirring at room temperature for 1 h, 27.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonyl propionate obtained by dissolving 25 mL of DMF in step S1 was slowly added dropwise to the above system at 30 The reaction was stirred at ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol) and a KOH 0.13 mol to a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. With 100 mL of DMF, stirring at room temperature for 1 h, 27.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonyl propionate obtained by dissolving 25 mL of DMF in step S1 was slowly added dropwise to the above system at 30 The reaction was stirred at ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol), K 2 CO to a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. 3 0.13mol and 100mL DMF, stirred at room temperature for 1h, 25mL of DMF dissolved step S1 prepared (S)-2-p-toluenesulfonyl propionate 27.25g (0.1mol) slowly added dropwise to the above system The reaction was stirred at 60 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol), Na 2 CO, into a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. 3 0.13mol and 100mL DMF, stirred at room temperature for 1h, 25mL of DMF dissolved step S1 prepared (S)-2-p-toluenesulfonyl propionate 27.25g (0.1mol) slowly added dropwise to the above system The reaction was stirred at 60 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process of the step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol), CH 3 ONa in a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. 0.13 mol and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 of dissolving 25 mL of DMF was slowly added dropwise to the above system. The reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol), t-BuOK, to a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. 0.13 mol and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 of dissolving 25 mL of DMF was slowly added dropwise to the above system. The reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a chlorine-containing o-cresol 18.85 g (0.13 mol) and DBU 0.13 mol into a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. And 100 mL of DMF, stirring at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 of dissolving 25 mL of DMF was slowly added dropwise to the above system at room temperature. The reaction was stirred, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of DMA, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained by the step S1 of dissolving 25 mL of DMA was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of NMP, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of NMP was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of DMSO, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMSO was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of DCM, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 of dissolving 25 mL of DCM was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 The difference between this embodiment and the embodiment 1 is that the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (S)-2-p-toluenesulfonyl propionic acid B prepared by the step S1 of dissolving 25 mL of 1,4-dioxane by stirring (1. 2 mol) and 100 mL of 1,4-dioxane at room temperature for 1 h.
  • step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of toluene, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of toluene was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask, 17.1 g (0.12 mol), NaOH 4.8 g. (0.12 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask containing 21.38 g (0.15 mol) and NaOH 6 g (0.15). Mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 of dissolving 25 mL of DMF was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. After the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 The difference between this embodiment and the first embodiment is that the specific step of the reaction process in the step S2 is: adding a 4-mL o-cresol to a 250 mL three-neck round bottom flask containing 19.95 g (0.14 mol) and NaOH 5.6 g. (0.14 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • the specific step of the reaction process in the step S2 is: adding a chlorine-containing o-cresol 18.53 g (0.13 mol) and NaOH 5.2 g in a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. (0.13 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a solution of 4-chloro-o-cresol 15.0 g (0.105 mol) and NaOH 4.2 g to a 250 mL three-neck round bottom flask equipped with a mechanical stirring device. (0.105 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of ethyl (S)-2-p-toluenesulfonylpropionate obtained in the step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S2 is: adding a chlorine-containing o-cresol to a 250 mL three-neck round bottom flask, 15.68 g (0.11 mol), NaOH 4.4 g. (0.11 mol) and 100 mL of DMF, stirred at room temperature for 1 h, and 25.25 g (0.1 mol) of (S)-2-p-toluenesulfonyl propionate prepared in step S1 in which 25 mL of DMF was dissolved was slowly added dropwise to the above system. The reaction was stirred at 30 ° C, and the progress of the reaction was monitored by TLC. When the sulfonation reaction product was consumed, the reaction was stopped. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of CF 3 SO 3 H in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil bath at 120 ° C The reaction was carried out, and the plate was plated every 3 hours or so, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of methanesulfonic acid in a 250 mL three-neck round bottom flask equipped with a reflux condenser, in an oil bath at 120 ° C Reaction, plate every 3 hours or so, TLC followed the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of KOH was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and the reaction was carried out in an oil bath at 120 °C. The plate was plated every 3 hours, and the TLC tracked the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of NaOH was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and the reaction was carried out in an oil bath at 120 °C. The plate was plated every 3 hours, and the TLC tracked the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of KOH was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and the reaction was carried out in an oil bath at 80 ° C. The plate was plated every 3 hours, and the TLC tracked the progress of the reaction. Others are the same as in embodiment 1.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of CH 3 ONa was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and was carried out in an oil bath at 80 ° C. Reaction, plate every 3 hours or so, TLC followed the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of DBU was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and the reaction was carried out in an oil bath at 80 ° C. The plate was plated every 3 hours, and the TLC tracked the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 12.63 g (0.02 mol) of T-12 placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 120 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 0.02 mol of T-9 was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and was carried out in an oil bath at 120 °C. Reaction, plate every 3 hours or so, TLC followed the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 12.63 g (0.02 mol) of T-12 were placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and the oil at 80 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 12.63 g (0.02 mol) of T-12 placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 60 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 The difference between this embodiment and Example 1 is that the specific step of the synthesis process of step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 23.55 mL (0.15 mol) n-octanol, 12.63 g (0.02 mol) T-12 was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 80 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 23.55 mL (0.15 mol) of n-octanol, 0.02 mol of T-9 was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, and was carried out in an oil bath at 80 °C. Reaction, plate every 3 hours or so, TLC followed the progress of the reaction. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 31.4 mL (0.2 mol) of n-octanol, 6.32 g (0.01 mol) of T-12 were placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 80 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 The difference between this embodiment and Example 1 is that the specific step of the synthesis process of step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 23.55 mL (0.15 mol) of n-octanol, 6.32 g (0.01 mol) of T-12 were placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 120 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 23.55 mL (0.15 mol) of n-octanol, 3.16 g (0.005 mol) of T-12 was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 120 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate), 23.55 mL (0.15 mol) of n-octanol, 1.89 g (0.003 mol) of T-12 were placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 120 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • step S3 The difference between this embodiment and Example 1 is that the specific step of the synthesis process of step S3 is: 24.3 g (0.1 mol) of the etherified product ((R)-2-(4-chloro-2-methyl) obtained in step S2 Ethylphenoxy)ethyl propionate, 23.55 mL (0.15 mol) n-octanol, 0.32 g (0.0005 mol) T-12 was placed in a 250 mL three-neck round bottom flask equipped with a reflux condenser, oil at 120 ° C The reaction was carried out in a bath, and the plate was plated every 3 hours, and the progress of the reaction was followed by TLC. Others are the same as in the first embodiment.
  • the weight of the reactants and the products of each reaction of each of the steps S1, S2 and S3 were determined by a weighing method and the product yield of each preparation step was determined by calculation.
  • optical rotation of the target products of steps S1, S2 and S3 was determined by digital polarimeter.
  • the optical rotation of the photoactive substance was closely related to its concentration, test temperature and wavelength of light wave. However, under certain conditions, the optical rotation of each photoactive substance is a constant, expressed as the specific optical rotation [ ⁇ ]:
  • ⁇ is the polarimeter test value
  • c is the sample solution concentration, expressed in grams of sample contained in 1 mL of solution
  • l is the length of the liquid tube, the unit is dm
  • ⁇ is the wavelength of the light source, usually using a sodium source, denoted by D
  • t is the test temperature.
  • Test conditions At 28 ° C, all the concentrations of the test solution were 0.01 g / mL of absolute ethanol solution, the length of the liquid tube was 2 dm, and the test was carried out using a sodium light source.
  • Optical purity is defined as the ratio of the specific product specific rotation to the optical rotation of the optically pure standard reference.

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Abstract

本发明公开了一种可用做阻根剂的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯的制备方法，包括：以L-乳酸乙酯为原料，与对甲苯磺酰氯磺化，得到相应的磺酰酯化合物；将磺酰酯化合物与4-氯邻甲酚醚化，得到相应的芳香醚酯化合物；该类醚酯化合物最后与正辛醇进行酯交换，得到(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。本发明提供的方法得到的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯光学含量高，原料的光学损失较小，收率较高。本发明建立了一种制备工艺简单，反应条件温和，成本低廉的反应体系，从而在一定程度上解决了该化合物依靠进口，来源稀缺的问题。

Description

一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法 技术领域
本发明涉及有机合成领域，更具体地，涉及一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法。
背景技术
1934年，Kogl Fritz等人发现苯氧羧酸类化合物是一类类似于吲哚乙酸的植物生长调节剂，这类植物生长调节剂在高剂量时具有良好的除草效果，是一类很好的化学除草剂。这类除草剂价格低廉、除草速度较快、除草谱较宽、无残留等优点，在整个化学除草中占据着重要地位。2，4-D、2-甲基-4-氯苯氧乙酸(MCPA)及2，4，5-三氯苯氧乙酸(2，4，5-T)在第二次世界大战末就已作为较好的除草剂商品化。2-甲-4-氯丙酸(MCPP)的除草效果与2，4-D类似可有效地防除藜、猪殃殃和繁缕。与其它除草剂混用，可以扩大杀草谱。
(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯作为MCPP的衍生物在合适的剂量下对根系较为发达的常绿灌木和小乔木根系的主根生长具有一定的抑制效果，起到培养侧根系生长的作用，可将此应用到屋面种植技术中。苯氧羧酸酯类化合物一般的合成方法是通过苯氧羧酸与醇的直接酯化进行，但是对于一些高级脂肪长链醇因为活性、位阻等影响较难通过直接的酯化以较高的收率得到最终目标产物。有关手性该类化合物的合成工艺更是少之甚少，于是寻找简便、环保、高产率的合成这类化合物的新方法既是挑战又是机遇。本发明以手性L-乳酸乙酯为原料，经过磺化、醚化和酯交换最终以较高产率合成了手性苯氧羧酸酯类衍生物(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。
发明内容
有鉴于此，本发明为克服上述现有技术所述的至少一种不足，提供一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，该制备方法反应条件温和、成本低廉、工艺操作简便，从而在一定程度上解决该化合物依靠进口，来源稀缺的问题。
为了解决上述存在的技术问题，本发明采用下述技术方案：
一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，包括如下制备步 骤：
S1.取L-乳酸乙酯与对甲苯磺酰氯进行磺化反应，得到(S)-2-对甲苯磺酰丙酸乙酯；
S2.将步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯与4-氯邻甲酚进行醚化反应，得到(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯；
S3.将步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇进行酯交换反应，得到(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。
本发明以手性L-乳酸乙酯为原料，先与对甲苯磺酰氯进行磺化反应、再与4-氯邻甲酚进行醚化反应，最后与正辛醇进行酯交换，得到目标产物手性苯氧羧酸酯类衍生物(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。该方法制备的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯产物收率高，制备过程中，反应物的光学活性损失较小，最终得到的具有光学活性的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯含量较高。本发明提供的制备方法工艺操作简便，反应条件温和，成本低廉，对环境产生的污染较小。
进一步地，步骤S1中，所述磺化反应在缚酸剂的作用下进行。优选地，所述缚酸剂为胺类碱；更优选地，所述缚酸剂为脂肪胺类化合物；最优选地，所述缚酸剂为三乙胺。优选地，所述L-乳酸乙酯、对甲苯磺酰氯与缚酸剂的摩尔比为1:1.0:1.0～1:1.0:1.5；更优选地，所述L-乳酸乙酯、对甲苯磺酰氯与缚酸剂的摩尔比为1:1.0:1.0～1:1.0:1.3；最优选地，所述L-乳酸乙酯、对甲苯磺酰氯与缚酸剂的摩尔比为1:1.0:1.2。在本发明中，优选将缚酸剂慢慢加入到L-乳酸乙酯和对甲苯磺酰氯的混合液中进行反应。
进一步地，步骤S1中，所述磺化反应的反应温度为20℃～50℃；更优选地，磺化反应的反应温度为25℃～40℃；最优选地，磺化反应的反应温度为28℃～35℃。
进一步地，步骤S1中，所述磺化反应在溶剂中进行，所述溶剂为甲苯或二氯甲烷，优选甲苯作为磺化反应的溶剂，反应后直接在体系中加水，分离有机相。
进一步地，步骤S2中，所述醚化反应在碱的促进下进行。优选地，所述碱为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、甲醇钠、叔丁醇钾或DBU(1,8-二氮杂二环十一碳-7-烯)的一种或多种；更优选地，所述碱为氢氧化锂、氢氧化钠或氢氧化钾的一种；最优选地，所述碱为氢氧化钠。优选地，所述(S)-2-对甲苯磺酰丙酸乙酯、4-氯邻甲酚与碱的摩尔比为1:1.0:1.0～1:1.5:1.5；更优选地， 所述(S)-2-对甲苯磺酰丙酸乙酯、4-氯邻甲酚与碱的摩尔比为1:1.05:1.05～1:1.3:1.3；最优选地，所述(S)-2-对甲苯磺酰丙酸乙酯、4-氯邻甲酚与碱的摩尔比为1:1.2:1.2。
进一步地，步骤S2中，所述醚化反应在溶剂中进行，所述溶剂为DMF(N,N-二甲基甲酰胺)、DMA(N,N-二甲基乙酰胺)、NMP(N-甲基吡咯烷酮)、DMSO(二甲亚砜)、DCM(二氯甲烷)或1,4-二氧六环中的一种或几种；更优选地，所述溶剂为DMF、NMP或DMSO的一种；最优选地，所述溶剂为DMF。
进一步地，步骤S2中，所述醚化反应的反应温度为20℃～60℃；更优选地，所述醚化反应的反应温度为25℃～40℃；最优选地，所述醚化反应的反应温度为28℃～32℃。
进一步地，步骤S2中，所述醚化反应的反应时间为5～48h；更优选地，所述醚化反应的反应时间为5～36h；最优选地，所述醚化反应的反应时间为5～12h。
进一步地，步骤S2中，醚化反应后，优选石油醚作为萃取溶剂，萃取2～4次，更优选为3次。
进一步地，步骤S3中，所述酯交换反应在催化剂的作用下进行。优选地，所述催化剂为三氟磺酸、甲磺酸、氢氧化钾、氢氧化钠、甲醇钠、DBU(1,8-二氮杂二环十一碳-7-烯)、T-12(二月桂酸二丁基锡)或T-9(辛酸亚锡)的一种或多种；更优选地，所述催化剂为T-12(二月桂酸二丁基锡)或T-9(辛酸亚锡)的一种；考虑到T-9化学性质极不稳定，相比T-12难操作，最优选地，所述催化剂为T-12(二月桂酸二丁基锡)。优选地，所述催化剂的用量为0.5％～20％摩尔量；更优选地，所述催化剂的用量为0.5％～10％摩尔量；最优选地，所述催化剂的用量为1％摩尔量。
进一步地，步骤S3中，所述(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇的摩尔比为1:1.0～1:2.0；更优选地，所述(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇的摩尔比为1:1.0～1:1.8；最优选地，所述(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇的摩尔比为1:1.5。
进一步地，步骤S3中，所述酯交换反应的反应温度为60℃～140℃；更优选地，所述酯交换反应的反应温度为90℃～130℃；最优选地，所述酯交换反应的反应温度为120℃。
进一步地，步骤S3中，所述酯交换反应的反应时间为5～50h；更优选地， 所述酯交换反应的反应时间为8～18h；最优选地，所述酯交换反应的反应时间为12～15h。
本发明与现有技术相比较有如下有益效果：本发明以手性L-乳酸乙酯为原料，经过磺化、醚化和酯交换最终以较高产率合成了手性苯氧羧酸酯类衍生物(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。制备过程中反应条件温和，工艺操作简便，成本低廉，在一定程度上解决该化合物依靠进口，来源稀缺的问题。得到的产物光学活性损失小，保持了手性化合物的优良化学性质。
附图说明
图1是实施例中步骤S1制得的产物的核磁共振氢谱图( 1H NMR(400MHz,CDCl 3)δ:7.84(d,J＝8.1Hz,2H),7.36(d,J＝8.0Hz,2H),4.95(q,J＝6.9Hz,1H),4.13(q,J＝7.0Hz,2H),2.46(s,3H),1.53(d,J＝6.9Hz,3H),1.23(t,J＝7.1Hz,3H).)；
图2是实施例中步骤S2制得的产物的核磁共振氢谱图( 1H NMR(400MHz,CDCl 3)δ:7.14(s,1H),7.07(d,J＝8.7Hz,1H),6.63(d,J＝8.7Hz,1H),4.71(q,J＝6.7Hz,1H),4.22(q,J＝7.1Hz,2H),2.27(s,3H),1.64(d,J＝6.7Hz,3H),1.27(t,J＝7.1Hz,3H).)；
图3是实施例中步骤S3制得的产物的核磁共振氢谱图( 1H NMR(400MHz,CDCl 3)δ:7.14(s,1H),7.06(d,J＝8.7Hz,1H),6.62(d,J＝8.6Hz,1H),4.73(q,J＝6.7Hz,1H),4.26–4.05(m,2H),2.27(s,3H),1.63(t,J＝9.1Hz,5H),1.34–1.20(m,10H),0.91(t,J＝6.7Hz,3H).)。
具体实施方式
为了让本领域的技术人员更好地理解本发明的技术方案，下面对本发明作进一步阐述。
实施例1
一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，包括如下制备步骤：
S1.(S)-2-对甲苯磺酰丙酸乙酯的合成，具体步骤如下：
向装有机械搅拌装置的2L三口圆底烧瓶中加入L-乳酸乙酯118.0g(1.0mol)，对甲苯磺酰氯191.0g(1.0mol)和700mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺168.0mL(1.2mol)，1h内滴毕。于28℃～35℃ 下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到270.0g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。
S2.(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯的合成，具体步骤如下：
于装有机械搅拌装置的500mL三口圆底烧瓶中加入4-氯邻甲酚34.2g(0.24mol)、NaOH 9.6g(0.24mol)和200mL DMF,室温(25℃)下搅拌1h,将50mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯54.5g(0.2mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后(约8h左右)，停止反应，于室温下加入饱和食盐水搅拌几分钟，石油醚萃取三次，合并有机相，质量分数为2％的稀氢氧化钠水溶液返洗有机相四至五次，有机相用无水硫酸钠干燥，过滤，脱溶，得36.4g淡黄色油状物(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯。
S3.(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯的合成，具体步骤如下：
将24.3g(0.1mol)醚化产物，23.55mL(0.15mol)正辛醇，0.63g(0.001mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。待醚化产物反应完后(约14h左右)，将反应体系温度降至室温，加入大量水搅拌半小时，二氯甲烷萃取两次，合并有机相，用水返洗有机相5-6次，无水硫酸钠干燥，过滤，减压浓缩，柱层析快速分离可得31.1g淡黄色油状产物(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。
实施例2
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加吡啶0.275mol，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到60.6g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例3
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加4-二甲氨基吡啶0.275mol，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到62.0g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例4
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加N,N-二甲基苯胺0.275mol，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到54.5g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例5
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺38.5mL(0.275mol)，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到66.1g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例6
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全 部溶解并混合均匀，开始滴加三乙胺35mL(0.25mol)，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到64.7g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例7
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺45.5mL(0.325mol)，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到66.1g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例8
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺52.5mL(0.375mol)，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到65.4g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例9
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和175mL甲苯，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺42mL(0.3mol)，0.5h内滴毕。于42℃～48℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有 机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到62.7g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例10
本实施例与实施例1的区别在于，S1.(S)-2-对甲苯磺酰丙酸乙酯的合成的具体步骤为：向装有机械搅拌装置的500mL三口圆底烧瓶中加入L-乳酸乙酯29.5g(0.25mol)，对甲苯磺酰氯47.8g(0.25mol)和180mL二氯甲烷，室温下搅拌使固体全部溶解并混合均匀，开始滴加三乙胺42.0mL(0.3mol)，0.5h内滴毕。于28℃～35℃下继续机械搅拌反应，TLC监测反应进程，待原料反应完后往反应体系中加入水继续搅拌半小时，分液漏斗分液，水相用二氯甲烷返洗两次，合并有机相，有机层用无水硫酸钠干燥、过滤。滤液浓缩，真空抽滤后得到60.0g淡黄色透明油状产物(S)-2-对甲苯磺酰丙酸乙酯。其他同实施例1。
实施例11
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、NaOH 5.2g(0.13mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例12
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、LiOH 0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例13
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、KOH0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅 拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例14
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、K 2CO 30.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于60℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例15
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、Na 2CO 3 0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于60℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例16
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、CH 3ONa 0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于室温下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例17
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、t-BuOK 0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于室温下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例18
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.85g(0.13mol)、DBU0.13mol和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于室温下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例19
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL DMA,室温下搅拌1h,将25mL DMA溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例20
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL NMP,室温下搅拌1h,将25mL NMP溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例21
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL DMSO,室温下搅拌1h,将25mL DMSO溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例22
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有 机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL DCM,室温下搅拌1h,将25mL DCM溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例23
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL 1,4-二氧六环,室温下搅拌1h,将25mL 1,4-二氧六环溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例24
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL toluene,室温下搅拌1h,将25mL toluene溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例25
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚17.1g(0.12mol)、NaOH4.8g(0.12mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例26
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚21.38g(0.15mol)、NaOH6g(0.15mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得 的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例27
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚19.95g(0.14mol)、NaOH5.6g(0.14mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例28
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚18.53g(0.13mol)、NaOH5.2g(0.13mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例29
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚15.0g(0.105mol)、NaOH4.2g(0.105mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他同实施例1。
实施例30
本实施例与实施例1的区别在于，步骤S2反应过程的具体步骤为：于装有机械搅拌装置的250mL三口圆底烧瓶中加入4-氯邻甲酚15.68g(0.11mol)、NaOH4.4g(0.11mol)和100mL DMF,室温下搅拌1h,将25mL DMF溶解的步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯27.25g(0.1mol)慢慢滴加到上述体系中，于30℃下搅拌反应，TLC监测反应进程，当磺化反应产物消耗完后，停止反应。其他 同实施例1。
实施例31
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol CF 3SO 3H置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例32
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol甲磺酸置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例33
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol KOH置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例34
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol NaOH置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例35
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol KOH置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其 他同实施例1。
实施例36
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol CH 3ONa置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例37
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol DBU置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例38
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，12.63g(0.02mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例39
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，0.02mol T-9置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例40
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，12.63g(0.02mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反 应进程。其他同实施例1。
实施例41
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，12.63g(0.02mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于60℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例42
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，12.63g(0.02mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例43
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，0.02mol T-9置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例44
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，31.4mL(0.2mol)正辛醇，6.32g(0.01mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于80℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例45
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，6.32g(0.01mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪 反应进程。其他同实施例1。
实施例46
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，3.16g(0.005mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例47
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，1.89g(0.003mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
实施例48
本实施例与实施例1的区别在于，步骤S3合成过程的具体步骤为：将24.3g(0.1mol)醚化产物(步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯)，23.55mL(0.15mol)正辛醇，0.32g(0.0005mol)T-12置于装有回流冷凝装置的250mL三口圆底烧瓶中，于120℃下的油浴锅中进行反应，每隔3小时左右点板，TLC跟踪反应进程。其他同实施例1。
测定方法：
1.产物产率的测定
通过称量法测定步骤S1、S2及S3每一步反应的反应物及生成物的重量并通过计算测得各制备步骤的产物产率。
2.产物光学含量的测定
选用数字旋光仪分别测定步骤S1、S2及S3目标产物的旋光度，光活性物质的旋光度与其浓度、测试温度、光波波长等因素密切相关。但是，在一定条件下，每一种光活性物质的旋光度为一常数，用比旋光度[α]表示：
Figure PCTCN2018099020-appb-000001
其中，α为旋光仪测试值；c为样品溶液浓度，以l mL溶液所含样品克数表示； l为盛液管长度，单位为dm；λ为光源波长，通常采用钠光源，以D表示；t为测试温度。
测试条件：28℃下，所有待测液浓度均为0.01g/mL的无水乙醇溶液，盛液管长度为2dm，使用钠光源进行测试。
光学纯度(P)定义为：实测产物比旋光度与光学纯标准对照品的比旋光度之比
Figure PCTCN2018099020-appb-000002
标准样品的比旋光度与产物(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯比旋光度的测试在相同的条件下进行，据以上方法测得的[α] D标样＝+17.2。
表1：实施例1～10合成(S)-2-对甲苯磺酰丙酸乙酯的测定结果
Figure PCTCN2018099020-appb-000003
表2：实施例1、11～30合成(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯的测定结果
Figure PCTCN2018099020-appb-000004
Figure PCTCN2018099020-appb-000005
表3：实施例1、25～合成(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯的测定结果
Figure PCTCN2018099020-appb-000006
Figure PCTCN2018099020-appb-000007
根据表1～3数据可知，以上实施例的反应条件都较为温和，产物光学含量较高，产率较高。从表1数据可知，实施例1以及实施例5～8步骤中S1制备的(S)-2-对甲苯磺酰丙酸乙酯的产率和旋光度都较为理想，尤其是实施例1；从表2数据可知，实施例1、实施例11以及实施例30中步骤S2制备的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯的产率和旋光度都较为理想，尤其是实施例1；从表3数据可知，实施例1以及实施例38～48中步骤S3制备的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯的产率和旋光度都较为理想，尤其是实施例1。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进 等，均应包含在本发明权利要求的保护范围之内。

Claims (13)

  1. 一种(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，包括如下制备步骤：
    S1.取L-乳酸乙酯与对甲苯磺酰氯进行磺化反应，得到(S)-2-对甲苯磺酰丙酸乙酯；
    S2.将步骤S1制得的(S)-2-对甲苯磺酰丙酸乙酯与4-氯邻甲酚进行醚化反应，得到(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯；
    S3.将步骤S2制得的(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇进行酯交换反应，得到(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯。
  2. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S1中，所述磺化反应在缚酸剂的作用下进行，所述缚酸剂为胺类碱。
  3. 根据权利要求2所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，所述L-乳酸乙酯、对甲苯磺酰氯与缚酸剂的摩尔比为1:1.0:1.0～1:1.0:1.5。
  4. 根据权利要求1～3任一项所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S1中，所述磺化反应的反应温度为20～50℃。
  5. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S2中，所述醚化反应在碱的促进下进行，所述碱为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、甲醇钠、叔丁醇钾或DBU的一种或多种。
  6. 根据权利要求5所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，所述(S)-2-对甲苯磺酰丙酸乙酯、4-氯邻甲酚与碱的摩尔比为1:1.0:1.0～1:1.5:1.5。
  7. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S2中，所述醚化反应在溶剂中进行，所述溶剂为DMF、DMA、NMP、DMSO、DCM或1,4-二氧六环中的一种或几种。
  8. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S2中，所述醚化反应的反应温度为20～60℃。
  9. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法， 其特征在于，步骤S2中，所述醚化反应的反应时间为5～48h。
  10. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S3中，所述酯交换反应在催化剂的作用下进行，所述催化剂为三氟磺酸、甲磺酸、氢氧化钾、氢氧化钠、甲醇钠、DBU、T-12或T-9一种或多种。
  11. 根据权利要求10所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，所述催化剂的用量为0.5～20mol％。
  12. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S3中，所述(R)-2-(4-氯-2-甲基苯氧)丙酸乙酯与正辛醇的摩尔比为1:1.0～1:2.0。
  13. 根据权利要求1所述的(R)-2-(4-氯-2-甲基苯氧)丙酸辛酯阻根剂的制备方法，其特征在于，步骤S3中，所述酯交换反应的反应温度为60～140℃。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1586462A (en) * 1976-08-02 1981-03-18 Shell Int Research Phenonyalkanoic acids and derivatives thereof useful as herbicides
JPS63218644A (ja) * 1987-03-09 1988-09-12 Nissan Chem Ind Ltd 光学活性なフエノキシプロピオン酸エステル誘導体
CN107473962A (zh) * 2017-08-09 2017-12-15 科顺防水科技股份有限公司 一种(r)‑2‑(4‑氯‑2‑甲基苯氧)丙酸辛酯阻根剂的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103755602B (zh) * 2013-12-24 2016-01-20 江苏天容集团股份有限公司 L-对甲苯磺酰乳酸乙酯的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1586462A (en) * 1976-08-02 1981-03-18 Shell Int Research Phenonyalkanoic acids and derivatives thereof useful as herbicides
JPS63218644A (ja) * 1987-03-09 1988-09-12 Nissan Chem Ind Ltd 光学活性なフエノキシプロピオン酸エステル誘導体
CN107473962A (zh) * 2017-08-09 2017-12-15 科顺防水科技股份有限公司 一种(r)‑2‑(4‑氯‑2‑甲基苯氧)丙酸辛酯阻根剂的制备方法

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