DE112018004066T5 - Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester - Google Patents

Abstract

The invention discloses a process for the preparation of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester which can be used as a root barrier, comprising: sulfonation of L-ethyl lactate as a starting material with tosyl chloride to give the corresponding compound of tosyl ester; Etherification of the compound of tosyl ester with 4-chloro-o-cresol to the corresponding aromatic ether-ester compound; and transesterification of the ether-ester compound with n-octanol to (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester. With the process of the invention, a (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester can be obtained with a high optical component and a high yield with a low optical loss of the starting material. The invention creates a reaction system with a simple process, mild reaction conditions and low cost, so that the problem that this connection is highly dependent on the import due to its lack is partially solved.

Description

Technical field

The invention relates to the field of organic syntheses, in particular a method for producing a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester.

State of the art

In 1934, Kogl Fritz et al. the fact that the compound phenoxycarboxylic acids is a kind of growth regulator similar to indole acetic acid, which has an excellent herbicidal action at a high concentration and serves as a good chemical weed killer. The weed killers of this type have the advantages of low costs, a high rate of weed control, a wide range of exterminations and freedom from residues and are of important importance in the field of chemical weed control. At the end of World War II, 2,4-D and 2-methyl-4-chlorophenoxyacetic acid (MCPA) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were already marketed as good weed killers. In addition, the compound 2-methyl-4-chloropropionic acid (MCPP) has a comparable effect as 2,4-D for the prevention and destruction of Chenopodium, Galium, and Stellaria media. Through the mixed use with other weed killers, the spectrum of extermination can be expanded.

As a derivative of MCPP, (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester at a suitable concentration has a suppressive effect on the growth of the main roots of the evergreen shrubs with a well-developed root system and the small trees, so that the secondary roots can grow. This can be used in green roof technologies. The general synthesis for compounds of phenoxycarboxylic acid esters is carried out by direct esterification of phenoxycarboxylic acid with alcohol. For some higher long chain aliphatic alcohols, however, because of the activity and steric hindrance, the actual target product is difficult to obtain in a high yield by direct esterification. Very little is known about the chiral synthesis of these compounds, and it is therefore a challenge and a possibility to synthesize these compounds easily and in an environmentally friendly manner with a high yield using a novel process. According to the invention, chiral L-ethyl lactate is used as the starting material, and finally a chiral derivative of phenoxycarboxylic acid ester, (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester, is obtained in high yield via sulfonation, etherification and transesterification.

Disclosure of the invention

In this connection, the invention provides a method for producing a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester to overcome at least one of the disadvantages in the prior art. The method can be carried out inexpensively and simply under mild conditions, in order to partially solve the problem that this connection, because of its lack, depends heavily on the import.

In order to solve the aforementioned technical problem, the following technical solutions are used in the invention.

• S1. Sulfonierung von L-Ethyllaktat mit Tosylchlorid zu (S)-2-Tosylpropionsäureethylester;
• S2. Veretherung des im Schritt S1 erhaltenen (S)-2-Tosylpropionsäureethylester mit 4-Chlor-o-kresol zu (R)-2-(4-Chlor-2-methylphenoxy)propionsäureethylester; und
• S3. Umesterung des im Schritt S2 erhaltenen (R)-2-(4-Chlor-2-methylphenoxy)propionsäureethylester mit n-Octanol zu (R)-2-(4-Chlor-2-methylphenoxy)propionsäureoctylester.

A method for producing a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester comprises the following process steps:

• S1. Sulfonation of L-ethyl lactate with tosyl chloride to (S) -2-tosylpropionic acid ethyl ester;
• S2. Etherification of the (S) -2-tosylpropionic acid ethyl ester obtained in step S1 with 4-chloro-o-cresol to give (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester; and
• S3. Transesterification of the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate obtained in step S2 with n-octanol to octyl (R) -2- (4-chloro-2-methylphenoxy) propionate.

According to the invention, chiral L-ethyl lactate is used as the starting material, and a chiral derivative of phenoxycarboxylic acid ester, (R) -2 is produced as the target via sulfonation with tosyl chloride, subsequent etherification with 4-chloro-o-cresol and the final transesterification with n-octanol - (4-Chloro-2-methylphenoxy) propionic acid octyl ester obtained. An octyl (R) -2- (4-chloro-2-methylphenoxy) propionate can be obtained with the process in a high yield. The optical activity of the Educts loses less. The optically active (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester ultimately obtained makes up a large proportion of the product. The process can be carried out easily and inexpensively under mild conditions, without great environmental pollution.

Furthermore, in step S1, the sulfonation is carried out under the action of an acid-reducing agent. The acid-reducing agent is preferably an amine base. More preferably the acid reducing agent is an aliphatic amine. The acid reducing agent is most preferably triethylamine. The molar ratio of L-ethyl lactate, tosyl chloride and the acid-reducing agent is preferably 1: 1.0: 1.0 to 1: 1.0: 1.5. More preferably, the molar ratio of L-ethyl lactate, tosyl chloride and the acid reducing agent is 1: 1.0: 1.0 to 1: 1.0: 1.3. Most preferably the molar ratio of L-ethyl lactate, tosyl chloride and the acid reducing agent is 1: 1.0: 1.2. In the invention, the acid reducing agent is preferably slowly added to the mixture of L-ethyl lactate and tosyl chloride for the reaction.

Furthermore, in step S1, the reaction temperature for the sulfonation is 20 ° C -50 ° C. The reaction temperature for the sulfonation is 25 ° C.-40 ° C. The reaction temperature for the sulfonation is most preferably 28 ° C. -35 ° C.

Furthermore, the sulfonation in step S1 takes place in a solvent which is toluene or dichloromethane, preferably toluene. After the reaction, water is added directly to the reaction mixture and then the organic phase is separated off.

In addition, etherification takes place in step S2 using a base. The base is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, potassium t-butoxide or DBU (1,8-diazabicycloundec-7-ene). More preferably the base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide. The base is most preferably sodium hydroxide. The molar ratio of (S) -2-tosylpropionate, 4-chloro-o-cresol and the base is preferably 1: 1.0: 1.0 to 1: 1.5: 1.5. The molar ratio of (S) -2-tosylpropionic acid ethyl ester, 4-chloro-o-cresol and the base is more preferably 1: 1.05: 1.05 to 1: 1.3: 1.3. Most preferably the molar ratio of (S) -2-tosylpropionate, 4-chloro-o-cresol and the base is 1: 1.2: 1.2.

Furthermore, the etherification in step S2 takes place in a solvent which contains one or more of DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), NMP (N-methylpyrrolidinone), DMSO (dimethyl sulfoxide), DCM (dichloromethane) or 1,4-dioxane. More preferably the solvent is one of DMF, NMP or DMSO. The solvent DMF is most preferred.

Furthermore, in step S2, the reaction temperature for the etherification is 20 ° C -60 ° C. The reaction temperature for etherification is more preferably 25 ° C.-40 ° C. The reaction temperature for etherification is most preferably 28 ° C. -32 ° C.

Furthermore, in step S2, the reaction time for etherification is 5-48 hours. The reaction time for etherification is more preferably 5-36 hours. The reaction time for etherification is most preferably 5-12 hours.

Furthermore, in step S2 after the etherification, the mixture is extracted 2-4 times, more preferably 3 times, with petroleum ether as the extractant.

Furthermore, in step S3 the transesterification takes place under the action of a catalyst. The catalyst is preferably one or more of triflate, methanesulfonic acid, potassium hydroxide, sodium hydroxide, sodium methoxide, DBU (1,8-diazabicycloundec-7-ene), T-12 (dibutyltin dilaurate) or T-9 (tin (II) octoate). More preferred is the catalyst T-12 (dibutyltin dilaurate) or T-9 (tin (II) octoate). Since the instability of the chemical properties of T-9 makes it more difficult to treat it than T-12, T-12 (dibutyltin dilaurate) is mostly preferred as the catalyst. The amount of catalyst used is preferably 0.5 mol% -20 mol%. The amount of catalyst used is more preferably 0.5 mol% -10 mol%. The amount of catalyst used is most preferably 1 mol%.

Furthermore, in step S3 the molar ratio of (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester and n-octanol is 1: 1.0 to 1: 2.0. The molar ratio of (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester and n-octanol is more preferably 1: 1.0 to 1: 1.8. The molar ratio of (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester and n-octanol is most preferably 1: 1.5.

Furthermore, in step S3 the reaction temperature for the transesterification is 60 ° C. -140 ° C. The reaction temperature for the transesterification is more preferably 90 ° C. -130 ° C. The reaction temperature for the transesterification is most preferably 120 ° C.

Furthermore, in step S3, the reaction time for the transesterification is 5-50 hours. The reaction time for the transesterification is more preferably 8-18 hours. The reaction time for the transesterification is most preferably 12-15 hours.

Compared to the prior art, the invention has the following advantageous aspects: According to the invention, chiral L-ethyl lactate is used as the starting material, and a chiral derivative of phenoxycarboxylic acid ester, (R) -2- (4-chloro- 2-methylphenoxy) propionic acid octyl ester, obtained in high yield. The synthesis process has a simple process, mild reaction conditions and low cost, so that the problem that this compound is highly dependent on the import due to its deficiency is partially solved. The optical loss in the product thus obtained is low, so that the excellent chemical properties of the chiral compounds are retained.

Figure list

• 1 shows a magnetic resonance imaging of the product produced in step S1 of an example ( ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.84 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.95 (q, J = 6.9 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 2.46 (s, 3H), 1 , 53 (d, J = 6.9 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).);
• 2nd shows a hydrogen magnetic resonance imaging of the product produced in step S2 of an example ( ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.14 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H) , 6.63 (d, J = 8.7 Hz, 1H), 4.71 (q, J = 6.7 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2 , 27 (s, 3H), 1.64 (d, J = 6.7 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).); and
• 3rd shows a hydrogen magnetic resonance tomography of the product produced in step S3 of an example ( ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.14 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H) , 6.62 (d, J = 8.6 Hz, 1H), 4.73 (q, J = 6.7 Hz, 1H), 4.26-4.05 (m, 2H), 2.27 ( s, 3H), 1.63 (t, J = 9.1 Hz, 5H), 1.34-1.20 (m, 10H), 0.91 (t, J = 6.7 Hz, 3H). ).

Detailed embodiments

In order that the person skilled in the art can better understand the technical solutions of the invention, the invention is described in more detail below.

example 1

• S1. Die Synthese von (S)-2-Tosylpropionsäureethylester, die wie folgend konkret durchgeführt wird. In einem 2 L Dreihals-Rundkolben mit einem mechanischen Rührer wurden 118,0 g (1,0 mol) L-Ethyllaktat, 191,0 g (1,0 mol) Tosylchlorid und 700 mL Toluol vorgelegt, und bei Raumtemperatur gerührt, bis die Festkörper völlig gelöst und homogen gemischt sind. Über 1 h wurde 168,0 mL (1,2 mol) Triethylamin zugetropft. Bei 28°C bis 35°C wurde das Gemisch weiter mechanisch gerührt. Der Fortschritt der Reaktion wurde durch TLC überwachtet. Nachdem die Ausgangsmaterialien umgesetzt wurden, wurde Wasser in das Reaktionssystem hinzugefügt und weiter eine halbe Stunde gerührt. Das Gemisch wurde durch einen Scheidetrichter abgetrennt. Die wässerige Phase wurde zweimal mit Dichlormethan gewaschen, während die organischen Phasen wurden zusammengelegt. Die organische Schicht wurde über anhydrisches Natriumsulfat getrocknet und gefiltert. Das Filtrat wurde aufkonzentriert, und nach der Filterung unter Vakuum wurde 270,0 g von einem hellgelben transparenten öligen Produkt (S)-2-Tosylpropionsäureethylester erhalten.
• S2. Die Synthese von (R)-2-(4-Chlor-2-methylphenoxy)propionsäureethylester, die wie folgend konkret durchgeführt wird. In einem 500 mL Dreihals-Rundkolben mit einem mechanischen Rührer wurden 34,2 g (0,24 mol) 4-Chlor-o-kresol, 9,6 g (0,24 mol) NaOH und 200 mL DMF vorgelegt, und bei Raumtemperatur (25°C) 1 h gerührt. Dazu wurde 54,5 g (0,2 mol) vom im Schritt S1 hergestellten (S)-2-Tosylpropionsäureethylester in 50 mL DMF langsam zugetropft und bei 30°C gerührt. Der Fortschritt der Reaktion wurde durch TLC überwachtet. Nachdem das Produkt aus der Sulfonierung völlig umgesetzt wurde (nach ca. 8 h), war die Reaktion abgeschlossen. Bei Raumtemperatur wurde gesättigtes Salzwasser hinzugegeben und über einige Minuten gerührt. Das Gemisch wurde dreimal mit Petrolether extrahiert, und die organischen Phasen wurden zusammengelegt und wiederum viermal bis fünfmal mit einer NatriumhydroxidLösung mit einer Konzentration von 2 Gew.% gewaschen. Die organische Phase wurde dann über anhydrisches Natriumsulfat getrocknet, gefiltert, und desolventiert, um schließlich 36,4 g von hellgelbem öligem (R)-2-(4-Chlor-2-methylphenoxy)propionsäureethylester zu erhalten.
• S3. Die Synthese von (R)-2-(4-Chlor-2-methylphenoxy)propionsäureoctylester, die wie folgend konkret durchgeführt wird. In einem 250 mL Dreihals-Rundkolben mit einem Rückflusskühler wurden 24,3 g (0,1 mol) Produkt der Veretherung, 23,55 mL (0,15 mol) n-Octanol, und 0,63 g (0,001 mol) T-12 vorgelegt. Die Reaktion wurde in einem Ölbad bei 120°C durchgeführt. Der Fortschritt der Reaktion wurde durch TLC überwachtet, indem je ca. 3 Stunden eine Probe entnommen und geprüft wurde. Nachdem das Produkt der Veretherung völlig umgesetzt wurde (nach ca. 14 h), wurde der Reaktionsansatz auf Raumtemperatur abgekühlt und nach dem Hinzugeben einer großen Menge an Wasser für eine halbe Stunde gerührt. Das Gemisch wurde zweimal mit Dichlormethan extrahiert, und die organischen Phasen wurden zusammengelegt, wiederum mit Wasser 5-6 mal gewaschen, über anhydrisches Natriumsulfat getrocknet, gefiltert, unter reduziertem Druck konzentriert und durch Säulenchromatographie schnell getrennt, um 31,1 g von hellgelbem öligem Produkt (R)-2-(4-Chlor-2-methylphenoxy)propionsäureoctylester zu erhalten.

A method for producing a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester comprises the following process steps:

• S1. The synthesis of (S) -2-tosylpropionate, which is specifically carried out as follows. 118.0 g (1.0 mol) of L-ethyl lactate, 191.0 g (1.0 mol) of tosyl chloride and 700 ml of toluene were placed in a 2 L three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 168.0 ml (1.2 mol) of triethylamine were added dropwise over 1 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 270.0 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained.
• S2. The synthesis of (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester, which is specifically carried out as follows. 34.2 g (0.24 mol) of 4-chloro-o-cresol, 9.6 g (0.24 mol) of NaOH and 200 ml of DMF were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature (25 ° C) stirred for 1 h. 54.5 g (0.2 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 in 50 ml of DMF were slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the product from the sulfonation was completely reacted (after about 8 h), the reaction was complete completed. Saturated salt water was added at room temperature and the mixture was stirred for a few minutes. The mixture was extracted three times with petroleum ether and the organic phases were combined and again washed four to five times with a sodium hydroxide solution with a concentration of 2% by weight. The organic phase was then dried over anhydrous sodium sulfate, filtered, and desolventized to finally obtain 36.4 g of light yellow oily (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester.
• S3. The synthesis of octyl (R) -2- (4-chloro-2-methylphenoxy) propionate, which is specifically carried out as follows. 24.3 g (0.1 mol) of etherification product, 23.55 ml (0.15 mol) of n-octanol, and 0.63 g (0.001 mol) of T- were placed in a 250 mL round-bottomed flask with a reflux condenser. 12 submitted. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. After the etherification product had been completely reacted (after about 14 h), the reaction mixture was cooled to room temperature and, after the addition of a large amount of water, stirred for half an hour. The mixture was extracted twice with dichloromethane and the organic phases were combined, washed again with water 5-6 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and quickly separated by column chromatography to give 31.1 g of light yellow oily product (R) -2- (4-Chloro-2-methylphenoxy) propionic acid octyl ester.

Example 2

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 0.275 mol of pyridine was added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 60.6 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 3

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 0.275 mol of 4-dimethylaminopyridine was added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 62.0 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 4

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 0.275 mol of N, N-dimethylaniline was added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and after filtering under vacuum, 54.5 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 5

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 38.5 ml (0.275 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and after filtering under vacuum, 66.1 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 6

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 35 ml (0.25 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 64.7 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 7

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 45.5 ml (0.325 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic Layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and after filtering under vacuum, 66.1 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 8

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 52.5 ml (0.375 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 65.4 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 9

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 175 ml of toluene were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 42 ml (0.3 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 42 ° C to 48 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 62.7 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 10

This example differs from example 1 in that the synthesis S1 of (S) -2-tosylpropionate is carried out specifically as follows. 29.5 g (0.25 mol) of L-ethyl lactate, 47.8 g (0.25 mol) of tosyl chloride and 180 ml of dichloromethane were placed in a 500 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature until the Solids are completely dissolved and mixed homogeneously. 42.0 ml (0.3 mol) of triethylamine were added dropwise over 0.5 h. The mixture was further mechanically stirred at 28 ° C to 35 ° C. The progress of the reaction was monitored by TLC. After the starting materials were reacted, water was added to the reaction system and stirring was continued for half an hour. The mixture was separated by a separatory funnel. The aqueous phase was washed twice with dichloromethane while the organic phases were combined. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and, after filtering under vacuum, 60.0 g of a light yellow transparent oily product (S) -2-tosylpropionate was obtained. It remains the same as in Example 1.

Example 11

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 5.2 g (0.13 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 12

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of LiOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. To this was added 27.25 g (0.1 mol) of the (S) -2- prepared in step S1 and dissolved in 25 mL DMF Ethyl tosylpropionate was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 13

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of KOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 14

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of K ₂ CO ₃ and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h . For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 60 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 15

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of Na ₂ CO ₃ and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h . For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 60 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 16

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of CH ₃ ONa and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 17

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of t-BuOK and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 18

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.85 g (0.13 mol) of 4-chloro-o-cresol, 0.13 mol of DBU and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 19

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of DMA were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2- prepared in step S1 and dissolved in 25 mL DMA Ethyl tosylpropionate was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 20

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of NMP were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of NMP were slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 21

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of DMSO were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMSO were slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 22

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of DCM were placed in a 250 ml round-bottomed flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DCM were slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 23

This example differs from example 1 in that the reaction in step S2 as follows specifically. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of 1,4-dioxane were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer , and stirred at room temperature for 1 h. To this was added 27.25 g (0.1 mol) of in the step S1 prepared, dissolved in 25 mL 1,4-dioxane (S) -2-tosylpropionate slowly added dropwise and stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 24

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of toluene were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. To this was added 27.25 g (0.1 mol) of the (S) -2- prepared in step S1 and dissolved in 25 mL toluene. Ethyl tosylpropionate was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 25

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 17.1 g (0.12 mol) of 4-chloro-o-cresol, 4.8 g (0.12 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 26

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 21.38 g (0.15 mol) of 4-chloro-o-cresol, 6 g (0.15 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer and at room temperature for 1 h touched. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 27

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 19.95 g (0.14 mol) of 4-chloro-o-cresol, 5.6 g (0.14 mol) of NaOH and 100 ml of DMF were placed in a 250 ml round-bottomed flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 28

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 18.53 g (0.13 mol) of 4-chloro-o-cresol, 5.2 g (0.13 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 29

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 15.0 g (0.105 mol) of 4-chloro-o-cresol, 4.2 g (0.105 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and the mixture was stirred at room temperature for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 30

This example differs from example 1 in that the reaction in step S2 is carried out specifically as follows. 15.68 g (0.11 mol) of 4-chloro-o-cresol, 4.4 g (0.11 mol) of NaOH and 100 ml of DMF were placed in a 250 ml three-necked round bottom flask with a mechanical stirrer, and at room temperature Stirred for 1 h. For this purpose, 27.25 g (0.1 mol) of the (S) -2-tosylpropionic acid ethyl ester prepared in step S1 and dissolved in 25 ml of DMF was slowly added dropwise and the mixture was stirred at 30 ° C. The progress of the reaction was monitored by TLC. After the sulfonation product was fully reacted, the reaction was complete. It remains the same as in Example 1.

Example 31

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of CF ₃ SO ₃ H. The reaction was performed in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 32

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of methanesulfonic acid. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 33

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of KOH. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 34

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of NaOH. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 35

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of KOH. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 36

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of CH ₃ ONa. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 37

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of DBU. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 38

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 12.63 g (0.02 mol) of T-12. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 39

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 0.02 mol of T-9. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 40

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 12.63 g (0.02 mol) of T-12. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 41

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 31 , 4 mL (0.2 mol) of n-octanol, and 12.63 g (0.02 mol) of T-12. The reaction was carried out in an oil bath at 60 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 42

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 12.63 g (0.02 mol) of T-12. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 43

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 0.02 mol of T-9. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 44

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the (R) -2- (4-chloro-2-methylphenoxy) prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser. ethyl propionate), 31.4 ml (0.2 mol) of n-octanol, and 6.32 g (0.01 mol) of T-12. The reaction was carried out in an oil bath at 80 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 45

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 6.32 g (0.01 mol) of T-12. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 46

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 3.16 g (0.005 mol) of T-12. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 47

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 1.89 g (0.003 mol) of T-12. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

Example 48

This example differs from example 1 in that the synthesis in step S3 is carried out specifically as follows. 24.3 g (0.1 mol) of the etherification product (ie the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate prepared in step S2) were placed in a 250 mL round-bottomed flask with a reflux condenser, 23 , 55 mL (0.15 mol) of n-octanol, and 0.32 g (0.0005 mol) of T-12. The reaction was carried out in an oil bath at 120 ° C. The progress of the reaction was monitored by TLC by taking and testing a sample for about 3 hours each. It remains the same as in Example 1.

1. 1. Bestimmung der Ausbeute des Produkts Durch Wägen der Edukte und Produkte in den Schritten S1, S2 und S3 und Berechnen werden die Ausbeuten der Produkte in den einzelnen Verfahrensschritten ermittelt.
2. 2. Bestimmung des optischen Anteils des Produkts Die optischen Drehungen der Zielprodukte in den Schritten S1, S2 und S3 werden mit einem digitalen Polarimeter bemessen, wobei die optische Drehung einer optisch aktiven Substanz mit seiner Konzentration, der Testtemperatur, der Wellenlänge des Lichts, usw. eng verbunden ist. Bei bestimmen Bedingungen bleibt jedoch die optische Drehung einer optisch aktiven Substanz konstant und wird durch die optische Drehung [α] dargestellt, $${\left[\alpha \right]}_{\lambda }^t=\frac{\alpha }{c\times l}$$
   
   wobei α für den gemessenen Wert der optischen Drehung steht; c für die Konzentration der Probenlösung in Gramm der Probe pro 1 mL von der Lösung steht; l für die Länge der Pipette in dm steht; λ für die Wellenlänge aus der Lichtquelle (normalerweise einer Natriumlichtquelle) in D steht; und t für die Testtemperatur steht.

Determination methods:

1. 1. Determination of the yield of the product By weighing the starting materials and products in steps S1, S2 and S3 and calculating, the yields of the products are determined in the individual process steps.
2. 2. Determination of the optical component of the product The optical rotations of the target products in steps S1, S2 and S3 are measured with a digital polarimeter, the optical rotation of an optically active substance with its concentration, the test temperature, the wavelength of the light, etc. is closely connected. Under certain conditions, however, the optical rotation of an optically active substance remains constant and is represented by the optical rotation [α], $${\left[\alpha \right]}_{\lambda }^t=\frac{\alpha }{c\times l}$$
   
   where α stands for the measured value of the optical rotation; c stands for the concentration of the sample solution in grams of the sample per 1 mL of the solution; l stands for the length of the pipette in dm; λ represents the wavelength from the light source (usually a sodium light source) in D; and t stands for the test temperature.

Test conditions: At 28 ° C, solutions in anhydrous ethanol with a concentration of 0.01 g / mL are tested in a pipette with a length of 2 dm with a sodium light source.

Optical purity (P) is defined as the quotient of the actually measured optical rotation of the product to the optical rotation of a chemically pure standard reference. $$\text{P}=\frac{{\left[\alpha \right]}_{DPrObe}}{{\left[\alpha \right]}_{DStandard}}\times 100\%$$

The optical rotation of the standard sample is determined under the same conditions as for the optical rotation of the product (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester. The [α] _{D of} the standard sample determined using the aforementioned method is +17.2. Table 1: Determination results of the (S) -2-tosylpropionic acid ethyl esters synthesized in Examples 1-10 example Acid reducing agent Amount of use / equivalent of the acid-reducing agent Solvent Reaction temperature / ° C Response time / h Yield /% [α] _D 1 Triethylamine 1.2 toluene 30th 18th 99 -27.8 2nd Pyridine 1.1 toluene 30th 24th 89 -19.7 3rd 4-dimethylaminopyridine 1.1 toluene 30th 24th 91 -27.1 4th N, N-dimethylaniline 1.1 toluene 30th 24th 80 -18.4 5 Triethylamine 1.1 toluene 30th 24th 97 -26.5 6 Triethylamine 1.0 toluene 30th 36 95 -25.9 7 Triethylamine 1.3 toluene 30th 18th 97 -23.9 8th Triethylamine 1.5 toluene 30th 16 96 -23.6 9 Triethylamine 1.2 toluene 45 18th 92 -24.5 10th Triethylamine 1.2 Dichloromethane 30th 48 88 -26.3 Note: The test for the specific optical rotation [α] _D was based on a 0.01 g / mL solution in anhydrous ethanol at 28 ° C. Table 2: Determination results of the (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl esters synthesized in Examples 1 and 11-30 Examples base Use of base / mol solvent Reaction temperature / ° C Response time / h Yield /% [α] _D 1 NaOH 0.24 DMF 30th 8th 75 +17.3 11 NaOH 0.13 DMF 30th 12th 71 +16.2 12th LiOH 0.13 DMF 30th 13 54 +16.4 13 KOH 0.13 DMF 30th 18th 58 +17.2 14 K ₂ CO ₃ 0.13 DMF 60 48 52 +17.1 15 Na ₂ CO ₃ 0.13 DMF 60 60 51 +17.0 16 CH ₃ ONa 0.13 DMF 25th 8th 53 +16.2 17th t-BuOK 0.13 DMF 25th 8th 55 +16.0 18th DBU 0.13 DMF 25th 48 59 +12.9 19th NaOH 0.12 DMA 30th 5 56 +13.0 20th NaOH 0.12 NMP 30th 5 55 +17.2 21 NaOH 0.12 DMSO 30th 7 73 +16.2 22 NaOH 0.12 DCM 30th 72 <5 / 23 NaOH 0.12 1,4-dioxane 30th 36 37 +12.9 24th NaOH 0.12 toluene 30th 72 <5 / 25th NaOH 0.12 DMF 30th 10th 69 +16.7 26 NaOH 0.15 DMF 30th 5 55 +16.8 27 NaOH 0.14 DMF 30th 10th 60 +16.6 28 NaOH 0.13 DMF 30th 18th 66 +17.1 29 NaOH 0.105 DMF 30th 36 68 +17.0 30th NaOH 0.11 DMF 30th 48 72 +17.1 Note: The test for the specific optical rotation [α] _D was based on a 0.01 g / mL solution in anhydrous ethanol at 28 ° C. Table 3: Determination results of the (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl esters synthesized in Examples 1 and 25 Examples catalyst Amount of catalyst used / mol% Amount of octanol / mol Reaction temperature / ° C Time / h Yield /% [α] _D 1 T-12 1 0.15 120 14 95 +14.7 31 CF ₃ SO ₃ H 20th 0.2 120 24th 83 + 9.8 32 Methanesulfonic acid 20th 0.2 120 24th 80 +10.2 33 KOH 20th 0.2 120 24th 74 +10.7 34 NaOH 20th 0.2 120 48 70 +11.5 35 KOH 20th 0.2 80 48 40 +12.9 36 CH ₃ ONa 20th 0.2 80 7 88 0 37 DBU 20th 0.2 80 24th 78 +7.6 38 T-12 20th 0.2 120 12th 90 +12.6 39 T-9 20th 0.2 120 16 92 +10.3 40 T-12 20th 0.2 80 36 91 +10.0 41 T-12 20th 0.2 60 42 91 +7.8 42 T-12 20th 0.15 80 36 90 +13.2 43 T-9 20th 0.15 80 40 93 +11.5 44 T-12 10th 0.2 80 30th 90 +13.7 45 T-12 10th 0.15 120 16 95 +10.0 46 T-12 5 0.15 120 16 96 +11.4 47 T-12 3rd 0.15 120 16 95 +13.6 48 T-12 0.5 0.15 120 20th 90 +13.8 Note: The test for the specific optical rotation was based on a 0.01 g / mL solution in anhydrous ethanol at 28 ° C.

It is known from the data in Tables 1-3 that the reaction conditions in these examples are relatively mild and the optical content and the yield of the products are high. It is known from the data in Table 1 that the (S) -2-tosylpropionate, which are prepared in steps S1 of Examples 1 and 5-8, in particular Example 1, have satisfactory yield and optical rotation. It is known from the data in Table 2 that the (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl esters which are prepared in steps S2 of Examples 1, 11 and 30, in particular Example 1, are satisfied Yield and optical rotation. It is known from the data in Table 3 that the octyl (R) -2- (4-chloro-2-methylphenoxy) propionate, which are prepared in steps S3 of Examples 1 and 38-48, in particular Example 1, are satisfied Yield and optical rotation.

Of course, the above examples of the invention are only exemplary to clearly explain the invention and are not intended to limit the embodiments of the invention. Those skilled in the art can also make other changes or modifications in various forms based on the description above. It would not be necessary or possible to exhaustively list all of the embodiments. All modifications, equivalent substitutions, and extensions that come within the scope of the idea and principle of the invention are intended to be included within the scope of the claims of the invention.

Claims (13)

Process for the production of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester, characterized in that the process comprises the following process steps: S1. Sulfonation of L-ethyl lactate with tosyl chloride to (S) -2-tosylpropionic acid ethyl ester; S2. Etherification of the (S) -2-tosylpropionic acid ethyl ester obtained in step S1 with 4-chloro-o-cresol to give (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester; and S3. Transesterification of the ethyl (R) -2- (4-chloro-2-methylphenoxy) propionate obtained in step S2 with n-octanol to octyl (R) -2- (4-chloro-2-methylphenoxy) propionate. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S1 the sulfonation is carried out under the action of an acid-reducing agent which is an amine base. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 2 , characterized in that the molar ratio of L-ethyl lactate, tosyl chloride and the acid-reducing agent is 1: 1.0: 1.0 to 1: 1.0: 1.5. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester according to one of the Claims 1 - 3rd , characterized in that in step S1 the reaction temperature for the sulfonation is 20-50 ° C. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S2 the etherification is carried out using a base which is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, potassium t-butoxide or DBU. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 5 , characterized in that the molar ratio of (S) -2-tosylpropionate, 4-chloro-o-cresol and the base is 1: 1.0: 1.0 to 1: 1.5: 1.5. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S2 the etherification is carried out in a solvent which is one or more of DMF, DMA, NMP, DMSO, DCM or 1,4-dioxane. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S2 the reaction temperature for the etherification is 20-60 ° C. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S2 the reaction time for etherification is 5-48 hours. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S3 the transesterification is carried out under the action of a catalyst which is one or more of triflate, methanesulfonic acid, potassium hydroxide, sodium hydroxide, sodium methoxide, DBU, T-12 or T-9. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 10 , characterized in that the amount of catalyst used is 0.5-20 mol%. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S3 the molar ratio of (R) -2- (4-chloro-2-methylphenoxy) propionic acid ethyl ester and n-octanol is 1: 1.0 to 1: 2.0. Process for the preparation of a root barrier of (R) -2- (4-chloro-2-methylphenoxy) propionic acid octyl ester Claim 1 , characterized in that in step S3 the reaction temperature for the transesterification is 60-140 ° C.

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