Synthesis method of 2-(4-chloro-2-methyl phenoxy) n-octyl propionate

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 2-(4-chloro-2-methyl phenoxy) n-octyl propionate. The synthesis method comprises the following steps: (1) in the presence of a Lewis acid catalyst, taking D (+)-lactide and sodium octanoate to carry out ring-opening reaction to obtain (2R)-2-octyl hydroxypropionate; and (2) in the presence of a copper catalyst and an inorganic base, carrying out an O-arylation coupling reaction on the (2R)-2-octyl hydroxypropionate and 4-chloro-2-methylphenol to obtain the 2-(4-chloro-2-methylphenoxy) n-octyl propionate. According to the invention, a two-step method route of metal-catalyzed ring opening and copper-catalyzed O-arylation is creatively adopted, and a brand-new technical thought which is simple, efficient and good in optical selectivity is provided for synthesis of chiral phenoxy carboxylic ester.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate. Background Technology

[0002] 2-(4-chloro-2-methylphenoxy)propionate n-octyl ester, especially its (R)-configuration isomer, is an effective chiral plant growth regulator and root inhibitor. Currently, the synthesis of this compound mainly relies on the classic multi-step derivatization route starting from chiral lactate esters.

[0003] Patent CN107473962A discloses a method for preparing the target product from L-ethyl lactate via a three-step reaction involving sulfonation, etherification, and transesterification. This method is mature and the raw materials are readily available, but it has the following areas for improvement: First, the synthetic route involves three independent reactions and corresponding separation and purification processes, and the overall yield is affected by the cumulative effect of multiple steps, leaving room for improvement in process efficiency. Second, to obtain the final long-chain octyl ester, a transesterification reaction is required in the last step. This step is usually carried out at high temperatures (>120°C) and in the presence of a metal catalyst, which may result in high energy consumption and the risk of slight racemization of the chiral center at high temperatures. Finally, this route uses sulfonyl chloride reagents, which require special attention in storage and use, and the reaction produces stoichiometric byproducts.

[0004] The development of biocatalysis and transition metal catalysis technologies has provided new tools for the efficient and highly selective synthesis of chiral molecules. Therefore, there is an urgent need in this field to explore novel synthetic routes that are simpler in procedure, can more gently construct key chemical bonds, and can more precisely control the chiral center, in order to enrich the preparation methods of this important compound and provide alternative options for process optimization. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, the primary objective of this invention is to provide a method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate. This invention innovatively employs a two-step route: metal-catalyzed ring-opening and copper-catalyzed O-arylation. The first step uses a Lewis acid catalyst to achieve highly selective ring-opening of sodium octanol by D-lactide, yielding a chiral intermediate in extremely high yield. The second step utilizes a copper-catalyzed cross-coupling reaction to efficiently construct the crucial CO-Ar aryl ether bond, providing a simple, efficient, and optically selective new technical approach for the synthesis of chiral phenoxycarboxylic acid esters.

[0006] The objective of this invention is achieved through the following technical solution: A method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate includes the following steps: (1) In the presence of a Lewis acid catalyst, D(+)-lactide was reacted with sodium n-octanol to undergo a ring-opening reaction to obtain octyl (2R)-2-hydroxypropionate; (2) In the presence of a copper catalyst and an inorganic base, octyl (2R)-2-hydroxypropionate is subjected to an O-arylation coupling reaction with 4-chloro-2-methylphenol to obtain octyl 2-(4-chloro-2-methylphenoxy)propionate.

[0007] Furthermore, the Lewis acid catalyst mentioned in step (1) is tetrabutyl titanate.

[0008] Further, in step (1), the molar ratio of D-lactide to sodium n-octanol is (1-1.2):1; and the molar ratio of sodium n-octanol to catalyst is 10 mmol: (0.05-0.06) mL.

[0009] Furthermore, the ring-opening reaction described in step (1) is carried out at a temperature of 25-30 °C for 6-8 h.

[0010] Furthermore, the copper catalyst in step (2) comprises a monovalent copper salt and carbon nitride material; the inorganic base is selected from any one of potassium tert-butoxide, sodium tert-butoxide, or sodium methoxide.

[0011] Furthermore, the carbon nitride material is polymeric carbon nitride. The carbon nitride material is a polymeric semiconductor material composed of carbon and nitrogen elements, such as the common graphitic carbon nitride (g-C3N4), whose abundant nitrogen sites can act as ligands to stabilize copper catalysts and improve catalytic efficiency.

[0012] Furthermore, the copper catalyst is prepared by dispersing carbon nitride material in water, mixing it with an acetonitrile dispersion containing monovalent copper salt, ultrasonically treating it, and then evaporating the solvent to obtain the catalyst.

[0013] Further, in step (2), the ratio of (2R)-2-hydroxypropionate octyl ester, 4-chloro-2-methylphenol, copper catalyst and inorganic base is 1 mmol: (1.25-1.5) mmol: (5-6) mg: (3-4) mmol.

[0014] Furthermore, the O-arylation coupling reaction is carried out in a sealed environment at a temperature of 70-80 °C for 18-20 h.

[0015] The present invention has the following advantages over the prior art: 1. This invention provides a novel synthetic route, innovatively employing a two-step approach of metal-catalyzed ring-opening and copper-catalyzed O-arylation. This simplifies the process from the outset, reducing the number of intermediate separation and purification steps. Compared to traditional methods using sulfonyl chloride as the leaving group, this invention avoids the generation of stoichiometric sulfonic acid byproducts, making it more environmentally friendly from an atom economy perspective. Furthermore, the key chiral ether bond (CO-Ar) of this invention is constructed at a relatively low temperature (70-80 °C) via a copper-catalyzed coupling reaction, which helps reduce energy consumption and potentially minimizes racemic side reactions at the chiral center caused by high temperatures. This provides a new approach for the stable control of the optical purity of the target product.

[0016] 2. The first step of this invention uses a Lewis acid catalyst to achieve highly selective ring-opening of D-lactide onto sodium octanol, obtaining a chiral intermediate in extremely high yield; the second step utilizes a copper-catalyzed cross-coupling reaction to efficiently construct the key CO-Ar aryl ether bond, providing a simple, efficient, and optically selective new technical approach for the synthesis of this type of chiral phenoxycarboxylic acid ester. Detailed Implementation

[0017] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0018] The preparation process of sodium n-octanol used in this invention is as follows: Dry a 150 mL airtight glass reaction vessel and set it aside. Purify n-octanol by drying with anhydrous magnesium sulfate under reduced pressure. Remove the oxide layer from metallic sodium and cut it into small pieces of approximately 500 mg (0.0217 mol), then immerse them in anhydrous kerosene. Purge the reaction vessel with high-purity argon for 30 minutes to purge air. Quickly add the sodium pieces, then slowly add an equimolar amount of n-octanol while stirring. Stop adding n-octanol when the sodium pieces no longer dissolve and there are no obvious bubbles. Maintain argon protection and recover excess n-octanol by vacuum distillation to obtain a milky white sodium octanol powder. Wash the powder 2-3 times with anhydrous n-hexane, filter, vacuum dry, and then store in a sealed brown bottle containing molecular sieves.

[0019] The preparation process of the CuI / PCN catalyst used in this invention is as follows: Polymeric carbon nitride (PCN) (200 mg) was mixed with 20 mL of deionized water and stirred in a magnetic stirrer for 30 min. Then, CuI (20 mg) was dispersed in 10 mL of acetonitrile and stirred continuously for 15 min. Next, both solutions were sonicated, and the CuI solution was added dropwise to the PCN dispersion while magnetically stirring (about 600 rpm) and heating to above 80°C until the solvent was completely evaporated. The dried product was washed five times with deionized water at 8000 rpm (20 min each time) and finally placed in an 80°C hot air oven overnight.

[0020] The methods for determining the yield, specific rotation, and optical purity of the product of this invention are as follows: (1) Yield: The actual mass of the product obtained in each step of the reaction is determined by weighing, and the yield is calculated based on the theoretical yield.

[0021] (2) All optical rotation tests were performed at room temperature (approximately 25°C) using an automated digital polarimeter equipped with a sodium light source (D line, 589 nm).

[0022] Specific rotation determination: Accurately weigh an appropriate amount of sample, dissolve and dilute to volume with anhydrous ethanol to prepare a solution with a concentration c of 1 g / 100 mL. Measure the rotation using a 1 dm polarimeter tube and read the optical rotation value (α). Calculate using the following formula: , where l is the length of the optical rotator (dm).

[0023] Optical purity determination: The optical purity (OP) of a product is calculated by comparing its measured specific rotation with the specific rotation reported in the literature or with that of a standard sample. Using a standard with an optical purity >99% verified by chiral HPLC, its specific rotation was measured to be +17.5° under the same conditions.

[0024] Example 1 A method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate includes the following steps: (1) Under nitrogen protection, sodium n-octanol (10 mmol) and D(+)-lactide (11 mmol) were added to anhydrous tetrahydrofuran (THF, 20 mL). D(+)-lactide was added in portions to control the reaction to proceed at a mild temperature. Then, tetrabutyl titanate (0.05 mL) was added dropwise. The reaction temperature was maintained at 25 °C and the mixture was stirred continuously for 7 h until the lactide was completely dissolved. After the reaction was completed, 1M hydrochloric acid (10 mL) was added to the system to quench the reaction. The organic phase was extracted with ethyl acetate (3 × 15 mL) through a separatory funnel. The mixture was washed successively with saturated NaHCO3 solution (15 mL) and deionized water (15 mL). After drying with anhydrous MgSO4, the crude product was concentrated under reduced pressure (40 °C / 15 mm Hg) to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to finally obtain octyl (2R)-2-hydroxypropionate, with a yield of 98.0%. 1 H NMR (C 11 H 22 O3, 400MHz, DMSO-d6) δ 4.72(s, 1H), 4.30(q,1H), 4.06(t, 2H), 1.64-1.61(m, 2H), 1.45-1.40(m, 5H), 1.35-1.29(m, 8H), 0.90(t, 3H); HRMS(ESI + ): [M+H] + The calculated value is 203.16, and the value of 203.16 is found; the above results indicate that this is the target compound.

[0025] Take a portion of the purified product and prepare a solution with c = 1.0 g / 100 mL (ethanol) according to the above determination method for testing. = -10.5°.

[0026] (2) Take a dried reaction tube with a screw cap, place a magnetic stir bar inside, and then add 4-chloro-2-methylphenol (0.28 mmol), (2R)-2-hydroxypropionate octyl ester (0.2 mmol), CuI / PCN (1.1 mg, containing 1.4 mol% Cu), potassium tert-butoxide (KOtBu, 0.7 mmol), and 2 mL of anhydrous dioxane in sequence. Seal the reaction tube tightly with a polytetrafluoroethylene-lined screw cap, remove it from the glove box, and place it in a container preheated to 75°C. The reaction mixture was stirred in an oil bath at °C for 19 h. After the reaction was completed, the reaction tube was cooled to room temperature, the cap was removed, and the reaction mixture was transferred to a suitable container. The mixture was concentrated under vacuum using a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1~10:1) to give (R)-2-(4-chloro-2-methylphenoxy)propionate n-octyl ester, with a yield of 91.0%. 1 H NMR (C 18 H 27 ClO3, 400MHz, DMSO-d6) δ 7.35(s, 1H), 7.29(d, 1H), 6.85(d, 1H), 4.89(q,1H), 4.06(t, 2H), 2.20(s, 3H), 1.64-1.60(m, 5H), 1.45-1.40(m, 2H), 1.35-1.29(m, 8H), 0.90(t, 3H); HRMS(ESI + ): [M+H] + The calculated value is 327.16, and the value found is 327.17; the above results indicate that this is the target compound.

[0027] A portion of the purified final product was taken and prepared into a solution with c = 1.0 g / 100 mL (ethanol) for testing. The results were obtained. = +17.2°, optical purity (OP) is 98.3%.

[0028] Example 2 A method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate includes the following steps: (1) Under nitrogen protection, sodium n-octanol (10 mmol) and D(+)-lactide (10 mmol) were added to anhydrous tetrahydrofuran (THF, 20 mL). D(+)-lactide was added in portions to control the reaction to proceed at a mild temperature. Then, a catalytic amount of tetrabutyl titanate (0.05 mL) was added dropwise. The reaction temperature was maintained at 30 °C and the mixture was stirred continuously for 6 h until the lactide was completely dissolved. After the reaction was completed, 1M hydrochloric acid (10 mL) was added to the system to quench the reaction. The organic phase was extracted with ethyl acetate (3 × 15 mL) through a separatory funnel. The mixture was washed successively with saturated NaHCO3 solution (15 mL) and deionized water (15 mL). After drying with anhydrous MgSO4, the crude product was concentrated under reduced pressure (40 °C / 15 mm Hg) to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to finally obtain octyl (2R)-2-hydroxypropionate with a yield of 97.2%.

[0029] Take a portion of the purified product and prepare a solution with c = 1.0 g / 100 mL (ethanol) according to the above determination method for testing. = -10.2°.

[0030] (2) Take a dried reaction tube with a screw cap, place a magnetic stir bar inside, and then add 4-chloro-2-methylphenol (0.25 mmol), (2R)-2-hydroxypropionate octyl ester (0.2 mmol), CuI / PCN (1.0 mg, containing 1.4 mol% Cu), potassium tert-butoxide (KOtBu, 0.6 mmol), and 2 mL of anhydrous dioxane in sequence. Seal the reaction tube tightly with a polytetrafluoroethylene-lined screw cap, remove it from the glove box, and place it in a container preheated to 70°C. The reaction was stirred in an oil bath at °C for 20 h. After the reaction was completed, the reaction tube was cooled to room temperature, the cap was removed, and the reaction mixture was transferred to a suitable container. The mixture was concentrated under vacuum using a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1~10:1) to give (R)-2-(4-chloro-2-methylphenoxy)propionate n-octyl ester, with a yield of 90.2%.

[0031] A portion of the purified final product was taken and prepared into a solution with c = 1.0 g / 100 mL (ethanol) for testing. The results were obtained. = +16.8°, optical purity (OP) is 96.0%.

[0032] Example 3 A method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate includes the following steps: (1) Under nitrogen protection, sodium n-octanol (10 mmol) and D(+)-lactide (12 mmol) were added to anhydrous tetrahydrofuran (THF, 20 mL). D(+)-lactide was added in portions to control the reaction to proceed at a mild temperature. Then, a catalytic amount of tetrabutyl titanate (0.06 mL) was added dropwise. The reaction temperature was maintained at 25 °C and the mixture was stirred continuously for 8 h until the lactide was completely dissolved. After the reaction was completed, 1M hydrochloric acid (10 mL) was added to the system to quench the reaction. The organic phase was extracted with ethyl acetate (3 × 15 mL) through a separatory funnel. The mixture was washed successively with saturated NaHCO3 solution (15 mL) and deionized water (15 mL). After drying with anhydrous MgSO4, the crude product was concentrated under reduced pressure (40 °C / 15 mm Hg) to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to finally obtain octyl (2R)-2-hydroxypropionate with a yield of 96.2%.

[0033] Take a portion of the purified product and prepare a solution with c = 1.0 g / 100 mL (ethanol) according to the above determination method for testing. = -9.8°.

[0034] (2) Take a dried reaction tube with a screw cap, put a magnetic stir bar into it, and then add 4-chloro-2-methylphenol (0.3 mmol), (2R)-2-hydroxypropionate octyl ester (0.2 mmol), CuI / PCN (1.2 mg, containing 1.4 mol% Cu), potassium tert-butoxide (KOtBu, 0.8 mmol) and 3 mL of anhydrous dioxane in sequence. Seal the reaction tube tightly with a polytetrafluoroethylene-lined screw cap, take it out of the glove box, and stir it in an oil bath preheated to 80 °C for 18 h. After the reaction is completed, cool the reaction tube to room temperature, remove the cap, transfer the reaction mixture to a suitable container, concentrate it under vacuum using a rotary evaporator, and purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1~10:1) to obtain (R)-2-(4-chloro-2-methylphenoxy)propionate n-octyl ester with a yield of 90.8%.

[0035] A portion of the purified final product was taken and prepared into a solution with c = 1.0 g / 100 mL (ethanol) for testing. The results were obtained. = +17.1°, optical purity (OP) is 97.7%.

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.

Claims

1. A method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate, characterized in that, Includes the following steps: (1) In the presence of a Lewis acid catalyst, D(+)-lactide was reacted with sodium n-octanol to undergo a ring-opening reaction to obtain octyl (2R)-2-hydroxypropionate; (2) In the presence of a copper catalyst and an inorganic base, octyl (2R)-2-hydroxypropionate is subjected to an O-arylation coupling reaction with 4-chloro-2-methylphenol to obtain octyl 2-(4-chloro-2-methylphenoxy)propionate.

2. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 1, characterized in that, The Lewis acid catalyst mentioned in step (1) is tetrabutyl titanate.

3. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 2, characterized in that, The molar ratio of D-lactide and sodium n-octanol in step (1) is (1-1.2):1; the molar ratio of sodium n-octanol to catalyst is 10 mmol: (0.05-0.06) mL.

4. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 1, characterized in that, The ring-opening reaction in step (1) is carried out at a temperature of 25-30 °C for 6-8 h.

5. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 1, characterized in that, The copper catalyst in step (2) comprises a monovalent copper salt and carbon nitride material; the inorganic base is selected from any one of potassium tert-butoxide, sodium tert-butoxide or sodium methoxide.

6. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 5, characterized in that, The carbon nitride material is polymeric carbon nitride.

7. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 5, characterized in that, The ratio of (2R)-2-hydroxypropionate octyl ester, 4-chloro-2-methylphenol, copper catalyst and inorganic base in step (2) is 1 mmol: (1.25-1.5) mmol: (5-6) mg: (3-4) mmol.

8. The method for synthesizing octyl 2-(4-chloro-2-methylphenoxy)propionate according to claim 1, characterized in that, The O-arylation coupling reaction was carried out in a sealed environment at a temperature of 70-80 °C for 18-20 h.

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