Synthesis method of (5S, 6R)-5, 6-epoxy-2-heptadecene-1-alcohol

Abstract

The invention discloses a synthesis method of (5S, 6R)-5, 6-epoxy-2-heptadecene-1-alcohol, which is characterized in that (2S, 3R)-p-toluenesulfonic acid-1, 2-epoxy-3-tetradecanol ester and substituted phenyl propargyl ether are used as raw materials to carry out nucleophilic addition ring-opening reaction, so that the yield is high; alcohol and an alkali system react at room temperature to carry out Williamson ether synthesis ring closing reaction, the operation is simple and convenient, the yield is good, and the chemical properties of all intermediates are stable; the substituted phenyl is mildly removed in the mixed solvent by using the oxidizing agent, the reaction is mild and controllable, and the yield is high. The method is low in production cost, has good economic benefits and can be popularized and applied.

Description

Technical Field

[0001] The invention relates to the fields of chemical production technology and biological pesticides, and in particular to a method for synthesizing (5S, 6R)-5,6-epoxy-2-heptadecane-1-ol. Background Art

[0002] The American gypsy moth, Hyphantria cunea (Drury), belongs to the order Lepidoptera and the family Arctiidae. It is an important international quarantine pest. It has a omnivorous diet, a large appetite, strong reproductive capacity, wide adaptability, fast spread, and serious damage. The American gypsy moth has a wide range of hosts. Its favorite tree species include poplar, mulberry, sycamore, and white wax maple. In addition, it also harms broad-leaved tree species such as willow, locust, camptotheca, and Ailanthus. In addition to forests and fruit trees, it also harms crops and vegetables. The larvae of the American gypsy moth have a large appetite. When a large outbreak occurs, they can eat all the leaves of the entire plant overnight, causing poor growth and development of the plant. In severe cases, it can even cause the death of trees and poor harvests of crops and vegetables, causing serious damage.

[0003] The invasion and spread of the gypsy moth are very diverse. Strengthening pest monitoring is the basic work of preventing and controlling the gypsy moth, and is of great significance for taking timely prevention and control measures to prevent the spread of the epidemic. Among them, using gypsy moth sex traps to trap and monitor male adults is a mature monitoring technology with high accuracy and significant effects.

[0004] The main attractant active ingredients of the sex pheromone of the American white moth are (3Z,6Z,9S,10R)-9,10-epoxy-3,6-heneicosadiene and (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicostriene, both of which need to be obtained from the key intermediate (5S,6R)-5,6-epoxy-2-heptadecyn-1-ol (4) through five steps of reaction (Scheme 1): The key intermediate 4 is a white solid at room temperature with a melting point of 69-70°C. The synthesis method reported in the literature is as follows: In a hexamethylphosphoric acid triamide and ether solvent system, (2S,3R)-2,3-epoxytetradecyl trifluoroacetate and propargyl trimethylsiloxy ether are used as raw materials and n-butyl lithium is used as a base to synthesize (5S,6R)-5,6-epoxy-2-heptadecan-1-ol [J.Org.Chem.2010,75,4619-4622]. The (2S,3R)-2,3-epoxytetradecyl trifluoroacetate involved in the reaction is easily deteriorated in the air after purification, and is difficult to store and scale up production; therefore, it is of great practical significance to develop an efficient and stable method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecan-1-ol and realize industrial production.

[0005] Summary of the invention

[0006] In view of the deficiencies in the prior art, the technical problem to be solved by the present invention is: how to obtain (5S, 6R)-5,6-epoxy-2-heptadecan-1-ol with simple reaction steps and obtain relatively high yield and purity as well as good stability.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecan-1-ol is provided. The method comprises taking substituted phenyl propargyl ether and (2S,3R)-p-toluenesulfonic acid-1,2-epoxy-3-tetradecyl ester shown in formula 1 as raw materials, carrying out a nucleophilic addition reaction in the presence of a base and boron trifluoride etherate to generate an intermediate compound 2, then carrying out a Williamson ether reaction under the action of a base to close the ring to generate an intermediate compound 3, and finally removing the substituted phenyl under the action of an oxidant to obtain a compound 4, namely the (5S,6R)-5,6-epoxy-2-heptadecan-1-ol. The reaction formula is as follows:

[0009]

[0010] The substituents on the benzene ring of the substituted phenyl propargyl ether are the same as the substituents R on the benzene ring of compound 2 and compound 3, the number of substituents R is 1-5, and each substituent R is independently selected from hydrogen, C1-C4 alkyl or C1-C4 alkoxy.

[0011] Furthermore, the synthesis method of (5S, 6R)-5,6-epoxy-2-heptadecan-1-ol specifically comprises the following steps:

[0012] 1) Under low temperature, argon protection, and the presence of a base and boron trifluoride etherate, a substituted phenyl propargyl ether and the (2S, 3R)-p-toluenesulfonic acid-1,2-epoxy-3-tetradecyl alcohol ester shown in formula 1 undergo a nucleophilic addition reaction in an organic solvent. After the reaction is completed, a saturated aqueous solution of ammonium chloride is added to the reaction solution in an ice bath to quench the reaction, and an organic extractant is used for extraction. The organic phases are combined, washed with saturated brine, dried, and concentrated to a viscous state to obtain a viscous product containing compound 2;

[0013] 2) The viscous product of step 1) is dissolved in an organic solvent, and a base is added and stirred at room temperature to cause a Williamson ether reaction to close the ring. After the reaction is completed, the product is filtered and concentrated to remove the organic solvent to obtain a concentrate containing compound 3;

[0014] 3) dissolving the concentrate described in step 2) in a mixed solvent, cooling to an ice bath, and performing a reaction of removing the substituted phenyl group in the presence of an oxidant. After the reaction is completed, post-treatment is performed to obtain compound 4, which is the (5S, 6R)-5,6-epoxy-2-heptadecan-1-ol.

[0015] Further, the low temperature in step 1) is -80°C to 0°C, preferably -80°C to -70°C, the base is n-butyl lithium, the organic solvent is diethyl ether or tetrahydrofuran, and the dispersion concentration of the compound of formula 1 in the organic solvent is 0.05-0.5 g / mL, preferably 0.08-0.2 g / mL;

[0016] The molar ratio of the base to the compound of formula 1 is 1-4:1, preferably 2-3:1;

[0017] The ratio of the volume of the boron trifluoride etherate to the molar amount of the compound of formula 1 is 0.1-0.5 mL:1 mmol, preferably 0.3-0.4 mL:1 mmol.

[0018] Furthermore, in step 1), the molar ratio of the compound of formula 1 to the substituted phenyl propargyl ether is 1:1-4, and the number of the substituent R is 1, selected from hydrogen, methyl, ethyl, isopropyl or methoxy.

[0019] Furthermore, the organic extractant in step 1) is diethyl ether.

[0020] Furthermore, the organic solvent in step 2) is methanol or ethanol, the base in step 2) is potassium carbonate, sodium carbonate or sodium hydroxide, and the molar ratio of the base in step 2) to the compound of formula 1 in step 1) is 5-10:1, preferably 8-9:1.

[0021] Furthermore, the reaction time of step 2) is 20-50 min, preferably 30-35 min.

[0022] Furthermore, the mixed solvent in step 3) is acetonitrile / water with a volume ratio of 5-20:1.

[0023] Furthermore, the oxidant in step 3) is ammonium cerium nitrate, dichlorodicyanobenzoquinone or Oxone, the molar ratio of the oxidant in step 3) to the compound of formula 1 in step 1) is 3-10:1, preferably 5-6:1, and the reaction time in step 3) is 20-50 min, preferably 30-35 min.

[0024] Furthermore, the post-treatment step in step 3) is: adding saturated sodium bicarbonate aqueous solution to quench the reaction, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous magnesium sulfate, concentrating, and purifying by column chromatography to obtain the target product, wherein the eluent for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5-20:1.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) A benzene ring-containing structure is used to undergo a nucleophilic addition reaction with compound 1 to form a double benzene ring structure, and a substituted phenyl group can still be retained for ultraviolet color development in the subsequent Williamson ether synthesis ring-closing reaction, which is convenient for monitoring the reaction in actual production;

[0027] (2) The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecan-1-ol provided by the present invention requires only simple post-treatment after the first two steps of reaction, and no special column chromatography purification treatment is required, which does not affect the yield of the final product. The three-step reaction is similar to a "one-pot" treatment method to obtain the final product (5S,6R)-5,6-epoxy-2-heptadecan-1-ol, which reduces the loss in the purification process, is simple to operate, and is suitable for large-scale production;

[0028] (3) The reaction conditions of Williamson ether reaction and ammonium cerium nitrate dephenylation are mild and controllable, and the yield is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the NMR detection spectrum of (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol. DETAILED DESCRIPTION

[0030] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0031] Example 1 Synthesis of Compound 2 (R = hydrogen, p-methoxy):

[0032] 4.8 g of p-methoxyphenyl propargyl ether was dissolved in 30 ml of tetrahydrofuran, cooled to -78°C, and 12 ml of 2.5 M n-butyl lithium / n-hexane solution was added dropwise within 30 minutes. After the addition was completed, the mixture was stirred and reacted for 1 hour. 10 ml of tetrahydrofuran solution containing 3.8 g of compound 1 was added dropwise, and after the addition was completed, 3.7 ml of boron trifluoride ether was added dropwise, and the mixture was reacted at -78°C for 5 hours. 20 ml of saturated ammonium chloride aqueous solution was added dropwise under an ice bath to quench the reaction, and the mixture was extracted with ether. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 10:1) to obtain 4.6 g of compound 2 (85% yield). 1H-NMR (400MHz, CDCl3): δ7.82-7.72(m,2H),7.30(d,J=8.1Hz,2H),6.94-6.86(m,2H),6.86-6.79(m,2H),4.67-4.54(m,3H),3.80(td,J=6.1 ,4.0Hz,1H),3.75(s,3H),2.42(s,4H),1.68(q,J=10.3,7.7Hz,1H),1.54(dt,J=15.0,8.0Hz,1H),1.37-1.02(m,16H),0.88(t,J=6.8Hz,3H).

[0033] Example 2 Synthesis of Compound 2 (R = Hydrogen):

[0034] 3.9 g of phenyl propargyl ether was dissolved in 30 ml of tetrahydrofuran, cooled to -78°C, and 12 ml of 2.5 M n-butyl lithium / n-hexane solution was added dropwise within 30 minutes. After the addition was completed, the mixture was stirred and reacted for 1 hour. 10 ml of tetrahydrofuran solution containing 3.8 g of compound 1 was added dropwise, and after the addition was completed, 3.7 ml of boron trifluoride ether was added dropwise, and the mixture was reacted at -78°C for 5 hours. 20 ml of saturated ammonium chloride aqueous solution was added dropwise under an ice bath to quench the reaction, and the mixture was extracted with ether. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 10:1) to obtain 4.3 g of compound 2 (84% yield). 1 H-NMR (400MHz, CDCl3): δ7.87-7.69(m,2H),7.39-7.30(m,4H),7.05-6.95(m,3H),4.72-4.67(m,2H),4.67-4.59(m,1H),3.83(td,J =6.1, 4.1Hz, 1H), 2.46 (s, 4H), 1.68 (q, J = 10.3, 7.7Hz, 1H), 1.54 (dt, J = 15.0, 8.0Hz, 1H), 1.37-1.02 (m, 16H), 0.88 (t, J = 6.8Hz, 3H).

[0035] Example 3 Synthesis of Compound 3 (R = hydrogen, p-methoxy):

[0036] 2.7 g of the compound 2 (R = hydrogen, p-methoxy) synthesized in Example 1 was dissolved in 25 ml of methanol, and 2.1 g of anhydrous potassium carbonate was added at room temperature at one time, stirred for 0.5 hours, filtered, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 4:1) to obtain 1.6 g of compound 3 (86% yield), 1H-NMR (400MHz, CDCl3): δ6.98-6.90(m,2H),6.89-6.81(m,2H),4.65(t,J=2.2Hz,2H),3.79(s,3H),3.15(ddd,J=7.0,5.6,4.1Hz,1H),2.97 (td,J=5.9,4.0Hz,1H),2.64(ddt,J=17.2,5.7,2.2Hz,1H),2.36(ddt,J=17.2,7.0,2.2Hz,1H),1.57-1.18(m,21H),0.90(t,J=6.7Hz,3H).

[0037] Example 4 Synthesis of Compound 3 (R = Hydrogen):

[0038] 2.6 g of the compound 2 (R = hydrogen) synthesized in Example 2 was dissolved in 25 ml of methanol, and 2.1 g of anhydrous potassium carbonate was added at room temperature at one time, stirred for 0.5 hours, filtered, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 4:1) to obtain 1.5 g of compound 3 (86% yield), 1 H-NMR (400MHz, CDCl3): δ7.32-7.25(m,2H),7.05-6.95(dd,J=8.6,7.5Hz,3H),4.65(t,J=2.2Hz,2H),3.12(ddd,J=7.0,5.6,4.1Hz,1H),2.9 5(td,J=5.9,4.0Hz,1H),2.63(ddt,J=17.2,5.7,2.2Hz,1H),2.34(ddt,J=17.2,7.0,2.2Hz,1H),1.59-1.19(m,21H),0.88(t,J=6.7Hz,3H).

[0039] Example 5 Synthesis of Compound 4:

[0040] 0.4 g of compound 3 (R = hydrogen, p-methoxy) synthesized in Example 3 was dissolved in a mixed solvent of acetonitrile / water (10 ml / 1 ml), cooled to 0°C, 1.1 g of cerium ammonium nitrate was added at once, stirred for 0.5 hours, quenched with 20 ml of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, combined organic phases, washed once with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 10:1) to obtain 0.26 g of compound 4 (93% yield). The NMR spectrum of the product (5S, 6R)-5,6-epoxy-2-heptadecan-1-ol is shown as follows: Figure 1 As shown by Figure 1 It can be seen that:

[0041] 1H-NMR (400MHz, CDCl3): δ4.26 (t, J=2.4Hz, 2H), 3.13 (td, J=6.3, 4.2Hz, 1H), 3. 02-2.90(m,1H),2.59(ddd,J=17.1,5.5,2.6Hz,1H),2.40-2.27(m,1H),1.71(br s, 2H), 1.59-1.13 (m, 21H), 0.87 (t, J = 6.7Hz, 3H).

[0042] Example 6 Synthesis of Compound 4

[0043] 0.4 g of compound 3 (R = hydrogen) synthesized in Example 4 was dissolved in a mixed solvent of acetonitrile / water (10 ml / 1 ml), cooled to 0°C, 1.1 g of cerium ammonium nitrate was added at one time, stirred for 0.5 hour, and the reaction was quenched with 20 ml of saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 10:1) to obtain 0.26 g of compound 4 (94% yield).

[0044] Example 7 "One-pot" synthesis of (5S,6R)-5,6-epoxy-2-heptadecan-1-ol

[0045] 4.8 g of p-methoxyphenyl propargyl ether was dissolved in 30 ml of tetrahydrofuran, cooled to -78°C, and 12 ml of 2.5 M n-butyl lithium / n-hexane solution was added dropwise within 30 minutes. After the addition was completed, the mixture was stirred and reacted for 1 hour. 10 ml of tetrahydrofuran solution containing 3.8 g of compound 1 was added dropwise, and after the addition was completed, 3.7 ml of boron trifluoride ether was added dropwise, and the mixture was reacted at -78°C for 5 hours. 20 ml of saturated ammonium chloride aqueous solution was added dropwise under ice bath to quench the reaction, and the mixture was extracted with ether. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to a viscous state. The mixture was dissolved in 30 ml of methanol, and 12.4 g of anhydrous potassium carbonate was directly added at room temperature. The mixture was stirred for half an hour, filtered, concentrated to remove methanol, and then dissolved in a mixed solvent of acetonitrile / water (30 ml / 3 ml), cooled to 0°C, and 31.4 g of ammonium cerium nitrate was added. The mixture was stirred for 0.5 hour, and the reaction was quenched with 60 ml of saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (V (petroleum ether): (ethyl acetate) = 10:1) to obtain 1.84 g of compound 4 (70% total yield).

[0046] Through the innovative route of the present invention, the synthetic stability of (5S,6R)-5,6-epoxy-2-heptadecan-1-ol is greatly improved. The reaction can be carried out in a "one-pot method", the difficulty of experimental operation is greatly reduced, and it is suitable for industrial application.

[0047] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecan-1-ol, characterized in that: Substituted phenyl propargyl ether and (2S,3R)-p-toluenesulfonic acid-1,2-epoxy-3-tetradecyl alcohol ester shown in formula 1 are used as raw materials, and a nucleophilic addition reaction occurs in the presence of a base and boron trifluoride ether to generate an intermediate compound 2, and then a Williamson ether reaction occurs under the action of a base to close the ring to generate an intermediate compound 3, and finally the substituted phenyl is removed under the action of an oxidant to obtain a compound 4, namely the (5S,6R)-5,6-epoxy-2-heptadecan-1-ol, and the reaction formula is as follows: The substituents on the benzene ring of the substituted phenyl propargyl ether are the same as the substituents R on the benzene ring of compound 2 and compound 3, the number of substituents R is 1-5, and each substituent R is independently selected from hydrogen, C1-C4 alkyl or C1-C4 alkoxy.

2. The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol according to claim 1, characterized in that: The specific steps include: 1) Under low temperature, argon protection, and the presence of a base and boron trifluoride etherate, a substituted phenyl propargyl ether and the (2S, 3R)-p-toluenesulfonic acid-1,2-epoxy-3-tetradecyl alcohol ester shown in formula 1 undergo a nucleophilic addition reaction in an organic solvent. After the reaction is completed, a saturated aqueous solution of ammonium chloride is added to the reaction solution in an ice bath to quench the reaction, and an organic extractant is used for extraction. The organic phases are combined, washed with saturated brine, dried, and concentrated to a viscous state to obtain a viscous product containing compound 2; 2) The viscous product of step 1) is dissolved in an organic solvent, and a base is added and stirred at room temperature to cause a Williamson ether reaction to close the ring. After the reaction is completed, the product is filtered and concentrated to remove the organic solvent to obtain a concentrate containing compound 3; 3) dissolving the concentrate described in step 2) in a mixed solvent, cooling to an ice bath, and performing a reaction of removing the substituted phenyl group in the presence of an oxidant. After the reaction is completed, post-treatment is performed to obtain compound 4, which is the (5S, 6R)-5,6-epoxy-2-heptadecan-1-ol.

3. A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol as claimed in claim 1, characterized in that: The low temperature in step 1) is -80°C to 0°C, preferably -80°C to -70°C, the base is n-butyl lithium, the organic solvent is diethyl ether or tetrahydrofuran, and the dispersion concentration of the compound of formula 1 in the organic solvent is 0.05-0.5 g / mL, preferably 0.08-0.2 g / mL; The molar ratio of the base to the compound of formula 1 is 1-4:1, preferably 2-3:1; The ratio of the volume of the boron trifluoride etherate to the molar amount of the compound of formula 1 is 0.1-0.5 mL:1 mmol, preferably 0.3-0.4 mL:1 mmol.

4. A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol as claimed in claim 1, characterized in that: In step 1), the molar ratio of the compound of formula 1 to the substituted phenyl propargyl ether is 1:1-4, and the number of the substituent R is 1, selected from hydrogen, methyl, ethyl, isopropyl or methoxy.

5. The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol according to claim 1, characterized in that: The organic extractant in step 1) is ether.

6. A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol as claimed in claim 1, characterized in that: The organic solvent in step 2) is methanol or ethanol, the base in step 2) is potassium carbonate, sodium carbonate or sodium hydroxide, and the molar ratio of the base in step 2) to the compound of formula 1 in step 1) is 5-10:1, preferably 8-9:

1.

7. A method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol as claimed in claim 1, characterized in that: Step 2) The reaction time is 20-50 min, preferably 30-35 min.

8. The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol according to claim 1, characterized in that: The mixed solvent in step 3) is acetonitrile / water with a volume ratio of 5-20:

1.

9. The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol according to claim 1, characterized in that: The oxidant in step 3) is ammonium cerium nitrate, dichlorodicyanobenzoquinone or Oxone, the molar ratio of the oxidant in step 3) to the compound of formula 1 in step 1) is 3-10:1, preferably 5-6:1, and the reaction time in step 3) is 20-50 min, preferably 30-35 min.

10. The method for synthesizing (5S,6R)-5,6-epoxy-2-heptadecyne-1-ol according to claim 1, characterized in that: The post-treatment step in step 3) is: adding saturated sodium bicarbonate aqueous solution to quench the reaction, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous magnesium sulfate, concentrating, and purifying by column chromatography to obtain the target product, wherein the eluent for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5-20:1.

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