A process for the preparation of spirodiclofen (2E,6Z,8E)-N-isobutyl-2,6,8-decatrienamide

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of spilanthol amide (2E, 6Z, 8E)-N-isobutyl-2, 6, 8-decatrienamide. The synthesis route of spilanthol amide is too long, and the operation is complex, so that the industrialized production is not easy. In view of the above problems, the application provides a preparation method of spilanthol amide (2E, 6Z, 8E)-N-isobutyl-2, 6, 8-decatrienamide. The target product is successfully synthesized through seven steps of quaternary phosphonium salt reaction, Wittig reaction, Wittig-horner reaction, dehydration condensation and the like, with cheap and easily obtained 4-bromobutyric acid ethyl ester as raw material. Each reaction condition is simple, and the operation is convenient, so that the method is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing genisteinamide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide. Background Technology

[0002] Globe amaranth is one of the nine major plant families, native to South Africa. It is an annual herb now widely cultivated worldwide. Globe amaranth extract has a strong stimulating and numbing effect, and is used to treat toothaches and headaches. Recent studies have found that globe amaranth extract improves dermal structure and firms the skin by stimulating fibroblast activity, and has therapeutic effects on dermatitis, free radical scavenging, and antioxidant properties that alleviate aging. Therefore, it is considered a natural alternative to botulinum toxin and is increasingly being used in various cosmetics.

[0003] There have been reports on the artificial synthesis of frans-affinin. In 1954, Martin et al. identified the structure of frans-affinin and provided a synthetic method. The raw materials for this synthetic route are readily available and easy to scale up, but the synthetic route is relatively long, and the final product has slight differences from the currently believed structure (Martin Jacobson. Constituents of Heliopsis Species. IV. The Total Synthesis of frans-affinin. J. Am. Chem. Soc., 2461-2463. (1955)).

[0004] In 1986, Yoshihiko Ikeda et al. provided a method for synthesizing 1,4-disubstituted 1,3-Diene from Aldehyde using a more ingenious approach to the construction of the two double bonds in the target product. However, the reactants used in this method were very expensive, and the steps were cumbersome, which was not conducive to industrial production (Yoshihiko Ikeda et al. Stereoselective Synthesis of 1,4-disubstituted 1,3-Diene from Aldehyde Using Organotitanium Reagent (Tetrahedron, 731-741 (1987)).

[0005] The above-mentioned synthetic routes for chamomile amide are too long and complicated. In order to obtain a large amount of active ingredients for further research, this invention explores a low-cost, efficient, simple, and easy-to-industrialize method for synthesizing chamomile amide. Summary of the Invention

[0006] The existing technology has the problem that the synthetic route of chamomile amide is too long and the operation is complicated, making it difficult to carry out industrial production. To address the above problems, this invention provides a method for preparing chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide, comprising the following steps:

[0007] (1) 4-Halobutyrate ethyl ester reacts with triphenylphosphine under reflux in an organic solvent to produce 4-(acetoxy)-butyltriphenylphosphine halide salt;

[0008] (2) Under nitrogen or an inert atmosphere, 4-acetyl-butyltriphenyl phosphonium halide reacts with crotonaldehyde in the presence of an alkaline environment to give (4Z,6E)-octadienoic acid ethyl ester;

[0009] (3) (4Z,6E)-octadienoic acid ethyl ester undergoes irreversible hydrolysis under alkaline conditions to give (4Z,6E)-octadienol;

[0010] (4) (4Z,6E)-octadienol is oxidized to (4Z,6E)-octadienal by an oxidizing agent;

[0011] (5) (4Z,6E)-octadienal reacts with triethyl phosphonoacetate in the presence of sodium hydride to give ethyl (2E,4Z,6E)-dectrienoate.

[0012] (6) (2E,4Z,6E)-decorienoic acid ethyl ester undergoes irreversible hydrolysis under alkaline conditions to give (2E,4Z,6E)-decorienoic acid;

[0013] (7) (2E,4Z,6E)-decytrienoic acid and isobutylamine undergo dehydration condensation under the action of a catalyst to obtain the target product.

[0014] Specifically, the ethyl 4-halobutyrate includes at least one of ethyl 4-bromobutyrate and ethyl 4-chlorobutyrate.

[0015] Specifically, the organic solvent mentioned in step (1) includes at least one of acetonitrile, tetrahydrofuran, and toluene.

[0016] Specifically, the temperature range for heating and reflux in step (1) is 80-90℃.

[0017] Specifically, the alkali mentioned in step (2) includes at least one of potassium tert-butoxide, sodium methoxide, and sodium ethoxide.

[0018] Specifically, the solvent used in step (2) includes at least one of THF and toluene.

[0019] Specifically, the alkali used in the irreversible hydrolysis of step (3) includes at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0020] Specifically, the solvent for the irreversible hydrolysis reaction is an aqueous methanol solution.

[0021] Specifically, the reaction solvent of Wittig-Horner in step (5) includes at least one of THF, N,N-dimethylformamide, and toluene.

[0022] Specifically, the catalyst mentioned in step (7) includes at least one of EDCI and DCC.

[0023] Specifically, the synthetic route for the genistein amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide is as follows:

[0024]

[0025] The present invention has the following beneficial effects:

[0026] This invention uses inexpensive and readily available ethyl 4-bromobutyrate as a raw material and successfully synthesizes the target product through seven steps: quaternary phosphonate reaction, Wittig reaction, irreversible alkaline hydrolysis, oxidation, Wittig-Horner reaction, hydrolysis, and dehydration condensation. Each step of the reaction has simple reaction conditions, is easy to operate, and is suitable for industrial-scale production. Detailed implementation method:

[0027] The present invention will be described in detail below with reference to embodiments. However, it should be understood that the following embodiments are merely illustrative examples of implementation of the present invention and are not intended to limit the scope of the present invention.

[0028] Step 1: Synthesis of 4-acetyl-butyltriphenylphosphonium halide salts

[0029] Example 1: Synthesis of 4-acetyl-butyltriphenylphosphonium bromide salt

[0030] Under a nitrogen atmosphere, ethyl 4-bromobutyrate (25 g, 128 mmol), triphenylphosphine (40 g, 154 mmol), and acetonitrile (100 mL) were added to a 500 mL single-necked flask. The mixture was heated and stirred in an oil bath at 90 °C for 48 h. After the reaction was completed, the acetonitrile was removed by vacuum distillation. 200 mL of toluene was added to the remaining yellow oily product, and the mixture was stirred and cooled to room temperature. The mixture was filtered to precipitate a white solid product. The obtained white solid product was dried under reduced pressure to give 53.1 g of 4-acetyl-butyltriphenylphosphonium bromide, designated as compound 2a, with a purity of 95% and a yield of 91%.

[0031] Example 2: Same as Example 1, except that the solvent used in Example 2 is an equal volume of tetrahydrofuran, and compound 2a is obtained by filtration and purification with a purity of 95% and a yield of 62%.

[0032] Example 3: Same as Example 1, except that the solvent used in Example 3 is an equal volume of toluene. Compound 2a was obtained by filtration and purification with a purity of 95% and a yield of 82%.

[0033] Example 4: Synthesis of 4-acetyl-butyltriphenylphosphonium chloride

[0034] Under a nitrogen atmosphere, ethyl 4-chlorobutyrate (25 g, 166 mmol), triphenylphosphine (52.4 g, 199 mmol), and acetonitrile (100 mL) were added to a 500 mL single-necked flask. The mixture was heated and stirred in an oil bath at 90 °C for 48 h. After the reaction was completed, the acetonitrile was removed by vacuum distillation. 200 mL of toluene was added to the remaining yellow oily product, and the mixture was cooled to room temperature. The mixture was filtered to precipitate a white solid product. The obtained white solid product was dried under reduced pressure to give 56.7 g of 4-acetyl-butyltriphenylphosphonium chloride, designated as compound 2b, with a purity of 95% and a yield of 83%.

[0035] Example 5: Same as Example 4, except that the solvent used in Example 5 is an equal volume of tetrahydrofuran, and compound 2a is obtained by filtration and purification with a purity of 95% and a yield of 42%.

[0036] Example 6: Same as Example 4, except that the solvent used in Example 6 is an equal volume of toluene. Compound 2a was obtained by filtration and purification with a purity of 95% and a yield of 64%.

[0037] Step 2, Synthesis of (4Z,6E)-Octadienoic Acid Ethyl Ester

[0038] Example 7: Under a nitrogen atmosphere, compound 2a (53.1 g, 116 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. Stirring was started at room temperature, and potassium tert-butoxide (15.7 g, 140.8 mmol) was slowly added. After the addition was complete, the temperature of the reaction system was lowered to 0 °C, and the reaction was stirred at this temperature for 30 min. Then, crotonaldehyde (22.2 g, 128 mmol) was added dropwise. After the addition was complete, the reaction was stirred at this temperature again, and the reaction was monitored by gas chromatography. The reaction proceeded until compound 2a in the reaction system was completely consumed. Then, a saturated ammonium chloride aqueous solution was added to the reaction system to quench the reaction. The organic phase was collected and concentrated. Then, 100 mL of n-hexane was added to the concentrate, and the filtrate was collected by vacuum filtration. After the filtrate was concentrated under reduced pressure, it was then subjected to silica gel column chromatography to obtain 14.2 g of (4Z,6E)-octadienoic acid ethyl ester, denoted as compound 3. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 96% and a yield of 73%.

[0039] Example 8: Same as Example 7, except that the base used in Example 8 is an equimolar amount of sodium methoxide, and compound 3 is obtained by column chromatography purification with a purity of 95% and a yield of 65%.

[0040] Example 9: Same as Example 7, except that the base used in Example 9 is an equimolar amount of sodium ethoxide, and compound 3 is obtained by column chromatography purification with a purity of 95% and a yield of 61%.

[0041] Example 10: Under a nitrogen atmosphere, compound 2b (56.7 g, 136 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. Potassium tert-butoxide (15.7 g, 140.8 mmol) was slowly added while stirring at room temperature. After the addition was complete, the temperature was lowered to 0 °C and stirred at a constant temperature for 30 min. Then, crotonaldehyde (22.2 g, 128 mmol) was added dropwise. After the addition was complete, the reaction was stirred at a constant temperature. The reaction was monitored by gas chromatography. After compound 2b reacted completely, a saturated ammonium chloride aqueous solution was added to the reaction product to quench the reaction. The organic phase was collected and concentrated. Then, 100 mL of n-hexane was added to the concentrate, and the filtrate was collected by vacuum filtration. The filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 9.8 g of compound 3. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 95% and a yield of 43%.

[0042] Example 11: Same as Example 10, except that the base used in Example 11 is an equimolar amount of sodium methoxide, and compound 3 is obtained by column chromatography purification with a purity of 95% and a yield of 55%.

[0043] Example 12: Same as Example 10, except that the base used in Example 12 was an equimolar amount of sodium ethoxide, and compound 3 was obtained by column chromatography purification with a purity of 95% and a yield of 49%.

[0044] Step 3, Synthesis of (4Z,6E)-octadienol

[0045] Example 13: Compound 3 (24 g, 142 mmol), sodium hydroxide (17 g, 426 mmol), water (50 mL), and methanol (50 mL) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 3 h. The reaction was monitored by gas chromatography. The reaction ended when compound 3 was completely consumed. Then, 50 mL of 4 M hydrochloric acid aqueous solution was added to the reaction system to quench the reaction and separate the organic phase. 100 mL of n-hexane was added to the aqueous phase to extract the organic phase. The organic phases were combined and washed successively with saturated brine, water, dried with anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography to obtain 16 g of (4Z,6E)-octadienol, designated as compound 4. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1, with a purity of 95% and a yield of 93%.

[0046] Step 4, Synthesis of (4Z,6E)-Octadienal

[0047] Example 14: Compound 4 (16 g, 126 mmol), sodium acetate (3.1 g, 37.8 mmol), silica gel (30 g), and dichloromethane (100 mL) were added to a 100 mL single-necked flask. Then, under ice-water bath conditions, pyridinium chlorochromate salt (40.8 g, 189 mmol) was slowly added in four batches of 10.2 g each. After the addition was complete, the mixture was stirred at a constant temperature for 3 h. The reaction was monitored by gas chromatography. After compound 4 was consumed, the solid was removed by filtration. The filtrate was concentrated and then subjected to silica gel column chromatography to obtain 10.6 g of (4Z,6E)-octadienal, designated as compound 5. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 95% and a yield of 68%.

[0048] Example 15: Same as Example 14, except that in Example 15, the molar ratio of compound 4 to pyridinium chlorochromate is 1:1.2. After the reaction is complete, compound 5 is obtained with a purity of 95% and a yield of 49%.

[0049] Example 16: Same as Example 14, except that in Example 16, the molar ratio of compound 4 to pyridinium chlorochromate is 1:1.3. After the reaction is complete, compound 5 is obtained with a purity of 95% and a yield of 55%.

[0050] Example 17: Same as Example 14, except that in Example 17, the molar ratio of compound 4 to pyridinium chlorochromate is 1:1.4. After the reaction is complete, compound 5 is obtained with a purity of 95% and a yield of 63%.

[0051] Step 5, Synthesis of (2E,4Z,6E)-decytrienoic acid ethyl ester

[0052] Example 18: Under nitrogen protection, sodium hydride (3.5 g, 147.5 mmol) and dry tetrahydrofuran (50 mL) were added to a 100 mL three-necked flask. The mixture was cooled to 0 °C, and triethyl phosphonoacetate (33 g, 147.5 mmol) was added dropwise over 30 min. Then, compound 5 (12.2 g, 98.3 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h. The reaction was monitored by gas chromatography until compound 5 was eliminated. After the reaction was exhausted, saturated ammonium chloride aqueous solution was added to quench the reaction. The organic phase was separated and extracted with 100 mL of n-hexane. The organic phases were combined and washed twice with deionized water, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain 12.0 g of (2E,4Z,6E)-decytrienoic acid ethyl ester, designated as compound 6. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 95% and a yield of 73%.

[0053] Example 19: Under nitrogen protection, sodium hydride (3.7 g, 154 mmol) and N,N-dimethylformamide (50 mL) were added to a 100 mL three-necked flask. The mixture was cooled to 0 °C, and triethyl phosphonoacetate (34.5 g, 154 mmol) was added dropwise over 30 min. Then, compound 5 (12.7 g, 102 mmol) was added dropwise. The mixture was kept at 0 °C and stirred for 2 h. The reaction was monitored by gas chromatography. After compound 5 was consumed, a saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was allowed to stand and the organic phase was separated. 100 mL of ethyl acetate was added to the aqueous phase and the organic phase was extracted by further separation. The organic phases were combined, and the obtained organic phase was washed twice with deionized water, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain compound 6. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 95% and a yield of 42%.

[0054] Example 20: Under nitrogen protection, sodium hydride (4.3 g, 179 mmol) and toluene (50 mL) were added to a 100 mL three-necked flask and cooled to 0 °C. Then, triethyl phosphonoacetate (40 g, 179 mmol) was added dropwise while stirring, and the addition was completed within 30 min. Then, compound 5 (14.8 g, 119 mmol) was added dropwise. The reaction was stirred at 0 °C for 2 h. The reaction was monitored by gas chromatography. After compound 5 was consumed, saturated ammonium chloride aqueous solution was added to the reaction system to quench the reaction. After separation, the organic phase was collected. 100 mL of n-hexane was added to the aqueous phase to extract the organic phase. The organic phases were combined, and the obtained organic phase was washed twice with deionized water, dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain compound 6. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1, with a purity of 95% and a yield of 63%.

[0055] Step 6, Synthesis of (2E,4Z,6E)-Decapterenoic Acid

[0056] Example 21: Compound 6 (12 g, 61.9 mmol), sodium hydroxide (7.4 g, 185.7 mmol), water (50 mL), and methanol (50 mL) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by gas chromatography. After compound 6 was consumed, 50 mL of 4 M hydrochloric acid aqueous solution was added to the reaction system to quench the reaction. After separation, the organic phase was collected, and the organic phase was extracted with n-hexane in the aqueous phase. The organic phases were combined, and the obtained organic phase was washed with saturated brine, washed with water, dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain 8.9 g of (2E,4Z,6E)-decytrienoic acid. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1. The purity was 96%, and the yield was 87%.

[0057] Step 7, Synthesis of (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide

[0058] Example 22: Compound 7 (8.9 g, 53.8 mmol), EDCI (15.5 g, 80.7 mmol), and dichloromethane (50 mL) were added to a 100 mL single-necked flask. Isobutylamine (3.9 g, 53.8 mmol) was added dropwise while stirring under ice-water bath conditions. After the addition was complete, the reaction was stirred for 2 h. The reaction was monitored by gas chromatography. After compound 7 was consumed, 50 mL of water was added to the reaction system to quench the reaction. The organic phase was extracted by liquid-liquid extraction. Hexane (50 mL) was added to the aqueous phase to extract the organic phase. The organic phases were combined and washed successively with saturated brine, water, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain 9.8 g of (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1. The purity was 96% and the yield was 83%.

[0059] Example 23: Same as Example 22, except that the condensing agent used in Example 23 is an equimolar amount of DCC. Compound 8 was obtained by column chromatography purification with a purity of 95% and a yield of 75%.

[0060] The NMR spectral data of the (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide are as follows:

[0061] 1HNMR (400MHz, CDCl3): δ6.79-6.72(m,1H),6.23-6.19(m,1H),5.96(m,1H),5.93(m,1H),5.75-5.71(m,1H),5.69-5.60(m ,1H),5.50-5.46(m,1H),3.09-3.06(t,2H),2.26-2.21(m,2H),2.20(m,2H),1.76(m,1H),1.76-1.65(m,3H),0.86(m,6H).

[0062] 13 C-NMR (CDCl3): δ165.97,143.69,131.34,129.97,127.67,126.68,124.11,46.85,32.11,31.96,28.60,26.38,20.14,18.34.

[0063] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing genisteinamide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide, characterized in that, Includes the following steps: (1) 4-Hydrobutylacetate reacts with triphenylphosphine in an organic solvent under reflux to generate 4-(acetoxy)butyltriphenylphosphine halide salt; (2) Under nitrogen or an inert atmosphere, 4-(acetoxy)butyltriphenyl phosphine halide salt reacts with crotonaldehyde in the presence of an alkaline environment to give (4Z,6E)-octadienyl acetate. (3) (4Z,6E)-octadienyl acetate undergoes irreversible hydrolysis under alkaline conditions to give (4Z,6E)-octadienol; (4) (4Z,6E)-octadienol is oxidized to (4Z,6E)-octadienal by an oxidizing agent; (5) (4Z,6E)-octadienal reacts with triethyl phosphonoacetate in the presence of sodium hydride to give ethyl (2E,4Z,6E)-dectrienoate. (6) (2E,4Z,6E)-decorienoic acid ethyl ester undergoes irreversible hydrolysis under alkaline conditions to give (2E,4Z,6E)-decorienoic acid; (7) (2E,4Z,6E)-decytrienoic acid and isobutylamine undergo dehydration condensation under the action of a catalyst to obtain the target product; The alkali mentioned in step (2) is potassium tert-butoxide; In step (5), the reaction solvent for Wittig-Horner is THF; The catalyst mentioned in step (7) includes at least one of EDCI and DCC; The oxidant is pyridinium chlorochromate; The 4-halobutylacetic acid ester is 4-bromobutylacetic acid ester or 4-chlorobutylacetic acid ester.

2. The method for preparing a chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide according to claim 1, characterized in that, The organic solvent mentioned in step (1) includes at least one of acetonitrile, tetrahydrofuran, and toluene.

3. The method for preparing a chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide according to claim 1, characterized in that, The temperature range for heating and reflux in step (1) is 80-90℃.

4. The method for preparing a chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide according to claim 1, characterized in that, The solvent used in step (2) includes at least one of THF and toluene.

5. The method for preparing a chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide according to claim 1, characterized in that, The alkali used in step (3) irreversible hydrolysis includes at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

6. The method for preparing a chamomile amide (2E,6Z,8E)-N-isobutyl-2,6,8-decanetrienamide according to claim 1, characterized in that, The solvent for the irreversible hydrolysis reaction is an aqueous methanol solution.

Images