A preparation method of tetraene acetate and its derivatives

Abstract

The present invention provides a preparation method of tetraene acetate and its derivatives, comprising the following steps: subjecting a compound I to an isocyano compound to an addition reaction, followed by dehydration to obtain a compound II, subjecting the compound II to a cyclization reaction with formaldehyde under the action of a strong base, subjecting the compound II to a hydrolysis and elimination reaction in an acidic solution to obtain a compound III, and subjecting the compound III to esterification to obtain the tetraene acetate and its derivative IV. Compared with the existing preparation method for synthesizing tetraene acetate using compound I as a raw material, the present invention obtains the product through isocyanation, cyclization, hydrolysis, and esterification reactions. The reagents used are cheap and readily available, no precious metals are used, the reaction conditions are simple, the process operation is simple, and the method is suitable for large-scale industrial production. After purification, the total yield is greater than 80%, and the purity is greater than 98%. The obtained tetraene acetate and its derivatives can be used to synthesize steroid drugs such as dexamethasone and betamethasone.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of steroid hormone drug intermediates, and in particular to a preparation method of tetraene acetate and its derivatives. Background Art

[0002] Tetraene acetate and its derivatives are key intermediates for the synthesis of steroidal drugs such as dexamethasone, betamethasone, and budesonide. The structural formula of tetraene acetate is as follows:

[0003]

[0004] Tetraene acetate, also known as 3TR, is generally synthesized by traditional methods, starting from 4-AD and performing carbonyl addition to introduce a side chain or performing halogenation at the 17th position followed by esterification. The raw materials used and the production cost are high, which is not conducive to large-scale industrial production.

[0005] Patent publication number CN102603843A reports a method for preparing a dexamethasone intermediate. This method uses 1,4,9(11)-triene-androstane-3,17-dione (Compound I) as a raw material, and obtains acetate tetraene through alkyne, esterification, oxidation, and rearrangement. The oxidation process uses precious metal catalysis, which has high production costs and causes certain environmental pollution. It is not suitable for industrial production. The weight yield of the acetate tetraene obtained in this patent is 50-70% and the purity is 98%.

[0006] Patent publication number CN105622699A reports a method for preparing tetraene acetate and its derivatives. This method uses 4,9(11)-diene-3,17-dione as a raw material, and obtains tetraene acetate through etherification, addition, hydrolysis, elimination, substitution, rearrangement, and dehydrogenation. The tetraene acetate obtained in this patent has a weight yield of 47% and a purity of 98.3%. The route yield is low, the production cost is high, and it is not suitable for industrial production.

[0007] Patent publication number CN107814824A reports a method for preparing tetraene acetate, which uses 1,4,9(11)-triene-androstane-3,17-dione as a raw material and sequentially undergoes several reaction steps including acetylenylation, esterification, bromodebromination, and displacement elimination to prepare tetraene acetate. The raw material for acetylenylation is potassium acetylene, which is chemically extremely unstable and easily ignites, making it unsuitable for large-scale production.

[0008] Patent publication number CN108912194B reports a method for preparing tetraene acetate, which uses 17-alkyne-pregnane-1,4,9(11)-triene-3-one-17-hydroxyacetic acid ester as a raw material, and reacts in an organic solvent under the catalysis of palladium acetate and the action of an oxidant, p-benzoquinone, to generate an intermediate 18-hydroxypregnane-1,4,9(11),17-tetraene-3,19-dione-18-acetic acid ester, which is then treated with 1,8-diazabicycloundec-7-ene to obtain tetraene acetate (21-hydroxypregnane-1,4,9(11),16-tetraene-3,20-dione-21-acetic acid ester). This scheme uses precious metals, which will result in metal residues and increase the reaction cost, making it unsuitable for large-scale production. In addition, p-benzoquinone is used as an oxidant, which produces phenolic pollutants and is not conducive to environmental protection. Summary of the Invention

[0009] In view of this, the present invention proposes a method for preparing tetraene acetate and its derivatives, which solves the technical problems of the prior art such as the use of precious metals, low product yield, poor safety and environmental pollution.

[0010] The technical solution of the present invention is achieved as follows:

[0011] The present invention provides a method for preparing tetraene acetate and its derivatives, comprising the following steps:

[0012] S1. Add arylsulfonylmethyl isocyanide to tetrahydrofuran under gas protection, cool to -40 to -50°C, add organic base, react for 2-3 hours, then add compound I, react at -30 to -40°C for 8-10 hours, add water to make pulp, filter with suction, dry the filter cake and dissolve it in tetrahydrofuran, add N,N-diisopropylamine at 0 to 10°C, add phosphorus oxychloride dropwise, react for 5-6 hours, add water to make pulp, filter with suction, and recrystallize to obtain solid product II;

[0013] S2, dissolving the solid product II obtained in step S1 in toluene, adding formaldehyde, methanol and a phase transfer catalyst, then adding sodium hydroxide solution, stirring at 20-25 ° C for 1-2 hours, collecting the organic layer, drying and concentrating to obtain a solid, then dissolving the solid in tetrahydrofuran, adding acid solution and continuing stirring for 12-16 hours, extracting, drying, concentrating, and recrystallizing to obtain tetraene III;

[0014] S3, dissolving the tetraene III obtained in step S2, reacting with acetic anhydride, and acid hydrolyzing to obtain a crude product IV;

[0015] S4. Refining the crude product IV obtained in step S3 to obtain tetraene acetate and its derivatives.

[0016] On the basis of the above technical solution, preferably, the structural formula of the tetraene acetate and its derivatives is wherein R1 comprises hydrogen or methyl.

[0017] Taking into account the preparation of isocyanide compounds, on the basis of the above technical solution, preferably, the arylsulfonylmethyl isocyanide in step S1 includes benzenesulfonylmethyl isocyanide or p-methylbenzenesulfonylmethyl isocyanide.

[0018] Based on the above technical solution, preferably, the organic base in step S1 includes potassium tert-butoxide or sodium tert-butoxide.

[0019] Based on the above technical solution, preferably, the structural formula of compound I in step S1 is wherein R1 comprises hydrogen or methyl.

[0020] In order to obtain an ideal yield of solid product II, based on the above technical solution, preferably, the molar ratio of sulfonylmethyl isocyanide compound, organic base, compound I, N,N-diisopropylamine and phosphorus oxychloride is (1.24-1.4):(1.4-1.5):1:3.2:1.12.

[0021] On the basis of the above technical solution, preferably, the organic solvents used for recrystallization in step S1 are dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 1:(4-5).

[0022] Based on the above technical solution, preferably, the mass concentration of formaldehyde in step S2 is 35-37%.

[0023] Based on the above technical solution, preferably, in step S2, the molar ratio of the solid product II, formaldehyde, methanol and phase transfer catalyst is 1:(6-8):(10-12):0.15.

[0024] Based on the above technical solution, preferably, the mass concentration of the sodium hydroxide solution in step S2 is 45-50%.

[0025] Based on the above technical solution, preferably, the organic solvent used for recrystallization in step S2 is diethyl ether.

[0026] A phase transfer catalyst is used to promote the hydrolysis ring-opening reaction. Based on the above technical solution, preferably, the phase transfer catalyst in step S2 is Triton B.

[0027] On the basis of the above technical solution, preferably, the specific preparation method of step S3 further includes the following steps:

[0028] S3. Under gas protection, the tetraene III obtained in step S2 is dissolved in pyridine, and then acetic anhydride is added dropwise. The mixture is stirred at 20-25° C. for 4-5 hours, and acid solution is added. The mixture is extracted, dried, and concentrated to obtain a crude product IV.

[0029] On the basis of the above technical solution, preferably, the specific preparation method of step S4 further includes the following steps:

[0030] S4. Dissolve the crude product IV obtained in step S3 in an organic solvent, add activated carbon and reflux for 0.5-1h, filter, concentrate, recrystallize and dry to obtain tetraene acetate and its derivatives.

[0031] On the basis of the above technical solution, preferably, the acid solution in steps S2 and S3 includes sulfuric acid or hydrochloric acid, and its gram equivalent concentration is 2-3N.

[0032] On the basis of the above technical solution, preferably, nitrogen, argon or helium is used as the gas protection.

[0033] Based on the above technical solution, preferably, the organic solvent in step S4 includes ethyl acetate or dichloromethane.

[0034] Based on the above technical solution, preferably, the drying temperature in step S4 is 50-55°C.

[0035] The preparation method of tetraene acetate and its derivatives of the present invention has the following beneficial effects compared with the prior art:

[0036] (1) Compared with the existing method for preparing tetraene acetate using 1,4,9(11)-triene-androstane-3,17-dione as raw material, the present invention allows 1,4,9(11)-triene-androstane-3,17-dione to undergo an addition reaction with an isocyano compound, followed by dehydration, and then undergoes a cyclization reaction with formaldehyde under the action of a strong base, undergoes hydrolysis and elimination reaction in an acidic solution, and finally undergoes esterification to obtain tetraene acetate and its derivatives. After purification, the total yield of the product is greater than 80% and the purity is greater than 98%.

[0037] (2) At the same time, the preparation method of the present invention has low-cost and easily available raw materials, simple reaction conditions, does not use precious metals and unstable reagents, and does not produce by-products that pollute the environment. It has good safety and is suitable for industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0039] Figure 1 This is the H NMR spectrum of the tetraene acetate of Example 1 of the present invention;

[0040] Figure 2 This is the H NMR spectrum of the tetraene acetate methylate of Example 2-4 of the present invention;

[0041] Figure 3 The invention relates to a method for preparing tetraene acetate and its derivatives. DETAILED DESCRIPTION

[0042] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0043] Example 1

[0044] A method for preparing tetraene acetate comprises the following steps:

[0045] S1. Isocyanation reaction: Under nitrogen protection, benzenesulfonylmethyl isocyanide (2.81 g, 15.5 mmol, 1.24 equivalents) was dissolved in tetrahydrofuran (60 mL), and then cooled to -50 ° C. Potassium tert-butoxide (1.97 g, 17.5 mmol, 1.4 equivalents) was added, and after reacting for 2 h, Androsta-1,4,9(11)-triene-3,17-dione (3.53 g, 12.5 mmol, 1.0 equivalents) was added, and stirring was continued at -40 ° C for 8 h, and then the mixture was poured into water (250 mL); extracted with dichloromethane 3 times (50, 25, 25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude formamide product; crude The product was dissolved in tetrahydrofuran (75 mL), diisopropylamine (5.6 mL, 40 mmol, 3.2 equivalents) was added, and the temperature was lowered to 0°C; phosphorus oxychloride (1.3 mL, 14 mmol, 1.12 equivalents) was slowly added dropwise, and the mixture was stirred in an ice bath for 5 h. The reaction solution was poured into ice water (400 mL) containing sodium bicarbonate (10.0 g). The solid was collected and dissolved in dichloromethane / methanol (1:5) by volume, and the product was recrystallized to obtain 5.18 g, molar yield 93%, purity 96%;

[0046] S2, cyclization and hydrolysis reaction: to a solution of isocyanide (8.73 g, 19.6 mmol, 1.0 equiv) in toluene (390 mL) were added aqueous formaldehyde solution (8.7 mL, 37%, 117.6 mmol, 6.0 equiv), methanol (8.0 mL, 196 mmol, 10.0 equiv), Triton B (1.4 mL, 40% in MeOH, 2.9 mmol, 0.15 equiv) and 50% aqueous sodium hydroxide solution (140 mL); the two-phase reaction solution was vigorously stirred at 20 ° C for 1 h; the organic phase was filtered through neutral alumina and concentrated to obtain a foam, which was then dissolved in tetrahydrofuran (270 mL) and 3N sulfuric acid solution (90 mL) and stirred for 12 h; after the reaction, the mixture was extracted with dichloromethane (3×250 mL), dried and concentrated to obtain a crude product, which was recrystallized from ether to obtain the product (5.91 g, molar yield 93%, purity 95%);

[0047] S3, esterification reaction: under nitrogen protection, tetraene III (5.91 g, 18.23 mmol) was dissolved in pyridine (50 mL), and then acetic anhydride (17 mL) was added dropwise, stirred for 4 h, and dilute sulfuric acid (160 mL) was added. After extraction with ethyl acetate (3×230 mL), the mixture was dried and concentrated to obtain crude tetraene acetate IV (6.41 g, molar yield 96%, purity 95%);

[0048] S4. Purification: The crude product IV (100.0 g) was dissolved in ethyl acetate (50 mL), activated carbon was added and refluxed for 30 min; hot filtering was carried out, the filtrate was concentrated, and then recrystallization was carried out and drying was carried out at 50° C. to obtain tetraene acetate (98 g, purification yield 98%, purity 99%).

[0049] 15 mg of the obtained tetraene acetate was sampled and dissolved in CDCl3 for nuclear magnetic hydrogen spectrum analysis. The hydrogen spectrum was shown in Figure 1 , the hydrogen spectrum data of compound IV (R1=H) is: 1 H NMR (400MHz, CDCl3): δ7.20(d,J=10.2Hz,1H),6.75(m,1H),6.25(dd,J=10.1,1.7Hz),6.07(s,1H),5.55(m,1H),5.00(d,J=16.0Hz,1H),4 .87(d,J=16.0Hz,1H),2.39–2.74(m,5H),2.04–2.23(m,3H),2.16(s,3H),1.47–1.55(m,1H),1.42(s,3H),1.15–1.30(m,1H),0.91(s,3H).

[0050] Example 2

[0051] A method for preparing a tetraene acetate derivative comprises the following steps:

[0052] S1. Isocyanation reaction: Under nitrogen protection, p-methylbenzenesulfonylmethyl isocyanide (3.42 g, 17.5 mmol, 1.4 equivalents) was dissolved in tetrahydrofuran (60 mL), and then cooled to -40°C; potassium tert-butoxide (2.10 g, 18.7 mmol, 1.5 equivalents) was added, and after reacting for 3 h, Androsta-1,4,9(11)-triene-3,17-dione (3.53 g, 12.5 mmol, 1.0 equivalents) was added, and stirring was continued at -30°C for 10 h, and then the mixture was poured into water (250 mL); extracted with dichloromethane 3 times (50 , 25, 25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude formamide product; the crude product was dissolved in tetrahydrofuran (75 mL), diisopropylamine (5.6 mL, 40 mmol, 3.2 equivalents) was added, and the temperature was lowered to 10°C; phosphorus oxychloride (1.3 mL, 14 mmol, 1.12 equivalents) was slowly added dropwise, and after stirring in an ice bath for 6 h, the reaction solution was poured into ice water (400 mL) containing sodium bicarbonate (10.0 g), the solid was collected, dissolved in dichloromethane / methanol = (1:4) by volume, and recrystallized to obtain the product (5.46 g, molar yield 95%, purity 96%);

[0053] S2, cyclization and hydrolysis reaction: to a solution of isocyanide (9.00 g, 19.6 mmol, 1.0 equiv) in toluene (390 mL) were added aqueous formaldehyde solution (8.9 mL, 35%, 117.6 mmol, 6.0 equiv), methanol (8.0 mL, 196 mmol, 10.0 equiv), Triton B (1.4 mL, 40% in MeOH, 2.9 mmol, 0.15 equiv) and 50% aqueous sodium hydroxide solution (140 mL); the two-phase reaction solution was vigorously stirred at 25 ° C for 2 h; the organic phase was filtered through neutral alumina and concentrated to obtain a foam, which was then dissolved in tetrahydrofuran (270 mL) and 3N sulfuric acid solution (90 mL) and stirred for 16 h; after the reaction, the mixture was extracted with dichloromethane (3×250 mL), dried and concentrated to obtain a crude product, which was recrystallized from diethyl ether to obtain the product (5.85 g, molar yield 92%, purity 98%);

[0054] S3, esterification reaction: under nitrogen protection, tetraene III (7.70 g, 23.73 mmol) was dissolved in pyridine (60 mL), and then acetic anhydride (20 mL) was added dropwise, stirred for 5 h, and dilute sulfuric acid (200 mL) was added. After extraction with ethyl acetate (3×250 mL), the mixture was dried and concentrated to obtain crude tetraene acetate IV (8.44 g, molar yield 97%, purity 93%);

[0055] S4. Purification: The crude product IV (100.0 g) was dissolved in ethyl acetate (50 mL), activated carbon was added and refluxed for 1 h; hot filtration was performed, the filtrate was concentrated, and then recrystallization was performed and dried at 55° C. to obtain an acetate tetraene derivative (98 g, purified yield 98%, purity 99%).

[0056] 15 mg of the obtained tetraene acetate derivative was sampled and dissolved in CDCl3 for H NMR analysis. The H NMR spectrum was shown in Fig. Figure 2 , the hydrogen spectrum data of compound IV (R1=CH3) is: 1 H NMR (400MHz, CDCl3): δ7.34(d,J=11.0Hz,1H),6.33(dd,J=9.92,1.8Hz,1H),6.08(s,1H),5.58(m,1H),5.06(d,J=16.1Hz,1H), 4.88(d,J=16.1Hz,1H),2.40–2.65(m,5H),2.06–2.20(m,7H),1.59–1.63(m,1H),1.42(s,3H),1.12–1.22(m,1H),0.85(s,3H).

[0057] Example 3

[0058] A method for preparing a tetraene acetate derivative comprises the following steps:

[0059] S1. Isocyanation reaction: Under helium protection, p-methylbenzenesulfonylmethyl isocyanide (3.05 g, 15.6 mmol, 1.25 equivalents) was dissolved in tetrahydrofuran (60 mL), and then cooled to -45 ° C; sodium tert-butoxide (1.69 g, 17.5 mmol, 1.4 equivalents) was added, and after reacting for 2.5 h, Androsta-1,4,9(11)-triene-3,17-dione (3.53 g, 12.5 mmol, 1.0 equivalents) was added, and stirring was continued at -35 ° C for 9 h, and then the mixture was poured into water (250 mL); extracted with dichloromethane 3 times (50 , 25, 25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude formamide product; the crude product was dissolved in tetrahydrofuran (75 mL), diisopropylamine (5.6 mL, 40 mmol, 3.2 equivalents) was added, and the temperature was lowered to 5°C; phosphorus oxychloride (1.3 mL, 14 mmol, 1.12 equivalents) was slowly added dropwise, and stirred in an ice bath for 5.5 h. The reaction solution was poured into ice water (400 mL) containing sodium bicarbonate (10.0 g), the solid was collected, dissolved in dichloromethane / methanol at a volume ratio of (1:4.5), and the product was recrystallized to obtain 5.40 g (molar yield 94%, purity 96%);

[0060] S2. Cyclization and hydrolysis reaction: To a solution of isocyanide (9.00 g, 19.6 mmol, 1.0 equivalent) in toluene (390 mL) was added aqueous formaldehyde solution (8.7 mL, 37%, 117.6 mmol, 6.0 equivalent), methanol (8.0 mL, 196 mmol, 10.0 equivalent), Triton B (1.4 mL, 40% in MeOH, 2.9 mmol, 0.15 equivalents) and 45% aqueous sodium hydroxide solution (180 mL); the two-phase reaction solution was vigorously stirred at 22°C for 1.5 hours; the organic phase was filtered through neutral alumina and concentrated to obtain a foamy product, which was then dissolved in tetrahydrofuran (270 mL) and 3N hydrochloric acid solution (100 mL) and stirred for 14 hours; after the reaction was completed, the product was extracted with dichloromethane (3×250 mL), dried, and concentrated to obtain a crude product, which was recrystallized from diethyl ether to obtain the product (5.90 g, molar yield 93%, purity 97%).

[0061] S3, esterification reaction: under helium protection, tetraene III (7.70 g, 23.73 mmol) was dissolved in pyridine (60 mL), and then acetic anhydride (20 mL) was added dropwise. After stirring for 4.5 h, dilute sulfuric acid (200 mL) was added, and the mixture was extracted with ethyl acetate (3×250 mL) and dried and concentrated to give crude tetraene acetate IV (8.44 g, molar yield 97%, purity 93%).

[0062] S4. Purification: The crude product IV (100.0 g) was dissolved in dichloromethane (50 mL), activated carbon was added and refluxed for 0.8 h; hot filtration was performed, the filtrate was concentrated, and then recrystallization was performed and dried at 52° C. to obtain the tetraene acetate derivative (98 g, purified yield 98%, purity 99%).

[0063] Example 4

[0064] A method for preparing a tetraene acetate derivative comprises the following steps:

[0065] S1. Isocyanation reaction: Under argon protection, dissolve p-toluenesulfonylmethyl isocyanide (3.03 g, 15.5 mmol, 1.24 equivalents) in tetrahydrofuran (60 mL), and then cool to -50 ° C; add potassium tert-butoxide (2.03 g, 17.5 mmol, 1.45 equivalents), react for 3 h, add (16beta)-16-methylandrosta-1,4,9(11)-triene-3,17-dione (3.71 g, 12.5 mmol, 1.0 equivalents), continue stirring at -40 ° C for 8 h, and then pour the mixture into water (250 mL); The mixture was extracted three times with dichloromethane (50, 25, and 25 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a crude formamide product. The crude product was dissolved in tetrahydrofuran (75 mL), and diisopropylamine (5.6 mL, 40 mmol, 3.2 equivalents) was added, and the temperature was lowered to 0°C. Phosphorus oxychloride (1.3 mL, 14 mmol, 1.12 equivalents) was slowly added dropwise. After stirring in an ice bath for 5 h, the reaction solution was poured into ice water (400 mL) containing sodium bicarbonate (10.0 g). The solid was collected and dissolved in dichloromethane / methanol (1:5) by volume to obtain the product (5.62 g, molar yield 95%, purity 95%).

[0066] S2. Cyclization and hydrolysis reaction: To a solution of isocyanide (9.28 g, 19.6 mmol, 1.0 equivalent) in toluene (390 mL) was added aqueous formaldehyde solution (11.6 mL, 36%, 156.8 mmol, 8.0 equivalent), methanol (9.6 mL, 235.2 mmol, 12.0 equivalent), Triton B (1.4 mL, 40% in MeOH, 2.9 mmol, 0.15 equivalent) and 48 % sodium hydroxide aqueous solution (160 mL); the two-phase reaction solution was vigorously stirred at 25°C for 1 hour; the organic phase was filtered through neutral alumina and concentrated to obtain a foamy product, which was then dissolved in tetrahydrofuran (270 mL) and 2N sulfuric acid solution (120 mL) and stirred for 16 hours; after the reaction was completed, it was extracted with dichloromethane (3×250 mL), dried, and concentrated to obtain a crude product, which was recrystallized from diethyl ether to obtain the product (5.84 g, molar yield 88%, purity 97%);

[0067] S3, esterification reaction: under argon protection, tetraene III (5.84 g, 17.25 mmol) was dissolved in pyridine (44 mL), and then acetic anhydride (15 mL) was added dropwise. After stirring for 4 h, dilute sulfuric acid (145 mL) was added, and the mixture was extracted with ethyl acetate (3×180 mL) and dried and concentrated to obtain crude tetraene acetate IV (6.30 g, molar yield 96%, purity 94%).

[0068] S4. Purification: The crude product IV (100.0 g) was dissolved in ethyl acetate (50 mL), activated carbon was added and refluxed for 30 min; hot filtering was carried out, the filtrate was concentrated, and then recrystallization was carried out and drying was carried out at 50° C. to obtain an acetate tetraene derivative (97 g, purification yield 97%, purity 99%).

[0069] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing tetraene acetate and its derivatives, characterized in that: The steps include: S1. Add arylsulfonylmethyl isocyanide to tetrahydrofuran under gas protection, cool to -40~-50°C, add organic base, react for 2-3 hours, then add compound I, react at -30~-40°C for 8-10 hours, add water to make pulp, filter with suction, dry the filter cake and dissolve it in tetrahydrofuran, add N,N-diisopropylamine at 0~10°C, add phosphorus oxychloride dropwise, react for 5-6 hours, add water to make pulp, filter with suction, and recrystallize to obtain solid product II; S2, dissolving the solid product II obtained in step S1 in toluene, adding formaldehyde, methanol and a phase transfer catalyst, then adding sodium hydroxide solution, stirring at 20-25 ° C for 1-2 hours, collecting the organic layer, drying and concentrating to obtain a solid, then dissolving the solid in tetrahydrofuran, adding acid solution and continuing stirring for 12-16 hours, extracting, drying, concentrating, and recrystallizing to obtain tetraene III; S3, dissolving the tetraene III obtained in step S2, reacting with acetic anhydride, and acid hydrolyzing to obtain a crude product IV; S4, refining the crude product IV obtained in step S3 to obtain tetraene acetate and its derivatives; in, The structural formula of the tetraene acetate and its derivatives is , wherein R1 is hydrogen or methyl; The structural formula of compound I in step S1 is , wherein R1 is hydrogen or methyl; the arylsulfonylmethyl isocyanide is benzenesulfonylmethyl isocyanide or p-toluenesulfonylmethyl isocyanide; In step S1, the molar ratio of arylsulfonylmethyl isocyanide, organic base, compound I, N,N-diisopropylamine and phosphorus oxychloride is (1.24-1.4):(1.4-1.5):1:3.2:1.12; The molar ratio of the solid product II, formaldehyde, methanol and phase transfer catalyst in step S2 is 1:(6-8):(10-12):0.

15.

2. The method for preparing tetraene acetate and its derivatives according to claim 1, wherein: The organic base in step S1 includes potassium tert-butoxide or sodium tert-butoxide.

3. The method for preparing tetraene acetate and its derivatives as claimed in claim 1, characterized in that: In step S1, the organic solvents used for recrystallization are dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 1: (4-5).

4. The method for preparing tetraene acetate and its derivatives according to claim 1, wherein: The acid solution in step S2 includes sulfuric acid or hydrochloric acid, and its gram equivalent concentration is 2-3N.

5. The method for preparing tetraene acetate and its derivatives according to claim 1, wherein: The specific preparation method of step S3 further includes the following steps: S3. Under gas protection, the tetraene III obtained in step S2 is dissolved in pyridine, and then acetic anhydride is added dropwise. The mixture is stirred at 20-25° C. for 4-5 hours, and acid solution is added. The mixture is extracted, dried, and concentrated to obtain a crude product IV.

6. The method for preparing tetraene acetate and its derivatives according to claim 1, wherein: The specific preparation method of step S4 further includes the following steps: S4. Dissolve the crude product IV obtained in step S3 in an organic solvent, add activated carbon and reflux for 0.5-1h, filter, concentrate, recrystallize and dry to obtain tetraene acetate and its derivatives.

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