Method for preparing halcinonide intermediate triene chloride

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for preparing halcinonide intermediate triene chloride, which comprises the following steps: by taking 21-chloro-17alpha-hydroxy-pregna-4, 9 (11)-diene-3, 20-diketone (diene chloride) as a raw material, reacting with a salt reagent of a semicarbazide compound in a weakly acidic buffer solution to generate a disemicarbazone intermediate state of the diene chloride; then 17alpha-hydroxyl elimination is carried out to generate 3-position semicarbazone and a product triene chloride, and then the 3-position semicarbazone and the product triene chloride are subjected to semicarbazone deprotection to obtain a target product. Conventional operation and reagents are used, the intermediate state is not separated and continues to react in the same reaction system, and the total weight yield reaches 86% or above. The method overcomes the defects of complex raw material structure, harsh reaction conditions, environmental pollution and the like in the prior art, is suitable for industrial mass production, and provides stable and reliable raw material support for preparation of halcinonide and related drugs thereof.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for preparing a halcinonide intermediate triene chloride, and specifically relates to a method for preparing 21-chloro-pregnane-4,9(11),16(17)-triene-3,20-dione. Background Art

[0002] Halcinonide, also known as clofosinate, is a synthetic, highly effective fluorinated and chlorinated corticosteroid. It has strong anti-inflammatory effects and is not likely to cause systemic side effects when applied topically. Clinical applications have shown that it has outstanding efficacy in treating psoriasis and eczematous dermatitis. It is used for psoriasis with a short course of treatment and few side effects. Currently, the preparations of halcinonide on the market include: topical liquid preparations, liquid preparations, liniments, creams, ointments and coatings.

[0003] In recent years, the incidence of dermatitis and eczema is high, the rate of medical consultation is high, and the market capacity of dermatology is expanding year by year, with huge room for future development. Halcinonide has outstanding efficacy, short treatment course and few side effects for skin diseases such as psoriasis and eczematous dermatitis. Therefore, the research and development of Halcinonide APIs and intermediates is of great significance.

[0004] The synthesis method of halcinonide is mainly carried out around the order of constructing the functional groups in the three regions of 9, 11, 16, 17 and 21. For example, in 1981, the method reported by Schering Aktiengesellschaft in patent US4404141A (such as route 1) used 21-chloro-pregnane-4,9(11),16(17)-triene-3,20-dione (halcinonide intermediate triene chloride) as raw material, first constructed the 16,17 propylene, then constructed the 9,11 epoxide, and finally used hydrogen fluoride (HF) to treat the 9, The 11-epoxy ring is opened with fluorine to obtain the product; the method reported in Tianjin Pharmaceutical's patent CN109206471A (such as route 2) uses the compound 9β,11β-epoxy-16α,17-[(1-methylethylidene)bis(oxy)]-21-hydroxy-pregnane-4-ene-3,20-dione with 9,11-epoxy and 16,17-propylene as the raw material, then constructs the 21-position chlorine, and finally uses HF to open the 9,11-epoxy ring to obtain the product.

[0005]

[0006]

[0007] Among them, although the route 2 is short, the raw material structure is complex and difficult to obtain, and it is highly dependent on the raw material supplier. The factory cannot well control the cost and the quality of each batch of raw materials during production; the route 1 has relatively simple raw materials and uncomplicated steps, which is a better method for synthesizing halcinonide. However, there are currently few reports on the synthesis of halcinonide intermediate triene chloride by eliminating 17α-hydroxyl from 21-chloro-17α-hydroxy-pregnane-4,9(11)-diene-3,20-dione (diene chloride). The 17α-hydroxy elimination methods of other analogs include: William S. Allen et al.'s J. Am. Chem. Soc. 1955, 77, 4, 1028-1032 uses thionyl chloride-pyridine to eliminate; Patent CN105254697 uses sulfur dioxide-pyridine to eliminate; SASzpilfogel et al.'s Recueil des Travaux Chimiques des Pays-Bas, Volume 74, Issue 12, 1955, 1462-1466 uses trichlorophosphine-pyridine to eliminate. They all use pyridine with an unpleasant odor, and during the reaction, they will produce highly corrosive hydrochloric acid waste gas and sulfur- or phosphorus-containing wastewater, which does not conform to the concept of environmentally friendly industrial production. Therefore, how to efficiently synthesize the raw material triene chloride in route 1 is of great significance to the synthesis of halcinonide. Summary of the invention

[0008] In view of the above problems, the present invention discloses a simple and efficient method for synthesizing triene chloride, an intermediate of halcinonide: using cheap plant sterol fermentation product 9α-OH-4AD as raw material, referring to the methods reported in patents US5565588, EP0263569B1, and US4921638, first cyanation of ketone at position 17 and then elimination of hydroxyl at position 9; referring to the methods reported in Upjohn's document J.Am.Chem.Soc.1990,112,6449-6450 and patents US4977255, US4921638, etc., first synthesizing silyl ether and then synthesizing diene chloride under the action of lithium diisopropylamide (LDA); this preparation process is a conventional operation in the synthesis of steroid drugs at this stage, and will not be described in detail in this patent. Diene chloride (compound A) reacts with a salt reagent of a semicarbazide compound (reagent II) in a weakly acidic buffer solution (reagent I) at 50-100°C to generate a disemicarbazone intermediate of diene chloride (compound B). Under the induction of the 20-position semicarbazide of compound B, the 17α-hydroxyl group is subsequently eliminated to generate the 3-position semicarbazide (compound C) and the product triene chloride (compound D). The temperature is then lowered and a semicarbazide deprotection reagent (reagent III) is added at 20-45°C. After compound C is completely converted into compound D, the reaction solution is post-treated and added to water at 0-5°C, precipitated, and filtered to obtain compound D (route 3).

[0009]

[0010] The present invention includes the following technical solutions:

[0011] The method of the present invention comprises the following steps:

[0012] (1) Using the compound of formula A as a starting material, reacting with a salt reagent of a semicarbazide compound (reagent II) in a weakly acidic buffer solution (reagent I) to generate a disemicarbazone intermediate of a diene chloride (compound B), followed by 17α-hydroxy elimination to generate compound C and compound D;

[0013] (2) Compound C is reacted in the presence of a semicarbazone deprotection reagent (reagent III), post-treated, and precipitated with water to obtain compound D;

[0014] The general reaction formula is as follows:

[0015]

[0016] In step (1), the compound of formula A is used as a starting material, and reacts with a salt reagent of a semicarbazide compound (reagent II) in a weakly acidic buffer solution (reagent I) to generate a disemicarbazone intermediate of a diene chloride (compound B), followed by 17α-hydroxy elimination to generate compounds C and D, comprising the following steps;

[0017] In a weakly acidic buffer solution (reagent I), a compound represented by formula A and a salt reagent of a semicarbazide compound (reagent II) are added, and the mixture is reacted at 50-100° C. to generate a disemicarbazone compound (compound B) of compound A, followed by elimination of the 17α-hydroxyl group. After 8-15 hours, TLC (PE:EA=2:1) ​​shows that compound A has reacted completely to generate compounds represented by formula C and formula D;

[0018] The general reaction formula is as follows:

[0019]

[0020] The weight ratio of each component is:

[0021] Weakly acidic buffer solution (reagent I): compound represented by formula A = 5-10:1;

[0022] Preferably, weakly acidic buffer solution (reagent I): compound represented by formula A = 7:1;

[0023] Salt reagent of semicarbazide compound (reagent II): compound represented by formula A = 0.6-3:1;

[0024] Preferably, the salt reagent of the semicarbazide compound (reagent II): the compound represented by formula A = 1.14:1;

[0025] The reaction time is 8 to 15 hours, preferably 12 hours;

[0026] The reaction temperature is 50-100°C, preferably 80°C;

[0027] The weak acid buffer solution (reagent I) is prepared by diluting a weak acid buffer saline solution with a lower alcohol, such as a potassium dihydrogen phosphate-hydrochloric acid-ethanol buffer solution with a pH of 2.5, an acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6, an acetic acid-ammonium hydroxide-methanol buffer solution with a pH of 3.7, an acetic acid-ammonium acetate-isopropanol buffer solution with a pH of 4.5, etc., preferably an acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6;

[0028] The weakly acidic buffer solution (reagent I) can be prepared by the following method:

[0029] Preparation process: Add a weak acid compound to a volumetric flask at room temperature, add water, stir, dissolve, then use an acidic or alkaline compound to adjust the pH value to the desired value, and then add a lower alcohol to make up the volume, and the specific preparation data is as described in the examples. Preferably, the acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6 is 7 parts by weight of compound A;

[0030] The salt reagent of the semicarbazide compound (reagent II) is a salt formed by a semicarbazide substituted or unsubstituted at the 4-position and a monoacid, such as semicarbazide hydrobromide, semicarbazide hydrochloride, semicarbazide nitrate, semicarbazide perchlorate, 4-phenyl semicarbazide hydrochloride, 4-phenyl semicarbazide perchlorate, etc., preferably semicarbazide nitrate.

[0031] The salt reagent of the semicarbazide compound (reagent II) can be prepared by the following method:

[0032] Preparation process: add 4-substituted or unsubstituted semicarbazide to the reaction bottle, add lower alcohol, stir, dissolve, cool to -5 to 0°C, control the temperature below 0°C, dropwise add an equivalent of acid of the corresponding semicarbazide compound, add, react for 1.5 to 3.5 hours, filter, drain, and dry to obtain. The specific preparation data is described in the examples. Preferably, the semicarbazide nitrate is 1.14 parts by weight of compound A;

[0033] In step (2), the compound of formula C is reacted in the presence of a deprotection reagent (reagent III) of semicarbazone, and post-treated to obtain compound D; comprising the following steps:

[0034] After the reaction in step (1) is completed, the system is cooled, and a semicarbazide deprotection reagent (reagent III) is added at 20-45° C. to react for 5-8 hours. After TLC (PE:EA=2:1) ​​shows that compound C is completely converted into compound D, the reaction solution is post-treated, added to water at 0-5° C., precipitated, filtered, and dried at 50-60° C. to obtain compound D;

[0035] The general reaction formula is as follows:

[0036]

[0037] The weight ratio of each component is:

[0038] Semicarbazone deprotection reagent (reagent III): compound represented by formula A = 0.2 to 1:1;

[0039] Preferably, the deprotection reagent of semicarbazone (reagent III): the compound represented by formula A = 0.45:1;

[0040] The reaction time is 5 to 8 hours, preferably 6 hours;

[0041] The reaction temperature is: 20-45°C, preferably, the reaction temperature is 30°C;

[0042] The deprotection reagent of semicarbazone (reagent III) is selected from pyruvic acid, acetaldehyde, formaldehyde, propionaldehyde, n-butyraldehyde, sodium nitrite, cupric chloride, 732 type cationic resin, etc., preferably formaldehyde;

[0043] In the synthesis process of the present invention, compound A and a semicarbazide compound form a 3,20 di-semicarbazone intermediate state. Under acidic conditions, the 20-position semicarbazide induces the elimination of the 17-position hydroxyl group, and at the same time, part of the 3-position semicarbazide is hydrolyzed under acidic conditions to obtain compound C and compound D. Compound C continues to undergo an exchange reaction with an aldehyde compound or an oxidation reaction with an oxidizing agent or a reaction with a cationic resin in an acidic system to generate compound D.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The invention discloses a method for preparing a halcinonide intermediate triene chloride. In the method, a weak acid buffer solution is used to reduce the risk of chlorine hydrolysis at position 21 and participation in the reaction; the hydrogen ion of the weak acid can protonate the carbonyl group, thereby increasing the polarity of the carbonyl group, that is, reducing the electron cloud density on the carbonyl carbon, which is conducive to nucleophilic addition to form a semicarbazone compound. The generated 3-position semicarbazone and the product triene chloride are directly deprotected from the 3-position semicarbazone without separation, so that the 3-position semicarbazone is completely converted into a product, reducing the reaction steps, shortening the production cycle, improving the production efficiency, and reducing the production cost. The salt reagent of the semicarbazide compound is used for the reaction, which reduces the amino groups participating in the reaction, reduces the reaction activity, and makes the reaction selectivity higher.

[0046] The process of the present invention uses conventional operations and conventional reagents, and the intermediate state is not separated and continues to react in the same reaction system. The total weight yield is more than 86% (the theoretical weight yield is 95%). The process is suitable for large-scale industrial production, promotes the technological innovation of the preparation process of halcinonide intermediates and derivatives thereof, provides stable and reliable raw material support for the preparation of halcinonide-related drugs, and also provides ideas for the preparation of other steroid compounds. Figure 1 This is the NMR spectrum of the product of Example 2. DETAILED DESCRIPTION

[0047] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are only exemplary to illustrate and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0048] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0049] The term "weight yield" is defined as follows:

[0050] Weight yield = (target product weight / reactant weight) × 100%

[0051] Wherein: the weight of the reactant is the weight of compound A;

[0052] Example 1

[0053] Preparation of potassium dihydrogen phosphate-hydrochloric acid-ethanol buffer solution with pH = 2.5: At room temperature, add 50g of potassium dihydrogen phosphate to a 500mL volumetric flask, add 250mL of water to the volumetric flask, stir to dissolve, then adjust the pH to 2.5 with hydrochloric acid, then add ethanol to make up to 500mL, stir evenly, and set aside.

[0054] Preparation process of semicarbazide hydrobromide: add 33.4g semicarbazide to a 500mL reaction bottle, add 278g ethanol, stir, dissolve, cool to -5~0℃, control the temperature below 0℃, add 76.8g 47% hydrobromic acid solution dropwise, stir, react for 2 hours, filter, drain, and dry in vacuo at 45℃ to obtain 68.3g semicarbazide hydrobromide.

[0055] Reaction: Under nitrogen protection, 30g of compound A and 270g of potassium dihydrogen phosphate-hydrochloric acid-ethanol buffer with pH = 2.5 prepared by the above method were added to the reaction bottle, stirred, and 58g of semicarbazide hydrobromide prepared by the above method was added at room temperature, stirred, heated to 60°C, reacted for 15 hours, TLC (developing solvent: PE: EA = 2:1), the raw materials reacted completely, but the product had two spots, cooled to 40°C, 27.9g of pyruvic acid was added, and the temperature was kept at 40°C after the addition, and reacted for 5 hours. TLC (developing solvent: PE: EA = 2:1), the two spots were converted into one spot, and the reaction was stopped. The reaction solution was cooled to 10-20°C, and the reaction solution was slowly added to 900g of water precooled to 0-5°C, stirred, crystallized, filtered after 2.5 hours, the filter cake was washed with water until neutral, drained, and dried at 50-60°C to obtain 27.1g of solid product (weight yield 90.3%).

[0056] mp: 130.8~131.3℃, MS (m / z): 368.2[M+Na]+, Elemental Analysis: C, 73.14; H, 7.31; Cl, ​​10.28; O, 9.28;, 1 H-NMR{400MHz, CDCl3(TMS), δ(ppm)}:0.9(s,3H),1.12–1.15(m,1H),1.36(s,3H),1.6–1.62(m,1H),2.12–2.16(m,1H ),2.18–2.22(m,4H),2.38–2.61(m,7H),4.34–4.43(q,2H),5.56–5.57(d,1H),5.76–5.77(d,1H),6.81–6.82(m,1H).

[0057] Example 2

[0058] Preparation of acetic acid-sodium acetate-isopropanol buffer solution with pH=3.6: At room temperature, add 10.2g of sodium acetate and 50mL of water to a 500mL volumetric flask, stir to dissolve, then add about 40g of glacial acetic acid to adjust the pH to 3.6, then add isopropanol to make up to 500mL, stir evenly and set aside.

[0059] Preparation process of semicarbazide hydrogen nitrate: add 29.2g semicarbazide to a 500mL reaction bottle, add 200g isopropanol, stir, dissolve, cool to -5~0℃, control the temperature below 0℃, add 36.6g 68% concentrated nitric acid dropwise, stir, react for 2.5 hours, filter, drain, and dry in vacuo at 45℃ to obtain 53g semicarbazide hydrogen nitrate.

[0060] Reaction: Under nitrogen protection, 40g of compound A and 280g of acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6 prepared by the above method were added to the reaction bottle, stirred, and 45.6g of semicarbazide hydrogen nitrate prepared by the above method was added at room temperature, stirred, heated to 80°C, reacted for 12 hours, TLC (developing agent: PE:EA=2:1), the raw materials reacted completely, but the product had two spots, cooled to 30°C, 18g of 37% formaldehyde solution was added, and the temperature was kept at 30°C after the addition, and reacted for 6 hours. TLC (developing agent: PE:EA=2:1), the two spots were converted into one spot, the reaction was stopped, the reaction solution was cooled to 10-20°C, the reaction solution was slowly added to 800g of water precooled to 0-5°C, stirred, crystallized, filtered after 3 hours, the filter cake was washed with water until neutral, drained, and dried at 50-60°C to obtain 37.2g of solid product (weight yield 93%).

[0061] mp: 130.8~131.3℃, MS (m / z): 368.2[M+Na]+, Elemental Analysis: C, 73.14; H, 7.31; Cl, ​​10.28; O, 9.28;, 1 H-NMR{400MHz,CDCl3(TMS),δ(ppm)}:0.9(s,3H),1.12–1.15(m,1H),1.36(s,3H),1.6–1.62(m,1H),2.12–2.16(m,1H),2.18–2.22(m,4H),2.38–2.61(m,7H),4.34–4.43(q,2H),5.56–5.57(d,1H),5.76–5.77(d,1H),6.81–6.82(m,1H), see NMR spectrum Figure 1 .

[0062] Example 3

[0063] Preparation of acetic acid-ammonium acetate-isopropanol buffer solution with pH = 4.5: At room temperature, add 23.1 g of ammonium acetate and 50 mL of water to a 300 mL volumetric flask, stir to dissolve, then add about 6 g of glacial acetic acid to adjust the pH to 4.5, then add isopropanol to make up to 300 mL, stir evenly, and set aside.

[0064] Preparation process of 4-phenylaminourea hydrochloride: Add 23g 4-phenylaminourea to a 500mL reaction bottle, add 300g methanol, stir, dissolve, cool to -5~0℃, control the temperature below 0℃, add 16g 36% hydrochloric acid dropwise, stir, react for 3 hours, filter, drain, and dry in vacuo at 45℃ to obtain 27.5g 4-phenylaminourea hydrochloride.

[0065] Reaction: Under nitrogen protection, add 20g of compound A and 120g of acetic acid-ammonium acetate-isopropanol buffer solution with pH = 4.5 prepared by the above method to the reaction bottle, stir, add 26g of 4-phenylaminourea hydrochloride prepared by the above method at room temperature, stir, heat to 95°C, react for 9 hours, TLC (developing solvent: PE:EA = 2:1), the raw materials reacted completely, but there were two spots of the product, cool to 25°C, add 10g 732 type cationic resin, add and keep warm at 25℃, react for 8 hours, TLC (developing solvent: PE:EA=2:1), two points are converted into one point, stop the reaction, filter out 732 type cationic resin, wash with 30g isopropanol, cool the combined filtrate to 10~20℃, slowly add the filtrate to 850g water precooled to 0~5℃, stir, crystallize, filter after 2 hours, wash the filter cake with water until neutral, drain, and dry at 50~60℃ to obtain 17.4g solid product (weight yield 87%).

[0066] mp: 130.8~131.3℃, MS (m / z): 368.2[M+Na]+, Elemental Analysis: C, 73.14; H, 7.31; Cl, ​​10.28; O, 9.28;, 1 H-NMR{400MHz, CDCl3(TMS), δ(ppm)}:0.9(s,3H),1.12–1.15(m,1H),1.36(s,3H),1.6–1.62(m,1H),2.12–2.16(m,1H ),2.18–2.22(m,4H),2.38–2.61(m,7H),4.34–4.43(q,2H),5.56–5.57(d,1H),5.76–5.77(d,1H),6.81–6.82(m,1H).

[0067] The above is only a preferred specific embodiment of the present invention. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a halcinonide intermediate triene chloride, characterized in that: The following steps are involved: (1) Using the compound of formula A as a starting material, reacting with a salt reagent of a semicarbazide compound (reagent II) in a weakly acidic buffer solution (reagent I) to generate a disemicarbazone intermediate of a diene chloride (compound B), followed by 17α-hydroxy elimination to generate compound C and compound D; (2) Compound C is reacted in the presence of a semicarbazone deprotection reagent (reagent III), post-treated, and precipitated with water to obtain compound D; The general reaction formula is as follows:

2. A method for preparing a halcinonide intermediate triene chloride according to claim 1, characterized in that: Step (1) comprises the following steps: In a weakly acidic buffer solution (reagent I), add the compound represented by formula A, add a salt reagent of a semicarbazide compound (reagent II), react at 50-100°C to generate a di-semicarbazone compound of compound A (compound B), and then eliminate the 17α-hydroxyl group. After 8-15 hours, TLC shows that the reaction of compound A is complete to generate compounds represented by formula C and formula D; The general reaction formula is as follows:

3. A method for preparing a halcinonide intermediate triene chloride according to claim 2, characterized in that: By weight ratio, weakly acidic buffer solution (reagent I): compound shown in formula A = 5-10:1; by weight ratio, salt reagent of aminourea compound (reagent II): compound shown in formula A = 0.6-3:1; reaction time: 8-15h; reaction temperature: 50-100°C.

4. A method for preparing a halcinonide intermediate triene chloride according to claim 3, characterized in that: By weight ratio, weakly acidic buffer solution (reagent I): compound shown in formula A = 7:1; by weight ratio, salt reagent of aminourea compound (reagent II): compound shown in formula A = 1.14:1; reaction time: 12h; reaction temperature: 80°C.

5. A method for preparing a halcinonide intermediate triene chloride according to claim 2, characterized in that: The weak acid buffer solution (reagent I) is prepared by diluting a weak acid buffer saline solution with a lower alcohol; including but not limited to one or more of potassium dihydrogen phosphate-hydrochloric acid-ethanol buffer solution with a pH of 2.5, acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6, acetic acid-ammonium hydroxide-methanol buffer solution with a pH of 3.7, and acetic acid-ammonium acetate-isopropanol buffer solution with a pH of 4.5; preferably, acetic acid-sodium acetate-isopropanol buffer solution with a pH of 3.6; The weakly acidic buffer solution (reagent I) is prepared by the following method: at room temperature, a weakly acidic compound is added to a volumetric flask, water is added, stirred, dissolved, and then an acidic or alkaline compound is used to adjust the pH value to the desired value, and then a lower alcohol is added to make up the volume to obtain the solution; The salt reagent of the semicarbazide compound (reagent II) is a salt formed by a semicarbazide substituted or unsubstituted at the 4-position and a monoacid, including but not limited to one or more of semicarbazide hydrobromide, semicarbazide hydrochloride, semicarbazide nitrate, semicarbazide perchlorate, 4-phenyl semicarbazide hydrochloride, and 4-phenyl semicarbazide perchlorate; preferably semicarbazide nitrate; The salt reagent of the semicarbazide compound (reagent II) is prepared by the following method: Add 4-substituted or unsubstituted semicarbazide to the reaction bottle, add lower alcohol, stir, dissolve, cool to -5-0°C, control the temperature below 0°C, add an equivalent of acid of the corresponding semicarbazide compound dropwise, react for 1.5-3.5h, filter, drain, and dry to obtain.

6. A method for preparing a halcinonide intermediate triene chloride according to claim 1, characterized in that: Step (2) comprises the following steps: After the reaction in step (1) is completed, the system is cooled, and a deprotection reagent (reagent III) of semicarbazone is added at 20-45°C for reaction for 5-8h. After TLC shows that compound C is completely converted into compound D, the reaction solution is post-treated, added to water at 0-5°C, precipitated, filtered, and dried at 50-60°C to obtain compound D. The general reaction formula is as follows:

7. A method for preparing a halcinonide intermediate triene chloride according to claim 6, characterized in that: By weight ratio: deprotection reagent of semicarbazone (reagent III): compound represented by formula A = 0.2-1:1; reaction time: 5-8h, reaction temperature: 20-45°C.

8. A method for preparing a halcinonide intermediate triene chloride according to claim 7, characterized in that: By weight ratio: deprotection reagent of semicarbazone (reagent III): compound represented by formula A = 0.45:1; reaction time: 6h, reaction temperature: 30°C.

9. A method for preparing a halcinonide intermediate triene chloride according to claim 6, characterized in that: The deprotection reagent (reagent III) of semicarbazone is selected from one or more of pyruvic acid, acetaldehyde, formaldehyde, propionaldehyde, n-butyraldehyde, sodium nitrite, cupric chloride, and 732 type cationic resin; preferably formaldehyde.

10. Halcinonide intermediate triene chloride, characterized in that The method is prepared by any one of claims 1 to 9.

Images