Industrial production method of teprenone and application thereof

Abstract

A method for the industrial production of teprenone and its application. The present invention belongs to the field of teprenone synthesis. The purpose of the present invention is to solve the technical problems of the existing teprenone synthesis method, which has a long route, many side reactions, and requires the use of special reagents. The method of the present invention comprises the following steps: first, farnesene is reacted with acetoacetate in the presence of a catalyst to obtain farnesene ketone ester, which is then decarboxylated to produce farnesene acetone, and then subjected to a reduction reaction, a halogenation reaction, and a Wittig reaction to obtain teprenone. The method avoids the shortcomings of existing processes, has fewer conversion steps in the synthesis route, and produces teprenone with high yield and purity, making it suitable for industrial production. The teprenone of the present invention is used as a drug for treating gastric diseases.

Description

Technical Field

[0001] The invention belongs to the field of teprenone synthesis, and particularly relates to an industrial production method of teprenone and application thereof. Background Art

[0002] Teprenone is a terpene compound with the molecular formula C 23 H 38 O, the chemical name of this compound is 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one, which is composed of a mixture of two geometric isomers (5E,9E,13E) and (5Z,9E,13E). It is colorless to light yellow and is an oily liquid with a special aroma.

[0003] Teprenone promotes the synthesis of high-molecular-weight glycoproteins, a key defensive factor in the gastric mucosa and gastric mucus, and increases the concentration of phospholipids in mucus, thereby protecting the gastric mucosa. Clinically, it is primarily used to improve gastric mucosal lesions (erosion, bleeding, flushing, and edema) during acute gastritis and acute exacerbations of chronic gastritis, and has a strong anti-gastric ulcer effect.

[0004] There are two main ways to synthesize teprenone reported. One is to prepare it through the Carroll reaction of geranyl linalool and alkyl acetoacetate, and the other is to use (2E, 6E)-farnesol or farnesyl acetone as the starting material to synthesize the intermediate geranyl linalool, and then to prepare it through the Carroll reaction. These methods generally have the problem of long preparation steps and the use of multiple special reagents such as Grignard reagents, etc. The reaction conditions are harsh and highly polluting, which is not conducive to industrial production. Alternatively, alkyl-substituted triphenylphosphine is used, but the ratio of trans isomers in the resulting product is very low, making it difficult to meet the requirements for the ratio of all-trans isomers in pharmaceutical standards. To overcome the above-mentioned drawbacks, it is particularly important to develop a new, economical, environmentally friendly and sustainable method to improve the efficiency of industrial production of teprenone. Summary of the Invention

[0005] The purpose of the present invention is to solve the technical problems of the existing teprenone synthesis method, which has a long route, many side reactions, and requires the use of special reagents such as geraniol and sulfonating reagents, and to provide an industrial production method of teprenone and its application.

[0006] One of the objects of the present invention is to provide an industrial production method of teprenone, which is carried out by the following steps:

[0007] Step 1: First, farnesene and acetoacetate are reacted in the presence of a catalyst to synthesize farnesene ketoate, which is then hydrolyzed and decarboxylated in the presence of a basic catalyst to obtain farnesyl acetone;

[0008] Step 2: Using a reducing agent to reduce farnesyl acetone to (5E,9E)-6,10,14-trimethyl-5,9,13-trien-2-ol;

[0009] Step 3: halogenating the product of step 2 with a halogenating agent in the presence of a catalyst to obtain a halogenated product of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol;

[0010] Step 4: reacting the product of step 3 with triphenylphosphine to obtain its hydrocarbyl phosphorus halide, dissolving the hydrocarbyl phosphorus halide in a reaction solvent, adding sodium hydroxide solution to synthesize (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane;

[0011] Step 5: reacting 4-hydroxyvaleraldehyde with the product of step 4 in a solvent in the presence of a catalyst to synthesize (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol;

[0012] Step 6: Add a solvent, acetone and a catalyst to the product of step 5, and react under nitrogen protection at room temperature to obtain teprenone.

[0013] It is further defined that in step 1, the farnesene is β-farnesene or α-farnesene.

[0014] It is further defined that the acetoacetate in step 1 includes methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isobutylpropyl acetoacetate, and tert-butyl acetoacetate.

[0015] It is further defined that the catalyst in step 1 is (acetylacetonate) dicarbonyl rhodium.

[0016] It is further defined that the alkaline catalyst in step 1 includes an aqueous solution of sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, lithium chloride, lithium bromide, or lithium iodide.

[0017] It is further defined that in step 1, the mass ratio of farnesene to acetoacetate and catalyst is (70-90):(50-70):1, and the mass ratio of farnesene ketoate to the dry weight of the alkaline catalyst is (900-1000):1.

[0018] It is further defined that the reducing agent in step 2 includes aluminum isopropoxide, and the reduction temperature is 50-120°C.

[0019] It is further defined that the mass ratio of the reducing agent to farnesyl acetone in step 2 is (1.2-1.8):1.

[0020] It is further defined that the halogenating agent in step 3 includes NCS, NBS, SOCl2, PCl3, and PCl5.

[0021] It is further defined that the catalyst in step 3 includes DMTU, pyridine, and a tertiary amine.

[0022] It is further defined that the mass ratio of the halogenating agent in step 3 to the catalyst and the product of step 2 is (4-6):1:(4-6).

[0023] It is further defined that the reaction solvent in step 4 includes dry ether, benzene, or toluene.

[0024] It is further defined that the reaction temperature in the two stages of step 4 is -15 to 10°C, and the reaction time is 2 to 7 hours.

[0025] It is further defined that in step 4, the mass ratio of the product of step 3 to triphenylphosphine is (1-5):1.

[0026] It is further defined that the catalyst in step 5 includes sodium hydroxide, sodium alkoxide, and sodium bis(trimethylsilyl)amide.

[0027] It is further defined that the solvent in step 5 includes diethyl ether, tetrahydrofuran, ethyl acetate, and dichloromethane.

[0028] It is further defined that the temperature in step 5 is -50 to 10°C.

[0029] It is further defined that in step 5, the mass ratio of the product of step 4 to 4-hydroxyvaleraldehyde and the catalyst is (4-5):1:(0.01-0.1).

[0030] It is further defined that the catalyst in step 6 is tertiary aluminum butoxide or aluminum isopropoxide.

[0031] It is further defined that the solvent in step 6 is benzene or toluene.

[0032] It is further defined that in step 6, the mass ratio of the product of step 5 to acetone and catalyst is (20-30):(27-35):1.

[0033] A second object of the present invention is to provide teprenone prepared according to the above method.

[0034] The third object of the present invention is to provide a teprenone prepared by the above method for use as a medicine for treating gastric disease.

[0035] Further defined, stomach diseases include acute gastritis, chronic gastritis, gastric ulcer, and gastric mucosal lesions.

[0036] Compared with the prior art, the present invention has the following significant effects:

[0037] 1) The present invention uses farnesene as a starting material, reacts it with acetoacetate in the presence of a catalyst to obtain farnesene ketoate, then decarboxylates it to generate farnesene acetone, and then undergoes reduction reaction, halogenation reaction, Wittig reaction and other steps to obtain teprenone.

[0038] 2) The present invention solves the problem that the current method for preparing teprenone requires the use of a Grignard reagent, vinyl magnesium chloride, which has harsh reaction conditions and high pollution, and the ratio of trans isomers in the product is very low, making it difficult to meet the requirements of the pharmaceutical standard for the ratio of all-trans isomers.

[0039] 3) The method of the present invention has a few synthetic steps and can produce teprenone with high yield and purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The synthetic route for the industrial production of teprenone according to the present invention is as follows;

[0041] Figure 2 This is the LC-MS identification chart of the product teprenone. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0043] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods, and instruments used are conventional in the art and can be obtained commercially by those skilled in the art unless otherwise specified.

[0044] As used in the following examples, the terms "comprising," "including," "having," "containing," or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0045] When amount, concentration or other value or parameter are represented with the range of scope, preferred range or a series of upper preferred value and lower preferred value limit, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value and any range lower limit or preferred value, and no matter whether this scope is disclosed separately.For example, when disclosing scope "1 to 5", described scope should be interpreted as including scope "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc.When numerical range is described in this article, unless otherwise stated, otherwise this scope is intended to include its end value and all integers and fractions within the scope.In this application specification and claims, range limitation can be combined and / or interchanged, and if these ranges are not otherwise stated, include all subranges contained therein.

[0046] The indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirement (i.e. the number of times they appear). Therefore, "a" or "an" should be interpreted as including one or at least one, and elements or components in the singular also include plural forms, unless the quantity clearly refers to only the singular form.

[0047] The specifications and sources of the reagents used in the following examples are shown in Table 1.

[0048] Table 1 Reagent specifications and sources

[0049] Reagent name Reagent specifications Manufacturer Farnesene >96％ Self-produced (CN111607545A) 4-Hydroxyvaleraldehyde >96％ AlfaChemistry Methanol >98％ AlfaChemistry Methyl acetoacetate >98％ AlfaChemistry ethanol >98％ AlfaChemistry acetone >98％ AlfaChemistry Triphenylphosphine >98％ AlfaChemistry Toluene >98％ AlfaChemistry Ether >98％ AlfaChemistry acetic acid >98％ AlfaChemistry (Acetylacetonato)dicarbonylrhodium >98％ AlfaChemistry Sodium hydroxide >99％ AlfaChemistry hydrochloric acid >97％ AlfaChemistry dichloromethane >98％ AlfaChemistry N,N'-dimethylthiourea >97％ AlfaChemistry N-Bromosuccinimide >99％ AlfaChemistry Aluminum isopropylate >98％ AlfaChemistry

[0050] The products obtained in the following examples were characterized by liquid chromatography-mass spectrometry (LC-MS). LC-MS conditions: Agilent 1260-6120 LC / MS system was used to perform qualitative and quantitative analysis of the raw materials, intermediates, and products in the reaction system. The products were separated by reverse chromatography on a ZORBAX SB-C18 (particle size of 1.8 μm; 2.1×50 mm) with a flow rate of 0.2 mL / min, an injection volume of 1 μL, a column oven at 40°C, a positive ion detection mode, a detection voltage of 1.56 kV, a nebulizing gas (N2) flow rate of 1.5 L / min, a drying gas (N2) pressure of 100 kPa, an ion collection time of 30 ms, a collision energy of 50%, and an MS scan range of 100-600 m / z. The samples were quantitatively analyzed by an external standard method.

[0051] Example 1: The industrial production method of teprenone of this embodiment is carried out by the following steps:

[0052] Step 1:

[0053] First, carry out the following reaction:

[0054]

[0055] To a reaction vessel, 1075 g of β-farnesene represented by formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetonato)rhodium dicarbonyl were added, stirred evenly, and reacted at 70° C. for 15 h. The mixture was then subjected to distillation and column chromatography to obtain methyl farnesyl ketoate with a purity of 85% and a yield of 80%.

[0056] Then proceed with the following reaction:

[0057]

[0058] To 1438 g of methyl farnesyl ketone was added 150 g of a 1% aqueous solution of sodium hydroxide, stirred evenly, and then heated to 90° C. for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid until neutral. The solvent and volatile components were removed by distillation, and then the mixture was subjected to distillation and column chromatography to obtain farnesyl ketone represented by formula (IV) with a purity of 90% and a yield of 92%.

[0059] Step 2:

[0060] Carry out the following reaction:

[0061]

[0062] To 1260 g of farnesyl acetone represented by formula (IV), 2040 g of aluminum isopropoxide and 5 L of benzene were added, and the reaction was carried out at 60° C. for 30 min. The reflux at the top of the fractionating tower was adjusted to maintain the top temperature between 55-60° C. to fractionate the by-product acetone, and then the reactor temperature was raised to 82-83° C., and the top reflux ratio was adjusted to 11. When the top temperature reached 80° C., the reaction was stopped, and the reactor temperature was lowered to below 40° C. The product was added to 5 L of a 15% hydrochloric acid solution with stirring, and the mixture was stirred for 30 min to separate the layers. The oil layer was washed with water twice, and the solvent was removed to obtain (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) with a purity of 87% and a yield of 82%.

[0063] Step 3:

[0064] Carry out the following reaction:

[0065]

[0066] To 1231 g of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) was added 5 L of dichloromethane, and after stirring, 243 g of N,N′-dimethylthiourea (DMTU) and 1245 g of N-bromosuccinimide (NBS) were added in sequence. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with 5 L of dichloromethane, and the organic layer was distilled and purified to obtain 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) with a purity of 85% and a yield of 80%.

[0067] Step 4:

[0068] Carry out the following reaction:

[0069]

[0070] 566 g of triphenylphosphine was added to 1304 g of 14-bromo-2,6,10-trimethyl-triene represented by formula (VI), and the mixture was reacted at 0°C for 6 h to obtain alkyl phosphonium bromide. 5 L of toluene was then added to dissolve the mixture, and then 20 g of a 20% sodium hydroxide solution was added. The mixture was reacted at 0°C for 2 h, and the mixture was distilled and chromatographed to obtain (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) with a purity of 88% and a yield of 70%.

[0071] Step 5:

[0072] Carry out the following reaction:

[0073]

[0074] To 1525 g of (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphine represented by formula (VII) were added 5 L of anhydrous tetrahydrofuran and 5 g of sodium bis(trimethylsilyl)amide. After stirring, 2 L of a methanol solution containing 320 g of 4-hydroxyvaleraldehyde represented by formula (IX) was added. After sampling and testing to confirm the completion of the reaction, the mixture was distilled and chromatographed to obtain (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraene-2-ol represented by formula (VIII) with a purity of 92% and a yield of 91%.

[0075] Step 6:

[0076] Carry out the following reaction:

[0077]

[0078] To 1330 g of (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol represented by formula (VIII) were added 4 L of toluene, 2 L of acetone, and 50 g of aluminum isopropoxide. The mixture was reacted at room temperature for 24 hours under nitrogen protection. After distillation and concentration, the mixture was separated by column chromatography to obtain teprenone with a purity of 99% and a yield of 85%.

[0079] The LC-MS characterization results of the product teprenone are as follows: m / z 331.2998 [M+H] + ,m / z 353.2819[M+Na] + , the results are shown in Figure 2 .

[0080] Example 2: The industrial production method of teprenone of this embodiment is carried out by the following steps:

[0081] Step 1:

[0082] First, carry out the following reaction:

[0083]

[0084] 1075 g of β-farnesene represented by formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetonato)rhodium dicarbonyl were added to a reaction vessel, stirred evenly, and reacted at 70° C. for 15 h. The solvent and volatile components were distilled off, and then distilled and column chromatography were performed to obtain methyl farnesyl ketoate with a purity of 85% and a yield of 80%.

[0085] Then proceed with the following reaction:

[0086]

[0087] To 1438 g of methyl farnesyl ketone was added 150 g of a 1% aqueous solution of sodium hydroxide, stirred evenly, and then heated to 90° C. for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid until neutral. The solvent and volatile components were removed by distillation, and then the mixture was subjected to distillation and column chromatography to obtain farnesyl ketone represented by formula (IV) with a purity of 90% and a yield of 92%.

[0088] Step 2:

[0089] Carry out the following reaction:

[0090]

[0091] To 1260 g of farnesyl acetone represented by formula (IV), 2040 g of aluminum isopropoxide and 5 L of benzene were added, and the reaction was carried out at 60° C. for 30 min. The reflux at the top of the fractionating tower was adjusted to maintain the top temperature between 55-60° C. to fractionate the by-product acetone. The reactor temperature was then raised to 82-83° C., the top reflux ratio was adjusted to 12, and the reaction was stopped when the top temperature reached 80° C. The reactor temperature was lowered to below 40° C., and the product was added to 5 L of a 15% hydrochloric acid solution under stirring. The product was stirred for 30 min, separated, and the oil layer was washed with water twice. The solvent was removed to obtain (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) with a purity of 87% and a yield of 82%.

[0092] Step 3:

[0093] Carry out the following reaction:

[0094]

[0095] To 1231 g of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) was added 5 L of dichloromethane, and after stirring, 243 g of N,N′-dimethylthiourea (DMTU) and 1245 g of N-bromosuccinimide (NBS) were added in sequence. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with 5 L of dichloromethane, and the organic layer was distilled and purified to obtain 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) with a purity of 85% and a yield of 80%.

[0096] Step 4:

[0097] Carry out the following reaction:

[0098]

[0099] 566 g of triphenylphosphine was added to 1304 g of 14-bromo-2,6,10-trimethyl-triene represented by formula (VI), and the mixture was reacted at 0°C for 6 h to obtain alkyl phosphonium bromide. 5 L of toluene was then added to dissolve the mixture, and then 20 g of a 20% aqueous solution of sodium hydroxide was added. The mixture was reacted at 0°C for 2 h, and the mixture was distilled and chromatographed to obtain (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) with a purity of 88% and a yield of 70%.

[0100] Step 5:

[0101] Carry out the following reaction:

[0102]

[0103] To 1525 g of (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) were added 5 L of anhydrous ethyl acetate and 10 g of sodium hydroxide. After stirring, 2 L of a methanol solution containing 320 g of 4-hydroxyvaleraldehyde represented by formula (IX) was added. After sampling and testing to confirm the completion of the reaction, distillation and chromatography were performed to obtain (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraene-2-ol represented by formula (VIII) with a purity of 89% and a yield of 87%.

[0104] Step 6:

[0105] Carry out the following reaction:

[0106]

[0107] To 1330 g of (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol represented by formula (VIII) were added 4 L of toluene, 2 L of acetone, and 50 g of aluminum isopropoxide. The mixture was reacted at room temperature for 24 hours under nitrogen protection. After distillation and concentration, the mixture was separated by column chromatography to obtain teprenone with a purity of 99% and a yield of 85%.

[0108] Example 3: The industrial production method of teprenone in this example is carried out by the following steps:

[0109] Step 1:

[0110] First, carry out the following reaction:

[0111]

[0112] 1075 g of β-farnesene represented by formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetonato)rhodium dicarbonyl were added to a reaction vessel, stirred evenly, and reacted at 70° C. for 15 h. The solvent and volatile components were distilled off, and then distilled and column chromatography were performed to obtain methyl farnesyl ketoate with a purity of 85% and a yield of 80%.

[0113] Then proceed with the following reaction:

[0114]

[0115] To 1438 g of methyl farnesyl ketone was added 150 g of a 1% aqueous solution of sodium hydroxide, stirred evenly, and then heated to 90° C. for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid until neutral. The solvent and volatile components were removed by distillation, and then the mixture was subjected to distillation and column chromatography to obtain farnesyl ketone represented by formula (IV) with a purity of 90% and a yield of 92%.

[0116] Step 2:

[0117] Carry out the following reaction:

[0118]

[0119] To 1260 g of farnesyl acetone represented by formula (IV), 2040 g of aluminum isopropoxide and 5 L of benzene were added, and the reaction was carried out at 60° C. for 30 min. The reflux at the top of the fractionating tower was adjusted to maintain the top temperature between 55-60° C. to fractionate the by-product acetone. The reactor temperature was then raised to 82-83° C., the top reflux ratio was adjusted to 11, and the reaction was stopped when the top temperature reached 80° C. The reactor temperature was lowered to below 40° C., and the product was added to 5 L of a 15% hydrochloric acid solution with stirring. The product was stirred for 30 min to separate the layers. The oil layer was washed with water twice, and the solvent was removed to obtain (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) with a purity of 87% and a yield of 82%.

[0120] Step 3:

[0121] Carry out the following reaction:

[0122]

[0123] To 1231 g of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) was added 5 L of dichloromethane, and after stirring, 243 g of N,N′-dimethylthiourea (DMTU) and 1245 g of N-bromosuccinimide (NBS) were added in sequence. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with 5 L of dichloromethane, and the organic layer was distilled and purified to obtain 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) with a purity of 85% and a yield of 80%.

[0124] Step 4:

[0125] Carry out the following reaction:

[0126]

[0127] To 1304 g of 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) was added 566 g of triphenylphosphine, and the mixture was reacted at 0° C. for 6 h to obtain a hydrocarbyl phosphonium bromide. 5 L of toluene was then added thereto and dissolved, followed by addition of 20 g of a 20% aqueous solution of sodium hydroxide. The mixture was reacted at 0° C. for 2 h, and distilled to obtain (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) with a purity of 88% and a yield of 70%.

[0128] Step 5:

[0129] Carry out the following reaction:

[0130]

[0131] To 1525 g of (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphine represented by formula (VII) were added 5 L of anhydrous ether and 15 g of sodium ethoxide. After stirring, 2 L of a methanol solution containing 320 g of 4-hydroxyvaleraldehyde represented by formula (IX) was added. After sampling and testing to confirm the completion of the reaction, distillation and chromatography were performed to obtain (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraene-2-ol represented by formula (VIII) with a purity of 83% and a yield of 67%.

[0132] Step 6:

[0133] Carry out the following reaction:

[0134]

[0135] To 1330 g of (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol represented by formula (VIII) were added 4 L of toluene, 2 L of acetone, and 50 g of aluminum isopropoxide. The mixture was reacted at room temperature for 24 hours under nitrogen protection. After distillation and concentration, the mixture was separated by column chromatography to obtain teprenone with a purity of 99% and a yield of 85%.

[0136] Example 4: The industrial production method of teprenone of this embodiment is carried out by the following steps:

[0137] Step 1:

[0138] First, carry out the following reaction:

[0139]

[0140] To a reaction vessel, 1075 g of α-farnesene represented by formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetonato)rhodium dicarbonyl were added, stirred evenly, and reacted at 70° C. for 15 h. The solvent and volatile components were distilled off, and then the mixture was subjected to distillation and column chromatography to obtain methyl farnesyl ketoate with a purity of 77% and a yield of 29%.

[0141] Then proceed with the following reaction:

[0142]

[0143] To 1438 g of methyl farnesyl ketone was added 150 g of a 1% aqueous solution of sodium hydroxide, stirred evenly, and then heated to 90° C. for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid until neutral. The solvent and volatile components were removed by distillation, and then the mixture was subjected to distillation and column chromatography to obtain farnesyl ketone represented by formula (IV) with a purity of 89% and a yield of 91%.

[0144] Step 2:

[0145] Carry out the following reaction:

[0146]

[0147] To 1260 g of farnesyl acetone represented by formula (IV), 2040 g of aluminum isopropoxide and 5 L of benzene were added, and the reaction was carried out at 60° C. for 30 min. The reflux at the top of the fractionating tower was adjusted to maintain the top temperature between 55-60° C. to fractionate the by-product acetone. The reactor temperature was then raised to 82-83° C., the top reflux ratio was adjusted to 12, and the reaction was stopped when the top temperature reached 80° C. The reactor temperature was lowered to below 40° C., and the product was added to 5 L of a 15% hydrochloric acid solution under stirring. The product was stirred for 30 min, separated, and the oil layer was washed with water twice. The solvent was removed to obtain (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) with a purity of 87% and a yield of 82%.

[0148] Step 3:

[0149] Carry out the following reaction:

[0150]

[0151] To 1231 g of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) was added 5 L of dichloromethane, and after stirring, 243 g of N,N′-dimethylthiourea (DMTU) and 1245 g of N-bromosuccinimide (NBS) were added in sequence. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with 5 L of dichloromethane, and the organic layer was distilled and purified to obtain 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) with a purity of 85% and a yield of 80%.

[0152] Step 4:

[0153] Carry out the following reaction:

[0154]

[0155] To 1304 g of 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) was added 566 g of triphenylphosphine, and the mixture was reacted at 0° C. for 6 h to obtain a hydrocarbyl phosphonium bromide. 5 L of toluene was then added thereto and dissolved, followed by addition of 20 g of a 20% aqueous solution of sodium hydroxide. The mixture was reacted at 0° C. for 2 h, and distilled to obtain (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) with a purity of 88% and a yield of 70%.

[0156] Step 5:

[0157] Carry out the following reaction:

[0158]

[0159] To 1525 g of (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) were added 5 L of anhydrous dichloromethane and 20 g of sodium propoxide. After stirring, 2 L of a methanol solution containing 320 g of 4-hydroxyvaleraldehyde represented by formula (IX) was added. After sampling and testing to confirm the completion of the reaction, the mixture was distilled and chromatographed to obtain (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraene-2-ol represented by formula (VIII) with a purity of 83% and a yield of 70%.

[0160] Step 6:

[0161] Carry out the following reaction:

[0162]

[0163] To 1330 g of (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol represented by formula (VIII) were added 4 L of toluene, 2 L of acetone, and 50 g of aluminum isopropoxide. The mixture was reacted at room temperature for 24 hours under nitrogen protection. After distillation and concentration, the mixture was separated by column chromatography to obtain teprenone with a purity of 99% and a yield of 85%.

[0164] Example 5:

[0165] Step 1:

[0166] First, the in-situ extraction fermentation broth obtained by fermentation with the strain described in patent CN111607545A is distilled and concentrated to obtain a concentrate with a farnesene concentration of 75%, which is used as a raw material for preparing teprenone;

[0167] Then the following reaction is carried out:

[0168]

[0169] To a reaction vessel, 1075 g of a concentrated solution of β-farnesene represented by formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetonato)rhodium dicarbonyl were added, stirred evenly, and reacted at 70° C. for 15 h. The mixture was then distilled and column chromatographed to obtain methyl farnesyl ketoate with a purity of 87% and a yield of 79%.

[0170] Then proceed with the following reaction:

[0171]

[0172] To 1438 g of methyl farnesyl ketone was added 150 g of a 1% aqueous solution of sodium hydroxide, stirred evenly, and then heated to 90° C. for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid until neutral. The solvent and volatile components were removed by distillation, and then the mixture was subjected to distillation and column chromatography to obtain farnesyl ketone represented by formula (IV) with a purity of 90% and a yield of 92%.

[0173] Step 2:

[0174] Carry out the following reaction:

[0175]

[0176] To 1260 g of farnesyl acetone represented by formula (IV), 2040 g of aluminum isopropoxide and 5 L of benzene were added, and the reaction was carried out at 60° C. for 30 min. The reflux at the top of the fractionating tower was adjusted to maintain the top temperature between 55-60° C. to fractionate the by-product acetone. The reactor temperature was then raised to 82-83° C., the top reflux ratio was adjusted to 12, and the reaction was stopped when the top temperature reached 80° C. The reactor temperature was lowered to below 40° C., and the product was added to 5 L of a 15% hydrochloric acid solution under stirring. The product was stirred for 30 min, separated, and the oil layer was washed with water twice. The solvent was removed to obtain (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) with a purity of 87% and a yield of 82%.

[0177] Step 3:

[0178] Carry out the following reaction:

[0179]

[0180] To 1231 g of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol represented by formula (V) was added 5 L of dichloromethane, and after stirring, 243 g of N,N′-dimethylthiourea (DMTU) and 1245 g of N-bromosuccinimide (NBS) were added in sequence. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the mixture was diluted with 5 L of dichloromethane, and the organic layer was distilled and purified to obtain 14-bromo-2,6,10-trimethyl-triene represented by formula (VI) with a purity of 85% and a yield of 80%.

[0181] Step 4:

[0182] Carry out the following reaction:

[0183]

[0184] 566 g of triphenylphosphine was added to 1304 g of 14-bromo-2,6,10-trimethyl-triene represented by formula (VI), and the mixture was reacted at 0°C for 6 h to obtain alkyl phosphonium bromide. 5 L of toluene was then added to dissolve the mixture, and then 20 g of a 20% aqueous solution of sodium hydroxide was added. The mixture was reacted at 0°C for 2 h, and the mixture was distilled and chromatographed to obtain (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphane represented by formula (VII) with a purity of 88% and a yield of 70%.

[0185] Step 5:

[0186] Carry out the following reaction:

[0187]

[0188] To 1525 g of (5E,9E)-10,14-dimethyl-5,9,13-triene-2-ylidene)triphenyl-15-phosphine represented by formula (VII) were added 5 L of anhydrous tetrahydrofuran and 5 g of sodium bis(trimethylsilyl)amide. After stirring, 2 L of a methanol solution containing 320 g of 4-hydroxyvaleraldehyde represented by formula (IX) was added. After sampling and testing to confirm the completion of the reaction, distillation and chromatography were performed to obtain (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraene-2-ol represented by formula (VIII) with a purity of 92% and a yield of 91%.

[0189] Step 6:

[0190] Carry out the following reaction:

[0191]

[0192] To 1330 g of (5E,9E,13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol represented by formula (VIII) were added 4 L of toluene, 2 L of acetone, and 50 g of aluminum isopropoxide. The mixture was reacted at room temperature for 24 hours under nitrogen protection. After distillation and concentration, the mixture was separated by column chromatography to obtain teprenone with a purity of 99% and a yield of 85%.

[0193] The foregoing are merely preferred embodiments of the present invention. These embodiments are all different implementations based on the overall concept of the present invention. The scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. An industrial production method of teprenone, characterized in that, The method proceeds as follows: Step 1: First, farnesene and acetoacetate are reacted in the presence of a catalyst to synthesize farnesene ketoate, which is then hydrolyzed and decarboxylated in the presence of a basic catalyst to obtain farnesyl acetone; Step 2: Using a reducing agent, farnesyl acetone is reduced to (5E,9E)-6,10,14-trimethyl-5,9,13-trien-2-ol; Step 3: halogenating the product of step 2 with a halogenating agent in the presence of a catalyst to obtain a halogenated product of (5E,9E)-6,10,14-trimethyl-5,9,13-triene-2-ol; Step 4: reacting the product of Step 3 with triphenylphosphine to obtain its hydrocarbyl phosphorus halide, dissolving the hydrocarbyl phosphorus halide in a reaction solvent, and adding sodium hydroxide solution to synthesize (5E,9E)-10,14-dimethyl-5,9,13-trien-2-ylidene)triphenyl-15-phosphane; Step 5: In the presence of a catalyst, 4-hydroxyvaleraldehyde and the product of step 4 are reacted in a solvent to synthesize (5E, 9E, 13E)-6,10,14,18-tetramethyl-5,9,13,17-tetraen-2-ol; Step 6: Add a solvent, acetone and a catalyst to the product of step 5, and react under nitrogen protection at room temperature to obtain teprenone.

2. The method according to claim 1, characterized in that In step 1, the farnesene is β-farnesene or α-farnesene, the acetoacetate includes methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isobutylpropyl acetoacetate, and tert-butyl acetoacetate, the catalyst is (acetylacetonate) dicarbonyl rhodium, and the alkaline catalyst includes an aqueous solution of sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, lithium chloride, lithium bromide, and lithium iodide. The mass ratio of farnesene to acetoacetate and catalyst is (70-90):(50-70):1, and the mass ratio of the dry weight of farnesene ketoate ester to the alkaline catalyst is (900-1000):

1.

3. The method according to claim 1, characterized in that In step 2, the reducing agent includes aluminum isopropoxide, the reduction temperature is 50-120° C., and the mass ratio of the reducing agent to farnesyl acetone is (1.2-1.8):

1.

4. The method according to claim 1, wherein In step 3, the halogenating agent includes NCS, NBS, SOCl2, PCl3, and PCl5, the catalyst includes DMTU, pyridine, and a tertiary amine, and the mass ratio of the halogenating agent to the catalyst and the product of step 2 is (4-6): 1: (4-6).

5. The method according to claim 1, wherein The reaction solvent in step 4 includes dry ether, benzene, and toluene. The reaction temperature in both stages is -15~10°C, the reaction time is 2-7 h, and the mass ratio of the product in step 3 to triphenylphosphine is (1-5):

1.

6. The method according to claim 1, characterized in that In step 5, the catalyst includes sodium hydroxide, sodium alkoxide, and sodium bis(trimethylsilyl)amide; the solvent includes diethyl ether, tetrahydrofuran, ethyl acetate, and dichloromethane; the temperature is -50~10°C; and the mass ratio of the product of step 4 to 4-hydroxyvaleraldehyde and the catalyst is (4~5):1:(0.01-0.1).

7. The method according to claim 1, characterized in that In step 6, the catalyst is tertiary aluminum butoxide or aluminum isopropoxide, the solvent is benzene or toluene, and the mass ratio of the product of step 5 to acetone and the catalyst is (20-30):(27-35):1.

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