CN117964484A - A method for synthesizing farnesene and its derivatives and its application - Google Patents

Abstract

A method for synthesizing gefarnate from farnesene and its derivatives and its application. The present invention belongs to the field of gefarnate synthesis. The purpose of the present invention is to solve the technical problems of the existing gefarnate synthesis method, such as long route, many side reactions, large toxicity and irritation of reaction reagents and low yield. The present invention uses farnesene as a starting material, reacts it with acetoacetate under the action of a catalyst to obtain farnesene ketoate, then decarboxylates it to generate farnesyl acetone, and then undergoes haloform reaction, esterification reaction and other steps to obtain gefarnate. The method of the present invention has fewer conversion steps in the synthesis route and a high yield for preparing gefarnate. The gefarnate of the present invention is used as a medicine for treating gastric disease.

Description

A method for synthesizing farnesene and its derivatives and its application

Technical Field

The invention belongs to the field of gefarnate synthesis, and specifically relates to a method for synthesizing gefarnate using farnesene and its derivatives and application thereof.

Background technique

Gefate can act on gastric mucosal epithelial cells, enhance their anti-ulcer factors, regulate gastrointestinal function and gastric acid secretion, and strengthen mucosal protection, thereby preventing and treating gastric and duodenal ulcers, acute and chronic gastritis, colitis, and gastric spasm.

The main synthetic routes of gefarbens reported so far are: (1) Patent CN101973879 adopts the method of first chlorinating acacia acetic acid and then reacting it with geraniol to generate gefarbens. This method must use chlorinated reagents such as thionyl chloride and phosphorus oxychloride, which are irritating and toxic and not conducive to environmental protection. (2) Patent CN102146039A adopts the method of reacting triphenylphosphine, diisopropyl azodicarboxylate (DIPA) with acacia acetic acid and geraniol to generate gefarbens. The disadvantages of this method are that more reagents are used, the cost is high, the control requirements for reaction conditions are also very high, and triphenylphosphine is relatively toxic. (3) Patent CN201110267137 uses nerolidol as a substrate to synthesize farnesene acetic acid through halogenation, decarboxylation and other pathways, but the process has a long reaction step and a low total yield. (4) Patent CN103012140A uses geranylacetone and phosphorus ylide reagent as substrates, synthesizes farnesene ethyl acetate through Witting reaction, then hydrolyzes to generate farnesene acetic acid, and then synthesizes geraniol with xylene as solvent under the action of inhibitor (such as phenol, hydroquinone, nitrophenol). The reaction temperature of this method is high, there are many by-products, the energy consumption of industrial production is large, and the toxicity and danger of xylene also increase with the increase of temperature. Therefore, it is urgent to develop a low-cost, simplified reaction industrial production process.

Summary of the invention

The purpose of the present invention is to solve the technical problems of the existing gefarnate synthesis method, such as long route, many side reactions, high toxicity and irritation of reaction reagents and low yield, and to provide a method for synthesizing gefarnate with farnesene and its derivatives and its application.

One of the objects of the present invention is to provide a method for synthesizing farnesyl esters with farnesene and its derivatives, which method is carried out according to the following steps:

Step 1: First, farnesene and acetoacetate are reacted in the presence of a catalyst to synthesize farnesene ketoate, and then the reaction is hydrolyzed and decarboxylated in the presence of an alkaline catalyst to obtain farnesene acetone;

Step 2: using a halogenating agent to carry out a haloform reaction on farnesyl acetone to obtain (4E, 8E, 12E)-5,9,13-trimethyl sodium tetradecanoate;

Step 3: Under the action of a catalyst, an esterification agent is used to carry out an esterification reaction on the product of step 2 to obtain a gefarin ester.

It is further defined that in step 1, the farnesene is one of β-farnesene and α-farnesene or a mixture of the two in any ratio.

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

It is further defined that the catalyst in step 1 is a rhodium-containing compound.

In a further embodiment, the rhodium-containing compound comprises rhodium (acetylacetonate) dicarbonyl.

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.

It is further defined that in step 1, the mass ratio of farnesene to acetoacetate and catalyst is (70-90):(50-70):1.

It is further defined that in step 1, the mass ratio of the farnesyl ketone ester to the dry weight of the alkaline catalyst is (900-1000):1.

It is further defined that in step 2, the halogenating reagent includes a mixture of elemental iodine and sodium hydroxide solution, and a sodium hypochlorite solution.

It is further defined that when the halogenating agent is a mixture of elemental iodine and sodium hydroxide solution, the mass ratio of elemental iodine, sodium hydroxide and farnesyl acetone is (2-5):(0.5-2):1, and when the halogenating agent is a sodium hypochlorite solution, the mass ratio of sodium hypochlorite to farnesyl acetone is (0.5-2.5):1.

It is further defined that the haloform reaction temperature in step 2 is 20-70°C.

In a further embodiment, the esterification agent in step 3 comprises 1-bromo-3,7-dimethyl-2,6-octadiene.

It is further defined that the catalyst in step 3 is sodium p-toluenesulfonate.

It is further defined that in step 3, the mass ratio of the product of step 2, the esterification reagent and the catalyst is (15-25):(10-20):1.

It is further defined that the esterification reaction temperature in step 3 is 50-140°C.

A second object of the present invention is to provide a gefarmed ester prepared by the above method.

The third object of the present invention is to provide a method for preparing gefarnate for use as a medicine for treating gastric disease.

Further limited, gastric diseases include acute gastritis, chronic gastritis, gastric ulcer, and gastric mucosal lesions.

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

1) The present invention uses farnesene as a starting material, reacts it with acetoacetate under the action of a catalyst to obtain farnesene ketoate, then decarboxylates it to generate farnesene acetone, and then undergoes haloform reaction, esterification reaction and other steps to obtain gefarnesyl ester. The method of the present invention has fewer conversion steps in the synthetic route and a high yield for preparing gefarnesyl ester.

2) The synthetic method of the present invention has easy-to-obtain raw materials and easy-to-separate intermediates, which can reduce product losses caused in traditional separation processes, and make the overall reaction process have higher purity and yield.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is the synthetic route diagram of gefarbenyl ester of the present invention;

FIG2 is a hydrogen NMR spectrum of the product gefarnate of Example 1;

FIG. 3 is a carbon NMR spectrum of the product gefarnate of Example 1.

Detailed ways

In order to make the purpose, technical solution 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 used to limit the present invention.

The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

The terms "comprising," "including," "having," "containing," or any other variation thereof, as used in the following examples, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

When equivalent, concentration or other value or parameter is represented by the range limited by range, preferred range or a series of upper preferred value and lower preferred value, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the scope is disclosed separately. For example, when disclosing range "1 to 5", described range should be interpreted as including range "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, the scope is intended to include its end value and all integers and fractions within the scope. In the present application specification and claims, range limitation can be combined and/or interchanged, if these ranges are not otherwise stated, include all sub-ranges contained therein.

The indefinite articles "a" and "an" before the elements or components of the present invention have no limitation on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the number obviously refers to the singular form only.

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

Table 1 Reagent specifications and sources

The products obtained in the following examples were characterized by 400M nuclear magnetic resonance, instrument model: Bruker ASCEND 400M nuclear magnetic resonance. Liquid chromatography-mass spectrometry (LC-MS) conditions: liquid chromatography-Q-TOF high-resolution mass spectrometry, Brooke Maxis UHRTOF, qualitatively and quantitatively analyzed the raw materials, intermediates and products in the reaction system, and the products were separated by reverse chromatography ZORBAXSB-C18 (particle size of 1.8μm; 2.1×50mm), flow rate of 0.2mL/min, injection volume of 1μL, column oven of 40°C, detection mode of positive ion mode, detection voltage of 1.56kV, nebulizer gas (N ₂ ) flow rate of 1.5L/min, dry gas (N ₂ ) pressure of 100kPa, ion collection time of 30ms, collision energy of 50%, MS scanning range of 100-600m/z, and quantitative analysis of the samples was performed by external standard method.

Embodiment 1: A kind of synthetic method of gefarnate of this embodiment is carried out according to the following steps:

step 1:

First, the following reaction is carried out:

1075 g of β-farnesene as shown in formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetone) dicarbonyl rhodium were added to a reaction container, stirred evenly, reacted at 70° C. for 15 h, and then distilled and column chromatographed to obtain methyl farnesene ketone with a purity of 92% and a yield of 89%;

Then the following reaction is carried out:

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

Step 2:

Carry out the following reaction:

To 270 g of farnesyl acetone of formula (IV), 2 L of 10 wt% sodium hydroxide solution and 780 g of iodine were added, and the mixture was heated to 60° C. and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained and purified to obtain (4E, 8E, 12E)-5,9,13-trimethyltetradecanoate of formula (V) with a purity of 91% and a yield of 81%.

Step 3:

Carry out the following reaction:

A total of 1 L of a methanol solution containing 285 g of (4E, 8E, 12E)-5,9,13-trimethyltetradecanoic acid sodium represented by formula (V) was added to a reaction vessel, followed by the addition of 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid. The mixture was stirred evenly and heated to reflux at 90° C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefarmed ester with a purity of 95% and a yield of 80%.

¹ H NMR (400 MHz, CDCl ₃ ) of the obtained product gefarnate ester δ 5.32m 1H, 5.08m 4H, 4.57d (J = 7.06) 2H, 2.31d (J = 2.56) 2H, 2.29d (J = 2.25) 2H, 2.05m 12H, 1.96dt (J = 9.50, 5.59) 6H, 1.68m 9H, 1.66m 6H.

¹³ C NMR (101 MHz, CDCl ₃ ) δ of the obtained gefarmate was 173.34, 141.94, 136.54, 134.96, 131.71, 131.15, 124.39, 124.06, 123.77, 123.14, 118.49, 61.20, 39.71, 39.53, 34.52, 31.87, 26.75, 26.70, 26.53, 26.30, 23.47, 23.38, 17.64, 17.61, 16.41, 15.96, 15.94.

Embodiment 2: A kind of synthetic method of gefarnate of this embodiment is carried out according to the following steps:

step 1:

First, the following reaction is carried out:

1075 g of α-farnesene represented by formula (III), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetone) dicarbonyl rhodium were added to a reaction container, stirred evenly, reacted at 70° C. for 15 h, and then distilled and column chromatographed to obtain methyl farnesene ketone with a purity of 87% and a yield of 83%;

Then the following reaction is carried out:

To 1438 g of methyl farnesyl ketone, 150 g of an aqueous solution of sodium hydroxide having a mass concentration of 1% was added, and the mixture was stirred evenly, and then heated to 90° C. for reaction for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid to neutrality. The solvent and volatile components were removed by distillation, and then the farnesyl ketone represented by formula (IV) was obtained by distillation and column chromatography, with a purity of 90% and a yield of 93%;

Step 2:

Carry out the following reaction:

To 270 g of farnesyl acetone represented by formula (IV), 2 L of 10 wt% sodium hydroxide solution and 780 g of iodine were added, and the mixture was heated to 60° C. and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained and purified to obtain (4E, 8E, 12E)-5,9,13-trimethyltetradecanoate represented by formula (V) with a purity of 87% and a yield of 81%.

Step 3:

Carry out the following reaction:

A total of 1 L of a methanol solution containing 285 g of (4E, 8E, 12E)-5,9,13-trimethyltetradecanoic acid sodium represented by formula (V) was added to a reaction vessel, followed by the addition of 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid. The mixture was stirred evenly and heated to reflux at 90° C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefarmed ester with a purity of 95% and a yield of 80%.

Embodiment 3: A kind of synthetic method of gefarnate of this embodiment is carried out by the following steps:

step 1:

First, the following reaction is carried out:

1075 g of a 1:1 mixture of α-farnesene and β-farnesene as shown in formula (II)-(III), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetone) dicarbonyl rhodium were added to a reaction container, stirred evenly, reacted at 70° C. for 15 h, and then distilled and column chromatographed to obtain methyl farnesenone with a purity of 90% and a yield of 94%;

Then the following reaction is carried out:

To 1438 g of methyl farnesyl ketone, 150 g of an aqueous solution of sodium hydroxide having a mass concentration of 1% was added, and the mixture was stirred evenly, and then heated to 90° C. for reaction for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid to neutrality. The solvent and volatile components were removed by distillation, and then the farnesyl ketone represented by formula (IV) was obtained by distillation and column chromatography, with a purity of 88% and a yield of 87%;

Step 2:

Carry out the following reaction:

To 270 g of farnesyl acetone of formula (IV), 2 L of 10 wt% sodium hydroxide solution and 780 g of iodine were added, and the mixture was heated to 60° C. and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained and purified to obtain (4E, 8E, 12E)-5,9,13-trimethyltetradecanoate of formula (V) with a purity of 89% and a yield of 80%.

Step 3:

Carry out the following reaction:

A total of 1 L of a methanol solution containing 285 g of (4E, 8E, 12E)-5,9,13-trimethyltetradecanoic acid sodium represented by formula (V) was added to a reaction vessel, followed by the addition of 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid. The mixture was stirred evenly and heated to reflux at 90° C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefarmed ester with a purity of 95% and a yield of 80%.

Embodiment 4: A kind of synthetic method of gefarnate of this embodiment is carried out by the following steps:

step 1:

Firstly, the in-situ extraction fermentation liquid fermented by the strain 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 gefarnate;

Then the following reaction is carried out:

1075 g of β-farnesene as shown in formula (II), 714 g of methyl acetoacetate, 5 L of ethanol, and 12 g of (acetylacetone) dicarbonyl rhodium were added to a reaction container, stirred evenly, reacted at 70° C. for 15 h, and then distilled and column chromatographed to obtain methyl farnesene ketone with a purity of 87% and a yield of 79%;

Then carry out the following reaction:

To 1438 g of methyl farnesyl ketone, 150 g of an aqueous solution of sodium hydroxide having a mass concentration of 1% was added, and the mixture was stirred evenly, and then heated to 90° C. for reaction for 4 h. After cooling, the mixture was separated, and the organic layer was neutralized with acetic acid to neutrality. The solvent and volatile components were removed by distillation, and then the farnesyl ketone represented by formula (IV) was obtained by distillation and column chromatography, with a purity of 83% and a yield of 82%;

Step 2:

Carry out the following reaction:

To 270 g of farnesyl acetone represented by formula (IV), 1.5 L of a 20 wt% sodium hypochlorite solution was added, and the mixture was heated to 60° C. and stirred for 4 h. After cooling, the mixture was separated, and the aqueous layer was retained and purified to obtain (4E, 8E, 12E)-5,9,13-trimethyltetradecanoate represented by formula (V) with a purity of 80% and a yield of 82%.

Step 3:

Carry out the following reaction:

A total of 1 L of a methanol solution containing 285 g of (4E, 8E, 12E)-5,9,13-trimethyltetradecanoic acid sodium represented by formula (V) was added to a reaction vessel, followed by the addition of 220 g of 1-bromo-3,7-dimethyl-2,6-octadiene and 15 g of p-toluenesulfonic acid. The mixture was stirred evenly and heated to reflux at 90° C. After the reaction was completed, the mixture was separated, concentrated by distillation, and analyzed by column chromatography to obtain gefarmed ester with a purity of 95% and a yield of 80%.

The above are only preferred specific embodiments of the present invention, which are all different implementations based on the overall concept of the present invention, and the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims (10)

1. A method for synthesizing gefarnate by farnesene and derivatives thereof, which is characterized by comprising the following steps:

Step 1: synthesizing a farnesene keto ester by using farnesene and acetoacetate under the action of a catalyst, and hydrolyzing and decarboxylating the farnesene and the acetoacetate under the action of an alkaline catalyst to obtain farnesene acetone;

Step 2: carrying out haloform reaction on farnesyl acetone by adopting a halogenating reagent to obtain (4E, 8E, 12E) -5,9, 13-trimethyl sodium tetradecanoate;

step 3: and (3) under the action of a catalyst, carrying out esterification reaction on the product in the step (2) by adopting an esterification reagent to obtain gefarnate.

2. The method according to claim 1, wherein the farnesene in step 1 is one or a mixture of two of beta-farnesene and alpha-farnesene, the acetoacetate ester comprises methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, isopropyl acetoacetate and tert-butyl acetoacetate, the catalyst is a rhodium-containing compound, and the basic catalyst comprises aqueous solutions of sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, lithium chloride, lithium bromide and lithium iodide.

3. The method of claim 2, wherein the rhodium-containing compound comprises rhodium (acetylacetonate) dicarbonyl.

4. The process according to claim 1, wherein the mass ratio of farnesene to acetoacetate and catalyst in step 1 is (70-90): (50-70): 1 and the mass ratio of farnesenone acid ester to dry weight of basic catalyst is (900-1000): 1.

5. The method according to claim 1, wherein the halogenating agent in step 2 comprises a mixture of elemental iodine and sodium hydroxide solution, sodium hypochlorite solution, and the haloform reaction temperature is 20-70 ℃.

6. The method according to claim 5, wherein when the halogenating agent is a mixture of elemental iodine and sodium hydroxide solution, the mass ratio of elemental iodine, sodium hydroxide and farnesylacetone is (2-5): (0.5-2): 1, when the halogenating reagent is sodium hypochlorite solution, the mass ratio of sodium hypochlorite to farnesylacetone is (0.5-2.5): 1.

7. The method according to claim 1, wherein the esterification reagent in the step 3 comprises 1-bromo-3, 7-dimethyl-2, 6-octadiene, the catalyst is sodium paratoluenesulfonate, the mass ratio of the product of the step 2, the esterification reagent and the catalyst is (15-25): (10-20): 1, and the esterification reaction temperature is 50-140 ℃.

8. Gefarnate produced by the process of any one of claims 1-7.

9. Use of gefarnate produced according to the method of any one of claims 1-7 as a medicament for the treatment of gastric disorders.

10. The use according to claim 9, wherein the stomach disorder comprises acute gastritis, chronic gastritis, gastric ulcer, gastric mucosal lesions.