CN115490609A - Preparation method and application of high farnesol compound - Google Patents
Preparation method and application of high farnesol compound Download PDFInfo
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- CN115490609A CN115490609A CN202111420709.3A CN202111420709A CN115490609A CN 115490609 A CN115490609 A CN 115490609A CN 202111420709 A CN202111420709 A CN 202111420709A CN 115490609 A CN115490609 A CN 115490609A
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
The invention relates to the technical field of A62D3/37, in particular to a preparation method and application of a high farnesol compound. The preparation method of the homofarnesol compound comprises the following steps: reacting trans-nerolidol with N, N-dimethylformamide dimethyl acetal to obtain an intermediate amide 1; reacting the intermediate amide 1 at 30-80 ℃ under the action of inorganic base to obtain an intermediate acid 2; the intermediate acid 2 reacts at-10 to 10 ℃ under the action of a reducing agent to obtain the high farnesol compound. The method develops a cheap and easily-obtained raw material through three-step reaction by taking trans-nerolidol as a raw material, avoids using a noble metal catalyst which is expensive in the prior art, has mild reaction conditions, does not relate to gas high-pressure and ultralow-temperature reaction and chromatographic column purification, is simple to operate, has few byproducts, is high in yield, reduces energy consumption, greatly improves production efficiency, and can be used for preparing the high farnesol compound on a large scale.
Description
Technical Field
The invention relates to the technical field of A62D3/37, in particular to a preparation method and application of a high farnesol compound.
Background
Ambroxide (-) -Ambroxide has strong and special Ambroxide fragrance, is a synthetic spice with special natural Ambroxide fragrance, is one of the best substitutes of the natural Ambroxide fragrance, and has wide application. Along with the improvement of the life quality of people, the market demand of ambergris reducing is also getting bigger and bigger. The high farnesol is used as a key intermediate for preparing ambergris ether, and the existing preparation method cannot meet the large demand of the market. Therefore, the development of an industrial route which has easily available raw materials, is environment-friendly and economical and has safe production is urgently needed to realize the kilogram-level production of the high farnesol compound.
Currently, methods for preparing high farnesol are mainly classified into the following three groups. 1. (E/Z) -nerolidol is used as a raw material, and is subjected to distillation separation, buchi rearrangement, chromatographic column separation and reduction to obtain (3E, 7E) -homofarnesol, however, the yield of the route is not high, and a chromatographic column separation step is needed. 2. Taking (E/Z) -nerolidol as a raw material, distilling and separating to obtain (E) -nerolidol, and then performing high-pressure reaction and carbonylation by using a palladium catalyst and carbon monoxide to obtain (3E/Z, 7E) -homofarnesic acid. The palladium catalyst used in the reaction is expensive and involves a gas high-pressure reaction, and in addition, the route cannot obtain the target product (3e, 7e) -precursor of high farnesol (3e, 7e) -high farnesic acid, and is a route which has little industrial value. 3. The target product (3E, 7E) -homofarnesol is finally obtained by 5 steps through multi-step alkylation of homoallylic iodide compounds and ring opening reaction catalyzed by Ni by taking dihydrofuran as a raw material. Although the reaction gives the desired product in high yield, the reaction requires the use of ultra-low temperatures and expensive metal catalysts.
The high farnesol compounds are expensive and scarce due to process limitations. In order to reduce the cost, the development of an industrial route which has easily available raw materials, is environment-friendly and economical and realizes the kilogram-level production of the high farnesol compound is urgently needed.
Disclosure of Invention
In view of the problems of the prior art, the first aspect of the present invention provides a method for preparing high farnesol compounds, comprising the following steps:
(1) Reacting trans-nerolidol with N, N-dimethylformamide dimethyl acetal to obtain an intermediate amide 1;
(2) Reacting the intermediate amide 1 at 30-80 ℃ under the action of inorganic base to obtain an intermediate acid 2;
(3) The intermediate acid 2 reacts at-10 to 10 ℃ under the action of a reducing agent to obtain the high farnesol compound.
In one embodiment, the step (1) comprises: mixing trans-nerolidol, organic solvent 1 and N, N-dimethylformamide dimethyl acetal, heating to reflux reaction, cooling to room temperature, and removing the organic solvent 1.
The methods for removing organic solvent 1 described herein are routine choices within the art.
Preferably, the weight ratio of the trans-nerolidol, the organic solvent 1 and the N, N-dimethylformamide dimethyl acetal is 1: (5-10): (1-5), more preferably 1.1.
Preferably, the organic solvent 1 is one or more selected from toluene, xylene, nitrobenzene and N, N-dimethylformamide, and is more preferably xylene.
In one embodiment, the intermediate amide 1 and the inorganic base in step (2) are reacted at 30 to 80 ℃, preferably at 75 ℃, in the presence of the organic solvent 2 and water.
Preferably, the weight ratio of the intermediate amide 1, the inorganic base, the organic solvent 2 and the water is 1: (0.4-1): (2-5): (0.15-0.5), more preferably 1: (0.4-0.5): (2-3): (0.15-0.3), more preferably 1.
Preferably, the organic solvent 2 is selected from one or more of methanol, ethanol, isopropanol and tert-butanol, and is more preferably methanol.
The inorganic base used in the present invention is not particularly limited, and those skilled in the art can select the inorganic base in a conventional manner, and examples thereof include sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, lithium hydroxide, and the like, and sodium hydroxide is preferable.
The intermediate acid 2 obtained by hydrolyzing the intermediate amide 1 in the step (2) is difficult to obtain, and the intermediate acid 2 with a considerable yield can be obtained only by heating for a long time, and the applicant has found that, unexpectedly, when the organic solvent 2 is methanol, and the weight ratio of the intermediate amide 1, the inorganic base, the organic solvent 2 and the water is 1: (0.4-1): (2-5): (0.15-0.5), in particular in a weight ratio of 1: (0.4-0.5): (2-3): (0.15-0.3), the intermediate acid 2 can be obtained in a shorter time with higher yield and purity.
Preferably, after the reaction at 30-80 ℃ is completed in step (2), cooling to room temperature, removing the organic solvent 2, diluting with water, washing with methyl tert-butyl ether, separating the aqueous phase, adjusting to acidity with an aqueous solution of hydrochloric acid, extracting with methyl tert-butyl ether again, drying, filtering, and removing the methyl tert-butyl ether to obtain the intermediate acid 2.
Preferably, the number of washing times of the methyl tert-butyl ether in the step (2) is 2 or more, and more preferably 2.
Preferably, the concentration of the aqueous solution of hydrochloric acid in step (2) is 1to 3M, more preferably 2M.
Preferably, the number of times of extraction using methyl t-butyl ether in step (2) is 2 or more, more preferably 3.
In one embodiment, in the step (3), the intermediate acid 2 is firstly mixed with the organic solvent 3 and the activating reagent, stirred and reacted for 2-12h at 0-50 ℃ to obtain an activated ester solution, and then reacted at-10-10 ℃ under the action of the reducing agent; preferably, the intermediate acid 2 is first mixed with the organic solvent 3 and the activating reagent, stirred and reacted at 25 ℃ for 5 hours to obtain an activated ester solution, and then reacted at 5 ℃ under the action of the reducing agent.
Preferably, the organic solvent 3 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylmorpholine, ethylene glycol dimethyl ether, more preferably 2-methyltetrahydrofuran.
Preferably, the activating reagent is selected from one or more of cyanuric chloride, N, N '-carbonyldiimidazole, N, N' -dicyclohexylcarbodiimide, and more preferably cyanuric chloride.
Preferably, in the activated ester solution, the weight ratio of the intermediate acid 2 to the organic solvent 3 to the activating reagent is 1: (2-5): (1-3), preferably 1.
In one embodiment, in step (3), the reaction of the activated ester solution and the reducing agent is specifically performed as follows: mixing the organic solvent 4 and water, cooling to-10-10 ℃, adding a reducing agent under the condition of stirring, and then dropwise adding an activated ester solution for reaction.
Preferably, the weight ratio of the organic solvent 4, the water and the intermediate acid 2 is (3-5): (2-5): 1, more preferably 4.
Preferably, the organic solvent 4 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N-methylmorpholine and ethylene glycol dimethyl ether, and more preferably 2-methyltetrahydrofuran.
Preferably, the reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride, and is more preferably sodium borohydride.
Preferably, after the reaction in step (3) is completed, an aqueous solution of citric acid is added for dilution, followed by extraction with ethyl acetate, after liquid separation, the organic phase is washed successively with a dilute sulfuric acid and a saturated aqueous solution of ammonium carbonate, and after liquid separation, drying, solvent removal, and rectification purification, a homofarnesol compound is obtained.
Preferably, the concentration of the aqueous solution of citric acid is 2-4M, more preferably 3M.
Preferably, the concentration of dilute sulfuric acid is 1-3M, more preferably 2M.
In a second aspect, the present application provides a method for preparing farnesol compounds for use in preparing ambergris ether.
Those skilled in the art who have not disclosed the methods of preparation of the present application may make routine selections.
In the present application, the high farnesol compound has one more carbon than the farnesol compound.
Compared with the prior art, the invention has the following beneficial effects:
(1) The method develops a cheap and easily-obtained raw material through three-step reaction by taking trans-nerolidol as a raw material, avoids using a noble metal catalyst which is expensive in the prior art, has mild reaction conditions, does not relate to gas high-pressure and ultralow-temperature reaction and chromatographic column purification, is simple to operate, has few byproducts, is high in yield, reduces energy consumption, greatly improves production efficiency, and can be used for preparing the high farnesol compound on a large scale.
(2) In the application, xylene is used as a solvent in the reaction process of synthesizing the intermediate amide 1 by using trans-nerolidol, so that the yield and the purity of the obtained intermediate amide 1 are high, and the removal of the organic solvent is facilitated, so that the next operation step can be performed on the obtained intermediate amide 1 without purification, and the purity and the yield of a target yield cannot be influenced.
(3) Methanol is adopted as an organic solvent 2, and the weight ratio of an intermediate amide 1, an inorganic base, the organic solvent 2 and water is controlled to be 1: (0.4-1): (2-5): (0.15-0.5), in particular in a weight ratio of 1: (0.4-0.5): (2-3): (0.15-0.3) to avoid the problems of slow hydrolysis and low efficiency of the intermediate amide 1 in the step (2).
(4) In the step (4) of the present application, the intermediate acid 2 and the activating reagent are reacted under the condition of 2-methyltetrahydrofuran, and especially when the activating reagent is cyanuric chloride, the yield of the target product obtained after the subsequent participation in the reduction reaction is significantly improved.
(5) In the reduction reaction process of the intermediate 2, the intermediate 2 and an activating agent are firstly reacted to obtain an activated ester solution, the activated ester solution is reacted with sodium borohydride again, the reaction is mild, the reaction rate is high, the activated ester solution is washed by 2M dilute sulfuric acid and a saturated sodium bicarbonate aqueous solution in sequence at the later stage, the purification efficiency is improved, and the high farnesol compound is high in purity and yield only by the step of rectification and purification at the later stage.
Drawings
FIG. 1 is a 1HNMR chart of a homofarnesol compound obtained in example 1 of the present application.
Detailed Description
The present invention is illustrated by the following specific embodiments, but is not limited to the specific examples given below.
Examples
Example 1
Example 1 of the present invention provides a high farnesol compound, which is specifically prepared by the following method:
(1) 500g of reaction substrate trans-nerolidol, 2.5Kg of dimethylbenzene and 550g of N, N-dimethylformamide dimethyl acetal are sequentially added into a 10L reaction bottle, the mixture is heated to reflux reaction under stirring, the reaction process is tracked by gas chromatography, after the reaction is finished, the heating is stopped, the temperature is reduced to room temperature, the dimethylbenzene is removed by screwing, 625g of crude reaction intermediate amide 1 is obtained, and the crude reaction intermediate amide 1 is directly used in the next step without purification.
(2) 1.5Kg of methanol, 625g of reaction intermediate amide 1, 157g of water and 270g of sodium hydroxide are sequentially added into a 10L reaction flask, the mixture is heated to 75 ℃ under stirring for reaction, the reaction process is tracked by gas chromatography, after the reaction is finished, the heating is stopped, the methanol is removed after the mixture is cooled to room temperature, the mixture is diluted by adding water, the mixture is washed 2 times by methyl tert-butyl ether, the aqueous phase is separated, the pH value is adjusted to acidity by 2M hydrochloric acid aqueous solution, the mixture is extracted 3 times by methyl tert-butyl ether, the organic phases are combined, dried, filtered and the solvent is removed by rotation, so that 420g of reaction intermediate acid 2 is obtained.
(3) 1Kg of reaction intermediate acid 2,2.5Kg of 2-methyltetrahydrofuran and 1.5Kg of cyanuric chloride are sequentially added into a 10L reaction flask, and stirred and reacted for 5 hours at 25 ℃, so as to obtain an activated ester solution for standby, 4Kg of 2-methyltetrahydrofuran and 3Kg of water are sequentially added into a 50L reaction kettle, sodium borohydride is added after the temperature is reduced to 5 ℃, then the prepared activated ester solution is slowly and dropwise added, the reaction is carried out overnight, a gas chromatography is used for tracking the reaction process, after the reaction is finished, a 3M citric acid aqueous solution is added for dilution, ethyl acetate is used for extraction and liquid separation, an organic phase is sequentially washed by a 2M dilute sulfuric acid and a saturated sodium bicarbonate aqueous solution, liquid separation is carried out, drying and filtering are carried out, a solvent is spun off, and the residual liquid is rectified and purified (under the pressure of 0.1torr, a fraction with the boiling point of 140 ℃) to obtain 650g of homofarnesol compound (1 HNMR (CDCl 3): 5.10 (3H, M), 3.60 (2H, t), 2.26 (2H, t), 1.96-2.06 (9H, M), 1.59-1.66 (12H, M)).
Example 2
Example 2 of the present invention provides a high farnesol compound, which is specifically prepared by the following method:
(1) Adding 500g of reaction substrate trans-nerolidol, 2.5Kg of DMF and 550g of N, N-dimethylformamide dimethyl acetal into a 10L reaction bottle in sequence, heating to reflux reaction under stirring, tracking the reaction process by gas chromatography, stopping heating after the reaction is finished, cooling to room temperature, and then removing DMF to obtain 420g of crude reaction intermediate amide 1 which is not purified and directly used in the next step.
(2) 1.5Kg of methanol, 625g of reaction intermediate amide 1, 157g of water and 380g of sodium hydroxide are sequentially added into a 10L reaction flask, the mixture is heated to 75 ℃ under stirring for reaction, a gas chromatograph tracks the reaction process, after the reaction is finished, the heating is stopped, the methanol is removed after the mixture is cooled to room temperature, the mixture is diluted with water, the mixture is washed 2 times with methyl tert-butyl ether, the aqueous phase is separated, 2M hydrochloric acid aqueous solution is used for adjusting the pH value to be acidic, the mixture is extracted 3 times with the methyl tert-butyl ether, the organic phases are combined, dried, filtered and the solvent is removed by rotation, so 380g of reaction intermediate acid 2 is obtained.
(3) 1Kg of 2-methyltetrahydrofuran as a reaction intermediate acid, 2,2.5Kg and 1.3Kg of N, N' -carbonyldiimidazole are sequentially added into a 10L reaction bottle, stirred and reacted at 25 ℃ for 5h to obtain an activated ester solution for standby, 4Kg of 2-methyltetrahydrofuran and 3Kg of water are added into a 50L reaction kettle, after the temperature is reduced to 5 ℃, sodium borohydride is added under stirring, the prepared activated ester solution is slowly and dropwise added, the reaction is carried out overnight, the reaction process is tracked by gas chromatography, after the reaction is finished, 3M citric acid aqueous solution is added for dilution, ethyl acetate is extracted, liquid separation is carried out, an organic phase is sequentially washed by 2M dilute sulfuric acid and saturated sodium bicarbonate aqueous solution, liquid separation is carried out, drying and filtering are carried out, the solvent is spun off, and the residual liquid is rectified and purified (at the pressure of 0.1torr, the fraction with the boiling point of 140 ℃) to obtain g of the high-594 alcohol compound.
Claims (10)
1. A method for preparing a high farnesol compound is characterized by comprising the following steps:
(1) Reacting trans-nerolidol with N, N-dimethylformamide dimethyl acetal to obtain an intermediate amide 1;
(2) Reacting the intermediate amide 1 at 30-80 ℃ under the action of inorganic base to obtain an intermediate acid 2;
(3) The intermediate acid 2 reacts at-10 to 10 ℃ under the action of a reducing agent to obtain the high farnesol compound.
2. The method of preparing a homofarnesol compound according to claim 1, wherein the step (1) comprises: mixing trans-nerolidol, organic solvent 1 and N, N-dimethylformamide dimethyl acetal, heating to reflux reaction, cooling to room temperature, and removing the organic solvent 1.
3. The method of claim 2, wherein the weight ratio of trans-nerolidol, organic solvent 1, and N, N-dimethylformamide dimethyl acetal is 1: (5-10): (1-5).
4. The method of preparing a homofarnesol compound according to claim 3, wherein the intermediate amide 1 is reacted with the inorganic base in the presence of the organic solvent 2 and water at 30 to 80 ℃ in the step (2).
5. The method of claim 4, wherein the weight ratio of the intermediate amide 1, the inorganic base, the organic solvent 2, and the water is 1: (0.4-1): (2-5): (0.15-0.5).
6. The method of claim 5, wherein the organic solvent 2 is one or more selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol.
7. The method of preparing homofarnesol compound according to any one of claims 1to 6, wherein in the step (3), the intermediate acid 2 is first mixed with the organic solvent 3 and the activating reagent, and the mixture is stirred and reacted at 0 to 50 ℃ for 2 to 12 hours to obtain an activated ester solution, and then the activated ester solution is reacted at-10 to 10 ℃ under the action of the reducing agent.
8. The method of claim 7, wherein the activating reagent is one or more selected from cyanuric chloride, N, N '-carbonyldiimidazole, and N, N' -dicyclohexylcarbodiimide.
9. The method of claim 8, wherein the reaction between the activated ester solution and the reducing agent in step (3) is performed as follows: mixing the organic solvent 4 and water, cooling to-10-10 ℃, adding a reducing agent under the condition of stirring, and then dropwise adding an activated ester solution for reaction.
10. Use of the homofarnesol compounds according to any of claims 1to 9 for the preparation of ambergris ether.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101490027A (en) * | 2006-07-31 | 2009-07-22 | 花王株式会社 | Method for preparing (+/-)-3a,6,6,9a-tetramethyldecahydro-naphtho[2,1-b]furan-2(1H)-ones |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490027A (en) * | 2006-07-31 | 2009-07-22 | 花王株式会社 | Method for preparing (+/-)-3a,6,6,9a-tetramethyldecahydro-naphtho[2,1-b]furan-2(1H)-ones |
Non-Patent Citations (1)
| Title |
|---|
| MASSIMO FALORNI: "Mild reduction of carboxylic acids to alcohols using cyanuric chloride and sodium borohydride", TETRAHEDRON LETTERS, vol. 40, pages 4395 - 4396, XP004164657, DOI: 10.1016/S0040-4039(99)00734-0 * |
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