CN102351706A - Method for synthesizing ethyldivaricatinate and application of ethyldivaricatinate - Google Patents
Method for synthesizing ethyldivaricatinate and application of ethyldivaricatinate Download PDFInfo
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Abstract
The invention discloses a method for synthesizing ethyldivaricatinate and application of the ethyldivaricatinate. The method comprises the following steps of: reacting 3-hepten-2-one and diethyl malonate which are taken as raw materials to obtain 3,5-dibromo-2,4-dihydroxy-6-ethyl propylbenzoate; adding liquid bromine to perform bromination aromatization reaction on beta-diketone cyclohexane; performing debromination hydrogenation reaction on a product obtained in the previous step and hydrogen; and finally performing alkylation reaction on an obtained product and dimethyl carbonate (DMC) to obtain a target product. Raw materials and reagents which are used in the method are readily available, the reaction route is short, reaction conditions are mild, and the yield of organic intermediates and a final product is high; meanwhile, the ethyldivaricatinate also has broader industrial application prospect.
Description
Technical field
The present invention relates to the preparation field of essence and flavoring agent, relate to the blue or green fragrant perfume main note of a kind of tongue composition---the preparation method and use of divaricatic acid ethyl ester particularly.
Background technology
The blue or green fragrant perfume of tongue mainly comprises medicinal extract, the absolute oil goods of tree moss and oak moss, and they all adopt a kind of Lecanorales lichen that belongs to the Usneaceae Evernia to make through certain processing technique as raw material.The raw material of producing tree moss concrete, absolute oil is a tree moss; The raw material of oakmoss concrete, absolute oil is an oak moss; Wherein, it is the best to grow in the quality of the blue or green fragrant fragrant perfume of tongue of lichens feedstock production of country such as Yugoslavia, France and Italy of the European middle and south and Mediterranean Sea bank.Because the restriction of conditions such as the place of production that is processed raw material and complete processing, the price of the blue or green fragrant fragrant perfume of tongue is very expensive, is also monopolized by European countries such as France always.
In the natural perfume world market, the blue or green fragrant perfume of tongue is widely used in fields such as cigarette additive and daily cosmetics owing to have the blue or green fragrant of a kind of uniqueness, gracefulness, has become indispensable a member in the essence and flavoring agent industry.But, when preparation medicinal extract and absolute oil, also have many problems that can not be ignored.At first; Because tree moss, oakmoss concrete and absolute oil on the market mainly separate the enrichment means through organic solvent lixiviate, wet distillation, supercritical extraction etc. and prepare; This just make in medicinal extract and the absolute oil more or less contain invalid components such as pigment and vegetable wax, cause the quality of fragrance and purity not good enough.Secondly, in the course of processing, reactions such as hydrolysis, pyrolysis, addition and condensation take place in some compositions in medicinal extract and the absolute oil easily, and these bring negative impact all can for the quality and the yield of product.At last, in medicinal extract and absolute oil, also often contain some and cause people's composition hypersensitive and a considerable amount of heavy metal, for the quality product of food service industry and daily use chemicals industry has been buried potential safety hazard.Along with the demand of domestic and international essence and flavoring agent industry to oak moss spices increases day by day; The extraction of natural resource; Distillation; The mode of processing can not satisfy the demand in the society; Therefore people have carried out about tree moss; The chemosynthesis work of the main note composition of oak moss; Expectation is from the simple raw material of easy acquisition; Through one the step or polystep reaction prepare required main note composition; Through a large amount of; Prepare the active principle in the natural product efficiently; Be further analyzing and testing; Scientific research; Industrial application provides necessary material guarantee; Thereby make people break away from undue dependence, for The development in society and economy provides to natural product; Huge help.
As far back as the forties in last century, the analysis and research of people with regard to beginning the main component of lichens plants such as oak moss, tree moss is correlated with.Beginning, focus mostly on polyose and the analysis of low-carbon (LC) aliphatic hydroxycarboxylic acid class material in the oak moss extract, result of study afterwards shows that this constituents is little to the fragrance effect of oak moss.Great deal of research results confirms, single aryl compound that compounds such as some depside of tree moss, oak moss, depsidone class form through degraded, hydrolysis has constituted the blue or green fragrant odour characteristics of typical tongue of tree moss, oak moss.Roelofter Heide etc. are on the basis of previous work; Oak moss extract to after concentrating carries out the classification elution; Collect different cuts; Find 17 kinds of single aryl derivatives altogether, mainly contained orcinol monomethyl ether, β-orcinol monomethyl ether, sparassol, everninic acid ethyl ester, divaricatic acid methyl esters, divaricatic acid ethyl ester, β-orcinol carboxylate methyl ester etc.
To the chemosynthesis of above single aryl compound more existing research report and patents.As Chinese Academy of Sciences Shanghai organic Wu Guosheng etc. in the chemosynthesis of patent the main essence of oak moss, the main note composition of a kind of oak moss of openly knowing clearly---3, the preparation method of 6-dimethyl-β-resorcylic acid methyl esters (being β-orcinol carboxylate methyl ester).What this patent was announced contains 2; The synthesis method of the compound of 4-dihydroxyl-benzoic ether class formation mainly is to adopt the vitriol oil and acetic anhydride as reaction reagent; Under the condition of heat; Carry out beta-diketon cyclohexyl aromizing; Reacting the employed reagent vitriol oil is highly corrosive and strong oxidizing property strong acid; Temperature of reaction is also than higher, and reaction conditions is relatively harsher.To from now on 2,4-dihydroxyl-benzoates intermediate large batch of synthetic with use, certainly will need to seek a kind of method and make the beta-diketon cyclohexyl can under the condition of gentleness, carry out aromizing.Other like preceding West Germany in publication 2,359,233 (1974) report uses reagent such as N-bromo caprolactone amine to make beta-diketon cyclohexyl aromatize; But required long reaction time, bromide reagent is expensive, and the yield of product is not high yet, only limits to the specimen preparation in the laboratory, is difficult to carry out industrialized mass production.
As the main aroma component of the blue or green fragrant perfume of tongue, divaricatic acid ethyl ester content is bigger, particularly in homemade oak moss, tree moss goods, the content of divaricatic acid ethyl ester nearly 20%.But, do not see various documents and patent report at present as yet relevant for the chemosynthesis of divaricatic acid ethyl ester.The approach of separation and concentration realizes not too easily from some natural products and the hope that obtains Chinese oak moss, tree moss main note composition divaricatic acid ethyl ester in a large number relies on; Therefore; Be necessary to develop a kind of fast effectively, be suitable for the chemical synthesis process of industrialized mass production; And then the source that increases aromatoising substance; Enrich the kind in perfume formulation field; For the blending staff development of essence and flavoring agent industry goes out better perfume formulation necessary perfume material is provided, reduces dependency degree natural perfume.
Summary of the invention
First technical problem that the present invention will solve provides the synthesis method of divaricatic acid ethyl ester; The present invention is a raw material with 3-hepten-2-one and diethyl malonate, obtains final product divaricatic acid ethyl ester through four-step reaction; The present invention reacts employed raw material, reagent is easy to get; Reaction scheme is short; Reaction conditions is gentle; The productive rate of organic intermediate and final product is all than higher; For the synthetic fragrant composition spices of post divaricatic acid ethyl ester a kind of efficient ways is provided, has also possessed higher prospects for commercial application simultaneously with the blue or green odor type of tongue.
Second technical problem that the present invention will solve provides the purposes of divaricatic acid ethyl ester.
For solving the problems of the technologies described above, the invention provides the synthesis method of divaricatic acid ethyl ester, may further comprise the steps:
A. under alkaline condition, 3-hepten-2-one and diethyl malonate react, and generate 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester;
B. under acidic conditions, steps A generate 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine reaction, generation 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester;
C. step B is generated 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester dissolving adds the Cu/Co catalyzer, under the catalysis of Cu/Co, reactant and hydrogen is carried out the debrominate hydrogenation, generation 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester;
D. with 2 of step C generation, 4-dihydroxyl-6-propylbenzoic acid ethyl ester and methylcarbonate carry out alkylated reaction, generate the divaricatic acid ethyl ester.
Further, in the said steps A, 3-hepten-2-one and diethyl malonate are 1.05～1.2: 1 with mol ratio; Under 40～80 ℃ condition, reacted 3～5 hours, the pH value of regulator solution is 3～4 afterwards, stirs; Obtain 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester.
Said alkaline condition can be through adding any acquisition in the highly basic such as sodium methylate, sodium ethylate, sodium hydride, potassium hydride KH, potassium tert.-butoxide or sodium amide in reaction vessel.
Further, among the said step B, 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine are with mol ratio 1: 3～4.5; Under 25～40 ℃ of conditions, reacted 10～15 hours, in system, add entry afterwards, stir; Obtain 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester.
Said acidic conditions is in reaction vessel, to add any in the organic acids such as acetate or propionic acid to use as solvent.
Further; Among the said step C; Under atmosphere of hydrogen; Be dissolved in 3 among the NaOH, 5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co reacted under 25～40 ℃ condition 18～24 hours; The pH value of regulator solution is 3～4 afterwards; Stir, obtain 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 3,5-two bromo-2, the mol ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and NaOH is 1: 5～10; 3,5-two bromo-2, the mass ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co is 1: 0.15～0.25.
Further, said step D is with 2, and 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the acetone soln that contains Anhydrous potassium carbonate, adds methylcarbonate afterwards, under 25～40 ℃ condition, reacts 3～5 hours, obtains the divaricatic acid ethyl ester; Wherein, 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester: Anhydrous potassium carbonate: the mol ratio of methylcarbonate is 1: 1.3～2: 1.3～2.
Further, in said each step, comprise also the gained target product adopted organic solvent extraction that washing concentrates, column chromatography for separation, recrystallization separation etc. are further handled.
Said column chromatography for separation is the mixed solvent with sherwood oil and ethyl acetate, uses polarity different change of proportioning according to target compound.
The invention provides the synthesis method of divaricatic acid ethyl ester, may further comprise the steps:
A. under alkaline condition, 3-hepten-2-one and diethyl malonate reacted under 40～80 ℃ condition 3～5 hours, obtained faint yellow solid, and the pH value of regulator solution is 3～4, obtains yellow oily liquid 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester; Wherein, the mol ratio of 3-hepten-2-one and diethyl malonate is 1.05～1.2: 1;
B. under acidic conditions; Add 2 of steps A generation; 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester to wherein adding the liquid bromine, reacted 10～15 hours under 25～40 ℃ of conditions after reaction finishes; To wherein adding entry to change the solvability of product in solvent; To wherein adding S-WAT,, stir and separate out yellow solid 3 to remove excessive liquid bromine; 5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 2, the mol ratio of 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine is 1: 3～4.5;
C. with 3 of step B generation; 5-two bromo-2; 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the NaOH aqueous solution, adds the Cu/Co catalyzer, vacuumizes the back and feeds hydrogen; Make solution under atmosphere of hydrogen; Under 25～40 ℃ condition, reacted 18～24 hours, elimination Cu/Co, the pH value of regulator solution is 3～4; Solid 2 is separated out in stirring, 4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 3,5-two bromo-2, the mol ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and NaOH is 1: 5～10; 3,5-two bromo-2, the mass ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co is 1: 0.15～0.25;
D. with 2 of step C generation; 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the acetone soln that contains Anhydrous potassium carbonate; Add methylcarbonate, under 25-40 ℃ condition, reacted 3～5 hours, extraction obtains yellow oily liquid 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester after concentrating; Wherein, 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester: Anhydrous potassium carbonate: the mol ratio of methylcarbonate 1: 1.3～2: 1.3～2.
Said alkaline condition can be through adding any acquisition in the highly basic such as sodium methylate, sodium ethylate, sodium hydride, potassium hydride KH, potassium tert.-butoxide or sodium amide in reaction vessel.
Said acidic conditions is in reaction vessel, to add any in the organic acids such as acetate or propionic acid to use as solvent.
The final product process of this synthesis method
1H NMR,
13C NMR, HR-MS composes detection, confirms that all product is 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester, i.e. the main note composition divaricatic acid ethyl ester of the blue or green fragrant perfume of tongue.
First step A of reaction be with sodium ethylate as basic catalyst, the annulation that carries out Michael reaction and ketone ester condensation reaction as initial feed with 3-hepten-2-one and diethyl malonate; The second step B of reaction be with acetate as an acidic catalyst, impel the beta-diketon cyclohexyl to carry out aromatization through adding the liquid bromine; React the 3rd step C and utilize hydrogen and Cu/Co catalyst system to make the bromine atoms on the aromatic ring replaced, carry out the debrominate hydrogenation by hydrogen atom; React the 4th step D and a hydroxyl of certain bits on the aromatic ring is carried out etherificate, obtain ultimate aim product divaricatic acid ethyl ester with methylcarbonate (DMC) methylating reagent.
For solving above-mentioned second technical problem, the invention provides the divaricatic acid ethyl ester as the application of a kind of novel tobacco aromatics using in perfuming cigarette.
The synthetic divaricatic acid ethyl ester that obtains of the present invention is applied in the perfume formulation of cigarette industry; Be spices of the present invention and concentration that the propylene glycol solution of 50%-95% is mixed with cigaret additive and adds in the cigarette promptly; The adding proportion of this spices is the 0.01%-0.05% of tobacco quality, has obtained result of use preferably.In the test of short run; After the spices that use contains the divaricatic acid ethyl ester of the present invention preparation carries out perfuming cigarette; The judging panel with professional qualification in industry smokes panel test; Obtain consistent approval: compare as the cigarette of spices with the use oakmoss concrete absolute oil of contrast; After using the divaricatic acid ethyl ester of the present invention's preparation, the flue gas Harmony of cigarette improves, and oral stimulation property is minimum; The blue or green fragrance of tongue is outstanding, the fragrance mellow and full exquisiteness that becomes.
The present invention has following advantage:
1) becomes the ring method according to common in the document with ethyl crotonate and methyl aceto acetate reaction; Use 2-hexenoic acid ethyl ester and methyl aceto acetate Synthetic 2; During 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester; The transformation efficiency of finding its reaction is very low, does not therefore adopt this method in the present invention.When using 3-hepten-2-one and diethyl malonate as reaction raw materials, obtained gratifying transformation efficiency, solved the low problem of organic intermediate productive rate effectively;
2) in the reaction of aromizing, room temperature or a little heat down use liquid bromine reaction substrate carried out the bromination aromizing avoided the needed hot conditions of acetyl aromatization method.Reacted liquid bromine is also removed than acid anhydrides and hydrolysate thereof that acetyl aromizing is used more easily.Through adding sodium sulfite solution, excessive liquid bromine and S-WAT carry out redox reaction, generate colourless Sodium Bromide and metabisulfite solution.This method has reduced the workload of experiment aftertreatment, has also effectively avoided the pollution problem of liquid bromine to environment simultaneously;
3) the divaricatic acid ethyl ester synthetic route of this patent design, taken into full account its be simple and easy to requirement, be raw material with 3-hepten-2-one and the diethyl malonate of buying easily on the market, can obtain target compound through four-step reaction; The reaction conditions of whole piece synthetic route is all very gentle, and in room temperature or can react under the situation of heat a little, productive rate is also satisfactory, is convenient to the suitability for industrialized production preparation.
Description of drawings
Fig. 1 is a synthetic route chart of the present invention.
Embodiment
Synthetic route chart of the present invention as shown in fig. 1, embodiment 1 to embodiment 4, and embodiment 5 is all according to this figure preparation.
Embodiment 1
Organic intermediate (3): 2, synthesizing of 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester may further comprise the steps:
In the single port flask of 50ml, take by weighing the sodium ethylate of 0.71g (10.5mmol), add the 15ml ethanol solution, be stirred to sodium ethylate and dissolve fully.To the diethyl malonate (2) that wherein adds 1.6g (10mmol) successively, the 3-hepten-2-one (1) of 1.12g (10mmol) is loaded onto condensing reflux and drying installation, is warming up to 40 ℃, reacts 5 hours.Along with the carrying out of reaction, the solution colour flavescence, and separate out with a large amount of pale yellow powder shape solids.
Reaction is used hcl acidifying after finishing, dichloromethane extraction, and rotary evaporation is removed methylene dichloride, obtains yellow oily liquid 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester 1.88g, yield 83%.
MS(EI)：m/z(％)＝226(M
+，10)，183(75)，155(20)，143(25)，137(78)，113(40)，97(100)。This spectrogram numerical value and literature value are consistent.
Embodiment 2
Organic intermediate (4): 3,5-two bromo-2, synthesizing of 4-dihydroxyl-6-propylbenzoic acid ethyl ester may further comprise the steps:
In the single port flask of 50ml, add make among 1.13g (5mmol) embodiment 12,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester again to the acetate that wherein adds 15ml, stirs and makes its dissolving evenly; The liquid bromine of measuring 0.77ml (15mmol) again is added drop-wise in the reaction solution, after dropwising, reacts 15h. under 25 ℃ of conditions.
Reaction is poured reaction solution in the 50ml water into after finishing, and adds a spot of sodium sulphite anhydrous 99.3, removes excessive liquid bromine, makes the color fade of solution.Stir moments later, have a large amount of yellow solids to generate, filter, washing obtains the 1.69g yellow solid, yield 88% after the drying.The yellow solid that obtains is separated purification through silica gel column chromatography, and (sherwood oil: ethyl acetate 6: 1) wash-out, the collection main ingredient concentrates to remove and desolvates, and obtains faint yellow solid 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester with mixed solvent.
Fusing point: 131-133 ℃ (literature value: 132-134);
1H NMR (400MHz, CDCl
3) δ (ppm): 5.36 (s, 1H), 5.32 (s, 1H), 4.30 (q, 2H), 2.62 (t, 3H), 1.65 (m, 2H), 1.29 (t, 2H), 0.90 (t, 3H);
13C NMR (100MHz, CDCl
3) δ (ppm): 172.4,162.4,158.2,145.1,109.1,105.6,110.8,71.0,31.9,23.4,14.3,13.9; HR-MS (EI) for C
12H
14Br
2O
2, Calc:381.9238, Found:381.9237.This spectrogram numerical value and literature value are consistent.
Embodiment 3
Organic intermediate (5): 2, synthesizing of 4-dihydroxyl-6-propylbenzoic acid ethyl ester may further comprise the steps:
With 1.14g (3mmol) embodiment 2 make 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester is put in the single port reaction flask of 50ml; Add 7.5ml 2N NaOH solution; Stirring drops into 0.17g 10%Cu/Co catalyzer after making its dissolving again, stirs to make catalyst distribution even.In reaction flask, load onto T-valve, T-valve puts the balloon that is full of hydrogen, regulates the T-valve valve place, and after the air in the reaction flask was vacuumized, the re-adjustment valve imported to the hydrogen in the balloon in the reaction flask, repeats 1 time.Under 25 ℃ of conditions, stirring reaction 24h, balloon replenishes 2 hydrogen in the way.
Reaction is removed the Cu/Co in the reaction solution with sand core funnel after finishing, and obtains clarifying browning reaction liquid.The reaction solution hcl acidifying, the pH value that makes solution is 3-4.Stir moments later, have a large amount of brown solid to separate out.Suction filtration obtains 0.56g beige solid, yield 83% after the drying.The beige solid that obtains is separated purification through silica gel column chromatography, and (sherwood oil: ethyl acetate 4: 1) wash-out, the collection main ingredient concentrates to remove and desolvates, and obtains white solid 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester with mixed solvent.
Fusing point: 112-114 ℃ (literature value: 112-113 ℃);
1H NMR (400MHz, CDCl
3) δ (ppm): 6.70 (s, 1H), 6.12 (s, 1H), 5.37 (s, 1H), 5.33 (s, 1H), 4.31 (q, 2H), 2.63 (t, 3H), 1.65 (m, 2H), 1.30 (t, 2H), 0.91 (t, 3H);
13C NMR (100MHz, CDCl
3) δ (ppm): 171.3,164.8,162.9,148.2,111.3,101.4,100.8,60.8,38.6,24.0,14.1,13.6; HR-MS (EI) for C
12H
16O
4, Calc:224.1049, Found:224.1051.This spectrogram numerical value and literature value are consistent.
Embodiment 4
Divaricatic acid ethyl ester (6): synthesizing of 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester may further comprise the steps:
In the single port flask of 50ml, add successively that 0.45g (2mmol) embodiment 3 makes 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester, 0.41g (3mmol) Anhydrous potassium carbonate, the anhydrous propanone of 10ml.Stir moments later, the methylcarbonate of measuring 0.27g (3mmol) is added drop-wise in the reaction solution lentamente, after dropwising, is warming up to 25 ℃, continues reaction 5h.
Reaction filters Anhydrous potassium carbonate after finishing, and revolves to steam to remove acetone.Product is through dichloromethane extraction, and anhydrous sodium sulfate drying obtains yellow oily liquid 0.42g, yield 88% after concentrating.To obtain yellow oily liquid and separate purification with silica gel column chromatography, (sherwood oil: ethyl acetate 5: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains purified white solid 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester with mixed solvent.
Fusing point: 52-54oC (literature value: 53-54oC); 1H NMR (400MHz, CDCl3) δ (ppm): 6.74 (s, 1H), 6.47 (s, 1H), 5.35 (s, 1H), 4.29 (q, 2H), 3.83 (s, 1H), 2.61 (t, 3H), 1.64 (m, 2H), 1.28 (t, 2H), 0.89 (t, 3H); 13CNMR (100MHz, CDCl3) δ (ppm): 171.4,166.4,164.4,147.8,111.1,101.1,100.5,60.9,55.8,38.7,24.1,14.1,13.7; HR-MS (EI) for C13H18O4, Calc:238.1205, Found:238.1203.This spectrogram numerical value and literature value are consistent.
Embodiment 5
The synthesis method of divaricatic acid ethyl ester-2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester may further comprise the steps:
A. in the single port flask of 250ml, take by weighing 2.42g (0.105mol) sodium Metal 99.5, add the 80ml ethanol solution, be stirred to sodium Metal 99.5 and dissolve fully.To the diethyl malonate that wherein adds 16g (0.1mol) successively, the 3-hepten-2-one of 11.2g (0.1mol) is loaded onto condensing reflux and drying installation in reaction flask, is warming up to 80 ℃, reacts 3 hours.Along with reaction carry out the solution colour flavescence, and separate out with a large amount of pale yellow powder shape solids.After reaction finishes, hcl acidifying, dichloromethane extraction, washing, after the methylene dichloride drying, rotary evaporation obtains yellow oily liquid 19.2g, yield 85% after removing methylene dichloride.
B. in the single port flask of 100ml, add that 11.3g (0.05mol) prepares 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester, the acetate of 20ml stirs and makes its dissolving evenly.The liquid bromine of measuring 7.7ml (0.15mol) again joins in the constant voltage separating funnel that contains the 20ml propionic acid.The rate of addition of control liquid bromine joins in the reaction solution it slowly.After dropwising, react 10h under 40 ℃ of conditions.Reaction is poured reaction solution in the 150ml water into after finishing, and adds a spot of sodium sulphite anhydrous 99.3, removes excessive liquid bromine, makes the color fade of solution.Stir moments later, have a large amount of yellow solids to generate, filter, washing obtains the 15.6g yellow solid, yield 82% after the drying.The yellow solid that obtains is passed through silica gel column chromatography separate purification, (sherwood oil: ethyl acetate 6: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains faint yellow solid 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester with mixed solvent.
C. 11.4g (0.03mol) compound is put in the single port reaction flask of 100ml, added 50ml 3N NaOH solution, stirring drops into 1.71g 10%Cu/Co catalyzer after making its dissolving again, stirs to make catalyst distribution even.In reaction flask, load onto T-valve, T-valve puts the balloon that is full of hydrogen, regulates the T-valve valve place, and after the air in the reaction flask was vacuumized, the re-adjustment valve imported to the hydrogen in the balloon in the reaction flask, repeats 2 times.Under 40 ℃ of conditions, stirring reaction 18h, balloon replenishes 1 hydrogen in the way.Reaction is removed the Cu/Co in the reaction solution with sand core funnel after finishing, and obtains clarifying browning reaction liquid.The reaction solution hcl acidifying, the pH value that makes solution is 3-4, stirs moments later, has a large amount of beige solids to separate out.Suction filtration obtains 5.7g beige solid, yield 85% after the drying.The beige solid that obtains is passed through silica gel column chromatography separate purification, (sherwood oil: ethyl acetate 4: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains white solid 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester with mixed solvent.
D. in the single port flask of 50ml, add 3.36g (15mmol) 2 successively, 4-dihydroxyl-6-propylbenzoic acid ethyl ester, 2.76g (20mmol) Anhydrous potassium carbonate, the anhydrous propanone of 15ml.Stir moments later, measure the methylcarbonate of 1.8g (20mmol), make in its anhydrous propanone that is dissolved in 15ml, use constant pressure funnel to be added drop-wise to lentamente in the reaction solution, after dropwising, be warming up to 40 ℃, continue reaction 3h.Reaction filters Anhydrous potassium carbonate after finishing, and revolves to steam to remove acetone.Product is through dichloromethane extraction, and anhydrous sodium sulfate drying obtains yellow oily liquid 3.2g, yield 90% after concentrating.To obtain yellow oily liquid and separate purification with silica gel column chromatography, (sherwood oil: ethyl acetate 5: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains purified white solid 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester with mixed solvent.
Embodiment 6
The synthesis method of divaricatic acid ethyl ester may further comprise the steps:
A. in the single port flask of 250ml, take by weighing 2.42g (0.105mol) sodium Metal 99.5, add the 80ml absolute methanol solution, be stirred to sodium Metal 99.5 and dissolve fully.To the diethyl malonate that wherein adds 16g (0.1mol) successively, the 3-hepten-2-one of 11.76g (0.105mol) is loaded onto condensing reflux and drying installation in reaction flask, is warming up to 40 ℃, reacts 3 hours.Along with reaction carry out the solution colour flavescence, and separate out with a large amount of pale yellow powder shape solids.After reaction finished, hcl acidifying was 3 to pH, dichloromethane extraction, and washing after the methylene dichloride drying, after rotary evaporation is removed methylene dichloride, obtains yellow oily liquid.
B. in the single port flask of 100ml, add that 11.3g (0.05mol) prepares 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester, the acetate of 20ml stirs and makes its dissolving evenly.The liquid bromine of measuring 34.6ml (0.15mol) again joins in the constant voltage separating funnel that contains the 30ml propionic acid.The rate of addition of control liquid bromine joins in the reaction solution it slowly.After dropwising, react 15h under 25 ℃ of conditions.Reaction is poured reaction solution in the 150ml water into after finishing, and adds a spot of sodium sulphite anhydrous 99.3, removes excessive liquid bromine, makes the color fade of solution.Stir moments later, have a large amount of yellow solids to generate, filter, washing obtains 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester after the drying.
C. 11.4g (0.03mol) compound is put in the single port reaction flask of 100ml, added 100ml 3N NaOH solution, stirring drops into 2.85g 10%Cu/Co catalyzer after making its dissolving again, stirs to make catalyst distribution even.In reaction flask, load onto T-valve, T-valve puts the balloon that is full of hydrogen, regulates the T-valve valve place, and after the air in the reaction flask was vacuumized, the re-adjustment valve imported to the hydrogen in the balloon in the reaction flask, repeats 2 times.Under 25 ℃ of conditions, stirring reaction 24h, balloon replenishes 1 hydrogen in the way.Reaction is removed the Cu/Co in the reaction solution with sand core funnel after finishing, and obtains clarifying browning reaction liquid.The reaction solution hcl acidifying, the pH value that makes solution is 3-4, stirs moments later, has a large amount of beige solids to separate out.Suction filtration obtains the beige solid after the drying.The beige solid that obtains is passed through silica gel column chromatography separate purification, (sherwood oil: ethyl acetate 4: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains white solid 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester with mixed solvent.
D. in the single port flask of 50ml, add 3.36g (15mmol) 2 successively, 4-dihydroxyl-6-propylbenzoic acid ethyl ester, 2.69g (19.5mmol) Anhydrous potassium carbonate, the anhydrous propanone of 15ml.Stir moments later, measure the methylcarbonate of 1.76g (19.5mmol), make in its anhydrous propanone that is dissolved in 15ml, use constant pressure funnel to be added drop-wise to lentamente in the reaction solution, after dropwising, be warming up to 25 ℃, continue reaction 5h.Reaction filters Anhydrous potassium carbonate after finishing, and revolves to steam to remove acetone.Product is through dichloromethane extraction, and anhydrous sodium sulfate drying obtains yellow oily liquid after concentrating.To obtain yellow oily liquid and separate purification with silica gel column chromatography, (sherwood oil: ethyl acetate 5: 1) wash-out, the collection main ingredient concentrates except that after desolvating and obtains purified white solid 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester with mixed solvent.
Embodiment 7
The synthesis method of divaricatic acid ethyl ester may further comprise the steps:
A. in the presence of sodium hydride, 3-hepten-2-one and diethyl malonate reacted 4 hours under 60 ℃ condition, obtained faint yellow solid, and the pH value of regulator solution is 4, obtains yellow oily liquid 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester; Wherein, the mol ratio of 3-hepten-2-one and diethyl malonate is 1.1: 1;
B. in the presence of propionic acid; Add 2 of steps A generation; 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester, to wherein adding the liquid bromine, reaction was 12 hours under 32 ℃ of conditions after reaction finished; To wherein adding entry to change the solvability of product in solvent; To wherein adding S-WAT,, stir and separate out yellow solid 3 to remove excessive liquid bromine; 5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 2, the mol ratio of 4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine is 1: 4;
C. with 3 of step B generation; 5-two bromo-2; 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the NaOH aqueous solution, adds the Cu/Co catalyzer, vacuumizes the back and feeds hydrogen; Make solution under atmosphere of hydrogen; Reaction is 20 hours under 30 ℃ condition, elimination Cu/Co, and the pH value of regulator solution is 3; Solid 2 is separated out in stirring, 4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 3,5-two bromo-2, the mol ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and NaOH is 1: 8; 3,5-two bromo-2, the mass ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co is 1: 0.20;
D. with 2 of step C generation; 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the acetone soln that contains Anhydrous potassium carbonate; Add methylcarbonate, reaction is 4 hours under 30 ℃ condition, and extraction obtains yellow oily liquid 2-hydroxyl-4-methoxyl group-6-propylbenzoic acid ethyl ester after concentrating; Wherein, 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester: Anhydrous potassium carbonate: the mol ratio of methylcarbonate 1: 15: 1.5.
Embodiment 8
With embodiment 7, unique variation is that steps A is in the presence of potassium hydride KH, to carry out.
Embodiment 9
With embodiment 7, unique variation is that steps A is in the presence of potassium tert.-butoxide, to carry out.
Embodiment 10
With embodiment 7, unique variation is that steps A is in the presence of sodium amide, to carry out.
Embodiment 11
The application of divaricatic acid ethyl ester spices:
With the divaricatic acid ethyl ester spices that embodiment 4 obtains, the propylene glycol solution dilution with 50% adds in the cigarette uniformly, and the adding proportion of spices is 0.05% of a tobacco quality.The cigarette of processing is smoked panel test through the judging panel with industry qualification and is thought: with the contrast cigarette compare, use product of the present invention after, the aroma quality of cigarette obviously promotes, fragrance is pure and fresh, bright, pure, oral stimulation property is little, mouthfeel improves.
Embodiment 12
The application of divaricatic acid ethyl ester spices:
With the divaricatic acid ethyl ester spices that embodiment 5 obtains, the Ucar 35 dilution with 95% adds in the cigarette uniformly, and the adding proportion of spices is 0.01% of a tobacco quality.The cigarette of processing is smoked panel test through the judging panel with industry qualification and is thought: compare with the contrast cigarette, uses product of the present invention after, the flue gas Harmony of cigarette improves, fragrance is graceful fine and smooth, wooden breath reduces, perfume quantity increase, pleasant impression Hui Tian.
Obviously, the above embodiment of the present invention only be for clearly the present invention is described and is done for example, and be not to be qualification to embodiment of the present invention.For the those of ordinary skill in affiliated field, on the basis of above-mentioned explanation, can also make other multi-form variation or change.Here can't give exhaustive to all embodiments.Everyly belong to the row that conspicuous variation that technical scheme of the present invention extends out or change still are in protection scope of the present invention.
Claims (10)
1. the synthesis method of divaricatic acid ethyl ester is characterized in that, may further comprise the steps:
A. under alkaline condition, 3-hepten-2-one and diethyl malonate react, and generate 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester;
B. under acidic conditions, steps A generate 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine reaction, generation 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester;
C. step B is generated 3,5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester dissolving adds the Cu/Co catalyzer, under the catalysis of Cu/Co, reactant and hydrogen is carried out the debrominate hydrogenation, generation 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester;
D. with 2 of step C generation, 4-dihydroxyl-6-propylbenzoic acid ethyl ester and methylcarbonate carry out alkylated reaction, generate the divaricatic acid ethyl ester.
2. the synthesis method of divaricatic acid ethyl ester according to claim 1; It is characterized in that; In the said steps A; 3-hepten-2-one and diethyl malonate are 1.05～1.2: 1 with mol ratio; Under 40～80 ℃ condition, reacted 3～5 hours, the pH value of regulator solution is 3～4 afterwards, stirs; Obtain 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester.
3. the synthesis method of divaricatic acid ethyl ester according to claim 1 is characterized in that, in the said steps A, said alkaline condition is in reaction vessel, to add sodium methylate, sodium ethylate, sodium hydride, potassium hydride KH, potassium tert.-butoxide or sodium amide.
4. the synthesis method of divaricatic acid ethyl ester according to claim 1; It is characterized in that; Among the said step B, 2,4-dioxy-6-propyl group-cyclohexyl carboxylic acid, ethyl ester and liquid bromine are with mol ratio 1: 3～4.5; Under 25～40 ℃ of conditions, reacted 10～15 hours; In system, add entry afterwards, stir, obtain 3; 5-two bromo-2,4-dihydroxyl-6-propylbenzoic acid ethyl ester.
5. the synthesis method of divaricatic acid ethyl ester according to claim 1 is characterized in that, among the said step B, said acidic conditions is in reaction vessel, to add acetate or propionic acid.
6. the synthesis method of divaricatic acid ethyl ester according to claim 1; It is characterized in that; Among the said step C, under atmosphere of hydrogen, be dissolved in 3 among the NaOH; 5-two bromo-2; 4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co reacted under 25～40 ℃ condition 18～24 hours, and the pH value of regulator solution is 3～4 afterwards, stirred; Obtain 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester; Wherein, 3,5-two bromo-2, the mol ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and NaOH is 1: 5～10; 3,5-two bromo-2, the mass ratio of 4-dihydroxyl-6-propylbenzoic acid ethyl ester and Cu/Co is 1: 0.15～0.25.
7. the synthesis method of divaricatic acid ethyl ester according to claim 1; It is characterized in that; Said step D is with 2; 4-dihydroxyl-6-propylbenzoic acid ethyl ester is dissolved in the acetone soln that contains Anhydrous potassium carbonate; Add methylcarbonate afterwards; Under 25～40 ℃ condition, reacted 3～5 hours, and obtained the divaricatic acid ethyl ester; Wherein, 2,4-dihydroxyl-6-propylbenzoic acid ethyl ester: Anhydrous potassium carbonate: the mol ratio of methylcarbonate is 1: 1.3～2: 1.3～2.
8. the synthesis method of divaricatic acid ethyl ester according to claim 1 is characterized in that, in said each step, comprises also products therefrom is adopted organic solvent extraction that washing concentrates, column chromatography for separation, and recrystallization separates further to be handled.
9. the synthesis method of divaricatic acid ethyl ester according to claim 8 is characterized in that, said column chromatography for separation is the mixed solvent with sherwood oil and ethyl acetate.
10. like the purposes of the arbitrary described divaricatic acid ethyl ester of claim 1-9, it is characterized in that it can be used in the perfume formulation of cigarette industry.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837442A (en) * | 2016-04-29 | 2016-08-10 | 江苏中烟工业有限责任公司 | Separation method for aromatic component divaicatic acid ethyl ester in moss fen-flavor spice |
| CN109096113A (en) * | 2018-09-13 | 2018-12-28 | 天津市安凯特科技发展有限公司 | A method of synthesis oak moss aromatisation |
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| CN85106638A (en) * | 1985-08-30 | 1987-04-15 | 昆明香料厂 | The extracting method of China oak moss |
| CN86100869A (en) * | 1986-01-10 | 1987-07-22 | 中国科学院上海有机化学研究所 | The chemosynthesis of the main essence of oak moss |
| CN102041174A (en) * | 2011-01-07 | 2011-05-04 | 江苏中烟工业有限责任公司 | Preparation method of moss-scented tobacco flavor and application of moss-scented cigarette flavor in cigarette flavoring |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN85106638A (en) * | 1985-08-30 | 1987-04-15 | 昆明香料厂 | The extracting method of China oak moss |
| CN86100869A (en) * | 1986-01-10 | 1987-07-22 | 中国科学院上海有机化学研究所 | The chemosynthesis of the main essence of oak moss |
| CN102041174A (en) * | 2011-01-07 | 2011-05-04 | 江苏中烟工业有限责任公司 | Preparation method of moss-scented tobacco flavor and application of moss-scented cigarette flavor in cigarette flavoring |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105837442A (en) * | 2016-04-29 | 2016-08-10 | 江苏中烟工业有限责任公司 | Separation method for aromatic component divaicatic acid ethyl ester in moss fen-flavor spice |
| CN109096113A (en) * | 2018-09-13 | 2018-12-28 | 天津市安凯特科技发展有限公司 | A method of synthesis oak moss aromatisation |
| CN109096113B (en) * | 2018-09-13 | 2021-05-25 | 天津市安凯特科技发展有限公司 | Method for aromatizing synthetic oak moss |
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