CN102850309B - Synthesis method of menthalactone - Google Patents
Synthesis method of menthalactone Download PDFInfo
- Publication number
- CN102850309B CN102850309B CN201210361022.1A CN201210361022A CN102850309B CN 102850309 B CN102850309 B CN 102850309B CN 201210361022 A CN201210361022 A CN 201210361022A CN 102850309 B CN102850309 B CN 102850309B
- Authority
- CN
- China
- Prior art keywords
- pyruvate
- methylcyclohexanone
- synthetic method
- anhydrous
- substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of menthalactone [5,6,7,7a-tetrahydro-3,6-dimethyl-2(4H)-benzofuranone], wherein the method comprises the following steps: using 3-methyl cyclohexanone and pyruvate as raw materials, performing aldol condensation reaction under a catalytic function of Lewis acid to obtain 2-(2-oxo-4-methyl cyclohexylidene)propionate, performing saponification and then reducing by sodium borohydride and acidifying to obtain the menthalactone. The synthesis method provided by the invention has advantages of simple synthesis process, mild reaction condition, concise operation and environmental protection, and is suitable for industrial production of the menthalactone on a large scale.
Description
Technical field
The invention belongs to organic synthesis and essence and flavoring agent technical field, be specifically related to the method for a kind of synthetic peppermint lactone [5,6,7,7a-tetrahydrochysene-3,6-dimethyl-2(4H)-benzofuranone].
Background technology
Peppermint lactone is the minor component of mentha piperita oil, sweet, the fragrant feature quality that shows high-quality mentha piperita oil of beans that it is strong
[1], it can be used as food (FEMA 3764) and cigarette additive, also can be used as the intermediate of synthesizing dihydro peppermint lactone, menthofuran etc.
The synthetic of peppermint lactone attracts wide attention, within 2002, Ferraz is to its synthetic summary, starting raw material comprises dextrorotation menthofuran, dextrorotation geranial, left-handed isopulegol, Geraniol and vernol, 4-methylcyclohexanone, (1R, 5R)-5-methyl cyclohexane-2-alkene-1-alcohol, 3-methylcyclohexanone etc.
[2]; Afterwards, Bates etc., Tsubuki philosophy report are made (5R)-5-methyl-2-vinylidene hexalin, are reacted and synthesize peppermint lactone afterwards with propadiene alcohol cyclocarbonyl by polystep reaction
[3,4], Gao etc. have reported rhodinol demethylation, oxidation have been made to (3S)-3-methyl-6-alkynes octanal, the synthetic peppermint lactone of hetero-Pauson-Khand reaction in rear molecule
[5].The method of these synthetic peppermint lactones all has certain stereoselectivity, but exists synthesis step many, or the shortcoming that raw material is rare and preparation cost is high.Tanabe etc. have reported that titanium tetrachloride/tri-n-butyl amine promotes 3-methylcyclohexanone and 1,1-dimethoxy condensation of acetone to prepare the method for peppermint lactone
[6], building-up reactions is only a step, but need reaction system dewater and argon shield under, at-78 DEG C, carry out, severe reaction conditions, should not amplify and carry out mass-producing preparation and suitability for industrialized production.Therefore, find a kind of technique simple, cost again lower preparation peppermint lactone synthetic method is those skilled in the art institute urgent problem always.
Reference
（1）Eric F.,Alain B.,Christine V.,Flavour Fragr. J.,2002,17:218-226.
（2）Ferraz H.M.C.,Jr L.S.L.,Grazini M.V. A.Synthesis,2002,(15),2155-2164.
（3）Bates R.W.,Sridhar S.J. Org.Chem.2008,73,8104-8105.
（4）Tsubuki M.,Takahashi K.,Honda T.J. Org.Chem.2009,74,1422-1425.
（5）Gao P.,Xu P.F.,Zhai H.B.J. Org.Chem.2009,74,2592-2593.
（6）Tanabe Y.,Mitarai K.,Higashi T.,et al,Chem.Commun.2002,2542-2543
Summary of the invention
The object of the present invention is to provide a kind of technique simple, reaction conditions gentleness, the method for lower-cost applicable large-scale commercial production peppermint lactone [5,6,7,7a-tetrahydrochysene-3,6-dimethyl-2(4H)-benzofuranone].
For reaching above-mentioned purpose, technical scheme of the present invention is: taking 3-methylcyclohexanone as starting raw material, at 70-120 DEG C, under solvent-free condition, with Louis acid catalysis and pyruvic acid or pyruvate cross aldol condensation formation 2-(2-oxo-4-methyl cyclohexane fork base) propionic ester, then by 2-(2-oxo-4-methyl cyclohexane fork base) propionic ester reduces, acidifying becomes peppermint lactone.
Method of the present invention specifically comprises following two steps:
Step 1: aldol condensation: under Louis acid catalysis, promote raw material 3-methylcyclohexanone and pyruvate to carry out aldol condensation with conventional heating to 70-120 DEG C or microwave heating and make 2-(2-oxo-4-methyl cyclohexane and pitch base) propionic ester;
Step 2: reduction: by 2-(2-oxo-4-methyl cyclohexane fork base) for propionic ester sodium borohydride reduction, rear acidifying become peppermint lactone, reaction formula is as follows:
The mol ratio of raw material 3-methylcyclohexanone and pyruvic acid or pyruvate can be between 2/1 to 1/10.1/1-1/3 is better input amount, and 1/1.2-1/1.8 is best input amount.
Lewis acidic kind can be Anhydrous Ferric Chloride, anhydrous cupric chloride, zinc chloride, aluminum chloride, tin tetrachloride and the corresponding crystal containing crystal water thereof, as ferric chloride hexahydrate, copper chloride dihydrate, stannic chloride pentahydrate etc., input amount can be 0.2 times to 3 times of 3-methylcyclohexanone amount of substance (unit: mole), and preferably 1-1.5 doubly.
In reaction of the present invention, do not need to add in addition other solvents as reaction medium, heating can be passed through conventional heating, as water-bath, oil bath, steam, electrically heated etc., or microwave heating.
Two-step reaction provided by the present invention is prepared the method for peppermint lactone, very easy on operating procedure, reaction conditions is gentle, and total recovery can reach 60%.Be applicable to large-scale commercial production peppermint lactone, efficiently solve in the original preparation process of target product synthesis step too much, high cost or the problem of severe reaction conditions.
In sum, method of the present invention can make preparation technology more simplify, and yield is better, and the industrial applications prospect of target product is had to great contribution, efficiently solves the technical barrier of the large-scale production of peppermint lactone.
Embodiment
Following examples are intended to illustrate the present invention instead of limitation of the invention further.
Embodiment 1
3-methylcyclohexanone 2.0g and pyruvate 3.0g and anhydrous chlorides of rase iron powder 2.0g are mixed in 100mL single port bottle, stirring reaction 6h at 90 DEG C.GC-MS detection reaction process.Reaction is finished, and in reaction mixture, adds methylene dichloride 70mL, and suction filtration falls solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.4g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 1.70g that purifies to obtain, yield is 57%.The spectral data of peppermint lactone is:
1h NMR: δ 0.91-1.08 (m, 2H), 1.01 (d, J=6.4Hz, 3H, CH
3-C6), 1.68-1.76 (m, 1H), 1.81 (t, J=1.6Hz, 3H, CH
3-C3), 1.92-1.97 (m, 1H), 1.17-2.24 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 4.63 (dd, J=6.4, J=11.6,1H, H7a);
13c NMR: δ 8.2,21.2,25.4,29.7,34.5,42.0,79.9,119.5,162.3,174.8.MS m/z (100%): 166 (m
+, 100), 151 (3), 137 (56), 123 (18), 109 (39), 95 (37), 81 (41), 67 (38), 54 (6), 41 (16).
Embodiment 2
3-methylcyclohexanone 2.0g and pyruvate 1.0g and anhydrous cupric chloride 1.5g are mixed in 100mL single port bottle, stirring reaction 4h at 95 DEG C.GC-MS detection reaction process.Reaction is finished, and in reaction mixture, adds methylene dichloride 70mL, filters out solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.4g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 0.82g that purifies to obtain, yield is 55%.
Embodiment 3
3-methylcyclohexanone 2.0g and pyruvate 3.0g and aluminum trichloride (anhydrous) powder 2.0g are mixed in 100mL single port bottle, stirring reaction 6h at 90 DEG C.GC-MS detection reaction process.Reaction is finished, and in reaction mixture, adds methylene dichloride 70mL, and suction filtration falls solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.4g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 0.36g that purifies to obtain, yield is 12%.
Embodiment 4
3-methylcyclohexanone 1.0g and pyruvate 4.0g and Zinc Chloride Anhydrous 2.0g are mixed in 100mL single port bottle, stirring reaction 3h at 90 DEG C.Reaction is finished, and adds methylene dichloride 70mL, by dichloromethane layer saturated common salt water washing in reaction mixture, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.3g in batches, treat that it rises to room temperature naturally, stir altogether 5h, with 20% sulfuric acid acidation solution to pH=1, use dichloromethane extraction water layer, concentrated, the column chromatography peppermint lactone 0.46g that purifies to obtain, yield is 31%.
Embodiment 5
3-methylcyclohexanone 2.0g and pyruvate 3.6g and ferric chloride hexahydrate 3.6g are mixed in 100mL single port bottle, stirring reaction 6h at 95 DEG C.GC-MS detection reaction process.Reaction is finished, and in reaction mixture, adds methylene dichloride 70mL, and suction filtration falls solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.4g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 1.81g that purifies to obtain, yield is 61%.
Embodiment 6
3-methylcyclohexanone 1.0g and pyruvate 2.0g and ferric chloride hexahydrate 2.0g are mixed in 100mL single port bottle, microwave (power: 365W ± 5% grade) reacting by heating 10 minutes.Reaction is finished, and in reaction mixture, adds methylene dichloride 50mL, and suction filtration falls solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.3g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 0.81g that purifies to obtain, yield is 54%.
Embodiment 7
3-methylcyclohexanone 2.0g and pyruvate 3.0g and two water chlorinated ketone powder 2.0g are mixed in 100mL single port bottle, stirring reaction 6h at 90 DEG C.GC-MS detection reaction process.Reaction is finished, and in reaction mixture, adds methylene dichloride 70mL, and suction filtration falls solid salt wherein, by dichloromethane layer saturated common salt water washing, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.4g in batches, treat that it rises to room temperature naturally, stir altogether 5h, to pH=1, use dichloromethane extraction water layer with 20% sulfuric acid acidation solution, concentrated, the column chromatography peppermint lactone 1.43g that purifies to obtain, yield is 48%.
Embodiment 8
3-methylcyclohexanone 2.0g and pyruvate 3.0g and stannic chloride pentahydrate 1.5g are mixed in 100mL single port bottle, stirring reaction 6h at 90 DEG C.GC-MS detection reaction process.Reaction is finished, and adds methylene dichloride 70mL, by dichloromethane layer saturated common salt water washing in reaction mixture, remove solvent under reduced pressure, add 10% sodium hydroxide solution saponification 3h at 50 DEG C, after bath temperature is chilled to 5 DEG C, add sodium borohydride solids 0.5g in batches, treat that it rises to room temperature naturally, stir altogether 5h, with 20% sulfuric acid acidation solution to pH=1, use dichloromethane extraction water layer, concentrated, the column chromatography peppermint lactone 1.54g that purifies to obtain, yield is 52%.
Claims (7)
1. a peppermint lactone [5,6,7,7a-tetrahydrochysene-3,6-dimethyl-2 (4H)-benzofuranone] synthetic method, it is characterized in that, taking 3-methylcyclohexanone as raw material, under Louis acid catalysis, at 70-120 DEG C, under solvent-free condition, obtain 2-(2-oxo-4-methyl cyclohexane fork base) propionic ester with pyruvate cross aldol condensation; Again 2-(2-oxo-4-methyl cyclohexane fork base) propionic ester is become to peppermint lactone through reduction, acidifying; Described Lewis acid is the crystal that Anhydrous Ferric Chloride, anhydrous cupric chloride, aluminum trichloride (anhydrous), Zinc Chloride Anhydrous, tin tetrachloride or above-claimed cpd contain crystal water accordingly.
2. synthetic method according to claim 1, is characterized in that, described pyruvate is Pyruvic Acid Methyl ester, Pyruvic Acid Ethyl ester, Propyl pyruvate or n-Butyl pyruvate.
3. synthetic method according to claim 1 and 2, is characterized in that, the mol ratio of raw material 3-methylcyclohexanone and pyruvate is between 2/1 to 1/10.
4. synthetic method according to claim 3, described lewis acidic consumption is 0.2-3.0 times of 3-methylcyclohexanone amount of substance.
5. synthetic method according to claim 3, described lewis acidic consumption is 1.0-1.5 times of 3-methylcyclohexanone amount of substance.
6. synthetic method according to claim 3, is characterized in that, the ratio of the amount of substance of 3-methylcyclohexanone and pyruvate is between 1/1 to 1/3.
7. synthetic method according to claim 3, is characterized in that, the ratio of the amount of substance of 3-methylcyclohexanone and pyruvate is between 1/1.2 to 1/1.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210361022.1A CN102850309B (en) | 2012-09-25 | 2012-09-25 | Synthesis method of menthalactone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210361022.1A CN102850309B (en) | 2012-09-25 | 2012-09-25 | Synthesis method of menthalactone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102850309A CN102850309A (en) | 2013-01-02 |
| CN102850309B true CN102850309B (en) | 2014-08-06 |
Family
ID=47397342
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210361022.1A Active CN102850309B (en) | 2012-09-25 | 2012-09-25 | Synthesis method of menthalactone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102850309B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113989B (en) * | 2013-03-07 | 2014-02-26 | 华宝食用香精香料（上海）有限公司 | Tobacco essence capable of improving cigarette taste and aroma |
| EP4032882A1 (en) | 2015-09-11 | 2022-07-27 | P2 Science, Inc. | Preparation of 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one and derivatives thereof |
| CN106810519A (en) * | 2015-12-02 | 2017-06-09 | 中国科学院大连化学物理研究所 | A kind of method for being catalyzed aldol reaction |
| WO2023122724A1 (en) | 2021-12-23 | 2023-06-29 | P2 Science, Inc. | Improved synthetic methods for making carboxylic acids, esters and lactones |
-
2012
- 2012-09-25 CN CN201210361022.1A patent/CN102850309B/en active Active
Non-Patent Citations (6)
| Title |
|---|
| An Efficient Entry Into Butenolides:Synthesis Of (±) Mintlactone;Subhash P. Chavan et al.;《Tetrahedron Letters》;19921231;第33卷(第32期);Scheme 2 * |
| Efficient one-step synthesis of trialkylsubstituted 2(5H)-furanones utilizing direct Ti-crossed aldol condensation and its application to the straightforward synthesis of (R)-mintlactone and (R)-menthofuran;Yoo Tanabe et al.;《Chemical Communication》;20021001;Scheme 3，第2543页右栏第2段 * |
| Miguel Carda et al..Total Synthesis of the Monoterpenes (-)-Mintlactone and ( + )-Isomintlactone.《Tetrahedron》.1992,第48卷(第44期),Scheme 1. |
| Subhash P. Chavan et al..An Efficient Entry Into Butenolides:Synthesis Of (±) Mintlactone.《Tetrahedron Letters》.1992,第33卷(第32期),Scheme 2. |
| Total Synthesis of the Monoterpenes (-)-Mintlactone and ( + )-Isomintlactone;Miguel Carda et al.;《Tetrahedron》;19921231;第48卷(第44期);Scheme 1 * |
| Yoo Tanabe et al..Efficient one-step synthesis of trialkylsubstituted 2(5H)-furanones utilizing direct Ti-crossed aldol condensation and its application to the straightforward synthesis of (R)-mintlactone and (R)-menthofuran.《Chemical Communication》.2002,Scheme 3，第2543页右栏第2段. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102850309A (en) | 2013-01-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Begum et al. | Catalysis by mont K-10 supported silver nanoparticles: a rapid and green protocol for the efficient ipso-hydroxylation of arylboronic acids | |
| JP5477557B2 (en) | Process for producing alcohols by hydrogen reduction of esters or lactones | |
| CN102850309B (en) | Synthesis method of menthalactone | |
| US8420847B2 (en) | Bis-phosphate compound and asymmetric reaction using the same | |
| Hanyu et al. | Enantioselective addition of diethylzinc to aldehydes catalyzed by optically active 1, 4-aminoalcohols | |
| CN113735701A (en) | Preparation method of 8-hydroxy-2,2,14, 14-tetramethylpentadecanedioic acid | |
| CN100364950C (en) | Process for preparing 2-(alkyl) cyclic ketone | |
| Rajendran et al. | A domino green synthesis of bis (indolyl) methanes catalyzed by ionic liquid [Et3NH][HSO4] | |
| CN105017099B (en) | Sitagliptin chiral intermediate and asymmetric synthesis method thereof | |
| Yamamoto et al. | A novel synthetic method for (R)-and (S)-muscones by enantioselective hydrogenation of (E)-and (Z)-3-methyl-2-cyclopentadecen-1-ones catalyzed by p-tolyl-BINAP-Ru (II) complexes | |
| He et al. | Synthesis of dibenzo [b, d] furans through one-pot cascade reactions of 1-arylpenta-3, 4-dien-2-ones with activated ketones | |
| CN103387560A (en) | Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate | |
| JP4407896B2 (en) | Method for producing 2- (alkyl) cycloalkenone | |
| JP2011529865A (en) | Process for producing phenylalkane-1-ol | |
| Cosgrove et al. | Exploring the versatility of the Johnson–Claisen rearrangement: access to functionally versatile δ-ethoxycarbonyl-α, β-unsaturated nitriles | |
| CN107880011B (en) | The synthetic method of Lu Makatuo key intermediate | |
| CN101967102A (en) | Synthesizing method of N,N-diethyl-3,7-dimethyl-(E)-2,6-octadiene-1-amine | |
| CN104230880A (en) | Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate | |
| AU2008358758A1 (en) | A process for preparing atovaquone and associate intermediates | |
| JP2009137876A (en) | Method for producing carbonyl group-containing compound and large cyclic ketone | |
| JP5212177B2 (en) | Method for producing γ-ketoacetal compound and pyrrole derivative | |
| CN103467261B (en) | Synthesizing method of ethyl vanillin | |
| CN109970520B (en) | Preparation method of thermosensitive paper sensitizer benzyl-2-naphthyl ether | |
| WO2010100833A1 (en) | 2-fluoro-1,3-benzodithiol 1,1,3,3-tetraoxide derivatives, process for the preparation of same, and process for the preparation of monofluoromethyl-containing compounds using same | |
| CN105367502A (en) | Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |