Method for preparing megastigmatrienone

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a method for preparing megastigmatrienone, and the method for preparing megastigmatrienone comprises the following steps: taking 5-bromo-1, 3-pentadiene as an initial raw material, and reacting with trivalent phosphine to prepare phosphine salt; carrying out alkali treatment to obtain a Wittig reagent, and carrying out Wittig reaction on the Wittig reagent and acetyl vinyl acetate to obtain acetate-substituted conjugated tetraene; under the co-catalysis of copper and a large-steric-hindrance ligand, carrying out a Diels-Alder reaction with isobutene to construct a six-membered ring; hydrolyzing to obtain alcohol, and oxidizing to obtain ketone; under the acidic condition, conjugated diene at the tail end is subjected to rearrangement isomerization, and megastigmatrienone is obtained; the raw materials and reagents are simple, cheap and easy to obtain, the reaction steps are short, the yield is high, separation is easy, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing megastigmatrienone. Background Art

[0002] Megastigmatrienones are carotenoid degradation products, are important aroma compounds in tobacco, are oily liquids, have tobacco fragrance and spicy base rhyme, can significantly enhance the aroma of tobacco, improve the taste of smoking, reconcile smoke, reduce irritation, are indispensable spices in cigarette manufacturing, and have also been widely used in perfumes, cosmetics, beverages and food flavors. Extracting megastigmatrienones from natural products is one of its important sources, but the content of megastigmatrienones in plants is very small. Therefore, it is obviously impossible to meet the demand of the spice market by extracting megastigmatrienones from natural products alone.

[0003] The cross-aldol condensation reaction of β-diketone enol ether with α,β-unsaturated aldehyde converts dimedone into enol ether, which is then condensed with crotonaldehyde under the action of lithium diisopropylamide, followed by mesylation elimination and methylation to obtain megastigmatrienon (J.Am.Chem.Soc., 1973, 95, 3310; Chem.Lett. 1977, 495; Bull.Chem.Soc.Jpn.1799, 52(4), 1233). Starting from isophorone (3,5,5-trimethyl-2-cyclohexene-1-one), cross-condensation with crotonaldehyde after enol silyl etherification and elimination can be used to obtain megastigmatrienon (Bull.Chem.Soc.Jpn.1982, 5, 1907). Starting from oxygen isophorone, the carbonyl group is selectively protected by ethylene glycol, reacted with butynol lithium, and then reduced and hydrolyzed to obtain megastigmatrienoside. This method has poor selectivity and is difficult to separate (Helv. Chim. Acta. 1974, 57, 2087). Starting from oxygen isophorone, it is first added with ethynyl lithium, then rearranged, reacted with Grignard reagent, eliminated, and the yield is improved (US5072019 (191)). Oxyisophorone selectively protected by ethylene glycol reacts with 4-bromo-1-butene / lithium, and then bromination, rearrangement, etc. can also prepare megastigmatrienoside (J. Chem. Soc. Perkin Trans I., 1977, (10), 1571). These routes have difficult raw materials, long steps, low selectivity, difficult separation, high production costs, and are difficult to prepare on a large scale. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing megastigmatrienone to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solution, a method for preparing megastigmatrienone, and a synthetic route for preparing megastigmatrienone:

[0006]

[0007] The method for preparing megastigmatrienone comprises the following steps:

[0008] 5-Bromo-1,3-pentadiene is used as a starting material and reacted with trivalent phosphine to prepare phosphine salt.

[0009] The Wittig reagent obtained by alkali treatment is then subjected to Wittig reaction with acetyl vinyl acetate to obtain acetate-substituted conjugated tetraene.

[0010] Under the joint catalysis of copper and a large steric ligand, it undergoes a Diels-Alder reaction with isobutylene to construct a six-membered ring.

[0011] It is then hydrolyzed to give the alcohol and then oxidized to the ketone.

[0012] Under acidic conditions, the terminal conjugated diene undergoes rearrangement isomerization to give megastigmatrienone.

[0013] The intermediate acetovinyl acetate can be obtained from the commercially available raw material acetoacetaldehyde by sodium hydrogen treatment and then adding Ac2O dropwise.

[0014] As preferred in the present invention, the trivalent phosphine is one of triaryl phosphine, trialkyl phosphine, or aryl alkyl phosphine, preferably triphenyl phosphine, tricyclohexyl phosphine, or tributyl phosphine.

[0015] As preferred in the present invention, the base is one or more of NaH, NaOtBu, KOtBu, nBuLi, sBuLi, tBuLi, LiHMDS, NaHMDS, and KHMDS, preferably NaH, NaOtBu, and KOtBu.

[0016] As preferred in the present invention, the bulky steric ligand is a bulky steric dinitrogen ligand, preferably one of the following two:

[0017]

[0018] As preferred in the present invention, in the Diels-Alder reaction, the ratio of tetraene to isobutylene is 1:1-1:10, the ratio of tetraene to copper salt is 5:1-1000:1; and the ratio of copper to ligand is 1:1-1:2.

[0019] As a preferred embodiment of the present invention, the temperature of the Diels-Alder reaction is 40 to 150 degrees, preferably 80 to 120 degrees, and more preferably 100 degrees.

[0020] As preferred in the present invention, the oxidation can be Dess Martin oxidation, or MnO2 oxidation, DDQ or Swern oxidation, preferably Dess Martin oxidation.

[0021] As preferred in the present invention, the acid is a Bronsted acid which may be one or more of HCl, HNO3, H2SO4, sulfonic acid RSO3H (R is aromatic, alkyl, fluoroalkyl), preferably one or more of TsOH, PhSO3H, CF3SO3H, MeSO3H.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The raw materials and reagents of the invention are simple, cheap and easy to obtain, the reaction steps are short, the yield is high, the separation is easy, and the method is suitable for large-scale production. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] The present invention provides a technical solution, a synthetic route for preparing megastigmatrienone:

[0026]

[0027] The method for preparing megastigmatrienone comprises the following steps:

[0028] 5-Bromo-1,3-pentadiene is used as a starting material and reacted with trivalent phosphine to prepare phosphine salt.

[0029] The Wittig reagent obtained by alkali treatment is then subjected to Wittig reaction with acetyl vinyl acetate to obtain acetate-substituted conjugated tetraene.

[0030] Under the joint catalysis of copper and a large steric ligand, it undergoes a Diels-Alder reaction with isobutylene to construct a six-membered ring.

[0031] It is then hydrolyzed to give the alcohol and then oxidized to the ketone.

[0032] Under acidic conditions, the terminal conjugated diene undergoes rearrangement isomerization to give megastigmatrienone.

[0033] The intermediate acetovinyl acetate can be obtained from the commercially available raw material acetoacetaldehyde by sodium hydrogen treatment and then adding Ac2O dropwise.

[0034] The trivalent phosphine is one of triarylphosphine, trialkylphosphine, or arylalkylphosphine, preferably triphenylphosphine, tricyclohexylphosphine, or tributylphosphine.

[0035] The base is one or more of NaH, NaOtBu, KOtBu, nBuLi, sBuLi, tBuLi, LiHMDS, NaHMDS, and KHMDS, preferably NaH, NaOtBu, and KOtBu.

[0036] The bulky sterically hindered ligand is a bulky dinitrogen ligand, preferably one of the following two:

[0037]

[0038] In the Diels-Alder reaction, the ratio of tetraene to isobutylene is 1:1 to 1:10, the ratio of tetraene to copper salt is 5:1 to 1000:1; and the ratio of copper to ligand is 1:1 to 1:2.

[0039] The temperature of the Diels-Alder reaction is 40 to 150 degrees, preferably 80 to 120 degrees, and more preferably 100 degrees.

[0040] The oxidation may be Dess Martin oxidation, MnO2 oxidation, DDQ or Swern oxidation, preferably Dess Martin oxidation.

[0041] The acid is a Bronsted acid which may be one or more of HCl, HNO3, H2SO4, sulfonic acid RSO3H (R is aryl, alkyl, fluoroalkyl), preferably one or more of TsOH, PhSO3H, CF3SO3H, MeSO3H.

[0042] Preparation of intermediate acetyl vinyl acetate 2

[0043]

[0044] Acetoacetaldehyde (100 mmol) was dissolved in 200 mL of anhydrous THF and cooled in an ice bath. NaH (105 mmol) was added in batches under a nitrogen atmosphere. Stir for 30 minutes after addition. Acetic anhydride was added dropwise under an ice bath, and after addition, the mixture was returned to room temperature and stirred overnight. Water was added to quench the reaction, extracted with ether, dried over sodium sulfate, filtered and dried, and separated by column chromatography (PE / EA) to obtain 10.378 g (81 mmol, 81%) of the product.

[0045] Preparation of phosphonium salt 4

[0046]

[0047] 5-Bromo-1,3-pentadiene (100 mmol) and triphenylphosphine (100 mmol) were dissolved in 200 mL THF and stirred at room temperature overnight. The solvent was removed and the product was used directly in the next step.

[0048] Preparation of conjugated tetraene 5 by Wittig reaction

[0049]

[0050] Phosphine salt 4 (70 mmol) was mixed with 200 mL of anhydrous THF, cooled in an ice bath, and NaH (75 mmol) was added under a nitrogen atmosphere, and stirred for 4 hours under an ice bath. Acetyl vinyl acetate 2 (70 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour, and heated to 60 degrees to react for 10 hours. ZnCl2 was added and stirred for 1 hour, and the insoluble matter was filtered out. The solvent was removed by rotation, and 59.8 g (55 mmol, 79%) of tetraene was obtained by column chromatography (PE / EA).

[0051] Diels-Alder reaction

[0052]

[0053] Under anhydrous and oxygen-free conditions, tetraene 5 (1 mmol), isobutylene (5 mmol), Cu(OTf)2 (0.05 mmol), 6,6'-diisopropyl-2,2'-bipyridine (0.05 mmol), and anhydrous toluene 4 mL were reacted in a pressure tube at 100 degrees for 10 hours. Filtered with diatomaceous earth, the solvent was removed by vortexing, and the product 171 mg (73%) was obtained by column chromatography (PE / EA).

[0054] Deprotection-oxidation-isomerization

[0055]

[0056] The product 6 (1mmol) was dissolved in 5mL THF, 1mL water and LiOH (10mmol) were added, and the mixture was stirred at room temperature overnight. 15mL water was added, and the mixture was extracted with ether, washed with water, dried over sodium sulfate, and the solvent was removed by spinning, and the mixture was dried. The crude product was directly dissolved in 5mL dichloromethane, and DMP (1.5mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the TLC reaction was complete, p-toluenesulfonic acid (1mmol) was added and stirred overnight. The solvent was removed by spinning, 20mL hexane and 3mL ether were added to dissolve the product, the insoluble matter was filtered out, the solvent was removed by spinning, and the product was purified by column chromatography to obtain 164mg (86%, three steps) of megastigmatrienone.

[0057] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing megastigmatrienone, characterized in that: The synthetic route for preparing megastigmatrienone: The method for preparing megastigmatrienone comprises the following steps: Using 5-bromo-1,3-pentadiene as a starting material, the phosphine salt is prepared by reacting the phosphine with a trivalent phosphine; The Wittig reagent obtained by alkali treatment is then subjected to Wittig reaction with acetylvinyl acetate to obtain acetate-substituted conjugated tetraene; Under the co-catalysis of copper and bulky sterically hindered ligands, it undergoes a Diels-Alder reaction with isobutylene to construct a six-membered ring; It is then hydrolyzed to give an alcohol, which is then oxidized to a ketone; Under acidic conditions, the terminal conjugated diene undergoes rearrangement isomerization to give megastigmatrienone.

2. A method for preparing megastigmatrienone according to claim 1, characterized in that: The trivalent phosphine is one of triaryl phosphine, trialkyl phosphine, or aryl alkyl phosphine.

3. A method for preparing megastigmatrienone according to claim 1, characterized in that: The base is NaH, NaO t Bu, KO t Bu, n BuLi, s BuLi, t One or more of BuLi, LiHMDS, NaHMDS, KHMDS.

4. A method for preparing megastigmatrienone according to claim 1, characterized in that: The bulky sterically hindered ligand is a bulky sterically hindered dinitrogen ligand.

5. A method for preparing megastigmatrienone according to claim 1, characterized in that: In the Diels-Alder reaction, the ratio of tetraene to isobutylene is 1:1-1:10, the ratio of tetraene to copper salt is 5:1-1000:1; and the ratio of copper to ligand is 1:1-1:

2.

6. A method for preparing megastigmatrienone according to claim 1, characterized in that: The temperature of the Diels-Alder reaction is 40 to 150 degrees.

7. A method for preparing megastigmatrienone according to claim 1, characterized in that: The oxidation can be selected from DessMartin oxidation, MnO2 oxidation, DDQ or Swern oxidation.

8. A method for preparing megastigmatrienone according to claim 1, characterized in that: The acid is a Bronsted acid, which is one or more of HCl, HNO3, H2SO4, and sulfonic acid RSO3H.

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