Method for preparing solanone

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a method for preparing solanone, which comprises the following steps: taking 3-butene-2-ketone and isovaleraldehyde as initial raw materials, and preparing (S)-2-isopropyl-5-carbonyl hexanal in one step under the common catalysis of bivalent ruthenium and diphosphine sulfonamide chiral ligand and a catalytic amount of alkali; (S, E)-solanone is specifically obtained from the aldehyde and a Wittig reagent under the combined action of phenyl lithium and LiBr; preparing (R, E)-solanone with the opposite configuration by utilizing the chiral ligand with the opposite configuration; the (R, E)-solanone with the opposite configuration can be prepared through the chiral ligand with the opposite configuration, raw materials and reagents are simple, cheap and easy to obtain, the reaction steps are short, the yield is high, a product with high optical purity can be obtained through two steps, 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 solanone. Background Art

[0002] Solanone is an important component of tobacco aroma and plays a major role in aroma. It can significantly enhance tobacco aroma, improve the taste, blend smoke, and reduce irritation. At present, solanone has been verified to be safe to use and is widely used in tobacco fields such as cigarettes and electronic cigarettes. Its uses are becoming more and more diverse due to its unique aromatic aroma.

[0003] Because the content of solanone and megastigmatrienone in natural tobacco is extremely small, it is impractical to extract these natural substances from tobacco. In recent years, a small number of methods have been developed through research to prepare solanone. Isovaleraldehyde and hexahydropyridine generate enamine in the presence of a dehydrating agent, and the enamine reacts with acrylonitrile in a 1,4-addition reaction. After hydrolysis, it reacts with Wittig reagent, and then adds with methyl magnesium iodide Grignard reagent to obtain racemic solanone (J.Org.Chem.1965,30,2981). A similar method is that isovaleraldehyde and morpholine generate enamine in the presence of a dehydrating agent, and the enamine reacts with acrylonitrile in a 1,4-addition reaction. After hydrolysis, it condenses with acetone under alkaline conditions of barium hydroxide, and then reacts with two molecules of methyl lithium, hydrolyzes and dehydrates to generate solanone (US4412083). (R)-(+)-p-menthene is ring-opened under ferric chloride catalytic photooxidation, carbonyl protection, dehydrochlorination under strong base conditions to generate alkyne, alkyne is converted into alkenyl boron under the action of catechol borane, and then coupled with isopropyl bromide under palladium catalysis to prepare conjugated diene, and finally oxidized to obtain (S)-(+)-solanone. These routes have long steps, low selectivity, difficult separation, high production cost, and are difficult to prepare on a large scale. The raw materials for preparing (S)-(+)-solanone are not easy to obtain and are expensive. Summary of the invention

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

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

[0006]

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

[0008] (S)-2-isopropyl-5-carbonylhexanal can be prepared in one step from 3-butene-2-one and isovaleraldehyde as starting materials under the co-catalysis of divalent ruthenium, bisphosphine sulfonamide chiral ligand and catalytic amount of base.

[0009] The aldehyde can specifically obtain (S,E)-solanone by the combined action of phenyllithium and LiBr with the Wittig reagent.

[0010] The (R, E)-solanone with the opposite configuration can be prepared by using the chiral ligand with the opposite configuration. The raw material source of this method is wide, the price is low, the reaction steps are simple, and the preparation of chiral solanone can be achieved in two steps.

[0011] As preferred embodiments of the present invention, the ratio of 3-butene-2-one to isovaleraldehyde is 5:1 to 1:5; the ratio of (S)-2-isopropyl-5-carbonylhexanal to Wittig reagent is 2:1 to 1:3; the ratio of Wittig reagent to PhLi is 1:1 to 1:2; the ratio of Wittig reagent to LiBr is 1:0.2 to 1:2.

[0012] As preferred in the present invention, the ruthenium catalyst can be one or more of RuCl2, RuCl2(COD), p-isopropylbenzene dichlororuthenium, and dichlorophenylruthenium (II) dimer.

[0013] As preferred in the present invention, R1 in the bisphosphine sulfonamide chiral ligand can be an aryl group, a heteroaryl group, an alkyl group, or a cycloalkyl group, and is preferably a phenyl group or a 4-methylphenyl group.

[0014] As preferred in the present invention, the ratio of Ru(II) to the bisphosphine sulfonamide chiral ligand is 1:1 to 1:4, preferably 1:1. The amount of Ru used is 0.01 mol% to 10 mol%, preferably 0.1 mol%.

[0015] Bisphosphine sulfonamide has the following structure:

[0016]

[0017] As preferred in the present invention, the catalyst may be a Ru-ligand complex prepared in advance by Ru and metal.

[0018] As a preferred embodiment of the present invention, the base used in the step of preparing (S)-2-isopropyl-5-carbonylhexanal is an inorganic base, which can be one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium carbonate and potassium carbonate. The amount of the base is 1mol% to 50mol%, preferably 3mol% to 10mol%.

[0019] As a preferred embodiment of the present invention, the solvent for the reaction in the step of preparing (S)-2-isopropyl-5-carbonylhexanal can be toluene, benzene, or methyl tert-butyl ether.

[0020] As preferred in the present invention, the base in the Wittig reaction is alkyl or aryl lithium, preferably phenyl lithium; the additive is a lithium salt, preferably one or both of LiCl and LiBr.

[0021] As preferred in the present invention, R2 in the phosphine salt in the Wittig reaction is an aryl group, an alkyl group or a cycloalkyl group, preferably a phenyl group, a n-butyl group or a cyclohexyl group.

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

[0023] The present invention can prepare (R, E)-solanone of opposite configuration through chiral ligands of opposite configuration. The raw materials and reagents are simple, cheap and easy to obtain. The reaction steps are short and the yield is high. A high optical purity product can be obtained in two steps. The product is easy to separate and is suitable for large-scale production. DETAILED DESCRIPTION

[0024] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. 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 making 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 solanone:

[0026]

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

[0028] (S)-2-isopropyl-5-carbonylhexanal can be prepared in one step from 3-butene-2-one and isovaleraldehyde as starting materials under the co-catalysis of divalent ruthenium, bisphosphine sulfonamide chiral ligand and catalytic amount of base.

[0029] The aldehyde can specifically obtain (S,E)-solanone by the combined action of phenyllithium and LiBr with the Wittig reagent.

[0030] The (R, E)-solanone with the opposite configuration can be prepared by using the chiral ligand with the opposite configuration. The raw material source of this method is wide, the price is low, the reaction steps are simple, and the preparation of chiral solanone can be achieved in two steps.

[0031] The ratio of 3-butene-2-one to isovaleraldehyde is 5:1 to 1:5; the ratio of (S)-2-isopropyl-5-carbonylhexanal to Wittig reagent is 2:1 to 1:3; the ratio of Wittig reagent to PhLi is 1:1 to 1:2; the ratio of Wittig reagent to LiBr is 1:0.2 to 1:2.

[0032] The ruthenium catalyst may be one or more of RuCl2, RuCl2(COD), p-isopropylbenzene ruthenium dichloride, and dichlorophenylruthenium (II) dimer.

[0033] R1 in the bisphosphine sulfonamide chiral ligand can be an aryl group, a heteroaryl group, an alkyl group, or a cycloalkyl group, and is preferably a phenyl group or a 4-methylphenyl group.

[0034] The ratio of Ru(II) to the bisphosphine sulfonamide chiral ligand is 1:1 to 1:4, preferably 1:1. The amount of Ru used is 0.01 mol% to 10 mol%, preferably 0.1 mol%.

[0035] Bisphosphine sulfonamide has the following structure:

[0036]

[0037] The catalyst may be a pre-prepared Ru-ligand complex of Ru and metal.

[0038] The base used in the step of preparing (S)-2-isopropyl-5-carbonylhexanal is an inorganic base, which can be one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium carbonate or potassium carbonate. The amount of the base is 1mol% to 50mol%, preferably 3mol% to 10mol%.

[0039] The solvent for the reaction in the step of preparing (S)-2-isopropyl-5-carbonylhexanal can be toluene, benzene, or methyl tert-butyl ether.

[0040] The base in the Wittig reaction is an alkyl or aryl lithium, preferably phenyl lithium; the additive is a lithium salt, preferably one or both of LiCl and LiBr.

[0041] In the Wittig reaction, R2 in the phosphine salt is an aryl group, an alkyl group or a cycloalkyl group, preferably a phenyl group, a n-butyl group or a cyclohexyl group.

[0042] In summary, the specific embodiments of the present invention are:

[0043]

[0044] General procedure: Under anhydrous and oxygen-free conditions, 3-butene-2-one (10 mmol) and isovaleraldehyde (15 mmol) were mixed evenly, 10 mL of anhydrous toluene was added, and anhydrous sodium carbonate (0.5 mmol), Ru (0.01 mmol), and ligand L1 (0.01 mmol) were added in sequence. The mixture was stirred at room temperature for 24 hours. TLC showed that the enone reaction was complete. The mixture was filtered through diatomaceous earth, the toluene was removed by spinning, and the product was separated by column chromatography (PE / EA).

[0045]

[0046]

[0047]

[0048] Under anhydrous and oxygen-free conditions, Wittig reagent (7mmol), LiBr (14mmol), and 30mL of anhydrous THF were mixed, cooled to minus 78 degrees, phenyl lithium (7mmol) was added dropwise, and the mixture was returned to room temperature and stirred for 30 minutes. The mixture was further cooled to -78 degrees, (S)-2-isopropyl-5-carbonylhexanal (7mmol) was added, and stirred for 1 hour. Phenyl lithium (7mmol) was continued to be added, and the mixture was stirred at -78 degrees for 1 hour, returned to room temperature and stirred for 6 hours, and the reaction was quenched with saturated ammonium chloride, extracted with ether, dried with sodium sulfate, filtered, the solvent was removed by rotation, and the product (S,E)-solanone 1.069g (79%) was obtained by column chromatography.

[0049] 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 solanone, characterized in that: The synthetic route for preparing solanone: The method for preparing solanone comprises the following steps: From 3-butene-2-one and isovaleraldehyde as starting materials, (S)-2-isopropyl-5-carbonylhexanal is prepared in one step under the catalysis of divalent ruthenium and bisphosphine sulfonamide chiral ligand and catalytic amount of base; The aldehyde reacts with Wittig reagent in the presence of phenyllithium and LiBr to specifically give (S,E)-solanone. The (R,E)-solanone with opposite configuration was prepared by using chiral ligands with opposite configuration.

2. A method for preparing solanone according to claim 1, characterized in that: The ratio of the 3-butene-2-one to isovaleraldehyde is 5:1 to 1:5; the ratio of (S)-2-isopropyl-5-carbonylhexanal to the Wittig reagent is 2:1 to 1:3; the ratio of the Wittig reagent to PhLi is 1:1 to 1:2; and the ratio of the Wittig reagent to LiBr is 1:0.2 to 1:

2.

3. A method for preparing solanone according to claim 1, characterized in that: The ruthenium catalyst may be one or more of RuCl2, RuCl2(COD), p-isopropylbenzene ruthenium dichloride, and dichlorophenylruthenium (II) dimer.

4. The method for preparing solanone according to claim 1, characterized in that: R1 in the bisphosphine sulfonamide chiral ligand can be an aryl group, a heteroaryl group, an alkyl group, or a cycloalkyl group.

5. The method for preparing solanone according to claim 1, characterized in that: The ratio of Ru(II) to the bisphosphine sulfonamide chiral ligand is 1:1-1:4; the amount of Ru is 0.01 mol%-10 mol%.

6. The method for preparing solanone according to claim 1, characterized in that: The catalyst may be a Ru-ligand complex prepared in advance between Ru and a metal.

7. The method for preparing solanone according to claim 1, characterized in that: The base used in the step of preparing (S)-2-isopropyl-5-carbonylhexanal is an inorganic base, which can be one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. The amount of the base is 1mol% to 50mol%, preferably 3mol% to 10mol%.

8. The method for preparing solanone according to claim 1, characterized in that: The solvent for the reaction in the step of preparing (S)-2-isopropyl-5-carbonylhexanal can be toluene, benzene, or methyl tert-butyl ether.

9. The method for preparing solanone according to claim 1, characterized in that: The base in the Wittig reaction is alkyl or aryl lithium; the additive is lithium salt.

10. The method for preparing solanone according to claim 1, characterized in that: In the Wittig reaction, R2 in the phosphine salt is an aryl group, an alkyl group or a cycloalkyl group.

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