CN108033879B

CN108033879B - Method for preparing chiral muscone

Info

Publication number: CN108033879B
Application number: CN201711013374.7A
Authority: CN
Inventors: 于斌成; 张永振; 黎源; 孙启魁; 蔺海政
Original assignee: Wanhua Chemical Group Co Ltd
Current assignee: Wanhua Chemical Group Co Ltd
Priority date: 2017-10-26
Filing date: 2017-10-26
Publication date: 2021-02-02
Anticipated expiration: 2037-10-26
Also published as: CN108033879A

Abstract

The invention provides a method for preparing chiral muscone, which takes 3-methyl-1, 5-cyclopentadecanedione as a starting material, chiral rhodium and Bronsted acid as catalysts, hydrogen as a reducing agent, and synthesizes a chiral muscone product by a one-pot method through reactions such as asymmetric hydrogenation, hydrogenolysis and the like. The method has the advantages of short route, high total yield and less three wastes, and is suitable for industrial production of chiral muscone.

Description

Method for preparing chiral muscone

Technical Field

The invention belongs to the fields of flavors and fragrances and pharmaceutical engineering, and particularly relates to a method for preparing chiral muscone.

Background

Muscone, namely 3-methylcyclopentadecanone, is a main source of the rare fragrance of natural musk, can play excellent roles of fixing, baking, mellowing and the like in essence, and is extremely precious in fragrance blending. Meanwhile, the musk ketone also has the functions of inducing resuscitation, removing dirt, dredging collaterals and dissipating blood stasis, and can be mainly used for treating apoplexy, phlegm syncope, fright epilepsy, middle-jiao aversion and vexation, heart and abdomen sudden pain, traumatic injury, carbuncle and cellulitis and pyogenic infections. The muscone has a chiral center, the natural muscone is in R configuration, and the synthetic muscone is basically racemic, i.e. equal amount of mixture of R-muscone and S-muscone. The aroma value of the R-muscone is full and strong, the aroma value of the aqueous solution of the Guadagini method is 61 mu g/kg, while the aroma value of the S-muscone is not full and weak, and is 233 mu g/kg, which is only one fourth of the aroma value of the R-muscone. At present, the biological activity, pharmacological efficacy, toxicological research and the like of non-natural S-muscone are unknown, and the S-muscone does not meet the internationally-used pharmaceutical standard when being used as a medicine. In conclusion, the development of the synthesis of R-muscone is of great significance to flavors and fragrances and related medicaments.

Cyclododecanone is a large and relatively cheap raw material, and the synthesis of muscone by using cyclododecanone as a starting material is a very economic and feasible synthetic route. At present, a plurality of routes for synthesizing R-muscone starting from cyclododecanone have been developed, and these routes can be roughly divided into two types, one is directly introducing chiral side chain, then expanding ring, converting functional group and the like to synthesize R-muscone, and the other is introducing achiral side chain, then synthesizing chiral muscone through asymmetric conversion. The first method is of great interest because of its long route and inability to achieve chiral addition. Cyclododecanone can be converted in high yield into 3-methyl-1, 5-cyclopentadecanedione, which is a very ideal precursor for R-muscone synthesis at present, by three-step conversions, such as allylation, cyclization, cleavage of double bonds (CN102786398, WO 2016948, WO2016193330, WO 2016104474).

For Example, in the document An effective Enantioselective Synthesis of (+) - (R, Z) -5-Muscone-none and (-) - (R) -Muscone-An amplification of a Kinetic Resolution and Enantioconversion Transformation, Eur.J.Org.Chem.2004,1953-1957, aldol condensation in a 3-methyl-1, 15-pentadecanedione molecule is catalyzed by potassium hydroxide as a catalyst to give racemic 14-methyl-bicyclo [9,4,0] pentadec-1-en-12-one, which is then partially reduced by CBS to give chiral 14-methyl-bicyclo [9,4,0] pentadec-1-en-12-one in 35% yield and 97% ee. The chiral 14-methyl-bicyclo [9,4,0] pentadec-1-alkene-12-ketone is subjected to ring opening and hydrogenation to obtain the R-muscone, and the total yield is only 23 percent. In the literature of the Synthesis of the Musk oxygenates (R) -Muscone and (R, Z) -5-Muscone, Angew. chem.2007,119,1329-1332, the authors use up to 4 equivalents of N-methylephedrine alcohol sodium salt as a catalyst to promote Intramolecular aldol condensation of 3-methyl-1, 5-cyclopentadecanedione, can only use 64% of ee value as a chiral intermediate, after two recrystallizations, the intermediate reaches optical purity, and finally R-Muscone is obtained by ring opening and hydrogenation.

Patent CN1918100A discloses a series of chiral sodium, potassium or cesium alkoxides to promote intramolecular aldol condensation of 3-methyl-1, 15-pentadecanedione to obtain chiral 14-methyl-bicyclo [9,4,0] pentadec-1-en-12-one. The best catalyst is ephedrine alcohol sodium salt, the catalyst dosage is up to 8 equivalent, the product yield is 99%, but the ee value is only 74%. Patent CN101932545A discloses a chiral amino acid promoted aldol condensation reaction in 3-methyl-1, 15-pentadecanedione molecule, the best catalyst is D-methionine, the dosage of the catalyst is 0.5 equivalent, the yield of chiral 14-methyl-bicyclo [9,4,0] pentadec-1-en-12-one is 77%, and the ee value is 63%.

In summary, the main methods for synthesizing R-muscone from 3-methyl-1, 15-pentadecanedione at present are intramolecular asymmetric aldol condensation or kinetic resolution methods, and these methods generally have the disadvantages of large catalyst consumption, multiple reaction steps, low total yield and the like, and are not suitable for industrial production of R-muscone. If asymmetric hydrogenation of 3-methyl-1, 15-pentadecanedione can be realized to obtain a chiral 3-methyl-5-hydroxycyclopentadecanone intermediate, and then in-situ dehydration and hydrogenolysis are carried out, one-pot synthesis of R-muscone can be realized, however, relevant reports are not available in the patent.

Disclosure of Invention

The invention provides a method for preparing chiral muscone, which solves the problems of large catalyst dosage, more reaction steps and low total recovery rate in the current production method and realizes the industrial production of R-muscone.

The invention provides a one-pot preparation process of R-muscone, which adopts the following technical scheme:

under the action of a chiral rhodium catalyst and a Bronsted acid, 3-methyl-1, 5-cyclopentadecanedione takes hydrogen as a reducing agent to carry out asymmetric hydrogenation and hydrogenolysis reactions, and a chiral musk ketone product is synthesized by a one-pot method.

Preferably, the chiral rhodium catalyst is selected from [ Rh (COD) (R-BINAP)]BF₄，[Rh(COD)(R-Tol-BINAP)]BF₄，[Rh(COD)(R-P-Phos)]BF₄，[Rh(COD)(R-SegPhos)]BF₄，[Rh(COD)(R-MeO-BiPhep)]BF₄，[Rh(COD)(R-PhanePhos)]BF₄，[Rh(COD)(R-BINAP)]PF₆，[Rh(COD)(R-BINAP)]Cl or the like, preferably [ Rh (COD) (R-Tol-BINAP)]BF₄. Further, the chiral rhodium catalyst is used in an amount of 0.01 to 10.0 mol%, preferably 0.05 to 5 mol%, more preferably 0.1 to 1.0 mol%, relative to the 3-methyl-1, 5-cyclopentadecanedione substrate.

Preferably, the bronsted acid catalyst is selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and the like, wherein trifluoroacetic acid is preferred as the catalyst.

Further, the amount of the Bronsted acid catalyst used is 1.0 to 100.0 mol%, further 5.0 to 100.0 mol%, preferably 10.0 to 100.0 mol%, further preferably 10.0 to 20.0 mol%, relative to the 3-methyl-1, 5-cyclopentadecanedione substrate.

The hydrogen is a reducing agent for asymmetric hydrogenation and hydrogenolysis, and it is preferable to introduce the hydrogen at a pressure of 0.5 to 10.0MPa, more preferably 1.0 to 8.0MPa, still more preferably 5.0 to 6.0 MPa.

When 3-methyl-1, 5-cyclopentadecanedione is reacted, the solvent used is preferably one or more selected from the group consisting of ethyl acetate, benzene, toluene, tetrahydrofuran, acetone, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, etc., and tetrahydrofuran is preferred.

When 3-methyl-1, 5-cyclopentadecanedione is reacted, the reaction temperature is 50-120 ℃, preferably 70-90 ℃.

The following is a process route for chiral muscone:

wherein:

1 is 3-methyl-1, 5-cyclopentadecanedione, C₁₆H₂₈O₂Molecular weight 252.39;

[Rh(COD)(R-Tol-BINAP)]BF₄is a rhodium catalyst, C56H52BF4P2Rh, molecular weight 976.67;

TFA is trifluoroacetic acid, C₂HF₃O₂Molecular weight 114.02;

R-Muscone is chiral Muscone, C₁₆H₃₀O, molecular weight 238.41.

Compared with other musk ketone production processes, the method has the following advantages:

1. the production flow is short, the post-treatment is convenient, and the large-scale production is easy;

2. the production process is environment-friendly, the atom economy is high, and the three wastes are less;

3. the product has high optical purity, and is suitable for use in biological, medical, pharmaceutical, perfume, cosmetic, etc. fields.

4. The total yield of the product is high.

Detailed Description

3-methyl-1, 5-cyclopentadecanedione (98 wt%), synthesized according to literature reports (WO2016184948), [ Rh (COD) (R-Tol-BINAP)]BF₄(98 wt%), Jiangsu Xinnoco catalyst Co., Ltd; trifluoroacetic Acid (AR), tetrahydrofuran (AR), a pharmaceutical agent; hydrogen (99.9%), linde gas.

The gas chromatography test conditions of the present invention are as follows:

the instrument model is as follows: BETA-DEX-225

A chromatographic column: DB-5(30m 0.25mm 0.25 μm)

Column temperature: the initial temperature is 100 ℃, the temperature is raised to 200 ℃ at the speed of 20 ℃/min, and the temperature is kept for 25min

Sample inlet temperature: 220 deg.C

FID detector temperature: 280 deg.C

Split-flow sample injection with a split-flow ratio of 100: 1.

Sample introduction amount: 2.0. mu.L

N₂Flow rate: 88.7 mL/min.

H₂Flow rate: 35.0 mL/min.

Example 1

In a glove box, 3-methyl-1, 5-cyclopentadecanedione (50.478g,200.0mmol), anhydrous tetrahydrofuran (200mL) and [ Rh (COD) (R-Tol-BINAP)]BF₄(1.953g,2.0mmol) was added sequentially to a 500mL autoclave and finally trifluoroacetic acid (2.280g,20.0mmol) was added. The autoclave was sealed, taken out of the glove box, nitrogen was replaced with hydrogen for 3 times, and finally hydrogen was charged at 5.0 MPa. The autoclave was heated to 90 ℃ and reacted for 24 hours with rapid stirring. After the reaction is finished, hydrogen is carefully discharged, a small amount of reaction liquid is taken for gas phase analysis, and the substrate conversion rate>99 percent, 86 percent of musk ketone selectivity, 7 percent of 3-methyl-5-hydroxycyclopentadecane ketone selectivity, 5 percent of 3-methyl-1, 5-dihydroxycyclopentadecane selectivity and 2 percent of 3-methylcyclopentadecanol selectivity. The tetrahydrofuran was removed by rotary evaporation and isolated by rectification to give 37.669g of the target product in 79% yield with an ee value of 98% as determined by chiral gas column chromatography.

Example 2

In a glove box, 3-methyl-1, 5-cyclopentadecanedione (50.478g,200.0mmol) was addedTetrahydrofuran (200mL) and [ Rh (COD) (R-Tol-BINAP)]BF₄(0.195g,0.2mmol) was added sequentially to a 500mL autoclave, and finally trifluoroacetic acid (2.280g,20.0mmol) was added. The autoclave was sealed, taken out of the glove box, nitrogen was replaced with hydrogen for 3 times, and finally hydrogen was charged at 5.0 MPa. The autoclave was heated to 90 ℃ and reacted for 24 hours with rapid stirring. After the reaction is finished, hydrogen is carefully released, a small amount of reaction liquid is taken for gas phase analysis, the substrate conversion rate is 90%, the muscone selectivity is 85%, the 3-methyl-5-hydroxycyclopentadecane ketone selectivity is 8%, the 3-methyl-1, 5-dihydroxycyclopentadecane selectivity is 6%, and the 3-methylcyclopentadecanol selectivity is 1%. The tetrahydrofuran was removed by rotary evaporation and isolated by rectification to give 32.873g of the target product in 70% yield with an ee value of 98% as determined by chiral gas column chromatography.

Example 3

In a glove box, 3-methyl-1, 5-cyclopentadecanedione (50.478g,200.0mmol), anhydrous tetrahydrofuran (200mL) and [ Rh (COD) (R-BINAP)]BF₄(0.0195g,0.02mmol) was added sequentially to a 500mL autoclave, and finally trifluoroacetic acid (1.140g,10.0mmol) was added. The autoclave was sealed, taken out of the glove box, nitrogen was replaced with hydrogen for 3 times, and finally hydrogen was charged at 5.0 MPa. The autoclave was heated to 90 ℃ and reacted for 24 hours with rapid stirring. After the reaction is finished, hydrogen is carefully discharged, a small amount of reaction liquid is taken for gas phase analysis, and the substrate conversion rate>95 percent, 84 percent of musk ketone selectivity, 7 percent of 3-methyl-5-hydroxy cyclopentadecanone selectivity, 5 percent of 3-methyl-1, 5-dihydroxy cyclopentadecanone selectivity and 1 percent of 3-methyl cyclopentadecanol selectivity. The tetrahydrofuran was removed by rotary evaporation and isolated by rectification to give 33.475g of the target product in 70% yield with an ee value of 98% as determined by chiral gas column chromatography.

Claims

1. A process for the preparation of chiral muscone comprising the steps of:

under the action of chiral rhodium catalyst and Bronsted acid, hydrogen is used as reducing agent to carry out asymmetric hydrogenation and hydrogenolysis reaction to 3-methyl-1, 5-cyclopentadecanedione, and chiral muscone product is synthesized by one-pot method, wherein the chiral rhodium catalyst is selected from [ Rh (COD) (R-BINAP)]BF₄，[Rh(COD)(R-Tol-BINAP)]BF₄，

[Rh(COD)(R-P-Phos)]BF₄，[Rh(COD)(R-SegPhos)]BF₄，

[Rh(COD)(R-MeO-BiPhep)]BF₄，[Rh(COD)(R-PhanePhos)]BF₄，

[Rh(COD)(R-BINAP)]PF₆，[Rh(COD)(R-BINAP)]And Cl, wherein the Bronsted acid is selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid.

2. The method of claim 1, wherein the chiral rhodium catalyst is used in an amount of 0.01 to 10.0 mol% relative to the 3-methyl-1, 5-cyclopentadecanedione substrate and the bronsted acid is used in an amount of 5.0 to 100.0 mol% relative to the 3-methyl-1, 5-cyclopentadecanedione substrate.

3. The process according to claim 1 or 2, wherein the chiral rhodium catalyst is [ rh (cod) (R-Tol-BINAP)]BF₄The Bronsted acid is trifluoroacetic acid.

4. The process according to claim 1 or 2, wherein the chiral rhodium catalyst is used in an amount of 0.1 to 1.0 mol% relative to the 3-methyl-1, 5-cyclopentadecanedione substrate and the bronsted acid is used in an amount of 10.0 to 20.0 mol% relative to the 3-methyl-1, 5-cyclopentadecanedione substrate.

5. The process according to claim 1 or 2, wherein the hydrogen is a reducing agent for asymmetric hydrogenation and hydrogenolysis and the pressure of the introduced hydrogen is 0.5 to 10.0 MPa.

6. The process according to claim 1 or 2, wherein the hydrogen is a reducing agent for asymmetric hydrogenation and hydrogenolysis and the pressure of the introduced hydrogen is 5.0-6.0 MPa.

7. The process according to claim 1 or 2, wherein a solvent is used in the reaction, and the solvent used is selected from one or more of ethyl acetate, benzene, toluene, tetrahydrofuran, acetone, dichloromethane, 1, 2-dichloroethane, and N, N-dimethylformamide.

8. The process according to claim 1 or 2, wherein the reaction temperature is 50-120 ℃.

9. The process according to claim 1 or 2, wherein the reaction temperature is 70-90 ℃.