CN104370714A - Preparation method of 2-methylcyclopentadecanon - Google Patents
Preparation method of 2-methylcyclopentadecanon Download PDFInfo
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- CN104370714A CN104370714A CN201410495221.0A CN201410495221A CN104370714A CN 104370714 A CN104370714 A CN 104370714A CN 201410495221 A CN201410495221 A CN 201410495221A CN 104370714 A CN104370714 A CN 104370714A
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- cyclopentadecanone
- methylene radical
- benzene
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Abstract
The invention discloses a preparation method of 2-methylcyclopentadecanon. The method comprises the following steps: cyclizing a raw material dimethyl pentadecanedioate, adding a thiophenylmethylene group, dehydroxylating, and removing athiophenyl group to obtain 2-methylcyclopentadecanon. The raw material can be industrially produced and easily obtained. The method using cheap methyl phenylthio acetate to carry out a methylation reaction avoids the difficult industrial production of a methyl Grignard reaction, the method not using expensive iodide or bromide saves the cost and also avoids the use of ether solvents with production safety problems, and the method also has the advantages of milder reaction condition and easy industrialization.
Description
Technical field
The present invention relates to chemical synthesis process, specifically a kind of preparation method of 2-muscone.
Background technology
2-muscone (CAS 52914-66-6) trace is present in the secretory product of the animals such as musquash, civet and musk deer deer, is one of aroma component of precious leopard cat perfume and Moschus.Because the molecular structure of 2-muscone is similar with 3-muscone (muskone), for the Methyl Isomers of the latter, so 2-muscone also has the gracefulness similar with muskone and soft fragrance, also there is effect (synthesis of huge ring muskone compounds such as inducing resuscitation of having one's ideas straightened out, promoting blood circulation to restore menstrual flow, swelling and pain relieving simultaneously, Shanghai daily-use chemical industry, 1974,2,28-41.).
Because the main source-musk deer deer of natural musk reduces day by day, endangered, but market increases the demand not anti-reflection as the Moschus of required medicinal ingredients and high-grade spices in the many traditional famous Chinese patent medicines of China.In addition, owing to having the cheap synthetic perfume kind of similar fragrance such as the synthetic perfumes such as nitro musk, many lopps Moschus class to be found there is carcinogenic, the effect such as genetoxic and endocrine disruption to the mankind in recent years as with natural musk, not easily be degraded at nature and easily affect the reasons such as ecological, its use is more and more restricted.The megacyclic musk compounds such as 2-muscone itself are natural products, are present in the secretory product of musquash, civet and musk deer deer etc.Its structure and human compatibility good, therefore safety, without ecological risk.There is again natural musk fragrance, soft aroma and, diffusive force is strong and lasting, is a kind of surrogate of excellent natural musk.Therefore the study on the synthesis of this compounds comes into one's own again with exploitation.
Because this compounds holds the methyl structural of large ring and specific position, the difficulty of synthesis is very large.Existing 2-muscone preparation method is listed below:
The people such as Walter Scares Leal (Walter Scares Leal, * Shigefumi Kuwahara, Xiongwei Shi, HiroyaHiguchi,
4claudia E.B.Marino, Mikio Ono, and Jerrold Meinwald, .Journal of Chemical Ecology, Vol.24, No.11,1998.) using cyclopentadecanone as raw material, first generate corresponding hydrazone with (S)-(-)-1-amino-2-methoxypicoline (SAMP) by condensation reaction, then by this hydrazone under the existence of lithium diisopropylamine and methyl iodide, maintain the low-temp reaction of-110 DEG C after two hours, then reflux 20 hours, obtain (R)-2-muscone finally by hydrochloric acid hydrogenolysis.The method is using the cyclopentadecanone of costliness as raw material, and also cost is higher for methyl iodide simultaneously; Reaction needed is carried out under the pole cold condition of-110 DEG C, and condition is harsh, and the method can only be carried out in the lab, is difficult to suitability for industrialized production.
The people such as B.D.MOOKHERJ (B.D.Mookherjee, * R.W.Trenkle, AND R.R.Pate., J.Org.Chem., Vol.36, No.92,1971.) utilize 1,9-ring 16 carbon diene as raw material, the 2-muscone through nine step Reactive Synthesis.It is higher that this reaction scheme respectively walks productive rate, but need temperature of reaction to be down to zero degree when second step uses butyllithium, and this makes reaction conditions become comparatively harsh; 5th step is counter applies the methyl Grignard reaction in ether; The mixture of what final step obtained is 2-muscone and 3-muscone, is difficult to be separated; And this reaction scheme step is also longer.These problems limit the application industrially of this route.
Kazutsugu Matsumoto(Kazutsugu Matsumoto,Seiji Tsutsumi,Tamiko Ihori,and HiromichiOhta.,,J.Am.Chem.Soc.1990,112,9614-9619。) etc. utilize Pichia miso IAM4682 (primary yeast) 2-methyl-2-acetoxyl group cyclopentadecylene to be converted into 2-muscone, reaction times is 24 hours, reaction yield is 38%, but reaction need be carried out in phosphate buffered saline buffer, comparatively harsh to the conditional request of reaction, and reaction yield is lower; Reaction raw materials is not easy to obtain, and difficult synthesis, is also not suitable for suitability for industrialized production.
In view of above analysis, exploitation synthesis step is short, and reaction conditions is gentle, and raw material is relatively cheap, and synthesis 2-muscone variation route simple to operate has very large realistic meaning and the positive social benefit such as environment protection, raising people quality of life.
Summary of the invention
Object of the present invention aims to provide the route of a new synthesis 2-muscone, and can reach industrialized requirement, namely raw material is relatively cheap, and reaction conditions is gentle, simple to operate.
The object of the present invention is achieved like this:
A preparation method for 2-muscone, the method for raw material, obtains 2-muscone through cyclisation, upper benzene sulphur methylene radical, dehydroxylation and de-thiophenyl with pertadecane diacid dimethyl ester; Specifically comprise the following steps:
The first step for raw material, is obtained by reacting cyclopentadecylene adjacent two silicon ethers with sodium and trimethylchlorosilane with pertadecane diacid dimethyl ester.The mass ratio of pertadecane diacid dimethyl ester and sodium and trimethylchlorosilane three kinds of materials is (2 ~ 4): (0.5 ~ 1.5): (3 ~ 5), and the best is: (2.5 ~ 3.5): (0.8 ~ 1.2): (3.5 ~ 4.5); Reaction solvent is benzene or toluene or hexanaphthene, and the best is toluene; The ratio of pertadecane diacid dimethyl ester and reaction solvent is 0.5 ~ 2.0g/10mL, and the best is 0.8 ~ 1.5g/10mL; Reflux time is 20 ~ 30 hours.
Adjacent for the cyclopentadecylene obtained two silicon ethers and acetic acid benzene thiomethyl ester react and generate 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone by second step under zinc bromide effect.The mass ratio of the adjacent two silicon ethers of cyclopentadecylene and acetic acid benzene thiomethyl ester and zinc bromide three kinds of materials is (4 ~ 7): (2 ~ 4): (1 ~ 5), and the best is: (4.5 ~ 6.5): (2.5 ~ 3.5): (1.5 ~ 2.5); Reaction solvent is methylene dichloride or tetrahydrofuran (THF) or hexanaphthene, and the best is methylene dichloride; The ratio of the adjacent two silicon ethers of cyclopentadecylene and reaction solvent is 4 ~ 8g/10mL, is preferably 5 ~ 7g/10mL; Reaction times is 20 ~ 30 hours.
The hydroxyl of 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone is sloughed by the 3rd step hydroiodic acid HI, obtains 2-benzene sulphur methylene radical cyclopentadecanone.The mass ratio of hydroiodic acid HI and 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone is (2 ~ 4): (0.5 ~ 2), and the best is: (2.5 ~ 3): (0.8 ~ 1.5); Reaction solvent is acetic acid; The ratio of 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone and acetic acid is 1 ~ 8g/10mL, and the best is 1 ~ 3g/10mL; Reflux time is 5 ~ 10 hours.
4th step Raney Ni and the effect of 2-benzene sulphur methylene radical cyclopentadecanone, slough thiophenyl, obtain described 2-muscone.The mass ratio of Raney Ni and 2-benzene sulphur methylene radical cyclopentadecanone is (3 ~ 7): (0.5 ~ 2), is preferably: (4 ~ 6): (0.8 ~ 1.5); Reaction solvent is the acetone containing 5 ~ 15% ethanol; The ratio of 2-benzene sulphur methylene radical cyclopentadecanone and solvent is 0.1 ~ 3g/10mL, is preferably 0.3 ~ 2g/10mL; Reaction times is 5 ~ 10 hours.
Concrete synthetic route is as follows:
Raw material of the present invention (pertadecane diacid dimethyl ester) can suitability for industrialized production, is easy to get.Importantly, present invention utilizes more cheap acetic acid benzene thiomethyl ester and carry out methylation reaction, avoid and be difficult to the reaction of suitability for industrialized production methyl Grignard, do not need to use expensive methyl iodide or monobromethane, provide cost savings, it also avoid the ether solvent using and have production safety problem, simultaneous reactions condition is gentleer simultaneously, is easier to implement industrialization.
Embodiment
Embodiment 1
The preparation of acetic acid benzene thiomethyl ester:
In reaction flask, add 4.3g chloromethylbenzene thioether, 8.6g sodium acetate, 14.3ml acetic acid, stir, be heated to backflow, after raw material reaction, cross after post is separated and obtain product 3.5g, productive rate 70%.
1H NMR(500 MHz,CDCl
3)δ7.38(d,J=7.4Hz,2H),7.25(t,J=7.5Hz,2H),7.21–7.18(m,1H),5.34(s,2H),2.03(s,3H)。
Embodiment 2
The preparation of silicon ether:
Add toluene 20ml, sodium 1g in reaction flask, after being heated to backflow, add pertadecane diacid dimethyl ester 3g, trimethylchlorosilane 4g.React 24 hours, toluene wash, suction filtration process product, then wash by ethyl acetate, revolve steaming and desolventize, obtain product 3g, productive rate 84%, product is pale yellow oily liquid body.
Embodiment 3
The synthesis of 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone:
1.7g zinc bromide is added in 10ml methylene dichloride, add 5.9g silicon ether, 2.8g acetic acid benzene thiomethyl ester, stirred at ambient temperature reacts 24 hours, target product is obtained after column chromatography, the proportioning of eluent is v (sherwood oil): v (ethyl acetate)=50:1, product is 2.56g, and productive rate is 46%.
1H NMR(500MHz,CDCl
3)δ7.31(d,J=7.2Hz,2H),7.19(t,J=7.6Hz,2H),7.12(t,J=7.3Hz,1H),3.95(s,1H),3.24(s,2H),2.55–2.47(m,1H),2.29–2.18(m,1H),1.80–1.54(m,4H),1.54–1.43(m,2H),1.37–1.13(m,18H)。
Embodiment 4
The preparation of 2-benzene sulphur methylene radical cyclopentadecanone:
Add 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone 1g, 10ml acetic acid, 2.7g hydroiodic acid HI in reaction flask after, be heated to backflow, reaction 5 is little to disappear up to raw material, is chilled to room temperature.Add 10%KOH under ice bath and be neutralized to neutrality, extraction into ethyl acetate, anhydrous sodium sulfate drying process, revolve and desolventize, cross post and be separated, the proportioning of eluent is v (sherwood oil): v (ethyl acetate)=100:1, revolve and desolventize, obtain 0.68g target product, productive rate 71%.
1H NMR(500MHz,CDCl
3)δ7.27–7.17(m,4H),7.12(t,J=7.2Hz,1H),3.08(dd,J=13.1,8.6Hz,1H),2.85(dd,J=13.1,5.7Hz,1H),2.72(m,1H),2.45(m,1H),2.36–2.24(m,1H),1.69–1.57(m,2H),1.48–1.38(m,2H),1.27–1.17(m,20H)。
Embodiment 5
The preparation of 2-muscone:
0.68g2-benzene sulphur methylene radical cyclopentadecanone is put in reaction flask, after 20mL acetone solution, adds 3.5g Raney Ni, then measure 2mL ethanol, add in single neck bottle, stirring at room temperature, react 6 hours.Cross and filter Raney Ni, revolve steaming and desolventize, obtain product 0.39g, productive rate 83%.
1H NMR(500MHz,CDCl
3)δ2.58–2.48(m,1H),2.44-2.31(m,3H),1.67–1.44(m,4H),1.31–1.14(m,20H),0.98(d,J=6.9Hz,3H)。
Claims (1)
1. a preparation method for 2-muscone, is characterized in that the method with pertadecane diacid dimethyl ester for raw material, obtains 2-muscone through cyclisation, upper benzene sulphur methylene radical, dehydroxylation and de-thiophenyl; Specifically comprise the following steps:
The first step for raw material, is obtained by reacting cyclopentadecylene adjacent two silicon ethers with sodium and trimethylchlorosilane with pertadecane diacid dimethyl ester; The mass ratio of pertadecane diacid dimethyl ester, sodium and trimethylchlorosilane three kinds of materials is (2 ~ 4): (0.5 ~ 1.5): (3 ~ 5); Reaction solvent is benzene, toluene or hexanaphthene; The ratio of pertadecane diacid dimethyl ester and reaction solvent is 0.5 ~ 2.0g/10mL; Reflux time is 20 ~ 30 hours;
Adjacent for the cyclopentadecylene obtained two silicon ethers and acetic acid benzene thiomethyl ester react and generate 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone by second step under zinc bromide effect; The mass ratio of cyclopentadecylene adjacent two silicon ethers, acetic acid benzene thiomethyl ester and zinc bromide three kinds of materials is (4 ~ 7): (2 ~ 4): (1 ~ 5); Reaction solvent is methylene dichloride, tetrahydrofuran (THF) or hexanaphthene; The ratio of the adjacent two silicon ethers of cyclopentadecylene and reaction solvent is 4 ~ 8g/10mL; Reaction times is 20 ~ 30 hours;
The hydroxyl of 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone is sloughed by the 3rd step hydroiodic acid HI, obtains 2-benzene sulphur methylene radical cyclopentadecanone; The mass ratio of hydroiodic acid HI and 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone is (2 ~ 4): (0.5 ~ 2); Reaction solvent is acetic acid; The ratio of 2-benzene sulphur methylene radical-2-hydroxyl cyclopentadecanone and acetic acid is 1 ~ 8g/10mL, and reflux time is 5 ~ 10 hours;
4th step Raney Ni and the effect of 2-benzene sulphur methylene radical cyclopentadecanone, slough thiophenyl, obtain described 2-muscone; The mass ratio of Raney Ni and 2-benzene sulphur methylene radical cyclopentadecanone is (3 ~ 7): (0.5 ~ 2); Reaction solvent is the acetone containing 5 ~ 15% ethanol; The ratio of 2-benzene sulphur methylene radical cyclopentadecanone and solvent is 0.1 ~ 3g/10mL, and the reaction times is 5 ~ 10 hours.
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CN105732353A (en) * | 2016-03-17 | 2016-07-06 | 福建师范大学 | Preparation method of alpha-hydroxycyclopentadecanone |
Citations (1)
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JPS5547024B2 (en) * | 1972-07-26 | 1980-11-27 |
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JPS5547024B2 (en) * | 1972-07-26 | 1980-11-27 |
Non-Patent Citations (4)
Title |
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HIROAKI TAGUCHI,ET AL.: "A Facile Ring Enlargement Reaction via β-Oxido Carbenoid", 《BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN》, vol. 50, no. 6, 31 December 1977 (1977-12-31), pages 1592 - 1595 * |
HIROAKI TAGUCHI,ET AL.: "A Facile Route to d,l-Muscone", 《TETRAHEDRON LETTERS》, no. 30, 31 December 1976 (1976-12-31), pages 2617 - 2620 * |
KAZUTSUGU MATSUMOTO,ET AL.: "Enzyme-Mediated Enantioface-Differentiating Hydrolysis of α-Substituted Cycloalkanone Enol Esters", 《J.AM.CHEM.SOC.》, vol. 112, no. 26, 31 December 1990 (1990-12-31), pages 9614 - 9619 * |
RONALD J.GRAHAM,ET AL.: "The Stereoselective Alkylation and Conformational Analysis of 15-Hexadecanolide", 《TETRAHEDRON LETTERS》, vol. 32, no. 8, 31 December 1991 (1991-12-31), pages 1027 - 1030 * |
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CN105732353A (en) * | 2016-03-17 | 2016-07-06 | 福建师范大学 | Preparation method of alpha-hydroxycyclopentadecanone |
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