CN101003501B - Method for synthesizing coenzyme Q10 in high efficiency - Google Patents
Method for synthesizing coenzyme Q10 in high efficiency Download PDFInfo
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- CN101003501B CN101003501B CN2006100018034A CN200610001803A CN101003501B CN 101003501 B CN101003501 B CN 101003501B CN 2006100018034 A CN2006100018034 A CN 2006100018034A CN 200610001803 A CN200610001803 A CN 200610001803A CN 101003501 B CN101003501 B CN 101003501B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
This invention provides a method for synthesizing coenzyme Q10 with high efficiency from solanesol (I). The method comprises: performing bromination reaction on solanesol (I) to obtain compound (II),reacting with compound (III) to obtain compound (IV), removing the protective groups, and oxidizing to obtain solanesol. The method simplifies the process, improves the operation safety, and has suchadvantages as high selectivity and high yield.
Description
Technical field
The present invention relates to a kind of is the method for raw material synthesizing coenzyme Q 10 in high efficiency with the solanesol.
Background technology
Coenzyme Q10 99.0 (Coenzyme Q10 is called for short CoQ10, is called ubiquinone Ubiquinone-50 again), the IUPAC-IUB-CBN name is called Ubiquinone-10, and nomenclature of drug is Ubibecarenone, and its structural formula is as follows:
Coenzyme Q10 99.0 is to obtain by separating in the myocardial mitochondria of ox at first, it combines with mitochondrial inner membrane in cell paste such as animal, plant, microorganism, it is the important hydrogen carrier in the respiratory chain, it is the natural antioxidants that cell self produces, the cellular metabolism activator can improve the immunizing power of body.Coenzyme Q10 99.0 is a kind of medicine with high using value, effective prophylaxis of heart failure, and diseases such as heart disorder, apoplexy, hypertension, arteriosclerosis, amyotrophy, gingival atrophy can also be as the adjuvant therapy medicaments of acquired immune deficiency syndrome (AIDS), malignant tumour.
Coenzyme Q10 99.0 has broad application prospects, and its preparation method mainly contains two classes, and a class is earlier by the synthetic C50 long-chain of polystep reaction, again the C50 long-chain is directly introduced female ring (.Helv.Chim.Acta such as R.Ruegg, 1959,42:2616-2621).Another kind of is earlier the C5 chain to be introduced female ring, thus connect again the C45 chain form the C50 chain (J.Chem.Soc.Chem.Commun. such as Sato K., 1982,153-154).Back one class methods are more promising class methods, and in these class methods, the C5 chain is introduced female ring multiple mode:
1979, and the mode of S.Terao etc. (J.Org.Chem., 1979,44:868-869)
1981, and the mode of Y.Fujita etc. (Bull.Chem.Soc.Jpn., 1982,1325-1326)
2003, and the mode of Jae-Hong Min etc. (J.Org.Chem., 2003,68:7925-7927)
The 1st, 2 kind of mode route is long, and step is many, handles loaded down with trivial detailsly, and the 3rd kind of mode route is shorter, but reaction preference is not high, and protecting group removes difficulty, has offset the short benefit of route, and therefore, 3 kinds of modes all lack actual application value.
At above-mentioned shortcoming, the inventor creates technical scheme of the present invention through long term studies and test.
Summary of the invention
The purpose of this invention is to provide a kind of compound III that is used for synthesizing coenzyme Q 10 in high efficiency, it is characterized in that said composition III comprises following structure:
R1 is alkyl, substituted alkyl (as methyl, ethyl, methoxyl methyl, benzyl, propenyl, MEM etc.) or acyl group, substituted acyl (as ethanoyl, propionyl, benzoyl, benzenesulfonyl, the benzoyl of replacement etc.);
R2 is alkyl, substituted alkyl (as methyl, ethyl, methoxyl methyl, benzyl, propenyl, MEM etc.) or acyl group, substituted acyl (as ethanoyl, propionyl, benzoyl, benzenesulfonyl, the benzoyl of replacement etc.);
When R1 was alkyl or substituted alkyl, R2 was acyl group or substituted acyl;
When R1 was acyl group or substituted acyl, R2 was alkyl or substituted alkyl;
Ar is phenyl or substituted-phenyl (as phenyl, p-methylphenyl, o-methyl-phenyl-, ortho-nitrophenyl base, p-nitrophenyl etc.).
It is the method for raw material synthesizing coenzyme Q 10 in high efficiency with solanesol (I) that a further object of the present invention provides a kind of; this method is a starting raw material with solanesol (I); bromo obtains trans-Solanesyl bromide (II); trans-Solanesyl bromide (II) obtains compound (IV) with compound (III) reaction; compound (IV) obtains Coenzyme Q10 99.0 by removing protecting group and oxidation.This method has been simplified production technique, has been improved the security of production operation, good reaction selectivity, product yield height.
Specifically, the invention provides a kind of is the method for feedstock production Coenzyme Q10 99.0 with solanesol (I), and this method comprises the steps:
1) the solanesol bromo-reaction obtains trans-Solanesyl bromide (II).
2) compound (V) and compound (VI) directly carry out friedel-crafts reaction and obtain compound (III) in the presence of catalyzer.
3) trans-Solanesyl bromide (II) obtains compound (IV) with compound (III) substitution reaction.
4) compound (IV) obtains Coenzyme Q10 99.0 by removing protecting group and oxidation.
The Coenzyme Q10 99.0 synthetic route:
Compound (III) building-up reactions formula:
Present method can adopt for example following specific embodiments:
1) solanesol and phosphorus tribromide react in the presence of solvent, and crystallization obtains trans-Solanesyl bromide.
2) compound (V) and compound (VI) be in the presence of catalyzer, 10～45 ℃ of temperature of reaction, and friedel-crafts reaction obtains compound (III).
3) trans-Solanesyl bromide (II) and compound (III) are in the presence of catalyzer, and temperature of reaction-60 a ℃ substitution reaction obtains compound (IV).
4) compound (IV) obtains Coenzyme Q10 99.0 by removing protecting group and oxidation.
Compound described in the present invention (III) synthetic be by compound (V) and compound (VI) in the presence of catalyzer, directly carry out friedel-crafts reaction and obtain.
Reaction solvent described in the present invention is the mixture of ethers (as THF, ether, dioxane, isopropyl ether and DME etc.), alkanes (as hexane, octane, sherwood oil etc.), arene (as benzene,toluene,xylene etc.), haloalkane hydro carbons (as methylene dichloride, 1,2-ethylene dichloride, trichloromethane etc.) or described solvent.
Temperature of reaction described in the present invention is 0 ℃-65 ℃.
Catalyzer described in the present invention is that Lewis acid is (as AlCl
3, BF
3, ZnCl
2, SnCl
4, MgCl
2, Mg (Me)
2Deng), protonic acid is (as H
2SO
4, H
3PO
4, HAc, CF
3COOH etc.), compound of resin cation (R.C.), silicon or sial (as silicic acid, silicoaluminate, molecular sieve, carclazyte, permutite etc.) or described mixture of catalysts.
The present invention has following advantage:
Reactions steps of the present invention is short, yield is high, convenient post-treatment; Described compound (III) can directly obtain by friedel-crafts reaction.
Embodiment
The present invention can be further described with indefiniteness embodiment hereinafter.
Embodiment 1
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
2,3,4-trimethoxy-6-methyl phenyl acetate salt compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), 1-((E)-4-chloro-2-methyl-2-butene base sulphonyl) benzene compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and methylene dichloride 100ml places reaction flask, and the anhydrous BF of adding is down stirred in nitrogen protection
3Et
2O 0.013mol (1.83g), 25 ℃ of temperature of reaction reaction 8 hours, stopped reaction, be cooled to room temperature after, material in the reaction flask is poured in the 100ml frozen water, tell organic layer, with the washing of NaCl saturated aqueous solution, anhydrous MgSO
4Drying after 6 hours, leaches siccative, concentrating under reduced pressure reclaims solvent, obtains light brown oily thing, separate and obtain 2,3,4-trimethoxy-6-methyl-5-((E)-3-methyl-4-(benzene sulfonyl)-crotyl) phenyl sulphate cpd (III) 0.0020mol (0.89g).Purity 98.4%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).2,3,4-trimethoxy-6-methyl-5-((E)-3-methyl-4-(benzene sulfonyl)-crotyl) phenyl sulphate cpd (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound 2,3,4-trimethoxy-6-methyl-5-((2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E)-3,7,11,15,19,23,27,31,35,39-decamethyl-4-(benzene sulfonyl) tetracontyl-2,6,10,14,18,22,26,30,34,38-ten alkene) phenyl acetate compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 2
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and 1,2-ethylene dichloride 100ml places reaction flask, and the anhydrous AlCl of adding is down stirred in nitrogen protection
30.013mol (1.80g), 10 ℃ of reactions of temperature of reaction 10 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0018mol (0.80g), purity 98.0%, yield 21.7%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 3
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and trichloromethane 100ml places reaction flask, and the anhydrous SnCl of adding is down stirred in nitrogen protection
40.013mol (3.39g), 5 ℃ of reactions of temperature of reaction 10 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0018mol (0.79g), purity 97.9%, yield 21.7%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 4
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and dioxane 100ml places reaction flask, and the anhydrous MgCl of adding is down stirred in nitrogen protection
20.013mol (1.24g), 40 ℃ of reactions of temperature of reaction 6 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0021mol (0.94g).Purity 98.3%, yield 25.3%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 5
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and ether 100ml places reaction flask, and adding anhydrous Mg (Me) is down stirred in nitrogen protection
20.013mol (0.71g), 55 ℃ of reactions of temperature of reaction 12 hours, stopped reaction, post processing mode obtains brown oil with embodiment 1, separates to obtain compound (III) 0.0018mol (0.79g), purity 97.9%, yield 21.7%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 6
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and THF100ml places reaction flask, and adding H is down stirred in nitrogen protection
3PO
40.013mol (1.27g), 63 ℃ of reactions of temperature of reaction 4 hours, stopped reaction, post processing mode obtains brown oil with embodiment 1, separates to obtain compound (III) 0.0020mol (0.89g).Purity 98.4%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 7
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g); compound (VI) is 0.0090mol (2.2g) (Ar=Ph); isopropyl ether 100ml places reaction flask, nitrogen protection; stir and add HAc 0.013mol (0.57g) down; 48 ℃ of reactions of temperature of reaction 9 hours, stopped reaction, post processing mode is with embodiment 1; obtain light brown oily thing, separate obtaining compound (III) 0.0019mol (0.85g).Purity 98.3%, yield 22.9%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 8
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and DME100ml places reaction flask, and adding CF is down stirred in nitrogen protection
3COOH 0.013mol (1.48g), 0 ℃ of reaction of temperature of reaction 15 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0017mol (0.78g), purity 97.9%, yield 20.5%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 9
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g); compound (VI) is 0.0090mol (2.2g) (Ar=Ph); benzene 100ml places reaction flask, nitrogen protection; stir and add resin cation (R.C.) 1.8g down; 15 ℃ of reactions of temperature of reaction 13 hours, stopped reaction, post processing mode is with embodiment 1; obtain light brown oily thing, separate obtaining compound (III) 0.0020mol (0.89g).Purity 98.2%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100m1 mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 10
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g); compound (VI) is 0.0090mol (2.2g) (Ar=Ph); toluene 100ml places reaction flask, nitrogen protection; stir and add silicic acid 0.013mol (0.79g) down; 20 ℃ of reactions of temperature of reaction 8 hours, stopped reaction, post processing mode is with embodiment 1; obtain light brown oily thing, separate obtaining compound (III) 0.0020mol (0.89g).Purity 98.2%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 11
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH3; R2=CH3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), dimethylbenzene 100ml; place reaction flask; adding silicoaluminate 1.5g is down stirred in nitrogen protection, 25 ℃ of reactions of temperature of reaction 8 hours; stopped reaction; post processing mode obtains light brown oily thing with embodiment 1, separates to obtain compound (III) 0.0020mol (0.89g).Purity 98.2%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 12
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g); compound (VI) is 0.0090mol (2.2g) (Ar=Ph); hexane 100ml places reaction flask, nitrogen protection; stir and add the dry molecular sieve 3g that crosses down; 30 ℃ of reactions of temperature of reaction 7 hours, stopped reaction, post processing mode is with embodiment 1; obtain light brown oily thing, separate obtaining compound (III) 0.0020mol (0.89g).Purity 98.2%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 13
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and octane 100ml places reaction flask, and adding AlCl is down stirred in nitrogen protection
3And H
2SO
4Mixture, any proportioning, 1.8g, 45 ℃ of reactions of temperature of reaction 5 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0020mol (0.89g).Purity 98.4%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
Embodiment 14
Solanesol (I) 0.010mol (6.31g) reacts in the presence of solvent with phosphorus tribromide, and crystallization obtains trans-Solanesyl bromide (II) 0.009mol (6.25g), purity: 95%, and yield: 90%.
Compound (V) (R1=COCH
3, R2=CH
3) 0.0083mol (2.0g), compound (VI) is 0.0090mol (2.2g) (Ar=Ph), and sherwood oil 100ml places reaction flask, and the anhydrous AlCl of adding is down stirred in nitrogen protection
30.013mol (1.8g), 25 ℃ of reactions of temperature of reaction 8 hours, stopped reaction, post processing mode obtain light brown oily thing with embodiment 1, separate to obtain compound (III) 0.0020mol (0.89g).Purity 98.4%, yield 24.0%.
Bromo solanesol (II) 0.010mol (7.1g).Compound (III) (R1=COCH
3, R2=CH
3, Ar=C
6H
5) 0.0067mol (3.0g); THF 100ml places the exsiccant reaction flask, nitrogen protection; the butyllithium hexane solution that in the time of-60 ℃, adds 9ml 15%; react after 2 hours, temperature of reaction is risen to room temperature, reacted again 5 hours; material in the reaction flask is poured in rare HCl water of ice-cold 200ml0.5%; extract with 3 * 100ml isopropyl ether, the isopropyl ether layer is with saturated NaCl solution washing, MgSO
4Drying, concentrating under reduced pressure obtain compound (IV).Compound (IV) is dissolved (THF: EtOH=10: 1) with the 100ml mixed solvent, careful 0.043mol (1.0g) Na that adds, stirring reaction 2 hours, after being chilled to room temperature, observe Na whether have residual, confirm that no Na is residual after, add 200ml water, with 3 * 100ml normal hexane extraction, in hexane solution, add the 100ml Virahol, add FeCl again
36H
2O 0.019mol (5g), room temperature reaction added 200ml water after 2 hours, told the normal hexane layer, with saturated NaCl solution washing, MgSO
4Drying leaches siccative, concentrate the Coenzyme Q10 99.0 crude product, separate obtaining pure product Coenzyme Q10 99.0 0.0047mol (4.1g), m.p.48-49 ℃, purity (HPLC): 99.7%, yield: 70.1%.
The comparative example 1
With solanesol 2 is raw material, makes (all-E)-3,7,11,15,19,23,27,31,35 through four-step reaction, 39-decamethyl-2,6,10,14,18,22,26,30,34, and 38-40 carbon ten alkene-1-alcohol 3, total recovery is 63%.Reaction equation is as follows:
With 2,3-dimethoxy-5-methyl cyclohexane-2,5-diene-1, (9.1g 50mmol) is dissolved in the 50ml chloroform 4-diketone 4, adds 5%Pd/C (0.5g) as catalyzer, and normal pressure feeds hydrogen down, becomes colorless up to solution.Pd/C is removed by filter, under nitrogen protection, distill, obtain 9.1g white solid 2,3-dimethoxy-5-methyl-Resorcinol 5.Yield 100%, 75～77 ℃ of mp, reaction equation is as follows:
With 2, (0.48g 2.6mmol), is dissolved in absolute ether (20ml) lining to 3-dimethoxy-5-methyl-Resorcinol 5, adds (all-E)-3 successively; 7,11,15,19,23; 27,31,35,39-decamethyl-2,6; 10,14,18,22,26; 30,34, and 38-40 carbon ten alkene-1-alcohol 3 (1.8g, 2.6mmol), exsiccant zinc chloride (0.28g; 2.1mmol), Glacial acetic acid (0.02ml, 0.4mmol), stirring at room 2h under nitrogen protection.Then, stop logical nitrogen, add excessive liquor ferri trichloridi, stir 10min, ether layer is separated, the salt washing, dried over mgso obtains crude product 2.2g after the distillation.Column chromatography (elutriant: 1,2-ethylene dichloride-benzene (1: 1)) after, obtain Coenzyme Q10 99.0 0.0006mol (0.56g), light yellow solid, coupling productive rate 20%.
Claims (9)
1. intermediate compound (III) that is used for synthesizing coenzyme Q 10 in high efficiency is characterized in that this compound is following structure:
Compound (III)
Wherein, R
1Be ethanoyl; R
2Be methyl; Ar is a phenyl.
2. one kind is the method for raw material synthesizing coenzyme Q 10 in high efficiency with solanesol (I); it is characterized in that with solanesol (I) be starting raw material; reaction obtains trans-Solanesyl bromide (II); trans-Solanesyl bromide (II) obtains compound (IV) with compound (III) reaction; compound (IV) is by removing protecting group and oxidation; obtain Coenzyme Q10 99.0, described compound III and compound IV are following structure:
Compound (III) compound (IV)
Wherein, R
1Be ethanoyl, R
2For methyl, Ar are phenyl.
3. method according to claim 2 wherein, is the method for feedstock production Coenzyme Q10 99.0 with solanesol (I), and this method comprises the steps:
1) the solanesol bromination reaction obtains trans-Solanesyl bromide (II);
2) compound (V) and compound (VI) directly carry out friedel-crafts reaction and obtain compound (III) in the presence of catalyzer, and described compound V and compound VI are following structure:
Compound (V) compound (VI),
R wherein
1Be ethanoyl, R
2For methyl, Ar are phenyl;
3) trans-Solanesyl bromide (II) obtains compound (IV) with compound (III) reaction;
4) compound (IV) obtains Coenzyme Q10 99.0 by removing protecting group and oxidation.
4. method according to claim 2, wherein, reaction solvent is tetrahydrofuran (THF) or ether or dioxane or isopropyl ether or dme or hexane or octane or sherwood oil or benzene or toluene or dimethylbenzene or methylene dichloride or 1,2-ethylene dichloride or trichloromethane.
5. temperature of reaction method according to claim 3, wherein, step 2) is 10 ℃-45 ℃.
6. catalyzer method according to claim 3, wherein, step 2) is the compound or the described mixture of catalysts of Lewis acid, protonic acid, resin cation (R.C.), silicon or sial.
7. want its 6 described method according to right, wherein, lewis acid catalyst is AlCl
3Or BF
3Or ZnCl
2Or SnCl
4Or MgCl
2Or Mg (Me)
2
8. method according to claim 6, wherein, protonic acid is H
2SO
4Or H
3PO
4Or HAc or CF
3COOH.
9. method according to claim 6, wherein, the compound of silicon or sial is silicic acid or silicoaluminate or molecular sieve or carclazyte or permutite.
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| Title |
|---|
| JAE-HONG MIN et al..the friedel-crafts allylation of a prenyl group stabilized by asulfone moiety:expeditious syntheses of ubiquinones andmenaquinones.J.ORG.CHEM. 68.2003,(68),7925-7927. |
| JAE-HONG MIN et al..the friedel-crafts allylation of a prenyl group stabilized by asulfone moiety:expeditious syntheses of ubiquinones andmenaquinones.J.ORG.CHEM. 68.2003,(68),7925-7927. * |
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