CN103044204A - Method for asymmetric synthesis of levorotation menthol - Google Patents
Method for asymmetric synthesis of levorotation menthol Download PDFInfo
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Abstract
The invention discloses a method for asymmetric synthesis of levorotation menthol. The method comprises the following steps: citral is taken as an initial raw material, a dihydropyridine derivant is taken as a negative hydrogen source, chiral amine serves as a chiral auxiliary agent for catalytic and asymmetric hydrogenization synthesis of dextrorotation citronellal, the dextrorotation citronellal is catalyzed by Lewis acid for ring-closing synthesis of levorotation isopulegol, and the levorotation isopulegol is subject to catalytic hydrogenation to finally produce the levorotation menthol. The total yield of the levorotation menthol produced by adopting the method is larger than 60 percent, and the ee (enantiomeric excess) value is larger than 90 percent. The method has the characteristics of mild reaction conditions, simple synthetic process, simplicity in catalyst preparation, convenience in catalyst recovery and the like and is suitable for large-scale industrial production of levorotation menthol.
Description
Technical field
The invention belongs to organic chemistry asymmetric synthesis technical field, be specifically related to a kind of method of synthesizing levorotatory menthol take citral as starting raw material through three-step reaction.
Background technology
Menthol (also claiming mentha camphor and Peppermint Oil) has special fragrance, pungent sense and cool feeling.As one of the most salable spices in the world, menthol is widely used in the aspects such as foodstuffs industry, daily fine chemistry industry and medical and health.
Menthol has 3 chiral centres, has 8 kinds of steric isomers, and wherein levorotatory menthol has very strong refrigerant effect with brisk sweet pungent odour; The dextrorotation menthol does not almost have refrigerant effect with pungent pungent odour.Because the using value of levorotatory menthol is higher, what exist on the market all is levorotatory menthol basically.It is widely used in cigarette, makeup, toothpaste, chewing gum, sweet food refreshment drink, medicine and the inuncts.
Menthol all extracts from plant mostly in history, and output is affected by season, cultivated area, natural disaster etc.Along with the development of society, natural menthol can not satisfy the growing consumers demand of people, and therefore, the study on the synthesis of carrying out menthol has higher researching value and economic outlook preferably.
Synthetic menthol method probably is divided into following three kinds: then (1) preparation racemization menthol splits; (2) obtain chiral source with the asymmetric synthesis technology, thereby make menthol; (3) utilize natural chiral precurser, obtain levorotatory menthol by simple conversion, such as obtaining levorotatory menthol with natural left-handed piperitone direct hydrogenation.
It below is the levorotatory menthol synthetic method of two kinds of reports.
Japan STOL company has developed industrialized asymmetric synthesis levorotatory menthol route (Tani, a K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S.J.Am.Chem.Soc.1984,106,5208.).The first step is that myrcene and the reaction of diethyl amido lithium obtain N, N-diethyl geranyl amine.Crucial second step is N, and N-diethyl geranyl amine is at (S)-BINAP-Rh
+Carry out asymmetric hydrogen migration under the type catalyst and obtain the dextrorotation geranial, obtain levorotatory menthol by hydrolysis, acid catalysis pass ring and hydrogenation.Concrete synthetic route is as follows:
This route is the industrialized asymmetric synthesis levorotatory menthol of article one route, and the quality product of producing is higher; But wherein the asymmetric isomerization catalyst preparation condition of catalysis is harsh and recycle difficulty.
BASF Aktiengesellschaft has developed one take citral as the starting raw material synthetic route (Heydrich, G et al.US 2010/0249467 A1,2010.), and this route is successful suitability for industrialized production now.This synthetic route at first obtains the cis citral with the rectifying of citral cis-trans isomerism mixture, obtains the dextrorotation geranial through rhodium catalyst catalysis asymmetric hydrogenation again, finally makes levorotatory menthol by steps such as closing ring, hydrogenation.Concrete synthetic route is as follows:
This synthetic route synthesis technique is simple, yet rectifying citral cis-trans isomerism mixture obtains cis-configuration production unit is had relatively high expectations, and the trans citral that obtains simultaneously is difficult to re-use.
2005, MacMillan reported a kind of with organic micromolecule catalyst and dihydropyridine compound catalysis α, the novel method of the hydrogen transfer reduction of beta-unsaturated aldehyde.In this hydrogen transfer reduction process, respectively with a kind of amine salt of imidazolone as chirality assistant agent and a kind of dihydropyridine compound as negative hydrogen source, negative hydrogen is optionally transferred in two keys of unsaturated aldehyde, thereby has been obtained the aldehyde (Quellet of saturated beta substitution, S, G.; Tuttle, J, B.; MacMillan, W, C.J.AM.Chem.Soc.2005,127,32).Synthetic method is as follows:
Summary of the invention
The purpose of this invention is to provide that a kind of reaction conditions is gentle, synthesis technique is simple, the catalyzer preparation is simple and reclaim the easily method of asymmetric synthesis levorotatory menthol, be fit to the large-scale commercial production levorotatory menthol.
For reaching above-mentioned purpose, the method of a kind of asymmetric synthesis levorotatory menthol provided by the invention, it is characterized in that, take citral as starting raw material, dihydrogen pyridine derivative is negative hydrogen source, and with Chiral Amine as the synthetic dextrorotation geranial of chirality assistant agent catalysis asymmetric hydrogenation, the dextrorotation geranial is through the synthetic left-handed isopulegol of Lewis acid cyclization, left-handed isopulegol finally makes levorotatory menthol through catalytic hydrogenation again.Specifically comprise following reactions steps:
(1) asymmetric hydrogenation: asymmetric hydrogenation occurs and generates the dextrorotation geranial in citral under dihydrogen pyridine derivative and Chiral Amine assistant agent dual catalyst system, reaction formula is as follows:
(2) Louis acid catalysis dextrorotation geranial closes ring: ring closure reaction occurs and generates left-handed isopulegol in the dextrorotation geranial that asymmetric hydrogenation obtains under Louis acid catalysis, reaction formula is as follows:
(3) catalytic hydrogenation: the hydrogenation under the Pd/C catalyst action of left-handed isopulegol obtains levorotatory menthol, and reaction formula is as follows:
The described starting raw material citral of step (1) is the cis-trans isomerism mixture, and wherein the ratio of two kinds of cis-trans-isomers is indefinite, does not need rectifying separation to obtain the sterling of certain configuration.
The described Chiral Amine of step (1) is (R)-2-[two (4-ethylphenyl)] the methyl Pyrrolidine, its salt has following structure:
Wherein X is the used acid of Chiral Amine salify, and used acid is HCl, acetic acid, Mono Chloro Acetic Acid, trifluoroacetic acid (TFA) or trichoroacetic acid(TCA) (TCA).
The negative hydrogen source of the described dihydrogen pyridine derivative of step (1) is 2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-diethyl dicarboxylate, and its structure is as follows:
The described asymmetric hydrogenation medium of step (1) is the organic solvents such as tetrahydrofuran (THF), chloroform, toluene, methylene dichloride or dimethylbenzene, preferred tetrahydrofuran (THF), toluene; Described asymmetric hydrogenation temperature is-30～100 ℃, preferred-20～60 ℃; The described asymmetric hydrogenation time is 5～48h, preferred 10～24h.
The catalytic amount of the described Chiral Amine assistant agent of step (1) is 0.01～10mol%, preferred 0.1～2.5mol%; The consumption of the negative hydrogen source of described dihydrogen pyridine derivative is 10～800mol%, preferred 100～400mol%.
The medium of the described ring closure reaction of step (2) is toluene, hexanaphthene, ethyl acetate or normal hexane, preferred toluene, hexanaphthene, and temperature is 5～10 ℃.
The described Lewis acid of step (2) is zinc bromide, silicon-dioxide, zinc chloride or iron(ic) chloride, preferred zinc bromide, silicon-dioxide.
The medium of the described catalytic hydrogenation of step (3) is ethanol, methyl alcohol, Virahol or propyl carbinol, particular methanol, ethanol, and temperature is-20～120 ℃, preferred 20～80 ℃, hydrogen pressure is 1～10atm.
Adopt the synthetic levorotatory menthol total recovery of synthetic method of the present invention greater than 60%, ee value greater than 90%, have the reaction conditions gentleness, synthesis technique is simple, the catalyzer preparation is simple and reclaim the characteristics such as convenient, suitable large-scale commercial production levorotatory menthol.
Embodiment
Embodiment 1
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 10h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 12.9g, productive rate 84%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 92%.
Embodiment 2
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg; 0.1mmol), 2; 6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids;-20 ℃ of lower 20h that stir; removal of solvent under reduced pressure, column chromatography are purified and are obtained (R)-geranial weak yellow liquid 8.7g, productive rate 71%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 90%.
Embodiment 3
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.40 ℃ of lower 10h that stir, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 10.3g, productive rate 74%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 88%.
Embodiment 4
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (146.5mg; 0.5mmol), trifluoroacetic acid (60mg, 0.5mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml toluene dissolved solids.Stir 18h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 10.9g, productive rate 71%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 68%.
Embodiment 5
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (25.3g, 0.1mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 24h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 7.4g, productive rate 48%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 73%.
Embodiment 6
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 10h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 12.9g, productive rate 84%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the ethyl acetate (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 2.43g of colorless oil product, productive rate 51%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 84%.
Embodiment 7
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 10h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 12.9g, productive rate 84%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with FeCl
3Go in the stirred solution of the toluene (30mL) of (0.97g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing FeCl
3Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.36g of colorless oil product, productive rate 73%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 670mg, productive rate 95%, ee value 82%.
Embodiment 8
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 10h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 12.9g, productive rate 84%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, propyl carbinol 50mg) (20mL) solution is at room temperature H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 547mg, productive rate 77%, ee value 90%.
Embodiment 9
1. catalysis asymmetric hydrogenation
Get a 250ml three-necked flask; under nitrogen protection to wherein adding successively citral (15.2g; 0.1mol), (R)-2-[two (4-ethylphenyls)] methyl Pyrrolidine (29.3mg; 0.1mmol), trifluoroacetic acid (12mg, 0.1mmol), 2,6-dimethyl-1; 4-dihydropyridine-3; 5-diethyl dicarboxylate (75.9g, 0.3mol), and add 80ml tetrahydrofuran (THF) dissolved solids.Stir 10h under the room temperature, removal of solvent under reduced pressure, column chromatography is purified and is obtained (R)-geranial weak yellow liquid 12.9g, productive rate 84%.
2. ring closure reaction
5 ℃, N
2Under the atmosphere, with ZnBr
2Go in the stirred solution of the toluene (30mL) of (1.35g, 6mmol) a copy by a copy adding (R)-geranial (4.6g, 30mmol), the gained compound of reaction continues to stir 0.5h at 5-10 ℃.Filter, with normal hexane (10mL) drip washing ZnBr
2Filtrate is used H successively
2O (30mL), saturated NaHCO
3Solution (30mL), saturated aqueous common salt (30mL) washing.Put anhydrous MgSO
4Dry final vacuum desolventizing, resistates is crossed quick column chromatogram chromatography and is provided the left-handed isopulegol 3.72g of colorless oil product, productive rate 81%.
3. catalytic hydrogenation
(10%, ethanol 50mg) (20mL) solution is at 0 ℃, H for left-handed isopulegol (702mg, 4.55mmol) and Pd/C
2(5atm) vibration 20h. removes by filter catalyzer under the atmosphere, with ethanol (10mL) washing.Removal of solvent under reduced pressure, resistates are crossed flash column chromatography and are provided colorless solid product levorotatory menthol 411mg, productive rate 58%, ee value 88%.
It should be noted that at last: the above is only own for the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment the present invention is had been described in detail, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment puts down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. the method for an asymmetric synthesis levorotatory menthol, it is characterized in that, take citral as starting raw material, dihydrogen pyridine derivative is negative hydrogen source, and with Chiral Amine as the synthetic dextrorotation geranial of chirality assistant agent catalysis asymmetric hydrogenation, the dextrorotation geranial is through the synthetic left-handed isopulegol of Lewis acid cyclization, and left-handed isopulegol finally makes levorotatory menthol through catalytic hydrogenation again.
2. the method for asymmetric synthesis levorotatory menthol according to claim 1 is characterized in that, comprises following reactions steps:
(1) asymmetric hydrogenation: asymmetric hydrogenation occurs and generates the dextrorotation geranial in citral under dihydrogen pyridine derivative and Chiral Amine assistant agent dual catalyst system, reaction formula is as follows:
(2) Louis acid catalysis dextrorotation geranial closes ring: ring closure reaction occurs and generates left-handed isopulegol in the dextrorotation geranial that asymmetric hydrogenation obtains under Louis acid catalysis, reaction formula is as follows:
(3) catalytic hydrogenation: the hydrogenation under the Pd/C catalyst action of left-handed isopulegol obtains levorotatory menthol, and reaction formula is as follows:
3. the method for asymmetric synthesis levorotatory menthol according to claim 2, it is characterized in that, the described starting raw material citral of step (1) is the cis-trans isomerism mixture, and wherein the ratio of two kinds of cis-trans-isomers is indefinite, does not need rectifying separation to obtain the sterling of certain configuration.
4. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the described Chiral Amine of step (1) is (R)-2-[two (4-ethylphenyl)] the methyl Pyrrolidine, its salt has following structure:
Wherein X is the used acid of Chiral Amine salify, and used acid is HCl, acetic acid, Mono Chloro Acetic Acid, trifluoroacetic acid or trichoroacetic acid(TCA).
5. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the negative hydrogen source of the described dihydrogen pyridine derivative of step (1) is 2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-diethyl dicarboxylate, and its structure is as follows:
6. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the described asymmetric hydrogenation medium of step (1) is tetrahydrofuran (THF), chloroform, toluene, methylene dichloride or dimethylbenzene; Described asymmetric hydrogenation temperature is-30～100 ℃; The asymmetric hydrogenation time is 5～48h.
7. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the catalytic amount of the described Chiral Amine assistant agent of step (1) is 0.01～10mol%; The consumption of the negative hydrogen source of described dihydrogen pyridine derivative is 10～800mol%.
8. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the medium of the described ring closure reaction of step (2) is toluene, hexanaphthene, ethyl acetate or normal hexane, and temperature is 5～10 ℃.
9. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the described Lewis acid of step (2) is zinc bromide, silicon-dioxide, zinc chloride or iron(ic) chloride.
10. the method for asymmetric synthesis levorotatory menthol according to claim 2 is characterized in that, the medium of the described catalytic hydrogenation of step (3) is ethanol, methyl alcohol, Virahol or propyl carbinol, and temperature is-20～120 ℃, and hydrogen pressure is 1～10atm.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724170A (en) * | 2013-12-26 | 2014-04-16 | 广东省食品工业研究所 | Asymmetric synthesis method of dextral citronellal |
| CN105541579A (en) * | 2015-12-30 | 2016-05-04 | 浙江新和成股份有限公司 | Method for preparing optically active carbonyl compound |
| CN106421506A (en) * | 2016-12-18 | 2017-02-22 | 广东伊茗药业有限公司 | Throat drops for relieving uncomfortableness of throat |
| CN110845305A (en) * | 2019-11-25 | 2020-02-28 | 安徽一帆香料有限公司 | Method for preparing L-menthol by adopting modified homogeneous catalyst |
| CN110922316A (en) * | 2019-12-04 | 2020-03-27 | 万华化学集团股份有限公司 | Method for preparing L-menthone from R-citronellal |
| CN110963889A (en) * | 2019-12-13 | 2020-04-07 | 万华化学集团股份有限公司 | Method for synthesizing left-optical-activity citronellol by asymmetric hydrosilylation of citral |
| CN112573996A (en) * | 2020-11-26 | 2021-03-30 | 万华化学集团股份有限公司 | Preparation method of optically active menthol |
| CN116003462A (en) * | 2022-12-02 | 2023-04-25 | 南开大学 | Silicon-based substituted chiral amine and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101932543A (en) * | 2007-11-30 | 2010-12-29 | 巴斯夫欧洲公司 | Method for producing optically active, racemic menthol |
-
2012
- 2012-12-24 CN CN2012105682455A patent/CN103044204A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101932543A (en) * | 2007-11-30 | 2010-12-29 | 巴斯夫欧洲公司 | Method for producing optically active, racemic menthol |
Non-Patent Citations (2)
| Title |
|---|
| HIRONORI MAEDA ET AL.: "A dual catalyst system provides the shortest pathway for L-menthol synthesis", 《CHEMICAL COMMUNICATIONS》 * |
| STEPHANE G. OUELLET ET AL.: "Enantioselective Organocatalytic Hydride Reduction", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724170A (en) * | 2013-12-26 | 2014-04-16 | 广东省食品工业研究所 | Asymmetric synthesis method of dextral citronellal |
| CN105541579A (en) * | 2015-12-30 | 2016-05-04 | 浙江新和成股份有限公司 | Method for preparing optically active carbonyl compound |
| CN106421506A (en) * | 2016-12-18 | 2017-02-22 | 广东伊茗药业有限公司 | Throat drops for relieving uncomfortableness of throat |
| CN110845305A (en) * | 2019-11-25 | 2020-02-28 | 安徽一帆香料有限公司 | Method for preparing L-menthol by adopting modified homogeneous catalyst |
| CN110845305B (en) * | 2019-11-25 | 2022-06-28 | 安徽一帆香料有限公司 | Method for preparing L-menthol by adopting modified homogeneous catalyst |
| CN110922316A (en) * | 2019-12-04 | 2020-03-27 | 万华化学集团股份有限公司 | Method for preparing L-menthone from R-citronellal |
| CN110922316B (en) * | 2019-12-04 | 2022-11-08 | 万华化学集团股份有限公司 | Method for preparing L-menthone from R-citronellal |
| CN110963889A (en) * | 2019-12-13 | 2020-04-07 | 万华化学集团股份有限公司 | Method for synthesizing left-optical-activity citronellol by asymmetric hydrosilylation of citral |
| CN110963889B (en) * | 2019-12-13 | 2022-07-12 | 万华化学集团股份有限公司 | Method for synthesizing left-optical-activity citronellol by asymmetric hydrosilylation of citral |
| CN112573996A (en) * | 2020-11-26 | 2021-03-30 | 万华化学集团股份有限公司 | Preparation method of optically active menthol |
| CN116003462A (en) * | 2022-12-02 | 2023-04-25 | 南开大学 | Silicon-based substituted chiral amine and preparation method and application thereof |
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