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CN102010297A - Method for chiral synthesis of levorotatory menthol - Google Patents

Method for chiral synthesis of levorotatory menthol Download PDF

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Publication number
CN102010297A
CN102010297A CN2010105549074A CN201010554907A CN102010297A CN 102010297 A CN102010297 A CN 102010297A CN 2010105549074 A CN2010105549074 A CN 2010105549074A CN 201010554907 A CN201010554907 A CN 201010554907A CN 102010297 A CN102010297 A CN 102010297A
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handed
menthol
chirality
synthetic
catalyst
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CN102010297B (en
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王三永
李春荣
段泽斌
杨定乔
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Guangdong Food Industry Institute Co ltd
South China Normal University
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GUANGDONG PROV FOOD INDUSTRY INST
South China Normal University
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Abstract

The invention discloses a method for chiral synthesis of levorotatory menthol. In the process, dextrorotatory pulegone is used as a starting material; catalytic hydrogenation is carried out on the dextrorotatory pulegone by a chiral rhodium catalyst to generate levorotatory menthone; and the catalytic hydrogenation is carried out on the levorotatory menthone by a chiral ruthenium catalyst to synthesize the levorotatory menthol. In the process for synthesizing the levorotatory menthol through an asymmetric synthesis technology, the yield of the levorotatory menthone is more than 90%, the ee value of the levorotatory menthone is more than 99%, the total yield of the levorotatory menthol is greater than 83%, the ee value of the levorotatory menthol is greater than 98%, and the specific rotation is from-49 degrees to -50 degrees. The synthetic process is simple and is suitable for industrial production of the levorotatory menthol in a large scale, and the prepared levorotatory menthol has the advantages of high yield, good selectivity, high catalyst activity and other characteristics, is simple to recover.

Description

The method of the synthetic left-handed menthol of a kind of chirality
Technical field
The invention belongs to organic chemistry chirality synthesis technical field, being specifically related to a kind of is the method for raw material through the synthetic left-handed menthol of two-step reaction chirality with the dextrorotation pulegone.
Background technology
Menthol (also claiming mentha camphor and Peppermint Oil) has special fragrance, pungent sense and cool sense, as one of the most salable spices in the world, is widely used in aspects such as foodstuffs industry, daily fine chemistry industry and medical and health.Perfuming as toothpaste, food, tobacco, wine, refreshment drink, makeup, perfumed soap; In pharmaceutically being widely used in wind dispelling, anticorrosion, anti-inflammatory, analgesia, antipruritic, medicine such as be good for the stomach.Left-handed menthol has three chiral centres, therefore, has 8 kinds of steric isomers, but in these 8 kinds of steric isomers, has only left-handed menthol (l-menthol) to have higher economic value.It has brisk sweet pungent odour, very strong refrigerant effect is arranged, cooling effect mechanism is the cold receptor on the skin irritation but does not cause actual temperature change, and other isomer have bigger influence to the cooling effect of left-handed menthol, the content purity of left-handed menthol has determined the quality of product.Present global menthol annual production estimates more than 19000 tons, and what exist on the market all is left-handed menthol basically.
Menthol is all from plant extract in history, and it is bigger that output is influenced by seasonal variation, cultivated area, bad farming etc., and main producing region the nations of China and India also is difficult to provide stable product to be supplied with, and the price volalility amplitude that causes is very big.And the plantation amount of natural peppermint also is difficult to satisfy the market requirement that enlarges day by day, and insufficient section then need synthesize menthol to be filled up.Synthetic menthol mouthfeel is stable, and natural menthol and synthetic menthol can exchange fully on the sense organ, and synthetic menthol does not contain the impurity that exists in the natural menthol, so its mouthfeel good taste, price is relatively cheap in addition, and special advantages is arranged, and is easier to be accepted by producer.
When falling sharply and the influence of factor such as labor cost rising of preceding destruction because of physical environment, cultivated area, the output of natural menthol is more and more lower, and the market requirement increases day by day in addition, has aggravated the rise of menthol price jointly.Therefore the synthetic menthol economic outlook of industry is wide, room for promotion is big.
The synthetic method of menthol can be divided into two kinds: (1) preparation racemization menthol, carry out chiral separation then and make left-handed menthol; (2) utilize the asymmetric synthesis technology, do not need fractionation directly to obtain left-handed menthol.
The shortcoming of first method is, splitting step is numerous and diverse, and productive rate is generally not high.The sixties in last century, the route of He Ke man of great strength company (Hercules) research and development of the U.S. is exactly through synthesizing left-handed menthol (Acharya, S.P. with Split Method; Brown, H.C.J.Am.Chem.Soc.1967,89,1925.Leffingwell, J.C.﹠amp; R.E.Shackelford, Laevo-Menthol syntheses and organoleptic properties, Cosmeticsand Perfumery, 1974,89 (6), 69-89), but fail to realize suitability for industrialized production so far.But the fragrant company of German moral relies on its superb hydrogenation technology and isomerization reformation technology (Kuhn, W.; Funk, H.; Senft, G.; Koerber, K.A.DE 10239274,2002[Chem.Abstr.2002,140,217823] .), with left-handed menthol success industrialization.The fragrant company of nearest German moral has invented the lipase disassemble technique a kind of, and the left-handed menthol ee value that obtains is near 100%, but cost is too high and fail industrial applications (Gatfield, I.; Hilmer, E.; Bornscheuer, U.; Schmidt, R.; Vorlova, S.EP 1223223,2002[Chem.Abstr.2002,137,78009] .).
Japan high sand company is that starting raw material synthesizes the left-handed menthol of preparation through five steps with the myrcene, and its core reaction is chirality rhodium catalyst [Rh ((S)-BINAP) 2] ClO 4(Synthesis 1996,665 for S.Otsuka, K.Tani in the asymmetric hydrogen migration reaction of catalysis allyl amine; EP 0068506,1982).Japan high sand company is that first utilizes the company of the synthetic left-handed menthol of asymmetric synthesis technology in the world.
Peppermint in southern Europe and the plantation of north African wide range of commercial, its main moiety pulegone (dextrorotation pulegone, pulegone, also claim pulegone), the cheaper raw material that can be used as the synthetic left-handed menthol of commercial chirality of price, the Bordas of Spain company is that starting raw material prepares left-handed menthol (Leffingwell, J.C.﹠amp through two step hydrogenations with it; R.E.Shackelford, Laevo-Menthol syntheses and organolepticproperties, Cosmetics and Perfumery, 89 (6), 69-89,1974), reaction formula is as follows:
Figure BDA0000033717250000021
d-pulegone d-isomenthone l-methone l-menthol
The route of this method is: at first the dextrorotation pulegone uses trichlorine silicon hydrogen at HMPA catalytic hydrogenation (Sugiura, M. down at 0 ℃; Sato, N.; Kotani, S.; Nakajima, M.Chem.Commun.2008,4309) obtain the mixture of left-handed piperitone, d-isomenthone and l-piperitone, productive rate 84% obtains the l-piperitone through fractionation by distillation; Last catalytic hydrogenation l-piperitone makes the l-menthol.But this route selection is bad, complex process is harsh, and overall yield is not high.
Summary of the invention
The purpose of this invention is to provide the method for the synthetic left-handed menthol of a kind of chirality, this method synthesis technique is simple, productive rate is high, selectivity good, the high recovery of catalyst activity is simple, is fit to the left-handed menthol of large-scale commercial production.
For reaching above-mentioned purpose, the method of the synthetic left-handed menthol of a kind of chirality provided by the invention is characterized in that, is starting raw material with the dextrorotation pulegone, earlier generate left-handed piperitone, again through the synthetic left-handed menthol of the left-handed piperitone of chirality ruthenium catalyst catalytic hydrogenation through chirality rhodium catalyst catalytic hydrogenation.Specifically comprise following two steps:
Step 1: selective hydration: dextrorotation pulegone selective hydration under the chirality rhodium catalyst generates left-handed piperitone, and reaction formula is as follows:
Figure BDA0000033717250000031
[Rh ((S)-Ligand) wherein 2] X has following structure:
(S)-BINAP：Ar＝C 6H 5
(S)-p-Tol-BINAP：Ar＝4-CH 3C 6H 4
(S)-XylBINAP：Ar＝3.5-(CH 3) 2C 6H 3
X＝BF 4，SbF 6，PF 6，ClO 4，Cl
Rhodium catalyst [Rh ((S)-Ligand) 2] part of X is (S)-2,2 '-two [two (p-methylphenyl) phosphino-s]-1,1 '-dinaphthalene ((S)-p-Tol-BINAP), (S)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP) or (S)-2,2 '-two [two (3, the 5-phenylbenzene) phosphino-]-1,1 '-((S)-XylBINAP) waits two phenyl or heteroaryl chiral ligand to dinaphthalene, preferred (S)-2,2 '-two [two (p-methylphenyl) phosphino-s]-1,1 '-dinaphthalene ((S)-p-Tol-BINAP); The negatively charged ion X of rhodium catalyst is BF 4, SbF 6, PF 6, ClO 4Or Cl etc., preferred BF 4The catalytic amount of rhodium catalyst is between 0.1～5mol%, and 0.5mol% is best catalytic amount.The reaction medium of rhodium catalyst is tetrahydrofuran (THF), methylene dichloride, ethanol, Virahol, N, dinethylformamide or acetone etc., preferred tetrahydrofuran (THF).Dextrorotation pulegone chirality rhodium catalyst catalytic hydrogenation generates left-handed piperitone and carries out under 1atm～100atm hydrogen pressure.
Step 2: asymmetric hydrogenation: left-handed piperitone asymmetric hydrogenation under the catalysis of ruthenium chiral catalyst generates left-handed menthol, and reaction formula is as follows:
Figure BDA0000033717250000041
[RuX wherein 2(phosphane) (diamine)] have following structure:
Figure BDA0000033717250000042
(S)-BINAP：Ar＝C 6H 5 (S，S)-DPEN：R 1＝R 4＝C 6H 5；
(S)-p-Tol-BINAP：Ar＝4-CH 3C 6H 4 R 2＝R 3＝H
(S)-XylBINAP：Ar＝3，5-(CH 3) 2C 6H 3 (S)-DAIPEN：R 1＝R 2＝
X＝Cl，Br，l，F 4-CH 3OC 6H 4；
R 3＝H；R 4＝(CH 3) 2CH
Ruthenium catalyst [RuX 2(phosphane) (diamine) part] comprises phosphine part, halogen ligands and two amine ligands, wherein the phosphine part is (S)-2,2 '-two [two (3, the 5-phenylbenzene) phosphino-]-1,1 '-dinaphthalene ((S)-XylBINAP), (S)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP) or (S)-2,2 '-two [two (p-methylphenyl) phosphino-s]-1,1 '-dinaphthalene ((S)-p-Tol-BINAP), preferred (S)-2,2 '-two [two (3, the 5-phenylbenzene) phosphino-]-1,1 '-dinaphthalene ((S)-XylBINAP); Halogen ligands X is Cl, Br, I or F etc., preferred Cl; Two amine ligands are (S)-1,1-two (4-p-methoxy-phenyl)-3-sec.-propyl-1, the 2-diamines ((S)-DAIPEN) or (1S, 2S)-1,2-phenylbenzene-1, the 2-diamines ((S, S)-DPEN), preferred (S)-1,1-two (4-p-methoxy-phenyl)-3-sec.-propyl-1,2-diamines ((S)-DAIPEN).The catalytic amount of ruthenium catalyst is between 0.05～5mol%, and 0.1mol% is best catalytic amount.The hydrogen that adds dividing potential drop 1atm～80atm during the synthetic left-handed menthol of the left-handed piperitone of chiral ruthenium catalyst catalytic hydrogenation.The reaction medium of ruthenium catalyst is Virahol, N, dinethylformamide, ethanol, methyl alcohol, tetrahydrofuran (THF) or acetone etc., preferred Virahol.The alkaline system of ruthenium catalyst is salt of wormwood, potassium hydroxide, potassium tert.-butoxide (t-BuOK) or potassium isopropoxide (KOCH (CH 3) 2) etc., preferred potassium isopropoxide.
Method by the synthetic left-handed menthol of asymmetric synthesis technology provided by the present invention, left-handed piperitone yield is greater than 90%, the ee value is greater than 99%, the left-handed menthol total recovery of gained is greater than 83%, the ee value is greater than 98%, specific rotatory power-49 °～-50 ° has characteristics such as synthesis technique is simple, productive rate is high, selectivity is good, the high recovery of catalyst activity is simple, is fit to the left-handed menthol of large-scale commercial production.
Embodiment
Embodiment 1
1. Preparation of catalysts
(1) catalyst precursor [Rh (COD) Cl] 2Synthetic
In the 150mL three-necked flask, add three rhodium trichloride hydrate (2.0g; 7.6mmol); after putting into magnetic stir bar; ethanol (30mL), the water (12mL) and 1 of adding 95% under nitrogen protection; 5-cyclooctadiene (6mL; 49mmol), stirring and refluxing 24h generates orange-yellow precipitation; be cooled to room temperature; filter, product washs to remove unreacted 1 with cold methanol-water mixed liquid, the 5-cyclooctadiene; soak into solid with a little cold diethyl ether again; at 25 ℃ of following vacuum-drying 8h, remove and desolvate then, obtain orange-yellow crystal [Rh (COD) Cl] 2(1.593g, productive rate 85%) m.p.243 ℃.
(2) catalyzer [Rh ((S)-p-Tol-BINAP) 2] BF 4Preparation
Under the nitrogen protection, in the round-bottomed flask of 25mL, add 0.123g (0.25mmol) [Rh (COD) Cl] 2And 0.339g (0.5mmol) (S)-p-Tol-BINAP, add 5.0mL and newly steam CH 2Cl 2Dissolved solids is put into magnetic stir bar, and mixture at room temperature stirred 10 minutes.System is replaced as H 2Atmosphere, stirring at room 30 minutes, with mixed solution concentrate to do the red-brown solid.Be dissolved in 5mL and newly steam CH 2Cl 2After, add 70mg (0.5mmol) AgBF4, solution becomes tawny rapidly, and there is light-yellow precipitate to generate, stir after 30 minutes, the centrifugal precipitation of removing, in light red centrifugate, add 0.339g (0.5mmol) (S)-p-Tol-BINAP stirs and to obtain red solution [Rh ((S)-p-Tol-BINAP) in 10 minutes 2] BF 4(0.5mmol), TLC detects no free ligand and exists, and need not separate to be directly used in catalyzed reaction.
(3) catalyzer [RuCl 2(S)-XylBINAP (S)-DAIPEN] preparation
[the RuCl that in 50mL exsiccant round-bottomed flask, adds 1g (2mmol) 2(benzene)] 2And 2.940g (4mmol) (S)-XylBINAP, put into magnetic stir bar, logical nitrogen protection system.Add the N of the 15mL degassing with syringe, dinethylformamide, mixture generates red tan solution 100 ℃ of reactions 15 minutes down, system is chilled to room temperature after, add 1.258g (4mmol) (S)-DAIPEN and stirring reaction 12h.Reaction is chilled to room temperature after finishing, and removal of solvent under reduced pressure adds the dissolving of 40mL anhydrous diethyl ether in residuum, suction filtration removes the insolubles of black removal, and solution concentration to 3mL, is added the sherwood oil of the 3mL degassing again, separate out brown solid, suction filtration reject filtrate, the precipitation drying under reduced pressure gets 3.13g[RuCl 2(S)-and XylBINAP (S)-DAIPEN] (productive rate 63%) m.p.178.5 ℃.
2. selective hydrogenation
In the autoclave of 100mL, add 20mL anhydrous tetrahydro furan and 76.1g (0.5mol) dextrorotation pulegone, feed nitrogen, syringe slowly adds the above-mentioned catalyst solution [Rh ((S)-p-Tol-BINAP) with the dilution of 10mL tetrahydrofuran (THF) 2] BF 4(5mmol 0.1mol%), probably added in ten minutes, temperature to 70 ℃ behind the sealed high pressure reactor, H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 100atm, the 23h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed piperitone of product (70.13g, 0.495mol) productive rate 91%, it is 100% that chromatography of gases records product purity.
3. asymmetric hydrogenation
In the autoclave of 100mL, feed nitrogen, add the 20mL degassing Virahol, 6.9g (0.05mol) salt of wormwood and 610mg (0.5mmol, 0.1mol%) [RuCl 2(S)-and XylBINAP (S)-DAIPEN] title complex, add the left-handed piperitone of 77.1g (0.5mol) degassing with syringe, temperature to 35 ℃ behind the sealed high pressure reactor, H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 80atm, the 24h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed menthol of product (71.90g, 0.46mol) yield 92%, it is 99.6% that chromatography of gases records product purity.
Embodiment 2
1. Preparation of catalysts
(1) catalyst precursor [Rh (COD) Cl] 2Synthetic
In the 100mL three-necked flask, add three rhodium trichloride hydrate (1.0g; 3.8mmol) and Anhydrous potassium carbonate (0.55g; 4mmol); the ethanol (17mL) of adding 95% under nitrogen protection; water (8.5mL) and 1; (3mL 24.5mmol), puts into magnetic stir bar to the 5-cyclooctadiene; stirring and refluxing 24h; produce orange-yellow precipitation, be cooled to room temperature, filter; product washs to remove unreacted 1 with cold methanol-water mixed liquid; the 5-cyclooctadiene soaks into solid with a little cold diethyl ether, at last then at 25 ℃ of vacuum-drying 8h; remove and desolvate, obtain orange-yellow product [Rh (COD) Cl] 2(0.778g, productive rate 83%) m.p.242 ℃.
(2) catalyzer [Rh ((S)-BINAP) 2] BF 4Preparation
Under the nitrogen protection, in the round-bottomed flask of 10mL, add 0.15g (0.3mmol) [Rh (COD) Cl] 2, 3mL newly steams the 2.5mL HBF of tetrahydrofuran (THF) and 70% 4, add 1 with syringe, 5-cyclooctadiene (0.208g, 1.8mL) and the new mixed solution that steams tetrahydrofuran (THF) 3mL, put into magnetic stir bar, behind the stirring at room 15min, add 0.747g (12mmol) (S)-BINAP, mixture is replaced as H with system after at room temperature stirring 10 minutes 2Atmosphere, stirring at room 30 minutes, mixed solution is concentrated into 1mL has the red-brown solid to separate out, and suction filtration is used the cold methanol washing precipitation, obtains red solid [Rh ((S)-BINAP) 2] BF 4(0.72g, 0.5mmol, productive rate 83%) m.p.283 ℃.
(3) catalyzer [RuCl 2(S)-XylBINAP (S, S)-DPEN] preparation
[the RuCl that in 50mL exsiccant round-bottomed flask, adds 1g (2mmol) 2(benzene)] 2And (S)-XylBINAP of 2.94g (4mmol), put into magnetic stir bar after, logical nitrogen protection system.Add the N of the 15mL degassing with syringe, dinethylformamide, mixture generates red tan solution 100 ℃ of reactions 15 minutes down, say system is chilled to room temperature after, add 850mg (4mmol) (S, S)-DPEN and stirring reaction 12h.Reaction is chilled to room temperature after finishing, removal of solvent under reduced pressure, and residuum adds the dissolving of 40mL anhydrous diethyl ether, suction filtration removes the insolubles of black removal, and solution concentration to 3mL, is added the sherwood oil of the 3mL degassing again, separate out brown solid, suction filtration reject filtrate will be precipitated the dry 2.688g[RuCl of getting of pressurization 2(S)-and XylBINAP (S, S)-DPEN] (productive rate 60%) m.p.183.5 ℃.
2. selective hydrogenation
In the autoclave of 50mL, add 5mL anhydrous tetrahydro furan and 3.80g (0.025mol) dextrorotation pulegone, feed nitrogen, add with the above-mentioned catalyzer of 5mL tetrahydrofuran (THF) dissolved [Rh ((S)-BINAP) with syringe 2] BF 4(0.360g, 0.25mmol) solution probably added in ten minutes, and temperature to 70 ℃ behind the sealed high pressure reactor is used H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 80atm, the 23h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed piperitone of product (3.198g, 0.021mol) productive rate 83%, it is 88.5% that chromatography of gases records product purity.
3. asymmetric hydrogenation
In the autoclave of 50mL, feed nitrogen, add 10mL degassing Virahol, 1.0molL -1Potassium tert.-butoxide/t-butanol solution (5ml, 0.08mmol) and 56mg (0.05mmol, 0.1mol%) [RuCl 2(S)-and XylBINAP (S, S)-DPEN] catalyzer and magnetic stir bar, add the left-handed piperitone of 7.707g (0.05mol) degassing with syringe, temperature to 35 ℃ behind the sealed high pressure reactor, H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 4atm, the 24h reaction is finished.After air distillation removes and to desolvate, decompression steam the left-handed menthol of product (6.25g, 0.04mol) productive rate 80%, it is 87% that chromatography of gases records product purity.
Embodiment 3
1. Preparation of catalysts
(1) catalyst precursor [Rh (COD) Cl] 2Synthetic
In the 50mL three-necked flask, add three rhodium trichloride hydrate (0.5g, 1.9mmol), methyl alcohol (9mL), the water (4mL) and 1 of adding 95% under condition of nitrogen gas, 5-cyclooctadiene (0.14g, 122mmol), put into magnetic stir bar, stirring and refluxing 24h, produce orange-yellow precipitation, be cooled to room temperature, filter, product washs to remove unreacted 1 with cold methanol-water mixed liquid, the 5-cyclooctadiene, soak into solid with a little cold diethyl ether at last,, remove and desolvate then at 25 ℃ of vacuum-drying 8h, with methylene dichloride/ether recrystallization, obtain orange-yellow product [Rh (COD) Cl] 2(0.393g, productive rate 84%) m.p.243 ℃.
(2) catalyzer [Rh ((S)-XylBINAP) 2] BF 4Preparation
Under the nitrogen protection, in the round-bottomed flask of 10mL, add 0.47g (0.95mmol) [Rh (COD) Cl] 2Add 0.209g (1.9mmol) NaBF 4, put into magnetic stir bar, add 3mL tetrahydrofuran (THF) dissolving back and generate white precipitate rapidly, stir after 30 minutes, suction filtration is removed precipitation, washs with tetrahydrofuran (THF), in filtrate, add 1.396g (1.9mmol) (S)-XylBINAP, mixture at room temperature stirred 10 minutes, and system is replaced as H 2Atmosphere, stirring at room 30 minutes is concentrated into 1mL with mixed solution and gets brown-red solution, adds after 3mL newly steams tetrahydrofuran (THF), in light red solution, add 1.396g (19mmol) (S)-XylBINAP stirs and obtained red solution [Rh ((S)-XylBINAP) in 10 minutes 2] BF 4, need not separate to be directly used in catalyzed reaction.
(3) catalyzer [RuCl 2(S)-BINAP (S)-DAIPEN] preparation
[the RuCl that in 50mL exsiccant round-bottomed flask, adds 1g (2mmol) 2(benzene)] 2And 2.490g (4mmol) (S)-BINAP, put into magnetic stir bar, logical nitrogen protection system.Add the N of the 15mL degassing with syringe, dinethylformamide, mixture generates red tan solution 100 ℃ of reactions 15 minutes down, system is chilled to room temperature after, add 1.258g (4mmol) (S)-DAIPEN and stirring reaction 12h.Reaction is chilled to room temperature after finishing, and removal of solvent under reduced pressure adds the dissolving of 40mL anhydrous diethyl ether in residuum, suction filtration removes the insolubles of black removal, and solution concentration to 3mL, is added the sherwood oil of the 3mL degassing again, separate out brown solid, suction filtration reject filtrate, the precipitation drying under reduced pressure gets 2.750g[RuCl 2(S)-and BINAP (S)-DAIPEN] (productive rate 62%) m.p.188 ℃.
2. selective hydrogenation
In the autoclave of 50mL, add 10mL anhydrous tetrahydro furan and 30g (0.2mol) D-menthone, feed nitrogen, add the above-mentioned catalyzer [Rh (S)-XylBINAP) that dilutes with the 5mL tetrahydrofuran (THF) with syringe 2] BF 4(1.9mmol) solution probably added in ten minutes, and temperature to 70 ℃ behind the sealed high pressure reactor is used H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 8atm, the 23h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed piperitone of product (26.20g, 0.17mol) productive rate 85%, it is 92% that chromatography of gases records product purity.
3. asymmetric hydrogenation
In the autoclave of 50mL, feed nitrogen, add 20mL degassing Virahol, 1.0molL -1Potassium tert.-butoxide/aqueous isopropanol (5ml, 0.08mmol) and 55mg (0.05mmol) [RuCl 2(S)-and BINAP (S)-DAIPEN] title complex, add the left-handed piperitone that 7.707g (0.05mol) outgases with syringe, probably in ten minutes, add, the sealed high pressure reactor is used H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 10atm, the 23h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed piperitone of product (6.641g, 0.0425mol) productive rate 85%, it is 92% that chromatography of gases records product purity.
Embodiment 4
1. Preparation of catalysts
(1) catalyst precursor [Rh (COD) Cl] 2Synthetic
In the 100mL three-necked flask, add three rhodium trichloride hydrate (1.0g, 3.8mmol), ethanol (17mL), the water (8.5mL) and 1 of adding 95% under condition of nitrogen gas, 5-cyclooctadiene (3mL, 24.5mmol), put into magnetic stir bar, stirring and refluxing 24h produces orange-yellow precipitation, be cooled to room temperature, filter, product washs to remove unreacted 1 with cold methanol-water mixed liquid, the 5-cyclooctadiene, soak into solid with a little cold diethyl ether again, at 25 ℃ of following vacuum-drying 8h, remove and desolvate then, obtain orange-yellow product [Rh (COD) Cl] 2(0.815g, productive rate 87%) m.p.243 ℃.
(2) catalyzer [Rh ((S)-p-Tol-BINAP) (COD)] BF 4Preparation
Under the nitrogen protection, in the round-bottomed flask of 50mL, add 0.235g (0.475mmol) [Rh (COD) Cl] 2And 645mg (0.95mmol) (S)-p-Tol-BINAP, add 10mL CH 2Cl 2Magnetic stir bar is put in dissolving, and mixture at room temperature stirred 10 minutes, and system is replaced as H 2Atmosphere, stirring at room 30 minutes, with mixed solution concentrate the red-brown solid, be dissolved in 5mL and newly steam CH 2Cl 2After, add 0.185g (9.5mmol) AgBF 4, solution becomes tawny rapidly, and has light-yellow precipitate to generate, and stirs after 30 minutes, and the centrifugal precipitation of removing obtains light red centrifugate (need not separate and can be directly used in catalyzed reaction).
(3) catalyzer [RuCl 2(S)-p-Tol-BINAP) (S)-DAIPEN] preparation
[the RuCl that in 50mL exsiccant round-bottomed flask, adds 1g (2mmol) 2(benzene)] 2And 2.715g (4mmol) (S)-p-Tol-BINAP, put into magnetic stir bar, logical nitrogen protection system.Add the N of the 15mL degassing with syringe, dinethylformamide, mixture generates red tan solution 100 ℃ of reactions 15 minutes down, system is chilled to room temperature after, add 1.258g (4mmol) (S)-DAIPEN and stirring reaction 12h.Reaction is chilled to room temperature after finishing, and removal of solvent under reduced pressure adds the dissolving of 40mL anhydrous diethyl ether in residuum, suction filtration removes the insolubles of black removal, and solution concentration to 3mL, is added the sherwood oil of the 3mL degassing again, separate out brown solid, suction filtration reject filtrate, the precipitation drying under reduced pressure gets 3.000g[RuCl 2(S)-and p-Tol-BINAP (S)-DAIPEN] (productive rate 65%) m.p.181.5 ℃.
2. selective hydrogenation
In the autoclave of 50mL, add 10mL anhydrous tetrahydro furan and 30g (0.2mol) dextrorotation pulegone, feed nitrogen, add above-mentioned catalyst solution with the dilution of 5mL tetrahydrofuran (THF) [Rh ((S)-p-Tol-BINAP) (COD)] BF with syringe 4(0.95mmol), probably add in half an hour, temperature to 70 ℃ behind the sealed high pressure reactor is used H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 80atm, the 48h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed piperitone of product (17.3g, 0.112mol) productive rate 56%, it is 99.7% that chromatography of gases records product purity.
3. asymmetric hydrogenation
In the autoclave of 50mL, feed nitrogen, add 20mL degassing Virahol, 1.0molL -1Potassium tert.-butoxide/t-butanol solution (5ml, 0.08mmol) and 58mg (0.05mmol) [RuCl 2(S)-p-Tol-BINAP) (S)-DAIPEN] title complex, add the left-handed piperitone of 7.707g (0.05mol) degassing with syringe, probably in half an hour, add, the sealed high pressure reactor is used H 2After the atmosphere displacement system 3 times, hydrogen pressure is risen to 10atm, the 24h reaction is finished.Inclining reaction solution, after air distillation removes and to desolvate, decompression steam the left-handed menthol of product (6.40g, 0.041mol) productive rate 82%, it is 98.5% that chromatography of gases records product purity.
In addition to the implementation, also can employing table one and the described material of table two and parameter prepare left-handed menthol (concrete grammar can with reference to the foregoing description).
Table one rhodium catalyst selective hydration dextrorotation pulegone generates left-handed piperitone
Reaction?were?carried?out?in?THF?at?70℃?for?23?hrs?except?special?notice.undr?H 2?atmospherewith?the?ratio?of?substrate?to?catalyst?of?200.
The left-handed piperitone of table two ruthenium catalyst asymmetric hydrogenation generates left-handed menthol
Reaction?was?carried?out?in?solvent?at?35℃?undr?H 2，[substrate?2]/[catalyst]＝1000，for?24?hrs.
Scope of the present invention is not subjected to the restriction of described specific embodiments, and described embodiment is only desired also to comprise method and component that function is equal in the scope of the invention as the single example of illustrating all respects of the present invention.In fact, except that content as herein described, the technology scientific and technical personnel of this area can be easy to grasp multinomial improvement of the present invention with reference to above description and reaction formula and chart, and many reactions steps transposes can obtain the ideal effect equally.Described improvement also falls in the scope of claims.Every piece of reference mentioned above is listed this paper reference all in full in.

Claims (10)

1. the method for the synthetic left-handed menthol of chirality is characterized in that, is starting raw material with the dextrorotation pulegone, generates left-handed piperitone through chirality rhodium catalyst catalytic hydrogenation earlier, again through the synthetic left-handed menthol of the left-handed piperitone of chirality ruthenium catalyst catalytic hydrogenation.
2. the method for the synthetic left-handed menthol of chirality according to claim 1 is characterized in that described rhodium catalyst is [Rh ((S)-Ligand) 2] X, the part of rhodium catalyst is (S)-2,2 '-two [two (p-methylphenyl) phosphino-s]-1,1 '-dinaphthalene ((S)-p-Tol-BINAP), (S)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP) or (S)-2,2 '-two [two (3, the 5-phenylbenzene) phosphino-]-1,1 '-dinaphthalene ((S)-XylBINAP); The negatively charged ion X of rhodium catalyst is BF 4, SbF 6, PF 6, ClO 4Or Cl.
3. the method for the synthetic left-handed menthol of chirality according to claim 1 is characterized in that described ruthenium catalyst is [RuX 2(phosphane) (diamine)], the part of ruthenium catalyst comprises phosphine part, halogen ligands and two amine ligands, wherein the phosphine part is (S)-2,2 '-two [two (3, the 5-phenylbenzene) phosphino-s]-1,1 '-dinaphthalene ((S)-XylBINAP), (S)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP) or (S)-2,2 '-two [two (p-methylphenyl) phosphino-s]-1,1 '-dinaphthalene ((S)-p-Tol-BINAP); Halogen ligands X is Cl, Br, I or F; Two amine ligands are (S)-1,1-two (4-p-methoxy-phenyl)-3-sec.-propyl-1, the 2-diamines ((S)-DAIPEN) or (1S, 2S)-1,2-phenylbenzene-1, the 2-diamines (S, S)-DPEN).
4. the method for the synthetic left-handed menthol of chirality according to claim 2 is characterized in that the catalytic amount of described rhodium catalyst is between 0.1～5mol%.
5. the method for the synthetic left-handed menthol of chirality according to claim 2 is characterized in that the reaction medium of described rhodium catalyst is tetrahydrofuran (THF), methylene dichloride, ethanol, Virahol, N, dinethylformamide or acetone.
6. the method for the synthetic left-handed menthol of chirality according to claim 3 is characterized in that the catalytic amount of described ruthenium catalyst is between 0.05～5mol%.
7. the method for the synthetic left-handed menthol of chirality according to claim 1 is characterized in that described dextrorotation pulegone chirality rhodium catalyst catalytic hydrogenation generates left-handed piperitone and carries out under 1atm～100atm hydrogen pressure.
8. the method for the synthetic left-handed menthol of chirality according to claim 1 is characterized in that, adds the hydrogen of dividing potential drop 1atm～80atm during the synthetic left-handed menthol of the left-handed piperitone of described chiral ruthenium catalyst catalytic hydrogenation.
9. the method for the synthetic left-handed menthol of chirality according to claim 3 is characterized in that the reaction medium of described ruthenium catalyst is Virahol, N, dinethylformamide, ethanol, methyl alcohol, tetrahydrofuran (THF) or acetone.
10. the method for the synthetic left-handed menthol of chirality according to claim 3 is characterized in that the alkaline system of described ruthenium catalyst is salt of wormwood, potassium hydroxide, potassium tert.-butoxide or potassium isopropoxide.
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CN114011463A (en) * 2021-11-24 2022-02-08 万华化学集团股份有限公司 Catalyst and method for preparing high-purity L-menthol
CN118239990A (en) * 2024-05-28 2024-06-25 北京元延医药科技股份有限公司 Complex of rare noble metal and chiral phosphine for asymmetric hydrogenation catalytic synthesis of medicine

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CN106061933A (en) * 2014-03-07 2016-10-26 巴斯夫欧洲公司 Method for producing menthones from isopulegol in the gas phase
CN106061933B (en) * 2014-03-07 2019-07-09 巴斯夫欧洲公司 In the gas phase by the method for isopulegol production menthones
CN104909992A (en) * 2015-06-03 2015-09-16 黄山天香科技股份有限公司 Method for preparing (1R,2S,5R)-2-isopropyl-5-methyl cyclohexanol from 2S-trans-5-methyl-2-(1-methylethyl)cyclohexanone
CN106148431A (en) * 2016-09-04 2016-11-23 安徽爱有澄生物科技有限公司 The preparation method of pulegium ketone derivatives
CN114011463A (en) * 2021-11-24 2022-02-08 万华化学集团股份有限公司 Catalyst and method for preparing high-purity L-menthol
CN118239990A (en) * 2024-05-28 2024-06-25 北京元延医药科技股份有限公司 Complex of rare noble metal and chiral phosphine for asymmetric hydrogenation catalytic synthesis of medicine

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