CN105330550A - Optical activity 1-cyclohexyl ethylamine preparation method - Google Patents
Optical activity 1-cyclohexyl ethylamine preparation method Download PDFInfo
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Abstract
The present invention discloses an optical activity 1-cyclohexyl ethylamine preparation method, which comprises that: in water and under the effect of HBr, N-acetylamino-1-cyclohexyl ethylamine represented by a formula 4 or 4' is subjected to a hydrolysis reaction to correspondingly prepare the optical activity 1-cyclohexyl ethylamine represented by a formula 5 or 5'. The preparation method of the present invention can further comprise that a compound represented by a formula I is subjected to an oximation reaction, a reduction acylation reaction and an asymmetric catalysis reaction to prepare the N-acetylamino-1-cyclohexyl ethylamine represented by the formula 4 or 4'. According to the present invention, the preparation method has characteristics of simple operation, low production cost, high product chemical purity, high product optical purity, high product yield, and green environmental protection. The formulas such as 4, 4', 5 and 5' are defined in the specification.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of optically active 1-cyclohexylethylamine.
Background technology
Most drug and synthetic compound all contain Chiral Amine functional group, and therefore the asymmetric synthesis application of Chiral Amine compounds is very extensive.The 1-cyclohexylethylamine that the present invention relates to is exactly a kind of Chiral Amine compounds, and its configuration has R and S two kinds.
In prior art, for optically active R-1-cyclohexylethylamine or S-1-cyclohexylethylamine, its synthetic method is similar, and the present invention sets forth with the example that synthesizes of R-1-cyclohexylethylamine.
Early stage research is for starting raw material with the α phenylethylamine of chirality, under different metal catalyzer exists, aromatic ring Hydrogenation is standby, if the people such as Herlinger were at (JustusLiebigsAnnalenderChemie in 1967,1967, Vol706P37-46) report for work and used the ruthenium catalysis R-1-phenyl-ethyl amine Hydrogenation of aluminium sesquioxide load for R-1-cyclohexylethylamine.
The people such as (J.Org.Chem., 1972,37 (6), 902-906) McGahren in 1972 then report and prepare with platinum dioxide shortening in acetic acid.
The common ground of these methods all uses expensive heavy metal as catalyzer, causes synthetic method cost higher.
The people such as (Tetrahedron, 1994, Vol50 (15), P4399-4428) Burk in 1994 report the cyclohexylethylamine utilizing asymmetric hydrogenation to carry out synthesis of chiral.Its gordian technique introduces chiral centre for utilizing asymmetric hydrogenation, then in a mild condition hydrazides is converted into amine, but the ee value of step of hydrogenation only has 72%, needs to be improved by crystallization.
The raw material of above-mentioned hydrogenation is hydrazide derivatives, with its unlike people such as Zhang in (J.Am.Chem.Soc. in 2009,2009,131, the asymmetric hydrogenation of inferior amine salt hydrochlorate of 9882-9883) having reported for work carrys out synthesis of chiral amine compound, but also only has 73% for the ee value of R-1-cyclohexylethylamine.
Chirality t-butyl sulfonamide is a kind of Medicine intermediate that development in recent years is got up, and be also the crucial chiral source of synthesis of chiral amine drug and intermediate thereof, its correlative study is subject to the extensive concern of researchist.The people such as DavidGuijarro report in 2013 (OrganicSynthesis2013, Vol90, P338-349) and synthesize R-1-cyclohexylethylamine with chirality t-butyl sulfonamide as induction agent; Technique comprises three-step reaction, and the shortcoming of this technique uses relatively large sulfinyl amine, and this reagent is more expensive, cause synthesis cost high, and the consumption of tiron is large, aftertreatment difficulty, and has potential risk of environmental pollution.
In addition, as the enamides as shown in Equation 3 of one of the intermediate of synthesis of chiral 1-cyclohexylethylamine, its synthetic method is at Angew.Chem.Int.Ed.2012,51, report was had in 1400-1404, the defect of the method is to use four a large amount of isopropyl oxygen titaniums, and aftertreatment is difficult, and environmental pollution is large.
Therefore, provide a kind of simple to operate, production cost is low, product optical purity is high, chemical purity is high, the preparation method of optically active 1-cyclohexylethylamine of environmental protection, is this area technical problem urgently to be resolved hurrily.
Summary of the invention
The defects such as the technical problem to be solved in the present invention is expensive starting materials existing in the preparation method in order to overcome optically active 1-cyclohexylethylamine in prior art, production cost is high, product optical purity is lower, environment is unfriendly, and provide a kind of preparation method of optically active 1-cyclohexylethylamine.Preparation method of the present invention is simple to operate, production cost is low, product chemistry purity and optical purity is all higher, product yield is higher, environmental protection.
The invention provides a kind of preparation method of optically active 1-cyclohexylethylamine, it comprises the steps: in water, under HBr effect, by the reaction that is hydrolyzed such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ', corresponding obtained such as formula the optically active 1-cyclohexylethylamine shown in 5 or formula 5 '; Described HBr and the described molar ratio such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' are 8 ~ 15;
According to this area general knowledge, in the present invention, described hydrolysis reaction is when carrying out, and the chiral configuration of compound remains unchanged.
Preferably, in described hydrolysis reaction, the mass values of described HBr and described water is 0.6 ~ 0.9.
In described hydrolysis reaction, described HBr and described water the form of the HBr aqueous solution can participate in reaction.Preferably, the mass concentration of the described HBr aqueous solution is 40 ~ 47%, and per-cent is the per-cent that the quality of HBr accounts for described HBr aqueous solution total mass.
Preferably, in described hydrolysis reaction, described HBr and the described molar ratio such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' are 9 ~ 10.
Preferably, the temperature of described hydrolysis reaction is 100 DEG C ~ 130 DEG C; It is more preferably 110 DEG C ~ 130 DEG C; Be 120 DEG C ~ 130 DEG C best, such as 124 DEG C ~ 126 DEG C.
In the preparation method of described optically active 1-cyclohexylethylamine, the process of described hydrolysis reaction can adopt routine monitoring method (such as TLC, HPLC, NMR or GC) in this area to monitor, generally with described to disappear such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' or be less than amount before reaction 5% time for reaction end, preferably 30 hours ~ 70 hours time of described hydrolysis reaction, preferably 45 hours ~ 65 hours further, such as 50 hours.
The preparation method of described optically active 1-cyclohexylethylamine, after described hydrolysis reaction terminates, preferably, also can comprise the operation of aftertreatment further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, preferably adopt following post-processing step: after reaction terminates, regulate reaction system pH to 11 ~ 14 (more preferably 12), extraction, it is concentrated.Described adjustment reaction system pH to 12 ~ 14 are preferably carry out under the condition of 20 DEG C ~ 40 DEG C at temperature of reaction system.Described adjustment reaction system pH to 11 ~ 14 preferably adopt adds mineral alkali realization.The preferred sodium hydroxide of described mineral alkali or its aqueous solution.The mass concentration of sodium hydroxide preferably 40% in described aqueous sodium hydroxide solution.The extraction agent preferable methyl tertbutyl ether of described extraction and/or halogenated hydrocarbon solvent, the preferred methylene dichloride of described halogenated hydrocarbon solvent.Described extraction agent and the described volume mass such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' are than preferred 5mL/g ~ 15mL/g.Described extraction preferably carries out twice extraction.Described be concentrated in carry out before preferably first drying and filtration are carried out to the organic phase after extraction.The preferred anhydrous sodium sulphate of siccative of described drying.Described concentrating preferably is carried out under rotary evaporation and/or underpressure distillation condition.Preferred 25mmHg ~ the 30mmHg of pressure of described underpressure distillation.Fraction collection temperature preferably 85 DEG C ~ 86 DEG C in described underpressure distillation.
Preferably, the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under hydrogen and catalyst action, compound is as shown in Equation 3 carried out asymmetric hydrogenation, obtained described such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ';
In described asymmetric hydrogenation, described solvent can be Conventional solvents in this type of reaction of this area, preferred alcohols kind solvent.Described alcoholic solvent particular methanol.Described solvent is preferably stripped of the solvent of oxygen.
In described asymmetric hydrogenation, the preferred 5mL/g ~ 15mL/g of volume mass ratio of described solvent and described compound as shown in Equation 3; More preferably 5mL/g ~ 10mL/g.
In described asymmetric hydrogenation, the pressure of described hydrogen can be conventional pressure in this type of reaction of this area, preferred 1atm ~ 25atm; More preferably 5atm ~ 20atm; Most preferably 10atm ~ 15atm.
In described asymmetric hydrogenation, described catalyzer can be conventional catalyst in this type of reaction of this area, the title complex class catalyzer that preferred Rh and phosphine are formed.The preferred Rh of title complex class catalyzer [(Rc, Sp)-Duanphos] (COD) BF that described Rh and phosphine are formed
4, Rh [(Sc, Rp)-Duanphos] (COD) BF
4, Rh [(Rc, Sp)-Duanphos] (NBD) BF
4with Rh [(Sc, Rp)-Duanphos] (NBD) BF
4in one or more.Described Rh [(Sc, Rp)-Duanphos] (COD) BF
4and/or described Rh [(Sc, Rp)-Duanphos] (NBD) BF
4under effect, asymmetric hydrogenation can be carried out by catalysis compound as shown in Equation 3, and obtained (R)-N-(1-cyclohexyl-ethyl) ethanamide.Described Rh [(Rc, Sp)-Duanphos)] (COD) BF
4and/or described Rh [(Rc, Sp)-Duanphos] (NBD) BF
4under effect, asymmetric hydrogenation can be carried out by catalysis compound as shown in Equation 3, and obtained (S)-N-(1-cyclohexyl-ethyl) ethanamide.
In described asymmetric hydrogenation, the molar ratio of described catalyzer and described compound as shown in Equation 3 preferably 0.01 ~ 0.0001; More preferably 0.001 ~ 0.0002.
According to this area general knowledge, when carrying out asymmetric hydrogenation, a kind of catalyzer often mainly obtains a kind of product of configuration, and such as, described catalyzer is Rh [(Rc, Sp)-Duanphos] (NBD) BF
4time, the product of described asymmetric hydrogenation is mainly (S)-N-(1-cyclohexyl-ethyl) ethanamide as shown in Equation 4.Again such as, described catalyzer is Rh [(Sc, Rp)-Duanphos] (NBD) BF
4time, the product of described asymmetric hydrogenation is mainly (R)-N-(1-cyclohexyl-ethyl) ethanamide as shown in Equation 4.
The temperature of described asymmetric hydrogenation can be ordinary temperature in this type of reaction of this area, preferably 10 DEG C ~ 35 DEG C, more preferably 20 DEG C ~ 30 DEG C.
In the preparation method of described optically active 1-cyclohexylethylamine, the process of described asymmetric hydrogenation can adopt routine monitoring method (such as TLC, HPLC, NMR or GC) in this area to monitor, the time of described asymmetric hydrogenation can be Conventional Time in this type of reaction of this area, preferably 1 hour ~ 8 hours, preferably 1 hour ~ 4 hours further, such as 2 ~ 3 hours.
The preparation method of described optically active 1-cyclohexylethylamine, after described asymmetric hydrogenation terminates, preferably, also can comprise the operation of aftertreatment further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, preferably adopt following post-processing step: after reaction terminates, concentrated.Described concentrated preferred concentrating under reduced pressure.Described be concentrated in carry out after, preferably also carry out the operation of recrystallization again.Preferably, the solvent of described recrystallization is esters solvent.Described esters solvent ethyl acetate.The solvent of described recrystallization and the preferred 4mL/g ~ 10mL/g of volume mass ratio of described compound as shown in Equation 3; More preferably 5mL/g ~ 7mL/g.
Preferably, the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under catalyzer, reductive agent and acylating reagent effect, compound is as shown in Equation 2 carried out reductive acylation reaction, obtained described compound as shown in Equation 3;
More preferably; the preparation method of described optically active 1-cyclohexylethylamine; described solvent is comprised the steps: to mix with described compound as shown in Equation 2 further; then described reductive agent and described catalyzer is added; under 30 DEG C ~ 35 DEG C conditions after insulated and stirred 30min; be heated to 50 DEG C ~ 60 DEG C, then control under 50 DEG C ~ 60 DEG C conditions, add described acylating reagent at temperature of reaction system and carry out described reductive acylation reaction.If described acylating reagent is liquid, then the mode dripped preferably is adopted to add described acylating reagent.The reinforced process of described reductive acylation reaction, preferably carries out under a nitrogen atmosphere.
In described reductive acylation reaction, described solvent can be Conventional solvents in this type of reaction of this area, preferred amide kind solvent.The preferred DMF of described amide solvent.In described reductive acylation reaction, the preferred 3mL/g ~ 10mL/g of volume mass ratio of described solvent and described compound as shown in Equation 2; More preferably 4mL/g ~ 6mL/g, such as 4.6mL/g.
In described reductive acylation reaction, described catalyzer can be conventional catalyst in this type of reaction of this area, preferred trimethylchlorosilane.In the reaction of described reductive acylation, the molar ratio of described catalyzer and described compound as shown in Equation 2 preferably 0.01 ~ 0.1; More preferably 0.02 ~ 0.06, such as 0.05.
In described reductive acylation reaction, described reductive agent can be conventional reduction agent in this type of reaction of this area, preferred iron.Described iron preferably participates in reaction with the form of iron powder.The molar ratio of described reductive agent and described compound as shown in Equation 2 preferably 1.5 ~ 4; More preferably 2 ~ 3; Most preferably 2.5; Also can be such as 2.3.
In described reductive acylation reaction, described acylating reagent can be conventional acylating reagent in this type of reaction of this area, preferred aceticanhydride.The molar ratio of described acylating reagent and described compound as shown in Equation 2 preferably 1.5 ~ 3.5; More preferably 2 ~ 2.7; Most preferably 2.5; Also can be such as 2.3.
The temperature preferably 30 DEG C ~ 100 DEG C of described reductive acylation reaction; More preferably 40 DEG C ~ 70 DEG C; Most preferably 50 DEG C ~ 60 DEG C.
In the preparation method of described optically active 1-cyclohexylethylamine; the process of described reductive acylation reaction can adopt routine monitoring method (such as TLC, HPLC, NMR or GC) in this area to monitor; generally disappear with described compound as shown in Equation 2 or be less than amount before reaction 0.5% time for reaction end; preferably 1 hour ~ 5 hours time of described reductive acylation reaction; preferably 2 hours ~ 4 hours further, such as 3 hours.
The preparation method of described optically active 1-cyclohexylethylamine, after described reductive acylation reaction terminates, preferably, also can comprise the operation of aftertreatment further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, preferably adopt following post-processing step: after reaction terminates, make temperature of reaction system reach room temperature, add the aqueous solution processing reaction system of mineral alkali, concentrated after extraction.Reaction system partial extraction dilution agent, before carrying out, preferably first filters, preferably washs with another part extraction agent and collect filtrate during filtration by the aqueous solution processing reaction system of described mineral alkali.The preferred sodium hydroxide of described mineral alkali.The preferred 2M of the volumetric molar concentration of mineral alkali in the aqueous solution of described mineral alkali.The aqueous solution processing reaction system of described mineral alkali, when carrying out, preferably controls temperature of reaction system at 20 DEG C ~ 30 DEG C.The aqueous solution processing reaction system of described mineral alkali, when carrying out, preferably adds the aqueous solution of described mineral alkali in the mode dripped.The aqueous solution processing reaction system of described mineral alkali, after having carried out, preferably stirs 30min.The preferred esters solvent of described extraction agent.The ratio preferably 10 ~ 12mL/g of the volume of described extraction agent and the quality of described compound as shown in Equation 2.Described esters solvent ethyl acetate.Described extraction, after carrying out, preferably also carries out drying.The preferred anhydrous sodium sulphate of siccative of described drying.Described drying also can comprise vacuum drying step.
Preferably, the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under alkaline condition, compound as shown in Equation 1 and oxammonium hydrochloride is carried out oximation reaction, compound as shown in Equation 2 described in obtained;
More preferably, the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: described solvent and described compound as shown in Equation 1 further, be cooled to 10 ~ 15 DEG C, then oxammonium hydrochloride is added, regulate reaction system to described alkaline condition again, then be naturally warming up to room temperature, carry out described oximation reaction.The reinforced process of described oximation reaction, preferably carries out under a nitrogen atmosphere.
The solvent of described oximation reaction can be Conventional solvents in this type of reaction of this area, preferred alcohols kind solvent.Described alcoholic solvent preferred alcohol.Described solvent such as, preferably through the solvent of Non-aqueous processing, dehydrated alcohol.The solvent of described oximation reaction and the preferred 3mL/g ~ 10mL/g of volume mass ratio of described compound as shown in Equation 1; More preferably 4mL/g ~ 8mL/g, such as 5ml/g.
In described oximation reaction, the molar ratio of described oxammonium hydrochloride and described compound as shown in Equation 1 preferably 3 ~ 1.1; More preferably 2 ~ 1.1; Most preferably 1.5 ~ 1.1.
In described oximation reaction, described alkaline condition can be conventional pH condition in this type of reaction of this area, and preferred pH is 7 ~ 8.Described alkaline condition realizes preferably by the mode of adding mineral alkali.The preferred sodium bicarbonate of described mineral alkali.The molar ratio of described sodium bicarbonate and described compound as shown in Equation 1 preferably 1.5.
The temperature of described oximation reaction can be ordinary temperature in this type of reaction of this area, preferably 10 DEG C ~ 35 DEG C.
In the preparation method of described optically active 1-cyclohexylethylamine, the process of described oximation reaction can adopt routine monitoring method (such as TLC, HPLC, NMR or GC) in this area to monitor, generally disappear with described compound as shown in Equation 1 or be less than amount before reaction 0.5% time for reaction end.Preferably 1 hour ~ 4 hours time of described oximation reaction, preferably 1 hour ~ 3 hours further, such as 2 ~ 3 hours.
The preparation method of described optically active 1-cyclohexylethylamine, after described oximation reaction terminates, preferably, also can comprise the operation of aftertreatment further.The method of described aftertreatment and condition can be method and the condition of this type of post-reaction treatment routine of this area, preferably adopt following post-processing step: after reaction terminates, filter and wash, and collect filtrate, concentrated, and extraction is concentrated.The leacheate preferred alcohols kind solvent of described washing, such as dehydrated alcohol.The preferred 1.5mL/g of ratio of the volume of described leacheate and the quality of described compound as shown in Equation 1.The extraction agent preferred fragrance varsol of described extraction, such as toluene.Described extraction preferably also comprises the step of washing and salt washing.The preferred 5mL/g of ratio of the volume of described extraction agent and the quality of described compound as shown in Equation 1.The water that it is 1mL/g that described washing preferably adopts with the ratio of the volume mass with described compound is as shown in Equation 1 washed.Described salt washing preferably adopts and washes with the salt solution that the ratio of the volume mass of described compound is as shown in Equation 1 1mL/g.The preferred saturated aqueous common salt of described salt solution.Described concentrated preferred concentrating under reduced pressure.
In the present invention, the preparation method of described optically active 1-cyclohexylethylamine preferably adopts following route:
Present invention also offers a kind of preparation method such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ', it comprises the steps: in solvent, under hydrogen and catalyst action, compound is as shown in Equation 3 carried out asymmetric hydrogenation, obtained such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ';
The method of the preparation method such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' of the present invention and condition ditto described in.
Present invention also offers a kind of preparation method of compound as shown in Equation 3, it comprises the steps: in solvent, under catalyzer, reductive agent and acylating reagent effect, compound is as shown in Equation 2 carried out reductive acylation reaction, obtained compound as shown in Equation 3;
The method of the preparation method of compound as shown in Equation 3 of the present invention and condition ditto described in.
Present invention also offers a kind of preparation method of compound as shown in Equation 2, it comprises the steps: in solvent, under alkaline condition, compound as shown in Equation 1 and oxammonium hydrochloride is carried out oximation reaction, obtained compound as shown in Equation 2;
The method of the preparation method of compound as shown in Equation 2 of the present invention and condition ditto described in.
In the present invention, described room temperature refers to that envrionment temperature is 10 ~ 35 DEG C, such as 25 DEG C ~ 30 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method of the present invention is simple to operate, production cost is low, product chemistry purity and optical purity all compared with high (all can reach 99% and more than), product yield compared with high, the three wastes are few, environmental protection, are applicable to industrialization.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Wherein used catalyst [Rh ((Rc, Sp)-Duanphos) (NBD)] BF
4for Chiral Quest Biochemical (Suzhou) Co., Ltd.) product, and can buy from STREM company.
Embodiment 1: the synthesis of cyclohexyl methyl ketoxime 1
In 2000 milliliters of round-bottomed flasks, add 200 grams of cyclohexyl methyl ketone, 1000 milliliters of dehydrated alcohols, nitrogen protection, is cooled to 10-15 DEG C, adds 165 grams of oxammonium hydrochlorides, adds 200 grams of sodium bicarbonates in batches, and system pH is 7 ~ 8.Finish in 30 minutes, be naturally warming up to room temperature, react GC monitoring after 2 ~ 3 hours, raw material is less than 0.5%, filters, with 300 milliliters of dehydrated alcohol drip washing, is then evaporated to dry.Add 1000 milliliters of toluene, successively with 200 milliliters of washings, 200 mL of saline are washed.Layering, organic layer is evaporated to dry, and obtain product about 242 grams, GC purity about about 97%, directly throws next step.
1H-NMR(400MHz,CDCl
3):δ＝9.59(brs,1H),2.19～2.11(m,1H),1.87(s,3H),1.84-1.67(m,5H),1.34-1.17(m,5H)。
The synthesis of embodiment 2:N-(1-cyclohexylvinyl) ethanamide
In 2000 milliliters of round-bottomed flasks, logical nitrogen, adds 218 grams of cyclohexyl methyl ketoximes, 1000 milliliters of DMF.Then stir, add 199.7 grams of iron powders, add 8 milliliters of trimethylchlorosilanes, 30-35 DEG C of insulated and stirred 30 minutes, is heated to 50-60 DEG C.Drip 364 grams of diacetyl oxides, temperature control 50-60 DEG C, within about 2 hours, drip and finish, insulation reaction 3 hours, HPLC monitors, and raw material is less than 1%, is cooled to room temperature, adds 1200 milliliters of ethyl acetate, filters.With 500 milliliters of ethyl acetate drip washing, in filtrate, drip 2N aqueous sodium hydroxide solution (wherein containing 285 grams of sodium hydroxide and 3250 grams of water), temperature control 20-30 DEG C, drips off for about 2 hours, drips complete stirring 30 minutes.Layering, water layer 600 milliliters of extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate drying, and filter, after concentrating under reduced pressure, vacuum-drying obtains 114.4 grams of products, HPLC purity: 99.7%, yield 44.3%.
1H-NMR(400MHz,CDCl
3):δ＝6.50(brs,1H),5.59(s,1H),4.57(s,1H),2.07(s,3H),1.93-1.78(m,5H),1.74-1.70(m,1H),1.34-1.13(m,5H)。
The synthesis of embodiment 3:N-(1-cyclohexylvinyl) ethanamide
In 2000 milliliters of round-bottomed flasks, logical nitrogen, adds 218 grams of cyclohexyl methyl ketoximes, 1000 milliliters of DMF.Then stir, add 199.7 grams of iron powders, add 8 milliliters of trimethylchlorosilanes, 30-35 DEG C of insulated and stirred 30 minutes.Drip 364 grams of diacetyl oxides, temperature control 30-35 DEG C, react after 3 hours, sample with HPLC monitoring, raw material residual 45%.Raise system temperature to 55 ~ 60 DEG C, continue reaction 2 hours, sample with HPLC monitoring, raw material residual about 5%, impurity increases obviously.Be cooled to room temperature, add 1200 milliliters of ethyl acetate, filter.With 500 milliliters of ethyl acetate drip washing, in filtrate, drip 2N aqueous sodium hydroxide solution (wherein containing 285 grams of sodium hydroxide and 3250 grams of water), temperature control 20-30 DEG C, drips off for about 2 hours, drips complete stirring 30 minutes.Layering, water layer 600 milliliters of extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate drying, and filter, after concentrating under reduced pressure, vacuum-drying obtains 38.5 grams of products, HPLC purity: 95.3%, yield 15%.
Embodiment 4:(R) synthesis of-N-(1-cyclohexyl-ethyl) ethanamide
In 600 milliliters of hydriding reactors, add 60 grams of N-(1-cyclohexylvinyl) ethanamide and 0.049g catalyzer Rh [(Sc, Rp)-Duanphos] (NBD) BF
4, add 300 milliliters of deoxidation methyl alcohol, hydrogenation is to 1.5MPa, and stirring at room temperature 2-3 hour, HPLC monitoring is to reacting completely, and ee:80%, is evaporated to dry.Add 180 milliliters of re-crystallizing in ethyl acetate, recrystallization solid dries to obtain 42.2 grams of products in 45 DEG C, HPLC purity: 99.8%, ee:99%, yield 69.5%.
1H-NMR(400MHz,CDCl
3):5.36(brs,1H),3.90～3.82(m,1H),1.97(s,3H),1.78-1.65(m,5H),1.35-1.12(m,4H),1.09～1.07(d,3H),1.06-0.92(m,2H)。
Embodiment 5:(S) synthesis of-N-(1-cyclohexyl-ethyl) ethanamide
In 250 milliliters of hydriding reactors, add 15 grams of N-(1-cyclohexylvinyl) ethanamide and 0.012g catalyzer Rh [(Rc, Sp)-Duanphos] (NBD) BF
4, add 75 milliliters of deoxidation methyl alcohol, hydrogenation is to 1.5MPa, and stirring at room temperature 2-3 hour, HPLC monitoring is to reacting completely, and ee:80%, is evaporated to dry.Add 45 milliliters of re-crystallizing in ethyl acetate, recrystallization solid dries to obtain 10 grams of products in 45 DEG C, HPLC purity: 99.8%, ee:99%, yield 65.9%.
Embodiment 6:(R) synthesis of-1-cyclohexylethylamine
20 grams of (R)-N-(1-cyclohexyl-ethyl) ethanamides are added in 500 milliliters of round-bottomed flasks, 239 grams of concentration be 40% Hydrogen bromide (per-cent is the per-cent that the quality of HBr accounts for described Hydrogen bromide total mass, described Hydrogen bromide is the aqueous solution of HBr), be heated to reflux about 124-126 DEG C, insulation reaction 50 hours, GC monitors, raw material is less than 5%, be cooled to room temperature, under ice-water bath, drip 40% aqueous sodium hydroxide solution, temperature control is less than 30 DEG C, adjust pH to about 12, use 100 milliliters of methyl tertiary butyl ether (MTBE) extracting twice respectively.Merge organic layer, anhydrous sodium sulfate drying, filter, be spin-dried for obtain crude product.Underpressure distillation, collects cut (25mmHg collects 85-86 DEG C of cut) and obtains 10.5 grams of products, GC purity: 99.8%, ee:99.3%, yield 70%.
1H-NMR(400MHz,CDCl
3):2.71～2.65(q,1H),1.82～1.66(m,5H),1.43(br,2H),1.31～1.10(m,4H),1.06～1.04(d,3H),1.03～0.91(m,2H)。
[α]
D 25-1.8(c＝0.02g/mL,CHCl
3)。
The optically-active data of document [JournalofOrganicChemistry, 2010, vol.75,5265 ~ 5270] report (R)-1-cyclohexylethylamine are [α]
d 20-1.1 (c=0.02g/mL, CHCl
3, 69%ee).
Comparative example 1:(R) synthesis of-1-cyclohexylethylamine, hydrochloric acid hydrolysis
In 250 milliliters of round-bottomed flasks, add 17 grams of (R)-N-(1-cyclohexyl-ethyl) ethanamides, 105 grams of concentration are the hydrochloric acid of 35%, are heated to backflow, insulation reaction 50 hours, GC monitors, and raw material residual about 88%, reaction transforms not exclusively.Continue insulation to reaction 70 hours, GC monitors, and raw material residual about 85%, reaction transforms very slow.
Comparative example 2:(R) synthesis of-1-cyclohexylethylamine, dilute hydrobromic acid is hydrolyzed
20 grams of (R)-N-(1-cyclohexyl-ethyl) ethanamides are added in 500 milliliters of round-bottomed flasks, 239 grams of concentration be 40% Hydrogen bromide (per-cent is the per-cent that the quality of HBr accounts for described Hydrogen bromide total mass, described Hydrogen bromide is the aqueous solution of HBr), add the dilution of about 239mL water, be heated to reflux about 120-125 DEG C, insulation reaction 50 hours, and GC monitors, residual about 90%, reaction transforms not exclusively.Continue insulation to reaction 70 hours, GC monitors, and raw material residual about 86%, reaction transforms very slow.
Claims (10)
1. the preparation method of an optically active 1-cyclohexylethylamine, it is characterized in that, it comprises the steps: in water, under HBr effect, by the reaction that is hydrolyzed such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ', corresponding obtained such as formula the optically active 1-cyclohexylethylamine shown in 5 or formula 5 '; Described HBr and the described molar ratio such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' are 8 ~ 15;
2. preparation method as claimed in claim 1, is characterized in that:
In described hydrolysis reaction, described HBr and described water participate in reaction with the form of the HBr aqueous solution; The mass concentration of the described HBr aqueous solution is 40 ~ 47%, and per-cent is the per-cent that the quality of HBr accounts for described HBr aqueous solution total mass;
And/or in described hydrolysis reaction, described HBr and the described molar ratio such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ' are 9 ~ 10;
And/or the temperature of described hydrolysis reaction is 100 DEG C ~ 130 DEG C;
And/or the time of described hydrolysis reaction is 30 hours ~ 70 hours.
3. preparation method as claimed in claim 2, is characterized in that:
The temperature of described hydrolysis reaction is 110 DEG C ~ 130 DEG C;
And/or the time of described hydrolysis reaction is 45 hours ~ 65 hours.
4. preparation method as claimed in claim 1, it is characterized in that: the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under hydrogen and catalyst action, compound is as shown in Equation 3 carried out asymmetric hydrogenation, obtained described such as formula the N-acetylaminohydroxyphenylarsonic acid 1-cyclohexylethylamine shown in 4 or formula 4 ';
5. preparation method as claimed in claim 4, is characterized in that:
In described asymmetric hydrogenation, described solvent is alcoholic solvent;
And/or in described asymmetric hydrogenation, the volume mass ratio of described solvent and described compound is as shown in Equation 3 5mL/g ~ 15mL/g;
And/or in described asymmetric hydrogenation, the pressure of described hydrogen is 1atm ~ 25atm;
And/or in described asymmetric hydrogenation, described catalyzer is the title complex class catalyzer that Rh and phosphine are formed;
And/or in described asymmetric hydrogenation, the molar ratio of described catalyzer and described compound is as shown in Equation 3 0.01 ~ 0.0001;
And/or the temperature of described asymmetric hydrogenation is 10 DEG C ~ 35 DEG C;
And/or the time of described asymmetric hydrogenation is 1 hour ~ 8 hours.
6. preparation method as claimed in claim 5, is characterized in that:
In described asymmetric hydrogenation, described alcoholic solvent is methyl alcohol;
And/or in described asymmetric hydrogenation, the volume mass ratio of described solvent and described compound is as shown in Equation 3 5mL/g ~ 10mL/g;
And/or in described asymmetric hydrogenation, the pressure of described hydrogen is 5atm ~ 20atm;
And/or in described asymmetric hydrogenation, the title complex class catalyzer that described Rh and phosphine are formed is Rh (RcSp-DuanPhos) (COD) BF
4and/or Rh (RcSp-DuanPhos) (NBD) BF
4;
And/or in described asymmetric hydrogenation, the molar ratio of described catalyzer and described compound is as shown in Equation 3 0.001 ~ 0.0002;
And/or the temperature of described asymmetric hydrogenation is 20 DEG C ~ 30 DEG C;
And/or the time of described asymmetric hydrogenation is 1 hour ~ 4 hours.
7. preparation method as claimed in claim 4, it is characterized in that: the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under catalyzer, reductive agent and acylating reagent effect, compound is as shown in Equation 2 carried out reductive acylation reaction, obtained described compound as shown in Equation 3;
8. preparation method as claimed in claim 7, it is characterized in that: the preparation method of described optically active 1-cyclohexylethylamine, described solvent is comprised the steps: to mix with described compound as shown in Equation 2 further, then described reductive agent and described catalyzer is added, under 30 DEG C ~ 35 DEG C conditions after insulated and stirred 30min, be heated to 50 DEG C ~ 60 DEG C, then control under 50 DEG C ~ 60 DEG C conditions, add described acylating reagent at temperature of reaction system and carry out described reductive acylation reaction;
And/or in described reductive acylation reaction, described solvent is amide solvent;
And/or in described reductive acylation reaction, the volume mass ratio of described solvent and described compound is as shown in Equation 2 3mL/g ~ 10mL/g;
And/or in described reductive acylation reaction, described catalyzer is trimethylchlorosilane;
And/or in described reductive acylation reaction, the molar ratio of described catalyzer and described compound is as shown in Equation 2 0.01 ~ 0.1;
And/or in described reductive acylation reaction, described reductive agent is iron;
And/or in described reductive acylation reaction, the molar ratio of described reductive agent and described compound is as shown in Equation 2 1.5 ~ 4;
And/or in described reductive acylation reaction, described acylating reagent is aceticanhydride;
And/or in described reductive acylation reaction, the molar ratio of described acylating reagent and described compound is as shown in Equation 2 1.5 ~ 3.5;
And/or the temperature of described reductive acylation reaction is 30 DEG C ~ 100 DEG C;
And/or the time of described reductive acylation reaction is 1 hour ~ 5 hours.
9. preparation method as claimed in claim 7, it is characterized in that: the preparation method of described optically active 1-cyclohexylethylamine comprises the steps: in solvent further, under alkaline condition, compound as shown in Equation 1 and oxammonium hydrochloride are carried out oximation reaction, compound as shown in Equation 2 described in obtained;
10. preparation method as claimed in claim 9, is characterized in that:
The preparation method of described optically active 1-cyclohexylethylamine comprises the steps: described solvent and described compound as shown in Equation 1 further, be cooled to 10 ~ 15 DEG C, then oxammonium hydrochloride is added, regulate reaction system to described alkaline condition again, then be naturally warming up to room temperature, carry out described oximation reaction;
And/or the solvent of described oximation reaction is alcoholic solvent;
And/or the solvent of described oximation reaction and the volume mass ratio of described compound are as shown in Equation 1 3mL/g ~ 10mL/g;
And/or in described oximation reaction, the molar ratio of described oxammonium hydrochloride and described compound is as shown in Equation 13 ~ 1.1;
And/or in described oximation reaction, described alkaline condition is pH is 7 ~ 8;
And/or the temperature of described oximation reaction is 10 DEG C ~ 35 DEG C;
And/or the time of described oximation reaction is 1 hour ~ 4 hours.
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|---|---|---|---|---|
| CN110054563A (en) * | 2019-06-10 | 2019-07-26 | 江西隆莱生物制药有限公司 | The Preparation Method And Their Intermediate of butyrolactone compound |
| CN114524745A (en) * | 2022-03-03 | 2022-05-24 | 浙江工业大学 | Preparation method of (R) -N-acetyl-alpha-arylethylamine derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4277420A (en) * | 1979-09-24 | 1981-07-07 | Monsanto Company | Ephedrine and pseudoephedrine precursors |
| WO1999018065A1 (en) * | 1997-10-03 | 1999-04-15 | Chirotech Technology Limited | Chiral amines |
| WO2006064340A2 (en) * | 2004-12-13 | 2006-06-22 | Pfizer Limited | Process for the preparation of n-acyl beta-aminoaldehydes |
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2015
- 2015-10-13 CN CN201510657695.5A patent/CN105330550B/en active Active
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| US4277420A (en) * | 1979-09-24 | 1981-07-07 | Monsanto Company | Ephedrine and pseudoephedrine precursors |
| WO1999018065A1 (en) * | 1997-10-03 | 1999-04-15 | Chirotech Technology Limited | Chiral amines |
| WO2006064340A2 (en) * | 2004-12-13 | 2006-06-22 | Pfizer Limited | Process for the preparation of n-acyl beta-aminoaldehydes |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054563A (en) * | 2019-06-10 | 2019-07-26 | 江西隆莱生物制药有限公司 | The Preparation Method And Their Intermediate of butyrolactone compound |
| CN114524745A (en) * | 2022-03-03 | 2022-05-24 | 浙江工业大学 | Preparation method of (R) -N-acetyl-alpha-arylethylamine derivative |
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