CN103044302A - Method for preparing vitamin A acetate through one-pot method - Google Patents
Method for preparing vitamin A acetate through one-pot method Download PDFInfo
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Abstract
The invention relates to a method for preparing vitamin A acetate through a one-pot method, which comprises the following steps: reacting C14 aldehyde and an intermediate compound C1 (tetraethyl methylenediphosphonate or tetramethyl methylenediphosphonate) under alkaline conditions to generate C15 phosphonate; and under the condition of not separating the C15 phosphonate, directly reacting the C15 phosphonate and C5 aldehyde through a one-pot method, thus preparing the vitamin A acetate. According to the method, two Wittig reaction steps are combined and performed in one pot, the technical operation is simple, the use and separation of solvent are reduced, the drying of the C15 phosphonate is avoided, the technical process is short, and the reaction is performed at a preselected temperature, thereby improving the reaction selectivity, avoiding the cryogenic operation environment and lowering the energy consumption; and meanwhile, the waste water discharge is reduced, and the method is economical and environment-friendly. The obtained vitamin A acetate has high product purity, high yield and low cost, and is beneficial to industrial production.
Description
Technical field
The present invention relates to the method that a kind of one kettle way prepares retinyl acetate, belong to vitamin A and derivative production technical field thereof.
Background technology
Vitamin A and derivative thereof are the important medicine of a class and fodder additives, and the most frequently used vitamin A derivatives is retinyl acetate.Retinyl acetate has another name called, retinyl acetate, VITAMIN A ACETATE, and CAS number is 127-47-9, is a kind of light yellow solid powder, good fluidity.The structural formula of retinyl acetate is as follows:
Retinyl acetate has multiple important physiological function, is the growth of vision systems, growth, epithelium and bone, the generation of sperm and the essential nutrition of growing of fetus.Retinyl acetate is in many vital movement processes, and such as vision generation, growth, growth, differentiation, metabolism, and form formation etc. all plays an important role.The sick investigation of modern popular shows; retinyl acetate can be regulated the necessary factor of Epithelial cell growth and health; make coarse aging skin surface attenuation; promote cell metabolism normalizing; not only be used for the treatment of vitamin(e) A deficiency and various skin disease; but also to many cancers, has significant curative effect such as skin carcinoma, head and neck cancer, lung cancer, mammary cancer, prostate cancer and bladder cancer etc.It has been recognized that the great potential of retinyl acetate, retinyl acetate has been widely used in the industries such as medicine, food, fodder additives and makeup at present.
The annual requirement of world market retinyl acetate is about 10,002 kilotons to, 10,005 kilotons at present.Vitamin A and derivative thereof are as a kind of important basic nutrition, and its synthetic preparation receives much concern always, and retinyl acetate mainly adopts following three different technological lines at present.
The first, the C14+C6 route of Roche company (Roche method):
This synthetic route is starting raw material take the Grignard reaction as feature by alpha, beta-lonone, through Darzens reaction, Grignard reaction, hydrogenation, acetylize, hydroxyl bromination, dehydrobromination totally six step operations finish all-trans-vitamin A acetic acid ester synthesis.Although this method can obtain retinyl acetate, there are a series of defectives, reach kind more than 50 such as desired raw material, reactions steps is long; Device category is many, and reaction conditions requires harsh, and fixed investment is large; Reaction is not easy to production control for cascade reaction; There is larger potential safety hazard in the production of main intermediate six carbon alcohol.
The second, the synthetic route of Rhone-Poulenc company:
This route is take the sulfone compound intermediate as feature, and the people such as Chabardes under the potassium tert.-butoxide effect and the halide reaction of C5 alcohol acetic ester, slough the C15 sulfone again benzenesulfonyl and obtain retinyl acetate.This technique is typical cascade reaction, is set out by alpha, beta-lonone, makes 15 carbon esters through the Reformatsky reaction first, and its reduction, oxidation and Claisen-Schimidt condensation are got 18 carbon ketone; Make 20 carbon esters through a Reformatsky reaction again, its reduction is obtained tieing up the A acetic ester.The bottleneck of this route is that main intermediate C15 aldehyde, C18 ketone, C20 ester all will purify through the distillation of the hight atmospheric molecular of condition harshness, and output is little, is difficult to accomplish scale production.
Three, the C15+C5 route of BASF AG:
This route is that the people such as Pommer of BASF AG developed the fifties, take the Wittig reaction as feature, is to change first alcohol compound into halogenide to prepare its Wittig phosphonium salt in early days again; Later stage by people such as Sarneeki directly with vinyl-β-ionol and Ph
3The PHX mixture, or respectively with Ph
3P and HX effect obtain chlorine, bromine, iodine or hydrosulfate, and reaction solvent is methyl alcohol, ethanol, DMF etc.This method route is short, yield is high, and the trend of further replacement Roche method is arranged, but the ethinylation in the operation, low temperature and anhydrous etc. require still can not avoid than hi-tech.And synthesise vitamins A acetic ester in this way, the raw material triphenyl price of seeing is more expensive, generates a large amount of cis-isomerides and the oxidation triphenyl by product of seeing, be difficult to separate, and this synthesis technique need use the phosgene of severe toxicity, and technology and equipment is required height, the difficult large-scale industrial production of realizing.
Recently people mainly concentrate on improvement aspect to above-mentioned A Third Way line for the study on the synthesis of retinyl acetate.PCT2005058811, Ger10164041, JP06329623 and Chinese patent file CN101318975, CN101219983 and CN102190565 have reported that all use C14 aldehyde and C1 carry out the Wittig reaction, aftertreatment through complex steps, obtain the C15 phosphonic acid ester, yield is between 80-92%, but generally being lower than 80%, C15 phosphonic acid ester, actual recovery must can be used for second step Wittig reaction through (CN1097414A) after finish-drying or the processing.CN102180774 has reported that C15 phosphonic acid ester and C5 aldehyde carry out Wittig reaction preparation retinyl acetate, and the single step yield is 81%.
Above method is carried out respectively two step Wittig reactions, and reactions steps is complicated, and reaction time is long, and waste water and waste are many, and two steps, actual recovery was the highest to be only had about 60%.And the C15 phosphonic acid ester can be used for second step Wittig reaction after must or processing through finish-drying, and the existence of trace water can cause a series of side reactions such as C5 aldehyde self condensation, and yield is reduced, and aftertreatment is complicated.And can cause the industrial accidents such as on fire, be unfavorable for suitability for industrialized production.
Summary of the invention
For the deficiencies in the prior art, the invention provides the method that a kind of one kettle way prepares retinyl acetate.Method of the present invention is to utilize C14 aldehyde and intermediate C1 to react under alkaline condition to generate the C15 phosphonic acid ester; This C15 phosphonic acid ester is without separation, and direct and C5 aldehyde one pot reaction prepares retinyl acetate.
The term explanation:
Starting raw material C14 aldehyde is called trans 2-methyl-4-(2,6,6-trimethylammonium-1-tetrahydrobenzene entirely)-crotonic aldehyde.
Starting raw material C1 refers to utilize Wittig reaction, and for synthesise vitamins A acetic ester provides the basic material of 1 carbon unit, C1 is Tetraethyl diphosphonomethane or methylenediphosphonate (MDP) tetramethyl ester among the present invention.
Starting raw material C5 aldehyde, full 2-methyl-4-acetoxy-2-butylene aldehyde by name.
Intermediate C15 phosphonic acid ester refers to the first step Wittig reaction product of C14 aldehyde and C1, and the C15 phosphonic acid ester is directly used in the preparation retinyl acetate without separating and drying in the present invention.
Vapor detection: utilize gas chromatograph to carry out reaction monitoring and purity detecting.
Technical scheme of the present invention is as follows:
The method of the retinyl acetate of a kind of preparation formula (I),
By making the C14 aldehyde of formula (II):
Under alkaline condition, carry out the Wittig reaction first time with the C1 of formula (III),
The C15 phosphonic acid ester of production (IV):
This C15 phosphonic acid ester is without separation, and C5 aldehyde direct and formula V carries out the Wittig reaction second time in same reactor:
Described C14 aldehyde is trans 2-methyl-4-(2,6,6-trimethylammonium-1-tetrahydrobenzene)-crotonic aldehyde;
Described C1 is Tetraethyl diphosphonomethane or methylenediphosphonate (MDP) tetramethyl ester;
Described C5 aldehyde is 2-methyl-4-acetoxy-2-butylene aldehyde.
According to the present invention, the temperature of reaction of for the first time Wittig reaction and for the second time Wittig reaction all is controlled at-40 ℃ to 50 ℃, and wherein preferred-20 ℃ to 30 ℃, further preferred-5 ℃ to 5 ℃.
According to the present invention, more detailed, a kind of method for preparing retinyl acetate comprises that step is as follows:
(1) under the nitrogen protection, add successively solvent I, alkali in the reaction vessel of drying, keep certain temperature, drip the mixing solutions of C14 aldehyde and C1, insulation reaction generates intermediate C15 phosphonic acid ester until vapor detection C14 aldehyde transforms fully; Then,
(2) directly drip C5 aldehyde or add simultaneously alkali, insulation reaction, Liquid Detection intermediate C15 phosphonic acid ester transforms fully, generates retinyl acetate; Then,
(3) vacuum distillation recovered solvent, cooling adds saturated aqueous ammonium chloride and ethyl acetate, extraction, the organic phase anhydrous sodium sulfate drying filters, and reclaims ethyl acetate, 95% ethanol activated carbon decolorizing, filtered while hot, cooling liberating vitamin A acetic ester.
Above-mentioned C14 aldehyde is trans 2-methyl-4-(2,6,6-trimethylammonium-1-tetrahydrobenzene)-crotonic aldehyde.
Above-mentioned C1 is Tetraethyl diphosphonomethane or methylenediphosphonate (MDP) tetramethyl ester.
Above-mentioned C5 aldehyde is 2-methyl-4-acetoxy-2-butylene aldehyde.
According to the present invention, the mol ratio of preferred described C1, C5 aldehyde, C14 aldehyde is (1 ~ 3): (1 ~ 3): 1.The mol ratio of further preferred C1, C5 aldehyde, C14 aldehyde is (1 ~ 2): (1 ~ 2): 1
According to the present invention, preferred described alkali is one of sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium hydride or combination.Described alkali gets final product with the solid-state form adding.The mol ratio of preferred described alkali total amount and C14 aldehyde is 2 ~ 6:1.Further the mol ratio of preferred described alkali total amount and C14 aldehyde is 2 ~ 4.4:1.
According to the present invention, preferred, the amount of the solvent I in the step (1) in the front adding of the reaction reaction vessel and the mass ratio of described alkali dosage are solvent I: alkali=8-20:1.
According to the present invention, preferably, the mixing solutions of C14 aldehyde and C1 is that C14 aldehyde and C1 are dissolved in the solvent II in the step (1), the solvent II consumption is that meltage gets final product, this solvent II is preferably identical with the front solvent I that adds in the reaction vessel of reaction, will be steamed except recovery in step (3) last handling process.
According to the present invention, C5 aldehyde is dissolved among the solvent II I and drips in the preferred step (2), and solvent II I consumption is that meltage gets final product, and this solvent II I is preferably identical with the front solvent I that adds in the reaction vessel of reaction, will be steamed except recovery in step (3) last handling process.
Solvent described in the present invention, comprise solvent I, solvent II, solvent II I, be aprotic solvent, be preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, the combination of a kind of in dinethylformamide, N,N-dimethylacetamide, toluene, the methyl-sulphoxide or 2 kinds; Wherein further preferred DMF, toluene or methyl-sulphoxide.
According to the present invention, preferred, the insulation reaction temperature-20 of step (1) ℃ ~ 30 ℃, 2 ~ 3 hours reaction times.But transform the not exclusively then proper extension reaction times such as vapor detection C14 aldehyde.
According to the present invention, the insulation reaction temperature-20 of step (2) ℃ ~ 30 ℃, 2 ~ 3 hours reaction times.But transform the not exclusively then proper extension reaction times such as Liquid Detection intermediate C15 phosphonic acid ester.
According to the present invention, preferred, the underpressure distillation condition of step (3) is 4 ~ 6 mmhg, 60 ~ 80 ℃.
According to the present invention, during for the first time Wittig reaction of step (1), it is to utilize GC to detect fully that vapor detection C14 aldehyde transforms; In step (2) the Wittig process second time, the conversion of Liquid Detection C15 phosphonic acid ester intermediate is to utilize high performance liquid chromatography (HPLC) to detect fully.The finished product retinyl acetate is to utilize HPLC to detect purity (Area Ratio %), and calculated yield.
Technical characterstic of the present invention is: two step Wittig reactions are incorporated in one pot carry out, be used for simplifying the production process of preparation retinyl acetate, utilize starting raw material C14 aldehyde and C1 under alkaline condition, to carry out the Wittig reaction first time and generate the C15 phosphonic acid ester, this C15 phosphonic acid ester separates without aftertreatment, directly carries out the Wittig reaction second time with the C5 aldehyde that drips in same reactor.Level of response is utilized the gas phase monitoring, and raw material C14 aldehyde directly adds C5 aldehyde and prepares retinyl acetate after transforming fully.Reaction formula is as follows:
Excellent results of the present invention is:
The present invention is that to utilize two step Wittig to react required condition similar, does not separate the C15 phosphonic acid ester, directly and C5 aldehyde one pot reaction prepare retinyl acetate.The method is incorporated in two step Wittig reactions in one pot carries out, and technological operation is simple, has reduced using and separating of solvent, and avoided the drying of C15 phosphonic acid ester, technical process is short, is both reacting under the fixed temperature, improve reaction preference, avoided the cryogenic operations environment, reduced energy consumption; Reduced simultaneously discharge of wastewater, economic environmental protection.Retinyl acetate product purity with this one kettle way preparation is high, HPLC purity 98.3-99.7%, and yield can be up to more than 90%, and cost is low, is beneficial to suitability for industrialized production, and is significant to the commercial production levels that improves China's retinyl acetate.
Description of drawings
Fig. 1 is the GC ion flow graph of the C15 phosphonic acid ester of embodiment 1;
Fig. 2 is the GC mass spectrum of the C15 phosphonic acid ester of embodiment 1;
Fig. 3 is the LC ion flow graph of the retinyl acetate of embodiment 1;
Fig. 4 is the LC mass spectrum of the retinyl acetate of embodiment 1.
Embodiment
Describe the present invention in detail below in conjunction with embodiment, but the present invention not only is confined to this.
Among the embodiment, vapor detection is to carry out reaction monitoring and purity detecting with the Shimadzu gas chromatograph, and the instrument model is GC-1020PLUS; Liquid Detection: utilize the Shimadzu liquid chromatograph to carry out reaction monitoring and purity detecting, the instrument model is LC-20AT, and chromatographic column is C18 post ODS (250mm * 4.6mm * 5 μ m), and moving phase is methyl alcohol: water=3:2 volume ratio; The detection wavelength is 320nm.
Embodiment 1
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 200 gram N; dinethylformamide; 20.4 gram (0.3 mole) solid sodium ethanol; cooling maintains the temperature between-5 ℃ ~ 5 ℃, drips by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and 100 gram N; the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours.After this-5 ℃ ~ 5 ℃ insulation reaction 2.5 hours, the transformation efficiency of vapor detection C14 aldehyde was 99.9%.Gained intermediate C15 phosphonic acid ester is by the GC-MS analysis confirmation, referring to Fig. 1 and Fig. 2.
After the conversion of C14 aldehyde is complete, the reaction product intermediate need not to separate, reaction soln is continued to be cooled to-20 ℃, dripped again the mixing solutions of 17.0 gram (0.12 mole) C5 aldehyde and 50 gram DMFs by constant pressure funnel, dropping temperature is controlled at-10 ℃ ~-15 ℃, dropwised in about 1 hour ,-5 ℃ are incubated 2 ~ 3 hours after dropwising, after the Liquid Detection reaction is complete, underpressure distillation (about 5 mmhg, 75 ℃ of temperature) is reclaimed solvent to there not being material to steam; Then be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 ~ 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 28.5 grams, and HPLC purity is 98.9%, yield 86.7%.Product process and standard substance comparison, the liquid phase appearance time is identical, and product process LC-MS affirmation, and molecular weight is consistent, and the LC-MS spectrogram is seen spectrogram 3 and 4.
Under the nitrogen protection, in 1000 milliliters of glass flask of drying, add successively 300 gram N, dinethylformamide, 33.6 gram (0.3 mole) potassium tert.-butoxide solid, cooling keeps dripping by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and 100 gram N between the temperature-5 ℃ ~ 5 ℃, the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours; Insulation reaction 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, drip again 17.0 gram (0.12 mole) C5 aldehyde and 50 gram N, the mixing solutions of dinethylformamide, dropping temperature are controlled at-10 ℃ ~-15 ℃, dropwise in about 1 hour, after dropwising in-5 ℃ of insulations 2 to 3 hours, after Liquid Detection reaction is complete, underpressure distillation (about 5 mmhg, temperature 60-80 ℃), reclaim solvent after do not have material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 to 20 ℃ is stirred layering after 1 hour, water layer ethyl acetate extraction twice, each 50 grams, the combined ethyl acetate phase, add 10 gram anhydrous sodium sulfate dryings 4 hours, and filtered, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, is incubated 5 hours, filters to obtain retinyl acetate 30.5 grams, HPLC purity is 99.7%, yield 92.8%.
Embodiment 3
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 200 gram N; dinethylformamide; 21.6 gram (0.4 mole) sodium methylate solid; cooling keeps dripping by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and 100 gram N between the temperature-5 ℃ ~ 5 ℃; the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours.After this insulation reaction is 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, drip again 17.0 gram (0.12 mole) C5 aldehyde and 50 gram N, the mixing solutions of dinethylformamide, dropping temperature are controlled at-10 ℃ ~-15 ℃, dropwise in about 1 hour, be incubated 2 to 3 hours in-5 ℃ after dropwising, after Liquid Detection reaction was complete, underpressure distillation (about 5 mmhg, temperature 60-80 ℃) was reclaimed solvent after do not have material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 to 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 24.5 grams, and HPLC purity is 98.3%, yield 74.6%.
Embodiment 4
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 200 gram N; dinethylformamide; 10.0 the sodium hydride powder of gram (0.25 mole) 60%; cooling keeps dripping by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and 100 gram N between the temperature-5 ℃ ~ 5 ℃; the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours.After this insulation reaction is 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, drip again 17.0 gram (0.12 mole) C5 aldehyde and 50 gram N, the mixing solutions of dinethylformamide, dropping temperature are controlled at-10 ℃ ~-20 ℃, dropwise in about 1 hour, be incubated 2 to 3 hours in-5 ℃ after dropwising, after Liquid Detection reaction was complete, underpressure distillation (about 5 mmhg, temperature 60-80 ℃) was reclaimed solvent after do not have material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 to 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 29.3 grams, and HPLC purity is 99.2%, yield 89.2%.
Embodiment 5
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 300 gram N; dinethylformamide; 33.6 gram (0.3 mole) potassium tert.-butoxide solid; cooling keeps dripping by 20.6 gram (0.1 mole) C14 aldehyde, 27.8 gram (0.12 mole) methylenediphosphonate (MDP) tetramethyl esters and 100 gram N between the temperature-5 ℃ ~ 5 ℃; the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours.After this insulation reaction is 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, drip again 17.0 gram (0.12 mole) C5 aldehyde and 50 gram N, the mixing solutions of dinethylformamide, dropping temperature are controlled at-10 ℃ ~-20 ℃, dropwise in about 1 hour, be incubated 2 to 3 hours in-5 ℃ after dropwising, after Liquid Detection reaction was complete, underpressure distillation (about 5 mmhg, temperature 60-80 ℃) was reclaimed solvent after do not have material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 ~ 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 29.6 grams, and HPLC purity is 98.9%, yield 90.2%.
Embodiment 6
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 300 gram dimethyl sulfoxide (DMSO); 33.6 gram (0.3 mole) potassium tert.-butoxide solid; cooling; keep between the temperature-5 ℃ ~ 5 ℃; dropping was dropwised by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and the formulated mixing solutions of 100 gram dry toluenes in about 2 hours.After this insulation reaction is 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, drip again the mixing solutions of 17.0 gram (0.12 mole) C5 aldehyde and 50 gram dry toluenes, dropping temperature is controlled at-10 ℃ ~-20 ℃, dropwises in about 1 hour, is incubated 2 to 3 hours in-5 ℃ after dropwising, after the Liquid Detection reaction is complete, solvent toluene and methyl-sulphoxide are reclaimed in underpressure distillation (about 5 mmhg, 60-80 ℃), after not having material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 to 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 27.6 grams, and HPLC purity is 98.7%, yield 84.0%.
Embodiment 7
Under the nitrogen protection; in 1000 milliliters of glass flask of drying, add successively 200 gram N; dinethylformamide; 10.2 gram (0.15 mole) sodium ethylate solid; cooling keeps dripping by 20.6 gram (0.1 mole) C14 aldehyde, 34.6 gram (0.12 mole) Tetraethyl diphosphonomethanes and 100 gram N between the temperature-5 ℃ ~ 5 ℃; the mixing solutions that dinethylformamide is formulated dropwised in about 2 hours.After this insulation reaction is 2 to 3 hours.After the conversion of vapor detection C14 aldehyde is complete, reaction soln is continued to be cooled to-20 ℃, add again 16.8 gram (0.15 mole) potassium tert.-butoxide solids, after stirring, drip 17.0 gram (0.12 mole) C5 aldehyde and 50 gram N, the mixing solutions of dinethylformamide, dropping temperature is controlled at-10 ℃ ~-15 ℃, dropwised in about 1 hour, be incubated 2 to 3 hours in-5 ℃ after dropwising, after Liquid Detection reaction was complete, underpressure distillation (about 5 mmhg, temperature 60-80 ℃) was reclaimed solvent after do not have material to steam, be cooled to room temperature, add 200 gram saturated aqueous ammonium chlorides, 200 gram ethyl acetate, 0 to 20 ℃ is stirred layering after 1 hour, twice of ethyl acetate extraction of water layer, each 50 grams, the combined ethyl acetate phase added 10 gram anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, in residuum, add 90 grams, 95% ethanol, in 30 ℃ of lower stirring and dissolving, add again 2 gram gacs, 30 ℃ of lower stirrings 30 minutes, filtered while hot, filtrate is cooled to-5 ℃, be incubated 5 hours, filtration obtains retinyl acetate 28.9 grams, and HPLC purity is 98.9%, yield 88.0%.
Claims (10)
1. the method for the retinyl acetate of a preparation formula (I),
By making the C14 aldehyde of formula (II):
Under alkaline condition, carry out the Wittig reaction first time with the C1 of formula (III),
The C15 phosphonic acid ester of production (IV):
This C15 phosphonic acid ester is without separation, and C5 aldehyde direct and formula V carries out the Wittig reaction second time in same reactor:
2. the preparation method of retinyl acetate according to claim 1 is characterized in that, the temperature of reaction of for the first time Wittig reaction and for the second time Wittig reaction all is controlled at-40 ℃ to 50 ℃; Wherein preferred-20 ℃ to 30 ℃; Further preferred-5 ℃ to 5 ℃.
3. the preparation method of retinyl acetate according to claim 1 is characterized in that, comprises that step is as follows:
(1) under the nitrogen protection, add successively solvent I, alkali in the reaction vessel of drying, keep certain temperature, drip the mixing solutions of C14 aldehyde and C1, insulation reaction generates intermediate C15 phosphonic acid ester until vapor detection C14 aldehyde transforms fully; Then,
(2) directly drip C5 aldehyde or add simultaneously alkali, insulation reaction, Liquid Detection intermediate C15 phosphonic acid ester transforms fully, generates retinyl acetate; Then,
(3) vacuum distillation recovered solvent, cooling adds saturated aqueous ammonium chloride and ethyl acetate, extraction, the organic phase anhydrous sodium sulfate drying filters, and reclaims ethyl acetate, 95% ethanol activated carbon decolorizing, filtered while hot, cooling liberating vitamin A acetic ester.
4. the preparation method of retinyl acetate according to claim 3 is characterized in that, the mol ratio of described C1, C5 aldehyde, C14 aldehyde is (1 ~ 3): (1 ~ 3): 1; The mol ratio of preferred C1, C5 aldehyde, C14 aldehyde is (1 ~ 2): (1 ~ 2): 1.
5. the preparation method of retinyl acetate according to claim 3 is characterized in that, described alkali is one of sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium hydride or combination.
6. the preparation method of retinyl acetate according to claim 3 is characterized in that, the mol ratio of described alkali total amount and C14 aldehyde is 2 ~ 6:1; The mol ratio of preferred described alkali total amount and C14 aldehyde is 2 ~ 4.4:1.
7. the preparation method of retinyl acetate according to claim 3 is characterized in that, the amount of the solvent I in the step (1) in the front adding of the reaction reaction vessel and the mass ratio of described alkali dosage are solvent I: alkali=8-20:1.
8. the preparation method of retinyl acetate according to claim 3 is characterized in that, the mixing solutions of C14 aldehyde and C1 is that C14 aldehyde and C1 is miscible in solvent II in the step (1), and this solvent II is identical with the front solvent I that adds in the reaction vessel of reaction; C5 aldehyde is dissolved among the solvent II I and drips in the step (2), and this solvent II I is identical with the front solvent I that adds in the reaction vessel of reaction.
9. according to claim 3, the preparation method of 7 or 8 described retinyl acetates, it is characterized in that, described solvent I, solvent II and solvent II I are tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, the combination of a kind of in dinethylformamide, N,N-dimethylacetamide, toluene, the methyl-sulphoxide or 2 kinds; Preferred DMF, toluene or methyl-sulphoxide.
10. the preparation method of retinyl acetate according to claim 3 is characterized in that, the insulation reaction temperature-20 of step (1) ℃ ~ 30 ℃, 2 ~ 3 hours reaction times; The insulation reaction temperature-20 of step (2) ℃ ~ 30 ℃, 2 ~ 3 hours reaction times.
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| CN105949101A (en) * | 2016-05-31 | 2016-09-21 | 肇庆巨元生化有限公司 | Preparation method of vitamin A acetate |
| CN106008599A (en) * | 2016-06-01 | 2016-10-12 | 肇庆巨元生化有限公司 | Method for preparing pentadecane diethyl phosphate |
| CN109651150A (en) * | 2018-12-20 | 2019-04-19 | 万华化学集团股份有限公司 | A method of preparing vitamine A acetate |
| CN111484524A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Vitamin A acetate intermediate C15 and preparation method of vitamin A acetate |
| CN111484525A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Vitamin A ester intermediate C15 and preparation method of vitamin A ester |
| CN111995555A (en) * | 2020-09-22 | 2020-11-27 | 江西天新药业股份有限公司 | Preparation method of vitamin A acetate |
| CN112876395A (en) * | 2021-01-15 | 2021-06-01 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
| CN112961088A (en) * | 2021-03-29 | 2021-06-15 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
| CN114315674A (en) * | 2021-12-13 | 2022-04-12 | 万华化学集团股份有限公司 | Process for preparing light-coloured vitamin A |
| WO2023108327A1 (en) * | 2021-12-13 | 2023-06-22 | 万华化学集团股份有限公司 | Preparation method for light-colored vitamin a |
| DE112021007675T5 (en) | 2021-05-19 | 2024-03-07 | Wanhua Chemical Group Co., Ltd. | PRODUCTION PROCESS FOR VITAMIN A ACETATE |
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| CN105949101A (en) * | 2016-05-31 | 2016-09-21 | 肇庆巨元生化有限公司 | Preparation method of vitamin A acetate |
| CN106008599A (en) * | 2016-06-01 | 2016-10-12 | 肇庆巨元生化有限公司 | Method for preparing pentadecane diethyl phosphate |
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| CN109651150B (en) * | 2018-12-20 | 2022-02-18 | 万华化学集团股份有限公司 | Method for preparing vitamin A acetate |
| CN109651150A (en) * | 2018-12-20 | 2019-04-19 | 万华化学集团股份有限公司 | A method of preparing vitamine A acetate |
| CN111484525B (en) * | 2019-01-25 | 2023-01-06 | 新发药业有限公司 | Vitamin A ester intermediate C15 and preparation method of vitamin A ester |
| CN111484525A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Vitamin A ester intermediate C15 and preparation method of vitamin A ester |
| CN111484524B (en) * | 2019-01-25 | 2022-04-12 | 新发药业有限公司 | Vitamin A acetate intermediate C15 and preparation method of vitamin A acetate |
| CN111484524A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Vitamin A acetate intermediate C15 and preparation method of vitamin A acetate |
| CN111995555A (en) * | 2020-09-22 | 2020-11-27 | 江西天新药业股份有限公司 | Preparation method of vitamin A acetate |
| CN112876395A (en) * | 2021-01-15 | 2021-06-01 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
| CN112961088A (en) * | 2021-03-29 | 2021-06-15 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
| CN112961088B (en) * | 2021-03-29 | 2023-03-03 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
| DE112021007675T5 (en) | 2021-05-19 | 2024-03-07 | Wanhua Chemical Group Co., Ltd. | PRODUCTION PROCESS FOR VITAMIN A ACETATE |
| CN114315674A (en) * | 2021-12-13 | 2022-04-12 | 万华化学集团股份有限公司 | Process for preparing light-coloured vitamin A |
| WO2023108327A1 (en) * | 2021-12-13 | 2023-06-22 | 万华化学集团股份有限公司 | Preparation method for light-colored vitamin a |
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Denomination of invention: One-pot method for preparing vitamin A acetate Effective date of registration: 20220729 Granted publication date: 20140827 Pledgee: Industrial and Commercial Bank of China Co., Ltd. Dongying Kenli Sub-branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980011404 |