CN1090271A - A kind of chemical synthesis process of β-Hu Luobusu - Google Patents
A kind of chemical synthesis process of β-Hu Luobusu Download PDFInfo
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- CN1090271A CN1090271A CN 93117490 CN93117490A CN1090271A CN 1090271 A CN1090271 A CN 1090271A CN 93117490 CN93117490 CN 93117490 CN 93117490 A CN93117490 A CN 93117490A CN 1090271 A CN1090271 A CN 1090271A
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- luobusu
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Abstract
A kind of chemical synthesis process of β-Hu Luobusu.The inventive method comprises three steps, gets vitamin A by the VITAMIN acetic ester through the aqueous sodium hydroxide solution hydrolysis, makes axerophthal with oxygenant oxidation vitamin A again, makes β-Hu Luobusu by divalence titanium coupling axerophthal at last.Simple, the easy row of the inventive method route, cost is low, the yield height.
Description
The invention relates to the chemical synthesis process of β-Hu Luobusu, particularly relate to the synthetic and link coupled method of axerophthal.
In the prior art, from vitamin A is the synthetic β-Hu Luobusu of raw material, generally be to make vitamin A through hydrolysis, again it made phosphorus Yi Lide and axerophthal respectively, again phosphorus Yi Lide and axerophthal are carried out making β-Hu Luobusu after the Willg reaction at last with.See French Patent Er1383944, Deutsches Reichs-Patent Gerl148542 and the 2nd the 6th page of article of " medicine industry " the 16th volume for details.The reactions steps of the synthetic β-Hu Luobusu of prior art report is more at present, needed to divide four steps, use expensive and highly toxic triphenyl phosphine, the Willg reaction is restive for high thermopositive reaction, the product that the Willg reaction obtains is suitable often, transconfiguration has concurrently, still need and put in order, the total yield of whole process is lower.More than the yield of three pieces of reported in literature be respectively 19.11%, 21.36%, 26.07%.Being oxidized to the existing method for oxidation of axerophthal by vitamin A in addition, is not that oxygenant is difficult to preparation, the oxygenant substrate is bigger than too, is exactly that reaction raw materials costliness, yield are low, and severe reaction conditions, complexity besides see for details:
R.A.Morlon，et.al.，Biochem.J.42，518（1948）;
DE-A-2，4151928（1973）;
JP-A-63-233943;
Karrer，et.al.Helv.Chim.Acla，40，265（1957）;
Hawkins，et.al.J.Chem.SOC.，411（1944）;
EP-438052（1991）。
The object of the invention is to provide that a kind of route is simple, cost is low, the chemical synthesis process of the β-Hu Luobusu of high yield.
The present invention adopts to get vitamin A with the aqueous sodium hydroxide solution hydrolysis, the VITAMIN that obtains A oxygenant oxidation in certain solvent, get axerophthal through separation, purifying, the axerophthal that obtains with the coupling of divalence titanium gets β-Hu Luobusu through separation and purification again.The inventive method is simple and direct, only needs three-step reaction just can obtain product, and the oxygenant of use is inexpensive, be easy to get, and the oxygenant substrate is than little, has overcome oxygenant costliness in the prior art, is difficult to make, the oxygenant substrate is than too big defective.The total yield of β-Hu Luobusu is up to 61.5%, and is the alltrans structure, avoided in the prior art because of must be suitable, complex process that transconfiguration needs arrangement, simplified reactions steps greatly, thereby realized purpose of the present invention.
The inventive method divided for three steps carried out, and is specific as follows:
The first step: vitamin A is produced in the hydrolysis of
A certain amount of is dissolved in the alcoholic solvent, gets vitamin A with sodium hydroxide hydrolysis.
Second step: axerophthal is produced in the vitamin A oxidation
The vitamin A that will be obtained by the first step is used oxygenant CrO in solvent
3NR
1R
2R
3The HX oxidation makes axerophthal through separation, purifying.
Second goes on foot in the reaction at general formula CrO
3NR
1R
2R
3The oxygenant of HX, R
1, R
2, R
3Identical or different, R
1, R
2, R
3Can be CnH
2n+1The aliphatic hydrocarbon substituting group of (n=0～20) and aromatic hydrocarbon substituting group also can R
2R
3Can be-(CH
2) m-(m=4,5,6) ,-(CH
2) 2-A-(CH
2) 2-(A=0, NH, NMe, NEt, S) and substituting group.Also can NR
1R
2R
3Be pyridine and homologue.HX can be HCl, HBr, H
3PO
4, H
2SO
4, citric acid, fumaric acid and the polyprotonic acid mentioned acid salt.This oxygenant can be by CrO
3, NR
1R
2R
3, HX three makes this constituent earlier, or wherein the two constituent and the third party or three adds solvent respectively and evenly uses.
The solvent that the reaction of second step is used is water, aliphatic hydrocarbon (as sherwood oil, pentane, hexane, hexanaphthene), aliphatic ketone (as acetone), ethers (as ether, tetrahydrofuran (THF)), substituted amide (N, dinethylformamide, N,N-dimethylacetamide), at least a solvent in the aromatic hydrocarbon (as benzene,toluene,xylene), chloroparaffin (as methylene dichloride, chloroform), ester class (as ethyl acetate).
In the second step oxidizing reaction, the mol ratio of vitamin A and oxygenant is 1: 1.0～5.0, and wherein 1: 1.1～3.0 is preferred range; The weight ratio of vitamin A and solvent is 1: 5～100, and wherein 1: 10～50 is preferred range.Temperature of reaction is 0-150 ℃, considers the stability of reaction time and axerophthal, and 20-80 ℃ is preferred range.Reaction times is 0.5～36 hour.
In the oxidizing reaction in second step, the vitamin A solvent is also stirred in 1: 5～100 adding containers, add the oxygenant of aforementioned ratio then, add entry and extraction solvent during the reaction end.Extraction solvent is selected the wherein a kind of solvent in benzene, toluene, sherwood oil, ether, chloroform, methylene dichloride, the ethyl acetate for use, tell organic layer after, with salt washing, dried over mgso, concentrate after, by column chromatography or recrystallization purifying.
The 3rd step: axerophthal coupling system β-Hu Luobusu
The axerophthal that is obtained by second step is added to linked reaction in the ready made divalence titanium, obtains β-Hu Luobusu through separation and purification.
The divalence titanium is to be got with reductive agent (as lithium aluminum hydride, zinc powder) reduction by titanium salt (as titanium tetrachloride, titanium tetrabromide, titanous chloride) (as tetrahydrofuran (THF), dioxane) in solvent.
In the 3rd step linked reaction, temperature of reaction is 0-100 ℃, and wherein 20 ℃～80 ℃ is good.Axerophthal, reductive agent, titanium salt three's mol ratio is 1: 0.5～2.5: 2～5, wherein 1: 1～2: 2.5～4 the bests.The weight ratio of axerophthal and solvent is 1: 10～80 wherein 1: 20～60 for good.Reaction times was at 5-24 hour.
In the 3rd step linked reaction, earlier titanium salt reductive agent, solvent are added in the container by aforementioned ratio, after reaction makes the divalence titanium for some time, carry out linked reaction by adding axerophthal, when reaction finishes, add dilute hydrochloric acid or 10% solution of potassium carbonate and extraction solvent, extraction solvent can be benzene, toluene, chloroform, sherwood oil, hexane, hexanaphthene etc. tell organic layer after, through washing, dry, concentrated, with column chromatography or recrystallization purifying.Entire reaction is promptly to carry out under nitrogen, argon atmospher at anhydrous and oxygen-free,
The inventive method synthetic β-Hu Luo element is red crystallization or powder, fusing point is 180～182 ℃, and the ultraviolet maximum absorption is 497, the 466nm(chloroform), can be used for preparing the β-Hu Luobusu of various formulations (water-soluble dry powder, emulsion, oil solution), use for food, healthcare products, medicine.Compared with the prior art, the inventive method step is simple, and raw material sources are easy and cheap, solved the cost problem of higher that exists in the prior art, changed the complicated process of being made β-Hu Luobusu by vitamin A, overcome the low shortcoming of yield.
Embodiment 1: 3.3 gram s (10.0mmol) are dissolved in the 15ml methyl alcohol, add the 1.4ml50% aqueous sodium hydroxide solution, stir 1 hour at ambient temperature after, add entry and sherwood oil, tell organic layer, through washing, concentrate the thick vitamin A of 3.0 grams.
The thick vitamin A of 3.0 grams that is obtained by aforesaid method is dissolved in 30mlN, N, in the dinethylformamide, nitrogen atmosphere stirs and adds 3.0 gram CrO down
3H
2NCH
3HCl(11.0mmol) [organic chemistry 382(1992)] be dissolved in 10mlN, in the solution of dinethylformamide, stirring at room 10 hours adds entry and sherwood oil is told organic layer, through washing, concentrated, gets 2.50 gram axerophthals with the sherwood oil recrystallization at last.Fusing point is 60-2 ℃, and the ultraviolet maximum absorption is the 373nm(hexanaphthene).
In nitrogen atmosphere, 2.71 gram titanous chlorides (17.6mmol) are dissolved in the solution of 40ml anhydrous tetrahydro furan, divide three addings, 0.33 gram lithium aluminum hydride (8.8mmol) at room temperature to stir 4 hours, add 2.50 gram axerophthal (8.8mmol) 10ml anhydrous tetrahydrofuran solutions then, stirring at room 5 hours, add dilute hydrochloric acid and chloroform, tell organic layer, through washing, dry, concentrated, get 1.65 gram β-Hu Luobusus with benzene-recrystallizing methanol, total yield is 61.5%.
Embodiment 2: 3.3 gram s (10.0mmol) are dissolved in the 15ml methyl alcohol, add 1.4ml 50% aqueous sodium hydroxide solution, at room temperature stir 1 hour after, add entry and sherwood oil, tell organic layer, through washing, concentrate the thick vitamin A of 3.0 grams.
Earlier with 1.3 gram CrO
3(13.0mmol), 2.7 the gram dodecyl dimethyl amine (13.0mmol), 1.5 the gram (85%) phosphoric acid (13.0mmol) be dissolved in 10ml distilled water, be added to then 3.0 the gram thick vitamin A the 30ml acetone soln in, N
2Stirring at room adds entry and sherwood oil after 12 hours again under the atmosphere, tells organic layer, and through washing, dry, concentrated, (sherwood oil: ethyl acetate=4: 1) purifying gets 1.45 gram axerophthals to column chromatography.(fusing point is 60～61 ℃).
1.33 gram zinc powders (20.4mmol) are added in the anhydrous dioxane of 40ml, adding 1.95 gram titanium tetrachlorides (10.2mmol) under stirring in nitrogen atmosphere refluxed 10 hours, the anhydrous dioxane solution of 10ml that adds 1.45 gram axerophthals (5.1mmol) again, refluxed 4 hours, add 10% solution of potassium carbonate and chloroform, tell organic layer, through washing, dry, concentrated, column chromatography (sherwood oil: ethyl acetate=9: 1) purifying gets 1.10 gram β-Hu Luobusus, and total yield is 180-182 ℃ for the 41%(fusing point).
Claims (10)
1, a kind of chemical synthesis process of β-Hu Luobusu, it is characterized in that comprising following three steps: the first step gets vitamin A by with the aqueous sodium hydroxide solution hydrolysis, second step got axerophthal with the oxygenant oxidation through separation and purification with vitamin A in certain solvent, the 3rd step made β-Hu Luobusu with divalence titanium coupling axerophthal through separation and purification.
2, the chemical synthesis process of β-Hu Luobusu according to claim 1 is characterized in that the oxygenant general formula in described second step reaction is:
R wherein
1, R
2, R
3Identical or different, R
1, R
2, R
3Can be CnH
2n+1(n=0-20) aliphatic hydrocarbon substituting group or aromatic hydrocarbon substituting group, R
2R
3Can be-(CH
2) m-(m=4,5,6) or-(CH
2) 2-A-(CH
2) 2-(A=0, NH, NMe, NEt, S) and substituting group, also can NR
1R
2R
3Be pyridine and homologue, HX is HCl, HBr, H
3PO
4, H
2SO
4, citric acid, fumaric acid and the polyprotonic acid mentioned acid salt.
3, the chemical synthesis process of β-Hu Luobusu according to claim 1, it is characterized in that the solvent in described second step reaction is that water, aliphatic hydrocarbon (as sherwood oil, pentane, hexane, hexanaphthene), aromatic hydrocarbon (as benzene,toluene,xylene), aliphatic ketone (as acetone), ethers (as ether, tetrahydrofuran (THF)), substituted amide are (as N, dinethylformamide, N,N-dimethylacetamide), at least a in chloroparaffin (as methylene dichloride, chloroform), the ester class (as ethyl acetate).
4, the chemical synthesis process of β-Hu Luobusu according to claim 1 is characterized in that the mol ratio of vitamin A and oxygenant is 1: 1～5 in the second step reaction.
5, the chemical synthesis process of β-Hu Luobusu according to claim 1 is characterized in that the weight ratio of vitamin A and solvent is 1: 5～100 in the second step reaction.
6, according to the chemical synthesis process of claim 1 or 2 or 3 or 4 or 5 described β-Hu Luobusus, it is characterized in that the described second step temperature of reaction is 0-150 ℃, the reaction times is 0.5～36 hour.
7, the chemical synthesis process of β-Hu Luobusu according to claim 1, it is characterized in that the divalence titanium described in the described three-step reaction be by high price titanium salt (as titanium tetrachloride, titanium tetrabromide, titanous chloride etc.) in solvent (as tetrahydrofuran (THF), dioxane), make with reductive agent (as lithium aluminum hydride, zinc powder) reduction.
8, the chemical synthesis process of β-Hu Luobusu according to claim 1 is characterized in that vitamin A, the reductive agent in the described three-step reaction, the mol ratio of titanium salt are 1: 0.5～2.5: 2～5.
9, according to the chemical synthesis process of claim 1 or 7 or 8 described β-Hu Luobusus, it is characterized in that the temperature of described the 3rd step linked reaction is 0-100 ℃, the time is 5-24 hour.
10,, it is characterized in that described linked reaction is to carry out under anhydrous and oxygen-free (under nitrogen, the argon atmospher) condition according to the chemical synthesis process of claim 1 or 7 or 8 described β-Hu Luobusus.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100564356C (en) * | 2006-06-02 | 2009-12-02 | 浙江医药股份有限公司新昌制药厂 | The synthesis technique of β-Hu Luobusu |
| CN110483356A (en) * | 2019-08-28 | 2019-11-22 | 上海克琴科技有限公司 | A kind of synthetic method for the retinene that copper complex promotes |
| CN114534729A (en) * | 2022-03-07 | 2022-05-27 | 万华化学集团股份有限公司 | Catalyst, preparation method thereof and application thereof in preparing beta-carotene by electrochemical method |
| CN114957075A (en) * | 2022-06-13 | 2022-08-30 | 万华化学集团股份有限公司 | Preparation method of beta-carotene |
-
1993
- 1993-09-20 CN CN 93117490 patent/CN1090271A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100564356C (en) * | 2006-06-02 | 2009-12-02 | 浙江医药股份有限公司新昌制药厂 | The synthesis technique of β-Hu Luobusu |
| CN110483356A (en) * | 2019-08-28 | 2019-11-22 | 上海克琴科技有限公司 | A kind of synthetic method for the retinene that copper complex promotes |
| CN114534729A (en) * | 2022-03-07 | 2022-05-27 | 万华化学集团股份有限公司 | Catalyst, preparation method thereof and application thereof in preparing beta-carotene by electrochemical method |
| CN114534729B (en) * | 2022-03-07 | 2024-05-03 | 万华化学集团股份有限公司 | Catalyst, preparation method thereof and application of catalyst in preparation of beta-carotene by electrochemical method |
| CN114957075A (en) * | 2022-06-13 | 2022-08-30 | 万华化学集团股份有限公司 | Preparation method of beta-carotene |
| CN114957075B (en) * | 2022-06-13 | 2023-09-19 | 万华化学集团股份有限公司 | Preparation method of beta-carotene |
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