CN101774954B - Method for preparing all-trans tretinoin - Google Patents
Method for preparing all-trans tretinoin Download PDFInfo
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- CN101774954B CN101774954B CN 200910076646 CN200910076646A CN101774954B CN 101774954 B CN101774954 B CN 101774954B CN 200910076646 CN200910076646 CN 200910076646 CN 200910076646 A CN200910076646 A CN 200910076646A CN 101774954 B CN101774954 B CN 101774954B
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- retinoic acid
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Abstract
The invention provides a method for transforming 11-cis-tretinoin into all-trans tretinoin, which is characterized by using a palladium nitrate composite catalyst. The invention also provides a method for synthesizing the all-trans tretinoin, which comprises the following steps of: using compounds (II) and (III) as raw materials to perform WITTIG reaction under the action of alkali so as to obtain a mixture of all-trans retinoic acid ester and 11-cis-retinoic acid ester; performing hydrolysis and acidification to obtain a mixture of the all-trans tretinoin and an isomer 11-cis-tretinoin; and transforming the isomer to obtain the target product namely the all-trans tretinoin. The method can be finished by two steps and has the advantages of complete reaction, high yield, less isomer content in the finished product and low cost, and is suitable for industrial production.
Description
Technical field:
The present invention relates to the preparation method of all-trans-retinoic acid, particularly a kind of 11-cis-retinoic acid is made the transition is the method for all-trans-retinoic acid.
Background technology:
All-trans-retinoic acid is the metabolic intermediate of vitamin A, has multiple pharmacological effect, and its Chinese name is called 3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene)-2,4,6,8 alltrans nona tetraenoic acids, and structural formula is suc as formula I:
The preparation of present disclosed all-trans-retinoic acid mainly contains following several method:
It is raw material that US3746730 discloses with dimension A acetic ester, through hydrolysis, directly obtains all-trans-retinoic acid through the silver suboxide oxidation again, and this method yield is low, the cost height, and serious three wastes is not suitable for suitability for industrialized production.
The technology of 0563825 couple of above-mentioned US3746730 of European patent EP is improved, and is raw material with dimension A acetic ester, and hydrolysis obtains tieing up A under the effect of alkali, obtains tieing up A aldehyde through oxidation, obtains all-trans-retinoic acid through the hypochlorite oxidation again, as shown in the formula:
Though whole process is relatively stable, whole process total recovery has only 40-45%, the cost height, and content is low.Prior art also has other method can synthesize vitamin A acid, though overcome the deficiency of above method, the product that obtains all is mixtures of all-trans-retinoic acid and isomer 11-cis-retinoic acid ester, and content of isomer is higher.By the synthetic vitamin A acid ester of WITTIG reaction, hydrolysis obtains the mixture of alltrans and 11-cis vitamin A acid as patent DE1068710, crosses preparative column then and isolates isomer.Like this, surplus all-trans-retinoic acid yield is low, cost height, and operational difficulty.
Therefore, be a long felt need for a kind of easy to operately, yield is higher, and lower-cost method, obtains all-trans-retinoic acid, to adapt to suitability for industrialized production at the isomer 11-cis-retinoic acid transition with being mixed in the all-trans-retinoic acid.
Summary of the invention:
The purpose of this invention is to provide a kind of preparation all-trans-retinoic acid method, wherein most important purpose provides and a kind of 11-cis-retinoic acid transition is the method for all-trans-retinoic acid, and is more easy to operate than the method for prior art, and cost is lower, yield is higher.
Vitamin A acid isomer method transition provided by the invention is to be all-trans-retinoic acid with the composite catalyst of Palladous nitrate with 11-cis-retinoic acid transition.
Concrete operation method is to add the Palladous nitrate complex catalyst in the solution of reactant, 20-60 ℃ of reaction 1～10 hour, steams partial solvent, and cooling crystallization filters and obtains all-trans-retinoic acid; Described reactant is the 11-cis-retinoic acid, or the mixture of all-trans-retinoic acid and 11-cis-retinoic acid ester.
Described Palladous nitrate composite catalyst is that the mol ratio of each component is in the Palladous nitrate composite catalyst with Palladous nitrate, triphenylphosphine, triethylamine and acetonitrile formulated mixture by a certain percentage:
Palladous nitrate: triphenylphosphine: triethylamine=1: 4～30: 2～20,
Optimum ratio is: Palladous nitrate: triphenylphosphine: triethylamine=1: 6: 4.
The consumption mol ratio of the Palladous nitrate in isomer 11-cis-retinoic acid and the Palladous nitrate composite catalyst is 1: 0.01～1%, preferred 1: 0.05～0.5%.
During reaction, described Palladous nitrate composite catalyst is added in the organic solvent, add in the reaction system again.In embodiments of the invention, will carry out in the Palladous nitrate composite catalyst adding acetonitrile.
The preferred 45-55 of temperature of reaction ℃.
The present invention also provides a kind of synthetic all-trans-retinoic acid method, and step is:
(a) be raw material with compound (II) and β-formyl radical crotonate (III), the mixture that the WITTIG reaction obtains all-trans-retinoic acid ester (IV) and isomer 11-cis-retinoic acid ester (V) takes place under the effect of alkali;
The structural formula of formula II compound and formula III compound is as follows:
In the formula II compound, X is halogen, as Cl, Br, I, F;
In the formula III compound, R is C1～C4 alkyl, and preferred R is normal-butyl, i.e. β-positive butyl ester of formyl radical Ba Dousuan.
(b) mixture that obtains of step (a) obtains the mixture of target product all-trans-retinoic acid (I) and isomer 11-cis-retinoic acid (VI) through hydrolysis, acidifying; Isomer 11-cis-retinoic acid VI obtains the target product all-trans-retinoic acid through transition.
Following formula is the reaction formula of an example of the present invention:
In the step (a), ester is selected from methyl esters, ethyl ester, propyl ester or butyl ester described in β-formyl radical crotonate;
Described alkali is oxyhydroxide, sodium alkoxide or carbonate.Described oxyhydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide; Sodium alkoxide such as sodium methylate, sodium ethylate; Carbonate such as salt of wormwood, yellow soda ash; Preferred alkali is potassium hydroxide;
Reaction solvent is alcohol, and as ethanol, Virahol, methyl alcohol etc., the consumption of alcohol is 1～5 times of reactant volume;
Temperature of reaction is-20 ℃～0 ℃, 1～4 hour reaction times.After finishing, reaction with in the reactant impouring water, extracts, washing, and decompression steams solvent, obtains the mixture of IV and V.
In the step (b), described hydrolysis can be undertaken by this area usual method, carries out as heating under the effect of alkali; Reaction solvent is alcohol/water mixed solvent, and wherein alcohol is selected from methyl alcohol, ethanol, Virahol, preferred Virahol; Described alkali is sodium hydroxide;
With the acid neutralization, with the ethyl acetate extraction washing, drying obtains the ethyl acetate solution (abbreviation mixed acid solution) of I and VI then after the hydrolysis, is used for transition in step down.
Described isomer is undertaken by the composite catalyst of preceding method with Palladous nitrate transition.
After method of the present invention had solved C15-WITTIG salt and β-formyl radical crotonate generation WITTIG reaction, gained isomers product was difficult to the problem of separation.In one embodiment of the invention, the transformation efficiency of isomer 11-cis-retinoic acid reaches more than 90%.
Present method only two the step can synthesize all-trans-retinoic acid, react completely, the yield height, cost is low, content height (isomer is few) is suitable for suitability for industrialized production, is specific embodiment below:
Embodiment:
The preparation of the mixture of embodiment 1 all-trans-retinoic acid (I) and 11-cis-retinoic acid (VI)
Under the condition of logical nitrogen; 500.4g [3-methyl-5-(2; 6; 6-trimethylammonium-1-tetrahydrobenzene-1-yl)-2; the 4-pentadiene]-β-formyl radical butyl crotonate of triphenylphosphine villaumite (WITTIG salt) and 187g is dissolved in the Virahol of 1947ml; be cooled to-10 ℃; drip the potassium hydroxide aqueous isopropanol of the 2N of 1250ml; temperature remains between-10～0 ℃ during dropping; finish, reacted 1 hour, reaction soln is added in the water; Petroleum ether extraction with 2 * 1000ml; merge organic layer, use 2 * 300ml water washing then, decompression steams solvent; obtain the brown oily liquids of 325g (yield 99.0%), detect through HPLC and comprise 61% all-trans-retinoic acid butyl ester and 36.1% 11-cis-retinoic acid butyl ester.
Under the condition of logical nitrogen, the mixture 325g of the above-mentioned all-trans-retinoic acid butyl ester that makes and 11-cis-retinoic acid butyl ester is dissolved in the Virahol of 980ml, 25% the sodium hydroxide solution that adds 222g, be heated to 80 ℃, reacted 3 hours, TLC detection reaction terminal point (sherwood oil: ethyl acetate=8: 1), in the impouring 1980ml water, use the 1000ml Petroleum ether extraction then, water layer is with 3N hydrochloric acid pH3.5～4.5 that neutralize, with 2 * 800ml ethyl acetate extraction, saturated salt washing, anhydrous magnesium sulfate drying, filter, obtain mixed acid solution, detect through HPLC, contain all-trans-retinoic acid 151g in the solution, 11-cis-retinoic acid 89g.
Embodiment 2 11-cis-retinoic acids make the transition and are all-trans-retinoic acid ()
Under the condition of logical nitrogen, the mixed acid solution that makes by embodiment 1 is heated to 50 ℃, the mixture that adds 330mg Palladous nitrate, 2160mg triphenylphosphine, 1600mg triethylamine and 250ml acetonitrile then, reacting 1 hour, is the 11-cis-retinoic acid of 95.3% all-trans-retinoic acid and 1.1% through the HPLC detected result, and decompression steams 600～700g solvent, cool to 0 ℃, be incubated 2 hours, filter the 226.2g all-trans-retinoic acid, HPLC detection level 99.6%.
Embodiment 3 11-cis-retinoic acids make the transition and are all-trans-retinoic acid (two)
Under the condition of logical nitrogen, the mixed acid solution that makes by embodiment 1 is heated to 50 ℃, the mixture that adds 116mg Palladous nitrate, 796mg triphenylphosphine, 528mg triethylamine and 132ml acetonitrile then, reacting 2 hours, is the 11-cis-retinoic acid of 93.3% all-trans-retinoic acid and 3.1% through the HPLC detected result, and decompression steams 600～700g solvent, cool to 0 ℃, be incubated 2 hours, filter the 214.2g all-trans-retinoic acid, HPLC detection level 99.6%.
Embodiment 4 11-cis-retinoic acids make the transition and are all-trans-retinoic acid (three)
Under the condition of logical nitrogen, the mixed acid solution that makes by embodiment 1 is heated to 50 ℃, the mixture that adds 52.8mg Palladous nitrate, 480mg triphenylphosphine, 1156mg triethylamine and 1420ml acetonitrile then, reacting 4.5 hours, is the 11-cis-retinoic acid of 84.3% all-trans-retinoic acid and 11.8% through the HPLC detected result, and decompression steams 600～700g solvent, cool to 0 ℃, be incubated 2 hours, filter the 192.5g all-trans-retinoic acid, HPLC detection level 99.5%.
Embodiment 5 11-cis-retinoic acids make the transition and are all-trans-retinoic acid (four)
Under the condition of logical nitrogen, the mixed acid solution that makes by embodiment 1 is heated to 30 ℃, the mixture that adds 26.4mg Palladous nitrate, 480mg triphenylphosphine, 1156mg triethylamine and 1420ml acetonitrile then, reacting 8 hours, is the 11-cis-retinoic acid of 76.6% all-trans-retinoic acid and 19.5% through the HPLC detected result, and decompression steams 600～700g solvent, cool to 0 ℃, be incubated 2 hours, filter the 179.1g all-trans-retinoic acid, HPLC detection level 98.5%.
Claims (7)
1. the synthetic method of an all-trans-retinoic acid, step is:
(a) be raw material with formula II compound and formula III compound, reaction obtains the mixture of all-trans-retinoic acid ester and isomer 11-cis-retinoic acid ester under the effect of alkali;
Among the formula II, X is halogen;
In the formula III, R is C1～C4 alkyl;
(b) mixture that obtains of step (a) obtains the mixture of target product all-trans-retinoic acid and isomer 11-cis-retinoic acid through hydrolysis, acidifying, and the isomer 11-cis-retinoic acid that is mixed in the all-trans-retinoic acid is obtained the target product all-trans-retinoic acid transition;
It is characterized in that: isomer 11-cis-retinoic acid reaction transition Palladous nitrate composite catalyst, described Palladous nitrate composite catalyst is the mixture of Palladous nitrate, triphenylphosphine, triethylamine, and the mol ratio of each component is: Palladous nitrate: triphenylphosphine: triethylamine=1:4～30:2～20.
2. the described method of claim 1, in the formula III compound, R is normal-butyl; Alkali is oxyhydroxide, sodium alkoxide or carbonate described in the step (a).
3. claim 1 or 2 described methods, the mol ratio of each component is in the described Palladous nitrate composite catalyst: Palladous nitrate: triphenylphosphine: triethylamine=1:6:4.
4. claim 1 or 2 described methods, the mol ratio of the Palladous nitrate consumption in 11-cis-retinoic acid and the Palladous nitrate composite catalyst is 1:0.05～0.5%.
5. claim 1 or 2 described methods add described Palladous nitrate composite catalyst in the organic solvent earlier, add in the reaction system again.
6. the described method of claim 5, described organic solvent is acetonitrile.
7. claim 1 or 2 described methods, transition, temperature of reaction was 45 ℃～55 ℃.
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102775338B (en) | 2011-05-13 | 2016-09-21 | 重庆华邦胜凯制药有限公司 | All-trans-retinoic acid synthetic method |
| CN103058850B (en) * | 2011-10-21 | 2015-10-28 | 重庆华邦胜凯制药有限公司 | A kind of method preparing A Li vitamin A acid |
| CN102558007B (en) * | 2011-12-31 | 2014-02-26 | 湖南师范大学 | Synthetic method of all-trans vitamin A acid medicament |
| CN111499662B (en) * | 2020-04-26 | 2022-12-20 | 上海新华联制药有限公司 | Isotretinoin C15-triphenylphosphine chloride and preparation method and application thereof |
| CN113214126B (en) * | 2021-05-19 | 2023-07-25 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1068710B (en) * | 1958-08-06 | 1959-11-12 | Badische Anilin- &. Soda-Fabrik Aktiengesellschaft, Ludwigshafen/Rhein | Process for the preparation of compounds of the beta-ionylidene ethylidene series |
| US4556518A (en) * | 1982-12-10 | 1985-12-03 | Hoffmann-La Roche Inc. | Preparation of 13-cis retinoic acid |
-
2009
- 2009-01-12 CN CN 200910076646 patent/CN101774954B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1068710B (en) * | 1958-08-06 | 1959-11-12 | Badische Anilin- &. Soda-Fabrik Aktiengesellschaft, Ludwigshafen/Rhein | Process for the preparation of compounds of the beta-ionylidene ethylidene series |
| US4556518A (en) * | 1982-12-10 | 1985-12-03 | Hoffmann-La Roche Inc. | Preparation of 13-cis retinoic acid |
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