CN103058850A - Method for preparing alitretinoin - Google Patents
Method for preparing alitretinoin Download PDFInfo
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- CN103058850A CN103058850A CN2011103226769A CN201110322676A CN103058850A CN 103058850 A CN103058850 A CN 103058850A CN 2011103226769 A CN2011103226769 A CN 2011103226769A CN 201110322676 A CN201110322676 A CN 201110322676A CN 103058850 A CN103058850 A CN 103058850A
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- compound
- pdcl
- formula
- palladium compound
- organic solvent
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Abstract
The invention provides a method for preparing a compound disclosed as Formula I. Under the catalytic action of a palladium compound, a compound disclosed as Formula is subjected to isomerization reaction in an organic solvent to obtain the compound disclosed as Formula I. The method is simple to operate, has the advantages of low cost and controllable conditions, and is convenient for industrial production. After the after-treatment steps, the alitretinoin with the purity of higher than 99% can be obtained, and the product yield is up to higher than 12%.
Description
Technical field
The present invention relates to a kind of method of the A Li of preparation vitamin A acid, particularly relating to a kind of is raw material prepares the A Li vitamin A acid through isomerization reaction method with all-trans-retinoic acid.
Background technology
A Li vitamin A acid (formula I) is the important drugs in treatment tetter field, and its chemistry is by name: 3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene-1-yl)-and 2E, 4E, 6Z, the 8E-nona tetraenoic acid is all-trans-retinoic acid (formula II, chemical name: 3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene-1-yl)-2E, 4E, 6E, 8E-alltrans nona tetraenoic acid) 9-along isomer.
Because A Li vitamin A acid (formula I) is only different in the sterie configuration existence from all-trans-retinoic acid (formula II), therefore, can be with formula II compound as the synthetic A Li vitamin A acid of raw material.
(Bioorganic ﹠amp in the prior art; Medicinal Chemistry Letter, vol.4, No.2, p349-350,1994), adopt photochemical reaction, under the tungsten lamp illuminate condition, formula II compound is refluxed in chromatographically pure acetonitrile, obtain the A Li vitamin A acid.
The method has following shortcoming:
1, cost is high, and adopting chromatographically pure acetonitrile is solvent, and cost is higher;
2, complicated operation is difficult to illumination condition is control effectively, and has limited its application in suitability for industrialized production;
3, yield is low, and product purity is low: the product purity that the method obtains is 97.8%, and yield only is 5%.
Therefore, be necessary to provide a kind of easy and simple to handle, cost is lower and the method for the suitable industrial A Li of preparation vitamin A acid.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, preparing in the process of A Li vitamin A acid (formula I) for raw material with all-trans-retinoic acid (formula II), find the method that a kind of cost is lower, simple to operate, reaction conditions is easy to control; Further purpose is that the product yield that the method is obtained is higher, purity is better.
The inventor finds that through experiment under catalytic condition, all-trans-retinoic acid can isomerization reaction occur in solvent, obtains the A Li vitamin A acid, and this reaction can be carried out in common technical grade solvent, thereby has solved the problems referred to above.
Technical scheme of the present invention is as follows:
Method with formula II compound preparation I compound is characterized in that:
Isomerization reaction occurs in formula II in organic solvent under palladium compound catalysis, obtain formula I; The existence form of palladium is zeroth order, divalence or tetravalence in the described palladium compound.
Among the above-mentioned preparation method, described palladium compound is selected from PdCl
2, PdBr
2, PdI
2, PdF
2, Pd (NO
3)
4(NH
4)
2, Pd (NH
3)
2Cl
2, Pd (OAc)
2, (PhCN)
2PdCl
2, PdS, (CH
3CN)
2PdS
2, K
2PdCl
6, Pd (NH
3)
2(NO
2)
2, Pd (NO
2)
4(NH
3)
2, (PhCN)
2PdBr
2, (NH
4)
2PdCl
4, (NH
4)
2PdCl
6, (Ph
3P)
4Pd (0), (Et
3P)
4Pd (0), (Ph
3P)
3PdCl
2Or Pd (NO
3)
2, its consumption is catalytic amount;
Preferred catalyzer and raw material amount ratio (mol ratio) are: palladium catalyst: formula II compound=0.0001～0.02: 1.
Described organic solvent does not need to be particularly limited, and can be the technical grade organic solvent, as long as can dissolve the raw material all-trans-retinoic acid, can be selected from C
1-5Alkyl alcohol or C
2-8Alkyl ester in one or more, be specifically as follows methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol, methyl-formiate, ethyl formate, ethyl acetate, methyl propionate, ethyl propionate or propyl propionate; Preferred organic solvent is ethyl acetate.
Described isomerization reaction, temperature are too low, and isomerized speed is slow, and reaction efficiency is low; Temperature is too high, and isomerized speed is fast, and impurity increases easily.Preferred temperature of reaction is 30～80 ℃, can reach preferably reaction efficiency, and preferred temperature of reaction is 50～60 ℃.
In the above-mentioned method for preparing the A Li vitamin A acid, can make the A Li vitamin A acid purity that obtains higher by increasing post-processing step.As reaction solution being placed 5～180 minutes at 0 ℃～20 ℃, filter, collect filtrate, obtain the A Li vitamin A acid of higher degree; Above-mentioned filtrate can also be placed 5-360 minute at-20 ℃～-2 ℃, filter, collect filter cake, obtain more highly purified A Li vitamin A acid.
Method provided by the invention take all-trans-retinoic acid as raw material, adopts palladium compound catalysis, can obtain the A Li vitamin A acid in common technical grade organic solvent.Method is easy and simple to handle, and cost is low, and condition is controlled, is convenient to industrial production; Through behind the post-processing step, can obtain the A Li vitamin A acid of purity more than 99%, product yield reaches more than 12%, has higher using value.
Embodiment
The below is illustrated technical scheme of the present invention with the form of embodiment, but does not limit content of the present invention.
The purity of product adopts high performance liquid chromatography (HPLC) to measure among the embodiment 1～4, and chromatographic condition is as follows:
Chromatographic column: Waters ODS (4.6x 150mm, 3 μ m)
Moving phase: methanol-water-glacial acetic acid (800: 225: 5)
Flow velocity: 1ml/min
Column temperature: 30 ℃
Detect wavelength: 355nm
The preparation (one) of embodiment 1 formula I compound
Under nitrogen protection, in reaction flask, add ethanol 2L, all-trans-retinoic acid 100g, stir, then be warming up to 50～55 ℃, add PdCl2 89mg.Behind the reaction 1.5h, detecting product purity through HPLC is 21%.Reaction solution slow cooling to 0～5 ℃ are incubated 180 minutes, suction filtration; Filtrate adds in another clean reaction flask, continues to be cooled to-10～-6 ℃, is incubated 20 minutes, and suction filtration obtains product 12.1g, total recovery 12.1%, HPLC purity 99.60%.
The preparation (two) of embodiment 2 formula I compounds
Under nitrogen protection, in reaction flask, add propyl propionate 3.5L, all-trans-retinoic acid 100g, stir, then be warming up to 30～35 ℃, add (Et3P) 4Pd (0) 80mg, behind the reaction 2h, detecting product purity through HPLC is 20.3%.Reaction solution slow cooling to 2～5 ℃ are incubated 10 minutes, suction filtration, and filtrate adds in another clean reaction flask, continues to be cooled to-20～-16 ℃, is incubated 60 minutes, and suction filtration obtains product 11.0g, and total recovery is 11.0%, HPLC purity 99.49%.
The preparation (three) of embodiment 3 formula I compounds
Under nitrogen protection, in reaction flask, add ethyl formate 2L, all-trans-retinoic acid 100g, stir, then be warming up to 75～80 ℃, add K2PdCl6300mg, behind the reaction 1.5h, detecting product purity through HPLC is 20.1%.Reaction solution slow cooling to 15～20 ℃ are incubated 50 minutes, suction filtration, and filtrate adds in another clean reaction flask, continues to be cooled to-5～-9 ℃, is incubated 360 minutes, and suction filtration obtains product 11.3g, and total recovery is 11.3%, HPLC purity 99.38%.
Embodiment 4 suitability for industrialized production A Li vitamin A acids (formula I compound)
Under nitrogen protection, then suction ethyl acetate 900L in the retort adds raw material all-trans-retinoic acid 45kg from the tank mouth, stirs, and then is warming up to 55～60 ℃, adds Pd (OAc) 240g, and behind the reaction 2.5h, detecting product purity through HPLC is 21.3%.Reaction solution slow cooling to 10～14 ℃ are incubated 30 minutes, and are centrifugal, in another clean retort of filtrate suction, continue to be cooled to-6～-2 ℃, are incubated 160 minutes, centrifugal, obtain product 5.53kg, and total recovery is 12.3%, HPLC purity 99.58%.
Claims (10)
1. be the method for raw material preparation I compound with formula II compound, it is characterized in that:
Isomerization reaction occurs in formula II in organic solvent under palladium compound catalysis, obtain formula I;
The existence form of palladium is zeroth order, divalence or tetravalence in the described palladium compound.
2. method claimed in claim 1, described palladium compound is selected from PdCl
2, PdBr
2, PdI
2, PdF
2, Pd (NO
3)
4(NH
4)
2, Pd (NH
3)
2Cl
2, Pd (OAc)
2, (PhCN)
2PdCl
2, PdS, (CH
3CN)
2PdS
2, K
2PdCl
6, Pd (NH
3)
2(NO
2)
2, Pd (NO
2)
4(NH
3)
2, (PhCN)
2PdBr
2, (NH
4)
2PdCl
4, (NH
4)
2PdCl
6, (Ph
3P)
4Pd (0), (Et
3P)
4Pd (0), (Ph
3P)
3PdCl
2Or Pd (NO
3)
2
3. method claimed in claim 1, described palladium compound is selected from PdCl
2, (Et
3P)
4Pd (0), K
2PdCl
6Or Pd (OAc)
2
4. claim 2 or 3 described methods, the mol ratio of described palladium compound and raw material is:
Palladium compound: formula II compound=0.0001～0.02: 1.
5. method claimed in claim 1, described organic solvent is selected from C
1-5Alkyl alcohol or C
2-8Alkyl ester in one or more.
6. method claimed in claim 1, described organic solvent is selected from one or more in methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol, methyl-formiate, ethyl formate, ethyl acetate, methyl propionate, ethyl propionate or the propyl propionate.
7. method claimed in claim 1, described isomerization reaction temperature is 30～80 ℃.
8. method claimed in claim 1, described isomerization reaction temperature is 50～60 ℃.
9. method claimed in claim 1, the post-treating method of reaction product is: reaction solution was placed 5～180 minutes at 0 ℃～20 ℃, filtered, collect the filtrate that contains formula I compound.
10. method claimed in claim 9, the post-treating method of reaction product is: described filtrate was placed 5～360 minutes at-20 ℃～-2 ℃, filter, collect filter cake, obtain formula I compound.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110322676.9A CN103058850B (en) | 2011-10-21 | 2011-10-21 | A kind of method preparing A Li vitamin A acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110322676.9A CN103058850B (en) | 2011-10-21 | 2011-10-21 | A kind of method preparing A Li vitamin A acid |
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| Publication Number | Publication Date |
|---|---|
| CN103058850A true CN103058850A (en) | 2013-04-24 |
| CN103058850B CN103058850B (en) | 2015-10-28 |
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| CN201110322676.9A Active CN103058850B (en) | 2011-10-21 | 2011-10-21 | A kind of method preparing A Li vitamin A acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610252A (en) * | 2016-12-12 | 2018-10-02 | 重庆华邦胜凯制药有限公司 | The new method of Acitretin acid isomerization |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4556518A (en) * | 1982-12-10 | 1985-12-03 | Hoffmann-La Roche Inc. | Preparation of 13-cis retinoic acid |
| WO1994022818A1 (en) * | 1993-04-05 | 1994-10-13 | Pfizer Inc. | Method for the preparation of 9-cis retinoic acid |
| CN101265181A (en) * | 2007-11-05 | 2008-09-17 | 重庆胜凯科技有限公司 | Isomerization method for substituted aromatic nonatetraenes derivatives |
| CN101774954A (en) * | 2009-01-12 | 2010-07-14 | 重庆胜凯科技有限公司 | Method for preparing all-trans tretinoin |
-
2011
- 2011-10-21 CN CN201110322676.9A patent/CN103058850B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4556518A (en) * | 1982-12-10 | 1985-12-03 | Hoffmann-La Roche Inc. | Preparation of 13-cis retinoic acid |
| WO1994022818A1 (en) * | 1993-04-05 | 1994-10-13 | Pfizer Inc. | Method for the preparation of 9-cis retinoic acid |
| CN101265181A (en) * | 2007-11-05 | 2008-09-17 | 重庆胜凯科技有限公司 | Isomerization method for substituted aromatic nonatetraenes derivatives |
| CN101774954A (en) * | 2009-01-12 | 2010-07-14 | 重庆胜凯科技有限公司 | Method for preparing all-trans tretinoin |
Non-Patent Citations (1)
| Title |
|---|
| 游长江等: "烯烃光敏顺反异构化反应", 《感光科学与光化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610252A (en) * | 2016-12-12 | 2018-10-02 | 重庆华邦胜凯制药有限公司 | The new method of Acitretin acid isomerization |
| CN108610252B (en) * | 2016-12-12 | 2022-03-08 | 重庆华邦胜凯制药有限公司 | Novel method for isomerizing abamectin A acid |
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| Publication number | Publication date |
|---|---|
| CN103058850B (en) | 2015-10-28 |
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Address after: 401121 No. 666 Rongjun Road, Nanjin Street Subdistrict Office, Hechuan District, Chongqing Patentee after: Chongqing Huapont Pharm. Co., Ltd. Address before: 401121 No. 666 Rongjun Road, Nanjin Street Subdistrict Office, Yubei District, Chongqing Patentee before: Chongqing Huapont Pharm. Co., Ltd. |
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