CN103058850B - A kind of method preparing A Li vitamin A acid - Google Patents
A kind of method preparing A Li vitamin A acid Download PDFInfo
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- CN103058850B CN103058850B CN201110322676.9A CN201110322676A CN103058850B CN 103058850 B CN103058850 B CN 103058850B CN 201110322676 A CN201110322676 A CN 201110322676A CN 103058850 B CN103058850 B CN 103058850B
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- pdcl
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- compound
- vitamin
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- SHGAZHPCJJPHSC-YCNIQYBTSA-N CC1(C)C(/C=C/C(/C)=C/C=C/C(/C)=C/C(O)=O)=C(C)CCC1 Chemical compound CC1(C)C(/C=C/C(/C)=C/C=C/C(/C)=C/C(O)=O)=C(C)CCC1 SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N CC1(C)C(/C=C/C(/C)=C\C=C\C(\C)=C\C(O)=O)=C(C)CCC1 Chemical compound CC1(C)C(/C=C/C(/C)=C\C=C\C(\C)=C\C(O)=O)=C(C)CCC1 SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
Abstract
The invention provides a kind of method of preparation I compound: formula II, under palladium compound catalysis, in organic solvent isomerization reaction occurs, and obtains formula I.Present method is easy and simple to handle, and cost is low, and condition is controlled, is convenient to industrial production; After post-processing step, can obtain the A Li vitamin A acid of purity more than 99%, product yield reaches more than 12%.
Description
Technical field
The present invention relates to a kind of method preparing A Li vitamin A acid, particularly relating to a kind of all-trans-retinoic acid is that raw material prepares the method for A Li vitamin A acid through isomerization reaction.
Background technology
A Li vitamin A acid (formula I) is the important drugs for the treatment of dermatological field, and its chemistry is by name: 3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene-1-base)-2E, 4E, 6Z, 8E-nona tetraenoic acid is all-trans-retinoic acid (formula II, chemical name: 3,7-dimethyl-9-(2,6,6-trimethyl cyclohexene-1-base)-2E, 4E, 6E, 8E-alltrans nona tetraenoic acid) 9-along isomer.
Because A Li vitamin A acid (formula I) only exists different from all-trans-retinoic acid (formula II) in sterie configuration, therefore, can with formula II compound as Material synthesis A Li vitamin A acid.
(Bioorganic & Medicinal Chemistry Letter, vol.4, No.2 in prior art, p349-350,1994), adopt photochemical reaction, under tungsten lamp illuminate condition, formula II compound is refluxed in chromatographically pure acetonitrile, obtain A Li vitamin A acid.
The method has following shortcoming:
1, cost is high, and adopt chromatographically pure acetonitrile to be solvent, cost is higher;
2, complicated operation, is difficult to control effectively to illumination condition, limits 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 is only 5%.
Therefore, be necessary to provide a kind of easy and simple to handle, cost is lower and the applicable industrial method preparing A Li vitamin A acid.
Summary of the invention
The object 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 a kind of method that cost is lower, simple to operate, reaction conditions is easy to control; Further object is that the product yield that the method is obtained is higher, purity is better.
The present inventor finds through experiment, and under catalytic condition, all-trans-retinoic acid in a solvent isomerization reaction can occur, and obtains A Li vitamin A acid, and this reaction can be carried out in common technical grade solvent, thus solves the problems referred to above.
Technical scheme of the present invention is as follows:
By the method for formula II preparation of compounds of formula I, it is characterized in that:
Under palladium compound catalysis, there is isomerization reaction in formula II, obtains formula I in organic solvent; In described palladium compound, the existence form of palladium is zeroth order, divalence or tetravalence.
In 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 with raw material dosage ratio (mol ratio) is: palladium catalyst: formula II compound=0.0001 ~ 0.02: 1.
Described organic solvent does not need to be particularly limited to, and can be technical grade organic solvent, as long as can dissolve 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 is too low, and isomerized speed is slow, and reaction efficiency is low; Temperature is too high, and isomerized speed is fast, and impurity easily increases.Preferred temperature of reaction is 30 ~ 80 DEG C, can reach good reaction efficiency, and preferred temperature of reaction is 50 ~ 60 DEG C.
Above-mentionedly prepare in the method for A Li vitamin A acid, can be higher by increasing the A Li vitamin A acid purity that post-processing step makes to obtain.As reaction solution placed 5 ~ 180 minutes at 0 DEG C ~ 20 DEG C, 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 DEG C ~-2 DEG C, 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 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; After 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
With the form of embodiment, technical scheme of the present invention is illustrated below, but does not limit content of the present invention.
In embodiment 1 ~ 4, the purity of product adopts high performance liquid chromatography (HPLC) to measure, and chromatographic condition is as follows:
Chromatographic column: Waters ODS (4.6x 150mm, 3 μm)
Moving phase: methanol-water-glacial acetic acid (800: 225: 5)
Flow velocity: 1ml/min
Column temperature: 30 DEG C
Determined wavelength: 355nm
The preparation (one) of embodiment 1 formula I
Under nitrogen protection, in reaction flask, add ethanol 2L, all-trans-retinoic acid 100g, stir, be then warming up to 50 ~ 55 DEG C, add PdCl2 89mg.After reaction 1.5h, detecting product purity through HPLC is 21%.Reaction solution slow cooling to 0 ~ 5 DEG C, are incubated 180 minutes, suction filtration; Filtrate adds in another clean reaction flask, continues to be cooled to-10 ~-6 DEG C, and be incubated 20 minutes, suction filtration, obtains product 12.1g, total recovery 12.1%, HPLC purity 99.60%.
The preparation (two) of embodiment 2 formula I
Under nitrogen protection, add propyl propionate 3.5L, all-trans-retinoic acid 100g in reaction flask, stir, be then warming up to 30 ~ 35 DEG C, add (Et3P) 4Pd (0) 80mg, after reaction 2h, detecting product purity through HPLC is 20.3%.Reaction solution slow cooling to 2 ~ 5 DEG C, be incubated 10 minutes, suction filtration, filtrate adds in another clean reaction flask, continues to be cooled to-20 ~-16 DEG C, and be incubated 60 minutes, suction filtration, obtains product 11.0g, and total recovery is 11.0%, HPLC purity 99.49%.
The preparation (three) of embodiment 3 formula I
Under nitrogen protection, add ethyl formate 2L, all-trans-retinoic acid 100g in reaction flask, stir, be then warming up to 75 ~ 80 DEG C, add K2PdCl6300mg, after reaction 1.5h, detecting product purity through HPLC is 20.1%.Reaction solution slow cooling to 15 ~ 20 DEG C, be incubated 50 minutes, suction filtration, filtrate adds in another clean reaction flask, continues to be cooled to-5 ~-9 DEG C, and be incubated 360 minutes, 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 acid (formula I)
Under nitrogen protection, suction ethyl acetate 900L in retort, then adds raw material all-trans-retinoic acid 45kg from tank mouth; stir, be then warming up to 55 ~ 60 DEG C, add Pd (OAc) 240g; after reaction 2.5h, detecting product purity through HPLC is 21.3%.Reaction solution slow cooling to 10 ~ 14 DEG C, are incubated 30 minutes, centrifugal, in another clean retort of filtrate suction, continue to be cooled to-6 ~-2 DEG C, are incubated 160 minutes, centrifugal, and obtain product 5.53kg, total recovery is 12.3%, HPLC purity 99.58%.
Claims (8)
1. be the method for raw material preparation I compound with formula II compound, it is characterized in that:
Under palladium compound catalysis, there is isomerization reaction in formula II, obtains formula I in organic solvent;
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, (CH3CN)
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;
The mol ratio of described palladium compound and raw material is:
Palladium compound: formula II compound=0.0001 ~ 0.02: 1.
2. method according to claim 1, described palladium compound is selected from PdCl
2, (Et
3p)
4pd (0), K
2pdCl
6or Pd (OAc)
2.
3. method according to claim 1, described organic solvent is selected from C
1-5 alkyl alcohols or C
2-8alkyl ester in one or more.
4. method according to claim 1, described organic solvent be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol, methyl-formiate, ethyl formate, ethyl acetate, methyl propionate, ethyl propionate or propyl propionate one or more.
5. method according to claim 1, described isomerization reaction temperature is 30 ~ 80 DEG C.
6. method according to claim 1, described isomerization reaction temperature is 50 ~ 60 DEG C.
7. method according to claim 1, the post-treating method of reaction product is: placed 5 ~ 180 minutes at 0 DEG C ~ 20 DEG C by reaction solution, filters, and collects the filtrate containing formula I.
8. method according to claim 7, the post-treating method of reaction product is: described filtrate placed 5 ~ 360 minutes at-20 DEG C ~-2 DEG C, filters, and collects filter cake, obtains formula I.
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|---|---|---|---|
| CN201110322676.9A CN103058850B (en) | 2011-10-21 | 2011-10-21 | A kind of method preparing A Li vitamin A acid |
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|---|---|---|---|
| CN201110322676.9A CN103058850B (en) | 2011-10-21 | 2011-10-21 | A kind of method preparing A Li vitamin A acid |
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| CN103058850A CN103058850A (en) | 2013-04-24 |
| CN103058850B true CN103058850B (en) | 2015-10-28 |
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| 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 |
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 |
|---|
| 烯烃光敏顺反异构化反应;游长江等;《感光科学与光化学》;20030223;第21卷(第02期);147-155页 * |
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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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