CN105130899A - Synthetic method for eslicarbazepine acetate - Google Patents
Synthetic method for eslicarbazepine acetate Download PDFInfo
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- CN105130899A CN105130899A CN201510535988.6A CN201510535988A CN105130899A CN 105130899 A CN105130899 A CN 105130899A CN 201510535988 A CN201510535988 A CN 201510535988A CN 105130899 A CN105130899 A CN 105130899A
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- synthetic method
- eslicarbazepine acetate
- eslicarbazepine
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- 0 Cc(cc1)ccc1*([C@@]([C@@](C(O[C@@](C1)c(cccc2)c2N(C(N)=O)c2c1cccc2)=O)*(c1ccc(C)cc1)=O)C(O)=O)=O Chemical compound Cc(cc1)ccc1*([C@@]([C@@](C(O[C@@](C1)c(cccc2)c2N(C(N)=O)c2c1cccc2)=O)*(c1ccc(C)cc1)=O)C(O)=O)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Abstract
The invention discloses a synthetic method for eslicarbazepine acetate. The synthetic method comprises the following steps: (1) carrying out a reduction reaction on oxcarbazepine under the action of a reducer to obtain licarbazepine; (2) splitting the licarbazepine obtained in the step (1) under the action of D-p-methyl diphenylethanedione tartrate and after splitting, carrying out post-treatment to obtain a compound V; (3) carrying out a hydrolysis reaction on the compound V obtained in the step (2) to obtain eslicarbazepine; and (4) carrying out an esterification reaction on the eslicarbazepine obtained in the step (3) and acetic acid, and after reaction, carrying out post-treatment to obtain eslicarbazepine acetate. By adopting a novel splitting agent, the preparation method simplifies the operating process and improves the reaction yield and product purity.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of synthetic method of eslicarbazepine acetate.
Background technology
Eslicarbazepine acetate, structure, as shown in formula I, is the prodrug of (S)-licarbazepine, and (S)-(+)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide is the major active metabolite product of oxcarbazepine, can blocking voltage dependency Na
+passage, compared with oxcarbazepine, the tolerance of eslicarbazepine acetate is better.
Publication number is the preparation method that the Chinese patent application of CN1543454A discloses a kind of eslicarbazepine, this preparation method is first by racemic licarbazepine and (2R, 3R)-two-O, O '-replacement tartrate anhydride reactant obtains a pair non-corresponding isomer, then water is added to precipitate the diastereomer not too dissolved, and by filtering separation, and then with the diastereomer that alkali catalyzed hydrolysis not too dissolves, obtain optically pure licarbazepine.Wherein, (2R, 3R) used-two-O, the structure of O '-replacement winestone acid anhydrides is shown below:
Wherein, R is C
1~ C
6alkyl or phenyl.This preparation method is simple to operate, and yield is higher, even if but the eslicarbazepine obtained have passed through complicated purification process, ee value is still not high enough.
Summary of the invention
The invention provides a kind of synthetic method of eslicarbazepine acetate, this synthetic method improves yield and the optical purity of product.
A synthetic method for eslicarbazepine acetate, comprises the following steps:
(1) oxcarbazepine carries out reduction reaction and obtains licarbazepine under the effect of reductive agent;
(2) licarbazepine that step (1) obtains splits under D-is to the effect of methyldiphenyl formyl winestone acid anhydrides, obtains compound V after having split through process later;
Described D-to the tartaric structure of methyldiphenyl formyl as shown in formula IV:
The structure of described compound V is such as formula shown in (V):
(3) the compound V that step (2) obtains obtains eslicarbazepine through hydrolysis reaction;
(4) eslicarbazepine that obtains of step (3) and acetic acid carry out esterification, obtain described eslicarbazepine acetate after reacting completely through process later.
In the present invention, D-is adopted to replace dibenzoyl tartaric acid acid anhydride of the prior art or diacetyl tartaric anhydride to methyldiphenyl formyl winestone acid anhydrides, have unexpectedly discovered that the purity of yield and product obtains larger raising, especially the ee value of the finished product is far above prior art.
Concrete reaction process is shown below:
As preferably, in step (1), described reductive agent is sodium borohydride;
Described reduction reaction is carried out in the mixed solvent of second alcohol and water;
The temperature of described reduction reaction is 10 ~ 15 DEG C.
As preferably, in step (2), described fractionation is carried out under the effect of DMAP and pyridine;
The temperature of described fractionation is 20 ~ 30 DEG C.
As preferably, in step (2), described fractionation is carried out in methylene dichloride;
Described aftertreatment comprises: in reaction solution, add water wash, then organic phase evaporate to dryness, and the product obtained is dissolved in heating for dissolving in acetonitrile, and then freezing and crystallizing, drying obtain described compound V.Adopt acetonitrile as the solvent of recrystallization, effectively can remove impurity, improve yield and the purity of compound V, and operating process is simple.
The consumption of acetonitrile is too much, and yield can be caused to decline, and consumption is very few, can reduce the purity of compound V, and then causes the ee value of product to decline, and as further preferred, the consumption of described acetonitrile and the amount ratio of licarbazepine are 4 ~ 6L:1kg.
As preferably, the temperature of freezing and crystallizing is-10 ~-5 DEG C, and the time of freezing and crystallizing is 10 ~ 15 hours.
As preferably, in step (3), described hydrolysis reaction, under the effect of sodium hydroxide, carries out in the mixed solvent of first alcohol and water.
As preferably, in step (4), described esterification is carried out under the effect of DMAP and pyridine;
The solvent of described esterification is methylene dichloride.
As preferably, in step (4), described aftertreatment comprises: reaction solution with hydrochloric acid and saturated sodium-chloride washing, obtains described eslicarbazepine acetate through recrystallization after decompression removing organic solvent successively.
As further preferred, described recrystallization comprises twice recrystallization: first use acetone recrystallization, and tetrahydrofuran (THF) recrystallization used again by the solid obtained.By twice recrystallization, the impurity in product can be reduced to greatest extent, improve the purity of product, meet medicinal standard.
Compared with the existing technology, the present invention, by adopting new resolving agent, simplifies operation steps, improves yield and the purity of resolved product, meet medicinal standard.
Embodiment
Embodiment 110-hydroxyl-10,11-dihydro-5H-dibenzo [b, f] azepine
the preparation of-5-methane amide (licarbazepine, III)
In the 50L reactor that electric mixer is housed, add 3.0kg (11.9mol) oxcarbazepine, 14L95% ethanol and 7L purified water, stir and make it dissolve.Under 10 ~ 15 DEG C of conditions, slowly in mixing solutions, add 360g (9.13mol) sodium borohydride (about 1h adds) in batches, continue stirring reaction after 10 minutes, be slowly warming up to 45 DEG C, insulation reaction 2 hours.TLC detects (ethyl acetate: methyl alcohol=2:3), after reaction terminates, reaction solution is cooled to 10 DEG C ~ 15 DEG C, slowly adds 5.2L acetone.Mixture, in 40 DEG C of underpressure distillation near dry, stirs and adds 13L purified water, having a large amount of solid to separate out, cooling crystallization.Filter, washing (2 × 1.5L water), gained solid, in 100 DEG C of dryings 6 ~ 8 hours, obtains white solid licarbazepine 3.0Kg, yield 99%, fusing point: 187 DEG C ~ 189 DEG C.
Embodiment 2 (2S, 3S)-4-[((S)-5-formamyl-10,11-dihydro-5H-dibenzo [b, f] azepine
-10-base) oxygen] preparation of-2,3-two ((4-methyl benzoyl) oxygen base)-4-oxygen bases butyric acid (V)
In the reactor that electric mixer is housed, add 15L methylene dichloride, 2.21kg (8.7mol) licarbazepine, 47g (0.38mol) DMAP, D-successively to methyldiphenyl formyl winestone acid anhydrides 3.64kg (9.88mol) stirring at room temperature 30min, drip 635g (8.03mol) pyridine.Mixture stirring reaction 24 hours under 20 DEG C of conditions, TLC detects after (ethyl acetate: methyl alcohol=3:2) reaction terminates and washes with water (10L × 2), and organic layer evaporated under reduced pressure obtains 5kg to white powder.Gained powder 11L acetonitrile heating for dissolving, stirs 1h, and refrigerator and cooled freezes 12h (-7 DEG C) left and right.Separate out solid suction filtration, filter cake is dried, and obtains white solid (2S, 3S)-4-[((S)-5-formamyl-10,11-dihydro-5H-dibenzo [b, f] azepine
-10-base) oxygen]-2,3-two ((4-methyl benzoyl) oxygen base)-4-oxygen base butyric acid 1.8kg, yield 61.5%.
Embodiment 3 (S)-10-hydroxyl-10,11-dihydro-5H-dibenzo [b, f] azepine
the preparation of-5-methane amide (eslicarbazepine, VI)
In the there-necked flask that electric mixer is housed, add 1.8kg (2.91mol) V, 3L methyl alcohol and 3L water and 140gNaOH, under room temperature condition, make its stirring reaction 2 hours.TLC detects (ethyl acetate: methyl alcohol=2:3), after reaction terminates, filters, washing (2 × 1L methyl alcohol), collects filtrate, concentrates steam methyl alcohol at about 45 DEG C.Under 10-15 DEG C of condition, in residuum, add 2L water, have a large amount of solid to separate out, cooling crystallization.Filter, washing (2 × 1L water), gained solid was in 45 DEG C of-50 DEG C of dryings 2 hours, and temperature rises to 100 DEG C of dry 6-8 hour, obtained white solid LKXP-VI 628g, and yield 85%, ee value is 96.7%, fusing point 186 DEG C-187 DEG C.
Embodiment 4 (S)-10-acetoxyl group-10,11-dihydro-5H-dibenzo [b, f] azepine
the preparation of-5-methane amide (eslicarbazepine acetate, LKXP-I)
In the 10L there-necked flask that electric mixer is housed, add 600g (2.36mol) V, 5L methylene dichloride, Acetyl Chloride 98Min. 222g (2.83mol), 29g (0.24mol) DMAP, 205g (2.59mol) pyridine (slowly dripping with constant pressure funnel) successively.Its stirring reaction 6 hours are made under 20 DEG C of-25 DEG C of conditions.After TLC detection (developping agent: ethyl acetate) reaction terminates, mixture first washs (2 × 1L) with the hydrochloric acid soln of 5%, then washs with saturated nacl aqueous solution 1L.Collect organic phase in 40 DEG C of underpressure distillation, obtain white solid.Gained solid adds 450ml acetone and heated and stirred is dissolved, suction filtration while hot, filtrate cooling crystallization.Filter, washing (2 × 100ml acetone), gained solid, in 60 DEG C of dry 6-8 hour, obtains white solid LKXP-I 580g, and yield 83%, ee value is 99.2%, fusing point: 183 DEG C-186 DEG C.
Comparative example: replace D-with D-dibenzoyl tartaric acid acid anhydride and contrast experiment is carried out to methyldiphenyl formyl winestone acid anhydrides, investigate the impact of different resolving agent on product.
Two (benzoyloxy)-4-(((S)-5-formamyl-10,11-dihydro-5H-dibenzo [b, the f] azepine of embodiment 5 (2S, 3S)-2,3-
-10-base) oxygen) preparation of-4-oxygen base butyric acid
In the reactor that electric mixer is housed, add 5L methylene dichloride, 0.74kg (2.9mol) licarbazepine, 15g (0.12mol) DMAP, D-dibenzoyl tartaric acid acid anhydride 1.15kg (3.38mol) stirring at room temperature 30min successively, drip 210g (2.65mol) pyridine.Mixture stirring reaction 24 hours under 20 DEG C of conditions, TLC detects after (ethyl acetate: methyl alcohol=3:2) reaction terminates and washes with water (5L × 2), and organic layer evaporated under reduced pressure obtains 1.5kg to white powder.Gained powder 3.8L acetonitrile heating for dissolving, stirs 1h, and refrigerator and cooled freezes 12h (-7 DEG C) left and right.Separate out solid suction filtration, filter cake is dried, and obtains two (benzoyloxy)-4-(((S)-5-formamyl-10,11-dihydro-5H-dibenzo [b, the f] azepine of white solid (2S, 3S)-2,3-
-10-base) oxygen)-4-oxygen base butyric acid 417g, yield 48.4%.
Embodiment 6 (S)-10-hydroxyl-10,11-dihydro-5H-dibenzo [b, f] azepine
the preparation of-5-methane amide (eslicarbazepine, VI)
In the there-necked flask that electric mixer is housed, add 417g (0.7mol) V, 1L methyl alcohol and 1L water and 35gNaOH, under room temperature condition, make its stirring reaction 2 hours.TLC detects (ethyl acetate: methyl alcohol=2:3), after reaction terminates, filters, washing (2 × 0.5L methyl alcohol), collects filtrate, concentrates steam methyl alcohol at about 45 DEG C.Under 10-15 DEG C of condition, in residuum, add 2L water, have a large amount of solid to separate out, cooling crystallization.Filter, washing (2 × 1L water), gained solid was in 45 DEG C of-50 DEG C of dryings 2 hours, and temperature rises to 100 DEG C of dry 6-8 hour, obtained white solid LKXP-VI 138g, and yield 77.5%, ee value is 33.4%, fusing point 186 DEG C-187 DEG C.
Claims (10)
1. a synthetic method for eslicarbazepine acetate, is characterized in that, comprises the following steps:
(1) oxcarbazepine carries out reduction reaction and obtains licarbazepine under the effect of reductive agent;
(2) licarbazepine that step (1) obtains splits under D-is to the effect of methyldiphenyl formyl winestone acid anhydrides, obtains compound V after having split through process later;
Described D-to the tartaric structure of methyldiphenyl formyl as shown in formula IV:
The structure of described compound V is such as formula shown in (V):
(3) the compound V that step (2) obtains obtains eslicarbazepine through hydrolysis reaction;
(4) eslicarbazepine that obtains of step (3) and acetic acid carry out esterification, obtain described eslicarbazepine acetate after reacting completely through process later.
2. the synthetic method of eslicarbazepine acetate according to claim 1, is characterized in that, in step (1), described reductive agent is sodium borohydride;
Described reduction reaction is carried out in the mixed solvent of second alcohol and water;
The temperature of described reduction reaction is 10 ~ 15 DEG C.
3. the synthetic method of eslicarbazepine acetate according to claim 1, is characterized in that, in step (2), described fractionation is carried out under the effect of DMAP and pyridine;
The temperature of described fractionation is 20 ~ 30 DEG C.
4. the synthetic method of eslicarbazepine acetate according to claim 1, is characterized in that, in step (2), described fractionation is carried out in methylene dichloride;
Described aftertreatment comprises: in reaction solution, add water wash, then organic phase evaporate to dryness, and the product obtained is dissolved in heating for dissolving in acetonitrile, and then freezing and crystallizing, drying obtain described compound V.
5. the synthetic method of eslicarbazepine acetate according to claim 4, is characterized in that, the consumption of described acetonitrile and the amount ratio of licarbazepine are 4 ~ 6L:1kg.
6. the synthetic method of eslicarbazepine acetate according to claim 4, is characterized in that, the temperature of freezing and crystallizing is-10 ~-5 DEG C, and the time of freezing and crystallizing is 10 ~ 15 hours.
7. the synthetic method of eslicarbazepine acetate according to claim 1, is characterized in that, in step (3), described hydrolysis reaction, under the effect of sodium hydroxide, carries out in the mixed solvent of first alcohol and water.
8. the synthetic method of eslicarbazepine acetate according to claim 1, is characterized in that, in step (4), described esterification is carried out under the effect of DMAP and pyridine;
The solvent of described esterification is methylene dichloride.
9. the synthetic method of eslicarbazepine acetate according to claim 1, it is characterized in that, in step (4), described aftertreatment comprises: reaction solution with hydrochloric acid and saturated sodium-chloride washing, obtains described eslicarbazepine acetate through recrystallization after decompression removing organic solvent successively.
10. the synthetic method of eslicarbazepine acetate according to claim 9, is characterized in that, described recrystallization comprises twice recrystallization: first use acetone recrystallization, and tetrahydrofuran (THF) recrystallization used again by the solid obtained.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1193965A (en) * | 1995-06-30 | 1998-09-23 | 波特拉和卡公司 | 10-acyloxy-10,11-dihydrodibenz/b, f/azepine-5-carboxamides useful for treating nervous system disorders |
| CN1543454A (en) * | 2001-05-11 | 2004-11-03 | Method for preparation of (s)-(+)-and(r)-(-)10,11-dihydro-10-hydrodoxy-5h-dibenz/b,f/azephine-5-carboxamide | |
| CN1823047A (en) * | 2003-05-12 | 2006-08-23 | 坡特拉有限公司 | Method for racemisation of (S)-(+)- and (R)-(-)-10,11-dihydro-10-hydroxy-5h-dibenz[b,f]azepine-5-carboxamide and optically enriched mixtures thereof |
| WO2010113179A2 (en) * | 2009-04-02 | 2010-10-07 | Glenmark Generics Limited | A process for the purification of eslicarbazepine acetate |
| CN102465159A (en) * | 2010-11-15 | 2012-05-23 | 浙江九洲药物科技有限公司 | Synthesis process for preparing eslicarbazepine with microbial method |
| WO2012120356A2 (en) * | 2011-03-08 | 2012-09-13 | Jubilant Life Sciences Limited | Process for the preparation of (s)-(+)-or (r)-(-)-10 hydroxy dihydrodibenz[b,f]azepines by enantioselective reduction of 10, 11-dihydro-10-oxo-5h-dibenz[b,f]azepines and polymorphs thereof |
| WO2013008194A2 (en) * | 2011-07-13 | 2013-01-17 | Ranbaxy Laboratories Limited | Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof |
| WO2014049550A1 (en) * | 2012-09-26 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate |
-
2015
- 2015-08-25 CN CN201510535988.6A patent/CN105130899A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1193965A (en) * | 1995-06-30 | 1998-09-23 | 波特拉和卡公司 | 10-acyloxy-10,11-dihydrodibenz/b, f/azepine-5-carboxamides useful for treating nervous system disorders |
| CN1543454A (en) * | 2001-05-11 | 2004-11-03 | Method for preparation of (s)-(+)-and(r)-(-)10,11-dihydro-10-hydrodoxy-5h-dibenz/b,f/azephine-5-carboxamide | |
| CN1823047A (en) * | 2003-05-12 | 2006-08-23 | 坡特拉有限公司 | Method for racemisation of (S)-(+)- and (R)-(-)-10,11-dihydro-10-hydroxy-5h-dibenz[b,f]azepine-5-carboxamide and optically enriched mixtures thereof |
| WO2010113179A2 (en) * | 2009-04-02 | 2010-10-07 | Glenmark Generics Limited | A process for the purification of eslicarbazepine acetate |
| CN102465159A (en) * | 2010-11-15 | 2012-05-23 | 浙江九洲药物科技有限公司 | Synthesis process for preparing eslicarbazepine with microbial method |
| WO2012120356A2 (en) * | 2011-03-08 | 2012-09-13 | Jubilant Life Sciences Limited | Process for the preparation of (s)-(+)-or (r)-(-)-10 hydroxy dihydrodibenz[b,f]azepines by enantioselective reduction of 10, 11-dihydro-10-oxo-5h-dibenz[b,f]azepines and polymorphs thereof |
| WO2013008194A2 (en) * | 2011-07-13 | 2013-01-17 | Ranbaxy Laboratories Limited | Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof |
| WO2014049550A1 (en) * | 2012-09-26 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate |
Non-Patent Citations (2)
| Title |
|---|
| 刘友平等: "《理化基本技能训练》", 31 August 2014 * |
| 陈建超: "Eslicarbazepine acetate", 《中国药物化学杂质》 * |
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Application publication date: 20151209 |