CN105085276A - Eltrombopag intermediate and preparation method therefor and application thereof - Google Patents
Eltrombopag intermediate and preparation method therefor and application thereof Download PDFInfo
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- CN105085276A CN105085276A CN201410198050.5A CN201410198050A CN105085276A CN 105085276 A CN105085276 A CN 105085276A CN 201410198050 A CN201410198050 A CN 201410198050A CN 105085276 A CN105085276 A CN 105085276A
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Abstract
The present invention provides a novel preparation method for an eltrombopag intermediate. The raw materials of the intermediate is easily available, and the preparation method therefor is simple and high in safety; According to a reaction step section for preparing eltrombopag by using a novel intermediate, the yield is as twice as that in the prior art, so that the cost is lowered significantly, and the method is suitable for large-scale industrial production application. (img file='DDA0000503880400000011.TIF'wi='488'he='336'/).
Description
Technical field
The present invention relates to preparation method's technical field of eltrombopag olamine.
Background technology
Eltrombopag olamine is small molecules, non-peptide thrombopoietin (TPO) receptor stimulant of stimulating megakaryocyte propagation and differentiation.Eltrombopag olamine with the form of di-methylcarbinol amine salt by GlaxoSmithKline and LigandPharmaceuticals with trade(brand)name
sell, be used for the treatment of and cause thrombocytopenic disease.The chemical name of eltrombopag olamine is 3'-{ (2Z)-2-[1-(3,4-3,5-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazoles-4-subunit] diazanyl }-2'-hydroxyl-3-biphenyl acid, there is following chemical structure:
Its synthetic route of synthetic method disclosing a kind of eltrombopag olamine in US Patent No. 2004019190A1 is as follows:
This method is with 3'-amino-2'-hydroxyl-[1,1'-biphenyl]-3-carboxylic acid (formula 1 compound) is raw material, under first acidic conditions condition, diazotization obtains diazonium salt, again in the basic conditions with 3-methyl isophthalic acid-(3,4-3,5-dimethylphenyl)-2-pyrazolin-5-one (formula 2 compound) is obtained by reacting 3'-{ (2Z)-2-[1-(3,4-3,5-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazoles-4-subunit] diazanyl }-2'-hydroxyl-3-biphenyl acid (i.e. eltrombopag olamine).
But the defect of aforesaid method is that formula (1) compound is as the important source material preparing eltrombopag olamine; industrial goods commercially not cheap at present can be bought; and in prior art disclosed in US Patent No. 2004019190A1; its synthetic method is for raw material with 2-nitro-6-bromophenol; phenolic hydroxyl group is protected with iodomethane reaction; again with the coupling of 3-Carboxybenzeneboronic acid, then in Hydrogen bromide deprotection, last palladium carbon catalytic hydrogenation obtains formula 1 compound.This method need use severe toxicity and the methyl iodide not easily bought, step is more, and suzuki coupling yield is only 47%, and total recovery is only 28%, is not suitable for large-scale industrial production.
Therefore need to develop a kind of raw material to be easy to get, safety, the method for what yield was high prepare eltrombopag olamine intermediate.
Summary of the invention
Object of the present invention is just to solve prior art problem, provides a kind of new eltrombopag olamine intermediate, uses this intermediate synthesis eltrombopag olamine to overcome the above-mentioned defect of prior art, be very suitable for the large production of industry, and yield is higher than existing method.
Another object of the present invention is to provide new eltrombopag olamine Intermediate Preparation method and application.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
Prepare the new intermediate of eltrombopag olamine, i.e. the new compound (V) of following formula:
The preparation method of new compound 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid (V), the method is that the bromo-3-oil of mirbane of 2-benzyloxy-1-and 3-Carboxybenzeneboronic acid generation suzuki coupling obtain:
Above-mentioned 3'-amino-2'-hydroxyl-[1,1'-biphenyl] preparation method of-3-carboxylic acid, suzuki linked reaction selects palladium catalyst, described palladium catalyst can be palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, tetrakis triphenylphosphine palladium or other catalyzer be applicable to; Preferably [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, the reaction times is short, and yield is high.The solvent used comprises the mixed solvent etc. of toluene, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane etc. and water, and the mixed solvent of preferred Isosorbide-5-Nitrae-dioxane and water, effectively can improve yield.The alkali used comprises sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide and potassium hydroxide etc., preferred sodium carbonate or salt of wormwood.
The preparation method of above-mentioned new compound (V), further, there is nucleophilic substitution reaction and obtain in raw material 2-benzyloxy-1-bromo-3-oil of mirbane through type 2-nitro-6-bromophenol and halogen benzyl, wherein X represents Br or Cl in the basic conditions
The solvent used in above-mentioned nucleophilic reaction comprises ester class, methylene dichloride, tetrahydrofuran (THF), toluene and acetonitrile etc., preferred acetonitrile.Alkali used can be sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide etc., preferred sodium carbonate or salt of wormwood.Suitable solvent and alkali further can improve the yield of target product.
When above-mentioned new compound (V) is for the preparation of eltrombopag olamine, comprise the steps:
1) 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid hydrogenation and debenzylation under Pd/C catalysis is obtained 3'-amino-2'-hydroxyl-[1,1'-biphenyl]-3-carboxylic acid
2) 3'-amino-2'-hydroxyl-[1,1'-biphenyl] diazotization obtains diazonium salt under the first acidic conditions condition of-3-carboxylic acid, target product eltrombopag olamine is obtained by reacting in the basic conditions again with 3-methyl isophthalic acid-(3,4-3,5-dimethylphenyl)-2-pyrazolin-5-one (formula 2 compound)
The applying step 1 of new compound (V)) reaction time, target carbon amounts is more, and the reaction times is shorter.
Beneficial effect of the present invention: the invention provides a kind of newly prepare eltrombopag olamine intermediate, this intermediate feed is easy to get, and preparation method is simple, and security is high; Utilize the reactions steps section of new Intermediate Preparation eltrombopag olamine, yield is that the twice of prior art is many, has greatly saved cost, is applicable to industrial large-scale production and application.
Embodiment
The preparation of the bromo-3-oil of mirbane of embodiment 1-3:2-benzyloxy-1-
2-nitro-6-bromophenol 10.9g (50mmol), it is little of reacting completely that cylite 9g (52mmol), salt of wormwood 7.6g (55mmol) are blended in back flow reaction 3 in acetonitrile (120ml), is cooled to room temperature, filter, be concentrated into and dryly obtain enriched material, add ethyl acetate (100ml) and dissolve, with water (50ml), saturated aqueous common salt (50ml) is washed, drying, is concentrated into and dryly obtains yellow crystals 15g, yield 97.4%.
2-nitro-6-bromophenol (4.36g), cylite (3.6g), salt of wormwood (4.14g) are mixed with tetrahydrofuran (THF) (50ml), return stirring 3 hours, cooling, filter, filtrate is concentrated into dry, add ethyl acetate (30ml) and water (50ml), separatory, aqueous layer with ethyl acetate (30ml × 2) extracts, and merges organic layer, washing, saturated common salt is washed, dry, filters, concentrate and obtain title compound 2-benzyloxy-1-bromo-3-oil of mirbane 5.9g, yield 95.7%.
2-nitro-6-bromophenol (13.08g), cylite (10.8g), salt of wormwood (12.42g) are mixed with acetonitrile (150ml), return stirring 3 hours, cooling, filter, filtrate is concentrated into dry, add ethyl acetate (90ml) and water (150ml), separatory, aqueous layer with ethyl acetate (70ml × 2) extracts, and merges organic layer, washing, saturated common salt is washed, dry, filters, concentrate and obtain title compound 2-benzyloxy-1-bromo-3-oil of mirbane 18.1g, yield 97.9%.
1HNMR(400MHz,CDCl
3)δ7.86(dd,J＝8.0,1.6Hz,1H),7.81(dd,J＝8.2,1.5Hz,1H),7.58(dd,J＝7.7,1.4Hz,2H),7.47–7.37(m,3H),7.18(t,J＝8.1Hz,1H),5.23(s,2H).ESI-MS(m/z):331[M+Na]
+
The preparation of embodiment 4-5:3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid
By the compound 12.32g (40mmol) obtained in embodiment 1; 3-Carboxybenzeneboronic acid 7.97g (48mmol); salt of wormwood 8.28g (60mmol); [1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride 2.04g (2.8mmol); be blended in 1; in 4-dioxane (200ml) and water (40ml), 60 DEG C of nitrogen protections react 4 hours; cold filtration, concentrates Isosorbide-5-Nitrae-dioxane; add water (100ml); adjust PH to acid with 1mol/L dilute hydrochloric acid, have solid to separate out, filter and obtain dark brown solid 14g.With Virahol (60ml) and water (20ml) recrystallization, finally obtain hazel-color solid 11.5g, yield 82.4%.
1HNMR(400MHz,CDCl3)δ8.30(s,1H),8.18(d,J＝7.7Hz,1H),7.85(d,J＝7.7Hz,1H),7.81(dd,J＝8.1,1.4Hz,1H),7.62(dd,J＝7.6,1.3Hz,1H),7.55(t,J＝7.7Hz,1H),7.33(t,J＝7.9Hz,1H),7.26–7.20(m,3H),7.05(dd,J＝6.6,2.5Hz,2H),4.66(s,2H).ESI-MS(m/z):348[M-H]
-
The bromo-3-oil of mirbane (12.32g) of 2-benzyloxy-1-, 3-Carboxybenzeneboronic acid (7.97g), sodium carbonate (6.36g), palladium (0.63) are blended in 1; in 4-dioxane (200ml) and water (40ml), 60 DEG C of nitrogen protections react 12 hours; cold filtration; concentrate 1; 4-dioxane, add water (100ml), adjusts PH to acid with 1mol/L dilute hydrochloric acid; there is solid to separate out, filter and obtain crude product 7.3g.With Virahol (60ml) and water (20ml) recrystallization, finally obtain title compound 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid 5.1g, yield 36.5%.
The preparation of embodiment 6-7:3'-amino-2'-hydroxyl-[1,1'-biphenyl]-3-carboxylic acid
Be dissolved in ethyl acetate (350ml) by the compound 10.47g (30mmol) obtained in embodiment 4, add 10% palladium carbon 1.05g, 50 DEG C of logical hydrogen reactions of pressurization 10 hours, cooling, filters, and is concentrated into dryly to obtain yellow solid 6.6g.Yield 96%.
1HNMR(400MHz,DMSO-d
6)δ8.08(s,1H),7.93(d,J＝7.7Hz,1H),7.73(d,J＝7.8Hz,1H),7.58(t,J＝7.7Hz,1H),7.44(dd,J＝7.8Hz,1H),7.26(dd,J＝7.7,1.4Hz,1H),7.04(t,J＝7.8Hz,1H).ESI-MS(m/z):228[M-H]
-
Be dissolved in ethyl acetate (350ml) by the compound 10.47g (30mmol) obtained in embodiment 4, add 10% palladium carbon 2.1g, 50 DEG C of logical hydrogen reactions of pressurization 8 hours, cooling, filters, and is concentrated into dryly to obtain yellow solid 6.7g.Yield 97.5%.
Embodiment 8: the preparation of eltrombopag olamine
By 3'-amino-2'-hydroxyl-[1, 1'-biphenyl]-3-carboxylic acid (4.58g) joins in the hydrochloric acid (60ml) of 1mol/L and the mixing solutions of methyl alcohol (75ml), stirring at room temperature 30 minutes, then cooling solution to 0 ~ 5 DEG C, the aqueous solution 15ml containing Sodium Nitrite (1.38g) is added in 20 minutes, guarantee in adition process, the temperature of reaction solution is no more than 10 DEG C, about 5 DEG C stirred reaction mixtures 1 hour, slowly rise to room temperature, about adjusting pH to 7 ~ 8 with triethylamine, by 3-methyl isophthalic acid-(3, 4-3,5-dimethylphenyl)-2-pyrazolin-5-one (4g) is disposable adds in reaction mixture, stirred at rt for another 2 hours, about adding 1mol/L hydrochloric acid tune PH to 1 ~ 2 under stirring, be settled out solid, filter, wash filter cake with water, drying obtains orange title compound 8.4g (yield 95%).
1HNMR(400MHz,DMSO-d
6))δ8.13(s,1H),7.96(d,J＝7.8Hz,1H),7.79(d,J＝7.8Hz,1H),7.74–7.68(m,2H),7.61(t,J＝7.8Hz,2H),7.19(d,J＝8.3Hz,1H),7.17–7.12(m,2H),2.32(s,3H),2.26(s,3H),2.22(s,3H).ESI-MS(m/z):443[M+H]
+。
Claims (12)
1. the compound (V) of following formula:
The preparation method of 2.3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid, the method is that the bromo-3-oil of mirbane of 2-benzyloxy-1-and 3-Carboxybenzeneboronic acid generation suzuki coupling obtain:
3. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 2, it is characterized in that, suzuki linked reaction selects palladium catalyst.
4. 3'-nitro-2'-benzyloxy-[1 as claimed in claim 3,1'-biphenyl] preparation method of-3-carboxylic acid, it is characterized in that, palladium catalyst is palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride or tetrakis triphenylphosphine palladium.
5. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 4, is characterized in that, palladium catalyst is [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride.
6. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 2, is characterized in that, the mixed solvent that the solvent that reaction uses is Isosorbide-5-Nitrae-dioxane and water.
7. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 2, is characterized in that, the alkali that reaction uses is sodium carbonate or salt of wormwood.
8. as claim 2-7 arbitrarily as described in 3'-nitro-2'-benzyloxy-[1,1'-biphenyl] preparation method of-3-carboxylic acid, it is characterized in that, there is nucleophilic substitution reaction and obtain in raw material 2-benzyloxy-1-bromo-3-oil of mirbane through type 2-nitro-6-bromophenol and halogen benzyl, wherein X represents Br or Cl in the basic conditions
9. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 8, is characterized in that reacting the solvent used is acetonitrile.
10. the preparation method of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid as claimed in claim 8, is characterized in that reacting the alkali used is sodium carbonate or salt of wormwood.
11. compounds (V) are for the preparation of eltrombopag olamine.
12. compounds according to claim 11 (V) are for the preparation of eltrombopag olamine, and it comprises the steps:
1) 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid hydrogenation and debenzylation under Pd/C catalysis is obtained 3'-amino-2'-hydroxyl-[1,1'-biphenyl]-3-carboxylic acid
2) 3'-amino-2'-hydroxyl-[1,1'-biphenyl] diazotization obtains diazonium salt under the first acidic conditions condition of-3-carboxylic acid, target product eltrombopag olamine is obtained by reacting in the basic conditions again with 3-methyl isophthalic acid-(3,4-3,5-dimethylphenyl)-2-pyrazolin-5-one (formula 2 compound)
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107021928A (en) * | 2017-04-01 | 2017-08-08 | 常州制药厂有限公司 | New intermediate of eltrombopag olamine and its preparation method and application |
| CN107915678A (en) * | 2017-08-30 | 2018-04-17 | 孙婷婷 | A kind of preparation method for the medicine eltrombopag olamine for being used to treat Idiopathic Thrombocytopenic Purpura |
| CN108101845A (en) * | 2016-11-25 | 2018-06-01 | 苏州科伦药物研究有限公司 | A kind of preparation method of Ai Qu pools pa |
| CN108191763A (en) * | 2018-02-10 | 2018-06-22 | 扬子江药业集团四川海蓉药业有限公司 | A kind of synthetic method of Ai Qu pools pa ethanol amine |
| CN109096195A (en) * | 2018-09-27 | 2018-12-28 | 上海雅本化学有限公司 | A kind of preparation method of eltrombopag olamine |
| CN110526870A (en) * | 2019-09-29 | 2019-12-03 | 天津力生制药股份有限公司 | A kind of preparation method of eltrombopag olamine |
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| WO2013049605A1 (en) * | 2011-09-28 | 2013-04-04 | Assia Chemical Industries Ltd. | Processes for the preparation of an intermediate in the synthesis of eltrombopag |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108101845A (en) * | 2016-11-25 | 2018-06-01 | 苏州科伦药物研究有限公司 | A kind of preparation method of Ai Qu pools pa |
| CN108101845B (en) * | 2016-11-25 | 2020-05-15 | 苏州科伦药物研究有限公司 | Preparation method of eltrombopag |
| CN107021928A (en) * | 2017-04-01 | 2017-08-08 | 常州制药厂有限公司 | New intermediate of eltrombopag olamine and its preparation method and application |
| CN107021928B (en) * | 2017-04-01 | 2022-11-18 | 常州制药厂有限公司 | Eltrombopag intermediate, preparation method and application thereof |
| CN107915678A (en) * | 2017-08-30 | 2018-04-17 | 孙婷婷 | A kind of preparation method for the medicine eltrombopag olamine for being used to treat Idiopathic Thrombocytopenic Purpura |
| CN108191763A (en) * | 2018-02-10 | 2018-06-22 | 扬子江药业集团四川海蓉药业有限公司 | A kind of synthetic method of Ai Qu pools pa ethanol amine |
| CN109096195A (en) * | 2018-09-27 | 2018-12-28 | 上海雅本化学有限公司 | A kind of preparation method of eltrombopag olamine |
| CN110526870A (en) * | 2019-09-29 | 2019-12-03 | 天津力生制药股份有限公司 | A kind of preparation method of eltrombopag olamine |
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Application publication date: 20151125 |