CN104725318A - Synthetic method of eltrombopag olamine - Google Patents
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a synthetic method of eltrombopag olamine. The synthetic method comprises following steps: (a) o-nitrophenol and N-bromosuccinimide are subjected to bromination so as to obtain 2-bromo-6-nitrophenol; (b) under catalytic action of 10% Pd/C, 2-bromo-6-nitrophenol and 3-carboxybenzeneboronic acid are subjected to Suzuki coupling so as to obtain 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid; (c) ammonium formate is taken as a hydrogen donor, and under catalytic action of 10% Pd/C, 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid is obtained; (d) 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid is subjected to diazotization at low temperature, and then is subjected to coupling with intermediate 2-(3,4-dimethyl phenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one so as to obtain eltrombopag olamine; and (e) 3,4-dimethylphenylhydrazine hydrochloride and ethyl acetoacetate are subjected to dehydration condensation so as to obtain intermediate 2-(3,4-dimethyl phenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one. Reaction route of the synthetic method is simple; raw materials are cheap and easily available; reaction conditions are mild and are easy to control; production cost is low; and the synthetic method is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of methodology of organic synthesis, relate to a kind of synthetic method liking bent uncle's handkerchief specifically.
Background technology
Love bent uncle handkerchief (the eltrombopag olamine of GlaxoSmithKline PLC company of Britain exploitation, commodity are called Promacta) Chinese chemical name: 3c-{ (2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazoles-4-subunit] diazanyl }-2c-hydroxyl-3-biphenyl acid-2-monoethanolamine salt (1:2); Molecular formula:
C25H22N4O4; Relative molecular mass: 564.65; CAS registration number: 496775-61-2.Obtain FDA approval in U.S.'s listing in November, 2008, be used for the treatment of or Postsplenectomy chronic idiopathic thrombocytopenic purpura (ITP) patient invalid through glucocorticoid medicine, immunoglobulin therapy.Approval on November 19th, 2012 small molecules thrombopoietin receptor agonist eltrombopag(trade(brand)name: Promacta) treat for the thrombocytopenia of patients with chronic hepatitis C.Other local medicine beyond the U.S. is called Revolade.
At present, the synthesis of the love of bibliographical information bent uncle handkerchief is had to mainly contain following several method:
Two are reported about liking that the synthetic route methods of bent uncle's handkerchief are shown in following formula in the CN01813340 patent that Smithkline Beecham Corp applied in China in calendar year 2001:
Wherein route 1 take o-bromophenol as starting raw material, finally obtains through nitric acid nitrating, Suzuki coupling, nitro hydro-reduction and the chemosynthesis of diazo coupling reaction four step with bent ripple handkerchief finished product.This operational path step is less, but comes with some shortcomings.The first, low temperature is nitrated wayward, and especially in large-scale production process, there is certain danger, and selectivity is very poor, yield is only about 25%.The second, starting material procurement price is all more expensive, and yield is low, makes to like that the production cost of bent uncle's handkerchief is high, does not have actual industrialization value.3rd, coupling catalyst tetrakis triphenylphosphine palladium should not be deposited.Route 2 is route 1 comparatively, and reactions steps has more two step operations, and be the protection of phenolic hydroxyl group methyl and its corresponding deprotection steps respectively, the increase of reactions steps makes the yield of finished product lower, and the deficiency that the expensive production cost of its starting material is high is not solved at all.
The world patent WO2013072921 that GlaxoSmithKline PLC company of Britain applied in September, 2011.The synthetic route of bent uncle's handkerchief and analogue thereof is liked in the synthesis the patent describing a kind of novelty, and concrete synthetic route is as follows.
It is expensive equally to there is starting material in this synthetic method, the shortcoming that production cost is higher.
Summary of the invention
The object of this invention is to provide a kind of good reaction selectivity, and product yield is high, production cost is low, mild condition, is easy to industrialized love bent uncle handkerchief synthetic method.
A kind of preparation method liking bent uncle's handkerchief provided by the present invention, comprises the following steps:
A (), in suitable organic solvent, utilizes brominated reagent and TERTIARY BUTYL AMINE by the corresponding ammonium salt of o-bromophenol selectivity synthesis 2-bromo-6-nitrophenols, then extraction obtains the bromo-6-nitrophenols of 2-in diluted acid and organic solvent.
B () in the presence of base, makes catalyzer with palladium metal and salt thereof, make the bromo-6-nitrophenols of 2-and 3-Carboxybenzeneboronic acid carry out linked reaction in the solvent be applicable to, obtain 3 '-nitro-2 '-xenol-3-carboxylic acid.
C (), using palladium metal as catalyzer, under the effect of suitable hydrogen donor, nitroreduction obtains 3 '-amino-2 '-xenol-3-carboxylic acid.
D () is under the environment of dilute hydrochloric acid, 3 '-amino-2 '-xenol-3-carboxylic acid is added under low temperature, add Sodium Nitrite and carry out diazotization reaction, again with 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone carries out linked reaction under suitable alkali, finally obtain 3-[2-[(2Z)-1-(3,4-phenylbenzene)-1,5-dihydro-3--5-oxo-4H-pyrazoles-4-subunit] diazanyl]-2-hydroxyl-[1,1-biphenyl]-3-carboxylic acid, namely like the acid of bent uncle's handkerchief.
In one embodiment, also step (e) should be protected before step (d):
(e) 3,4-dimethyl hydrazinobenzene hydrochloride salt and methyl aceto acetate under catalyzer made by suitable acetate, using acetic acid as solvent, cyclization dehydration obtains 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone.
In one embodiment, step (a) uses brominated reagent, and described brominated reagent is N-bromosuccinimide, simple substance bromine or both mixtures.Described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF) or acetone and other organic solvent, or any mixture in them.The molar ratio range of o-NP and brominated reagent and TERTIARY BUTYL AMINE is 1:0.5-2:0.5-2, preferred 1:1.2:1.3.
In one embodiment, step (a) adopts following steps: be first dissolved in methylene dichloride by o-bromophenol, be cooled to about 0 degree, the solution of TERTIARY BUTYL AMINE and the mixing of a certain amount of methylene dichloride is slowly added drop-wise in above-mentioned reaction system under 0-5 degree, after dropwising, add N-bromosuccinimide in system, after reinforced in batches, rise to room temperature, follow the tracks of reaction extremely without raw material point with TLC.Suction filtration obtains brown solid powder, is the tert-butylamine salt of the bromo-6-nitrophenols of 2-.
In one embodiment, be mixed in by the tert-butylamine salt obtained in the system of ethyl acetate and dilute sulphuric acid, be heated to 50 degree, insulated and stirred 2 hours, extraction separatory obtains organic phase, is spin-dried for removal solvent, obtains the bromo-6-nitrophenols of 2-.The massfraction of described dilute sulphuric acid is 20%.
In one embodiment, the organic solvent described in step (b) is selected from the alcohol organic solvent such as anhydrous methanol, dehydrated alcohol or Virahol, or the water-miscible organic solvent such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, or with the mixture of water.Described alkali is the mineral alkalis such as sodium bicarbonate, sodium carbonate, salt of wormwood, preferred sodium carbonate.Metal palladium catalyst preferred 10%Pd/C, PdCl
2(pph
3)
2, Pd (pph
3)
4, Pd (OAc)
2, preferred 10%Pd/C.Specifically can adopt with the following method: first bromo-for 2-6-nitrophenols is mixed in the mixed solvent of first alcohol and water and joins in reactor (round-bottomed flask), then add 3-Carboxybenzeneboronic acid and anhydrous sodium carbonate, be stirred to and mix.Add a certain amount of 10%Pd/C under nitrogen protection, open and be heated to micro-backflow.The mol ratio of the bromo-6-nitrophenols of described 2-and anhydrous sodium carbonate is about 1:2.
In one embodiment, step (b) adopts following steps: be first dissolved in anhydrous methanol by bromo-for 2-6-nitrophenols, 3-Carboxybenzeneboronic acid is added under room temperature, then the aqueous solution of sodium carbonate is added in above-mentioned reaction system, stir, add a certain amount of palladium carbon again, under nitrogen protection, open the micro-backflow of the system of being heated to, react and follow the tracks of reaction to without raw material point being reaction complete (approximately reaction 4 hours) with TLC; Stop the water joining 2 times of methyl alcohol volumes after completion of the reaction, by dilute hydrochloric acid regulation system pH value to 1-2, filter, and priority volume ratio is methanol aqueous solution and the dilute hydrochloric acid washing of 1:1, obtains yellow solid 3 '-nitro-2 '-xenol-3-carboxylic acid.
In one embodiment, the hydrogen donor described in step (c) can formic acid ammonium, ammonium acetate, 80% hydrazine hydrate or two or more mixture arbitrarily, preferable formic acid ammonium.Reaction solvent can be anhydrous methanol, dehydrated alcohol, Virahol or its any two kinds or two or more mixtures.The preferred 10%Pd/C of metal catalyst.
In one embodiment, first by 3 '-nitro-2 '-xenol-3-carboxylic acid is mixed in anhydrous methanol, stir, quantitative ammonium formiate is joined in batches in above-mentioned system, open the micro-backflow of the system of being heated to, the reaction times is approximately 2-3 hour, follows the tracks of reaction to reacting complete with TLC.Reaction system filtered and remove palladium metal, filtrate is spin-dried for, and adds methyl tertiary butyl ether dispersion system, then filters, and filter cake methyl tertiary butyl ether washs, and with post-drying, obtains red brown solid powder, i.e. 3 '-amino-2 '-xenol-3-carboxylic acid.
In one embodiment, alkali described in step (d) is weak base, can be alkali-metal carbonate or supercarbonate or organic weak base, such as described alkali can be sodium carbonate, sodium bicarbonate, salt of wormwood, triethylamine, pyridine or any two kinds or two or more mixtures, is preferably sodium carbonate.The solvent that step (d) uses can be anhydrous methanol, dehydrated alcohol, tetrahydrofuran (THF) or its any two or more mixture, is preferably methyl alcohol.The molar ratio range of 3 '-amino-2 '-xenol-3-carboxylic acid and Sodium Nitrite is 1:0.8-1:2.4, preferred 1:1-1:1.2.
In one embodiment, also step (e) is comprised after the step (d):
E () is the preparation process to step (d) intermediate 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone.
In one embodiment, the alkali described in step (e) is alkalimetal oxide, can be sodium methylate or sodium ethylate or other alkali, preferred alcohol sodium.Described organic solvent can be methyl alcohol, ethanol or both mixtures.Concrete operation steps is: first by 3,4-dimethyl hydrazinobenzene hydrochloride salt is mixed in dehydrated alcohol, a certain amount of sodium ethylate is added under stirring at room temperature, then the ethanolic soln of methyl aceto acetate is slowly added drop-wise in above-mentioned system, open and be heated to micro-backflow, reaction 24 is little to be followed the tracks of without raw material point up to TLC.Stop heating, organic solvent is removed in decompression, add ethyl acetate and the extraction of moisture liquid, be spin-dried for system, add methyl tertiary butyl ether dispersion, then filter, the a small amount of methyl tertiary butyl ether of filter cake is washed, and with post-drying, namely obtains 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone.
The present invention for raw material, obtains the love bent uncle handkerchief of high yield with cheap o-NP through bromo, suzuki coupling, reduction, cyclization, linked reaction.Whole process reaction reagent is cheaply easy to get, and route is simple, and reaction conditions gentleness is easy to control, is particularly suitable for suitability for industrialized production.The method that the present invention prepares 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone can also be further used for preparing other love bent uncle handkerchief derivative.
Embodiment
Should be appreciated that, those skilled in the art, based on content disclosed herein, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should all drop in the scope of patent protection of claim definition of the application.In addition, should be appreciated that embodiment provided herein only for illustration of object of the present invention, and should not be construed as limitation of the present invention.
Below in conjunction with specific embodiment, the present invention is described in further detail.
According to a preferred embodiment of the invention, the method preparing love bent uncle handkerchief free acid comprises the following steps:
A () is that starting raw material and N-bromosuccinimide and TERTIARY BUTYL AMINE carry out bromo-reaction with o-NP, using methylene dichloride as reaction solvent, obtain the tert-butylamine salt of the bromo-6-nitrophenols of 2-, more freely obtains the bromo-6-nitrophenols of 2-.
B (), using sodium carbonate as mineral alkali, at 10%Pd/C as catalyzer, there is suzuki coupling and obtain 3 '-nitro-2 '-xenol-3-carboxylic acid in above-mentioned thing and 3-Carboxybenzeneboronic acid.
C () is solvent at methyl alcohol, ammonium formiate is as hydrogen donor, and 10%Pd/C obtains 3 '-amino-2 '-xenol-3-carboxylic acid as carrying out nitroreduction when catalyzer.
D () first makes above-mentioned 3 '-amino-2 '-xenol-3-carboxylic acid react with Sodium Nitrite at low temperatures and diazotization reaction occurs, again under organic weak base with intermediate 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone generation coupled reaction obtains liking bent uncle's handkerchief free acid.
(e) 3,4-dimethyl hydrazinobenzene hydrochloride salt when sodium ethylate makes alkali, in dehydrated alcohol, obtain intermediate 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone with methyl aceto acetate generation dehydration condensation.
This synthetic route can be represented by the formula.
The preparation of the bromo-6-nitrophenols of embodiment 1:2-
In three mouthfuls of round-bottomed flasks of 1000ml, add 50g (360mmol) o-NP and 500ml methylene dichloride, stirred at ambient temperature dissolves.Under ice-water bath, slowly drip 42g (575mmol) TERTIARY BUTYL AMINE, after dropwising, continue stirring 10 minutes.Then add 96g (540mmol) N-bromosuccinimide, holder ties up to 0-5 degree in batches.Insulated and stirred 30 minutes, then withdraws from refrigerating unit, is naturally warming up to room temperature, continue reaction 6 little up to without raw material point (with tlc (TLC) follow the tracks of react).After completion of the reaction, reaction mixture frozen water is cooled, filter, filter cake washed with dichloromethane, and drying obtains red brown solid powder under normal temperature decompression.By gained solid mixture in the dilute sulphuric acid of 300ml ethyl acetate and 300ml20%, open and be heated to 50 degree, insulation reaction 2 hours.Stop heating, be cooled to the extraction of room temperature separatory, ethyl acetate uses anhydrous sodium sulfate drying 10 minutes mutually, and 40 degree of lower decompressions are revolved and desolventized, and obtain yellow oil.Add 200ml sherwood oil dispersion system, under being cooled to 5-10 degree, stirring and crystallizing.Filter, filter cake petroleum ether, and at 25 times drying under reduced pressure, obtain 2-bromo-6-nitrophenols yellow powdery solid 67g (307mmol).
1H NMR(400MHz,CDCl
3)δ11.10(s,1H),8.13(d,1H),7.89(d,1H),6.90(t,1H)
The preparation of embodiment 2:3 '-nitro-2 '-xenol-3-carboxylic acid
Under room temperature, the bromo-6-nitrophenols of mixing 42g (192mmol) 2-, 35.2g (212mmol) 3-carboxylic acid phenylo boric acid, 10.8g10%Pd/C, 30.7g (290mmol) sodium carbonate, 400ml methyl alcohol and 400ml water.Stir 30 minutes to even.Isolated air under nitrogen protection, open and be heated to micro-backflow, stirred reaction mixture reacts 3 hours, and system becomes black muddy, follows the tracks of reaction to reacting complete with TLC.Stop heating, suction filtration Recover palladium carbon, with 100ml hot water drip washing filter cake.System with 5% dilute hydrochloric acid regulation system pH value to 1-2, continue stirring 1 hour.Filter, the filter cake dilute hydrochloric acid of 5% washs, and forced air drying 4 hours at ambient pressure, obtain 3 '-nitro-2 '-xenol-3-carboxylic acid 41.7g (161mmol) yellow powdery solid.
1H NMR(400MHz,DMSO-d
6):δ13.90(s,1H),10.66(s,1H),8.12(t,1H),8.07(dd,1H),7.98(dt,1H),7.79(dt,1H),7.74(dd,1H),7.62(t,1H),7.17(dd,1H)
The preparation of embodiment 3:3 '-amino-2 '-xenol-3-carboxylic acid
By product 3 '-nitro-2 '-xenol-3-carboxylic acid 30g (116mmol) of obtaining in embodiment 2 and the mixing of 600ml anhydrous methanol, under room temperature, add 3g10%Pd/C, disposablely in room temperature add 36.6g (581mmol) ammonium formiate.Open and be heated to micro-backflow, reaction 2-3 is little of without raw material point (TLC tracing and monitoring).Stop heating, be down to room temperature, suction filtration, Recover palladium carbon.Gained solution decompression revolves and desolventizes, and obtains brown viscous thing.Join 100ml deionized water, about regulation system pH value to 7, be cooled to 5-10 and spend night and lower the temperature crystallization.Suction filtration, filter cake deionized water wash, filter cake forced air drying 2 hours, obtains 3 ' purer-amino-2 '-xenol-3-carboxylic acid 24g (105mmol) pale pink pressed powder.
1H NMR(400MHz,DMSO-d
6):δ8.08(s,1H),7.86(d,1H),7.71(d,1H),7.51(t,1H),6.71(t,1H),6.67(dd,1H),6.49(dd,1H)
Embodiment: 4: the preparation liking bent uncle's handkerchief
Under frozen water cooling, the hydrochloric acid soln of mixing 20g (87mmol) 3 '-amino-2 '-xenol-3-carboxylic acid and 300ml1M, is cooled to 0-5 degree.The solution of slow dropping 6.4g Sodium Nitrite (93mmol) and 100ml water, insulation reaction 1 hour.Then disposablely add 18g (89mmol) 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone, then add 400ml ethanol, stir, keep system temperature at 0-5 degree.Add 36g (428mmol) sodium bicarbonate in batches, make final system pH maintain 7.5-8.0.Withdraw from ice bath, be naturally warming up to room temperature, insulation reaction 24 hours.Suction filtration, filter cake water wash obtains red brown solid.Gained solids mixing in 600ml water, under vigorous stirring by the dilute hydrochloric acid regulation system pH value of 5% to 1-2.Continue stirring 2 hours, suction filtration, the filter cake dilute hydrochloric acid of 5% washs, and drying obtains liking bent uncle's handkerchief red brown solid powder 26.1g (59mmol) at ambient pressure.
1H NMR(400MHz,DMSO-d
6):δ13.75(brs,1H),13.09(brs,1H),9.69(s,1H), 8.13(s,1H),7.94-7.97(d,1H),7.79-7.82(d,1H),7.62-7.71(m,3H),7.16-7.21(m,3H),2.32(s,3H),2.26(s,3H),2.22(s,3H)
The preparation of embodiment 5:2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone
Under room temperature, mixing 100g (578mmol) 3.4-dimethyl hydrazinobenzene hydrochloride salt and 600ml dehydrated alcohol, add 62.8g (923mmol) sodium ethylate in batches, and stirring 1 is little all dissolves up to material.Be warming up to 40 degree, slowly drip 84g (646mmol) methyl aceto acetate, stir 30 minutes.Open and be heated to reflux state, insulation reaction 24 is little follows the tracks of reaction extremely without raw material point up to TLC.Stop heating, most of alcohol solvent is removed in system decompression.Gained brown viscous liquid.Add 300ml ethyl acetate, then add 300ml tap water in batches, stir, separatory extracts, and ethyl acetate anhydrous sodium sulfate drying dewaters.Decompression is revolved and is desolventized, and obtains faint yellow oily solid, adds 400ml methyl tertiary butyl ether dispersion system.Filter, filter cake methyl tertiary butyl ether drip washing, forced air drying obtains 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone 91g (450mmol) off-white powder shape solid.
1H NMR(400MHz,DMSO-d
6):δ11.30(brs,1H),7.49(d,1H),7.43(dd,1H),7.14(d,1H),5.31(s,1H),2.20(s,3H),2.22(s,3H),2.08(s,3H)。
Claims (7)
1. like a preparation method for bent uncle's handkerchief, comprise the following steps:
A () in organic solvent, utilizes brominated reagent by bromo-for o-NP selectivity synthesis 2-6-nitrophenols;
B () in the presence of base, makes catalyzer with metallic palladium or its metal-salt, make the bromo-6-nitrophenols of 2-and 3-Carboxybenzeneboronic acid carry out suzuki linked reaction, obtains 3 '-nitro-2 '-xenol-3-carboxylic acid;
C () in organic solvent, hydrogen donor is as hydrogen source, and palladium metal makes catalyzer, make 3 '-nitro-2 '-xenol-3-carboxylic acid carry out nitroreduction and obtain 3 '-amino-2 '-xenol-3-carboxylic acid.
D () above-mentioned 3 '-amino-2 '-xenol-3-carboxylic acid reacts with Sodium Nitrite at low temperatures and diazotization reaction occurs, again under organic weak base with intermediate 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone generation coupled reaction obtains liking bent uncle's handkerchief free acid.
2. method according to claim 1, is characterized in that, also comprises step (e) before step (d):
E () in organic solvent, when organic bases, 3,4-dimethyl hydrazinobenzene hydrochloride salt and methyl aceto acetate generation dehydration condensation obtain intermediate 2-(3,4-3,5-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazoles-3-ketone.
3. according to the method described in claim 1, it is characterized in that, step (a) uses brominated reagent, and described brominated reagent is N-bromosuccinimide, simple substance bromine or both mixtures.Described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF) or acetone and other organic solvent, or any mixture in them.The molar ratio range of o-NP and brominated reagent and TERTIARY BUTYL AMINE is 1:0.5-2:0.5-2, preferred 1:1.2:1.3.
4. according to the method described in claim 3, it is characterized in that, step (b) is specially: described organic solvent is selected from the alcohol organic solvent such as anhydrous methanol, dehydrated alcohol or Virahol, or tetrahydrofuran (THF), 1, the water-miscible organic solvents such as 4-dioxane, or with the mixture of water.Described alkali is the mineral alkalis such as sodium bicarbonate, sodium carbonate, salt of wormwood, preferred sodium carbonate.Metal palladium catalyst preferred 10%Pd/C, PdCl
2(pph
3)
2, Pd (pph
3)
4, Pd (OAc)
2, preferred 10%Pd/C.
5. according to the method described in claim 4, it is characterized in that, the hydrogen donor described in step (c) can formic acid ammonium, ammonium acetate, 80% hydrazine hydrate or two or more mixture arbitrarily, preferable formic acid ammonium.Reaction solvent can be anhydrous methanol, dehydrated alcohol, Virahol or its any two kinds or two or more mixtures.The preferred 10%Pd/C of metal catalyst.
6. according to the method described in claim 5, it is characterized in that, alkali described in step (d) is weak base, can be alkali-metal carbonate or supercarbonate or organic weak base, such as described alkali can be sodium carbonate, sodium bicarbonate, salt of wormwood, triethylamine, pyridine or any two kinds or two or more mixtures, is preferably sodium carbonate.The molar ratio range of 3 '-amino-2 '-xenol-3-carboxylic acid and Sodium Nitrite is 1:0.8-1:2.4, preferred 1:1-1:1.2.
7. according to the method described in claim 6, it is characterized in that, the alkali described in step (e) is alkalimetal oxide, can be sodium methylate or sodium ethylate or other alkali, preferred alcohol sodium.Described organic solvent can be methyl alcohol, ethanol or both mixtures.
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| CN110407702A (en) * | 2019-07-03 | 2019-11-05 | 武汉工程大学 | A kind of preparation method of eltrombopag olamine key intermediate 3 '-amino -2 '-xenol -3- carboxylic acid |
| 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 |
| CN113929626A (en) * | 2020-07-13 | 2022-01-14 | 苏州特瑞药业有限公司 | Method for synthesizing eltrombopag |
| CN112321454A (en) * | 2020-11-25 | 2021-02-05 | 湖南华腾制药有限公司 | Elotriporpa intermediate, preparation method thereof and method for preparing Elotriporpa by using intermediate |
| CN113214041A (en) * | 2021-04-29 | 2021-08-06 | 河北唯达生物医药产业技术研究有限公司 | Novel method for preparing 3-iodine-2 bromotoluene |
| CN114507186A (en) * | 2021-12-02 | 2022-05-17 | 天津力生制药股份有限公司 | Preparation method of eltrombopag |
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