CN109485580A - A kind of synthetic method of eltrombopag olamine intermediate - Google Patents
A kind of synthetic method of eltrombopag olamine intermediate Download PDFInfo
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- CN109485580A CN109485580A CN201710815755.0A CN201710815755A CN109485580A CN 109485580 A CN109485580 A CN 109485580A CN 201710815755 A CN201710815755 A CN 201710815755A CN 109485580 A CN109485580 A CN 109485580A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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Abstract
This application discloses a kind of synthetic methods of eltrombopag olamine intermediate, which comprises reacts the step of obtaining intermediate product shown in formula (IV) using Ortho-Aminophenol derivative shown in formula (II) as raw material with aromatic yl reagent-ing shown in formula (III)；And using intermediate product shown in formula (IV) as raw material formula (I) is prepared shown in eltrombopag olamine intermediate the step of, R1Selected from aminoderivative；R2Selected from halogen and sulfonyloxy.Reactions steps of this method is few, and starting material is simple, more simple economy and environmentally protective.
Description
Technical field
This application involves a kind of synthetic methods of eltrombopag olamine intermediate, belong to pharmaceutical synthesis field.
Background technique
Chronic idiopathic thrombocytopenic purpura (ITP) is a kind of autoimmune disease, by cause decrease of platelet
A kind of autoimmune response causes, it is characterized in that platelet count reduces, patient faces bleeding high risk, it is small to often lead to patient
Angiorrbagia, symptom are that green silt, nosebleed and bleeding gums, serious person may occur in which mortality gastrointestinal tract and intracerebral hemorrhage.It prevents
Blood platelet is destroyed the main method for always treating ITP patient.
Eltrombopag olamine (1, eltrombopag, trade name Promacta), is developed by Britain's GlaxoSmithKline PLC company, in
It obtains FDA approval in November, 2008 to list in the U.S., generates factor type drug for oral platelet, be small molecule thrombocytopoiesis
Plain receptor stimulating agent, it can interact with the thrombopoietin receptor of human body transmembrane region, generate signal cascade amplification,
To the proliferation and differentiation of inducing bone marrow megacaryocyte.It is mainly used for treatment to control through glucocorticoid medicine, immunoglobulin
Treat invalid or Postsplenectomy chronic idiopathic thrombocytopenic purpura (ITP) patient decrease of platelet.Currently, the drug
Also carrying out thrombopenia caused by treatment Hepatitis C Virus, chronic liver disease and the relevant thrombopenia of tumour
Research.
Eltrombopag olamine (eltrombopag), entitled 3 '-{ (2Z) -2- [1- (3,4- the xylyl) -3- methyl -5- of chemistry
Oxo -1,5- dihydro -4H- pyrazoles -4- subunit] diazanyl } -2 '-hydroxyl -3- biphenyl acids, there is following formula:
In terms of the structure of compound, two important intermediates: 3 '-amino -2 '-hydroxyl are contained in the synthesis of the compound
Base xenyl -3- formic acid (BPCA) and 1- (3,4- 3,5-dimethylphenyl) -3- methyl-1 H- pyrazoles -5H-4- ketone, this judgement is in patent
In be confirmed.
Patent US7160870/WO2001089457 discloses the synthetic method (Scheme 1) of eltrombopag olamine first, at this
3 ' in text-and amino -2 '-Hydroxybiphenyl -3- formic acid (BPCA) synthesizes by the following method: using 2- bromophenol as raw material,
BPCA is obtained by nitrification, hydroxyl protection, Suzuki coupling, hydroxyl deprotection and reduction.Since first step nitration reaction exists
A possibility that ortho position and contraposition replace, in addition reaction step excessively causes gross production rate lower.
It is that raw material improves the yield of nitration reaction that patent US7414040, which has used the chloro- 2- bromophenol of 4-, to make total anti-
Product yield increases, but technical process is still longer, and gross production rate is about in 10% (Scheme 2).
The step of reducing hydroxyl protection and deprotection in patent WO2013049605, entire process route shortens, overall
Yield is increased to 50~60% (Scheme 3).But starting material still uses the chloro- 2- bromophenol of complicated 4-, at
This is relatively high.
The synthetic method for the eltrombopag olamine intermediate B PCA having disclosed is analyzed, generally existing reaction step is more, environment pressure
Power is big, drawback at high cost.Seeking simpler convenience and the controllable technique of cost becomes the inevitable requirement of medical technological development.
Summary of the invention
According to the one aspect of the application, a kind of synthetic method of eltrombopag olamine intermediate, this method reaction step are provided
Rapid few, starting material is simple, more simple economy and environmentally protective.
The synthetic method of the eltrombopag olamine intermediate includes:
(1) it is reacted using Ortho-Aminophenol derivative shown in formula (II) as raw material with aromatic yl reagent-ing shown in formula (III)
The step of obtaining intermediate product shown in formula (IV)；And
(2) using intermediate product shown in formula (IV) as raw material formula (I) is prepared shown in eltrombopag olamine intermediate the step of:
Wherein, R1Selected from aminoderivative (the preferably described aminoderivative be selected from NHBoc, NHCbz, NHFmoc,
NHAlloc, first (or ethoxy) carbonylamino, acetylamino or nitro)；
R2Selected from halogen (preferably F, Cl, Br or I) and sulfonyloxy (preferably-OSO2CH3、-OSO2CF3Or to toluene
Sulfonyloxy).
Some specific embodiments according to the present invention, wherein the aminoderivative be selected from NHBoc, NHCbz, NHFmoc,
NHAlloc, first (or ethoxy) carbonylamino, acetylamino or nitro.
Wherein Boc is tertbutyloxycarbonyl；Cbz is benzyloxycarbonyl group, and Fmoc is fluorenylmethoxycarbonyl, and Alloc is allyloxycarbonyl.
Some specific embodiments according to the present invention, wherein the halogen is F, Cl, Br or I.
Some specific embodiments according to the present invention, wherein step (1) is derivative with Ortho-Aminophenol shown in formula (II)
Object is that raw material reacts to obtain in shown in formula (IV) with aromatic yl reagent-ing shown in formula (III) under metal reagent/ligand catalysis
Between product.
Some specific embodiments according to the present invention, wherein the metal reagent is selected from RhCl (PPh3)3、RhCl
(cod)2、[Rh(cod)2]BF4And RhCl (CO) (PPh3)2One of or a variety of combinations.
Some specific embodiments according to the present invention, wherein by the amount of substance of Ortho-Aminophenol derivative be 1 in terms of, metal
Reagent dosage is 0.01-0.20 equivalent；Ligand dosage is 0.01-0.40 equivalent.
Some specific embodiments according to the present invention, wherein the ligand is selected from one of such as flowering structure or a variety of
Combination:
Some specific embodiments according to the present invention, wherein step (1) is derivative with Ortho-Aminophenol shown in formula (II)
Object is that raw material reacts to obtain formula under metal reagent/ligand catalysis, in the presence of base with aromatic yl reagent-ing shown in formula (III)
(IV) intermediate product shown in.
Some specific embodiments according to the present invention, wherein the alkali is selected from lithium carbonate, sodium carbonate, potassium carbonate, carbonic acid
In caesium, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, ethyl diisopropylamine and potassium phosphate
One or more combinations.
Some specific embodiments according to the present invention, wherein the usage amount of alkali is 1.0-5.0 equivalent.
Some specific embodiments according to the present invention, wherein Ortho-Aminophenol derivative described in step (1) is selected from:
2- nitrophenol or Ortho-Aminophenol amido protecting product.
Some specific embodiments according to the present invention, wherein the Ortho-Aminophenol amido protecting product is selected from N- (2-
Hydroxy phenyl) acetamide, N- (2- hydroxy phenyl) t-butyl carbamate or N- (2- hydroxy phenyl) benzyq carbamate.
Some specific embodiments according to the present invention, wherein step (1) is derivative with Ortho-Aminophenol shown in formula (II)
Object is that raw material reacts to obtain intermediate product shown in formula (IV) with aromatic yl reagent-ing shown in formula (III) in a solvent.
Some specific embodiments according to the present invention, wherein the solvent is selected from benzene,toluene,xylene, N, N- diformazan
One of base formamide, dioxane, dimethyl sulfoxide, ethylbenzene and isopropylbenzene or a variety of mixing.
Some specific embodiments according to the present invention, wherein the reaction temperature of step (1) is 80~150 DEG C.
Some specific embodiments according to the present invention, wherein the reaction time of step (1) is 0.5-24 hours.
Some specific embodiments according to the present invention, wherein step (2) is using intermediate product shown in formula (IV) as raw material
It reacts by hydrogenation or in acid condition and obtains eltrombopag olamine intermediate shown in formula (I).
Some specific embodiments according to the present invention, wherein step (2) is using intermediate product shown in formula (IV) as raw material
Eltrombopag olamine intermediate shown in formula (I) is obtained by hydrogenation using palladium carbon as catalyst.
Some specific embodiments according to the present invention, wherein step (2) is using intermediate product shown in formula (IV) as raw material
Reaction obtains eltrombopag olamine intermediate shown in formula (I) in a solvent.
Some specific embodiments according to the present invention, wherein the solvent is selected from water, methanol, ethyl alcohol, propyl alcohol, isopropyl
One of alcohol, tetrahydrofuran and dioxane or a variety of mixing.
The beneficial effect that the application can generate includes: that this method applies novel reaction type and direct carbon-hydrogen bond activation
Method, reaction step significantly reduce；Starting material is simply easy purchase and production, directly reduction production cost；Less waste
Processing and simpler operation, economical and eco-friendly environmental protection.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
Unless otherwise instructed, the raw material in embodiments herein and catalyst are bought by commercial sources, in which:
2- nitrophenol and Ortho-Aminophenol are purchased from Beijing coupling Science and Technology Ltd., by protecting on Ortho-Aminophenol
Available Ortho-Aminophenol amido protecting product:
3- bromobenzoic acid, 3- iodo-benzoic acid and 3- hydroxybenzoic acid are purchased from Beijing coupling Science and Technology Ltd..3- hydroxy benzenes
Formic acid sulphonic acid ester is synthesized to obtain by 3- hydroxybenzoic acid with corresponding sulphonic acid anhydride or sulfonic acid chloride.
Rhodium reagent and ligand are purchased from lark prestige Science and Technology Ltd..
Various alkali and solvent are purchased from Chinese medicines group chemical reagents corporation.
Analysis method is as follows in embodiments herein:
Structural analysis is carried out using nuclear magnetic resonance and mass spectrum, uses instrument are as follows:
1100 LC-MS instrument LC/MSD TRAP-XCT of Agilent company, the U.S.
Bruker company, Switzerland AscendTM600M nuclear magnetic resonance spectrometer
Calculation of yield is as follows in embodiments herein:
In embodiments herein, yield is all based on molal quantity and is calculated (practical to obtain amount/theoretical amount × 100%):
One of the preparation method of 1 BPCA of embodiment:
10g N- (2- hydroxy phenyl) benzyq carbamate, 9g 3- bromobenzoic acid, 0.73g are added in 250ml reaction flask
RhCl(cod)2, 1.28g triple phenoxyl phosphine, 40g cesium carbonate and 100ml toluene, back flow reaction under nitrogen protection, TLC monitoring is anti-
It should be complete.Be added 100ml water, ethyl acetate extraction, it is dry be concentrated to get product (13g, yield: 87%, HPLC purity:
97%).
Above-mentioned product is added in hydriding reactor, 10% palladium carbon of 2g (aqueous about 63%) and 150ml methanol is added, is passed through
Hydrogen 0.1-0.3MPa is stirred at room temperature.After the reaction was completed, it filters, concentration, the dissolution of 100ml water is added, extremely with 1M salt acid for adjusting pH
About 5.5, solid is precipitated, filters, is dried to obtain red brown solid (9g, yield: 95%, HPLC purity: 99%).
1H NMR (600MHz, DMSO-d6): δ 6.50 (dd, J=1.8,7.2Hz, 1H), 6.67~6.73 (m, 2H),
7.52 (t, J=7.8Hz, 1H), 7.71~7.73 (m, 1H), 7.87 (dt, J=1.2,7.8Hz, 1H), 8.09 (t, J=
1.2Hz,1H),MS m/z:230.1[M+H+]。
One of the preparation method of 2 BPCA of embodiment:
10 grams of N- (2- hydroxy phenyl) t-butyl carbamates of addition in 250ml reaction flask, 13g 3- iodobenzoic acid,
0.85g RhCl(cod)2, 1.5g triple phenoxyl phosphine, 46g cesium carbonate and 100ml toluene, back flow reaction under nitrogen protection, TLC prison
Survey fully reacting.Be added 100ml water, ethyl acetate extraction, it is dry be concentrated to get product (13g, yield: 83%, HPLC purity:
97%).
Above-mentioned product is added in 100ml water, 120ml 1M hydrochloric acid is added and 4.4g benzenethiol is stirred at room temperature 5-8 hours,
It filters after the reaction was completed, solid is washed with 30ml ethyl alcohol, obtains faint yellow solid (9.5g, yield: 90%, HPLC purity: 99%)
1H NMR (600MHz, DMSO-d6): δ 6.52 (dd, J=1.8,7.2Hz, 1H), 6.67~6.73 (m, 2H),
7.52 (t, J=7.8Hz, 1H), 7.72~7.74 (m, 1H), 7.87 (dt, J=1.2,7.8Hz, 1H), 8.09 (t, J=
1.2Hz,1H),MS m/z:230.1[M+H+]。
One of the preparation method of 3 BPCA of embodiment:
10g 2- nitrophenol, 20g 3- iodobenzoic acid, 1.3g RhCl (cod) are added in 250ml reaction flask2,
1.3g tri- (dimethylamino) phosphine, 40g potassium carbonate and 100ml dimethylbenzene, the lower 120 DEG C of reactions of nitrogen protection, TLC monitoring have been reacted
Entirely.100ml water, ethyl acetate extraction is added, drying is concentrated to get product (12g, yield: 65%, HPLC purity: 98%).
Above-mentioned product is added in hydriding reactor, 10% palladium carbon of 2g (aqueous about 63%) and 150ml ethyl alcohol is added, is passed through
0.5-1.0MPa/50 DEG C of hydrogen reaction.After the reaction was completed, it filters, concentration, the dissolution of 100ml water is added, extremely with 1M salt acid for adjusting pH
About 5.5, solid is precipitated, filters, is dried to obtain faint yellow solid (9g, yield: 95%, HPLC purity: 99%).
1H NMR (600MHz, DMSO-d6): δ 6.51 (dd, J=1.8,7.2Hz, 1H), 6.68~6.74 (m, 2H),
7.53 (t, J=7.8Hz, 1H), 7.71~7.73 (m, 1H), 7.88 (dt, J=1.2,7.8Hz, 1H), 8.09 (t, J=
1.2Hz,1H),MS m/z:230.1[M+H+]。
One of the preparation method of 4 BPCA of embodiment:
10 grams of N- (2- hydroxy phenyl) urethanes of addition in 250ml reaction flask, 13g 3- bromobenzoic acid,
0.85g RhCl(PPh3)3, 1.5g tri- (dimethylamino) phosphine, 72g cesium carbonate and 150ml toluene, back flow reaction under nitrogen protection,
TLC monitors fully reacting.150ml water, ethyl acetate extraction is added, drying is concentrated to get product (13g, yield: 78%, HPLC
Purity: 97%).
Above-mentioned product is added in 100ml water, 50 DEG C of 20ml 6M hydrochloric acid stirrings are added, filter after the reaction was completed, solid is used
30ml ethyl alcohol is washed, and faint yellow solid (9.5g, yield: 90%, HPLC purity: 99%) are obtained
1H NMR (600MHz, DMSO-d6): δ 6.50 (dd, J=1.8,7.2Hz, 1H), 6.67~6.73 (m, 2H),
7.53 (t, J=7.8Hz, 1H), 7.71~7.73 (m, 1H), 7.87 (dt, J=1.2,7.8Hz, 1H), 8.10 (t, J=
1.2Hz,1H),MS m/z:230.1[M+H+]。
One of the preparation method of 5 BPCA of embodiment:
10 grams of N- (2- hydroxy phenyl) t-butyl carbamates, 13g 3- (tolysulfonyl are added in 250ml reaction flask
Oxygroup) benzoic acid, 1.6g RhCl (PPh3)3, 1.0g diisopropyl (2- tert-butyl) phenoxy group phosphine, 28g cesium carbonate and 150ml first
Benzene, back flow reaction under nitrogen protection, TLC monitor fully reacting.150ml water, ethyl acetate extraction is added, drying is concentrated to get production
Object (11g, yield: 82%, HPLC purity: 98%).
Above-mentioned product is added in 100ml water, 50 DEG C of 20ml 6M hydrochloric acid stirrings are added, filter after the reaction was completed, solid is used
30ml ethyl alcohol is washed, and faint yellow solid (5.8g, yield: 94%, HPLC purity: 99%) are obtained
1H NMR (600MHz, DMSO-d6): δ 6.51 (dd, J=1.8,7.2Hz, 1H), 6.67~6.73 (m, 2H),
7.52 (t, J=7.8Hz, 1H), 7.71~7.74 (m, 1H), 7.87 (dt, J=1.2,7.8Hz, 1H), 8.10 (t, J=
1.2Hz,1H),MS m/z:230.1[M+H+]。
Claims (10)
1. a kind of synthetic method of formula (I) eltrombopag olamine intermediate, which is characterized in that the described method includes:
(1) it reacts to obtain using Ortho-Aminophenol derivative shown in formula (II) as raw material with aromatic yl reagent-ing shown in formula (III)
The step of intermediate product shown in formula (IV)；And
(2) using intermediate product shown in formula (IV) as raw material formula (I) is prepared shown in eltrombopag olamine intermediate the step of:
Wherein, R1Selected from aminoderivative, (the preferably described aminoderivative is selected from NHBoc, NHCbz, NHFmoc, NHAlloc, first
(or ethoxy) carbonylamino, acetylamino or nitro)；
R2Selected from halogen (preferably F, Cl, Br or I) and sulfonyloxy (preferably-OSO2CH3、-OSO2CF3Or tolysulfonyl
Oxygroup).
2. synthetic method according to claim 1, which is characterized in that step (1) is with 2- aminobenzene shown in formula (II)
Amphyl is that raw material reacts to obtain shown in formula (IV) with aromatic yl reagent-ing shown in formula (III) under rhodium reagent/ligand catalysis
Intermediate product (optional, one or more combinations of the metal reagent, including RhCl (PPh3)3、RhCl(cod)2、
[Rh(cod)2]BF4And RhCl (CO) (PPh3)2Deng).
3. synthetic method according to claim 2, which is characterized in that by the amount of substance of Ortho-Aminophenol derivative be 1 in terms of,
Rhodium reagent dosage is 0.01~0.20 equivalent；Ligand dosage is 0.01-0.40 equivalent.
4. synthetic method according to claim 2, which is characterized in that the ligand is selected from one of such as flowering structure or more
The combination of kind:
5. synthetic method according to claim 2, which is characterized in that step (1) is with 2- aminobenzene shown in formula (II)
Amphyl is that raw material reacts under metal reagent/ligand catalysis, in the presence of base with aromatic yl reagent-ing shown in formula (III)
Obtaining intermediate product shown in formula (IV), (optional, the alkali is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, bicarbonate
One of sodium, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, ethyl diisopropylamine and potassium phosphate or
A variety of combination).
6. synthetic method according to claim 1, which is characterized in that Ortho-Aminophenol derivative described in step (1)
It is selected from: 2- nitrophenol or (optional, the described Ortho-Aminophenol amido protecting product choosing of Ortho-Aminophenol amido protecting product
From N- (2- hydroxy phenyl) acetamide, N- (2- hydroxy phenyl) t-butyl carbamate or N- (2- hydroxy phenyl) carbamic acid
Benzyl ester).
7. synthetic method according to claim 1, which is characterized in that step (2) is with intermediate product shown in formula (IV)
For raw material, by hydrogenation or in acid condition, reaction obtains eltrombopag olamine intermediate shown in formula (I).
8. synthetic method according to claim 6, which is characterized in that step (2) is with intermediate product shown in formula (IV)
Eltrombopag olamine intermediate shown in formula (I) is obtained by hydrogenation by catalyst of palladium carbon for raw material.
9. synthetic method according to claim 1, which is characterized in that step (1) is with 2- aminobenzene shown in formula (II)
Amphyl is that raw material reacts to obtain intermediate product shown in formula (IV) with aromatic yl reagent-ing shown in formula (III) in a solvent
(optional, the solvent is selected from benzene,toluene,xylene, n,N-Dimethylformamide, dioxane, dimethyl sulfoxide, ethylbenzene
With one of isopropylbenzene or a variety of mixing).
10. synthetic method according to claim 1, which is characterized in that step (2) is with intermediate product shown in formula (IV)
Reacted in a solvent for raw material eltrombopag olamine intermediate shown in the formula that obtains (I) (it is optional, the solvent be selected from water, methanol,
One of ethyl alcohol, propyl alcohol, isopropanol, tetrahydrofuran and dioxane or a variety of mixing).
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| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013049605A1 (en) * | 2011-09-28 | 2013-04-04 | Assia Chemical Industries Ltd. | Processes for the preparation of an intermediate in the synthesis of eltrombopag |
| CN104725318A (en) * | 2013-12-20 | 2015-06-24 | 北京蓝贝望生物医药科技股份有限公司 | Synthetic method of eltrombopag olamine |
-
2017
- 2017-09-12 CN CN201710815755.0A patent/CN109485580B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013049605A1 (en) * | 2011-09-28 | 2013-04-04 | Assia Chemical Industries Ltd. | Processes for the preparation of an intermediate in the synthesis of eltrombopag |
| CN104725318A (en) * | 2013-12-20 | 2015-06-24 | 北京蓝贝望生物医药科技股份有限公司 | Synthetic method of eltrombopag olamine |
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| Title |
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| BEDFORD, ROBIN B 等: "Catalytic Intermolecular Ortho-Arylation of Phenols", 《JOURNAL OF ORGANIC CHEMISTRY 》 * |
| BEDFORD, ROBIN B.等: "The catalytic intermolecular ortho-arylation of phenols", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
| KOCH, K.等: "A direct synthesis of pharmacologically active ortho-substituted biaryls: a combined directed metalation-palladium catalyzed cross coupling approach using aryl oxazolines or benzamides", 《SYNLETT 》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552194A (en) * | 2020-12-21 | 2021-03-26 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of drug intermediate for treating idiopathic blood diseases |
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