CN109485580B - Synthetic method of eltrombopag intermediate - Google Patents
Synthetic method of eltrombopag intermediate Download PDFInfo
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- CN109485580B CN109485580B CN201710815755.0A CN201710815755A CN109485580B CN 109485580 B CN109485580 B CN 109485580B CN 201710815755 A CN201710815755 A CN 201710815755A CN 109485580 B CN109485580 B CN 109485580B
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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
The application discloses a method for synthesizing an eltrombopag intermediate, which comprises the following steps: reacting a 2-aminophenol derivative shown in a formula (II) serving as a raw material with an arylating reagent shown in a formula (III) to obtain an intermediate product shown in a formula (IV); and a step of preparing an eltrombopag intermediate represented by formula (I) from an intermediate represented by formula (IV), R1Selected from amino derivatives; r2Selected from halogen and sulfonyloxy. The method has the advantages of few reaction steps, simple starting raw materials, simplicity, economy and environmental protection.
Description
Technical Field
The application relates to a synthesis method of an eltrombopag intermediate, belonging to the field of drug synthesis.
Background
Chronic Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disease, caused by an autoimmune response to thrombocytopenia, characterized by a reduced platelet count, which is subject to high risk of bleeding, often resulting in small vessel bleeding in patients with symptoms of bruise, nosebleed and gingival bleeding, and fatal gastrointestinal and intracerebral hemorrhage in severe cases. Prevention of platelet destruction has been the primary method of treating patients with ITP.
Eltrombopag (1, eltrombopag, trade name Promacta), developed by the company tomaglatin smith, uk, was approved by the FDA in the us at 11 months 2008, is an oral thrombopoietin-type drug, a small molecule thrombopoietin receptor agonist that interacts with the thrombopoietin receptor in the transmembrane region of the human body to produce a signal cascade amplification that induces proliferation and differentiation of bone marrow megakaryocytes. Is mainly used for treating thrombocytopenia of patients who are ineffectively treated by glucocorticoid medicaments and immunoglobulin or have chronic Idiopathic Thrombocytopenic Purpura (ITP) after splenectomy. Currently, research into the treatment of thrombocytopenia caused by hepatitis c virus, chronic liver disease and tumor-related thrombocytopenia is under way.
Eltrombopag (eltrombopag), chemically known as 3 '- { (2Z) -2- [1- (3, 4-xylyl) -3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene ] hydrazino } -2' -hydroxy-3-biphenylcarboxylic acid, has the formula:
from the structure of the compound, the synthesis of the compound comprises two important intermediates: 3 '-amino-2' -hydroxybiphenyl-3-carboxylic acid (BPCA) and 1- (3, 4-dimethylphenyl) -3-methyl-1H-pyrazol-5H-4-one, the argument being confirmed in the patent.
Patent US7160870/WO2001089457 firstly discloses a synthesis method of eltrombopag (Scheme 1), in which 3 '-amino-2' -hydroxybiphenyl-3-carboxylic acid (BPCA) is synthesized by: the BPCA is obtained by taking 2-bromophenol as a raw material and carrying out nitration, hydroxyl protection, Suzuki coupling, hydroxyl deprotection and reduction. Due to the possibility of ortho-and para-substitution in the first nitration stage, an excessive number of further reaction stages leads to a lower overall yield.
The patent US7414040 uses 4-chloro-2-bromophenol as raw material to improve the yield of nitration reaction, thereby improving the total reaction yield, but the process is still longer, and the total yield is about 10% (Scheme 2).
In the patent WO2013049605, the steps of hydroxyl protection and deprotection are reduced, the whole process route is shortened, and the total yield is improved to 50-60% (Scheme 3). But the starting material still adopts 4-chloro-2-bromophenol with complex structure, and the cost is higher.
The disclosed synthesis method of the eltrombopag intermediate BPCA is analyzed, and the defects of multiple reaction steps, high environmental pressure and high cost generally exist. The search for a simpler, more convenient and cost-controllable process has become an inevitable requirement for the development of pharmaceutical technology.
Disclosure of Invention
According to one aspect of the application, the synthesis method of the eltrombopag intermediate is provided, and has the advantages of few reaction steps, simple starting materials, simplicity, economy and environmental friendliness.
The synthesis method of the eltrombopag intermediate comprises the following steps:
(1) reacting a 2-aminophenol derivative shown in a formula (II) serving as a raw material with an arylating reagent shown in a formula (III) to obtain an intermediate product shown in a formula (IV); and
(2) a step of preparing an eltrombopag intermediate shown in formula (I) by using an intermediate shown in formula (IV) as a raw material:
wherein R is1Selected from amino derivatives (preferably said amino derivative is selected from NHBoc, NHCbz, NHFmoc, NHAlloc, methyl (or ethoxy) carbonylamino, acetamido or nitro);
R2selected from halogen (preferably F, Cl, Br or I) and sulfonyloxy (preferably-OSO)2CH3、-OSO2CF3Or p-toluenesulfonyloxy).
According to some embodiments of the invention, wherein the amino derivative is selected from NHBoc, NHCbz, NHFmoc, NHAlloc, methyl (or ethoxy) carbonylamino, acetamido or nitro.
Wherein Boc is tert-butyloxycarbonyl; cbz is benzyloxycarbonyl, Fmoc is fluorenyloxycarbonyl, and Alloc is allyloxycarbonyl.
According to some embodiments of the invention, the halogen is F, Cl, Br or I.
According to some embodiments of the present invention, in the step (1), the 2-aminophenol derivative represented by formula (II) is used as a raw material, and reacts with the arylating reagent represented by formula (III) under the catalysis of the metal reagent/ligand to obtain the intermediate product represented by formula (IV).
According to some embodiments of the invention, wherein the metal agent is selected from RhCl (PPh)3)3、RhCl(cod)2、[Rh(cod)2]BF4And RhCl (CO) (PPh)3)2One or more of the above.
According to some embodiments of the present invention, the metal reagent is used in an amount of 0.01 to 0.20 equivalent based on 1 mass of the 2-aminophenol derivative; the ligand is used in an amount of 0.01 to 0.40 equivalent.
According to some embodiments of the invention, the ligand is selected from the group consisting of one or more of the following structures:
according to some embodiments of the present invention, in the step (1), the 2-aminophenol derivative represented by formula (II) is used as a raw material, and the raw material is reacted with the arylating reagent represented by formula (III) in the presence of a base under the catalysis of a metal reagent/ligand to obtain the intermediate product represented by formula (IV).
According to some specific embodiments of the present invention, wherein the base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, ethyldiisopropylamine, and potassium phosphate.
According to some embodiments of the invention, the base is used in an amount of 1.0 to 5.0 equivalents.
According to some embodiments of the present invention, wherein the 2-aminophenol derivative in the step (1) is selected from the group consisting of: 2-nitrophenol or 2-aminophenol amino protects the product.
According to some embodiments of the invention, the 2-aminophenol amino protection product is selected from the group consisting of N- (2-hydroxyphenyl) acetamide, tert-butyl N- (2-hydroxyphenyl) carbamate, and benzyl N- (2-hydroxyphenyl) carbamate.
According to some embodiments of the present invention, in the step (1), the 2-aminophenol derivative represented by formula (II) is used as a raw material to react with the arylating reagent represented by formula (III) in a solvent to obtain the intermediate product represented by formula (IV).
According to some embodiments of the invention, the solvent is selected from the group consisting of benzene, toluene, xylene, N-dimethylformamide, dioxane, dimethyl sulfoxide, ethylbenzene, and cumene.
According to some embodiments of the present invention, the reaction temperature in step (1) is 80 to 150 ℃.
According to some embodiments of the invention, wherein the reaction time of step (1) is 0.5 to 24 hours.
According to some embodiments of the present invention, in the step (2), the intermediate product represented by formula (IV) is used as a raw material, and the intermediate product is subjected to hydrogenation reaction or reaction under acidic conditions to obtain the eltrombopag intermediate represented by formula (I).
According to some embodiments of the present invention, in the step (2), the intermediate product represented by formula (IV) is used as a raw material, and palladium carbon is used as a catalyst to perform a hydrogenation reaction to obtain the eltrombopag intermediate represented by formula (I).
According to some embodiments of the present invention, in the step (2), the intermediate product represented by formula (IV) is used as a raw material, and the reaction is performed in a solvent to obtain the eltrombopag intermediate represented by formula (I).
According to some embodiments of the invention, the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, and dioxane.
The beneficial effects that this application can produce include: the method applies a novel reaction type and a direct carbon-hydrogen bond activation method, and the reaction steps are obviously reduced; the initial raw materials are simple and easy to purchase and produce, and the production cost is directly reduced; less waste treatment and simpler operation, and is economic and environment-friendly.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
Unless otherwise specified, the starting materials and catalysts in the examples of the present application were purchased commercially, wherein:
2-Nitrophenol and 2-aminophenol were purchased from Beijing coupling technologies, Inc., and the amino-protected 2-aminophenol product was obtained by protecting the 2-aminophenol:
3-Bromobenzoic acid, 3-iodobenzoic acid, and 3-hydroxybenzoic acid were purchased from Beijing coupling technologies, Inc. The 3-hydroxybenzoic acid sulfonate is synthesized by 3-hydroxybenzoic acid and corresponding sulfonic anhydride or sulfonyl chloride.
Rhodium reagents and ligands were purchased from carbofuran technologies ltd.
Various bases and solvents are available from the national pharmaceutical group chemical company.
The analysis method in the examples of the present application is as follows:
performing structural analysis by using nuclear magnetic resonance and mass spectrometry, wherein the instrument is as follows:
agilent 1100 LC/MSD TRAP-XCT
Ascend of Bruker, SwitzerlandTM600M nuclear magnetic resonance spectrometer
Yields in the examples of the present application were calculated as follows:
in the examples of the present application, the yields are all calculated on a molar basis (actual/theoretical x 100%):
example 1 one of the preparation methods of BPCA:
a250 ml reaction flask was charged with 10g N- (2-hydroxyphenyl) carbamic acid benzyl ester, 9g 3-bromobenzoic acid, 0.73g RhCl (cod)21.28g of triphenoxyphosphine, 40g of cesium carbonate and 100ml of toluene were refluxed under nitrogen, and the reaction was monitored by TLC for completion. 100ml of water was added, extracted with ethyl acetate, dried and concentrated to give the product (13g, yield: 87%, HPLC purity: 97%).
The above product was put into a hydrogenation vessel, 2g of 10% palladium on carbon (containing about 63% water) and 150ml of methanol were added, and hydrogen gas was introduced thereinto at 0.1 to 0.3MPa and stirred at room temperature. After completion of the reaction, filtration and concentration were carried out, 100ml of water was added to dissolve it, the pH was adjusted to about 5.5 with 1M hydrochloric acid, a solid was precipitated, suction-filtered and dried to obtain a reddish brown solid (9g, yield: 95%, HPLC purity: 99%).
1H NMR(600MHz,DMSO-d6):δ6.50(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+]。
Example 2 one of the methods for preparing BPCA:
into a 250ml reaction flask were charged 10g of tert-butyl N- (2-hydroxyphenyl) carbamate, 13g of 3-iodobenzoic acid, 0.85g of RhCl (cod)21.5g of triphenoxyphosphine, 46g of cesium carbonate and 100ml of toluene were refluxed under nitrogen, and the reaction was monitored by TLC for completion. 100ml of water was added, extracted with ethyl acetate, dried and concentrated to give the product (13g, yield: 83%, HPLC purity: 97%).
The above product was added to 100ml of water, 120ml of 1M hydrochloric acid and 4.4g of thiophenol were added, stirred at room temperature for 5 to 8 hours, filtered after completion of the reaction, and the solid was washed with 30ml of ethanol to give a pale yellow solid (9.5g, yield: 90%, HPLC purity: 99%)
1H NMR(600MHz,DMSO-d6,):δ6.52(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+]。
Example 3 one of the methods for preparing BPCA:
in a 250ml reaction flask were charged 10g of 2-nitrophenol, 20g of 3-iodobenzoic acid, 1.3g of RhCl (cod)21.3g of tris (dimethylamino) phosphine, 40g of potassium carbonate and 100ml of xylene are reacted at 120 ℃ under nitrogen protection, and the reaction is monitored by TLC to be complete. 100ml of water was added, extracted with ethyl acetate, dried and concentrated to give the product (12g, yield: 65%, HPLC purity: 98%).
The above product was put into a hydrogenation vessel, 2g of 10% palladium on carbon (containing about 63% water) and 150ml of ethanol were added, and hydrogen gas was introduced at 0.5 to 1.0MPa/50 ℃ for reaction. After completion of the reaction, filtration and concentration were carried out, 100ml of water was added to dissolve it, the pH was adjusted to about 5.5 with 1M hydrochloric acid, a solid was precipitated, suction-filtered and dried to obtain a pale yellow solid (9g, yield: 95%, HPLC purity: 99%).
1H NMR(600MHz,DMSO-d6,):δ6.51(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+]。
Example 4 one of the methods for preparing BPCA:
a250 ml reaction flask was charged with 10g of ethyl N- (2-hydroxyphenyl) carbamate, 13g of 3-bromobenzoic acid, 0.85g of RhCl (PPh)3)31.5g of tris (dimethylamino) phosphine, 72g of cesium carbonate and 150ml of toluene are refluxed under nitrogen and the reaction is monitored by TLC for completeness. 150ml of water was added, extracted with ethyl acetate, dried and concentrated to give the product (13g, yield: 78%, HPLC purity: 97%).
The above product was added to 100ml of water, 20ml of 6M hydrochloric acid was added thereto, stirring was carried out at 50 ℃ and, after completion of the reaction, filtration was carried out and the solid was washed with 30ml of ethanol to give a pale yellow solid (9.5g, yield: 90%, HPLC purity: 99%)
1H NMR(600MHz,DMSO-d6,):δ6.50(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+]。
Example 5 one of the methods for preparing BPCA:
a250 ml reaction flask was charged with 10g of tert-butyl N- (2-hydroxyphenyl) carbamate, 13g of 3- (p-toluenesulfonyloxy) benzoic acid, 1.6g of RhCl (PPh)3)31.0g of diisopropyl (2-tert-butyl) phenoxyphosphine, 28g of cesium carbonate and 150ml of toluene are refluxed under nitrogen, and the reaction is monitored by TLC for completeness. 150ml of water was added, extracted with ethyl acetate, dried and concentrated to give the product (11g, yield: 82%, HPLC purity: 98%).
The above product was added to 100ml of water, 20ml of 6M hydrochloric acid was added thereto, stirring was carried out at 50 ℃ and, after completion of the reaction, filtration was carried out and the solid was washed with 30ml of ethanol to give a pale yellow solid (5.8g, yield: 94%, HPLC purity: 99%)
1H NMR(600MHz,DMSO-d6,):δ6.51(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 (7)
1. A method for synthesizing an eltrombopag intermediate of formula (I), comprising:
(1) reacting a 2-aminophenol derivative shown in a formula (II) serving as a raw material with an arylating reagent shown in a formula (III) in toluene under the catalysis of a rhodium reagent/ligand and in the presence of cesium carbonate to obtain an intermediate product shown in a formula (IV); the rhodium reagent is selected from RhCl (PPh)3)3Or RhCl (cod)2The ligand is selected from triphenoxy phosphine, and
(2) a step of preparing an eltrombopag intermediate shown in formula (I) by using an intermediate shown in formula (IV) as a raw material:
wherein R is1Selected from NHBoc or NHCbz;
R2selected from the group consisting of halogen and tosyloxy.
2. The method of claim 1, wherein the halogen is F, Cl, Br, or I.
3. The synthesis method according to claim 1, wherein the rhodium reagent is used in an amount of 0.01 to 0.20 equivalent based on 1 mass of the 2-aminophenol derivative; the ligand is used in an amount of 0.01 to 0.40 equivalent.
4. The synthesis method according to claim 1, wherein the intermediate product represented by the formula (IV) is used as a raw material in the step (2) and subjected to hydrogenation reaction or reaction under acidic conditions to obtain the Eltrombopag intermediate represented by the formula (I).
5. The synthesis method according to claim 1, wherein the intermediate product shown in formula (IV) is used as a raw material in step (2) and palladium carbon is used as a catalyst to perform hydrogenation reaction to obtain the Eltrombopag intermediate shown in formula (I).
6. The synthesis method according to claim 1, wherein the intermediate product represented by the formula (IV) is used as a raw material in the step (2) and is reacted in a solvent to obtain the eltrombopag intermediate represented by the formula (I).
7. The method of claim 6, wherein the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, and dioxane.
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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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| 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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