CN114507186A - Preparation method of eltrombopag - Google Patents
Preparation method of eltrombopag Download PDFInfo
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- CN114507186A CN114507186A CN202111456562.3A CN202111456562A CN114507186A CN 114507186 A CN114507186 A CN 114507186A CN 202111456562 A CN202111456562 A CN 202111456562A CN 114507186 A CN114507186 A CN 114507186A
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- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 title claims abstract description 51
- 229960001069 eltrombopag Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000012535 impurity Substances 0.000 claims abstract description 20
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 15
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000007858 starting material Substances 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 229960000583 acetic acid Drugs 0.000 claims abstract description 9
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000000967 suction filtration Methods 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 21
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 235000010288 sodium nitrite Nutrition 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004537 pulping Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 5
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 5
- 238000007605 air drying Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 5
- 238000005303 weighing Methods 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 229940126460 thrombopoietin receptor agonist Drugs 0.000 description 2
- GJBBAPXESBCGRU-UHFFFAOYSA-N 2-(3,4-dimethylphenyl)-5-methyl-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(C)C(C)=C1 GJBBAPXESBCGRU-UHFFFAOYSA-N 0.000 description 1
- AAPGMCIBKOSNAL-UHFFFAOYSA-N 3-(2-methoxy-3-nitrophenyl)benzoic acid Chemical compound C1=CC=C([N+]([O-])=O)C(OC)=C1C1=CC=CC(C(O)=O)=C1 AAPGMCIBKOSNAL-UHFFFAOYSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 102000005763 Thrombopoietin Receptors Human genes 0.000 description 1
- 108010070774 Thrombopoietin Receptors Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—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
- 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/48—Oxygen atom in position 3 or 5 and nitrogen atom in position 4 with hydrocarbon radicals attached to said nitrogen atom
Abstract
The invention discloses a preparation method of eltrombopag, which comprises the following steps: 1. and (3) continuously reacting the starting material I, glacial acetic acid and hydrobromic acid in sequence until the reaction is finished to obtain an intermediate I. 2. And reducing the intermediate I by ammonium formate under the action of palladium catalysis to obtain an intermediate II. 3. And diazotizing the intermediate II to obtain the eltrombopag. The method avoids directly reducing nitro group with hydrogen under the premise of ensuring the quality of the medicine, and can safely enlarge the production. Meanwhile, the reaction can be completed more quickly on the basis of controlling the single maximum impurity of the Eltrombopag not to exceed 0.1 percent and the total impurity not to exceed 1.0 percent, so that the time of the preparation process can be further shortened, the preparation speed of the Eltrombopag is improved, and the market competitiveness of the Eltrombopag is enhanced.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a preparation method of eltrombopag.
Background
Eltrombopag (chemical name 3' - [ (2Z) - [1- (3, 4-dimethylphenyl) -1, 5-dihydro-3-methyl-5-oxo-4H-pyridin-4-ylidene)]Hydrazino-2 '-carboxy- [1,1' -biphenylyl]-3-carboxylic acid of formula C25H22N4O4) Is an oral thrombopoietin drug developed by Kudzein Steck, UK, is a small molecule thrombopoietin receptor agonist, can interact with the thrombopoietin receptor of the transmembrane region of the human body,produces a signal cascade amplification effect to induce proliferation and differentiation of bone marrow megakaryocytes, which is approved by the Food and Drug Administration (FDA) in the united states for marketing in 2008, 11 months, for treating thrombocytopenia in patients with chronic Idiopathic Thrombocytopenic Purpura (ITP) who are ineffectively treated by glucocorticoids, immunoglobulins or splenectomy, and eltrombopag, which is the first oral nonpeptidic thrombopoietin receptor agonist approved for treating adult chronic ITP patients, is an important milestone in the approval of treating ITP patients, and is currently under clinical study for treating hepatitis c virus, chronic liver diseases and tumor-related thrombocytopenia.
For example, the preparation process of the drug eltrombopag for treating idiopathic thrombocytopenic purpura disclosed in chinese patent CN201710766607.4 reduces toxic components of the drug, is beneficial to the subsequent preparation of the drug and ensures the quality of the product, and can promote the economic and technical development of the bulk drug of eltrombopag, but according to the preparation process of the invention, the drug eltrombopag is prepared, wherein the chemical reaction process is complicated, the raw materials are difficult to obtain, the production cost is increased, the method is not suitable for mass production, and the nitro group is reduced by using hydrogen, which is not beneficial to the realization of industrialization, so that the preparation method of eltrombopag is provided to solve the problems.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of eltrombopag, which has the advantages of safer high-efficiency preparation process and the like, and solves the problems of difficult industrialization and long preparation process in the reaction process.
In order to realize the purpose that the high-efficiency preparation process is safer and more environment-friendly, the invention provides the following technical scheme:
the preparation method of eltrombopag is characterized by comprising the following steps:
1) sequentially taking the initial raw material I, glacial acetic acid and hydrobromic acid for reaction, performing suction filtration after the reaction is finished, and drying a filter cake to obtain an intermediate I
Starting material I intermediate I
Starting material I: glacial acetic acid: the equivalent ratio of hydrobromic acid is 1:11.7vol:5.85 vol;
2) the intermediate I generates an intermediate II under the reduction action of a palladium catalyst and ammonium formate in water;
intermediate II
An intermediate I: the palladium catalyst is as follows: the equivalent ratio of ammonium formate is 1:2% -12% w/w:2-5;
3) diazotizing the intermediate II and the initial raw material II under the action of hydrochloric acid and sodium nitrite to generate an eltrombopag crude product; recrystallizing to obtain Eltrombopag;
the molar ratio of the intermediate II to the sodium nitrite to the initial raw material II is 1:1.05: 1. Wherein the hydrobromic acid is an aqueous solution diluted to 48% with hydrobromic acid. The palladium catalyst is palladium carbon, palladium hydroxide or palladium chloride; the palladium on carbon means: 2 to 5 percent of palladium is loaded on the active carbon, and the content of the palladium carbon is 2 to 5 percent. The ammonium formate is anhydrous ammonium formate.
The recrystallization solvent is tetrahydrofuran/n-hexane or 2-methyltetrahydrofuran/petroleum ether. Preferably, the recrystallization solvent is tetrahydrofuran/n-hexane in a ratio of 1: 3.
the invention further discloses application of the eltrombopag prepared by the method in preparing high-quality eltrombopag; the high-quality Eltrombopag refers to that: the impurity amount of the Eltrombopag is effectively controlled, the single impurity is controlled to be 0.03 percent, and the total impurity is controlled to be 0.24 percent. The experimental results show that the individual and total miscellaneous amounts of each batch of Eltrombopag in the examples meet this criterion.
The present invention is described in more detail as follows:
a preparation method of eltrombopag comprises the following steps:
1) sequentially taking the starting material I, glacial acetic acid and hydrobromic acid for reaction, performing suction filtration after the reaction is finished, and drying a filter cake to obtain an intermediate I;
2) the intermediate I generates an intermediate II under the reduction action of a palladium catalyst and ammonium formate in water;
3) diazotizing the intermediate II and the initial raw material II under the action of hydrochloric acid and sodium nitrite to generate an eltrombopag crude product; then the eltrombopag is prepared by recrystallization.
The hydrobromic acid is an aqueous solution diluted to 48% with hydrobromic acid.
The palladium catalyst comprises palladium carbon, palladium hydroxide and palladium chloride.
The palladium carbon is prepared by loading 2-5% of palladium on active carbon, and the content of the palladium carbon is 2-5%.
The ammonium formate is anhydrous ammonium formate.
The recrystallization solvent is tetrahydrofuran/n-hexane, 2-methyltetrahydrofuran/petroleum ether, wherein when the recrystallization solvent is tetrahydrofuran/n-hexane, the ratio is 1: 3.
the quality control standard of the eltrombopag prepared by the invention mainly comprises the following steps: under the condition of normal temperature storage, the finished product is red or brown crystal powder, is slightly soluble in water, and has the single maximum impurity of not more than 0.1 percent and the total impurity of not more than 1.0 percent.
Compared with the prior art, the preparation method of eltrombopag disclosed by the invention has the following beneficial effects:
(1) according to the preparation method of the eltrombopag, the eltrombopag is obtained by performing demethylation and reduction on an initial raw material I, and performing diazotization addition on the initial raw material I and an initial raw material II. In the process, the initial raw materials are easy to obtain, the reaction route is simple, and the operability is strong.
(2) The preparation method of the Eltrombopag has the advantages that the nitro group is reduced by the ammonium formate in the step 2), so that the chemical reaction process is accelerated, the preparation time is shortened, and the problem that the nitro group is not beneficial to industrialization by hydrogen reduction is solved.
(3) The preparation method of the eltrombopag comprises the following steps of 3), controlling the ratio of the intermediate II, the initial raw material II and the sodium nitrite to be 1:1.05, the reaction can be faster on the basis of controlling the impurities (the single maximum impurity is not more than 0.1 percent, and the total impurity is not more than 1.0 percent), the time of the preparation process can be further shortened, the preparation speed of the Eltrombopag is improved, and the competitiveness of enterprises is enhanced.
(4) The reaction has high yield and purity and high safety, and meets the requirement of industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be described in detail and completely with reference to the specific embodiments of the present application. It should be apparent that the described embodiments are only some of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Wherein the starting material I (2 '-methoxy-3' -nitrobiphenyl-3-carboxylic acid) and the starting material II (3-methyl-1- (3, 4-dimethylphenyl) -2-pyrazoline-5-one) are purchased from Shanghai Baiyi Biotech limited company.
Example 1
The preparation method of the eltrombopag comprises the following steps:
1) 34.10g of the starting material I, 400ml of glacial acetic acid and 200ml of hydrobromic acid (48%) are weighed into a 1L three-necked flask, the stirring is started, the temperature is raised to 120 ℃, the reaction is carried out for 3 hours, and the reaction is stopped. Cooling to 25 ℃, carrying out suction filtration, pulping a filter cake by using about 400ml of water, carrying out suction filtration, and drying at 55 ℃ for 6 hours to obtain 30.7g of a yellow-green solid intermediate I, wherein the yield is 94.9%, and the purity is as follows: 96.5 percent;
1HNMR(400MHz,d6DMSO)δ13.90（s,1H）,10.66(s,1H),8.12(t,J=1.7Hz,1H),
8.07(dd,J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H),7.17(dd,J=8.4,7.5Hz,1H)；
2) weighing 30g of intermediate I, 1.2g of Pd/C, 21.89g of ammonium formate, 33.2g of sodium acetate and 150ml of water in a 500ml three-necked bottle, heating to 85 ℃, cooling to room temperature after reacting for two hours, carrying out suction filtration, cooling the filtrate to 5 ℃, adjusting the pH value to 7-8 with concentrated hydrochloric acid, carrying out suction filtration, washing the filter cake with 50ml of water, and carrying out forced air drying at 55 ℃. 19.05g of intermediate II are obtained as a light brown solid in 71.8% yield and with a purity: 97.6 percent;
1HNMR(400MHz,d6DMSO)11.3-8.7(brs,4H),8.08(s,1H),7.95(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),7.04(t,J=7.8Hz,1H)；
3) 19.05g of intermediate II and 285ml of hydrochloric acid (2M) are weighed into a 1L three-necked flask, 96ml of aqueous solution of 6.12g of sodium nitrite is added into the system at the temperature of 0 ℃, the starting material II is added at the temperature of 0 ℃, 379ml of ethanol is added after stirring for 0.5h, and the pH value is adjusted to 7-8 by sodium bicarbonate. Stirring for 24 hours at room temperature, then carrying out suction filtration, pulping a filter cake for 0.5 hour by using 421ml of water, carrying out suction filtration, acidifying and pulping the filter cake for 0.5 hour by using 421ml of concentrated hydrochloric acid, carrying out suction filtration, heating the filter cake to reflux and dissolve the filter cake clearly by using 126ml of tetrahydrofuran and 379ml of n-hexane, cooling to 0 ℃, continuously stirring for 2 hours, carrying out suction filtration, and after filtration, putting the solid into 55 ℃ for forced air drying for 12 hours to obtain 12.47g of dark red solid, wherein the yield is 33.9%, and the purity is as follows: 99.5 percent;
1HNMR(400MHz,d6DMSO)13.76(s,1H),13.12(s,1H),9.70(s,1H),8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),2.34(s,3H),2.27(s,3H),2.23(s,3H)；
the eltrombopag prepared by the formula and the process has the single impurity content of 0.06 percent and the total impurity content of 0.35 percent, is suitable for treating most of patients with platelet deficiency, and improves the competitiveness of enterprises.
Example 2
The preparation method of the eltrombopag comprises the following steps:
1) 341g of the starting material I, 4L of glacial acetic acid and 2L of hydrobromic acid (48%) are weighed into a 1L three-necked flask, the stirring is started, the temperature is raised to 120 ℃, and the reaction is stopped after 3 hours of reaction. Cooling to 25 ℃, performing suction filtration, pulping a filter cake by using about 4L of water, performing suction filtration, drying at 55 ℃ for 6 hours, obtaining 310g of a yellow-green solid intermediate I, wherein the yield is 95.8%, and the purity is as follows: 96.7 percent;
1HNMR(400MHz, d6DMSO)δ13.90（s,1H）,10.66(s,1H),8.12(t,J=1.7Hz,1H),8.07
(dd,J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(d d,J=7.5,1.7Hz,1H),7.17
(dd,J=8.4,7.5Hz,1H)；
2) weighing 300g of intermediate I, 6g of Pd/C, 265.26g of ammonium formate, 388.56g of sodium acetate and 1.5L of water in a 5L three-necked flask, heating to 85 ℃, reacting for two hours, cooling to room temperature for suction filtration, cooling the filtrate to 5 ℃, adjusting the pH to 7-8 with concentrated hydrochloric acid, suction filtration, washing the filter cake with 500ml of water, and drying by blowing at 55 ℃ to obtain 193.14g of light brown solid intermediate II, wherein the yield is 72.8%, and the purity is as follows: 97.3 percent;
1HNMR(400MHz,d6DMSO)1.3-8.7(brs,4H),8.08(s,1H),7.95(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),7.04(t,J=7.8Hz,1H)；
3) 190g of the intermediate II and 2.86L of hydrochloric acid (2M) are weighed into a 10L four-neck flask, 61.04g of 0.96L of aqueous solution of sodium nitrite is added into the system at the temperature of 0 ℃, the starting material II is added at the temperature of 0 ℃, 3.78L of ethanol is added after stirring for 0.5h, and the pH value of sodium bicarbonate is adjusted to 7-8. Stirring for 24 hours at room temperature, then carrying out suction filtration, pulping a filter cake for 0.5 hour by using 4.2L of water, carrying out suction filtration, acidifying and pulping the filter cake for 0.5 hour by using 4.2L of concentrated hydrochloric acid, carrying out suction filtration, heating the filter cake to reflux and dissolve the filter cake clearly by using 1.26L of tetrahydrofuran and 3.78L of n-hexane, cooling to 0 ℃, continuously stirring for 2 hours, carrying out suction filtration, putting the solid into 55 ℃, carrying out forced air drying for 12 hours to obtain 128.72g of dark red solid, wherein the yield is 35.1 percent, and the purity is as follows: 99.1 percent;1HNMR(400MHz,d6DMSO)13.76(s,1H),13.12(s,1H),9.70(s,1H),8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),2.34(s,3H),2.27(s,3H),2.23(s,3H)；
according to the formula and the process, the single impurity of the eltrombopag is 0.05 percent, the total impurity of the eltrombopag is 0.30 percent, and the mass ratio of the used palladium carbon to the intermediate I is 2 percent, so the preparation cost is low, and the eltrombopag is suitable for popularization, production and preparation.
Example 3
The preparation method of the eltrombopag comprises the following steps:
1) 3.41g of the starting material I, 40ml of glacial acetic acid and 20ml of hydrobromic acid (48%) are weighed into a 100ml three-necked flask, the stirring is started, the temperature is raised to 120 ℃ and the reaction is stopped after 3 hours of reaction. Cooling to 25 ℃, performing suction filtration, pulping a filter cake by using about 40ml of water, performing suction filtration, and drying at 55 ℃ for 6 hours to obtain 3.10g of a yellow-green solid intermediate I, wherein the yield is as follows: 92.7%, purity: 96.1 percent;
1HNMR(400MHz, d6DMSO)δ13.9（s,1H）,10.66(s,1H),8.12(t,J=1.7Hz,1H),
8.07(dd,J=8.4,1.7Hz,1H), 7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H)
,7.17(dd,J=8.4,7.5Hz,1H)；
2) weighing 3g of intermediate I, 0.3g of Pd/C, 1.33g of ammonium formate and 2.18g of sodium acetate 15ml of water, putting the mixture into a 100ml three-necked flask, heating the mixture to 85 ℃, reacting for two hours, cooling the mixture to room temperature, carrying out suction filtration, cooling the filtrate to 5 ℃, adjusting the pH value to 7-8 by using concentrated hydrochloric acid, carrying out suction filtration, washing the filter cake by using 5ml of water, and carrying out forced air drying at 55 ℃ to obtain 1.86g of light brown solid intermediate II, wherein the yield is 69.6 percent, and the purity is as follows: 98.0 percent;
1HNMR(400MHz,d6DMSO)1.3-8.7(brs,4H),8.08(s,1H) ,7.95(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),7.34(dd,J=7.8,1.4Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),7.04(t,J=7.8Hz,1H)；
3) weighing 1.86g of intermediate II and 28ml of 2M hydrochloric acid in a 100ml three-necked flask, adding 10ml of aqueous solution of 0.60g of sodium nitrite into the system at the temperature of 0 ℃, adding the starting material II at the temperature of 0 ℃, stirring for 0.5 hour, adding 37ml of ethanol, and adjusting the pH value to 7-8 by sodium bicarbonate. Stirring at room temperature for 24 hours, then carrying out suction filtration, pulping a filter cake for 0.5 hour by using 41ml of water, carrying out suction filtration, acidifying and pulping the filter cake for 0.5 hour by using 41ml of concentrated hydrochloric acid, carrying out suction filtration, heating the filter cake by using 12ml of tetrahydrofuran and 37ml of n-hexane until the filter cake is refluxed and dissolved, then cooling to 0 ℃, continuously stirring for 2 hours, then carrying out suction filtration, and after filtration, putting the solid into 55 ℃ for forced air drying for 12 hours to obtain 0.14g of dark red solid, wherein the yield is 31.9%, and the purity: 99.5 percent;
1HNMR(400MHz,d6DMSO) 13.76(s,1H),13.12(s,1H),9.70(s,1H),8.14(s,1H),7.81(dd,J=7.7Hz,1H),7.74-7.60(m,5H),7.22-7.13(m,3H),2.34(s,3H),2.27(s,3H),2.23(s,3H)；
the eltrombopag prepared by the formula and the process has the advantages of 0.03 percent of single impurity, 0.24 percent of total impurities, small reaction scale, high preparation speed, improved preparation efficiency of the product, and capability of being used as a common medicine.
The invention has the beneficial effects that the eltrombopag is obtained by demethylating and reducing the initial raw material I and diazotizing the initial raw material II. In the process, the initial raw materials are easy to obtain, the reaction route is simple, and the operability is strong. By reducing the nitro group with ammonium formate in the step 2, the chemical reaction process can be accelerated, the preparation time can be shortened, and the problem that the nitro group is not beneficial to industrialization by hydrogen reduction is solved. Controlling the ratio of the intermediate II, the initial raw material II and the sodium nitrite to be 1:1.05, the reaction can be faster on the basis of controlling impurities, the time of the preparation process can be further shortened, the preparation speed of the Eltrombopag is improved, and the competitiveness of enterprises is enhanced.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. The preparation method of eltrombopag is characterized by comprising the following steps:
1) sequentially taking the initial raw material I, glacial acetic acid and hydrobromic acid for reaction, performing suction filtration after the reaction is finished, and drying a filter cake to obtain an intermediate I
Starting Material I intermediate I
Starting material I: glacial acetic acid: the equivalent ratio of hydrobromic acid is 1:11-12vol:5-6 vol;
the hydrobromic acid refers to: 48% aqueous hydrobromic acid;
the intermediate I is subjected to reduction action of a palladium catalyst and ammonium formate in water to generate an intermediate II;
intermediate II
The equivalent ratio of the intermediate I, the palladium catalyst and the ammonium formate is 1: 2-12% w/w:2-5; the palladium catalyst is palladium carbon, palladium hydroxide or palladium chloride;
3) diazotizing the intermediate II and the initial raw material II under the action of hydrochloric acid and sodium nitrite to generate an eltrombopag crude product; recrystallizing to obtain Eltrombopag;
eltrombopag
The molar ratio of the intermediate II to the sodium nitrite to the initial raw material II is 1:1-2.5: 1-2.
2. The production method as described in claim 1, wherein the palladium on carbon in the palladium catalyst means: 2 to 5 percent of palladium is loaded on the active carbon, and the content of the palladium carbon is 2 to 5 percent.
3. The method according to claim 1, wherein the recrystallization solvent is tetrahydrofuran/n-hexane or 2-methyltetrahydrofuran/petroleum ether.
4. The process of claim 1 wherein the recrystallization solvent is tetrahydrofuran/hexane in a ratio of 1: 3-4.
5. Use of eltrombopag prepared by the method of claim 1 for preparing high quality eltrombopag; the high-quality Eltrombopag refers to that: the impurity amount of the Eltrombopag is effectively controlled, the single impurity is controlled to be 0.03 percent, and the total impurity is controlled to be 0.24 percent.
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| CN111518029A (en) * | 2020-06-04 | 2020-08-11 | 南京恒通医药开发有限公司 | Continuous production process of eltrombopag |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1444477A (en) * | 2000-05-25 | 2003-09-24 | 史密丝克莱恩比彻姆公司 | Thrombopoietin mimetics |
| 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 |
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444477A (en) * | 2000-05-25 | 2003-09-24 | 史密丝克莱恩比彻姆公司 | Thrombopoietin mimetics |
| 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 |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111518029A (en) * | 2020-06-04 | 2020-08-11 | 南京恒通医药开发有限公司 | Continuous production process of eltrombopag |
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