CN101921260B - Method for preparing imatinib - Google Patents
Method for preparing imatinib Download PDFInfo
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- CN101921260B CN101921260B CN 201010283894 CN201010283894A CN101921260B CN 101921260 B CN101921260 B CN 101921260B CN 201010283894 CN201010283894 CN 201010283894 CN 201010283894 A CN201010283894 A CN 201010283894A CN 101921260 B CN101921260 B CN 101921260B
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Abstract
The invention relates to a method for preparing imatinib, which comprises the following steps of: with a compound N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine shown as the structural formula (II) and a compound 4-[(4-Methylpiperazin-l-yl)methyl]benzoic acid shown as the structural formula (III) as initial raw materials, dropwise adding phosphite ester at 50-90 DEG C for 1-2 hours inthe presence of a catalyst in an organic solvent; and continuously insulating and reacting at 50-90 DEG C to obtain the compound imatinib shown as the structural formula (I). The organic solvent is N,N-dimethylformamide, N,N-dimethylacetylamide or N-methylpyrrolidone. The catalyst is pyridine; and the phosphite ester is trimethyl phosphate, triethyl phosphate or triphenyl phosphate. The technical scheme of the invention has the advantages of simple reaction step, easy control of reaction, short production cycle, low toxicity of used raw materials, less pollution to the environment and higher product quality, and the yield can reach 95 percent, and the purity reaches 99.5 percent.
Description
Technical field
The present invention relates to a kind of chronic myelocytic leukemia and gastrointestinal stromal tumors medicine preparation method, relate in particular to a kind of preparation method of imatinib.
Background technology
Imatinib is to be used for the treatment of chronic myelogenous leukemia (Chronic Myelogenous Leukemia, be called for short CML) adult patient of chronic phase patient after acute transformation phase, acceleration period or the alpha-interferon therapy failure and the treatment malignant gastrointestinal mesenchymal neoplasm (GastrointestInal stroml tumor is called for short GIST) that can not excise and/or shift.
Imatinib, trade(brand)name: imatinib mesylate, chemical name: 4-[(4-methyl isophthalic acid-piperazinyl) methyl] N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] the benzamide mesylate, white or off-white color crystalline powder, structural formula is as follows:
Chemagis Ltd discloses take N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (II) and 4-(4-methylpiperazine methyl) Benzoyl chloride (IV) as raw material at patent US 2006149061, the synthetic imatinib (I) take pyridine as acid binding agent, yield reaches 70%.Similarly, Natco Pharma Ltd discloses (II) and (IV) for raw material at patent WO2008136010 and WO2008117298 respectively, respectively take potassium hydroxide and salt of wormwood as the synthetic imatinib (I) of acid binding agent.The main drawback of the method is that cost is higher take acyl chlorides (IV) as raw material, and yield (I) is lower, and equipment is had corrosion, is not suitable for suitability for industrialized production.
Univ Texas discloses respectively take 4-(4-methylpiperazine methyl) phenylformic acid (III) as raw material at patent WO2008024829 and WO2008103305; add sulfur oxychloride and carry out acidylate one-tenth (IV); take pyridine as acid binding agent with (II) carry out condensation and prepare imatinib (I), yield reaches respectively 60% and 88%.The shortcoming of this technique is at first (III) will be carried out acyl chlorides to change into (IV), and synthesis step is long, and yield is low.
Patent IN2003MU01073 discloses sodium salt take (III) as raw material, with the pivaloyl chloride reaction, adds take diisopropylethylamine as acid binding agent and (II) carries out condensation and prepare imatinib (I) in methylene dichloride.This technique shortcoming mainly is to use pivaloyl chloride to participate in reaction in the building-up process, and step is long, and cost is high.
Patent WO2008135980 and US2008275055 disclose respectively in the THF solvent take (II) with (III) as raw material, take EDC as dehydrating agent, and synthetic imatinib (I), yield 76%.Similarly, Monatshefte fuerChemie, 2009,140 (6), 619-623 has also reported (II) and (III) take diimidazole base ketone as condensing agent, has synthesized imatinib (I), yield 85%.Although this technique synthesis step is short, can carry out one pot reaction, the yield of the finished product is low.
Patent IN2007CH00006 disclose with (III) hydrochloride with in the triethylamine and after, under benzotriazole and DCC condition, react preparation imatinib (I) with compound (II).But the shortcoming of this technique be reaction yield (85%) on the low side.
Summary of the invention
The application's goal of the invention is skill restriction and the shortcoming of improving imatinib preparation method worker in the prior art, develops the preparation method of a kind of imatinib of a cheaply environmental protection safe technology route.
Technical scheme of the present invention comprises:
Develop a kind of preparation method of imatinib, it is characterized in that:
Take the compound N shown in structural formula (II)-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine) and the compound 4-shown in structural formula (III) (4-methylpiperazine methyl) phenylformic acid (4-[(4-Methylpiperazin-1-yl) methyl] benzoic acid) as starting raw material, in organic solvent under the effect of catalyzer, drip phosphorous acid ester at 50～90 ℃, drip in 1～2 hour, continuation prepares the compound imatinib shown in structural formula (I) 50～90 ℃ of insulation reaction;
Described organic solvent is DMF, N,N-dimethylacetamide or N-Methyl pyrrolidone;
Described catalyzer is pyridine;
Described phosphorous acid ester is trimethyl phosphite, triethyl-phosphite or triphenyl phosphite.
The preparation method of above-mentioned a kind of imatinib is characterized in that the mol ratio of described reaction raw materials is:
Compound (II): compound (III): phosphorous acid ester=1: 0.8～1.2: 0.8～1.2.
The preparation method of above-mentioned a kind of imatinib is characterized in that described raw material and the mass/volume ratio of organic solvent are:
The quality summation of compound I I and compound III: organic solvent volume=1: 3.3～10.
The preparation method of above-mentioned a kind of imatinib is characterized in that the mass ratio of described compound I I and catalyzer is: 1: 0.001～0.1.
The preparation method of above-mentioned a kind of imatinib, the time that it is characterized in that described dropping phosphorous acid ester is 1～2 hour; The insulation reaction time is 1.5～3 hours; 50～90 ℃ of dropping and insulation reaction temperature.
Advantage of the present invention is:
1. reactions steps is simple, and reaction is easy to control, and is with short production cycle;
2. raw materials used is hypotoxicity, and environmental pollution is little;
3. quality product is better, and yield can reach 95%, and purity reaches 99.5%.
Embodiment:
With the following Examples the present invention is further detailed, but the scope of protection of present invention is not limited to the present invention the scope that represents among the embodiment in order better to explain.
Embodiment 1
Magnetic agitation, thermometer and reflux condensing tube are installed in the there-necked flask of 2000ml, the compound (II) that adds 27.7g (100mmol), 24.6g compound (III), 0.5ml pyridine and the N of 450ml, the N-N,N-DIMETHYLACETAMIDE, be heated to 80-85 ℃, drip the trimethyl phosphite of 32.6g in half an hour, under this temperature, continue reaction 2 hours.Be down to room temperature, add 450ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 46.9g imatinib (HPLC:99.6%), yield 95.0%.
Embodiment 2
Magnetic agitation, thermometer and reflux condensing tube are installed in the there-necked flask of 2000ml, the imatinib intermediate (II) that adds 27.7g (100mmol), 23.4g imatinib intermediate (III) (100mmol), 0.5ml pyridine and the N of 500ml, dinethylformamide, be heated to 50 ℃, drip the triphenyl phosphite of 31.0g (100mmol) in 2 hours, under this temperature, continue reaction 3 hours.Be down to room temperature, add 500ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 43.9g imatinib (HPLC:99.45%), yield 89.0%.
Embodiment 3
Magnetic agitation, thermometer and reflux condensing tube are installed in the there-necked flask of 2000ml, the imatinib intermediate (II) that adds 27.7g (100mmol), 28.1g imatinib intermediate (III) (120mmol), 0.1ml pyridine and the N-Methyl pyrrolidone of 180ml, be heated to 90 ℃, drip the triphenyl phosphite of 37.2g (120mmol) in 2 hours, under this temperature, continue reaction 1.5 hours.Be down to room temperature, add 180ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 40.0g imatinib (HPLC:99.6%), yield 81.2%.
Embodiment 4
Magnetic agitation, thermometer and reflux condensing tube are installed in the there-necked flask of 2000ml, the imatinib intermediate (II) that adds 22.1g (80mmol), 23.4g imatinib intermediate (III) (100mmol), 0.5ml pyridine and the N of 500ml, the N-N,N-DIMETHYLACETAMIDE, be heated to 50 ℃, drip the triethyl-phosphite of 16.6g (100mmol) in 2 hours, under this temperature, continue reaction 3 hours.Be down to room temperature, add 500ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 35.7g imatinib (HPLC:99.63%), yield 72.3%.
Embodiment 5
Stirring, thermometer and reflux condensing tube are installed in the reactor of 20 liters, the compound (II) that adds 277g, the compound of 246g (III), the pyridine of 5ml and the N of 4500ml, the N-N,N-DIMETHYLACETAMIDE, be heated to 80-85 ℃, drip the trimethyl phosphite of 326g in half an hour, under this temperature, continue reaction 2 hours.Be down to room temperature, add 4500ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 469g imatinib (HPLC:99.6%), yield 95.13%.
Embodiment 6
Stirring, thermometer and reflux condensing tube are being installed in the reactor of 20 liters, the imatinib intermediate (II) that adds 277g, the imatinib intermediate (III) of 234g, the pyridine of 5ml and the N of 5000ml, dinethylformamide, be heated to 50 ℃, drip the triphenyl phosphite of 310g in 2 hours, under this temperature, continue reaction 3 hours.Be down to room temperature, add 5000ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 439g imatinib (HPLC:99.7%), yield 89.05%.
Embodiment 7
Stirring, thermometer and reflux condensing tube are being installed in the reactor of 20 liters, the imatinib intermediate (II) that adds 277g, the imatinib intermediate (III) of 281g, the pyridine of 1ml and the N-Methyl pyrrolidone of 1800ml, be heated to 90 ℃, drip the triphenyl phosphite of 372g in 2 hours, under this temperature, continue reaction 1.5 hours.Be down to room temperature, add 1800ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 400g imatinib (HPLC:99.5%), yield 81.14%.
Embodiment 8
Stirring, thermometer and reflux condensing tube are being installed in the reactor of 20 liters, the imatinib intermediate (II) that adds 221g, the imatinib intermediate (III) of 234g, the pyridine of 5ml and the N of 5000ml, the N-N,N-DIMETHYLACETAMIDE, be heated to 50 ℃, drip the triethyl-phosphite of 166g in 2 hours, under this temperature, continue reaction 3 hours.Be down to room temperature, add 5000ml water, dichloromethane extraction is spin-dried for, and uses the acetonitrile recrystallization, and vacuum-drying gets 470.82g imatinib (HPLC:99.6%), yield 95.5%.
Claims (5)
1. the preparation method of an imatinib is characterized in that:
Take the compound N shown in structural formula (II)-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine and the compound 4-shown in structural formula (III) (4-methylpiperazine methyl) phenylformic acid as starting raw material, in organic solvent under the effect of catalyzer, drip phosphorous acid ester at 50～90 ℃, drip in 1～2 hour, continuation prepares the compound imatinib shown in structural formula (I) 50～90 ℃ of insulation reaction;
Described organic solvent is DMF, N,N-dimethylacetamide or N-Methyl pyrrolidone;
Described catalyzer is pyridine;
Described phosphorous acid ester is trimethyl phosphite, triethyl-phosphite or triphenyl phosphite.
2. according to the preparation method of a kind of imatinib claimed in claim 1, it is characterized in that the mol ratio of reaction raw materials is:
Compound (II): compound (III): phosphorous acid ester=1: 0.8～1.2: 0.8～1.2.
3. according to the preparation method of a kind of imatinib claimed in claim 1, it is characterized in that the mass volume ratio of described raw material and organic solvent is:
The quality summation of compound I I and compound III: organic solvent volume=1: 3.3～10.
4. according to the preparation method of a kind of imatinib claimed in claim 1, it is characterized in that the mass ratio of compound I I and catalyzer is: 1: 0.001～0.1.
5. according to the preparation method of a kind of imatinib claimed in claim 1, the time that it is characterized in that described dropping phosphorous acid ester is 1～2 hour; The insulation reaction time is 1.5～3 hours; 50～90 ℃ of dropping and insulation reaction temperature.
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| CN 201010283894 CN101921260B (en) | 2010-09-16 | 2010-09-16 | Method for preparing imatinib |
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| CN 201010283894 CN101921260B (en) | 2010-09-16 | 2010-09-16 | Method for preparing imatinib |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796079B (en) * | 2011-05-27 | 2016-06-29 | 江苏豪森药业集团有限公司 | A kind of preparation method of methanesulfonic acid fluorine imatinib |
| CN105585556A (en) * | 2014-11-13 | 2016-05-18 | 连云港杰瑞药业有限公司 | Synthetic method of imatinib |
| CN106905296B (en) * | 2017-03-02 | 2019-07-19 | 南京优科制药有限公司 | A kind of preparation method of imatinib mesylate |
| CN108752314A (en) * | 2018-06-02 | 2018-11-06 | 安徽海康药业有限责任公司 | A kind of synthetic method of Imatinib |
| CN111187283A (en) * | 2020-03-20 | 2020-05-22 | 陶志泽 | Synthesis process of cefazedone sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096364A (en) * | 2006-06-26 | 2008-01-02 | 山东金城医药化工有限公司 | New technique for catalytic synthesis of AE active ester |
| CN101677955A (en) * | 2007-03-12 | 2010-03-24 | 雷迪博士实验室有限公司 | imatinib mesylate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096364A (en) * | 2006-06-26 | 2008-01-02 | 山东金城医药化工有限公司 | New technique for catalytic synthesis of AE active ester |
| CN101677955A (en) * | 2007-03-12 | 2010-03-24 | 雷迪博士实验室有限公司 | imatinib mesylate |
Non-Patent Citations (2)
| Title |
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| 戈平等.含磷缩合剂在药物和肽合成中的应用.《中国医药工业杂志》.1990,第21卷(第1期),第33-36页. * |
| 曾加宁等.有机磷试剂在肽合成中的应用.《有机化学》.1988,第8卷(第5期),第398-406页. * |
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL GROUP CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL & CHEMICAL Co.,Ltd. |
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Effective date of registration: 20201215 Address after: No.26, Kunxin Road, Kui Si Village, Kunlun town, Zichuan District, Zibo City, Shandong Province Patentee after: Shandong Jincheng Kunlun Pharmaceutical Co.,Ltd. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL GROUP Co.,Ltd. |
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