CN102796074B - Method for preparing imatinib mesylate intermediate - Google Patents
Method for preparing imatinib mesylate intermediate Download PDFInfo
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- CN102796074B CN102796074B CN201210206262.4A CN201210206262A CN102796074B CN 102796074 B CN102796074 B CN 102796074B CN 201210206262 A CN201210206262 A CN 201210206262A CN 102796074 B CN102796074 B CN 102796074B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a method for preparing N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrilamine (I) serving as an imatinib mesylate intermediate. The method comprises the following steps of: performing condensation reaction by using 4-(3-pyridyl) pyrimidine-2-amine (II) and 2-bromo-4-amino-toluene (III) in a one-pot mode; and removing amino protecting groups of the 2-bromo-4-amino-toluene (III) by strong acid or weak base to generate the N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrilamine (I) serving as the imatinib mesylate intermediate in one step. By the method, the steps for preparing the imatinib are reduced obviously, and the cost is reduced substantially.
Description
Technical field
The present invention relates to methodology of organic synthesis design and bulk drug and Intermediate Preparation technology, particularly a kind of preparation method of imatinib mesylate intermediate.
Background technology
Imatinib mesylate is the tyrosine kinase inhibitor class medicine researched and developed by Novartis Co., Ltd of Switzerland, is used for the treatment of chronic lymphocytic leukemia (CML) and Gastrointestinal Stromal cell tumour (GIST).Imatinib, as the molecular targeted therapy of first listing, has started the epoch of tumor cells targeted therapy, is described as landmark discovery.Imatinib mesylate respectively at calendar year 2001 and 2002 with Glivec (imatinib mesylate) in the U.S. and Discussion on Chinese Listed.
The active pharmaceutical ingredients of imatinib mesylate is imatinib, chemistry 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-by name [(4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl] benzamide, molecular formula is as follows:
The report of the synthetic method of above-mentioned imatinib and intermediate is a lot, can with reference to following patent: EP223116, EP2152267, EP2146978, EP2076507, EP2074095, EP1966186, EP1896447, EP1833815, EP1804800, EP1696917, EP1599462, US7674901, US7507821, US7638627, US5521184, US20060149061, US20060223817, US20040248918, WO200306613, WO2004074502, WO20040108699, WO2008051597, CN101528700, CN101701015, CN102250062, CN102276518, CN1077713, CN1900073, CN1016293, it is, in the selection of synthon and the precedence of assembling, be summed up several synthetic methods as follows that difference in these synthetic methods is mainly reflected in:
Article 1, synthetic method, first passes through the link of piperazine fragment and nitro fragment, then by nitroreduction and guanidinated reaction, final and piperidines fragment is obtained by reacting imatinib.This design reactions steps is many, and each group constantly adds up, and total recovery is low, is not suitable with industrialized development.
Article 2 synthetic method, first by preparing piperazine fragment, then bromo-4-amido toluene is condensed into active piperazines fragment with 2-, then with intermediate 4-(3-pyridyl) pyrimidine-2-amine (II) condensation, obtain imatinib.This method of design make use of intermediate II as synthon, decreases reactions steps, and total recovery is increased.But the mode progressively added up owing to still adopting functional group in method of design, and the last two steps is the not too high condensation reaction of yield, therefore also constrains the practical application of the method.
Article 3 synthetic method is for raw material with 4-(3-pyridyl) pyrimidine, 2-chloro-4-(3-pyridyl) pyrimidine is generated through superchlorination, obtain important itrated compound fragment with p-nitro-o-aminotoluene coupling again, itrated compound fragment obtains aminate fragment by reduction.Then imatinib is obtained by condensation, salify.Required intermediate (or synthon) synthesizes by the method in advance, synthesis step is greatly reduced, improves total reaction yield, but use highly toxic product phosphorus oxychloride during the method chlorination, larger on affecting environmental influence.
Article 4 synthetic method, first with obtained guanidine derivative and piperidine derivative for raw material, through a step condensation directly obtained itrated compound fragment, then obtain aminate fragment by reduction.Then imatinib is obtained by condensation, salify.The method is also by first preparing aminate intermediate compound I, then synthesizes imatinib thus.But the step of the method is more, first to passes through itrated compound catalytic hydrogenation more equally, total yield is decreased.
Summary of the invention
The object of the invention is to, for above-mentioned defect of the prior art, provide a kind of preparation method of imatinib mesylate intermediate of improvement, it makes the manufacturing step of imatinib obviously reduce, and cost significantly reduces.
For achieving the above object, the invention provides a kind of for the preparation of the method such as formula the imatinib mesylate intermediate N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (abbreviation aminate) shown in I
The method comprising the steps of:
Condensation reaction is carried out by treating different things alike with the bromo-4-amino-toluene of 2-such as formula known imatinib intermediate 4-(3-pyridyl) pyrimidine-2-amine shown in II and formula III and amido protecting; then removed the amino protecting group of the bromo-4-amino-toluene of 2-of formula III by strong acid or weak base, get final product a step and obtain the imatinib mesylate aminate intermediate shown in formula I.
Wherein, the amino protecting group R of the 2-of formula III bromo-4-amino-toluene can be one of following: benzyl, trityl, p-toluenesulfonyl, fluorenes methoxy carbonyl acyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or acyl group (COR
1) etc., be shown below:
And acyl group (COR
1) R
1represent the fatty alkyl of 1-10 carbon, phenyl, substituted-phenyl benzyl, substituted benzyl or ethanoyl (R
1=-CH
3), preferred ethanoyl (R
1=-CH
3).
The acid binding agent of above-mentioned condensation reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, triethylamine (TEA), pyridine, 4-picoline or N, N-dimethyl-ethylenediamine (DMEDA), and the mixture system of these materials, the mixed system of preferred salt of wormwood and DMEDA.
And the catalyzer of condensation reaction is copper or cuprous inorganic salt, preferred cuprous iodide.
The solvent of condensation reaction is the mixture of Virahol, toluene, dimethylbenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dioxane or aforementioned substances, preferred dioxane.
In addition, above-mentioned setting-up point is 60-140 ° of C, is preferably 100 ° of C.
After completion of the condensation reaction, the amino protecting group of the bromo-4-amino-toluene of 2-of formula III directly can be sloughed by strong acid or highly basic.Wherein, strong acid can be concentrated hydrochloric acid, the vitriol oil, acetic acid or trifluoracetic acid, preferred trifluoracetic acid; And highly basic is potassium hydroxide, sodium hydroxide, salt of wormwood or cesium carbonate, preferred sodium hydroxide.
Compared to prior art, the invention has the advantages that: by the bromo-4-amino-toluene one pot reaction of 2-of intermediate 4-(3-pyridyl) pyrimidine-2-amine of formula III and the amido protecting of formula II, directly obtained aminate intermediate N (2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE shown in formula I, visible by improving Atom economy, concise in technology and environment friendly, one-step synthesis aminate intermediate compound I, the manufacturing step of imatinib is obviously reduced, cost significantly reduces, be conducive to quality control and the impurity transfer study of pharmaceutical production, the development of the economic technology of this bulk drug will be promoted.
Embodiment
Below in conjunction with preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
The invention provides a kind of for the preparation of the method such as formula the imatinib mesylate intermediate N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (abbreviation aminate) shown in I,
The method comprising the steps of:
Condensation reaction is carried out by treating different things alike with the bromo-4-amino-toluene of 2-such as formula known imatinib intermediate 4-(3-pyridyl) pyrimidine-2-amine shown in II and formula III and amido protecting; then removed the amino protecting group of the bromo-4-amino-toluene of 2-of formula III by strong acid or weak base, get final product a step and obtain the imatinib mesylate aminate intermediate shown in formula I.
Wherein, the amino protecting group R of the 2-of formula III bromo-4-amino-toluene can be one of following: benzyl, trityl, p-toluenesulfonyl, fluorenes methoxy carbonyl acyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or acyl group (COR
1) etc., be shown below:
And acyl group (COR
1) R
1represent the fatty alkyl of 1-10 carbon, phenyl, substituted-phenyl benzyl, substituted benzyl or ethanoyl (R
1=-CH
3), preferred ethanoyl (R
1=-CH
3).
The acid binding agent of above-mentioned condensation reaction is salt of wormwood, potassium hydroxide, potassium tert.-butoxide, sodium methylate, triethylamine (TEA), pyridine, 4-picoline or N, N-dimethyl-ethylenediamine (DMEDA), and the mixture system of these materials, the mixed system of preferred salt of wormwood and DMEDA.
And the catalyzer of condensation reaction is copper or cuprous inorganic salt, preferred cuprous iodide.
The solvent of condensation reaction is the mixture of Virahol, toluene, dimethylbenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dioxane or aforementioned substances, preferred dioxane.
In addition, above-mentioned setting-up point is 60-140 ° of C, is preferably 100 ° of C.
After completion of the condensation reaction, the amino protecting group of the bromo-4-amino-toluene of 2-of formula III directly can be sloughed by strong acid or highly basic.Wherein, strong acid can be concentrated hydrochloric acid, the vitriol oil, acetic acid or trifluoracetic acid, preferred trifluoracetic acid; And highly basic is potassium hydroxide, sodium hydroxide, salt of wormwood or cesium carbonate, preferred sodium hydroxide.
Corresponding to above-mentioned synthetic schemes, the present invention can be realized by following three specific embodiments:
Embodiment one:
Under nitrogen protection; solvent dioxane 400mL is added in 1L three-necked bottle; start stirring; add 4-(3-pyridyl) pyrimidine-2-amine (20.7g of formula II successively; 0.12mol), CuI (5.7g; 0.03mol), Anhydrous potassium carbonate (20.7g, 0.3mol).Stirring at room temperature, after 15 minutes, continues to add 2-bromo-4-acetylaminohydroxyphenylarsonic acid toluene (22.7g, 0.10mol) and the DMEDA (4.0mL, 0.04mol) of formula III.Be warming up to system backflow, and keep backflow 20 hours.Be cooled to room temperature, add trifluoracetic acid (9.2mL, 0.12mol) in system, stirring at room temperature 2 hours, reaction terminates.Regulate potential of hydrogen to pH=8-9 with strong aqua.Add the saturated 100mL saturated aqueous common salt of 400mL ethyl acetate, stir, leave standstill and layering, aqueous phase ethyl acetate is washed three times (100mLx3), merge organic phase, anhydrous magnesium sulfate drying, concentrate to obtain faint yellow solid, obtain the 22.6g off-white color solid (mp.140-142 ° of C) of formula I with recrystallized from acetonitrile, yield 81.5%.
Embodiment two:
Under nitrogen protection; solvent dioxane 400mL is added in 1L three-necked bottle; start stirring; add 4-(3-pyridyl) pyrimidine-2-amine (20.7g of formula II successively; 0.12mol), CuI (5.7g; 0.03mol), Anhydrous potassium carbonate (20.7g, 0.3mol).Stirring at room temperature, after 15 minutes, continues to add 2-bromo-4-acetylaminohydroxyphenylarsonic acid toluene III (22.7g, 0.10mol) and the DMEDA (4.0mL, 0.04mol) of formula III.Be warming up to system backflow, and keep backflow 20 hours.Be cooled to room temperature, add 6N HCl (20mL) in system, be heated to 50 ° of C, stirring reaction 1 hour, reaction terminates.Regulate potential of hydrogen to pH=8-9 with strong aqua.Add the saturated 100mL saturated aqueous common salt of 400mL ethyl acetate, stir, leave standstill and layering, aqueous phase ethyl acetate is washed three times (100mLx3), merge organic phase, anhydrous magnesium sulfate drying, concentrate to obtain yellow solid, obtain the 22.0g off-white color solid (mp.140-142 ° of C) of formula I with recrystallized from acetonitrile, yield 79.3%.
Embodiment three:
Under nitrogen protection; solvent dioxane 400mL is added in 1L three-necked bottle; start stirring; add 4-(3-pyridyl) pyrimidine-2-amine (20.7g of formula II successively; 0.12mol), CuI (5.7g; 0.03mol), Anhydrous potassium carbonate (20.7g, 0.3mol).Stirring at room temperature, after 15 minutes, continues to add 2-bromo-4-acetylaminohydroxyphenylarsonic acid toluene (22.7g, 0.1mol) and the DMEDA (4.0mL, 0.04mol) of formula III.Be warming up to system backflow, and keep backflow 20 hours.Be cooled to 0 ° of C, add 30% sodium hydroxide solution 10mL in system, keep 0 ° of C, stirring reaction 1 hour, reaction terminates.First regulate potential of hydrogen to pH=8-9 with dilute hydrochloric acid.Add the saturated 100mL saturated aqueous common salt of 400mL ethyl acetate, stir, leave standstill and layering, aqueous phase ethyl acetate is washed three times (100mLx3), merge organic phase, anhydrous magnesium sulfate drying, concentrate to obtain yellow-brown solid, obtain the 20.1g off-white color solid (mp.140-142 ° of C) of formula I with recrystallized from acetonitrile, yield 72.5%.
Visible, by the bromo-4-amino-toluene one pot reaction of 2-of intermediate 4-(3-pyridyl) pyrimidine-2-amine of formula III and the amido protecting of formula II, directly obtained aminate intermediate N (2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE shown in formula I, thus by improving Atom economy, concise in technology and environment friendly, one-step synthesis aminate intermediate compound I, the manufacturing step of imatinib is obviously reduced, cost significantly reduces, be conducive to quality control and the impurity transfer study of pharmaceutical production, the development of the economic technology of this bulk drug will be promoted.
It is pointed out that above-mentioned preferred embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. a preparation method of imatinib mesylate intermediate N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (I),
It is characterized in that described preparation method comprises the steps:
Condensation reaction is carried out by treating different things alike with the bromo-4-amino-toluene (III) of 2-of 4-(3-pyridyl) pyrimidine-2-amine (II) and amido protecting; then the amino protecting group of described 2-bromo-4-acetylaminohydroxyphenylarsonic acid toluene (III) is removed by trifluoracetic acid, concentrated hydrochloric acid or sodium hydroxide; get final product a step and generate described imatinib mesylate intermediate N-(2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (I)
The acid binding agent of wherein said condensation reaction is one of following: salt of wormwood, triethylamine, pyridine, 4-picoline or N, N-dimethyl-ethylenediamine, the catalyzer of described condensation reaction is cuprous iodide.
2. the preparation method of imatinib mesylate intermediate N-according to claim 1 (2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (I), is characterized in that: the solvent of described condensation reaction is one of following: Virahol, toluene, dimethylbenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or dioxane.
3. the preparation method of imatinib mesylate intermediate N-according to claim 1 (2-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (I), is characterized in that temperature of reaction is 60-140 DEG C.
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Effective date of registration: 20190308 Address after: 255000 Jinyang Road, Gaoqing Economic Development Zone, Zibo City, Shandong Province Patentee after: Shandong Lixin Pharmaceutical Co., Ltd. Address before: 215151 No. 21 Tangxi Road, Suzhou High-tech Zone, Jiangsu Province Patentee before: Suzhou Lixin Pharmacy Co., Ltd. |
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Denomination of invention: Preparation method of imatinib mesilate intermediate Effective date of registration: 20190422 Granted publication date: 20150408 Pledgee: Hengfeng Bank Co., Ltd. Zibo Branch Pledgor: Shandong Lixin Pharmaceutical Co., Ltd. Registration number: 2019370000082 |
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Date of cancellation: 20201111 Granted publication date: 20150408 Pledgee: Hengfeng Bank Co.,Ltd. Zibo Branch Pledgor: Shandong Lixin Pharmaceutical Co.,Ltd. Registration number: 2019370000082 |