CN103242245B - Preparation method of tandutinib - Google Patents
Preparation method of tandutinib Download PDFInfo
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- CN103242245B CN103242245B CN201310192198.3A CN201310192198A CN103242245B CN 103242245 B CN103242245 B CN 103242245B CN 201310192198 A CN201310192198 A CN 201310192198A CN 103242245 B CN103242245 B CN 103242245B
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- tandutinib
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- piperazine
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Abstract
The invention discloses a preparation method of tandutinib (I). The preparation method comprises the step that 6-methoxy-7-(3-piperidine-1-ylpropoxy)-3,4-dihydroquinazoline-4-ketone (II) and N-(4-isopropyloxophenyl)formamide-1-piperazine (III) carry out one-step condensation reaction in the presence of organic alkali and a condensing agent to prepare the tandutinib (I). Compared with the prior art, the preparation method is easy in obtainment of raw materials, concise in process and mild in conditions, optimizes the environment, improves the quality, is suitable for industrial production, and promotes the development of the economic technology of the active pharmaceutical ingredients.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of preparation method of Tandutinib.
Background technology
Tandutinib (Tandutinib) is a kind of new oral small molecules Mutiple Targets receptor tyrosine kinase inhibitors that Millennium Pharmaceuticals (Millennium) develops, belong to a kind of clonidine compounds of synthesis, primary treatment Acute Meyloid system leukemia, multiple myeloma and myelodysplastic syndrome.Clinical study shows, Tandutinib has restraining effect to receptor tyrosine kinases such as FMS sample Tyrosylprotein kinase-3 (FLT-3), PDGFR and stem cell factor receptor (c-KitR).
The chemistry of Tandutinib is called: chemistry 4-[6-methoxyl group-7-(3-piperidin-1-yl propoxy-) quinazoline-4-base]-N-(4-sec.-propyl oxygen phenyl) piperazine-1-methane amide by name.
According to the constitutional features of Tandutinib, the design of its synthetic route can be divided into two classes: the first kind is that the 4-position of quinazoline parent nucleus is first combined with piperazinyl side chain, then carries out the functional group conversions of 6-and 7-position successively; Equations of The Second Kind is the functional group conversions that quinazoline parent nucleus first carries out 6-and 7-position, then with piperazinyl side chain in the condensation of 4-position.
The patent WO2002/16351 reported first synthetic method of Tandutinib and analogue thereof.With fragrant grass acid for raw material, by Benzylation, nitrated, reduction and chlorination formed quinazoline intermediate (IV).After the piperazine condensation that intermediate (IV) and Boc protect, carry out the functional group conversions of 7-position, obtain intermediate (V).Intermediate (V) removes the Boc protecting group of piperazine, and this secondary amine and corresponding acyl chlorides, carboxylic acid or isocyanate reaction form the amide substituents of 4-position, obtained Tandutinib (I).
" Journal of Medicinal Chemistry " the 45th volume the 17th phase the 3772nd page in 2002 reports the preparation method of another kind of Tandutinib.Equally with fragrant grass acid for raw material, formed the quinazoline intermediate (II) of side chain functionalities by esterification, etherificate, nitrated, reduction, cyclisation.This intermediate (II) through superchlorination, then obtains Tandutinib (I) with 4-position side chain N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) condensation.Obviously; the method is in quinazoline cyclization and 4-position condensation reaction; eliminate the Benzylation protection of hydroxyl in fragrant grass acid and deprotection, the Boc protection of piperazine ring and deprotection, make whole synthetic route more rationally and quick, yield is also greatly improved.
Investigate the preparation method of current Tandutinib, although second method is more more succinct than first method, the condensation of quinazoline parent nucleus and bridged piperazine derivatives still needs to be realized by chlorination.Relate to the chlorizating agents such as environmentally harmful phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride due to chlorination reaction, sometimes also will relate to protection and the deprotection of related functional group.So be necessary the preparation method seeking a kind of energy Simplified flowsheet step, reduce the new Tandutinib (I) of environmental pollution and reduction production cost.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of new Tandutinib (I), this preparation method's concise in technology, raw material is easy to get, quality controllable, is applicable to suitability for industrialized production.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of Tandutinib (I),
The method comprising the steps of: 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3,4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III), under organic bases and condensing agent effect, carries out a step condensation reaction and obtains Tandutinib (I).
In addition, present invention also offers following attached technical scheme:
The raw material 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3 of described condensation reaction, the molar ratio of 4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) is 1: 1-2, preferably 1: 1.1-1.4.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promotor of described condensation reaction is triethylamine (TEA), pyridine, 2, 6-lutidine, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) or 1, 4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, DMF or acetonitrile, preferred acetonitrile.
The temperature of described condensation reaction is 0-120 DEG C, preferred 80-90 DEG C.
Compared to prior art, the invention has the advantages that the application by novel condensing agent, the more succinct and environmental protection of the preparation making Tandutinib, thus improve Atom economy, the selectivity of reaction and the controllability of operation, quality product increases, and facilitates the development of this raw material economic technology about.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.Wherein the preparation of 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3,4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) can see " the Journal of Medicinal Chemistry " description of the 45th volume the 17th phase the 3772nd page to this in 2002.
Embodiment one:
Under nitrogen protection; 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (II) (3.17g; 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 90 DEG C, continue reaction 12 hours.Underpressure distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M sodium hydroxide 20mL.Separate organic phase, dry, concentrating under reduced pressure.Resistates 100mL tetrahydrofuran (THF) dissolves, add N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) (3.42g, 13mmol) with sodium hydride (0.32g, 13mmol), be warming up to 80 DEG C, stirring reaction 5 hours, TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains off-white color solid.Obtain white solid Tandutinib (I) 4.77g with ethyl alcohol recrystallization, yield is 84.9%.
Embodiment two:
Under nitrogen protection; 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (II) (3.17g; 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Under stirring, drip 1,5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) (1.86g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 90 DEG C, continue reaction 12 hours.Underpressure distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M sodium hydroxide 20mL.Separate organic phase, dry, concentrating under reduced pressure.Resistates 100mL tetrahydrofuran (THF) dissolves, add N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) (3.42g, 13mmol) with sodium hydride (0.32g, 13mmol), be warming up to 80 DEG C, stirring reaction 5 hours, TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains off-white color solid.Obtain white solid Tandutinib (I) 4.63g with ethyl alcohol recrystallization, yield is 82.4%.
Embodiment three:
Under nitrogen protection; 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (II) (3.17g; 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g; 15mmol), N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) (3.42g; 13mmol) with DMF 50mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 90 DEG C, continue reaction 12 hours.Underpressure distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M sodium hydroxide 20mL.Separate organic phase, dry, concentrating under reduced pressure.Residue from ethanol recrystallization obtains off-white color solid Tandutinib (I) 4.0g, and yield is 71.2%.
It is pointed out that above-described 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 (4)
1. a preparation method for Tandutinib (I),
It is characterized in that described preparation method comprises the steps: 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3,4-dihydroquinazoline-4-ketone and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine are at organic bases 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene or 1, under 8-diazabicyclo [5.4.0]-ten one-7-alkene and condensing agent benzotriazole-1-base oxygen base three (dimethylamino) phosphorus phosphofluoric acid salt action, carry out a step condensation reaction and obtain Tandutinib (I).
2. the preparation method of Tandutinib according to claim 1, it is characterized in that: the molar ratio of raw material 6-methoxyl group-7-(3-piperidin-1-yl propoxy-)-3, the 4-dihydroquinazoline-4-ketone of described condensation reaction and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine is 1:1-2.
3. the preparation method of Tandutinib according to claim 1, is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, DMF or acetonitrile.
4. the preparation method of Tandutinib according to claim 1, is characterized in that: the temperature of described condensation reaction is 0-120 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002036587A2 (en) * | 2000-11-01 | 2002-05-10 | Cor Therapeutics, Inc. | Process for the production of 4-quinazolinylpiperazin-1-carboxylic acid phenylamides |
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
| WO2011147102A1 (en) * | 2010-05-28 | 2011-12-01 | 翔真生物科技股份有限公司 | Synthetic method for 6,7-substituents-4-aniline quinazoline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012118492A1 (en) * | 2011-03-01 | 2012-09-07 | Array Biopharma Inc. | Heterocyclic sulfonamides as raf inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002036587A2 (en) * | 2000-11-01 | 2002-05-10 | Cor Therapeutics, Inc. | Process for the production of 4-quinazolinylpiperazin-1-carboxylic acid phenylamides |
| WO2011147102A1 (en) * | 2010-05-28 | 2011-12-01 | 翔真生物科技股份有限公司 | Synthetic method for 6,7-substituents-4-aniline quinazoline |
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
Non-Patent Citations (3)
| Title |
|---|
| 医学编委会,会编.化学药物合成与环保.《10000个科学难题(医学卷)》.科学出版社,2011,985-986. * |
| 吴梧桐,主编.第一章氨基酸与多肽化学.《生物化学(第二版)》.中国医药科技出版社,2010,44-46. * |
| 马宇衡,主编.第8章合成酰胺.《有机合成反应速查手册》.化学工业出版社,2009,189-192. * |
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Effective date of registration: 20181204 Address after: 214425 No. 23 Huanxi Road, Zhutang Town, Jiangyin City, Jiangsu Province Patentee after: JIANGSU ADOPTION MEDICAL TECHNOLOGY CO., LTD. Address before: Room 1305, 1 Building, Lianfeng Commercial Plaza, Suzhou Industrial Park, Jiangsu Province Co-patentee before: Xu Xuenong Patentee before: Suzhou Mingyue Medical Technology Co., Ltd. |
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Effective date of registration: 20200409 Address after: 236200 Anhui province Fuyang City Yingshang Industrial Development Zone Patentee after: ANHUI GOLDEN SUN BIOPHARMACEUTICALS Co.,Ltd. Address before: 214425 No. 23 Huanxi Road, Zhutang Town, Jiangyin City, Jiangsu Province Patentee before: Jiangsu Caina Medical Technology Co.,Ltd. |
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Granted publication date: 20150520 Termination date: 20200522 |