CN103242245A - Preparation method of tandutinib - Google Patents
Preparation method of tandutinib Download PDFInfo
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- CN103242245A CN103242245A CN2013101921983A CN201310192198A CN103242245A CN 103242245 A CN103242245 A CN 103242245A CN 2013101921983 A CN2013101921983 A CN 2013101921983A CN 201310192198 A CN201310192198 A CN 201310192198A CN 103242245 A CN103242245 A CN 103242245A
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- buddhist nun
- smooth degree
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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 synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of smooth degree is for Buddhist nun's preparation method.
Background technology
Smooth degree is a kind of many target spots of new oral small molecules receptor tyrosine kinase inhibitors that Millennium Pharmaceuticals (Millennium) develops for Buddhist nun (Tandutinib), belong to a kind of synthetic piperazine quinazoline compounds, mainly treat acute myeloid lineage leukemia, multiple myeloma and myelodysplastic syndrome.Clinical study shows that smooth degree has restraining effect for the Buddhist nun to FMS sample Tyrosylprotein kinase-3 (FLT-3), PDGFR and STEM CELL FACTOR acceptor receptor tyrosine kinases such as (c-KitR).
Smooth degree is by name for Buddhist nun's chemistry: chemistry 4-[6-methoxyl group-7-by name (3-piperidines-1-base propoxy-) quinazoline-4-yl]-N-(4-sec.-propyl oxygen phenyl) piperazine-1-methane amide.
According to the constitutional features of smooth degree for the Buddhist nun, its synthetic route design can be divided into two classes: the first kind is to be combined with the piperazinyl side chain earlier in the 4-position of quinazoline parent nucleus, and the functional group that carries out 6-and 7-position more successively transforms; Second class is that the functional group that the quinazoline parent nucleus carries out 6-and 7-position earlier transforms, again with the piperazinyl side chain in the condensation of 4-position.
Patent WO2002/16351 reported first the synthetic method of smooth degree for Buddhist nun and analogue thereof.Be raw material with fragrant grass acid, form quinazoline intermediate (IV) by benzylization, nitrated, reduction and chlorination.Behind the piperazine condensation of intermediate (IV) and Boc protection, the functional group that carries out the 7-position transforms, and obtains 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, make smooth degree for Buddhist nun (I).
" Journal of Medicinal Chemistry " rolled up the 3772nd page of the 17th phase in 2002 the 45th and reported that another kind of smooth degree is for Buddhist nun's preparation method.Be raw material with fragrant grass acid equally, form the quinazoline intermediate (II) of side chain functionalitiesization by esterification, etherificate, nitrated, reduction, cyclisation.This intermediate (II) makes smooth degree for Buddhist nun (I) with 4-position side chain N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) condensation again through superchlorination.Obviously; this method is in quinazoline cyclization and 4-position condensation reaction; saved Boc protection and the deprotection of the benzyl protection of hydroxyl in the fragrant grass acid and deprotection, piperazine ring, made whole synthetic route more rationally and quick, yield also is greatly improved.
Investigate present smooth degree for Buddhist nun's preparation method, although second method is more succinct than first method, the condensation of quinazoline parent nucleus and bridged piperazine derivatives still needs to realize by chlorination.Because chlorination reaction relates to chlorizating agents such as environmentally harmful phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride, also to relate to protection and the deprotection of relevant functional group sometimes.So be necessary to seek a kind of new smooth degree that can simplify processing step, minimizing environmental pollution and reduce production costs for Buddhist nun's (I) preparation method.
Summary of the invention
The object of the present invention is to provide a kind of new smooth degree to replace Buddhist nun's (I) preparation method, this preparation method's technology is succinct, and raw material is easy to get, and is quality controllable, is fit to suitability for industrialized production.
For achieving the above object, the present invention has adopted following main technical schemes: a kind of smooth degree replaces Buddhist nun's (I) preparation method,
The method comprising the steps of: 6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3,4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) carries out a step condensation reaction and makes smooth degree for Buddhist nun (I) under organic bases and condensing agent effect.
In addition, the present invention also provides following attached technical scheme:
The raw material 6-methoxyl group-7-of described condensation reaction (3-piperidines-1-base propoxy-)-3, 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, preferred 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, the 6-lutidine, 4-Dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN), 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,4-diazabicylo [2.2.2] octane (DABCO), preferred 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (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, N, dinethylformamide or acetonitrile, preferred acetonitrile.
The temperature of described condensation reaction is 0-120 ℃, preferred 80-90 ℃.
Than prior art, the invention has the advantages that the application by novel condensing agent, make smooth degree replace Buddhist nun's the succinct more and environmental protection of preparation, thereby Atom economy, the selectivity of reaction and the controllability of operation have been improved, quality product increases, and has promoted the development of this raw material economic technology approximately.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3 wherein, the preparation of 4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) can be rolled up the 3772nd page of description to this of the 17th phase in 2002 the 45th referring to " Journal of Medicinal Chemistry ".
Embodiment one:
Under the nitrogen protection; in there-necked flask, add 6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3; 4-dihydroquinazoline-4-ketone (II) (3.17g, 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates is with the dissolving of 100mL tetrahydrofuran (THF), add N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) (3.42g, 13mmol) and sodium hydride (0.32g 13mmol), is warming up to 80 ℃, stirring reaction 5 hours, the end of TLC monitoring reaction.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets the off-white color solid.Get the smooth degree of white solid for Buddhist nun (I) 4.77g with ethyl alcohol recrystallization, yield is 84.9%.
Embodiment two:
Under the nitrogen protection; in there-necked flask, add 6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3; 4-dihydroquinazoline-4-ketone (II) (3.17g, 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL.Stir down, dropping 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-(1.86g 15mmol), drips and finishes room temperature reaction 12 hours 5-alkene (DBN).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates is with the dissolving of 100mL tetrahydrofuran (THF), add N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) (3.42g, 13mmol) and sodium hydride (0.32g 13mmol), is warming up to 80 ℃, stirring reaction 5 hours, the end of TLC monitoring reaction.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets the off-white color solid.Get the smooth degree of white solid for Buddhist nun (I) 4.63g with ethyl alcohol recrystallization, yield is 82.4%.
Embodiment three:
Under the nitrogen protection; in there-necked flask, add 6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3; 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) and N, dinethylformamide 50mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 90 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates gets the smooth degree of off-white color solid for Buddhist nun (I) 4.0g with ethyl alcohol recrystallization, and yield is 71.2%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (6)
1. a smooth degree is for Buddhist nun's (I) preparation method,
It is characterized in that described preparation method comprises the steps: 6-methoxyl group-7-(3-piperidines-1-base propoxy-)-3,4-dihydroquinazoline-4-ketone (II) and N-(4-sec.-propyl oxygen phenyl) methane amide-1-piperazine (III) carries out a step condensation reaction and makes smooth degree for Buddhist nun (I) under organic bases and condensing agent effect.
2. according to the preparation method of the described smooth degree of claim 1 for the Buddhist nun, it is characterized in that: the raw material 6-methoxyl group-7-of described condensation reaction (3-piperidines-1-base propoxy-)-3, 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.
3. according to the preparation method of the described smooth degree of claim 1 for the Buddhist nun, it is characterized in that: the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate.
4. according to the preparation method of the described smooth degree of claim 1 for the Buddhist nun, it is characterized in that: the alkali promotor of described condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane.
5. according to the preparation method of the described smooth degree of claim 1 for the Buddhist nun, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, N, dinethylformamide or acetonitrile.
6. according to the preparation method of the described smooth degree of claim 1 for the Buddhist nun, it is characterized in that: the temperature of described condensation reaction is 0-120 ℃.
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Citations (4)
| 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 |
| WO2012118492A1 (en) * | 2011-03-01 | 2012-09-07 | Array Biopharma Inc. | Heterocyclic sulfonamides as raf inhibitors |
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2013
- 2013-05-22 CN CN201310192198.3A patent/CN103242245B/en not_active Expired - Fee Related
Patent Citations (4)
| 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 |
| WO2012118492A1 (en) * | 2011-03-01 | 2012-09-07 | Array Biopharma Inc. | Heterocyclic sulfonamides as raf inhibitors |
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）》 * |
| 吴梧桐，主编: "第一章氨基酸与多肽化学", 《生物化学（第二版）》 * |
| 马宇衡，主编: "第8章合成酰胺", 《有机合成反应速查手册》 * |
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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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