CN104327078A - Novel synthetic method of CDK-4/6 inhibitor - Google Patents
Novel synthetic method of CDK-4/6 inhibitor Download PDFInfo
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- CN104327078A CN104327078A CN201410572841.XA CN201410572841A CN104327078A CN 104327078 A CN104327078 A CN 104327078A CN 201410572841 A CN201410572841 A CN 201410572841A CN 104327078 A CN104327078 A CN 104327078A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a novel synthetic method of a CDK-4/6 inhibitor. The method comprises the steps of mixing 1:2,4-dichloro, 5-acetyl pyrimidine and alkali in a solvent, reacting and carrying out crystallization and suction filtration to obtain a compound 2-chloro-4-cyclopentylamine-5-acetyl pyrimidine; dissolving fructone into anhydrous tetrahydrofuran, and performing recrystallization with ethyl acetate to obtain a compound 4,6-acetyl-2-chloro-8-cyclopentyl-5-methylpyridine (2,3-d) pyrimidino-7(8H)-ketone; mixing the 4,6-acetyl-2-chloro-8-cyclopentyl-5-methylpyridine (2,3-d) pyrimidino-7(8H)-ketone with alkali and a compound 5 tert-butyl4-(6-aminopyridine-3-yl) piperazine-1-carboxyl tert-butyl ester in DMF, methylbenzene and dimethylsulfoxide, heating and reacting to obtain a compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolame-2-yl)-7-oxo-7,8-dihydropyridino-(2,3-d) pyrimidine-2-yl) amino) pyridine-3-yl) piperazine-1-carboxyl tert-butyl ester; and finally, adding the compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolame-2-yl)-7-oxo-7,8-dihydropyridino-(2,3-d) pyrimidine-2-yl) amino) pyridine-3-yl) piperazine-1-carboxyl tert-butyl ester into acid liquid, and reacting to obtain the corresponding salt of 6-acetyl-8-cyclopentyl-5-methyl-2-((5(piperazine-1-yl) pyridine-2-yl) amino) pyridino-(2,3-d) pyrimidine-7(8H)-ketone. The synthetic process is low in cost, is simple and environment-friendly and is suitable for industrial volume production.
Description
Technical field
The present invention relates to medical industry, be specially a kind of synthetic method of protein dependent kinase 4 and 6 inhibitor.
Background technology
Palbociclib is a kind of experimental, oral, targeting preparation, can Selective depression cell cycle protein dependent kinase 4 and 6(CDK4/6), recovering the cell cycle controls, and blocks tumor cell proliferation.Before this, FDA authorizes the palbociclib breakthrough therapy identification for the treatment of late period or transitivity ER+/HER2-mammary cancer in April, 2013, it is a symbolic characteristic of cancer that cell cycle is out of control, and CDK4/6 is equal overacfivity in many cancers, causes uncontrolled cellular proliferation.CDK4/6 is the key regulator of cell cycle, can change from vegetative period (G1 phase) to the DNA replication dna phase (S1 phase) by trigger cell cycle.In estrogen receptor positive (ER+) mammary cancer (BC), the overacfivity of CDK4/6 is very frequent, and CDK4/6 is the crucial downstream targets of ER signal.Preclinical data shows, CDK4/6 and ER signal double inhibition has synergy, and can suppress the growth of G1 phase ER+BC cell.The main intermediate of palbociclib is 6-ethanoyl-2-chloro-8-cyclopentyl-5-picoline also [2,3-d] pyrimidine-7(8H)-ketone.The people such as Dirocco, Derek Paul disclose the preparation method of a kind of palbociblib at WO 2012068381, synthetic route is as follows:
The weak point of this technique is that reaction conditions is comparatively harsh, and yield low reaction step number is many, and building-up process needs to use tetrahydrochysene lithium aluminium, the inflammable and explosive substances such as sodium hydride; This route is only applicable to laboratory scale and produces, and produce in commercial scale, during namely kilogram rank is produced, purity and yield all do not reach requirement, so people are still constantly exploring new synthetic route.The people such as Erdman, David Thomas disclose the preparation method of another kind of a kind of palbociblib at WO2008032157, synthetic route is as follows:
Wherein above-mentioned second and the 5th step use very expensive homogeneous catalyst for twice, very harsh to the requirement of reaction unit; It is anhydrous and oxygen-free reaction, and cost is high, and this is not suitable for suitability for industrialized production; And use heavy metal catalyst in finished product first two steps, need to do corresponding precious metal palladium of removing as medicine intermediate and operate, this just considerably increases difficulty and the complicacy of technique.
Summary of the invention
In order to solve complex process and the high drawback of cost, the invention provides a kind of novel synthesis of CDK-4/6 inhibitor, technical scheme of the present invention is:
A) by compound 12,4-dichloro, 5-ethanoyl pyrimidine and the alkali be made up of organic bases triethylamine, diisopropylethylamine, inorganic carbonate potassium, sodium carbonate, sodium bicarbonate mix in a solvent, this solvent is by ethyl acetate, tetrahydrofuran (THF), methylene dichloride forms, control temperature-5 is spent to 80 degree, prioritizing selection-5 is spent to 5 degree, drip stirring at room temperature after cyclopentamine, until react completely, to add shrend and go out, separatory organic phase with mild acid wash to PH=7, concentrated most of solvent, crystallization suction filtration obtains compound 2-chloro-4-cyclopentamine base-5 ethanoyl pyrimidine;
B) getting apple ester melts in anhydrous tetrahydrofuran (THF), zero degree is cooled to arrive between negative 70 degree, prioritizing selection-5 is spent to 0 degree, LiHMDS, KHMDS, NaHMDS selects LiHMDS to be added drop-wise to reaction system, dropwise stirring 1 hour, the tetrahydrofuran solution of chloro-for compound 2-4-cyclopentamine base-5 ethanoyl pyrimidine is added drop-wise in reaction system, temperature control sub-zero zero reacts 1 hour, naturally be warmed up to room temperature reaction to spend the night, TLC display reacts completely, add saturated ammonium chloride cancellation, three times are extracted with methyl tertiary butyl ether, organic phase merging with brine It once, dry concentrated, the crude product re-crystallizing in ethyl acetate obtained obtains compound 4, the chloro-8-cyclopentyl of 6-ethanoyl-2--5-picoline also [2, 3-d] pyrimidine-7 (8H)-one,
C) by the chloro-8-cyclopentyl of compound 4 6-ethanoyl-2--5-picoline also [2,3-d] pyrimidine-7 (8H)-ketone, by organic bases triethylamine, diisopropylethylamine, inorganic carbonate potassium, sodium carbonate, alkali and compound 5 tertiary butyl 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester of sodium bicarbonate composition are blended in DMF, toluene, in methyl-sulphoxide, heat 70 degree of-150 degree, until react completely, be cooled to room temperature, add shrend to go out, a large amount of light yellow solids is had to separate out, suction filtration, filter cake with organic solvent washing once, obtain qualified compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl isophthalic acid, 3-dioxolane-2-base)-7-oxo-7, 8-dihydro pyrido [2, 3-d] pyrimidine-2-base) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester,
D) by 4-(6 – (8-cyclopentyl-5-methyl-6-(2-methyl isophthalic acid; 3-dioxolane-2-base)-7-oxo-7; 8-dihydro pyrido [2; 3-d] pyrimidine-2-base) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester joins in acid solution; stir; temperature is room temperature or heating; react complete; suction filtration just obtains the salt of corresponding 6-ethanoyl-8-cyclopentyl-5-methyl-2-((5 (piperazine-1-base) pyridine-2-base) is amino) pyrido [2,3-d] pyrimidine-7 (8H)-one.
The present invention adopts the beneficial effect of above technical scheme to be: the present invention does not need to use valuable homogeneous catalyst, shorten reaction step number, make synthesis technique cost lower, environmental protection more, applicable industrialization high-volume, the present invention is simple to operate, and the end avoiding synthesis technique uses heavy metal palladium, more meets the regulation of Bureau of Drugs Supervision as API.
Embodiment
The synthetic route of specific embodiments of the invention is as follows:
Its synthesis step is:
1. get compound 12, the 4-dichloro of 1mol, the cyclopentamine of 5-ethanoyl pyrimidine and 1.1mol; add the triethylamine of two equivalents in ethyl acetate, stirring at room temperature, it is complete that TLC shows raw material reaction; reaction system adds water; separatory, organic phase is concentrated goes 80%, cools to room temperature; after being cooled to 0 DEG C again; suction filtration, obtains compound 2 2-chloro-4-cyclopentamine base-5 ethanoyl pyrimidine of product as white crystals for twice, yield 86% by cold petroleum ether;
1h NMR (300 MHz, CDCl3) 8.21 (s, 1H), 4.7 (b, 1H), 2.65 (m, 1H), 2.55 (s, 3H), 1.88 (m, 4H), 1.77 (m, 4H).MS: m/z = 240.6 (M+H)
+；
2. compound 3 apple ester getting 1mol melts in anhydrous tetrahydrofuran (THF), zero degree is cooled to arrive between negative five degree, the LiHMDS of 1.9 equivalents is added drop-wise to reaction system, dropwise stirring 1 hour, the tetrahydrofuran (THF) of compound 2 2-chloro-4-cyclopentamine base-5 ethanoyl pyrimidine of 1mol is easily dripped into, temperature control sub-zero zero reaction 1 give hour, naturally be warmed up to room temperature reaction to spend the night, TLC display reacts completely, add saturated ammonium chloride cancellation, three times are extracted with methyl tertiary butyl ether, organic phase merging with brine It once, dry concentrated, the crude product re-crystallizing in ethyl acetate obtained obtains the chloro-8-cyclopentyl of compound 4 6-ethanoyl-2--5-picoline also [2, 3-d] pyrimidine-7 (8H)-one, yield 80%,
1h NMR (300 MHz, CDCl3) 7.55 (s, 1H), 4.20 (m, 4H), 3.68 (m, 1H), 2.45 (s, 3H), 1.88 (m, 4H), 1.84 (s, 3H) 1.80 (m, 4H) MS:m/z=350.6 (M+H)
+,
3. get the compound 4 of 1mol, the salt of wormwood of 2mol and the compound 5 of 1.0mol are blended in toluene, reflux is until react completely, be cooled to room temperature, add shrend to go out, a large amount of light yellow solids is had to separate out, suction filtration, filter cake methyl tertiary butyl ether washs once, totally starved compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl isophthalic acid, 3-dioxolane-2-base)-7-oxo-7,8-dihydro pyrido [2,3-d] pyrimidine-2-base) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester yield 90%;
1h NMR (300 MHz, CDCl3) 7.41 (s, 1H), 7.18 (s, 1H), 6.88 (d, 1H), 6.81 (d, 1H), 4.15 (m, 4H), 3.60 (m, 1H), 3.41 (t, 2H), 3.18 (t, 2H), 2.45 (s, 3H), 1.83 (m, 4H), 1.81 (s, 3H) 1.69 (m, 4H), 1.41 (s, 9H).
4. solid is dissolved in the ethanol solution hydrochloride of 3 N, reflux two hours, TLC detection reaction is complete, add ethyl acetate cooling, have a large amount of white solids to separate out, suction filtration, the cold ethyl acetate of filter cake washes twice, obtain qualified compound 76-ethanoyl-8-cyclopentyl-5-methyl-2-((5 (piperazine-1-base) pyridine-2-base) is amino) pyrido [2,3-d] pyrimidine-7 (8H)-one hydrochloride yield 93%;
1h NMR (300 MHz, H2O) 7.45 (s, 1H), 7.22 (s, 1H), 6.89 (d, 1H), 6.86 (d, 1H), 4.25 (m, 4H), 3.67 (m, 1H), 3.45 (t, 2H), 2.98 (t, 2H), 2.45 (s, 3H), 2.31 (s, 3H), 1.83 (m, 4H), 1.69 (m, 4H).MS: m/z = 448.6 (M+H)
+。
Although the foregoing describe the specific embodiment of the present invention, it will be understood by those of skill in the art that these only illustrate, protection scope of the present invention is defined by the appended claims.Those skilled in the art, under the prerequisite not deviating from principle of the present invention and essence, can make various changes or modifications to these embodiments, but these change and amendment all falls into protection scope of the present invention.Above-mentioned embodiment is exemplary, is to better enable those skilled in the art understand this patent, can not be interpreted as it is restriction this patent being comprised to scope; As long as any change that the technology contents essence that technical scheme is made disclosed in this patent is identical or equivalent or modification, all fall into the scope that this patent comprises.
Claims (1)
1. a novel synthesis for CDK-4/6 inhibitor, is characterized in that: adopt following steps to synthesize:
A) by compound 12,4-dichloro, 5-ethanoyl pyrimidine and the alkali be made up of organic bases triethylamine, diisopropylethylamine, inorganic carbonate potassium, sodium carbonate, sodium bicarbonate mix in a solvent, this solvent is by ethyl acetate, tetrahydrofuran (THF), methylene dichloride forms, control temperature-5 is spent to 80 degree, prioritizing selection-5 is spent to 5 degree, drip stirring at room temperature after cyclopentamine, until react completely, to add shrend and go out, separatory organic phase with mild acid wash to PH=7, concentrated most of solvent, crystallization suction filtration obtains compound 2-chloro-4-cyclopentamine base-5 ethanoyl pyrimidine;
B) getting apple ester melts in anhydrous tetrahydrofuran (THF), zero degree is cooled to arrive between negative 70 degree, prioritizing selection-5 is spent to 0 degree, LiHMDS, KHMDS, NaHMDS selects LiHMDS to be added drop-wise to reaction system, preferred LiHMDS dropwises stirring 1 hour, the tetrahydrofuran solution of compound 2 2-chloro-4-cyclopentamine base-5 ethanoyl pyrimidine is added drop-wise to reaction system, temperature control sub-zero zero reacts 1 hour, naturally be warmed up to room temperature reaction to spend the night, TLC display reacts completely, add saturated ammonium chloride cancellation, three times are extracted with methyl tertiary butyl ether, organic phase merging with brine It once, dry concentrated, the crude product re-crystallizing in ethyl acetate obtained obtains compound 4, the chloro-8-cyclopentyl of 6-ethanoyl-2--5-picoline also [2, 3-d] pyrimidine-7 (8H)-one,
C) by the chloro-8-cyclopentyl of compound 4 6-ethanoyl-2--5-picoline also [2,3-d] pyrimidine-7 (8H)-ketone, by organic bases triethylamine, diisopropylethylamine, inorganic carbonate potassium, sodium carbonate, alkali and compound 5 tertiary butyl 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester of sodium bicarbonate composition are blended in DMF, toluene, in methyl-sulphoxide, heat 70 degree to 150 degree, until react completely, be cooled to room temperature, add shrend to go out, a large amount of light yellow solids is had to separate out, suction filtration, filter cake with organic solvent washing once, obtain qualified compound 6 4-(6-(8-cyclopentyl-5-methyl-6-(2-methyl isophthalic acid, 3-dioxolane-2-base)-7-oxo-7, 8-dihydro pyrido [2, 3-d] pyrimidine-2-base) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester,
D) by 4-(6 – (8-cyclopentyl-5-methyl-6-(2-methyl isophthalic acid; 3-dioxolane-2-base)-7-oxo-7; 8-dihydro pyrido [2; 3-d] pyrimidine-2-base) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester joins in acid solution; stir; temperature is room temperature or heating; react complete; suction filtration just obtains the salt of corresponding 6-ethanoyl-8-cyclopentyl-5-methyl-2-((5 (piperazine-1-base) pyridine-2-base) is amino) pyrido [2,3-d] pyrimidine-7 (8H)-one.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
| CN104910149A (en) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | Palbociclib preparation method |
| CN105153149A (en) * | 2015-07-29 | 2015-12-16 | 江苏中邦制药有限公司 | Preparation method for selective kinases inhibitor Palbociclib |
| CN105213322A (en) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | Pharmaceutical composition prepared by a kind of dry granulation process |
| WO2017072543A1 (en) * | 2015-10-28 | 2017-05-04 | Egis Gyógyszergyár Zrt. | Palbociclib salts |
| CN113929675A (en) * | 2020-07-13 | 2022-01-14 | 苏州特瑞药业有限公司 | Method for synthesizing piperazine cypress Xili |
| CN115636826A (en) * | 2022-10-31 | 2023-01-24 | 常州英诺升康生物医药科技有限公司 | Preparation method of CDK inhibitor |
-
2014
- 2014-10-24 CN CN201410572841.XA patent/CN104327078A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910149A (en) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | Palbociclib preparation method |
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
| CN104892604B (en) * | 2015-06-19 | 2016-08-24 | 北京康立生医药技术开发有限公司 | A kind of synthetic method of CDK4 inhibitor |
| CN105153149A (en) * | 2015-07-29 | 2015-12-16 | 江苏中邦制药有限公司 | Preparation method for selective kinases inhibitor Palbociclib |
| WO2017072543A1 (en) * | 2015-10-28 | 2017-05-04 | Egis Gyógyszergyár Zrt. | Palbociclib salts |
| EA035346B1 (en) * | 2015-10-28 | 2020-05-29 | Эгиш Дьёдьсердьяр Зрт. | 4-toluenesulfonic acid palbociclib salt, method for production thereof and use thereof in medicine |
| CN105213322A (en) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | Pharmaceutical composition prepared by a kind of dry granulation process |
| CN113929675A (en) * | 2020-07-13 | 2022-01-14 | 苏州特瑞药业有限公司 | Method for synthesizing piperazine cypress Xili |
| CN115636826A (en) * | 2022-10-31 | 2023-01-24 | 常州英诺升康生物医药科技有限公司 | Preparation method of CDK inhibitor |
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