CN108558745A - A kind of pa wins the synthetic method of XiLin intermediate - Google Patents
A kind of pa wins the synthetic method of XiLin intermediate Download PDFInfo
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- CN108558745A CN108558745A CN201810473825.3A CN201810473825A CN108558745A CN 108558745 A CN108558745 A CN 108558745A CN 201810473825 A CN201810473825 A CN 201810473825A CN 108558745 A CN108558745 A CN 108558745A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
The present invention provides a kind of synthetic method of the rich XiLin intermediate of pa, more particularly to technical field of medicine synthesis, it refers to 4 (6 aminopyridine, 3 base) piperazine, 1 t-butyl formate that the pa of the present invention, which wins XiLin intermediate, using 2 amino, 5 bromopyridine as starting material, pass through oxidation, coupling, reduction obtains the process route of purpose product, the experimental study of system has been carried out to the influence factor of reaction, compared with traditional preparation process, the process route of the present invention is in production cost, technological operation, it is all significantly improved and improves in product yield and purity and environmental protection.
Description
Technical field
The invention belongs to pharmaceutical synthesis field technical fields, and in particular to a kind of pa wins the synthetic method of XiLin intermediate.
Background technology
It is a kind of new oral cell cycle protein dependent kinase 4/6 (CDK4/6) that pa, which wins XiLin (Palbociclib),
Inhibitor.It is mainly played a role by adjusting the cell cycle, prevents cell by the G1 phases to S phases by inhibiting CDK4/6 activity
And then inhibit the synthesis of DNA.It is developed by Pfizer Inc., and was ratified by the accelerated approval approach of FDA on 2 3rd, 2015
It is listed in the U.S., is clinically used for combining with Letrozole for treating postmenopausal estrogen receptor (ER) positive, human epidermal growth
The initial endocrine therapy of the advanced breast cancer patient metastatic disease of factor acceptor 2 (HER2) feminine gender. PalbociclibⅢ
HR+/HER2- patient of the standard fulvestrant Regimen Chemotherapy through controlling is added in palbociclib by the research that the phase tests PALOMA-3
Energy acquisition, which is more than twice of Progression free survival, to be improved, and Palbociclib has postponed disease developing time nearly 5 months.Therefore,
The research that XiLin intermediate is won to pa is also just of great significance, and existing pa wins XiLin intermediate 4- (6- aminopyridine -3- bases)
Piperazine -1- t-butyl formates its existing synthesis modes is such as：
Shown in being disclosed in Pfizer patent WO2014128588 under a kind of synthetic method, the route is with the tertiary fourth oxygen of 1-
Carboxypiperazin, 2- nitro -5- bromopyridines are starting material, and target product is made through being coupled, restoring two-step reaction.
The advantages of this method is that byproduct of reaction is few, and yield is higher, and the total recovery of two steps is 89%, and catalytic hydrogenating reduction is anti-
Answer environmentally protective, but the solvent dimethyl sulfoxide (DMSO) used of coupling is not easy to recycle, and it is complicated that product obtains process, the production of hydrogenation reaction
Product extraction, purifying complex, need further to optimize research.
Therefore, it is necessary to a kind of process routes in production cost, technological operation, product yield and purity and environmental protection
The pa for being all significantly improved and improving wins the synthetic method of XiLin intermediate.
Invention content
The object of the present invention is to provide the synthetic methods that a kind of pa wins XiLin intermediate, and process route is in production cost, work
It is all significantly improved and improves in skill operation, product yield and purity and environmental protection.
The present invention provides the following technical solutions：
A kind of pa wins the synthetic method of XiLin intermediate, is as follows：
S1：The synthesis of 2- nitro -5- bromopyridines (II)：First prepare solution A and solution B, solution A under cryogenic respectively
For the mixture of a certain amount of 30% hydrogen peroxide and a certain amount of 98% concentrated sulfuric acid, solution B be a certain amount of 98% concentrated sulfuric acid and
The mixture of 2- amino -5- bromopyridines, solution B is added portionwise in solution A under cryogenic, increases one section of thermotonus
Time obtains crude product, adds water stirring cooling to add lye stirring, filters, and repeats plus lye adjusts PH, then filter and obtain
Product, specific reaction equation are as follows：
The synthesis of S2,4- (6- nitropyridine -3- bases)-piperazine -1- t-butyl formates (III)：After a certain amount of acetonitrile is added,
2- nitro -5- bromopyridines, the tertiary fourth oxygen carboxypiperazins of 1-, lithium chloride are sequentially added, system carries out nitrogen displacement, and installs drying additional
Triethylamine is added in pipe, and then row heats, and slowly heats up, and cools down after reacting a period of time, and decompression boils off solvent, then adds water mistake
Filter, obtains crude product, reuses solvent and recrystallized, and then filters and obtains product, specific reaction equation is as follows：
The synthesis of S3,4- (6- aminopyridine -3- bases)-piperazine -1- t-butyl formates (III)：First is added in a kettle
Alcohol, 10% palladium carbon are uniformly dispersed, and 4- (6- nitropyridine -3- bases)-piperazine -1- t-butyl formates, system lock, inflated with nitrogen is added
To 0.3MPa, displacement twice, is passed through H2 to reactor pressure 0.3MPa, and displacement is primary, and then room temperature starts to react, and reacts one section
After time, vacuum rotary steam is filtered, obtains product, specific reaction equation is as follows：
Preferably, the temperature condition of the preparation solution A in step S1 and solution B is 5-15 DEG C, 2- amino -5- in solution A
Ratio of the bromopyridine in 98% concentrated sulfuric acid is 372-378g/L, the volume ratio of 30% hydrogen peroxide and 98% concentrated sulfuric acid in solution B
For 0.9-1.1：2, solution B is added in solution A in batches, and in mixed solution A and solution B, the concentrated sulfuric acid in solution A and
The content of the concentrated sulfuric acid is identical in solution B.
Preferably, the solution A in step S1 and solution B are reacted at least 3 hours at 50 DEG C, and raw material is analyzed to reach TLC
Point disappears.
Preferably, the pH described in the step S1 in step S1 is 7.
Preferably, the reaction condition in step S2 in order to control at 70-73 DEG C react 32 hours by temperature, is detected by TLC anti-
It answers liquid to show that raw material point disappears, after reaction, is cooled to 40 DEG C, decompression boils off solvent, and water 30ml, temperature control are added into flask
It 40-50 DEG C, heats 30 minutes, heat filtering later.
Preferably, the solvent that the recrystallization in step S2 uses is ethyl acetate, and the ratio that crude product accounts for ethyl acetate is
110-120g/L。
The beneficial effects of the invention are as follows：The process route of the present invention is in production cost, technological operation, product yield and purity
And it is all significantly improved and improves in environmental protection.
Specific implementation mode
It is specific as follows by the product needed for the synthesis of following three step：
1, the synthesis of 2- nitros -5- bromopyridines (II)
Be added to 160ml30% hydrogen peroxide in three mouthfuls of reaction bulbs of 1000ml, using low-temp reaction bath be cooled to 15 DEG C with
It is interior, the 320ml98% concentrated sulfuric acids are instilled in the hydrogen peroxide in reaction bulb with constant pressure funnel, solution temperature, which controls, in bottle exists
Within the scope of 5-15 DEG C, solution B is added dropwise to obtain.It is dense that 160ml98% is added in three mouthfuls of reaction bulbs of another 1000ml simultaneously
Sulfuric acid is bathed using low-temp reaction and is cooled down, 60.00g2- amino -5- bromopyridines are added portionwise, and temperature is controlled in 5-15 DEG C of range
Interior, charging finishes to obtain solution A.
A, B solution is prepared and is finished, and is added drop-wise to solution B in solution A in batches with constant pressure funnel, still utilizes low temperature anti-
Control reaction bulb temperature should be bathed within the scope of 0-10 DEG C, optimum temperature is 5 DEG C, and temperature change value is not more than 3 DEG C, is added dropwise,
Reaction solution is to slowly warm up to 50 DEG C, and the reaction was continued 3 hours, and sampling carries out TLC analysis raw material points and disappears.
5000ml water is added into three mouthfuls of reaction bulbs of 5000ml, is cooled within 15 DEG C, above-mentioned reaction solution is being stirred
In the case of be added to the water with constant pressure funnel, temperature control within the scope of -15 DEG C, after being added dropwise, continue stir 18-
20 minutes.Under the conditions of 5-15 DEG C, the liquid caustic soda of 720g30% is added, adds and continues stirring 0.5 hour and then decompression suction filtration, add
100ml water washings, filter cake, which is stirred to wash with diluted alkaline, is neutralized to pH=7, filters again, obtained solid recrystallizing methanol, heat filtering, does
Dry to obtain light yellow solid 51.13g products, yield 73.4%, product liquid chromatogram purity is more than 99%.
2, the synthesis of 4- (6- nitropyridine -3- bases)-piperazine -1- t-butyl formates (III)
In dry tetra- mouthfuls of reaction bulbs of 100ml, 96-100ml acetonitriles are added, sequentially add 2- nitro -5- bromopyridines
The tertiary fourth oxygen carboxypiperazin 28g of 16.00g, 1-, lithium chloride 0.80g, system carries out nitrogen displacement, and installs drying tube additional, and three second are added
Amine 5g, is then heated with oil bath, is slowly heated up, and control temperature is reacted 32 hours at 70-73 DEG C, is detected and is reacted by TLC
Liquid shows that raw material point disappears.
After reaction, 40 DEG C are cooled to, decompression boils off solvent, and into flask plus water 60ml, 40-50 DEG C of temperature control heat
30 minutes, heat filtering later.Crude product 23g is obtained after filtration cakes torrefaction, with 200ml re-crystallizing in ethyl acetate, solution is naturally cooling to
10 DEG C, filter to obtain 19.55g, yield 85%, product liquid chromatogram purity 99.1%.
3, the synthesis of 4- (6- aminopyridine -3- bases)-piperazine -1- t-butyl formates (IV)
30ml methanol is added in 100ml reaction kettles, 0.10g10% palladium carbons are uniformly dispersed, addition 1.8g4- (6- nitro pyrroles
Pyridine -3- bases)-piperazine -1- t-butyl formates, system lock, inflated with nitrogen to 0.3MPa, displacement twice, be passed through H2 to reaction kettle pressure
Power 0.3MPa, displacement is primary, and then room temperature starts to react, and reacts 12h, and HPLC analyzes reaction solution, and material content is less than 0.5%.
Reaction solution is depressurized by organic filter membrane of 0.45um and is filtered, and is filtered vacuum rotary steam, is obtained white solid 1.71g, product yield
95%, purity is more than 99%.
It these are only the preferred embodiment of the present invention, be not intended to restrict the invention, although with reference to the foregoing embodiments
Invention is explained in detail, for those skilled in the art, still can be to foregoing embodiments institute
The technical solution of record is modified or equivalent replacement of some of the technical features.It is all the present invention spirit and
Within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (6)
1. a kind of pa wins the synthetic method of XiLin intermediate, which is characterized in that be as follows：
S1：The synthesis of 2- nitro -5- bromopyridines (II)：First prepare solution A and solution B, solution A one under cryogenic respectively
Quantitative 30% hydrogen peroxide and a certain amount of 98% the concentrated sulfuric acid mixture, solution B is a certain amount of 98% concentrated sulfuric acid and 2- ammonia
The mixture of base -5- bromopyridines, solution B is added portionwise in solution A under cryogenic, when increasing one section of thermotonus
Between, crude product is obtained, adds water stirring cooling to add lye stirring, filters, repeats plus lye adjusts PH, then filter and produced
Object, specific reaction equation are as follows：
The synthesis of S2,4- (6- nitropyridine -3- bases)-piperazine -1- t-butyl formates (III)：After a certain amount of acetonitrile is added, successively
2- nitro -5- bromopyridines, the tertiary fourth oxygen carboxypiperazins of 1-, lithium chloride is added, system carries out nitrogen displacement, and installs drying tube additional, adds
Entering triethylamine, then heated, slowly heated up, is cooled down after reacting a period of time, decompression boils off solvent, then adds water filtering,
Crude product is obtained, solvent is reused and is recrystallized, then filters and obtains product, specific reaction equation is as follows：
The synthesis of S3,4- (6- aminopyridine -3- bases)-piperazine -1- t-butyl formates (III)：In a kettle be added methanol,
10% palladium carbon is uniformly dispersed, and 4- (6- nitropyridine -3- bases)-piperazine -1- t-butyl formates is added, system lock, inflated with nitrogen is extremely
0.3MPa, displacement twice, are passed through H2 to reactor pressure 0.3MPa, and displacement is primary, and then room temperature starts to react, when reacting one section
Between after, filter vacuum rotary steam, obtain product, specific reaction equation is as follows：
2. pa according to claim 1 wins the synthetic method of XiLin intermediate, which is characterized in that the preparation in step S1 is molten
The temperature condition of liquid A and solution B is 5-15 DEG C, and ratio of the 2- amino -5- bromopyridines in 98% concentrated sulfuric acid is 372- in solution A
378g/L, the volume ratio of 30% hydrogen peroxide and 98% concentrated sulfuric acid is 0.9-1.1 in solution B：2, solution B is added in solution A in batches,
And in mixed solution A and solution B, the concentrated sulfuric acid in solution A is identical with the content of the concentrated sulfuric acid in solution B.
3. pa according to claim 1 wins the synthetic method of XiLin intermediate, which is characterized in that the solution A in step S1
It reacts at 50 DEG C at least 3 hours with solution B, is disappeared with reaching TLC analysis raw material points.
4. pa according to claim 1 wins the synthetic method of XiLin intermediate, which is characterized in that the pH described in step S1
It is 7.
5. pa according to claim 1 wins the synthetic method of XiLin intermediate, which is characterized in that the reaction item in step S2
Part in order to control at 70-73 DEG C react 32 hours by temperature, and detecting reaction solution by TLC shows that raw material point disappears, after reaction,
It is cooled to 40 DEG C, decompression boils off solvent, into flask plus water 30ml, 40-50 DEG C of temperature control, heats 30 minutes, later heat filtering.
6. pa according to claim 1 wins the synthetic method of XiLin intermediate, which is characterized in that the recrystallization in step S2
The solvent used is ethyl acetate, and the ratio that crude product accounts for ethyl acetate is 110-120g/L.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551063A (en) * | 2019-10-17 | 2019-12-10 | 山东邹平大展新材料有限公司 | Method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine |
| CN111995569A (en) * | 2019-05-27 | 2020-11-27 | 成都博腾药业有限公司 | Preparation method of cyclin-dependent kinase inhibitor intermediate |
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| WO2008007123A2 (en) * | 2006-07-14 | 2008-01-17 | Astex Therapeutics Limited | Pharmaceutical compounds |
| CN102186856A (en) * | 2008-08-22 | 2011-09-14 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds as cdk inhibitors |
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| WO2017162215A1 (en) * | 2016-03-25 | 2017-09-28 | 正大天晴药业集团股份有限公司 | Substituted pyrrolopyrimidine cdk inhibitor, pharmaceutical composition containing same and use thereof |
-
2018
- 2018-05-17 CN CN201810473825.3A patent/CN108558745A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007123A2 (en) * | 2006-07-14 | 2008-01-17 | Astex Therapeutics Limited | Pharmaceutical compounds |
| CN102186856A (en) * | 2008-08-22 | 2011-09-14 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds as cdk inhibitors |
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| WO2017162215A1 (en) * | 2016-03-25 | 2017-09-28 | 正大天晴药业集团股份有限公司 | Substituted pyrrolopyrimidine cdk inhibitor, pharmaceutical composition containing same and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| ROBERT WODTKE ET AL.: ""Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling"", 《J. MED. CHEM.》 * |
| 刘景宝: ""帕博西林关键中间体的合成工艺研究"", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995569A (en) * | 2019-05-27 | 2020-11-27 | 成都博腾药业有限公司 | Preparation method of cyclin-dependent kinase inhibitor intermediate |
| CN111995569B (en) * | 2019-05-27 | 2023-12-05 | 成都博腾药业有限公司 | Preparation method of cyclin-dependent kinase inhibitor intermediate |
| CN110551063A (en) * | 2019-10-17 | 2019-12-10 | 山东邹平大展新材料有限公司 | Method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine |
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