CN105524059A - Palbociclib impurity preparation method - Google Patents
Palbociclib impurity preparation method Download PDFInfo
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- CN105524059A CN105524059A CN201610002252.7A CN201610002252A CN105524059A CN 105524059 A CN105524059 A CN 105524059A CN 201610002252 A CN201610002252 A CN 201610002252A CN 105524059 A CN105524059 A CN 105524059A
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- compound
- acid
- thebe
- handkerchief
- ripple
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a palbociclib critical impurity compound (I) preparation method, according to the method, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid and the like are used as proton acids for synthesis of a compound (I), the reaction is simple in post-treatment and efficient.
Description
Technical field
Pharmaceutical synthesis field of the present invention, is specifically related to a kind of preparation method of handkerchief ripple Thebe (Palbociclib) impurity.
Background technology
If above-mentioned structural compounds (I) is a kind of handkerchief ripple Thebe critical impurities; its chemistry is by name: 6-ethanoyl-8-cyclopentyl-5-methyl-2-[[5-(piperazine-1-BOC) pyridine-2-base] is amino]-8H-pyrido [2,3-D] pyrimidin-7-ones.
The chemical name of handkerchief ripple Thebe is 6-ethanoyl-8-cyclopentyl-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] is amino]-8H-pyrido [2,3-D] pyrimidin-7-ones.Be a kind of oral antitumor drug, by T suppression cell cyclin dependent kinase 4,6, regulate the cell cycle to play a role.Mainly through suppressing CDK4/6 active thus stoping cell by G1 phase to S phase and then the synthesis suppressing DNA.The visual field that it enters people is the earliest in San Antonio mammary cancer meeting in 2012 (SABCS), just causes industry extensive concern once issue.This medicine and letrozole drug combination are used for as a roentgenism x estrogen receptor positive (ER+), the negative advanced breast cancer postmenopausal women of human epidermal growth factor receptor 2 (HER2) that did not previously accept systematic treating.
The synthesis of handkerchief ripple Thebe has many routes, but final step is following steps:
Namely under the effect of protonic acid, the hydrolysis of the BOC protecting group of-1 step midbody compound (II) piperazine end is removed, and obtain handkerchief ripple Thebe simultaneously after 6 vinyl alkyl ethers hydrolysis are rearranged to ethanoyl on pyridine ring.As used isethionic acid in WO2005005426, water, methyl alcohol are solvent, complete the reaction of this step after being heated to 55 ~ 60 DEG C; Use hydrochloric acid in WO2008032157, WO2010039997 etc., methylene dichloride is that solvent completes this reaction; Use methylsulphonic acid in WO2014128588, the mixed solvent of water, methyl alcohol carries out this reaction.
Due to two groups in this step reaction needed Hydrolysis of compound (II), the inevitable incomplete phenomenon of radical reaction that there is one of them more difficult hydrolysis produces, thus becomes impurity and remain, and affects quality of finished.By great many of experiments, we find that this compound is compound (I).How effective acquisition compound (1) is significant to the quality controlling handkerchief ripple Thebe bulk drug.
Summary of the invention
In the R&D process of handkerchief ripple Thebe bulk drug, we find the preparation method of a kind of handkerchief ripple Thebe impurity, it is characterized in that:
The method adopts reacts using hydrochloric acid, methylsulphonic acid, tosic acid etc. as protonic acid.
A preparation method for handkerchief ripple Thebe impurity, is characterized in that:
The condition of stirring reaction is: solvent be methyl alcohol, water, 60 DEG C, 8h.The present invention explores and have developed the method that one prepares handkerchief ripple Thebe critical impurities compound (I), the method adopts and samples under different time as time protonic acid synthetic compound (I) using hydrochloric acid, methylsulphonic acid, tosic acid etc., after reaction is neutralized to pH >=8, the solid of precipitation is leached, drying, HPLC detects (C18 chromatographic column; Moving phase: A:0.05%TFA water, B: acetonitrile; Detector: UV357nm; Flow velocity: 4mL/min; Get 10mg sample 1mL methyl alcohol ultrasonic dissolution, loading after filtering), area normalization method determines each compound relative content, understands the state of hydrolysis reaction.And then determine the preparation condition of best compound (I).
Result is as shown in table 1.
The comparison of the lower hydrolysis reaction of the different acid of table 1
As seen from the above table, be more prone to 6 vinyl alkyl ethers on selective hydrolysis pyridine ring during the hydrolysis of tosic acid to compound (II), be more conducive to obtained compound (I).
The method generality preparing compound (I) provided by the invention operates as follows:
Compound (II) is dropped into proper volume methanol aqueous solution, adds the acid of proper concn, at moderate temperatures stirring reaction appropriate time, cooling, alkali lye neutralizes, and filters, and dry, purification by silica gel column chromatography obtains compound (I).
In above-mentioned preparation method, 1: 1 methanol/water solution that described " proper volume methanol aqueous solution " is the weightmeasurement ratio 1: 16 of compound (II)." acid of proper concn " is hydrochloric acid, methylsulphonic acid, the tosic acid of 2 equivalents, preferred tosic acid." at moderate temperatures stirring reaction appropriate time " is 55 ~ 60 DEG C of reactions 6 ~ 8 hours.
In gained solid, compound (I) content is high, is easier to separation and obtains.
Embodiment
In order to make those skilled in the art, the present invention may be better understood, referring to embodiment, the present invention is described.These embodiments, only for illustration of the present invention, are not limited to scope of the present invention.
The preparation of embodiment 1 handkerchief ripple Thebe impurity compound (I)
10g compound (II) is added in 500ml reaction flask, 80ml methyl alcohol, 80ml purified water, 12g tosic acid, stir 8 hours at 60 DEG C, TLC (developping agent: methyl alcohol: ethyl acetate=1: 1, rf raw material=0.1, rf impurity=0.6, rf handkerchief ripple Thebe=0.3) monitoring react completely, be cooled to less than 50 DEG C and adjust pH=8 ~ 9 with ammoniacal liquor, filtration, dry crude product 8g, column chromatography purification (eluent: methyl alcohol: ethyl acetate=1: 1) obtain compound (I) 2g.
1HNMR(400MHz，CDCl
3)δ8.84(s，1H)，δ8.18-8.20(d，1H)，δ8.07-8.07(d，1H)，δ7.27(s，1H)，δ5.86-5.86(m，1H)，δ3.61-3.63(t，4H)，δ3.12-3.14(t，4H)，δ2.08-2.55(m，5H)，δ2.05-2.08(m，2H)，δ1.87-1.90(m，2H)，δ1.68-1.71(m，2H)，δ1.64(s，3H)，δ1.49(s，9H)
C
29h
37n
7o
4the MS calculated value of-Boc+H: 491, measured value: 491
The detection method of embodiment 2 handkerchief ripple Thebe impurity compound (I)
Adopt and sample under different time as time protonic acid synthetic compound (I) using hydrochloric acid, methylsulphonic acid, tosic acid etc., HPLC detects (C18 chromatographic column; Moving phase: A:0.05%TFA water, B: acetonitrile; Detector: UV357nm; Flow velocity: 4mL/min; Get 10mg sample 1mL methyl alcohol ultrasonic dissolution, loading after filtering), area normalization method determines each compound relative content, understands the state of hydrolysis reaction.
Claims (2)
1. a preparation method for handkerchief ripple Thebe impurity, is characterized in that:
The method adopts reacts using hydrochloric acid, methylsulphonic acid, tosic acid etc. as protonic acid.
2. the preparation method of a kind of handkerchief ripple Thebe according to claim 1 impurity, is characterized in that:
The condition of stirring reaction is: solvent be methyl alcohol, water, 60 DEG C, 8h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610002252.7A CN105524059A (en) | 2016-01-06 | 2016-01-06 | Palbociclib impurity preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610002252.7A CN105524059A (en) | 2016-01-06 | 2016-01-06 | Palbociclib impurity preparation method |
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| CN105524059A true CN105524059A (en) | 2016-04-27 |
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| CN201610002252.7A Pending CN105524059A (en) | 2016-01-06 | 2016-01-06 | Palbociclib impurity preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106018655A (en) * | 2016-08-01 | 2016-10-12 | 合肥远志医药科技开发有限公司 | Method for detecting substances relevant with palbociclib raw material |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014128588A1 (en) * | 2013-02-21 | 2014-08-28 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
| 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 |
| CN105418603A (en) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib |
-
2016
- 2016-01-06 CN CN201610002252.7A patent/CN105524059A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014128588A1 (en) * | 2013-02-21 | 2014-08-28 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
| 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 |
| CN105418603A (en) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106018655A (en) * | 2016-08-01 | 2016-10-12 | 合肥远志医药科技开发有限公司 | Method for detecting substances relevant with palbociclib raw material |
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