CN106317053A - Preparation method of palbociclib crystal form A - Google Patents
Preparation method of palbociclib crystal form A Download PDFInfo
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- CN106317053A CN106317053A CN201510367937.7A CN201510367937A CN106317053A CN 106317053 A CN106317053 A CN 106317053A CN 201510367937 A CN201510367937 A CN 201510367937A CN 106317053 A CN106317053 A CN 106317053A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention provides a preparation method of a palbociclib crystal form A. The preparation method is simple and easy to perform. The used reagents are all common reagents. The preparation method is suitable for industrial massive production. The product purity is high and meets requirements of pharmaceutical crystal form.
Description
Technical field
The present invention provides a kind of handkerchief to win the preparation method of former times cloth crystal formation A, belongs to chemosynthesis technical field.
Background technology
Former times cloth won by handkerchief, English name: Palbociclib, molecular formula: C24H29N7O2,
No. CAS: 571190-30-2；Chemical constitution:
Palbociclib is that the one of Pfizer's exploitation is administered orally cyclin dependent kinase (CDKs) 4 and 6 inhibitor.
CDKs 4 and 6 is the critical regulatory factor of cell cycle, and it can trigger cell cycle progress.The indication of Palbociclib is
Associating letrozole is used for treating estrogen receptor positive, negative (ER+/HER2-) post menopausal of ErbB-2
Advanced breast cancer patient, as the Regimen Chemotherapy metastatic disease based on initial endocrine therapy.
Disclosing the preparation method of a kind of Palbociclib crystal formation A in WO2014128588A1, the method uses " one kettle way "
Direct for compound INB deprotection is prepared free base product by (such as following formula), and utilizes methyl phenyl ethers anisole/n-butyl alcohol system to be swum
Medicinal A crystal formation from alkali.
The shortcoming of the method is:
Though 1, the method operating procedure is few, but desired reaction temperature higher (> 120 DEG C), it is more difficult to the most extensively apply.
And methyl phenyl ethers anisole commercial Application is little, has special unpleasant abnormal flavour, inflammable, irritant to the skin of people, endanger environment.
2, " one-step synthesis " should experience deprotection, the preparation of free alkali, prepare three links of crystal formation, the method is easier to
Introduce unknown impuritie, be difficult to realize the purification of compound, it is difficult to ensure the purity of product.
Palbociclib is as medicinal raw material, in addition it is also necessary to develop more preferable method for crystallising, improves product purity, so that product reaches
The standard of medicinal crystal-form.
Summary of the invention
It is an object of the invention to provide a kind of handkerchief and win the preparation method of former times cloth (Palbociclib) crystal formation A, it is desirable to be simple,
Use reagent to be conventional reagent, be suitable for the demand of industrialized great production, and product purity is high, meets medicinal crystal-form to purity
Requirement.
The preparation method of former times cloth (Palbociclib) crystal formation A won by the handkerchief that the present invention provides is " two-step method ", specific as follows:
Step 1: with compound INB as starting material, with pharmaceutically acceptable acid reaction, prepare the salt of Palbociclib；
Step 2: by the reactant aqueous solution of the salt of Palbociclib Yu highly basic, prepares Palbociclib free alkali crystal formation A；
Synthetic route of the present invention is as follows；
Reaction equation 1:
In formula, boc represents tertbutyloxycarbonyl；HR represents pharmaceutically acceptable acid.
Preferably, the acid that in reaction equation 1, HR represents, the one in following acid: hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid,
Hydrobromic acid, hydroiodic acid, acetic acid, oxalic acid, valeric acid, oleic acid, Palmic acid, stearic acid, lauric acid, boric acid, benzoic acid, breast
Acid, benzene methanesulfonic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, naphthalene diacid, methanesulfonic acid, lactic acid, 12
Alkyl sulfonic acid, hydroxyethylsulfonic acid..
Further preferred acid includes: hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, acetic acid, oxalic acid, valeric acid, benzoic acid,
Lactic acid, benzene methanesulfonic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, hydroxyethylsulfonic acid. etc..
Preferably, the salt of Palbociclib refers to its pharmaceutically acceptable salt, is selected from: hydrochlorate, nitrate, phosphate,
Sulfate, hydrobromate, hydriodate, phosphate, pyrosulfate, disulfate, sulphite, bisulfites, phosphorus
Acid monohydric salt, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, oxalates,
Valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate, benzene methanesulfonic acid
Salt, citrate, maleate, fumarate, succinate, tartrate, naphthalene diacid salt, mesylate, lactate,
Dodecane sulfonate, isethionate etc..
Further preferred salt includes: hydrochlorate, nitrate, phosphate, sulfate, hydrobromate, phosphate, hydrogen sulfate
Salt, acetate, oxalates, valerate, benzoate, lactate, benzene methanesulfonic acid salt, citrate, maleate, richness
Horse hydrochlorate, succinate, tartrate, mesylate, isethionate etc..
Preferably, in preparation method of the present invention, the reaction dissolvent of step 1 is lower alcohol-water mixed solvent, wherein lower alcohol: water
Volume ratio preferably at 100:1～10:1, most preferably 80:1；Reaction temperature is 55～65 DEG C.
Preferably, in preparation method of the present invention, the reaction dissolvent of step 2 is water-lower alcohol mixed solvent, wherein the body of lower alcohol
Long-pending percentage ratio is 0～75%, water: the volume ratio of lower alcohol is most preferably 5:1；Reaction temperature is room temperature.
Preferably, described lower alcohol one in methanol, ethanol, normal propyl alcohol, isopropanol.
Preferably, the aqueous solution of highly basic is sodium hydrate aqueous solution, potassium hydroxide aqueous solution or Feldalat NM aqueous solution.
It is further preferred that the acid preferably hydroxyethylsulfonic acid. that HR of the present invention represents, corresponding, Palbociclib's pharmaceutically may be used
The preferred isethionate of salt accepted.The present inventor finds through substantial amounts of experiment: use hydroxyethylsulfonic acid. to obtain in step 1
To the isethionate of Palbociclib, product yield is more preferable, purity is higher；And use Palbociclib in step 2
Isethionate obtain the free alkali crystal formation of Palbociclib, same product yield more preferably, purity higher.
It is further preferred that as a example by hydroxyethylsulfonic acid., reaction scheme of the present invention is as follows:
In formula, boc represents tertbutyloxycarbonyl.
Invention also provides a midbody compound INC winning former times cloth crystal formation A for preparing handkerchief, intermediate of the present invention
The chemistry of compound INC is entitled: 6-acetyl group-8-cyclopenta-5-methyl-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyridine
And the double-isethionate of [2,3-d] pyrimidin-7-ones；Structural formula is as follows:
In the present invention, compound INB can be prepared according to the method disclosed in WO2014128588A1.
In the present invention, the preparation of the pharmaceutically-acceptable salts of Palbociclib, in addition to the method by step 1 disclosed by the invention,
Prepared by other method that those skilled in the art can also be used to grasp.
It is further preferred that step 1: with compound INB as starting material, with pharmaceutically acceptable acid reaction, preparation
The salt of Palbociclib, concrete operations are as follows:
Compound INB is added lower alcohol-water mixed solvent, is warming up to 55-65 DEG C；Drip pharmaceutically acceptable acid, pharmacy
Upper acceptable acid is more than 2:1 with the mol ratio of compound INB；55-65 DEG C continues stirring until precipitation solid；Filter, produced
Thing.
It is further preferred that the one that lower alcohol is in methanol, ethanol, normal propyl alcohol, isopropanol.
It is further preferred that the preferred hydroxyethylsulfonic acid. of pharmaceutically acceptable acid.
It is further preferred that step 2 uses the salt of Palbociclib as starting material, with the reactant aqueous solution of highly basic, prepare
Palbociclib free alkali crystal formation A, concrete operations are as follows:
The salt of Palbociclib is added lower alcohol-water mixed solvent, stirs to clarify；Filter, in filtrate, drip the water of highly basic
Solution, regulates solution ph > 8；Persistently it is stirred at room temperature to separating out solid, filters；Washing filter cake；Produced after dry cake
Thing.
It is further preferred that the one that lower alcohol is in methanol, ethanol, normal propyl alcohol, isopropanol.
It is further preferred that the aqueous solution of highly basic is selected from sodium hydrate aqueous solution, potassium hydroxide aqueous solution, Feldalat NM aqueous solution.
The advantage of preparation method of the present invention is as follows:
1, compound INB, CAS numbering 866084-31-3, is the important intermediate of synthesis Palbociclib, compound INB
On boc (tertbutyloxycarbonyl) group and butyl ether group be all protection group, next step react in remove.
In prior art WO2014128588A1, " one kettle way " is used to prepare free by direct for compound INB deprotection
Alkali product, and utilize methyl phenyl ethers anisole/n-butyl alcohol system to obtain the medicinal A crystal formation of free alkali.The method temperature required higher (> 120 DEG C),
And be easier to introduce unknown impuritie, it is difficult to realize the purification of compound, it is difficult to ensure the purity of product.
The present invention uses " two-step method ", first prepares the salt of Palbociclib, then the salt system with Palbociclib with compound INB
Standby Palbociclib free alkali crystal formation A；Temperature required relatively low, first step reaction temperature 55-65 DEG C, second step reaction temperature is room
Temperature.Preparation method of the present invention is simple, be suitable for the demand of industrialized great production, and product purity is high, meets medicinal crystal-form
Requirement to purity.
2, in prior art WO2014128588A1, employing methyl phenyl ethers anisole as recrystallisation solvent, methyl phenyl ethers anisole commercial Application is little,
Cost is high, has special unpleasant abnormal flavour, inflammable, irritant to the skin of people, endangers environment, and dissolvent residual is the most right
Human body has hazardness.
The present invention uses reagent to be conventional reagent, and water, lower alcohol (such as methanol) etc., low cost, to human body and environmental hazard
Little, post processing is prone to remove.
3, during compound INB becomes the step of salt with acid reaction, the amount such as fruit acid is not enough, it will obtain Palbociclib molecule with
The mono-salt of acid molecule 1:1, or mono-salt and the salt-mixture of double salt, in this case, compound INB can not sufficiently remove guarantor
Protecting base, purity and the yield of the Palbociclib alkali of next step synthesis are the most impacted.
The present invention adds the acid of excess during step 1 becomes salt, and acid is more than 2:1 with the mol ratio of compound INB, obtains
Double salt of intermediate Palbociclib, reaction can sufficient deprotection base, and post processing is easy, and impurity is prone to remove,
Purity and the yield of the Palbociclib alkali of next step synthesis are the highest.
4, the inventive method product purity is high, and product purity reaches more than 99.9%, meets the medicinal crystal-form requirement to purity.
Accompanying drawing explanation
Powder X-ray diffraction (PXRD) collection of illustrative plates of Fig. 1: Palbociclib free alkali crystal formation A.
Detailed description of the invention
The invention will be further described by the following examples, but this is not limitation of the present invention, those skilled in the art
According to the basic thought of the present invention, various modifications may be made or improves, but without departing from the basic thought of the present invention, all
Within the scope of the present invention.
Embodiment 1: prepare the salt of Palbociclib
Weigh Compound INB 10 grams, adds methanol 230 milliliters, 3 milliliters of water.Being warming up to 55 DEG C, solution is that yellow is suspended；
Dropping hydroxyethylsulfonic acid. 8.5 grams, solution is gradually clarified；It is warming up to 65 DEG C, stirs 12 hours；System separates out a large amount of solids, mistake
Filter, obtains 10.02 grams of product INC sample, yield 86.4%.
Embodiment 2: preparation Palbociclib free alkali crystal formation A
Weighing embodiment 1 product INC 10 grams, add 150 milliliters of water, methanol 30 milliliters, solution is clarified.Filter, mother solution
Dropping sodium hydroxide solution (5%W/W), regulates pH value of solution > 8.Persistently it is stirred at room temperature 3 hours, separates out a large amount of solid, mistake
Filter.Obtain solid, add 150 milliliters of water, stir 1 hour, filter, washing.Obtain product 5.4 grams, yield after drying
84.5%.Purity 99.9%.
Embodiment 3: the determination of crystal formation
Detection embodiment 2 powder product X-ray diffraction (PXRD):
Rigaku Rigaku Dmax/2400 type X-ray polycrystal powder diffractometer (condition: Cu K α, 40kV) is used to carry out
Measure；
Figure of description 1 is shown in by PXRD collection of illustrative plates:
The peak table of PXRD collection of illustrative plates:
Claims (11)
1. a preparation method of former times cloth crystal formation A won by handkerchief, comprises the following steps:
Step 1: with compound INB as starting material, with pharmaceutically acceptable acid reaction, prepare handkerchief and win the salt of former times cloth；
Step 2: handkerchief is won the salt of former times cloth and the reactant aqueous solution of highly basic, prepares handkerchief and wins former times cloth crystal formation A；
Reaction equation is:
In formula, boc represents tertbutyloxycarbonyl；HR represents pharmaceutically acceptable acid.
Preparation method the most according to claim 1, it is characterised in that the reaction dissolvent of step 1 is lower alcohol-water mixed solvent；
Reaction temperature is 55-65 DEG C.
Preparation method the most according to claim 1, it is characterised in that the reaction dissolvent of step 2 is lower alcohol-water mixed solvent；
Reaction temperature is room temperature.
Preparation method the most according to claim 1, it is characterised in that step 1 is: compound INB is added lower alcohol-water
Mixed solvent, wherein lower alcohol: the volume ratio of water preferably at 100:1～10:1, most preferably 80:1, be warming up to 55-65 DEG C；
Dripping pharmaceutically acceptable acid, the most pharmaceutically acceptable acid is more than 2:1 with the mol ratio of compound INB；55-65℃
Continue stirring until precipitation solid；Filter, obtain handkerchief and win the salt of former times cloth.
Preparation method the most according to claim 1, it is characterised in that step 2 is: the salt that handkerchief is won former times cloth adds water-rudimentary
Alcohol mixed solvent, wherein the percent by volume of lower alcohol is 0～75%, water: the volume ratio of lower alcohol is most preferably 5:1, stirs
Mix to clarification；Filter, in filtrate, drip the aqueous solution of highly basic, regulate solution ph 8；Persistently it is stirred at room temperature to precipitation
Solid, filters；Washing filter cake；Product is obtained after dry cake.
6. according to the arbitrary described preparation method of Claims 1 to 5, it is characterised in that described lower alcohol selected from methanol, ethanol, positive third
One in alcohol and isopropanol.
7. according to the arbitrary described preparation method of Claims 1 to 5, it is characterised in that the aqueous solution of the highly basic described in step 2 is hydrogen
Aqueous solution of sodium oxide, potassium hydroxide aqueous solution or Feldalat NM aqueous solution.
8. according to the arbitrary described preparation method of Claims 1 to 5, it is characterised in that described HR one in following acid: salt
Acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydroiodic acid, acetic acid, oxalic acid, valeric acid, oleic acid, Palmic acid, stearic acid,
Lauric acid, boric acid, benzoic acid, lactic acid, benzene methanesulfonic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid,
Naphthalene diacid, methanesulfonic acid, lactic acid, dodecyl sodium sulfonate and hydroxyethylsulfonic acid..
9. according to the arbitrary described preparation method of Claims 1 to 5, it is characterised in that the salt of former times cloth won by described handkerchief is its hydrochlorate, nitre
Hydrochlorate, phosphate, sulfate, hydrobromate, hydriodate, phosphate, pyrosulfate, disulfate, sulphite,
Bisulfites, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide,
Acetate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate,
Lactate, benzene methanesulfonic acid salt, citrate, maleate, fumarate, succinate, tartrate, naphthalene diacid salt,
Mesylate, lactate, dodecane sulfonate or isethionate.
Preparation method the most according to claim 1, it is characterised in that described HR is hydroxyethylsulfonic acid.；
Reaction equation is:
In formula, boc represents tertbutyloxycarbonyl.
Preparing handkerchief for 11. 1 kinds and win the midbody compound INC of former times cloth crystal formation A, chemistry is entitled: 6-acetyl group-8-cyclopenta-5-first
Double-the isethionate of base-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyrido [2,3-d] pyrimidin-7-ones；Knot
Structure formula is as follows:
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800553A (en) * | 2015-11-26 | 2017-06-06 | 上海科胜药物研发有限公司 | A kind of crystal formation of Pa Boxini dihydroxy ethyls sulfonate |
| CN108864078A (en) * | 2017-05-10 | 2018-11-23 | 江苏豪森药业集团有限公司 | The preparation method of Pa Boxini crystal form B |
| CN109897034A (en) * | 2017-12-07 | 2019-06-18 | 南京卡文迪许生物工程技术有限公司 | A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition |
| CN115667260A (en) * | 2022-08-26 | 2023-01-31 | 成都苑东生物制药股份有限公司 | Piperazine Bai Xili saccharine salt crystal form and preparation method thereof |
| WO2024040668A1 (en) * | 2022-08-26 | 2024-02-29 | 成都苑东生物制药股份有限公司 | Palbociclib saccharinate crystal form and preparation method therefor |
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| CN1835951A (en) * | 2003-07-11 | 2006-09-20 | 沃尼尔·朗伯有限责任公司 | Isethionate salt of a selective CDK4 inhibitor |
| CN101511829A (en) * | 2006-09-08 | 2009-08-19 | 辉瑞产品公司 | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| WO2014128588A1 (en) * | 2013-02-21 | 2014-08-28 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
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| CN1183595A (en) * | 1996-11-22 | 1998-06-03 | 张建平 | Commodity discrimination and processing method |
| CN1835951A (en) * | 2003-07-11 | 2006-09-20 | 沃尼尔·朗伯有限责任公司 | Isethionate salt of a selective CDK4 inhibitor |
| CN101511829A (en) * | 2006-09-08 | 2009-08-19 | 辉瑞产品公司 | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800553A (en) * | 2015-11-26 | 2017-06-06 | 上海科胜药物研发有限公司 | A kind of crystal formation of Pa Boxini dihydroxy ethyls sulfonate |
| CN108864078A (en) * | 2017-05-10 | 2018-11-23 | 江苏豪森药业集团有限公司 | The preparation method of Pa Boxini crystal form B |
| CN108864078B (en) * | 2017-05-10 | 2021-10-15 | 江苏豪森药业集团有限公司 | Preparation method of palbociclib crystal form B |
| CN109897034A (en) * | 2017-12-07 | 2019-06-18 | 南京卡文迪许生物工程技术有限公司 | A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition |
| CN115667260A (en) * | 2022-08-26 | 2023-01-31 | 成都苑东生物制药股份有限公司 | Piperazine Bai Xili saccharine salt crystal form and preparation method thereof |
| WO2024040668A1 (en) * | 2022-08-26 | 2024-02-29 | 成都苑东生物制药股份有限公司 | Palbociclib saccharinate crystal form and preparation method therefor |
| CN115667260B (en) * | 2022-08-26 | 2024-04-23 | 成都硕德药业有限公司 | Saccharin salt crystal form of piperaquine Bai Xili and preparation method thereof |
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