CN103333124B - Preparation method of hydrochloric acid erlotinib crystal form F - Google Patents
Preparation method of hydrochloric acid erlotinib crystal form F Download PDFInfo
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- CN103333124B CN103333124B CN201310203250.0A CN201310203250A CN103333124B CN 103333124 B CN103333124 B CN 103333124B CN 201310203250 A CN201310203250 A CN 201310203250A CN 103333124 B CN103333124 B CN 103333124B
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- hydrogen chloride
- hydrochloric acid
- free alkali
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention relates to a novel preparation method of hydrochloric acid erlotinib crystal form F. The method comprises steps that erlotinib free alkali in C4 alcohol is added into hydrogen chloride dissolved in an organic solvent, and the formed hydrochloric acid erlotinib is crystallized. The method has the advantages of suitability for mass production and good reproducibility. Furthermore, the invention also comprises a method of converting hydrochloric acid erlotinib crystal form F into other forms.
Description
Technical field
The present invention relates to a kind of new method preparing Eriotinib Hydrochloride form F.
Background technology
Tarceva has following formula I structure, and its chemical name is two (2-the methoxy ethoxy)-4-quinazoline amine of N-(3-ethynyl phenyl)-6,7-.Tarceva is the inhibitor of the erbB race of carcinogenic and former carcinogenic protein tyrosine kinase, and described protein tyrosine kinase is such as EGF-R ELISA (EGFR).Therefore Tarceva is used for the treatment of the hyperproliferative disorders of people, such as cancer.Tarceva is sold in the form of the hydrochloride salt.
Formula I.
Erlotinid hydrochloride (Erlotinib HCl) can be different polymorphic Form exist, these polymorphs are different from each other in stability, physical property, spectroscopic data and preparation method.
Eriotinib Hydrochloride form F is open in patent application WO2009025876A2 first.Describe in the embodiment 7 to 11 of this patent application in the DOX solution by concentrated hydrochloric acid being joined Tarceva free alkali and prepare Eriotinib Hydrochloride form F.But, find that this preparation method is not suitable for industrial scale preparation, this is because DOX is a kind of height flammable solvent not being suitable for industrial scale and preparing.In addition, this preparation method does not have reappearance for acquisition Eriotinib Hydrochloride form F.As shown in hereafter comparative example 1 ~ 4, be F or G type according to the Eriotinib Hydrochloride form that the method for WO2009025876A2 prepares.
Therefore be necessary that developing a kind of applicable industrially scalable prepares Eriotinib Hydrochloride form F and have the reliable method of good reproduction.
Summary of the invention
The object of the present invention is to provide a kind of new method preparing Eriotinib Hydrochloride form F, the method overcome the defect of prior art and allow to obtain required crystal formation F at industrial scale with good yield.
By providing a kind of method preparing Eriotinib Hydrochloride form F to realize this object, described method comprises at C
4tarceva free alkali in alcohol joins and is dissolved in the hydrogen chloride of organic solvent, and makes formed erlotinid hydrochloride crystallization.
In addition, the inventive method comprises further Eriotinib Hydrochloride form F is converted into other crystal formation.
The invention provides following technical scheme:
1. prepare a method of Eriotinib Hydrochloride form F, described method comprises at C
4tarceva free alkali in alcohol joins and is dissolved in the hydrogen chloride of organic solvent, and makes formed erlotinid hydrochloride crystallization.
2. the method according to technical scheme 1, wherein said C
4alcohol is selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
3. the method according to technical scheme 1 or 2, wherein said organic solvent is selected from one or more of C
3-6alcohol.
4. the method according to any one of technical scheme 1-3, wherein said organic solvent is one or more of C
3-6alcohol and the mixture being selected from following one or more of solvents: C
5-8alkane, C
5-8cycloalkane, C
6-8aromatic hydrocarbon, C
4-10alkyl ether, C
4-10cycloalkyl ethers, C
1-4carboxylic acid C
2-4arrcostab.
5. the method according to any one of technical scheme 1-4, wherein said organic solvent is one or more of C
3-6alcohol and one or more of C
1-4carboxylic acid C
2-4the mixture of Arrcostab.
6. the method according to any one of technical scheme 1-5, wherein carries out described method at the temperature of 0 ~ 60 DEG C.
7. the method according to any one of technical scheme 1-6, wherein carries out described method at the temperature of 20 ~ 50 DEG C.
8. the method according to any one of technical scheme 1-7, wherein said method is carried out at 30 DEG C.
9. the method according to any one of technical scheme 1-8, wherein relative to Tarceva free alkali, the consumption of hydrogen chloride is 1 to 1.5 molar equivalent, preferably 1.2 molar equivalents.
10. the method according to any one of technical scheme 1-9, its also comprise by filter, washing and drying reclaim Eriotinib Hydrochloride form F.
11. methods according to any one of technical scheme 1-10, wherein use C
4alcohol washing Eriotinib Hydrochloride form F.
12. methods according to any one of technical scheme 1-11, wherein said C
4alcohol is selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
13. methods according to any one of technical scheme 1-12, it also comprises Eriotinib Hydrochloride form F is converted into other crystal formation.
The present inventor is surprised to find that, the key solving technical problem of the present invention is two kinds of parameters, i.e. the addition sequence of hydrogen chloride and the character of solvent medium.
With regard to the addition sequence of hydrogen chloride, the present invention selects will at C
4tarceva free alkali in alcohol joins in the organic solution of hydrogen chloride, instead of joins the organic solution of hydrogen chloride at C
4in Tarceva free alkali in alcohol.As shown in hereafter comparative example 5, when preparing erlotinid hydrochloride in the 2-methylpropanol solution by the organic solution of hydrogen chloride being joined Tarceva free alkali, acquisition be the mixture of crystal formation F, G and A, and non-required single crystal form F.
In the methods of the invention, hydrogen chloride participates in reaction with the form of organic solution, but not participates in reaction in form of an aqueous solutions.The organic solution of hydrogen chloride can any appropriate method known in the art be prepared, such as, include but not limited to pass in target organic solvent by hydrogen chloride gas, also by commercially available.
With regard to solvent medium, in the methods of the invention, the solvent medium being applicable to Tarceva free alkali is C
4alcohol, is applicable to the organic solvent of dissolving hydrogen chloride as mentioned below.As shown in hereafter comparative example 6, when by the tetrahydrofuran solution of Tarceva free alkali is joined be dissolved in oxolane hydrogen chloride in prepare erlotinid hydrochloride time, acquisition be crystal form A, and non-required crystal formation F.
The Tarceva free alkali being used as initiation material is in the methods of the invention prepared by any method known in the art, such as, include but not limited to method described in the embodiment 20 in US Patent No. 5747498A.
In the special embodiment of one of the present invention, Tarceva free alkali is dissolved in C
4in alcohol.At 70 ~ 100 DEG C, preferably realize the dissolving of Tarceva free alkali.
In the special embodiment of the one of the inventive method, C
4alcohol is selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
According to one preferred embodiment, hydrogen chloride is dissolved in is selected from C
3-6in the organic solvent of alcohol and composition thereof.
In another kind of preferred embodiment, described organic solvent is one or more of C
3-6alcohol and the mixture being selected from following one or more of solvents: C
5-8alkane, C
5-8cycloalkane, C
6-8aromatic hydrocarbon, C
4-10alkyl ether, C
4-10cycloalkyl ethers, C
1-4carboxylic acid C
2-4arrcostab.In preferred embodiment, described organic solvent is one or more of C
3-6alcohol and one or more of C
1-4carboxylic acid C
2-4the mixture of Arrcostab.
For the present invention, suitable C
3-6the example of alcohol includes but not limited to normal propyl alcohol, isopropyl alcohol, n-butanol and the tert-butyl alcohol; Suitable C
5-8the example of alkane includes but not limited to heptane and hexane; Suitable C
5-8the example of cycloalkane includes but not limited to cyclohexane; Suitable C
6-8the example of aromatic hydrocarbon includes but not limited to benzene, toluene and dimethylbenzene; Suitable C
4-10the example of alkyl ether includes but not limited to ether; Suitable C
4-10the example of cycloalkyl ethers includes but not limited to oxolane; Suitable C
1-4carboxylic acid C
2-4the example of Arrcostab includes but not limited to isopropyl acetate.
In the special embodiment of one, relative to Tarceva free alkali, the consumption of hydrogen chloride is 1 to 1.5 molar equivalent, preferably 1.2 molar equivalents.
In a preferred embodiment, at 0 ~ 60 DEG C, implement the inventive method, preferably at 20 ~ 50 DEG C, implement the inventive method, most preferably at 30 DEG C, implement the inventive method.The enforcement temperature of the inventive method described here refers at C
4tarceva free alkali in alcohol mixes with the organic solution of hydrogen chloride and makes the temperature of erlotinid hydrochloride crystallization.
In the special embodiment of one, crystallization process of the present invention carries out under agitation.Preferably, keep stirring 30 ~ 90 minutes, period Precipitation solid product.
Method of the present invention comprises further is such as filtered by conventional method, to wash and Eriotinib Hydrochloride form F is reclaimed in drying.
In a preferred embodiment, C is used
4the crystal formation F of alcohol washing erlotinid hydrochloride, this C
4alcohol is preferably selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
In a preferred embodiment, under reduced pressure drying can be carried out until residual solvent content is reduced to required amount.
In another aspect of this invention, method of the present invention also comprises just Eriotinib Hydrochloride form F and is converted into other crystal formation.Other crystal formation described includes but not limited to crystal form A, B and C.
Crystal form A involved herein, B, F and G represent by the known crystal formation of bibliographical information respectively, its have as in WO2009025876A2 the XRPD characteristic peak that defines, that is:
Crystal form A:
at 5.7,9.8,10.1,10.3,18.9,19.5,21.3,24.2,26.2 and 29.2 ± 0.2o 2 θ place, there is XRPD characteristic peak.
Crystal form B: there is XRPD characteristic peak at 6.3,7.8,9.5,12.5,13.4,20.2,21.1,22.4 and 28.9 ± 0.2o 2 θ place.
Crystal formation F: there is XRPD characteristic peak at 5.6,9.7,11.2,16.9,21.1,24.0,25.3 and 26.0 ± 0.2o 2 θ place.
Crystal formation G: there is XRPD characteristic peak at 5.9,9.7,11.7,12.7,16.2 and 23.3 ± 0.2 o 2 θ place.
By reference WO2009025876A2 entirety is incorporated to herein.
Crystal C involved herein refers to 5.6,5.8,9.6,19.5,22.6 and 24.6 ± 0.2o 2 θ place there is the crystal formation of XRPD characteristic peak, it is 11.2,16.2,23.4 and 24.1 ± 0.2 o 2 θ places have XRPD characteristic peak further, and it has X-ray powder diffraction pattern substantially as shown in Figure 1.
Beneficial effect
Compared with art methods, the inventive method is more suitable for extensive preparation, and has more reappearance in acquisition Eriotinib Hydrochloride form F.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of crystal C prepared by the present invention.
Detailed description of the invention
Embodiment
Method of the present invention is illustrated in greater detail by following non-limiting example.Following examples limit the invention never in any form.
In following comparative example and embodiment, carry out X-ray powder diffraction analysis according to following condition:
PANalytical-X ' Pert diffractometer (using CuK alpha radiation) is utilized to obtain X-ray powder diffraction pattern.This system configuration is θ-θ, and transmission geometry is also provided with 3152/63 focus X-ray mirror, incident Suo Le (soller) slit of 0.5o divergence (divergence) and anti-scattering slit and 0.02 rad (rad).Sample is loaded on PW3064/60 reflection/transmission turntable.Detector is 3018/00 PIXcel detector, is provided with the 2 mm anti-scattering slits for transmission and 0.02 rad Suo Le slit.The sample of about 10-20 mg is loaded between two-layer hyaline membrane by the specimen holder of use standard.X ' Pert data collector (version 2 .2g) is used to collect data, and the blank sample of control film background correction process data.
In following comparative example and embodiment, the molar equivalent of hydrogen chloride, relative to Tarceva free base.
Comparative example 1 ~ 4
Tarceva free alkali (250 mg) and DOX (10 mL) are heated to the temperature of display in following table 1, and keep 1 hour at such a temperature.Then hydrochloric acid (0.053 mL, 37% aqueous solution, 1 molar equivalent) is added.Mixture is stirred 10 minutes, be cooled to 0 DEG C with the rate of temperature fall of 2 DEG C/min, keep 1 hour at 0 DEG C, filter and use DOX (1 mL) to wash.In 60 DEG C, vacuum drying is carried out to collected solid.By X-ray powder diffraction, product is analyzed, be defined as crystal formation shown in following table 1.
Table 1
| Comparative example No. | Temperature (DEG C) | Crystal formation |
| 1 | 0 | F |
| 2 | 40 | G |
| 3 | 60 | G |
| 4 | 70 | G |
Comparative example 5
Under stirring, by being heated to 60 DEG C, by Tarceva free alkali, (0.55 g) is dissolved in 2-methylpropanol (20 mL).Gained solution is cooled to 50 DEG C, and in 15 minutes, drips hydrogen chloride (in 0.28ml, 5.8M isopropyl alcohol, 1.2 molar equivalents).Mixture is stirred 1 hour at 50 DEG C, filters and use 2-methylpropanol (2 mL) to wash.In 50 DEG C, vacuum drying is carried out to collected solid.By X-ray powder diffraction, product is analyzed, be defined as the mixture of crystal formation F, G and A.Yield: 0.53 g (90%).
Comparative example 6
By Tarceva free alkali, (1.0 g) join in oxolane (10 mL), heat and dissolve at 60 DEG C.At 30 DEG C, gained solution was joined in 20 minutes in oxolane (5mL) solution of churned mechanically hydrogen chloride (in 0.55ml, 5.7M isopropyl alcohol, 1.2 molar equivalents).Mixture is stirred 90 minutes at 30 DEG C, filters and use oxolane (2 mL) to wash.In 60 DEG C, vacuum drying is carried out to collected solid.By powder x-ray diffraction, product is analyzed, be defined as crystal form A.
Embodiment 1 ~ 4
Tarceva free alkali (1.0-1.2 g) is joined in solvent shown in following table 2 (as shown in table 2 to application quantity), heats at 80-100 DEG C and dissolve.At 30 DEG C, gained solution was joined in 30 minutes churned mechanically hydrogen chloride (in 0.55 ~ 0.62 mL, 5.7M isopropyl alcohol, 1.2 molar equivalents) in table 2 shown in solvent (5 mL) solution in.Mixture is stirred 1 hour at 30 DEG C, filters and use the solvent wash (2 mL) shown in following table 2.In 50 DEG C, vacuum drying is carried out to collected solid.By powder x-ray diffraction, product is analyzed, be defined as crystal formation F.
Table 2
| Embodiment No. | Solvent | Volume (mL) | Yield | Crystal formation |
| 1 | N-butyl alcohol | 10 | 1.01g (90%) | F |
| 2 | 2-butanols | 10 | 0.99g (88%) | F |
| 3 | The tert-butyl alcohol | 15 | 0.97g (87%) | F |
| 4 | 2-methylpropanol | 10 | 1.00 g (82%) | F |
Embodiment 5
By Tarceva free alkali, (10 g) join in 2-methylpropanol (100 mL), heat and dissolve at 70 DEG C.At 30 DEG C, gained solution was joined churned mechanically hydrogen chloride (4.7 mL in 15 minutes, in 6M isopropyl alcohol, 1.1 molar equivalents) in the mixed solution of isopropyl acetate (50 mL) and 2-methylpropanol (50 mL).Mixture is stirred 30 minutes at 30 DEG C, filters and use 2-methylpropanol (20 mL) to wash.In 60 DEG C, vacuum drying is carried out to collected solid.By powder x-ray diffraction, product is analyzed, be defined as crystal formation F.Yield: 9.55g (87%).
Embodiment 6
Eriotinib Hydrochloride form F (100 mg) is suspended in acetone (1 mL), and at room temperature stirs 2 hours.Filter this mixture, and wash with acetone (1 mL × 2), vacuum drying 16 hours under 60oC.By powder x-ray diffraction, product is analyzed, be defined as crystal form A.
Embodiment 7
Eriotinib Hydrochloride form F (200 mg) is suspended in ethanol (1 mL), and stirs 17 hours under 60oC.Filter this mixture, and at room temperature carry out vacuum drying.By powder x-ray diffraction, product is analyzed, be defined as crystal form B.
Embodiment 8
Eriotinib Hydrochloride form F (200 mg) is suspended in 2-amylalcohol (2 mL), and at room temperature stirs 1 hour.Mixture is filtered also at room temperature vacuum drying 16 hours.By powder x-ray diffraction, product is analyzed, be defined as crystal C.
The description of the above-described embodiment and examples of the present invention, only for the object explained and illustrate, not limits the present invention by any way.Clearly, those skilled in the art can carry out multiple change and change according to the instruction of the context of the invention.These are changed and change all drops in the spirit and scope of the invention that claim limits.
Claims (6)
1. prepare a method of Eriotinib Hydrochloride form F, described method comprises at C
4tarceva free alkali in alcohol joins and is dissolved in the hydrogen chloride of organic solvent, and makes formed erlotinid hydrochloride crystallization, and wherein said organic solvent is selected from one or more of C
3-6alcohol or described organic solvent are one or more of C
3-6alcohol and one or more of C
1-4carboxylic acid C
2-4the mixture of Arrcostab, and described method is carried out at 20 ~ 50 DEG C.
2. method according to claim 1, wherein said C
4alcohol is selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
3. method according to claim 1, wherein carries out described method at 30 DEG C.
4. method according to claim 1, its also comprise by filter, washing and drying reclaim Eriotinib Hydrochloride form F.
5. method according to claim 4, wherein uses C
4alcohol washing Eriotinib Hydrochloride form F.
6. method according to claim 5, wherein said C
4alcohol is selected from n-butyl alcohol, 2-butanols, the tert-butyl alcohol, 2-methylpropanol and composition thereof.
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| CN201310203250.0A CN103333124B (en) | 2013-05-28 | 2013-05-28 | Preparation method of hydrochloric acid erlotinib crystal form F |
| PCT/CN2014/075094 WO2014190804A1 (en) | 2013-05-28 | 2014-04-10 | Method for preparing crystal form f of erlotinib hcl |
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| CN201310203250.0A CN103333124B (en) | 2013-05-28 | 2013-05-28 | Preparation method of hydrochloric acid erlotinib crystal form F |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| CN101602734A (en) * | 2009-04-24 | 2009-12-16 | 浙江九洲药业股份有限公司 | A kind of preparation method of Erlotinib hydrochloride crystal form A |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| RS49836B (en) * | 1999-03-31 | 2008-08-07 | Pfizer Products Inc., | Process and intermediates for preparing anti-cancer compounds |
| US7148231B2 (en) * | 2003-02-17 | 2006-12-12 | Hoffmann-La Roche Inc. | [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph |
| US7960545B2 (en) * | 2005-11-23 | 2011-06-14 | Natco Pharma Limited | Process for the prepartion of erlotinib |
| KR20100014512A (en) * | 2007-02-21 | 2010-02-10 | 낫코 파마 리미티드 | Novel polymorphs of erlotinib hydrochloride and method of preparation |
| EP2181099A2 (en) * | 2007-08-23 | 2010-05-05 | Plus Chemicals S.A. | Crystalline forms of erlotinib hcl and formulations thereof |
| CN103333124B (en) * | 2013-05-28 | 2015-03-25 | 埃斯特维华义制药有限公司 | Preparation method of hydrochloric acid erlotinib crystal form F |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| CN101602734A (en) * | 2009-04-24 | 2009-12-16 | 浙江九洲药业股份有限公司 | A kind of preparation method of Erlotinib hydrochloride crystal form A |
Non-Patent Citations (2)
| Title |
|---|
| 尹芳华，钟璟，主编.晶体的质量控制.《现代分离技术》.化学工业出版社,2009,第189-192页. * |
| 张新战，主编.晶核的形成与影响因素，晶体的成长与影响因素.《化工单元过程及操作》.化学工业出版社,2006,第269-261页. * |
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| CN103333124A (en) | 2013-10-02 |
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