CN104230825B - The preparation method of Erlotinib alkali monohydrate crystal form Form I - Google Patents
The preparation method of Erlotinib alkali monohydrate crystal form Form I Download PDFInfo
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- CN104230825B CN104230825B CN201410446612.3A CN201410446612A CN104230825B CN 104230825 B CN104230825 B CN 104230825B CN 201410446612 A CN201410446612 A CN 201410446612A CN 104230825 B CN104230825 B CN 104230825B
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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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Abstract
The invention belongs to pharmaceutical chemistry technical field, the preparation method being specifically related to a kind of Erlotinib alkali monohydrate crystal form Form I.It is stirred mixing with organic solvent by erlotinib Hydrochloride, alkali, or is stirred mixing with organic solvent by Erlotinib alkali；By reacted or molten clear after solution system, under agitation, be added drop-wise in water；Under stirring, it is cooled to 0-5 DEG C；Filtering, vacuum drying obtains Erlotinib alkali monohydrate crystal form Form I.The present invention adopts organic solvent cheap and easy to get, environmental protection, at room temperature carries out crystalline Erlotinib alkali monohydrate crystal form Form I, process route safety and environmental protection, simple to operate, cost is low, favorable reproducibility and stable, it is suitable for industrialized production, there is significantly high economic worth.Erlotinib alkali purity prepared by the present invention is high, it is possible to prepare highly purified erlotinib Hydrochloride.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, the preparation method being specifically related to a kind of Erlotinib alkali monohydrate crystal form Form I.
Background technology
Erlotinib alkali, also known as Erlotinib, chemical name: 4-(3-ethynyl phenyl amino)-6,7-bis-(2-methoxyethoxy) quinazoline-4-amine.Erlotinib alkali listed in the U.S. with the form of hydrochlorate in 2004, was a kind of reversible epidermal growth factor TYR enzyme (EGFR) inhibitor, it is adaptable to Locally Advanced and or Metastatic Nsclc.Structural formula is as follows:
The preparation method that patent US5747498 discloses erlotinib Hydrochloride at first, the preparation method silica gel column separating purification of the Erlotinib alkali that patent is mentioned, and patent is not mentioned the crystal formation problem of Erlotinib alkali.
At present, it has been disclosed that the process route preparing Erlotinib alkali monohydrate crystal form I mainly have following two:
Patent WO2008012105 refer to three kinds of novel crystal forms of Erlotinib alkali at first: FormI, FormII, FormIII, and reporting FormI, FormIII is hydrate forms, FormII is anhydride form, and wherein the preparation method of FormI is to be suspended in by erlotinib Hydrochloride in ethyl acetate/water (1:1, v/v), add alkali liquor to remove HCl, separatory, dry, steam solvent, obtain the crystalline solid of oldlace, i.e. Erlotinib alkali monohydrate crystal form FormI.
Patent CN103145628A reports a kind of new process route preparing crystal formation I, namely first prepares the n-butyl alcohol hot solution of Erlotinib alkali, then naturally cools to room temperature, precipitates out solid, obtains Erlotinib alkali monohydrate crystal form FormI.
Above-mentioned two all have obvious defect, the extraction of (1) method, separatory, dry, steam the process route of solvent, course of industrialization complicated operation；(2) the hot solution cooling crystallization utilizing n-butyl alcohol in method obtains brilliant Erlotinib alkali monohydrate crystal form FormI, and type of solvent used is single, does not have popularity.
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of Erlotinib alkali monohydrate crystal form Form I, stable preparation process, industrial operation difficulty is little, it is easy to industrialized production, and reaction condition is gentle, and solvent is cheap and easy to get, and optional scope is wide.
The preparation method of Erlotinib alkali monohydrate crystal form Form I of the present invention, step is as follows:
(1) it is stirred mixing with organic solvent by erlotinib Hydrochloride, alkali, or is stirred mixing with organic solvent by Erlotinib alkali；
(2) by reacted or molten clear after solution system, under agitation, be added drop-wise in water；
(3), under stirring, it is cooled to 0-5 DEG C；
(4) filtering, vacuum drying obtains Erlotinib alkali monohydrate crystal form Form I.
Organic solvent described in step (1) is one or more in methanol, ethanol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, acetone, oxolane, dioxane, acetonitrile, DMF or N,N-dimethylacetamide.
Alkali described in step (1) is one or more in sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or ammonia；The wherein preferred 15-30% ammonia of ammonia.
The mol ratio of the erlotinib Hydrochloride described in step (1) and alkali is 1.0:0.5-1.5, it is preferred to 1.0:0.8-1.2.
The ratio of the erlotinib Hydrochloride described in step (1) and organic solvent is 1g:3-10ml, it is preferred to 1g:6-8ml.
The ratio of the Erlotinib alkali described in step (1) and organic solvent is 1g:3-10ml, it is preferred to 1g:4-6ml.
The volume ratio of the organic solvent described in step (2) and water is 1:2-6, it is preferred to 1:3-5.
The temperature of the vacuum drying described in step (4) is 20-50 DEG C, it is preferred to 25-30 DEG C.
The invention solves the shortcomings such as the process conditions of Patents report are loaded down with trivial details, industrialization difficulty is big, type of solvent is single, meanwhile, Erlotinib alkali can also be purified by the present invention, prepares highly purified erlotinib Hydrochloride.
Compared with prior art, have the advantages that
The present invention adopts organic solvent cheap and easy to get, environmental protection, at room temperature carries out crystalline Erlotinib alkali monohydrate crystal form Form I, present invention process route safety and environmental protection, simple to operate, cost is low, favorable reproducibility and stable, it is suitable for industrialized production, there is significantly high economic worth.Erlotinib alkali purity prepared by the present invention is high, it is possible to prepare highly purified erlotinib Hydrochloride.
Accompanying drawing explanation
Fig. 1 is the X-powder diffraction spectrum of the Erlotinib alkali monohydrate crystal form FormI of embodiment 1 preparation；
Fig. 2 is the DSC collection of illustrative plates of the Erlotinib alkali monohydrate crystal form FormI of embodiment 1 preparation；
Fig. 3 is the infared spectrum of the Erlotinib alkali monohydrate crystal form FormI of embodiment 1 preparation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
10.0g erlotinib Hydrochloride, 0.93g sodium hydroxide, 60ml methanol is added in the reaction bulb of the 250ml of clean dried, stir 0.5h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 120ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.2g, productivity 89.5%, HPLC purity 99.8%.
Embodiment 2
10.0g erlotinib Hydrochloride, 1.24g sodium carbonate, 60ml methanol is added in the reaction bulb of the 250ml of clean dried, stir 1.0h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 240ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.3g, productivity 90.6%, HPLC purity 99.7%.
Embodiment 3
10.0g erlotinib Hydrochloride, 1.4g sodium hydroxide, 30ml dioxane is added in the reaction bulb of the 250ml of clean dried, stir 1.0h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 60ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 50 DEG C, obtains white solid, 8.1g, productivity 88.4%, HPLC purity 99.6%.
Embodiment 4
10.0g erlotinib Hydrochloride, 1.3g potassium hydroxide, 100ml methanol is added in the reaction bulb of the 250ml of clean dried, stir 0.5h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 600ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 7.9g, productivity 86.2%, HPLC purity 99.8%.
Embodiment 5
10.0g erlotinib Hydrochloride, 2.6g triethylamine, 40ml acetone is added in the reaction bulb of the 250ml of clean dried, stir 0.5h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 120ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.0g, productivity 87.3%, HPLC purity 99.8%.
Embodiment 6
10.0g erlotinib Hydrochloride, 2.0g25% ammonia, 50ml ethanol is added in the reaction bulb of the 250ml of clean dried, stir 1h under room temperature, take 1.0ml reactant liquor, add 0.5ml water, reactant liquor becomes clarification and illustrates that reaction completes, and is dropped to by reactant liquor in 150ml water, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 25 DEG C, obtains white solid, 8.1g, productivity 88.4%, HPLC purity 99.6%.
Embodiment 6
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 30ml acetonitrile, under room temperature, stir 1h, reactant liquor is dropped in 60ml water after becoming clarification by reactant liquor, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 30 DEG C, obtains white solid, 8.9g, productivity 89.0%, HPLC purity 99.8%.
Embodiment 7
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 100ml dioxane, under room temperature, stir 0.5h, reactant liquor is dropped in 600ml water after becoming clarification by reactant liquor, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 50 DEG C, obtains white solid, 9.1g, productivity 91.0%, HPLC purity 99.7%.
Embodiment 8
In the reaction bulb of the 250ml of clean dried, add 10.0g Erlotinib alkali, 50ml methanol, under room temperature, stir 1h, reactant liquor is dropped in 250ml water after becoming clarification by reactant liquor, and time for adding is 0.5h, after dropwising, under stirring, it is cooled to 0～5 DEG C, sucking filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.9g, productivity 89.0%, HPLC purity 99.8%.
Claims (6)
1. the preparation method of an Erlotinib alkali monohydrate crystal form Form I, it is characterised in that step is as follows:
(1) it is stirred mixing with organic solvent by erlotinib Hydrochloride, alkali, or is stirred mixing with organic solvent by Erlotinib alkali；
(2) by reacted or molten clear after solution system, under agitation, be added drop-wise in water；
(3), under stirring, it is cooled to 0-5 DEG C；
(4) filtering, vacuum drying obtains Erlotinib alkali monohydrate crystal form Form I；
Organic solvent described in step (1) is one or more in methanol, ethanol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, acetone, oxolane, dioxane, acetonitrile, DMF or N,N-dimethylacetamide；
Alkali described in step (1) is one or both in triethylamine or ammonia.
2. the preparation method of Erlotinib alkali monohydrate crystal form Form I according to claim 1, it is characterised in that the mol ratio of the erlotinib Hydrochloride described in step (1) and alkali is 1.0:0.5-1.5.
3. the preparation method of Erlotinib alkali monohydrate crystal form Form I according to claim 1, it is characterised in that the ratio of the erlotinib Hydrochloride described in step (1) and organic solvent is 1g:3-10ml.
4. the preparation method of Erlotinib alkali monohydrate crystal form Form I according to claim 1, it is characterised in that the ratio of the Erlotinib alkali described in step (1) and organic solvent is 1g:3-10ml.
5. the preparation method of Erlotinib alkali monohydrate crystal form Form I according to claim 1, it is characterised in that the volume ratio of the organic solvent described in step (2) and water is 1:2-6.
6. the preparation method of Erlotinib alkali monohydrate crystal form Form I according to claim 1, it is characterised in that the temperature of the vacuum drying described in step (4) is 20-50 DEG C.
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| CN106749048B (en) * | 2017-01-14 | 2020-03-20 | 山东裕欣药业有限公司 | Erlotinib hydrochloride crystal form compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547910A (en) * | 2006-07-28 | 2009-09-30 | 合成纤维有限公司 | Crystalline erlotinib |
| CN103145628A (en) * | 2013-03-18 | 2013-06-12 | 齐鲁制药有限公司 | Erlotinib-hydrate crystal form I preparation method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100136116A1 (en) * | 2007-08-17 | 2010-06-03 | Hetero Drugs Limited | Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547910A (en) * | 2006-07-28 | 2009-09-30 | 合成纤维有限公司 | Crystalline erlotinib |
| CN103145628A (en) * | 2013-03-18 | 2013-06-12 | 齐鲁制药有限公司 | Erlotinib-hydrate crystal form I preparation method |
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Address after: 255129 Zichuan Economic Development Zone, Shandong, China, Zibo Applicant after: SHANDONG JINCHENG PHARMACEUTICAL CO., LTD. Address before: 255129 Zichuan Economic Development Zone, Shandong, China, Zibo Applicant before: Shandong Jincheng Pharmaceutical & Chemical Co., Ltd. |
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: Shandong Jincheng Pharmaceutical Group Limited by Share Ltd Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO., LTD. |