CN104230825A - Preparation method of erlotinib base monohydrate crystal form I - Google Patents
Preparation method of erlotinib base monohydrate crystal form I Download PDFInfo
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- CN104230825A CN104230825A CN201410446612.3A CN201410446612A CN104230825A CN 104230825 A CN104230825 A CN 104230825A CN 201410446612 A CN201410446612 A CN 201410446612A CN 104230825 A CN104230825 A CN 104230825A
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- preparation
- crystal form
- monohydrate crystal
- organic solvent
- tarceva
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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
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and in particular relates to a preparation method of an erlotinib base monohydrate crystal form I. The preparation method comprises the following steps: stirring and mixing erlotinib hydrochloride, base and an organic solvent, or stirring and mixing erlotinib base and an organic solvent; dropwise adding a solution system after an reaction or after being classified to water under a stirring condition; while stirring, decreasing temperature to 0-5 DEG; and filtering and drying in a vacuum environment to obtain erlotinib base monohydrate crystal form I. The erlotinib base monohydrate crystal form I is prepared by crystallization at room temperature through an organic solvent which is cheap, easy to prepare, green and environment-friendly; and the preparation method is safe and environment-friendly in process route, simple to operate, low in cost, good in repeatability, stable, applicable to industrial production and quite high in economic value. The prepared erlotinib base disclosed by the invention has high purity, and can be used for preparing erlotinib hydrochloride high in purity.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of Tarceva alkali monohydrate crystal form Form I.
Background technology
Tarceva alkali, also known as Tarceva, chemical name: 4-(3-ethynyl phenyl is amino)-6,7-bis-(2-methoxyethoxy) quinazoline-4-amine.Tarceva alkali went on the market in the U.S. in 2004 with the form of hydrochloride, was a kind of reversible Urogastron TYR enzyme (EGFR) inhibitor, was applicable to Locally Advanced and or Metastatic Nsclc.Structural formula is as follows:
Patent US5747498 discloses the preparation method of erlotinid hydrochloride at first, preparation method's silicagel column separation and purification of the Tarceva alkali that patent is mentioned, and does not mention the crystal formation problem of Tarceva alkali in patent.
At present, the published operational path preparing Tarceva alkali monohydrate crystal form I mainly contains following two kinds:
Refer to three kinds of new crystal: Form I, Form II, FormIII of Tarceva alkali at first in patent WO2008012105, and reporting Form I, Form III is hydrate forms, Form II is anhydrate form, wherein erlotinid hydrochloride is suspended in ethyl acetate/water (1:1 by the preparation method of Form I, v/v) in, add alkali lye to remove HCl, separatory, dry, steam solvent, obtain the crystalline solid of oldlace, i.e. Tarceva alkali monohydrate crystal form Form I.
Patent CN103145628A reports a kind of new operational path preparing crystal formation I, namely first prepares the propyl carbinol hot solution of Tarceva alkali, then naturally cools to room temperature, separates out solid, obtains Tarceva alkali monohydrate crystal form Form I.
Above-mentioned two all have obvious defect, the extraction of (1) method, separatory, drying, steam the operational path of solvent, course of industrialization complicated operation; (2) utilize the hot solution cooling crystallization of propyl carbinol to obtain brilliant Tarceva alkali monohydrate crystal form Form I in method, type of solvent used is single, does not have popularity.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of Tarceva alkali monohydrate crystal form Form I, stable preparation process, industrial operation difficulty is little, is easy to suitability for industrialized production, and reaction conditions is gentle, and solvent is cheap and easy to get, and range of choices is wide.
The preparation method of Tarceva alkali monohydrate crystal form Form I of the present invention, step is as follows:
(1) erlotinid hydrochloride, alkali and organic solvent are uniformly mixed, or Tarceva alkali and organic solvent are uniformly mixed;
(2) by reacted or molten clear after solution system, under agitation, be added drop-wise in water;
(3), under stirring, 0-5 DEG C is cooled to;
(4) filter, vacuum drying obtains Tarceva alkali monohydrate crystal form Form I.
Organic solvent described in step (1) is one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, the trimethyl carbinol, acetone, tetrahydrofuran (THF), dioxane, acetonitrile, DMF or N,N-dimethylacetamide.
Alkali described in step (1) is one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine or ammoniacal liquor; The wherein preferred 15-30% ammoniacal liquor of ammoniacal liquor.
The mol ratio of the erlotinid hydrochloride described in step (1) and alkali is 1.0:0.5-1.5, is preferably 1.0:0.8-1.2.
The ratio of the erlotinid hydrochloride described in step (1) and organic solvent is 1g:3-10ml, is preferably 1g:6-8ml.
The ratio of the Tarceva alkali described in step (1) and organic solvent is 1g:3-10ml, is preferably 1g:4-6ml.
The volume ratio of the organic solvent described in step (2) and water is 1:2-6, is preferably 1:3-5.
The temperature of the vacuum drying described in step (4) is 20-50 DEG C, is preferably 25-30 DEG C.
Shortcoming that the processing condition that the invention solves Patents report are loaded down with trivial details, industrialization difficulty is large, type of solvent is single etc., meanwhile, the present invention also can carry out purifying to Tarceva alkali, prepares highly purified erlotinid hydrochloride.
Compared with prior art, there is following beneficial effect:
The present invention adopts organic solvent that is cheap and easy to get, environmental protection, at room temperature carries out crystalline Tarceva alkali monohydrate crystal form Form I, present invention process route safety and environmental protection, simple to operate, cost is low, favorable reproducibility and stable, be applicable to suitability for industrialized production, there is very high economic worth.Tarceva alkali purity prepared by the present invention is high, can prepare highly purified erlotinid hydrochloride.
Accompanying drawing explanation
Fig. 1 is the X-powder diffraction spectrum of Tarceva alkali monohydrate crystal form Form I prepared by embodiment 1;
Fig. 2 is the DSC collection of illustrative plates of Tarceva alkali monohydrate crystal form Form I prepared by embodiment 1;
Fig. 3 is the infared spectrum of Tarceva alkali monohydrate crystal form Form I prepared by embodiment 1.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
10.0g erlotinid hydrochloride is added, 0.93g sodium hydroxide, 60ml methyl alcohol in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 0.5h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 120ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.2g, productive rate 89.5%, HPLC purity 99.8%.
Embodiment 2
10.0g erlotinid hydrochloride is added, 1.24g sodium carbonate, 60ml methyl alcohol in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 1.0h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 240ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.3g, productive rate 90.6%, HPLC purity 99.7%.
Embodiment 3
10.0g erlotinid hydrochloride is added, 1.4g sodium hydroxide, 30ml dioxane in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 1.0h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 60ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 50 DEG C, obtains white solid, 8.1g, productive rate 88.4%, HPLC purity 99.6%.
Embodiment 4
10.0g erlotinid hydrochloride is added, 1.3g potassium hydroxide, 100ml methyl alcohol in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 0.5h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 600ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 7.9g, productive rate 86.2%, HPLC purity 99.8%.
Embodiment 5
10.0g erlotinid hydrochloride is added, 2.6g triethylamine, 40ml acetone in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 0.5h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 120ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.0g, productive rate 87.3%, HPLC purity 99.8%.
Embodiment 6
10.0g erlotinid hydrochloride is added, 2.0g 25% ammoniacal liquor, 50ml ethanol in the reaction flask of the 250ml of clean dried, stirred at ambient temperature 1h, gets 1.0ml reaction solution, adds 0.5ml water, reaction solution becomes clarification and illustrates that reaction completes, and dropped to by reaction solution in 150ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 25 DEG C, obtains white solid, 8.1g, productive rate 88.4%, HPLC purity 99.6%.
Embodiment 6
10.0g Tarceva alkali is added, 30ml acetonitrile, stirred at ambient temperature 1h in the reaction flask of the 250ml of clean dried, after reaction solution becomes clarification, dropped to by reaction solution in 60ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 30 DEG C, obtains white solid, 8.9g, productive rate 89.0%, HPLC purity 99.8%.
Embodiment 7
10.0g Tarceva alkali is added, 100ml dioxane, stirred at ambient temperature 0.5h in the reaction flask of the 250ml of clean dried, after reaction solution becomes clarification, dropped to by reaction solution in 600ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 50 DEG C, obtains white solid, 9.1g, productive rate 91.0%, HPLC purity 99.7%.
Embodiment 8
10.0g Tarceva alkali is added, 50ml methyl alcohol, stirred at ambient temperature 1h in the reaction flask of the 250ml of clean dried, after reaction solution becomes clarification, dropped to by reaction solution in 250ml water, time for adding is 0.5h, after dropwising, under stirring, be cooled to 0 ~ 5 DEG C, suction filtration, filter cake is vacuum drying at 20 DEG C, obtains white solid, 8.9g, productive rate 89.0%, HPLC purity 99.8%.
Claims (8)
1. a preparation method of Tarceva alkali monohydrate crystal form Form I, is characterized in that step is as follows:
(1) erlotinid hydrochloride, alkali and organic solvent are uniformly mixed, or Tarceva alkali and organic solvent are uniformly mixed;
(2) by reacted or molten clear after solution system, under agitation, be added drop-wise in water;
(3), under stirring, 0-5 DEG C is cooled to;
(4) filter, vacuum drying obtains Tarceva alkali monohydrate crystal form Form I.
2. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, it is characterized in that the organic solvent described in step (1) is methyl alcohol, ethanol, n-propyl alcohol, Virahol, the trimethyl carbinol, acetone, tetrahydrofuran (THF), dioxane, acetonitrile, N, one or more in dinethylformamide or N,N-dimethylacetamide.
3. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the alkali described in step (1) is one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine or ammoniacal liquor.
4. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the mol ratio of the erlotinid hydrochloride described in step (1) and alkali is 1.0:0.5-1.5.
5. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the ratio of the erlotinid hydrochloride described in step (1) and organic solvent is 1g:3-10ml.
6. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the ratio of the Tarceva alkali described in step (1) and organic solvent is 1g:3-10ml.
7. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the volume ratio of the organic solvent described in step (2) and water is 1:2-6.
8. the preparation method of Tarceva alkali monohydrate crystal form Form I according to claim 1, is characterized in that the temperature of the vacuum drying described in step (4) is 20-50 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749048A (en) * | 2017-01-14 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Eriotinib Hydrochloride form compound and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009024989A2 (en) * | 2007-08-17 | 2009-02-26 | Hetero Drugs Limited | A novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b |
| 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 |
-
2014
- 2014-09-03 CN CN201410446612.3A patent/CN104230825B/en active Active
Patent Citations (3)
| 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 |
| WO2009024989A2 (en) * | 2007-08-17 | 2009-02-26 | Hetero Drugs Limited | A novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b |
| CN103145628A (en) * | 2013-03-18 | 2013-06-12 | 齐鲁制药有限公司 | Erlotinib-hydrate crystal form I preparation method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749048A (en) * | 2017-01-14 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Eriotinib Hydrochloride form compound and preparation method thereof |
| 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 |
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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. |