CN103145628B - Erlotinib-hydrate crystal form I preparation method - Google Patents
Erlotinib-hydrate crystal form I preparation method Download PDFInfo
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Abstract
The invention relates to an erlotinib-hydrate crystal form I preparation method. The erlotinib-hydrate crystal form I preparation method comprises the following steps of: naturally cooling an n-butyl alcohol thermal solution containing erlotinib, and reducing temperature and devitrifying to obtain the erlotinib-hydrate crystal form I. The erlotinib-hydrate crystal form I preparation method is safe and simple, has strong operability and is easy for industrial production; an obtained product has the advantages of single crystal form, high purity and good stability; and the method can be used as an erlotinib purification method for preparing high-purity erlotinib hydrochloride.
Description
Technical field
The present invention relates to the preparation method of a kind of erlotinib-hydrate crystal form I, belong to and relate to pharmaceutical chemistry technical field.
Background technology
Tarceva (Erlotinib), chemical name is N-(3-acetylene phenyl)-6,7-bis-(2-methoxy ethoxy)-4-quinazoline amine, has the chemical structure shown in formula I, is a kind of human epidermal growth factor acceptor tyrosine kinase domain selective depressant.
The research of the nonsmall-cell lung cancer of Tarceva sensitivity is shown, activates the major cause of anti-apoptotic path when epidermal growth factor recipient tyrosine kinase domain gene suddenlys change.Within 2004, first Tarceva goes on the market in the U.S. with the form of hydrochloride, is mainly applicable to the treatment of Locally Advanced or Metastatic Nsclc and carcinoma of the pancreas.
Patent documentation WO1996030347 first reported compound Tarceva, and also discloses the preparation method of Tarceva and hydrochloride thereof.Crystal formation I, crystal form II, the crystal form II I of Tarceva is reported in WO2008012105 and Chinese CN101547910A of the same clan (crystalline erlotinib) thereof.Wherein crystal formation I and crystal form II I is hydrate forms, and crystal form II is anhydrate form.But method preparation method is comparatively loaded down with trivial details disclosed in this patent documentation, easily produces mixed crystal, and production efficiency is low, and employ the volatile lower boiling etoh solvent of appearance and acetone, be not suitable for commercial scale production.
Summary of the invention
For the deficiencies in the prior art, the invention provides the preparation method of a kind of applicable suitability for industrialized production, stable, easy and simple to handle Tarceva crystal formation I.The present invention can be used as the purification process of Tarceva for the preparation of highly purified erlotinid hydrochloride.
Tarceva of the present invention is the compound with formula I structure, and chemical name is N-(3-acetylene phenyl)-6,7-bis-(2-methoxy ethoxy)-4-quinazoline amine.
Technical scheme of the present invention is as follows:
A preparation method of erlotinib-hydrate crystal form I, comprises the following steps:
(1) preparation of Tarceva propyl carbinol hot solution
A: join in propyl carbinol by the aqueous solution of erlotinid hydrochloride and alkali, stirs lower heating 50 ~ 100 DEG C and makes dissolution of solid, leave standstill, separate organic phase while hot, obtain Tarceva propyl carbinol hot solution; Or,
B: added by Tarceva in propyl carbinol, heats 50 ~ 100 DEG C, drips and adds water to dissolution of solid, obtain Tarceva propyl carbinol hot solution;
Above-mentioned erlotinid hydrochloride or Tarceva and propyl carbinol mass volume ratio are 1:3 ~ 12, unit g/ml;
(2) step (1) gained Tarceva propyl carbinol hot solution is naturally cooled to room temperature, separate out solid, continue stirring 1 ~ 2 hour;
(3) suction filtration, gained filter cake dries obtained erlotinib-hydrate crystal form I through 40-60 DEG C.
According to the present invention, the heating for dissolving temperature in step (1) a, b is preferably 60 ~ 90 DEG C, preferably 70 ~ 80 DEG C further.
According to the present invention, the aqueous solution of alkali described in step (1) a to be selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus one or more the aqueous solution; In described erlotinid hydrochloride and described alkaline solution, the mole ratio of alkali is 1:0.5 ~ 2, preferred 1:1 ~ 1.5 mole ratio;
According to the present invention, the concentration of the aqueous solution of described alkali is the conventional concentration of lye of this area for desalinization reaction (neutralization reaction), preferably 0.5 ~ 4.0mol/L, more preferably 1.0 ~ 3.0mol/L, most preferably 2mol/L.
According to the present invention, the preferred 40-50 of filter cake bake out temperature DEG C or 50-60 DEG C in step (3).
Preferred according to the present invention, the erlotinid hydrochloride described in step (1) or Tarceva and propyl carbinol mass volume ratio are 1:3 ~ 8, more preferably 1:5 ~ 6, unit g/ml; Can comprehensively improve product yield and purity.
The method preparing erlotinib-hydrate crystal form I provided by the invention adopts boiling point is higher, toxicity is less propyl carbinol as solvent, reaction solvent is not volatile, and preparation method's security is good, easy to operate simple, workable, processing operation time can be shortened, effectively improve working efficiency and Industrial " three Waste " is few, reaction solvent is easy to reclaim and recycling, and products obtained therefrom crystal formation is single, purity high (purity can reach 99.9%), good stability, therefore, is more suitable for suitability for industrialized production.
Method gained Tarceva purity of the present invention is high, can be used for preparing highly purified erlotinid hydrochloride.In the present invention, Tarceva and hydrochloride Starting material thereof can be bought in market, or by prior art preparation, such as, the Tarceva HPLC purity prepared with reference to patent documentation CN1066142C embodiment 20 is 97.6%, and gained erlotinid hydrochloride HPLC purity is 98.5%.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the erlotinib-hydrate crystal form I of embodiment 5.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiments are only used for the use specifically describing the present invention more in detail, and should not be construed as and limit the present invention in any form.The material that the present invention is used in test is well known in the art or can prepares according to prior art.Described in the present invention, " room temperature " has implication well known in the art, particularly, refers to 15 ~ 30 DEG C.Moderate purity detection HPLC method of the present invention, can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex V D.
X-ray powder diffractometer used and detection method as follows:
INSTRUMENT MODEL: PANalytical; Sense environmental conditions: room temp 20 DEG C; Relative humidity < 60%.
Light source: X-ray (Cu, K α); Slit: 1/16 °; Sweep limit 2 θ (°): 3.0 ° ~ 45.0 °.Scan mode: continuously; Scanning step: 0.026 °; Cumulative time: 6min; Pipe pressure: 40kv; Guan Liu: 40mA.Data processing: HighScore Plus software package.
Embodiment Raw erlotinid hydrochloride, Tarceva are commercial technical grade product, and Tarceva purity is 97-98%, and erlotinid hydrochloride bulk drug purity is 98.5 ~ 99%.
The preparation of embodiment 1: erlotinib-hydrate crystal form I
By erlotinid hydrochloride 6.0g (14mmol), add 30ml propyl carbinol, add 1.0mol/L potassium hydroxide aqueous solution 15ml, 80 DEG C are heated under stirring, solid dissolves completely, stratification, aqueous phase discarded, separates organic phase while hot, and organic phase stirs lower naturally cooling and is cooled to room temperature, continue stirring after 1 hour, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 5.21g at 50-60 DEG C, yield 86.8%, HPLC purity is 99.7%, measures X-PRD and the Fig. 1 obtained basically identical.
The preparation of embodiment 2: erlotinib-hydrate crystal form I
By erlotinid hydrochloride 6.0g, add 36ml propyl carbinol, add 2.0mol/L aqueous sodium hydroxide solution 14ml, be heated to 85 DEG C under stirring, dissolve completely to solid, stratification, aqueous phase discarded, separate organic phase while hot, organic phase stirs lower naturally cooling and is cooled to room temperature, continues stirring after 1 hour, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 5.14g at 40-50 DEG C, and yield 85.7%, HPLC purity is 99.8%.
The preparation of embodiment 3: erlotinib-hydrate crystal form I
By erlotinid hydrochloride 6.0g, add 48ml propyl carbinol, add the wet chemical 15ml of 1.0mol/L, be heated to temperature under stirring and reach 70 DEG C, solid dissolves completely, stratification, aqueous phase discarded, separate organic phase while hot, organic phase stirs lower naturally cooling and is cooled to room temperature, continues stirring after 2 hours, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 5.03g at 50-60 DEG C, and yield 83.8%, HPLC purity is 99.9%.
The preparation of embodiment 4: erlotinib-hydrate crystal form I
By erlotinid hydrochloride 6.0g, add 30ml propyl carbinol, add 20ml saturated sodium bicarbonate aqueous solution, be heated to temperature under stirring and reach 90 DEG C, solid dissolves completely, stratification, aqueous phase discarded, separate organic phase while hot, organic phase stirs lower naturally cooling and is cooled to room temperature, continues stirring 1 hour after crystallization, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 5.32g at 45-55 DEG C, and yield 88.7%, HPLC purity is 99.8%.
The preparation of embodiment 5: erlotinib-hydrate crystal form I
By Tarceva 5.0g, add 30ml propyl carbinol, 80 DEG C are heated under stirring, dropwise add water complete clearly molten to solid, stir lower naturally cooling and be cooled to room temperature, continue stirring after crystallization 1 hour, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 4.63g at 50-60 DEG C, and yield 92.6%, HPLC purity is 99.8%; The X-RPD that mensuration obtains as shown in Figure 1.
The preparation of embodiment 6: erlotinib-hydrate crystal form I
By Tarceva 5.0g, add 20ml propyl carbinol, be heated to temperature under stirring and reach 90 DEG C, dropwise add water complete clearly molten to solid, stir lower self-heating and cool to room temperature, continue stirring after crystallization after 1 hour, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 4.67g at 50-60 DEG C, and yield 93.4%, HPLC purity is 99.8%.
The preparation of embodiment 7: erlotinib-hydrate crystal form I
By Tarceva 5.0g, add 15ml propyl carbinol, be heated to temperature under stirring and reach 80 DEG C, dropwise add water complete clearly molten to solid, stir lower naturally cooling and be cooled to room temperature, continue stirring after crystallization 1 hour, suction filtration, filter cake dries obtained erlotinib-hydrate crystal form I white crystalline solid 4.72g at 50-60 DEG C, and yield 94.4%, HPLC purity is 99.7%.
The stability test of embodiment 8: erlotinib-hydrate crystal form I
Erlotinib-hydrate crystal form I sample embodiment 1 and embodiment 5 prepared is airtight at 30 DEG C deposits January, February, June, December, and it is as shown in table 1 to measure its related substance data:
The stability test of table 1 erlotinib-hydrate crystal form I
| The sample retention phase | 0 month | 1 month | 2 months | 3 months | 6 months | 12 months |
| Embodiment 1 | 99.7% | 99.7% | 99.7% | 99.6% | 99.6% | 99.6% |
| Embodiment 5 | 99.8% | 99.8% | 99.8% | 99.7% | 99.8% | 99.7% |
After the sample of embodiment 1 and 5 is deposited 12 months, measure its X-RPD and Fig. 1 consistent, illustrate that the crystal formation that the present invention prepares has satisfactory stability.
Claims (7)
1. a preparation method of erlotinib-hydrate crystal form I, comprises the following steps:
(1) preparation of Tarceva propyl carbinol hot solution
A: join in propyl carbinol by the aqueous solution of erlotinid hydrochloride and alkali, stirs lower heating 60 ~ 90 DEG C and makes dissolution of solid, leave standstill, separate organic phase while hot, obtain Tarceva propyl carbinol hot solution; Or,
B: added by Tarceva in propyl carbinol, heats 60 ~ 90 DEG C, drips and adds water to dissolution of solid, obtain Tarceva propyl carbinol hot solution;
Above-mentioned erlotinid hydrochloride or Tarceva and propyl carbinol mass volume ratio are 1:3 ~ 12, unit g/ml;
In erlotinid hydrochloride described in above-mentioned a and described alkaline solution, the mole ratio of alkali is 1:0.5 ~ 2, and the aqueous solution of described alkali to be selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus one or more the aqueous solution;
(2) step (1) gained Tarceva propyl carbinol hot solution is naturally cooled to room temperature, separate out solid, continue stirring 1 ~ 2 hour;
(3) suction filtration, gained filter cake dries obtained erlotinib-hydrate crystal form I through 40-60 DEG C.
2. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that the heating for dissolving temperature in step (1) a, b is 70 ~ 80 DEG C.
3. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that the mole ratio of alkali in erlotinid hydrochloride described in step (1) a and described alkaline solution is 1:1 ~ 1.5.
4. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that the concentration of the aqueous solution of alkali described in step (1) a is 0.5 ~ 4.0mol/L.
5. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that in step (3), filter cake bake out temperature is 40-50 DEG C or 50-60 DEG C.
6. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that the erlotinid hydrochloride described in step (1) or Tarceva and propyl carbinol mass volume ratio are 1:3 ~ 8, unit g/ml.
7. the preparation method of erlotinib-hydrate crystal form I as claimed in claim 1, is characterized in that the erlotinid hydrochloride described in step (1) or Tarceva and propyl carbinol mass volume ratio are 1:5 ~ 6, unit g/ml.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002538A2 (en) * | 2007-06-25 | 2008-12-31 | Plus Chemicals S.A. | Amorphous erlotinib, processes for the preparation thereof, and processes to prepare additional forms of erlotinib |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| CN101484411A (en) * | 2006-06-27 | 2009-07-15 | 桑多斯股份公司 | New method for salt preparation |
| CN101547910A (en) * | 2006-07-28 | 2009-09-30 | 合成纤维有限公司 | Crystalline erlotinib |
| WO2012022240A1 (en) * | 2010-08-14 | 2012-02-23 | 浙江华海药业股份有限公司 | Novel crystal of erlotinib base and the preparation method thereof |
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2013
- 2013-03-18 CN CN201310086084.0A patent/CN103145628B/en not_active Expired - Fee Related
Patent Citations (5)
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|---|---|---|---|---|
| CN101484411A (en) * | 2006-06-27 | 2009-07-15 | 桑多斯股份公司 | New method for salt preparation |
| CN101547910A (en) * | 2006-07-28 | 2009-09-30 | 合成纤维有限公司 | Crystalline erlotinib |
| WO2009002538A2 (en) * | 2007-06-25 | 2008-12-31 | Plus Chemicals S.A. | Amorphous erlotinib, processes for the preparation thereof, and processes to prepare additional forms of erlotinib |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| WO2012022240A1 (en) * | 2010-08-14 | 2012-02-23 | 浙江华海药业股份有限公司 | Novel crystal of erlotinib base and the preparation method thereof |
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| Multicomponent crystals of erlotinib;B. Sridhar等;《Crystal Structure Communications》;20091209;第66卷(第1期);第o36页实验部分 * |
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