CN103145628A - Erlotinib-hydrate crystal form I preparation method - Google Patents
Erlotinib-hydrate crystal form I preparation method Download PDFInfo
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- CN103145628A CN103145628A CN2013100860840A CN201310086084A CN103145628A CN 103145628 A CN103145628 A CN 103145628A CN 2013100860840 A CN2013100860840 A CN 2013100860840A CN 201310086084 A CN201310086084 A CN 201310086084A CN 103145628 A CN103145628 A CN 103145628A
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- tarceva
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- 239000013078 crystal Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims abstract description 69
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims abstract description 36
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940120982 tarceva Drugs 0.000 claims description 65
- -1 Tarceva monohydrate Chemical class 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 20
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- 239000012065 filter cake Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
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- 238000004090 dissolution Methods 0.000 claims description 4
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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 Tarceva monohydrate 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-two (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.
To studies show that of the nonsmall-cell lung cancer of Tarceva sensitivity, when suddenling change, the epidermal growth factor recipient tyrosine kinase domain gene activates the major cause of anti-apoptosis pathway.At first Tarceva went on the market in the U.S. with the form of hydrochloride in 2004, mainly was applicable to the treatment of local late period or Metastatic Nsclc and carcinoma of the pancreas.
At first patent documentation WO1996030347 has reported the compound Tarceva, and discloses simultaneously the preparation method of Tarceva and hydrochloride thereof.Crystal formation I, crystal form II, the crystal form II I of Tarceva have been reported in WO2008012105 and Chinese CN101547910A of the same clan (crystalline erlotinib) thereof.Wherein crystal formation I and crystal form II I are hydrate forms, and crystal form II is anhydrate form.But the disclosed method preparation method of this patent documentation is comparatively loaded down with trivial details, easily produces mixed crystal, and production efficiency is low, and has used and held volatile lower boiling etoh solvent and acetone, is 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 suitable 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-two (2-methoxy ethoxy)-4-quinazoline amine.
Technical scheme of the present invention is as follows:
The preparation method of a kind of Tarceva monohydrate crystal form I comprises the following steps:
(1) preparation of Tarceva propyl carbinol hot solution
A: the aqueous solution of erlotinid hydrochloride and alkali is joined in propyl carbinol, stir 50～100 ℃ of lower heating and make dissolution of solid, standing, tell while hot organic phase, obtain Tarceva propyl carbinol hot solution; Or,
B: Tarceva is added in propyl carbinol, heat 50～100 ℃, drip and to add 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, the g/ml of unit;
(2) step (1) gained Tarceva propyl carbinol hot solution is naturally cooled to room temperature, separate out solid, continue to stir 1～2 hour;
(3) suction filtration, the gained filter cake makes Tarceva monohydrate crystal form I through 40-60 ℃ of oven dry.
According to the present invention, the heating for dissolving temperature in step (1) a, b is preferably 60～90 ℃, further preferred 70～80 ℃.
According to the present invention, the aqueous solution of alkali described in step (1) a is 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 ratios;
According to the present invention, the concentration of the aqueous solution of described alkali is the conventional concentration of lye that this area is used for desalinization reaction (neutralization reaction), preferred 0.5～4.0mol/L, more preferably 1.0～3.0mol/L, most preferably 2mol/L.
According to the present invention, middle the preferred 40-50 of filter cake bake out temperature ℃ or 50-60 ℃ of step (3).
Preferred according to the present invention, the erlotinid hydrochloride described in step (1) or Tarceva and propyl carbinol mass volume ratio are 1:3～8,1:5～6 more preferably, the g/ml of unit; Can comprehensively improve product yield and purity.
The propyl carbinol that method employing boiling point is higher, toxicity is less of Tarceva monohydrate crystal form I for preparing provided by the invention is as solvent, reaction solvent is not volatile, and preparation method's security is good, and is easy to operate simple, workable, can shorten the technological operation time, effectively improved working efficiency and Industrial " three Waste " is few, reaction solvent is easy to reclaim and recycling, and the products obtained therefrom crystal formation is single, purity high (purity 99.9%), therefore good stability, 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 raw material thereof can be bought in market, perhaps by the prior art preparation, for example, the Tarceva HPLC purity for preparing with reference to patent documentation CN1066142C embodiment 20 is 97.6%, and gained erlotinid hydrochloride HPLC purity is 98.5%.
Description of drawings
Fig. 1 is the X-ray powder diffraction of the Tarceva monohydrate crystal form I of embodiment 5.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiment are only used for specifically describing more in detail the present invention's use, limit in any form the present invention and should not be construed as.The material that the present invention uses 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 ℃.Moderate purity of the present invention detects and uses the HPLC method, can be with reference to the method for 2010 editions second appendix V D of Chinese Pharmacopoeia.
X-ray powder diffraction instrument used and detection method are as follows:
Instrument model: PANalytical; Sense environmental conditions: 20 ℃ of room temps; 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 is pressed: 40kv; Pipe stream: 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%.
Embodiment 1: the preparation of Tarceva monohydrate crystal form I
With erlotinid hydrochloride 6.0g (14mmol), add the 30ml propyl carbinol, add 1.0mol/L potassium hydroxide aqueous solution 15ml, be heated to 80 ℃ under stirring, solid dissolves fully, standing demix, aqueous phase discarded is told organic phase while hot, and organic phase stirs lower naturally cooling and is cooled to room temperature, continue to stir after 1 hour, suction filtration, filter cake are dried under 50-60 ℃ and are made Tarceva monohydrate crystal form I white crystalline solid 5.21g, yield 86.8%, HPLC purity is 99.7%, measures X-PRD and Fig. 1 of obtaining basically identical.
Embodiment 2: the preparation of Tarceva monohydrate crystal form I
With erlotinid hydrochloride 6.0g, add the 36ml propyl carbinol, add 2.0mol/L aqueous sodium hydroxide solution 14ml, be heated to 85 ℃ under stirring, dissolve standing demix to solid fully, aqueous phase discarded, tell while hot organic phase, organic phase stirs lower naturally cooling and is cooled to room temperature, continues to stir after 1 hour, suction filtration, filter cake is dried under 40-50 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 5.14g, yield 85.7%, and HPLC purity is 99.8%.
Embodiment 3: the preparation of Tarceva monohydrate crystal form I
With erlotinid hydrochloride 6.0g, add the 48ml propyl carbinol, add the wet chemical 15ml of 1.0mol/L, be heated to temperature under stirring and reach 70 ℃, solid dissolves fully, standing demix, aqueous phase discarded, tell while hot organic phase, organic phase stirs lower naturally cooling and is cooled to room temperature, continues to stir after 2 hours, suction filtration, filter cake is dried under 50-60 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 5.03g, yield 83.8%, and HPLC purity is 99.9%.
Embodiment 4: the preparation of Tarceva monohydrate crystal form I
With erlotinid hydrochloride 6.0g, add the 30ml propyl carbinol, add the 20ml saturated sodium bicarbonate aqueous solution, be heated to temperature under stirring and reach 90 ℃, solid dissolves fully, standing demix, aqueous phase discarded, tell while hot organic phase, organic phase stirs lower naturally cooling and is cooled to room temperature, continues after crystallization to stir 1 hour, suction filtration, filter cake is dried under 45-55 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 5.32g, yield 88.7%, and HPLC purity is 99.8%.
Embodiment 5: the preparation of Tarceva monohydrate crystal form I
With Tarceva 5.0g, add the 30ml propyl carbinol, be heated to 80 ℃ under stirring, dropwise add entry fully molten clear to solid, stir lower naturally cooling and be cooled to room temperature, continue after crystallization to stir 1 hour, suction filtration, filter cake is dried under 50-60 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 4.63g, yield 92.6%, and HPLC purity is 99.8%; The X-RPD that mensuration obtains as shown in Figure 1.
Embodiment 6: the preparation of Tarceva monohydrate crystal form I
With Tarceva 5.0g, add the 20ml propyl carbinol, be heated to temperature under stirring and reach 90 ℃, dropwise add entry fully molten clear to solid, stir lower self-heating and cool to room temperature, continue to stir after 1 hour after crystallization, suction filtration, filter cake is dried under 50-60 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 4.67g, yield 93.4%, and HPLC purity is 99.8%.
Embodiment 7: the preparation of Tarceva monohydrate crystal form I
With Tarceva 5.0g, add the 15ml propyl carbinol, be heated to temperature under stirring and reach 80 ℃, dropwise add entry fully molten clear to solid, stir lower naturally cooling and be cooled to room temperature, continue after crystallization to stir 1 hour, suction filtration, filter cake is dried under 50-60 ℃ and is made Tarceva monohydrate crystal form I white crystalline solid 4.72g, yield 94.4%, and HPLC purity is 99.7%.
Embodiment 8: the stability test of Tarceva monohydrate crystal form I
The Tarceva monohydrate crystal form I sample that embodiment 1 and embodiment 5 are prepared is airtight under 30 ℃ 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 Tarceva monohydrate 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 consistent with Fig. 1, illustrate that the crystal formation that the present invention prepares has satisfactory stability.
Claims (9)
1. the preparation method of a Tarceva monohydrate crystal form I comprises the following steps:
(1) preparation of Tarceva propyl carbinol hot solution
A: the aqueous solution of erlotinid hydrochloride and alkali is joined in propyl carbinol, stir 50～100 ℃ of lower heating and make dissolution of solid, standing, tell while hot organic phase, obtain Tarceva propyl carbinol hot solution; Or,
B: Tarceva is added in propyl carbinol, heat 50～100 ℃, drip and to add 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, the g/ml of unit;
(2) step (1) gained Tarceva propyl carbinol hot solution is naturally cooled to room temperature, separate out solid, continue to stir 1～2 hour;
(3) suction filtration, the gained filter cake makes Tarceva monohydrate crystal form I through 40-60 ℃ of oven dry.
2. the preparation method of Tarceva monohydrate crystal form I as claimed in claim 1, is characterized in that the heating for dissolving temperature in step (1) a, b is 60～90 ℃; Preferred 70～80 ℃.
3. the preparation method of Tarceva monohydrate crystal form I as claimed in claim 1, the aqueous solution that it is characterized in that alkali described in step (1) a is selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus one or more the aqueous solution.
4. the preparation method of Tarceva monohydrate 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 1:0.5～2.
5. the preparation method of Tarceva monohydrate 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 mole ratios.
6. the preparation method of Tarceva monohydrate 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.
7. the preparation method of Tarceva monohydrate crystal form I as claimed in claim 1, is characterized in that in step (3), the filter cake bake out temperature is 40-50 ℃ or 50-60 ℃.
8. the preparation method of Tarceva monohydrate 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, is preferably 1:5～6, the g/ml of unit.
9. the preparation method of Tarceva monohydrate 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, the g/ml of unit.
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Cited By (1)
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| CN104230825A (en) * | 2014-09-03 | 2014-12-24 | 山东金城医药化工股份有限公司 | Preparation method of erlotinib base monohydrate crystal form I |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104230825A (en) * | 2014-09-03 | 2014-12-24 | 山东金城医药化工股份有限公司 | Preparation method of erlotinib base monohydrate crystal form I |
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| CN103145628B (en) | 2015-04-22 |
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