CN102153518A - Preparation method of Gefitinib - Google Patents
Preparation method of Gefitinib Download PDFInfo
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- CN102153518A CN102153518A CN 201010109106 CN201010109106A CN102153518A CN 102153518 A CN102153518 A CN 102153518A CN 201010109106 CN201010109106 CN 201010109106 CN 201010109106 A CN201010109106 A CN 201010109106A CN 102153518 A CN102153518 A CN 102153518A
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- gefitinib
- preparation
- triphenylphosphine
- carboxylic acid
- reaction
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN1CCOCC1 Chemical compound COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN1CCOCC1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- JLVTVCRXFMLUIF-UHFFFAOYSA-N COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1O Chemical compound COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1O JLVTVCRXFMLUIF-UHFFFAOYSA-N 0.000 description 1
- VZKSLWJLGAGPIU-UHFFFAOYSA-N OCCCN1CCOCC1 Chemical compound OCCCN1CCOCC1 VZKSLWJLGAGPIU-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a preparation method of 4-(3-chloro-4-fluorophenylamido)-7-methoxy-6-(3-morpholinylpropoxy)quinazoline (Gefitinib, I). The preparation method of Gefitinib is characterized in that etherification reaction is carried out on a Gefitinib intermediate 4-(3-chloro-4-fluorophenylamido)-6-hydroxy-7-methoxy-quinazoline and 4-(3-hydroxypropyl)-morpholine under proper conditions to obtain the target product Gefitinib. Gefitinib (I).
Description
Technical field
The invention belongs to the technical field of chemicals preparation, relate to the preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib (Gefitinib)) particularly.
Background technology
Gefitinib (Gefitinib) is a kind of micromolecular inhibitor at the EGFR Tyrosylprotein kinase by the exploitation of Astra Zeneca company.Went on the market in Japan first in 2002, it is invalid or be not suitable for the local late period of chemotherapy or the nonsmall-cell lung cancer of recurrence to treat other chemotherapy, get permission as three-way single therapy medicine to be used for late period nonsmall-cell lung cancer in the U.S. and Australia in May, 2003, and it is first small molecules tyrosine kinase inhibitor at specific target spot that is used for treatment of solid tumors.
Gefitinib in Nikkei State Food and Drug Administration (SFDA) approval February 25 in 2005 formally in China's listing (trade(brand)name: Gefitinib) be used for the treatment of and accepted chemotherapeutical local late period or transitivity nonsmall-cell lung cancer.
Gefitinib is 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline of following formula:
Gefitinib
The patent document that relates to the Gefitinib preparation method has US5770599A1, WO2004/24703A1, WO2005/23738A1, WO2005/70909A1 etc., and they disclose the multiple different method for preparing Gefitinib.Comprising the method (US5770599) that is obtained Gefitinib by 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (II) and the reaction of morpholinyl propyl chloride, but its yield only has 50%.This method flow is as follows:
Therefore, need the new method for preparing Gefitinib of exploitation, provide highly purified Gefitinib with high yield.
Summary of the invention
The purpose of this invention is to provide a kind of new method for preparing Gefitinib.
For achieving the above object, the present invention is on the reference basis of relevant document, designed the new method that is different from existing patent of preparation Gefitinib, promptly obtained the target compound Gefitinib through etherification reaction under proper condition by 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (II) and 4-(3-hydroxypropyl)-morpholine (being the morpholinyl propyl alcohol).
Specifically, the preparation method of Gefitinib provided by the invention (I),
Gefitinib (I)
Make 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline compound of formula (II)
React in appropriate solvent and under proper temperature with 4-(3-hydroxypropyl)-morpholine and reaction promotor, obtain target compound Gefitinib (I).
Described preparation method of gefitinib, wherein this appropriate solvent is an inert solvent.
Described preparation method of gefitinib, wherein this inert solvent is selected from acetone, diox, tetrahydrofuran (THF), acetonitrile, benzene, toluene, N, dinethylformamide, methyl-sulphoxide, methylene dichloride, chloroform and similar solvent.
Described preparation method of gefitinib, wherein this proper temperature is a room temperature.
Described preparation method of gefitinib, wherein this proper temperature is 15 to 40 ℃.
Described preparation method of gefitinib, wherein this reaction promotor is selected from diethylazodicarboxylate (DEAD), diisopropyl azo-2-carboxylic acid (DIAD), azo-2-carboxylic acid's dipropyl (DPAD), azodicarboxy dimethyl phthalate (DMAD) and similar substance thereof.
Described preparation method of gefitinib, wherein this reaction promotor also comprises triphenylphosphine or triphenylphosphine-PEG-derivative.
Described preparation method of gefitinib wherein uses diisopropyl azo-2-carboxylic acid and triphenylphosphine as reaction promotor.
Described preparation method of gefitinib, wherein triphenylphosphine and diisopropyl azo-2-carboxylic acid's mol ratio is 1: 1-10: 1 or 1: 1-1: 10.
Described preparation method of gefitinib, wherein the mol ratio of 4-(3-hydroxypropyl)-morpholine and formula (II) compound is 1: 1-10: 1.
Described preparation method of gefitinib, wherein the mol ratio of triphenylphosphine and formula (II) compound is 1: 1-10: 1.
This method is compared with existing known technology, and advantage is can react under the room temperature, the reaction conditions milder, and product purity height (＞99%), and yield can reach 78%.
Embodiment
Be the detailed description of Gefitinib preparation below, specifically, the inventive method is that 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (II) and 4-(3-hydroxypropyl)-morpholine are reacted under appropriate reaction conditions, generates Gefitinib (I), and is as follows:
Need to use reaction promotor in the reaction of the inventive method, it is selected from diethylazodicarboxylate (DEAD), diisopropyl azo-2-carboxylic acid (DIAD), azo-2-carboxylic acid's dipropyl (DPAD), azodicarboxy dimethyl phthalate (DMAD) and similar substance thereof.Also needing to add triphenylphosphine or triphenylphosphine-PEG-derivative in the reaction reacts with promotion as reaction promotor.
With regard to preparation method of the present invention, reactant formula (II) compound and 4-(3-hydroxypropyl)-morpholine (being the morpholinyl propyl alcohol) is commercially available, or can the known method preparation of person of ordinary skill in the field itself.
In a preferred embodiments of the inventive method, the mol ratio of 4-(3-hydroxypropyl)-morpholine and formula (II) compound is 1: 1-10: 1.
In a preferred embodiments of the inventive method, use diisopropyl azo-2-carboxylic acid and triphenylphosphine as reaction promotor.
In a preferred embodiments of the inventive method, triphenylphosphine and diisopropyl azo-2-carboxylic acid's mol ratio is 1: 1-10: 1 or 1: 1-1: 10.
In a preferred embodiments of the inventive method, the mol ratio of triphenylphosphine and formula (II) compound is 1: 1-10: 1.
In the reaction of the inventive method, appropriate solvent can be an inert solvent, is preferably to be selected from acetone, diox, tetrahydrofuran (THF), acetonitrile, benzene, toluene, N, dinethylformamide, methyl-sulphoxide, methylene dichloride, chloroform and similar solvent.
With regard to preparation method of the present invention, temperature of reaction is preferably room temperature, is more preferred from about 15 ℃ 40 ℃.Reaction times disappears with TLC board monitoring reaction raw materials 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (formula (II) compound) and is as the criterion.After reaction is finished, make reaction soln through concentrating, acid-alkali treatment and recrystallize promptly can obtain the target product with high purity Gefitinib by high yield.
Compare with disclosed Gefitinib preparation method in the prior art, the present invention substitutes the morpholinyl propyl chloride with 4-(3-hydroxypropyl)-morpholine, with 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (II) reaction, directly obtain Gefitinib, avoid amino generation of going up the alkylation side reaction, improved reaction yield greatly.Simultaneously, the reaction conditions of the inventive method is gentle more, at room temperature can carry out.In addition, products obtained therefrom purity height.Raw material 4-(3-the hydroxypropyl)-morpholine that uses is more cheap more than morpholinyl propyl chloride, also is more prone to preparation simultaneously.
To more understand the present invention by following embodiment.Should be appreciated that following embodiment just is used for illustrating the present invention, rather than be used for limiting the present invention.
Raw material and reagent:
4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (Nanjing peace lattice medication chemistry company limited, 99%), triphenylphosphine (Chemical Reagent Co., Ltd., Sinopharm Group, 99%), diisopropyl azo-2-carboxylic acid's (extra large Qu Huagong company limited, 98%), morpholinyl propyl alcohol (Hengda Science and Technology Development Co Ltd, Shanghai, 98%), the solvent of other use and reagent provide by Chemical Reagent Co., Ltd., Sinopharm Group.
Embodiment: the preparation of Gefitinib
At room temperature (27 ℃), in 16 minutes, (2.01g, 7.66mmol) solution in THF (13mL) dropwise adds diisopropyl azo-2-carboxylic acid (1.5mL, 7.66mmol) solution in THF (2mL) to triphenylphosphine.The color transition yellowly of this clear solution.After 1 hour, at room temperature, in 20 minutes, (0.23mL, 1.69mmol) solution in THF (2mL) dropwise is added in this yellow solution with 4-(3-hydroxypropyl) morpholine.Then, under nitrogen, with formula (II) 4-(3 '-chloro-4 '-fluoroanilino)-6-hydroxyl-(0.50g 1.53mmol) is added in the reaction soln 7-methoxyl group quinazoline.The gained mixture was at room temperature stirred 4 hours, and in 20 minutes, (0.19mL, 1.38mmol) solution in THF (2mL) dropwise is added in this yellow reaction solution with 4-(3-hydroxypropyl) morpholine then.The gained mixture was at room temperature continued to stir 1 hour.Termination reaction, and evaporation is except that desolvating.Resistates is adjusted to pH=5-6 with rare HCl (10%).(20mLx3) extract mixture with ethyl acetate (EA), and with saturated NaHCO
3The aqueous solution is adjusted to pH=10-11 with water.Aqueous mixture is placed refrigerator (17 ℃) cool overnight, obtain suspension.Filter this suspension, and make the filtration agglomerate dry in a vacuum, obtain required compound (575.33mg, 84.21%), it with the ethanol recrystallize, is obtained title compound with 78% yield into white solid.
M.P.＝195-197℃；
1H-NMR(DMSO-d
6)：1.93-2.00(m，2H，CH
2CH
2CH
2)，2.34-2.51(m，6H，N(CH
3)
3)，3.54-3.59(m，4H，O(CH
2)
2)，3.92(s，3H，OCH
3)，4.12-4.18(m，2H，ArOCH
2)，7.16(s，1H，HAr.)，7.35-7.45(m，1H，HAr.)，7.45-7.82(m，2H，HAr.)，8.08-8.13(m，1H，HAr.)，8.48(s，1H，HAr.)，9.51(s，1H，HAr.)；HPLC：99％(214nm/254nm)。
Claims (11)
1. the preparation method of a Gefitinib (I),
It is characterized in that, make 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline compound of formula (II)
React in appropriate solvent and under proper temperature with 4-(3-hydroxypropyl)-morpholine and reaction promotor, obtain target compound Gefitinib (I).
2. preparation method of gefitinib according to claim 1 is characterized in that, this appropriate solvent is an inert solvent.
3. preparation method of gefitinib according to claim 2 is characterized in that, this inert solvent is selected from acetone, diox, tetrahydrofuran (THF), acetonitrile, benzene, toluene, N, dinethylformamide, methyl-sulphoxide, methylene dichloride, chloroform and similar solvent.
4. preparation method of gefitinib according to claim 1 is characterized in that, this proper temperature is a room temperature.
5. preparation method of gefitinib according to claim 1 is characterized in that, this proper temperature is 15 to 40 ℃.
6. preparation method of gefitinib according to claim 1 is characterized in that, this reaction promotor is selected from diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, azo-2-carboxylic acid's dipropyl, azodicarboxy dimethyl phthalate and similar substance thereof.
7. preparation method of gefitinib according to claim 1 is characterized in that, this reaction promotor also comprises triphenylphosphine or triphenylphosphine-PEG-derivative.
8. preparation method of gefitinib according to claim 1 is characterized in that, uses diisopropyl azo-2-carboxylic acid and triphenylphosphine as reaction promotor.
9. preparation method of gefitinib according to claim 8 is characterized in that, triphenylphosphine and diisopropyl azo-2-carboxylic acid's mol ratio is 1: 1-10: 1 or 1: 1-1: 10.
10. preparation method of gefitinib according to claim 1 is characterized in that, the mol ratio of 4-(3-hydroxypropyl)-morpholine and formula (II) compound is 1: 1-10: 1.
11. preparation method of gefitinib according to claim 1 is characterized in that, the mol ratio of triphenylphosphine and formula (II) compound is 1: 1-10: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201010109106A CN102153518B (en) | 2010-02-11 | 2010-02-11 | Preparation method of Gefitinib |
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| CN201010109106A CN102153518B (en) | 2010-02-11 | 2010-02-11 | Preparation method of Gefitinib |
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| CN102153518A true CN102153518A (en) | 2011-08-17 |
| CN102153518B CN102153518B (en) | 2012-10-10 |
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| CN201010109106A Expired - Fee Related CN102153518B (en) | 2010-02-11 | 2010-02-11 | Preparation method of Gefitinib |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617463A (en) * | 2012-02-28 | 2012-08-01 | 苏州卡耐博生物技术有限公司 | Quinoline derivative and quinazoline derivative and preparation method thereof |
| CN103012290A (en) * | 2011-09-28 | 2013-04-03 | 齐鲁制药有限公司 | Preparation method of high-purity gefitinib |
| CN113444052A (en) * | 2021-07-01 | 2021-09-28 | 江苏君若药业有限公司 | Synthesis of gefitinib |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1733738A (en) * | 2005-08-25 | 2006-02-15 | 江苏吴中苏药医药开发有限责任公司 | Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline |
-
2010
- 2010-02-11 CN CN201010109106A patent/CN102153518B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1733738A (en) * | 2005-08-25 | 2006-02-15 | 江苏吴中苏药医药开发有限责任公司 | Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline |
Non-Patent Citations (2)
| Title |
|---|
| 《中国医药工业杂志》 20080610 刁圆圆等 吉非替尼的合成 401-403 第39卷, 第6期 * |
| 《中国药物化学杂志》 20050228 袁立等 4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[3-(4-吗啉基)丙氧基]喹唑啉的合成 39-41 第15卷, 第1期 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012290A (en) * | 2011-09-28 | 2013-04-03 | 齐鲁制药有限公司 | Preparation method of high-purity gefitinib |
| CN103012290B (en) * | 2011-09-28 | 2015-05-13 | 齐鲁制药有限公司 | Preparation method of high-purity gefitinib |
| CN102617463A (en) * | 2012-02-28 | 2012-08-01 | 苏州卡耐博生物技术有限公司 | Quinoline derivative and quinazoline derivative and preparation method thereof |
| CN113444052A (en) * | 2021-07-01 | 2021-09-28 | 江苏君若药业有限公司 | Synthesis of gefitinib |
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| CN102153518B (en) | 2012-10-10 |
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Application publication date: 20110817 Assignee: Yung Shin Pharm. Ind. (Kunshan) Co., Ltd. Assignor: Jiangsu Farmtec Research Co.,Ltd. Contract record no.: 2013320010172 Denomination of invention: Preparation method of high-purity gefitinib Granted publication date: 20121010 License type: Exclusive License Record date: 20131203 |
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Granted publication date: 20121010 Termination date: 20160211 |