CN108218839A - A kind of preparation method of antitumor drug AZD9291 - Google Patents
A kind of preparation method of antitumor drug AZD9291 Download PDFInfo
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- CN108218839A CN108218839A CN201810227822.1A CN201810227822A CN108218839A CN 108218839 A CN108218839 A CN 108218839A CN 201810227822 A CN201810227822 A CN 201810227822A CN 108218839 A CN108218839 A CN 108218839A
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- 0 CIc(cc(c(*)c1)I)c1C#N Chemical compound CIc(cc(c(*)c1)I)c1C#N 0.000 description 3
- DJEQZVQFEPKLOY-UHFFFAOYSA-N CCCCN(C)C Chemical compound CCCCN(C)C DJEQZVQFEPKLOY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a kind of preparation methods of antitumor drug AZD9291, using 2 bromine, 4 aminoanisole as starting material, by nitration reaction, grignard reaction, acylation reaction, reduction reaction, grignard reaction and elimination reaction, obtain AZD9291 free alkalis.The beneficial effects of the invention are as follows：Have many advantages, such as that wide raw material sources, at low cost, easy to operate, recycled solvent, waste liquid discharging amount is small, product recovery rate is high, it is easy to accomplish industrialization.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are related to a kind of preparation method of antitumor drug AZD9291.
Background technology
At present, lung cancer is the highest malignant tumour of morbidity and mortality, wherein non-small cell lung cancer in worldwide
(non-small cell lungcancer, NSCLC) accounts for 80% or so of whole lung cancer, and has in NSCLC patient very one big
Divide and be in late period when making a definite diagnosis.
At the beginning of the last century 90's, lung cancer can be treated or be put by operation and chemotherapy combined radiotherapy in early days through histological classification
Chemotherapy.But due to when most of patients with lung cancer is diagnosed tumour be late period, lose operative chance, chemotherapy can only be carried out.
However, chemotherapeutic toxicity is larger, injured caused by patient body also quite seriously, and median survival interval is only 12 months.Therefore,
The treatment of advanced NSCLC is also increasingly valued by people.Although the standard care of advanced NSCLC is the double medicine connection of platiniferous
Combination is treated, but effect is extremely limited in terms of life cycle of the chemotherapeutics to improving advanced NSCLC patients, therefore seeks new control
Treatment mode is extremely urgent.
The research of II/III phase is had been enter at present for the third generation targeting trial drug AZD-9291 of T790M mutation, this examination
It is all oral medicine to test drug, is improved, therefore diarrhea, fash etc. for the shortcomings that first generation EGFR targeted drugs
Side effect is all fewer than first generation EGFR targeted drugs.ASCO conferences report through the first generation EGFR targeted drugs treatment after the state of an illness into
The effect of T790M mutation crowds of exhibition receive AZD-9291 treatments is 66% respectively.Receive the mutation positive patient of AZD-9291
Total disease control rate is 94%.AZD-9291 is authorized " breakthrough medicine " by Food and Drug Adminstration of the US (FDA)
(breakthrough medicine is defined as a kind of new product for treating certain serious disease, and preliminary clinical evidence shows it for qualification
There is comparable advantage compared with existing medicine on one or more important terminals of clinic).The new drug of this qualification is obtained,
The approval process of drug will significantly shorten participants and expect that these original new drugs can list as early as possible, be advanced Non-small cell lung
Patient brings hope.
AZD9291 its molecular formula is C28 H33 N7 O2, molecular weight 499.61, and structural formula is：
The present invention is closed using the bromo- 4- aminoanisoles of 2- as starting material prepare compound AZD9291 and its key intermediate
It is as follows into route：
The present invention is optimized and is transformed to the synthetic method of AZD-9291 according to document synthetic route, to find raw material
It is easy to get, route simplicity, environmental-friendly new departure, the industrialized developing for AZD9291 establishes certain technical foundation.
Invention content
The technical problem to be solved by the present invention is to：Based on the above problem, the present invention provides a kind of antitumor drug AZD9291
Preparation method.
A technical solution is used by the present invention solves its technical problem：A kind of system of antitumor drug AZD9291
Preparation Method includes the following steps：
(1) the bromo- 4- aminoanisoles of 2- are added in the concentrated sulfuric acid, potassium nitrate, nitration reaction, post processingization is added portionwise
Close object 1；(2) compound 1, which is dissolved in tetrahydrofuran, prepares grignard reagent I, adds in trimethyl ethylenediamine, and grignard reaction obtains chemical combination
Object 2；(3) compound 2 is dissolved in solvent I, and 3- chlorpromazine chlorides are added dropwise, and acylation reaction obtains compound 3；(4) compound 3 is dissolved in molten
In agent II, reduction reaction obtains compound 4；(5) compound 5 is dissolved in tetrahydrofuran and prepares grignard reagent II, add in chemical combination
Object 4, grignard reaction obtain compound 6；(6) for compound 6 under catalyst action, elimination reaction obtains compound 7；
Wherein, compound 1 is the bromo- 4- methoxyl groups -5- nitroanilines of 2-, and compound 2 is N1- (2- (dimethylamino) second
Base) -5- methoxyl group-N1- methyl -4- nitrobenzene -1,2- diamines, compound 3 is the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl)
(methyl) amino) -4- methoxyl group -5- nitre phenyl) propylamine, compound 4 is N- (5- amino -2- ((2- (dimethylamino) ethyl)
(methyl) amino) -4- methoxyphenyls) -3- chlorine propylamine, compound 5 is 3- (2- chloropyridine -4- bases) -1- Methvl-indoles, is changed
Close object 6 be the chloro- N- of 3- (2- ((2- (dimethylamino)-ethyl)-Methyl-amino) -4- methoxyl groups -5- (4- (1- methyl indols) -
2- pyridyl groups)-amino-phenyl-propylamine, compound 7 is N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxies
Base -5- [[4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides.
Further, reaction temperature is 10~20 DEG C in step (1).
Further, the volume mass ratio of the concentrated sulfuric acid and the bromo- 4- aminoanisoles of 2- is 5~10 in step (1)：1.
Further, the molar ratio of trimethyl ethylenediamine and compound 1 is 1.15~2 in step (2)：1.
Further, solvent I is ethyl acetate, in tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, DMF in step (3)
One or several kinds, the volume mass ratio of solvent I and compound 2 is 5~10：1,3- chlorpromazine chloride and mole of compound 2
Than being 1.1~1.5：1.
Further, step (4) solvent II is the one or several kinds in methanol, ethyl alcohol, ethyl acetate or toluene.
Further, reduction reaction is using palladium carbon or Raney's nickel as catalyst hydrogenation in step (4), and catalyst quality is changes
Close the 5~15% of the quality of object 3；Or reduction reaction is to be restored using iron powder ammonium chloride, iron powder quality is 3 mass of compound
10~20%, the molar ratio of ammonium chloride and compound 3 is 1.05~1.5：1.
Further, the molar ratio of compound 5 and compound 4 is 1.05~1.5 in step (5)：1.
Further, catalyst is diazabicylo in step (6), the molar ratio of catalyst and compound 6 for 0.1~
0.4：1.
Not for specific crystal form, any AZD9291 crystal forms reported can be obtained the method for the present invention using the method
Obtain qualified product.
The beneficial effects of the invention are as follows：Completely new route synthesizing antineoplastic medicament AZD9291 is employed, the present invention has original
Expect source is wide, at low cost, easy to operate, recycled solvent, the advantages that waste liquid discharging amount is small, product recovery rate is high, be easy to
Realize industrialization.
Specific embodiment
Presently in connection with specific embodiment, the invention will be further described, following embodiment be intended to illustrate invention rather than
Limitation of the invention further.
Embodiment
Concentrated sulfuric acid 150ml is added in there-necked flask (1L), is stirred at 10~20 DEG C, in the bromo- 4- of dropwise addition 2- at this temperature
Aminoanisole 30g.Potassium nitrate 21.9g is added in three batches, and temperature is kept to be no more than 20 DEG C.It is stirred after five minutes after adding.It will be anti-
Liquid is answered to pour into trash ice, with dilute sodium hydroxide solution tune pH to 9~10, the solid of precipitation filters, and filter cake is washed with water, and dries
Compound 1,34.1g is obtained, molar yield 93% is directly used in the next step without purifying.
150ml tetrahydrofurans, 20g magnesium chips are added in there-necked flask (1L), is cooled between 0~5 DEG C, drops under nitrogen protection
Temperature finishes, and with 60ml tetrahydrofurans dissolving 30g compounds 1, the tetrahydrofuran solution of compound 1 is added dropwise at 0~10 DEG C for control temperature,
It is added dropwise and finishes, the insulated and stirred 2h at 0~10 DEG C.Heat preservation is finished, and 18g front threes are added dropwise into reaction system at 0~10 DEG C for control temperature
Base ethylenediamine is added dropwise and finishes, insulated and stirred 2h.Heat preservation, which is finished, pours into reaction solution in 300ml ice water solutions, and split-phase takes organic phase, uses
100ml is washed 3 times, is concentrated to dryness, and is directly used in and is reacted in next step.
200ml ethyl acetate is added in into concentrate, dissolved clarification is stirred, is cooled between 10~20 DEG C, 17g 3- chlorine is added dropwise
Propionyl chloride, control temperature is between 10~20 DEG C.Dropwise addition is finished in 10~20 DEG C of insulated and stirred 2h, and heat preservation is finished, into reaction system
20% sodium hydroxide solution is added dropwise to pH=9 or so.Split-phase is stood, organic phase is taken to be concentrated to dryness.Add in 150ml methanol, drop
150ml water to a large amount of solids is added to be precipitated, filters, obtains 3 solid 37.2g of compound, molar yield 85%, HPLC purity is more than
99.5%.
150ml methanol is added in into 1L reaction bulbs, input 37.2g compounds 3 are stirred to dissolved clarification, added into reaction system
Enter the wet palladium carbon of 3.5g 10%, be passed through hydrogen under normal pressure, be warming up between 35~40 DEG C, middle control reaction is finished, and is filtered, is removed
150ml water is added dropwise into filtrate for palladium carbon, and a large amount of solids are precipitated at this time, is added dropwise and finishes stirring 1h, filters to obtain faint yellow solid compound
4,32.4g, molar yield 95%, HPLC purity is more than 99.5%.
150ml tetrahydrofurans are added in into 1L reaction bulbs, 15g magnesium chips is put into, is cooled between 10~15 DEG C, 50ml is added dropwise
Tetrahydrofuran+24.3g compounds 5 are added dropwise and finish, 1h is stirred between 10~15 DEG C.Start that 32.4g compounds 4+100ml is added dropwise
Tetrahydrofuran, dropwise addition is finished keeps the temperature 2h between 10~15 DEG C, and heat preservation is finished, and reaction solution is pumped into 150ml ice water, stirs 10min,
Split-phase is stood, organic phase is taken, is concentrated to dryness to obtain 6 concentrate of compound.
150ml methanol is added in into 6 concentrate of compound, dissolved clarification is stirred, is cooled between 0~5 DEG C, adds in 15g trifluoros
Sodium acetate stirs 30 minutes, and 2.5g diazabicylos are added dropwise in control temperature between 0~5 DEG C, are added dropwise and finish, and 3h are stirred, in starting
Control to the reaction of compound 6 is finished, and 9.5g Loprazolams are added dropwise, be added dropwise finish be warming up to 35~40 DEG C between stir 2h, be precipitated at this time solid
Target compound AZD9291, the 41.5g crude product of body.
Using above-mentioned desirable embodiment according to the present invention as enlightenment, by above-mentioned description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the content on specification, it is necessary to determine its technical scope according to right.
Claims (9)
1. a kind of preparation method of antitumor drug AZD9291, it is characterized in that：Include the following steps：
(1) the bromo- 4- aminoanisoles of 2- are added in the concentrated sulfuric acid, potassium nitrate, nitration reaction is added portionwise, post processing obtains compound
1；(2) compound 1, which is dissolved in tetrahydrofuran, prepares grignard reagent I, adds in trimethyl ethylenediamine, and grignard reaction obtains compound 2；
(3) compound 2 is dissolved in solvent I, and 3- chlorpromazine chlorides are added dropwise, and acylation reaction obtains compound 3；(4) compound 3 is dissolved in solvent II
In, reduction reaction obtains compound 4；(5) compound 5 is dissolved in tetrahydrofuran and prepares grignard reagent II, add in compound 4,
Grignard reaction obtains compound 6；(6) for compound 6 under catalyst action, elimination reaction obtains compound 7；Wherein, compound 1
It is the bromo- 4- methoxyl groups -5- nitroanilines of 2-, compound 2 is N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl -4-
Nitrobenzene -1,2- diamines, compound 3 are the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5-
Nitre phenyl) propylamine, compound 4 is N- (5- amino -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxybenzenes
Base) -3- chlorine propylamine, compound 5 is 3- (2- chloropyridine -4- bases) -1- Methvl-indoles, and compound 6 is the chloro- N- of 3- (2- ((2-
(dimethylamino)-ethyl)-Methyl-amino) -4- methoxyl groups -5- (4- (1- methyl indols) -2- pyridyl groups)-amino-phenyl-the third
Amine, compound 7 are N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl-1 H- Yin
Diindyl -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides.
2. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(1) reaction temperature is 10~20 DEG C in.
3. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(1) the volume mass ratio of the concentrated sulfuric acid and the bromo- 4- aminoanisoles of 2- is 5~10 in：1.
4. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(2) molar ratio of trimethyl ethylenediamine and compound 1 is 1.15~2 in：1.
5. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(3) in solvent I be ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, the one or several kinds in DMF, solvent I with
The volume mass ratio of compound 2 is 5~10：The molar ratio of 1,3- chlorpromazine chloride and compound 2 is 1.1~1.5：1.
6. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(4) solvent II is the one or several kinds in methanol, ethyl alcohol, ethyl acetate or toluene.
7. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(4) reduction reaction is using palladium carbon or Raney's nickel as catalyst hydrogenation in, and catalyst quality is the 5~15% of the quality of compound 3；
Or reduction reaction is to be restored using iron powder ammonium chloride, iron powder quality is the 10~20% of 3 mass of compound, and ammonium chloride is with changing
The molar ratio for closing object 3 is 1.05~1.5：1.
8. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(5) molar ratio of compound 5 and compound 4 is 1.05~1.5 in：1.
9. the preparation method of antitumor drug AZD9291 according to claim 1 a kind of, it is characterized in that：The step
(6) catalyst is diazabicylo in, and the molar ratio of catalyst and compound 6 is 0.1~0.4：1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104817541A (en) * | 2015-05-11 | 2015-08-05 | 苏州东南药业股份有限公司 | Synthetic method of anti-tumor medicine |
| CN106366022A (en) * | 2016-08-19 | 2017-02-01 | 上海工程技术大学 | Intermediate used for AZD9291 preparation, and preparation method and application thereof |
| CN107522690A (en) * | 2016-06-20 | 2017-12-29 | 江苏先声药业有限公司 | A kind of Osimertinib preparation method |
-
2018
- 2018-03-20 CN CN201810227822.1A patent/CN108218839A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104817541A (en) * | 2015-05-11 | 2015-08-05 | 苏州东南药业股份有限公司 | Synthetic method of anti-tumor medicine |
| CN107522690A (en) * | 2016-06-20 | 2017-12-29 | 江苏先声药业有限公司 | A kind of Osimertinib preparation method |
| CN106366022A (en) * | 2016-08-19 | 2017-02-01 | 上海工程技术大学 | Intermediate used for AZD9291 preparation, and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| M. RAYMOND V. FINLAY等: "Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor", 《J. MED. CHEM.》 * |
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Application publication date: 20180629 |