CN106967050A - A kind of AZD9291 preparation method - Google Patents
A kind of AZD9291 preparation method Download PDFInfo
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- CN106967050A CN106967050A CN201710332881.0A CN201710332881A CN106967050A CN 106967050 A CN106967050 A CN 106967050A CN 201710332881 A CN201710332881 A CN 201710332881A CN 106967050 A CN106967050 A CN 106967050A
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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
A kind of AZD9291 preparation method, belongs to field of medicine preparing technology.Using 3 (base of 2 chlorine pyrimidine 4) 1 methyl indols as raw material, occur substitution reaction with the nitroaniline of 4 fluorine, 2 methoxyl group 5 first, generate 3 [base of 2 [(nitro of 4 fluorine, 2 methoxyl group 5) anilino-] pyrimidine 4] 1 methyl indols (3)；Then, compound 3 in the presence of catalyst with N, N, N ' trimethyl ethylenediamine substitution generation 3 [2 [(4 (N, N, N ' trimethyl ethylenediamine) 2 methoxyl group, 5 nitro) anilino-] 4 base of pyrimidine] 1 methyl indol (5)；Then, the amidatioon of reduction and amido of the compound 5 through nitro, " one kettle way " synthesizes AZD9291.The preparation method concise in technology, environment-friendly, with low cost and suitable industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field, more particularly to one kind
For non-small cell lung cancer (NSCLC) medicine AZD9291 preparation method, belong to field of medicine preparing technology.
Background technology
AZD9291, common name is developed Osimertinib by Astrazeneca AB, in Nikkei FDA November 13 in 2015
Accelerate approval passage to be approved listing in the U.S., be the 3rd generation EGFR inhibitor of first listing, suppress as the EGFR of latest generation
Agent, with the first generation compared with second generation inhibitor, it has really in terms of drug resistance and selectivity is obviously improved, not only right
The double mutation of EGFR are effective, and also selective to Wild type EGFR, toxic side effect is also minimized.The medicine can be targetted simultaneously
EGFR is mutated and T790M mutation, for treating EGF-R ELISA (EGFR) T790M mutation or to other EGFR inhibitors
The advanced Non-small cell lung of resistance, not only overcomes 1st generation EGFR inhibitor resistance and 2nd generation EGFR inhibitor poor selectivity
The problem of, while having the advantage of high bioavilability and low cardiovascular risk concurrently, show huge market value.
AZD9291's is chemical entitled：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4-
(1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides, its structural formula is：
AZD9291 synthetic route one is reported in the A1 of international monopoly WO 2013014448, its using 1- methyl indols as
Initial feed, the main coupling by with dichloro pyrimidine, the substitution with anil, fluoride female ring and substitution diethylamine
AZD9291 is made in the steps such as substitution, the reduction of nitro, the amidatioon of amido and reduction dehydrogenation.This method step is relatively complicated,
The coupling reaction accessory substance of the especially first step is more, and yield is only 46%, so that cause whole piece route that there is higher cost,
It is unsuitable for large-scale industrial production.
MRV Finlay etc. are reported using indoles as initial feed, by the coupling with dichloro pyrimidine, with iodomethane
Alkylation, the step such as the substitution with anil, substitution, the reduction of nitro and the amidatioon of amido with replacing diethylamine
AZD9291 is made.This method has mainly carried out part to synthetic route one and optimized, and it is improved and optimization is mainly reflected in two sides
Face：One is the order of the N- methylation reactions of indoles, and methylation reaction is placed in after 3- coupling reactions；Two be to amidatioon
Reaction is optimized, and uses pi-allyl acyl chlorides instead and directly generates AZD9291 for acylating agent, and reaction step is simplified to a certain extent
Suddenly, reaction yield is improved.Also only it is the optimization of local reaction although changing synthetic route above-mentioned route is optimized, its
Core reaction route still progressively adds up to realize by the functional group of its raw material, however it remains step is more, cost is higher etc.
Defect.
Reported in the A of patent CN 104817541 using the fluoro- 2- methoxyl groups -5- nitroanilines of 4- as initial feed, through amido
Boc protections, fluoride female ring and the substitution substitution of diethylamine, the reduction of nitro, the amidatioon of amido, the substitution with chlorine pyrimidine
And AZD9291 is made into steps such as salt.For the synthetic route is with respect to route one and route two, reaction condition is gentle, after
Processing is simple, also more friendly for environment, but the synthetic route reactions steps are more, and total recovery is difficult to ensure that.
Disclosed method existing to AZD929 is analyzed, find generally it is pure synthetic route reactions steps it is more, into
The defect such as this higher and accessory substance is more, not only causes cost higher, and do not meet the theory of Modern Green Chemistry.
For existing shortcoming, the mechanism reacted according to each step considers raw material sources, production cost, technique amplification
The factor such as reliability and ease-to-operate, develops concise in technology, and reaction condition is gentle, and environment carrys out friendly technology of preparing,
Especially seek to the technology of industrialized production can be adapted to, with important economic and social benefit.
The content of the invention
It is an object of the invention to provide a kind of concise in technology, environment-friendly, with low cost and suitable industrialized production
AZD9291 preparation method, is post-processed simply, productivity ratio is higher using the inventive method.
The present invention according to each step react mechanism, consider raw material sources, production cost, technique amplification reliability and
The factors such as ease-to-operate, selected AZD9291 synthetic route is：It is initial using 3- (2- chlorine pyrimidine-4-yl) -1- methyl indols
Raw material, occurs substitution reaction with the fluoro- 2- methoxyl groups -5- nitroanilines of 4- first, generates 3- [2- [(the fluoro- 2- methoxyl groups -5- nitre of 4-
Base) anilino-] pyrimidine-4-yl] -1- methyl indols (3)；Then, compound 3 in the presence of catalyst with N, N, N '-front three
Base ethylenediamine substitution generation 3- [2- [(4- (N, N, N '-trimethyl ethylenediamine) -2- methoxyl group -5- nitros) anilino-] pyrimidine -4-
Base] -1- methyl indols (5)；Then, the amidatioon of reduction and amido of the compound 5 through nitro, " one kettle way " synthesizes
AZD9291。
Step a：By 3- (2- chlorine pyrimidine-4-yl) -1- methyl indols, the fluoro- water of 2- methoxyl groups -5- nitroanilines 2 and one of 4-
Close p-methyl benzenesulfonic acid to be dissolved in organic solvent, be heated to reflux, after completion of the reaction, recrystallize to obtain compound 3；The organic solvent is
2- amylalcohols, sec-butyl alcohol, butanol, 1,4- dioxane, glycol dimethyl ether, pyridine, ethanol, methanol, ethyl acetate, toluene, N,
Dinethylformamide, DMAC N,N' dimethyl acetamide or its mixture；Heating-up temperature is 60~120 DEG C；It is preferred that (2- chlorine is phonetic by 3-
Pyridine -4- bases) -1- methyl indols, the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, one hydration p-methyl benzenesulfonic acid mol ratio be 1:
(1.1-1.5)：(1.2-1.6)；
Step b：By compound 3 and N, N, N '-trimethyl ethylenediamine 4 is dissolved in organic solvent, adds catalyst, and nitrogen is protected
Shield, heating response after completion of the reaction, recrystallizes to obtain compound 5；The organic solvent is 2- amylalcohols, sec-butyl alcohol, butanol, 1,4-
Dioxane, glycol dimethyl ether, pyridine, ethanol, methanol, ethyl acetate, toluene, N,N-dimethylformamide, N, N- diformazans
Yl acetamide or its mixture；The catalyst is N, N- diisopropylethylamine, triethylamine, DMAP, pyridine, N-
Methylmorpholine, tetramethylethylenediamine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide；Heating-up temperature is 60~120 DEG C；
Preferred compound 3, N, N, N '-trimethyl ethylenediamine, catalyst mol ratio be 5:(5.1-5.4)：(12.2-12.8)；Step
c：Compound 5 and 5% palladium-carbon are dissolved in organic solvent, hydrogen is passed through, 2h is stirred at room temperature, filters and adds third into filtrate
Olefin(e) acid, catalyst and activator, nitrogen protection, are stirred at room temperature, after completion of the reaction, the AZD9291 isolated and purified；It is described organic molten
Agent is tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, acetone, ethanol, methanol, acetonitrile, N,N-dimethylformamide, second
Ether, 1,4- dioxane, toluene or its mixture；The catalyst is N, N- diisopropylethylamine, triethylamine, 4- dimethylaminos
Pyridine, pyridine, N- methylmorpholines, tetramethylethylenediamine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide；The activation
Agent is 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 2- (7- aoxidizes BTA)-N, N, N', N'- tetra-
MU hexafluorophosphoric acid ester, O- BTAs-tetramethylurea hexafluorophosphoric acid ester, I-hydroxybenzotriazole, O- BTAs-
N, N, N', N'- tetramethylurea tetrafluoro boric acid.
Preferred compound 5,5% palladium-carbon, acrylic acid, the mol ratio 5 of catalyst and activator：1:10:15:20.
Embodiment
In order to the clearer particular content for understanding the present invention, the present invention is made furtherly with reference to example
It is bright, but the present invention is not limited to following examples.
Embodiment 1：
3- (2- chlorine pyrimidine-4-yl) -1- methyl indols (2.430g, 10mmol) are added into 250mL there-necked flasks, 4- is fluoro-
2- methoxyl group -5- nitroanilines (2.418g, 13mmol) and a hydration p-methyl benzenesulfonic acid (2.850g, 15mmol), and add
80mL 2- amylalcohols, start stirring and heat, 80 DEG C of backflows 2.5h, TLC (CHCl3:MeOH=8:1, Rf=0.5) detection reaction
After finishing, heating is closed, a bottleneck from there-necked flask is with needle tubing is by plug gradation and slowly squeezes into ethanol in proper amount, with temperature
Degree reduction, separates out yellow solid, and ice bath continues to separate out solid, suction filtration, ethanol washing, dry the yellow solid of compound 3
3.419g, yield 87%.1H NMR(400MHz,DMSO-d6):δ(ppm)3.89(s,3H,-CH3),4.03(s,3H,-CH3),
7.16 (t, 1H, J=7.2Hz ,-CH3-N(C)-CH),7.26-7.55(m,4H,Ar-H),8.30-8.41(m,4H,Ar-H),
9.12 (d, 1H, J=8.4Hz ,-NH-)；HRMS(ESI),m/z calcd 394.1310 for C20H17FN5O3[M+H]+,
found 394.1314.
Compound 3 (1.965g, 5mmol), N, N, N are added into 250mL single port bottles '-trimethyl ethylenediamine (0.546g,
5.25mmol) and DIPEA (1.612g, 12.5mmol), and add appropriate sec-butyl alcohol and make solvent, stirring, 80 are started in nitrogen protection
DEG C back flow reaction 10h, TLC (CHCl3:MeOH=8:1, Rf=0.7) detection after completion of the reaction, closes heating, as temperature drops
It is low, red solid is separated out, ice bath continues to separate out solid, suction filtration, dry the red solid 1.995g of compound 5, yield 84%.1H
NMR(400MHz,DMSO-d6):δppm2.70(s,6H,-CH3),2.85(s,3H,-CH3),3.20(s,2H,-CH2-),3.55
(t, 2H, J=6.8Hz ,-CH2-),3.88(s,3H,-CH3),4.03(s,3H,-O-CH3),6.99-7.54(m,5H,Ar-H),
8.14-8.40(m,4H,Ar-H),8.80(s,1H,-NH-)；HRMS(ESI),m/z calcd 476.2405 for
C25H30N7O3[M+H]+,found 476.2404.
Compound 5 (2.375g, 5mmol) and 5% palladium-carbon (106mg, 1mmol) are added into 250mL single port bottles, with THF
(60mL) makees solvent, and substitution gas three times make reaction solution (ensure that hydrogen is enough) under atmosphere of hydrogen, 2h are stirred at room temperature, soon
Speed filters out solid palladium-carbon, and addition acrylic acid (0.72g, 10mmol), EDCHCl (2.865g, 15mmol) into filtrate
With DIPEA (2.580g, 20mmol), and protected with nitrogen, 4h, TLC (CHCl3 is stirred at room temperature:MeOH=8:1, Rf=
0.8) detection after completion of the reaction, is concentrated under reduced pressure, and chlorination is imitative and water is extracted three times, takes organic phase, adds anhydrous sodium sulfate drying, mistake
Filter, is spin-dried for, obtains the slightly yellow solid 1.521g of AZD9291, yield 61%.m.p.68.85℃；1H NMR(400MHz,CDCl3):δ
ppm 2.27(s,6H,N-(CH3)2), 2.29 (d, 2H, J=6.0Hz ,-CH2-),2.72(s,3H,-CH3),2.90(t,2H,J
=5.6Hz ,-CH2-),3.90(s,3H,-CH3),4.01(s,3H,-CH3), 5.72 (q, 1H, J=7.6Hz, C=C-H),
6.38-6.51 (m, 2H, 2C=C-H), 6.82 (s, 1H, Ar-H), 7.22-7.42 (m, 4H, Ar-H), 7.75 (s, 1H, Ar-H),
8.09 (q, 1H, J=3.2Hz, Ar-H), 8.41 (d, 1H, J=5.2Hz, Ar-H), 9.13 (s, 1H, Ar-H), 9.88 (s, 1H ,-
NH-),10.20(s,1H,-NH-)；13C NMR(100MHz,CDCl3):δppm 33.0,43.8,45.4,56.1,56.5,
57.4,104.7,107.9,109.9,110.0,113.7,120.2,120.9,121.7,125.3,126.0,127.7,129.7,
132.9,134.6,135.2,138.3,144.3,157.9,159.6,162.1,162.8；HRMS(ESI),m/z calcd
500.2768 for C28H34N7O2[M+H]+,found 500.2766.。
Claims (7)
1. a kind of AZD9291 preparation method, it is characterised in that pass through following steps：
Step a：By 3- (2- chlorine pyrimidine-4-yl) -1- methyl indols, the fluoro- hydrations pair of 2- methoxyl groups -5- nitroanilines 2 and one of 4-
Toluenesulfonic acid is dissolved in organic solvent, is heated to reflux, after completion of the reaction, recrystallizes to obtain compound 3；
Step b：By compound 3 and N, N, N '-trimethyl ethylenediamine 4 is dissolved in organic solvent, adds catalyst, nitrogen protection,
Heating response, after completion of the reaction, recrystallizes to obtain compound 5；
Step c：Compound 5 and 5% palladium-carbon are dissolved in organic solvent, hydrogen is passed through, 2h is stirred at room temperature, filtered and to filtrate
Middle addition acrylic acid, catalyst and activator, nitrogen protection are stirred at room temperature, after completion of the reaction, the AZD9291 isolated and purified.
2. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step a：Organic solvent is 2-
Amylalcohol, sec-butyl alcohol, butanol, 1,4- dioxane, glycol dimethyl ether, pyridine, ethanol, methanol, ethyl acetate, toluene, N, N-
Dimethylformamide, DMAC N,N' dimethyl acetamide or its mixture；Heating-up temperature is 60~120 DEG C.
3. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step a：3- (2- chlorine pyrimidine-
4- yls) -1- methyl indols, the fluoro- 2- methoxyl groups -5- nitroanilines of 4-, one hydration p-methyl benzenesulfonic acid mol ratio be 1:(1.1-
1.5)：(1.2-1.6).
4. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step b：The organic solvent
For 2- amylalcohols, sec-butyl alcohol, butanol, 1,4- dioxane, glycol dimethyl ether, pyridine, ethanol, methanol, ethyl acetate, toluene,
N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or its mixture；The catalyst is N, N- diisopropylethylamine, three second
Amine, DMAP, pyridine, N- methylmorpholines, tetramethylethylenediamine, potassium carbonate, sodium carbonate, potassium tert-butoxide, tertiary fourth
Sodium alkoxide；Heating-up temperature is 60~120 DEG C.
5. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step b：Compound 3, N, N,
N '-trimethyl ethylenediamine, the mol ratio of catalyst are 5:(5.1-5.4)：(12.2-12.8).
6. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step c：The organic solvent
For tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, acetone, ethanol, methanol, acetonitrile, N,N-dimethylformamide, ether,
1,4- dioxane, toluene or its mixture；The catalyst is N, N- diisopropylethylamine, triethylamine, 4- dimethylamino pyrroles
Pyridine, pyridine, N- methylmorpholines, tetramethylethylenediamine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide；The activator
For 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethyls
Base urea hexafluorophosphoric acid ester, O- BTAs-tetramethylurea hexafluorophosphoric acid ester, I-hydroxybenzotriazole, O- BTA-N,
N, N', N'- tetramethylurea tetrafluoro boric acid.
7. according to the preparation method of AZD9291 described in claim 1 a kind of, it is characterised in that step c：Compound 5,5%
Palladium-carbon, acrylic acid, the mol ratio 5 of catalyst and activator：1:10:15:20.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107556293A (en) * | 2017-09-19 | 2018-01-09 | 福建省微生物研究所 | Replace the synthesis technique of Buddhist nun in a kind of west difficult to understand |
| CN107727773A (en) * | 2017-11-23 | 2018-02-23 | 中山奕安泰医药科技有限公司 | Using the liquid chromatography detection methanesulfonic acid uncommon method for Buddhist nun's purity difficult to understand |
| CN109485638A (en) * | 2017-09-12 | 2019-03-19 | 新发药业有限公司 | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand |
| CN110317194A (en) * | 2019-08-13 | 2019-10-11 | 滨州市鸿源工程有限公司 | A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand |
| CN111606889A (en) * | 2019-02-25 | 2020-09-01 | 上海翰森生物医药科技有限公司 | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives |
| CN112480083A (en) * | 2020-11-06 | 2021-03-12 | 上海应用技术大学 | AZD9291 derivative containing alkynyl and preparation method and application thereof |
| CN112645934A (en) * | 2020-12-25 | 2021-04-13 | 中山奕安泰医药科技有限公司 | Ostinib intermediate and refining method thereof |
| WO2022132046A1 (en) * | 2020-12-16 | 2022-06-23 | Scinopharm Taiwan, Ltd. | Improved process for preparing osimertinib or a salt thereof |
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Cited By (12)
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| CN109485638A (en) * | 2017-09-12 | 2019-03-19 | 新发药业有限公司 | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand |
| CN109485638B (en) * | 2017-09-12 | 2020-07-17 | 新发药业有限公司 | Preparation method of oxitinib intermediate |
| CN107556293A (en) * | 2017-09-19 | 2018-01-09 | 福建省微生物研究所 | Replace the synthesis technique of Buddhist nun in a kind of west difficult to understand |
| CN107556293B (en) * | 2017-09-19 | 2019-12-03 | 福建省微生物研究所 | Replace the synthesis technology of Buddhist nun in a kind of west difficult to understand |
| CN107727773A (en) * | 2017-11-23 | 2018-02-23 | 中山奕安泰医药科技有限公司 | Using the liquid chromatography detection methanesulfonic acid uncommon method for Buddhist nun's purity difficult to understand |
| CN111606889A (en) * | 2019-02-25 | 2020-09-01 | 上海翰森生物医药科技有限公司 | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives |
| CN111606889B (en) * | 2019-02-25 | 2023-03-07 | 上海翰森生物医药科技有限公司 | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives |
| CN110317194A (en) * | 2019-08-13 | 2019-10-11 | 滨州市鸿源工程有限公司 | A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand |
| CN112480083A (en) * | 2020-11-06 | 2021-03-12 | 上海应用技术大学 | AZD9291 derivative containing alkynyl and preparation method and application thereof |
| WO2022132046A1 (en) * | 2020-12-16 | 2022-06-23 | Scinopharm Taiwan, Ltd. | Improved process for preparing osimertinib or a salt thereof |
| US11780824B2 (en) | 2020-12-16 | 2023-10-10 | Scinopharm Taiwan, Ltd. | Process for preparing osimertinib or a salt thereof |
| CN112645934A (en) * | 2020-12-25 | 2021-04-13 | 中山奕安泰医药科技有限公司 | Ostinib intermediate and refining method thereof |
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