CN107216313B - A kind of preparation method of anti-tumor drug AZD9291 - Google Patents
A kind of preparation method of anti-tumor drug AZD9291 Download PDFInfo
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Abstract
The invention discloses the preparation methods of anti-tumor drug AZD9291 a kind of.This method are as follows: the fluoro- 2- methoxyl group -5- nitroaniline of 4- is reacted to obtain intermediate 1 with 3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol;Intermediate 1 and N, N, N '-trimethyl reacting ethylenediamine obtain compound intermediate 2;The hydrogenated reduction reaction of intermediate 2 obtains compound intermediate 3, and intermediate 3 further introduces acryloyl group and generates AZD9291, characterized in that activator cuprous bromide is added in the preparation process of intermediate 2;The hydro-reduction of intermediate 3 is palladium carbon catalytic hydrogenating reduction, and the acryloyl group of AZD9291 is introduced as the mixed anhydride solution of acrylic acid.This method is effectively reduced the generation of solid waste, and improves product purity and yield.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of anti-tumor drug AZD9291.
Background technique
Lung cancer is one of most common malignant tumour in the world, it has also become China's urban population Death Cause for Malignant Tumors
1st.Non-small cell type lung cancer includes squamous cell carcinoma (squamous carcinoma), gland cancer, large cell carcinoma, its cancer cell compared with small cell carcinoma
Growth division is slower, and diffusion transfer is relatively late.Non-small cell lung cancer accounts for about the 80% of all lung cancer, about 75% Finding case
When be in middle and advanced stage, survival rate is very low within 5 years.In recent years, it for carcinogenic gene mutation, is constantly asked there are many targeting new drug
Generation.Compared with traditional chemotherapy, target medicine is mainly influenced with the cancer cell being accordingly mutated, and side effect is lower, has
Efficiency increases.Literature research shows that having one kind in non-small cell lung cancer is since epidermal growth element receptor (EGFR) is mutated
It is caused.
AZD9291 (Osimertinib) Chinese: is stepped auspicious for Buddhist nun, chemical name: N- [2- [[2- (dimethylamino)
Ethyl] methylamino] -4- methoxyl group -5- [[4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] amino] phenyl] -2- third
Acrylamide;Molecular formula C28H33N7O2·CH4O3S, structural formula are as follows.It was researched and developed by Astrazeneca AB, Britain, in 2015 11
The moon 13 listed in the U.S., trade name Tagasso, for treating the advanced stage of EGF-R ELISA (EGFR) T790M mutation
Patients with Non-small-cell Lung.
Compared with numerous similar competition medicines for EGFR mutation, AZD9291 has an outstanding advantage, it can not only press down
Carcinogenic EGFR mutation is made, and can continue to inhibit the EGFR mutation of drug resistance.Other EGFR inhibitors, such as
Gefitinib (AstraZeneca) and erlotinib (Genentech Genentech and Roche Group Roche), can also target
Property inhibition there is the growth of cancer cells of EGFR mutation, but these drugs of short duration can only all take effect, and cancer cell would generally develop
The mutation of drug resistance.In the case more than 60%, the drug-resistant mutation of EGFR saltant type non-small cell lung cancer occurs in EGFR
The 790th site in sequence becomes first propylhomoserin (T790M) by original threonine.This mutation can effectively obstruct general
EGFR inhibitor and EGFR are acted on, to achieve the purpose that the anti-medicine of cancer cell.But the interference that AZD9291 will not be mutated by EGFR,
It can continue to inhibit growth of cancer cells, be therefore particularly suitable for the middle and advanced stage patient of other EGFR inhibition from mutation agent treatment failures.
The synthetic route of AZD9291 mainly includes the following three types at present:
Synthetic route 1:WO2013014448 patent discloses the synthetic method of AZD9291, and reaction equation is as follows:
A large amount of iron cement solid waste are generated using sideramines reduction in the synthetic route, acryloyl group is introduced and uses acryloyl
Chlorine or 3- chlorpromazine chloride, intermediate N (2- dimethylarnino-ethyl) -2- methoxy-. N-methyl-N- [4- (1- methyl-1 H-
Indol-3-yl)-pyrimidine -2-base] -5- amino-benzene-multiple the sites of Isosorbide-5-Nitrae-diamines can react, and by-product is more, it is more difficult to pure
Change.
Synthetic route 2:CN104817541A patent discloses another AZD9291 synthetic method, and reaction equation is such as
Under:
The route introduces blocking group protection amino, increases reaction step, also increases AZD9291 industrialized production
Cost.
Synthetic route 3:CN104910049A discloses another synthetic method, and reaction equation is as follows:
The synthetic route is longer, and total recovery is lower, is unsuitable for industrialized production.
Summary of the invention
The purpose of the invention is to overcome above-mentioned the deficiencies in the prior art, on the basis of patent WO2013014448,
Process optimization has been carried out, activator cuprous bromide is wherein added in the preparation process of intermediate 2;The also reason sideramines of intermediate 3
Reduction method is changed to palladium carbon catalytic hydrogenating reduction, and the acryloyl group of AZD9291, which is introduced, is changed to third by acryloyl chloride or 3- chlorpromazine chloride
The mixed anhydride solution of olefin(e) acid, is effectively reduced the generation of solid waste, and improves product purity and yield.
The technical scheme is that a kind of preparation method of anti-tumor drug AZD9291, characterized in that
1) 3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol (SM1) and the fluoro- 2- methoxyl group -5- nitroaniline (SM2) of 4- into
Row reaction obtains intermediate 1: i.e. N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- Methyl-1H-indole -3- base)-phonetic
Pyridine -2- amine;
2) intermediate 1 and N, N, N '-trimethyl ethylenediamine are reacted to obtain intermediate 2, i.e. N- (2- dimethylamino-
Ethyl) -2- methoxy-. N-methyl-N- [4- (1- Methyl-1H-indole -3- base)-pyrimidine -2-base] -5- nitro-benzene -1,4- two
Amine;
3) the hydrogenated reduction reaction of intermediate 2 obtains intermediate 3, i.e. N- (2- dimethylarnino-ethyl) -2- methoxyl group -
N- methyl-N- [4- (1- Methyl-1H-indole -3- base)-pyrimidine -2-base] -5- amino-benzene -1,4- diamines;
4) intermediate 3 further introduces acryloyl group and generates AZD9291;
It is characterized in that the step 4) are as follows: intermediate 3 is reacted to obtain product with the mixed anhydride solution of acrylic acid
AZD9291。
Wherein, the mixed anhydride solution of acrylic acid the preparation method comprises the following steps: acyl chlorides and inorganic base are added in solvent, 0 DEG C~10
Acrylic acid is added under DEG C stirring, obtains the mixed anhydride solution of acrylic acid.The acyl chlorides is pivaloyl chloride, to Methyl benzenesulfonyl
At least one of chlorine, benzene sulfonyl chloride, mesyl chloride.The inorganic base is potassium carbonate, cesium carbonate, at least one in lithium carbonate
Kind.The solvent is at least one of acetonitrile, methyl tertiary butyl ether(MTBE), 1,4- dioxane.The acrylic acid, acyl chlorides with it is inorganic
The molar ratio of alkali is 1:1.0~1.2:1.0~1.5.
Further, it is additionally added fluorine of the cuprous bromide as activation of catalyst intermediate 1 in the step 2), promotes N, N,
The nucleophilic substitution of N '-trimethyl ethylenediamine improves the speed and yield of reaction;Cuprous bromide dosage is 1 weight of intermediate
1.5-2.5%.
Further, the hydro-reduction of the step 3) is palladium carbon catalytic hydrogenating reduction, and the dosage of palladium carbon is 2 weight of intermediate
The 2%~10% of amount.
Reaction dissolvent is preferably one in 2- amylalcohol, n-butanol, isobutanol and 1,4- dioxane in step 1) of the present invention
Kind is several.Preferable reaction temperature is 60 DEG C~110 DEG C, and the reaction time is 2h~6h.SM1 and SM2 molar ratio are preferably 1.0:
1.0~1.5.Since the 2- chlorine reactivity in pyrimidine ring reduces, acid is added and is used as activation of catalyst pyrimidine ring, to make
The nucleophilic substitution of aniline is able to carry out, and preferred acid is one of methanesulfonic acid, p-methyl benzenesulfonic acid, a hydration p-methyl benzenesulfonic acid
Or it is several, the molar ratio of it and SM1 are 2~2.5:1.
Reaction dissolvent is preferably N,N-dimethylformamide, dimethyl sulfoxide, N, N- dimethyl second in step 2) of the present invention
One or more of amide.This step reaction is nucleophilic substitution, and reaction has hydrofluoric acid generation, also needs that suitable alkali work is added
Promote the progress of reaction, preferably inorganic base or organic base for acid binding agent, inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate
One or more of;Organic base is selected from triethylamine, N, one or more of N- diisopropylethylamine.Intermediate 1, N, N,
The molar ratio of N '-trimethyl ethylenediamine and alkali is 1.0:1.0~1.2:1.2~2.0.Preferable reaction temperature is 90 DEG C~110 DEG C,
Reaction time is 2~8h.
Reaction dissolvent is preferably one or more of methanol, ethyl alcohol, isopropanol in step 3) of the present invention.It is preferred that reaction temperature
Degree is 15 DEG C~40 DEG C, and 2h~4h is reacted under normal pressure.
Reaction temperature is -10 DEG C~15 DEG C in step 4) of the present invention.The molar ratio of preferred intermediate 3 and acrylic acid is 1:
2~2.5.
Preferred embodiment of the invention is as follows:
1) preparation of intermediate 1
SM1, SM2 and a water p-methyl benzenesulfonic acid are added in isobutanol, reflux is warming up to, reacts 4~6h, has yellow solid
Body is precipitated, and is down to room temperature, is filtered, washed, is dried to obtain yellow solid intermediate 1;
2) preparation of intermediate 2
By intermediate 1, N, N, N '-trimethyl ethylenediamine and N, N- diisopropylethylamine are added to N,N-dimethylformamide
In, 95~105 DEG C of 4~6h of reaction are warming up to, room temperature is down to, elutriation is added and goes out solid, are obtained after filtering, washing, drying intermediate
Body 2;
Further, above-mentioned steps are additionally added cuprous bromide, and 2~4h of reaction time is cooled to room temperature and is filtered to remove bromine
Change cuprous;
3) preparation of intermediate 3
In nitrogen protection, intermediate 2 and palladium carbon are added in methanol, are passed through hydrogen 3~5h of synthesis under normal pressure, is filtered, filter
Liquid is concentrated to dryness, and obtains intermediate 3;
4) preparation of AZD9291
It will be reacted in mixed anhydride solution that intermediate 3 is added to acrylic acid at 0 DEG C;Water is added after fully reacting to terminate instead
It answers, through extraction, drying, concentration, after recrystallized from acetonitrile, obtains product AZD9291.
Beneficial effects of the present invention: the processing step is simple, easy to operate, and the solid waste of generation is few, easy to industrialized production,
Obtained product purity is higher (up to 99.8%), total recovery height (up to 72%).
Detailed description of the invention
Fig. 1 is AZD9291's prepared by present example 31H NMR figure;
Fig. 2 is AZD9291's prepared by present example 313C NMR figure;
The IR figure that Fig. 3 is AZD9291 prepared by present example 3;
Fig. 4 is the mass spectrogram of AZD9291 prepared by present example 3;
Fig. 5 is the HPLC map of AZD9291 prepared by present example 3;
Fig. 6 is the HPLC map of AZD9291 prepared by comparative example 2.
Specific embodiment
Following embodiments are not limited the scope of the invention for the present invention to be explained further.
Embodiment 1: the preparation of compound intermediate 1 to intermediate 3
1) preparation of intermediate 1:
By 40g (0.164mol) SM1,30.6g (0.164mol) SM2 and 62.3g (0.328mol) water p-methyl benzenesulfonic acid
It is added in 200ml isobutanol, is warming up to reflux, react 6h, have yellow solid precipitation, be down to room temperature, filter, isopropanol is washed
It washs, 50 DEG C are dried in vacuo to obtain 54.8g yellow solid, yield 85.0%.
2) preparation of intermediate 2:
Method 1: by 50g (0.127mol) intermediate 1,15.0g (0.147mol) N, N, N '-trimethyl ethylenediamine, 1g bromine
Change cuprous and 19.65g (0.152mol) n,N-diisopropylethylamine to be added in 350ml n,N-Dimethylformamide, rise to
100 DEG C of reaction 3h are down to room temperature and are filtered to remove cuprous bromide, 80ml water is added, have a large amount of solids to be precipitated, filter, washing, and 45 DEG C
It is dried in vacuo to obtain 57.2g Chinese red solid, yield 94.9%.
Method 2: by 50g (0.127mol) intermediate 1,15.0g (0.147mol) N, N, N '-trimethyl ethylenediamine and
19.65g (0.152mol) n,N-diisopropylethylamine is added in 350ml n,N-Dimethylformamide, rises to 100 DEG C of reactions
5h, is down to room temperature, and 80ml water is added, and has a large amount of solids to be precipitated, and filters, washing, 45 DEG C be dried in vacuo 50.7g Chinese red is solid
Body, yield 84.0%.
3) preparation of intermediate 3:
In nitrogen protection, 28.5 (0.060mol) intermediates 2,2.5g palladium carbon are added in 500ml methanol, led at 25 DEG C
Enter hydrogen synthesis under normal pressure 4h, filter, filtrate decompression is concentrated to dryness, and obtains 26g brown solid, yield 97.3%.
The synthesis of embodiment 2:AZD9291
Pivaloyl chloride 3.37g (28mmol), potassium carbonate 4.13g (30mmol) are added in 60ml Isosorbide-5-Nitrae-dioxane, In
0 DEG C is added to acrylic acid 2.02g (28mmol) in above-mentioned solution, stirs 1h, is made mixed anhydride solution, in the preparation of embodiment 1
Mesosome 3 is that 6.17g (13.8mmol) is added in mixed anhydride solution at 0 DEG C, and TLC monitors raw material and disappears.Water is added and stirs 0.5h, uses
Ethyl acetate 100ml extraction after organic phase anhydrous sodium sulfate is dry, is filtered, and it is thick to obtain AZD9291 for vacuum concentration at 45 DEG C of filtrate
Product.With 50ml recrystallized from acetonitrile, brown solid 6.29g is obtained;Yield 91.3%, purity 99.8%.
The preparation of intermediate 2 is with the calculating of method 1, and the total recovery of product is with 71.7%.The preparation of intermediate 2 is in terms of method 2
It calculates, the total recovery of product is with 63.2%.
The synthesis of embodiment 3:AZD9291
Mesyl chloride 3.2g (28mmol), lithium carbonate 2.22g (30mmol) are added in 100ml acetonitrile, are stirred at 10 DEG C,
Acrylic acid 2.02g (28mmol) is added in above-mentioned solution, 1.5h is stirred, intermediate 3 prepared by embodiment 1 is 6.17g
(13.8mmol) is added in mixed anhydride solution at 0 DEG C, and TLC monitors raw material and disappears.Water is added and stirs 1h, ethyl acetate 100ml extraction
It takes, after organic phase anhydrous sodium sulfate is dry, filters, vacuum concentration obtains AZD9291 crude product at 45 DEG C of filtrate.With 50ml acetonitrile weight
Crystallization, obtains brown solid 6.35g, yield 92.2%, purity 99.8%, and HPLC map is as shown in Figure 5.The preparation of intermediate 2
With the calculating of method 1, the total recovery of product is with 72.4%.The preparation of intermediate 2 with the calculating of method 2, the total recovery of product with
63.8%.
Its1H NMR、13C-NMR, IR and ESI-MS map difference are as shown in Figs 1-4, and specific data are as follows.
1H NMR (400MHz, D2O) δ ppm:2.39 (s, 1H), 2.64 (s, 6H), 2.70 (s, 3H), 3.01 (d, 7H),
3.69 (s, 1H), 5.74 (d, 1H), 6.07-6.16 (m, 2H), 6.33-6.39 (m, 1H), 6.68 (s, 2H), 6.74-6.85 (m,
2H), 7.18 (br, 1H), 7.31-7.38 (m, 2H), 8.11 (s, 1H).
(100MHz,D2O): 32.30,38.50,42.63,49.30,54.64,56.10,104.17,106.84,
110.02,111.99,116.02,120.55,121.11,122.07,123.70,124.76,124.93,128.47,130.35,
133.99,137.47,139.29,147.13,153.69,156.87,162.27,166.07.
IR(ATR,cm-1) m/z:3244.25 (vNH), 2932.57 (vCH), 1671.97 (C=H).
ESI-MS:m/z 500.3 [M+H]﹢。
Following comparative examples verify the experimental method the last two steps of route 1, WO2013014448 report.
Comparative example 1: the preparation of intermediate 3
Intermediate 2 prepared by 22g embodiment 1,15.5g iron powder and 1.7g ammonium chloride are added to 240ml ethyl alcohol and 80ml
In the mixed system of water, it is heated to reflux 2h, is cooled to 40 DEG C, filtering removes insoluble matter, is concentrated in vacuo to dry, mistake at 45 DEG C of filtrate
Column purification obtains 17g solid, yield 82.5%.
The synthesis of comparison example 2:AZD9291:
The methylene chloride 100ml solution of acryloyl chloride 3.45g (38mmol) is added drop-wise to the comparative example 1 in ice-water bath cooling
The intermediate 3 of preparation is the methylene chloride 250ml solution of 17g (38mmol) and N, N- diisopropylethylamine 7.2ml (42mmol)
In, stir 1.5h.Then it is diluted, is washed with 2 × 250ml of saturated sodium bicarbonate solution, water layer dichloro with methylene chloride 250ml
Methane extracts 2 times, merges organic phase, and anhydrous magnesium sulfate dries, filters, 40 DEG C of filtrate vacuum concentrations.Crude product crosses column purification, obtains
16.01g brown solid, yield 83.0%, purity 99.3%.
The synthesis of comparison example 3:AZD9291:
The intermediate 3 prepared at 0 DEG C to comparative example 1 is the mixing of 10g (22.4mmol) in THF 95ml and water 9.5ml
3- chlorpromazine chloride 3.28g (25.59mmol) is added dropwise in solution, after dripping off, is warmed to room temperature stirring 15min, sodium hydroxide is added
System is warming up to 65 DEG C of heat preservation 10h by 3.48g (85.28mmol).It is cooled to room temperature, methanol 40ml and water 70ml, room temperature is added
It is stirred overnight, filters, be washed to neutrality, 50 DEG C of vacuum drying obtain 9.50g solid AZD9291, yield 85.0%, purity
99.0%.
Embodiment according to the present invention 1~3, the AZD9291 for purity >=99.7% that the present invention obtains.According to route 1, obtain
Purity >=99.0% of the AZD9291 arrived, and have the generation of iron cement solid waste.It can be seen that the solid waste of generation is few using route of the invention,
Product purity and yield significantly improve.Simultaneously from the preparation of intermediate 2 it is also seen that: use cuprous bromide activated intermediate 1
Promote nucleophilic substitution to carry out, improve the speed and yield of reaction, the reaction time shortens 2 hours, and yield improves >=10%.
Claims (9)
1. a kind of preparation method of anti-tumor drug AZD9291, comprising the following steps:
1) 3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol and the fluoro- 2- methoxyl group -5- nitroaniline of 4- are reacted to obtain centre
Body 1;
2) intermediate 1 and N, N, N '-trimethyl ethylenediamine are reacted to obtain intermediate 2;
3) the hydrogenated reduction reaction of intermediate 2 obtains intermediate 3;
4) intermediate 3 further introduces acryloyl group and generates AZD9291;
It is characterized in that
Addition cuprous bromide is as activation of catalyst intermediate 1 in the step 2), using n,N-diisopropylethylamine as acid binding agent,
N,N-Dimethylformamide is reaction dissolvent, and reaction temperature is 90 DEG C~110 DEG C;
The hydro-reduction of the step 3) is palladium carbon catalytic hydrogenating reduction;
The step 4) are as follows: acyl chlorides and inorganic base are added in solvent, acrylic acid is added under 0 DEG C~10 DEG C stirrings, obtains
To the mixed anhydride solution of acrylic acid;Then intermediate 3 react with the mixed anhydride solution of acrylic acid and introduce acryloyl group generation
AZD9291, reaction temperature are -10 DEG C~15 DEG C;
Wherein, intermediate 1 isIntermediate 2 is
Intermediate 3 isAZD9291 is
2. a kind of preparation method of anti-tumor drug AZD9291 as described in claim 1, characterized in that described in step 4)
Acyl chlorides is at least one of pivaloyl chloride, p-methyl benzene sulfonic chloride, benzene sulfonyl chloride, mesyl chloride;The inorganic base is carbonic acid
At least one of potassium, cesium carbonate, lithium carbonate;The solvent be acetonitrile, methyl tertiary butyl ether(MTBE), in 1,4- dioxane at least
It is a kind of;The molar ratio of the acrylic acid, acyl chlorides and inorganic base is 1.0:1.0~1.2:1.0~1.5.
3. a kind of preparation method of anti-tumor drug AZD9291 as described in claim 1, characterized in that in the step 1)
Acid is additionally added as activation of catalyst 3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol, it and 3- (the chloro- pyrimidine-4-yl of 2-) -1-
The molar ratio of methyl indol is 2.0~2.5:1;It is described acid be methanesulfonic acid, p-methyl benzenesulfonic acid, one hydration p-methyl benzenesulfonic acid in extremely
Few one kind.
4. a kind of preparation method of anti-tumor drug AZD9291 as described in claim 1, characterized in that the step 3) palladium
The dosage of carbon is the 2%~10% of 2 weight of intermediate.
5. the preparation method of anti-tumor drug AZD9291 as described in any one of claim 1-4 a kind of, characterized in that
Cuprous bromide dosage is the 1.5-2.5% of 1 weight of intermediate in the step 2).
6. the preparation method of anti-tumor drug AZD9291 as described in any one of claim 1-4 a kind of, characterized in that
Reaction dissolvent is at least one of 2- amylalcohol, n-butanol, isobutanol and 1,4- dioxane in the step 1);The reaction
Temperature is 60 DEG C~110 DEG C, and the reaction time is 2h~6h;3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol and the fluoro- 2- methoxy of 4-
The molar ratio of base -5- nitroaniline is 1.0:1.0~1.5.
7. the preparation method of anti-tumor drug AZD9291 as described in any one of claim 1-4 a kind of, characterized in that
The molar ratio of intermediate 1, N in the step 2), N, N '-trimethyl ethylenediamine and N, N- diisopropylethylamine be 1.0:1.0~
1.2:1.2~2.0.
8. the preparation method of anti-tumor drug AZD9291 as described in any one of claim 1-4 a kind of, characterized in that
The molar ratio of intermediate 3 and acrylic acid is 1:2~2.5 in the step 4).
9. the preparation method of anti-tumor drug AZD9291 as described in any one of claim 1-4 a kind of, characterized in that
The following steps are included:
1) preparation of intermediate 1
By 3- (the chloro- pyrimidine-4-yl of 2-) -1- methyl indol, the fluoro- 2- methoxyl group -5- nitroaniline of 4- and a water p-methyl benzenesulfonic acid
It is added in isobutanol, is warming up to reflux, react 4~6h, have solid precipitation, be down to room temperature, be filtered, washed, be dried to obtain Huang
Color solid intermediate 1;
2) preparation of intermediate 2
By intermediate 1, N, N, N '-trimethyl ethylenediamine, n,N-diisopropylethylamine and cuprous bromide are added to N, N- dimethyl
In formamide, 95~105 DEG C of 2~4h of reaction are warming up to, is cooled to room temperature and is filtered to remove cuprous bromide;Elutriation is added and goes out solid,
Intermediate 2 is obtained after filtering, washing, drying;
3) preparation of intermediate 3
In nitrogen protection, intermediate 2, palladium carbon and methanol are added in reaction flask, synthesis under normal pressure 3 at 15 DEG C~40 DEG C of hydrogen is passed through
~5h, filtering, filtrate decompression are concentrated to dryness, and obtain intermediate 3;
4) preparation of AZD9291
It will be reacted in mixed anhydride solution that intermediate 3 is added to acrylic acid at 0 DEG C;Water is added after fully reacting and terminates reaction,
Through extraction, drying, concentration, after recrystallized from acetonitrile, product AZD9291 is obtained.
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