CN104817541B - A kind of synthetic method of antineoplastic - Google Patents
A kind of synthetic method of antineoplastic Download PDFInfo
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- CN104817541B CN104817541B CN201510236812.0A CN201510236812A CN104817541B CN 104817541 B CN104817541 B CN 104817541B CN 201510236812 A CN201510236812 A CN 201510236812A CN 104817541 B CN104817541 B CN 104817541B
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Abstract
The present invention relates to the synthetic method and its key intermediate of a kind of antineoplastic N [2 [[2 (dimethylamino) ethyl] methylamino] 4 methoxyl group 5 [[4 (base of 1 methyl 1H indoles 3) 2 pyrimidine radicals] amino] phenyl] 2 acrylamides (AZD9291),The nitroaniline of 4 fluorine, 2 methoxyl group 5 is obtained into the nitrobenzene amido t-butyl formate of 4 fluorine, 2 methoxyl group 5 through the protection of Boc acid anhydrides,Again with N,N,N ' trimethyl reacting ethylenediamines obtain 4 (N,N,N ' trimethyl ethylenediamines base) the nitrobenzene amido t-butyl formate of 2 methoxyl group 5,Then pass through reduction and obtain 2 (N,N,N ' trimethyl ethylenediamines base) the t-butyl carbamate aniline of 4 methoxyl group 5,Reacted with acryloyl chloride afterwards and directly taken off Boc protection groups and obtained the N of 2 methoxyl group 4,N,The acrylamido aniline of N ' trimethyl ethylenediamines base 5,Finally AZD9291 is obtained with the reaction of 3 (base of 2 chlorine pyrimidine 4) 1 methyl indols.The processing step is simple, and yield is higher, and reaction condition is gentle, it is easy to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of advanced lung cancer medicine N- [2- [[2- (dimethylamino) second
Base] methylamino] -4- methoxyl groups -5- [[4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- propylene
The preparation method of acid amides (AZD9291).
Background technology
Lung cancer is to be relatively difficult to one of tumour for capturing all the time.Classify by basic pathology, lung cancer is divided into non-small cell
Lung cancer and the major class of ED-SCLC two.Lung cancer is generally non-small cell lung cancer, and relative growth is slower, and squamous carcinoma can be subdivided into again
(squamouscell lung cancer), gland cancer (adenocarcinoma) and large cell carcinoma (large cell lung
cancer).In recent years, for carcinogenic gene mutation, many so-called targeting new drugs (targetedtherapy) constantly gush
It is existing.Compared with common chemotherapy, target medicine due to cancer cell of the main influence with corresponding mutation, side effect compared with
It is low, while efficient raise.Literature research shows that it is due to epidermal growth element acceptor to have a class in non-small cell lung cancer
(EGFR) caused by being mutated.With numerous same competition medicine phases ratios being mutated for EGFR, AZD9291 have one it is prominent excellent
Gesture：It can not only suppress carcinogenic EGFR mutation, while can also continue to suppress drug-fast EGFR mutation.Other EGFR suppress
Agent, such as gefitinib (AstraZeneca) and erlotinib (Genentech Genentech and Roche Group Roche),
It is capable of the lung cancer cell growth of the suppression with EGFR mutation of targeting.But unfortunately, these medicines of short duration can only all take effect,
Cancer cell would generally accordingly develop drug-fast mutation.In the case more than 60%, EGFR saltant type non-small cell lung cancers
Drug resistance mutations occur in EGFR sequences the 790th site, first propylhomoserin (T790M) is become by original threonine.This mutation
General EGFR inhibitor can be effectively obstructed to be had an effect with EGFR, so as to reach the purpose of the anti-medicine of cancer cell.But AZD9291
Will not be disturbed by EGFR T790M drug resistance mutations, still can continue to suppress the growth of cancer cell, be therefore particularly suitable for other
The middle and later periods patient of EGFR suppression therapies failure.
《Preparation of 2-(2,4,5-substituted-anilino)pyrimidine derivatives
as EGFR modulators useful for treating cancer》(WO201301444408) text is disclosed
The synthetic method of AZD9291, with the fluoro- 2- aminoanisoles of 4- as raw material, nitrification obtains the fluoro- 2- methoxyl groups -5- nitros of 4- first
Aniline, then reacted under the catalysis of p-methyl benzenesulfonic acid sulfuric monohydrate with 3- (2- chlorine pyrimidine-4-yl) -1- methyl indols and obtain N-
(the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine, afterwards N, N, N '-trimethyl second
Diamines nucleophilic displacement of fluorine fluorine atom, then nitro is reduced with iron ammonium, then elimination reaction is obtained again with the reaction of 3- chlorpromazine chlorides
AZD9291, the total recovery of reaction is 17.5%.Reaction equation is as follows：
The route reduces nitro using iron ammonium reducing process, and post-reaction treatment first has to spent ion exchange resin and carries out pre- place
Reason, makes AZD9291 industrialized productions become extremely difficult.
The content of the invention
Existing route is substituted the present invention seeks to find one, with simple to operate, yield is higher, and cost is relatively low, fits
The synthetic route for being suitable for the AZD9291 of industrialized production feature new.
Concrete technical scheme of the present invention is as follows：
A kind of N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl isophthalic acid H- Yin
Diindyl -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, comprise the following steps：
(1) the fluoro- 2- methoxyl groups -5- nitroanilines of 4- obtain the fluoro- 2- methoxyl groups -5- nitrobenzene of 4- after being protected through Boc acid anhydrides
The amidocarbonic acid tert-butyl ester：
Because the nucleophilicity of the fluoro- 2- methoxyl groups -5- nitroanilines of 4- is weaker, catalyst DMAP is preferably used
Or pyridine first forms reactive intermediate with di-tert-butyl dicarbonate (Boc acid anhydrides), then 2- methoxyl groups -5- nitre fluoro- with 4- again
There is the fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of 4- that nucleophilic substitution obtains single Boc protections in base aniline.
Reaction dissolvent preferably uses the one kind or several in dichloromethane, acetonitrile, 1,2- dichloroethanes, toluene in step (1)
Kind, preferable reaction temperature is 30~60 DEG C, and the reaction time is 4~10h.It is preferred that the fluoro- 2- methoxyl groups -5- nitroanilines of 4- and Boc
The mol ratio of acid anhydrides is 1.0:1.0~1.5.
(2) the fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of 4- and N, N, N that will be obtained in step (1) '-front three
Base reacting ethylenediamine obtains compound 4- (N, N, N '-trimethyl ethylenediamine base) -2- methoxyl group -5- nitrobenzene amidocarbonic acid uncles
Butyl ester：
Above-mentioned reaction is nucleophilic substitution, and reaction dissolvent must possess enough solvabilities, reaction can just sent out
It is raw, it is advantageous to aprotic polar solvent, more preferably DMF, dimethyl sulfoxide (DMSO), N, N- dimethylacetamides
One or more in amine, HMPA, 1,3- dimethyl-2-imidazolinones.
Because reaction has hydrofluoric acid to generate, add appropriate alkali (acid binding agent) that the carrying out of reaction can be promoted, it is preferably inorganic
Alkali or organic base, the inorganic base or organic base are selected from sodium carbonate, sodium acid carbonate, potassium carbonate, triethylamine, N, N- diisopropyls
One or more in ethamine.It is preferred that the fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of 4-, N, N, N '-trimethyl second two
Amine, the mol ratio of alkali are 1:1~1.2:1.2~1.8.
Above-mentioned reaction preferable temperature is 40~70 DEG C, and the reaction time is 1.5~8h.
(3) compound 4- (N, N, N '-trimethyl ethylenediamine the base) -2- methoxyl group -5- nitroanilines for obtaining step (2)
Base t-butyl formate obtains compound 2- (N, N, N '-trimethyl ethylenediamine base) -4- methoxyl group -5- amino first after reduction reaction
Tert-butyl acrylate aniline：
The above-mentioned preferred palladium carbon catalytic hydrogenating reduction of reduction reaction, preferable temperature is 15~30 DEG C, and the reaction time is 1~3h.
It is preferred that the consumption of palladium carbon is 4- (N, N, N '-trimethyl ethylenediamine base) -2- methoxyl group -5- nitrobenzene amido t-butyl formate weight
2%~10%.
In view of deliquescent factor, preferably react is carried out in alcohols solvent, more preferably methyl alcohol, ethanol, normal propyl alcohol, different
One or more in propyl alcohol.
(4) compound 2- (N, N, N '-trimethyl ethylenediamine the base) -4- methoxyl group -5- carbamic acids for obtaining step (3)
Tert-butyl ester aniline obtains compound 2- methoxyl groups -4-N, N, N after sloughing Boc protection groups after being reacted with acryloyl chloride '-trimethyl second
Two amido -5- acrylamido aniline：
Compound 2- in above-mentioned reaction (N, N, N '-trimethyl ethylenediamine base) -4- methoxyl group -5- t-butyl carbamate benzene
Amine first with acryloyl chloride reaction, slough Boc protection groups under the conditions of excess acid afterwards, preferably 2- (N, N, N '-trimethyl second
Two amidos) mole ratio of -4- methoxyl groups -5- t-butyl carbamates aniline and acryloyl chloride is 1:1.0~1.5.
It is preferred that by 2- (N, N, N '-trimethyl ethylenediamine base) -4- methoxyl group -5- t-butyl carbamate aniline under ice bath
Cyclic ether solvents are dissolved in, acryloyl chloride is added dropwise to, exothermic heat of reaction is stepped than very fast to reduce when due to acryloyl chloride is added dropwise
The generation of Ke Er addition reactions, preferably dropping temperature are 0~10 DEG C.5~30min is reacted after completion of dropping, 4N is subsequently adding
HCl (aq), reacts 2~12h at 15~35 DEG C, compound 2- methoxyl groups -4-N, N, N are obtained through in alkali and after extraction '-trimethyl
Ethylenediamine base -5- acrylamido aniline.
Above-mentioned cyclic ether solvents preferably are selected from tetrahydrofuran, 1,4- dioxane, 2- methylfurans, 1,3- dioxolanes
One or more.
(5) compound 2- methoxyl groups -4-N, N, N '-(2- chlorine is phonetic with 3- for trimethyl ethylenediamine base -5- acrylamidos aniline
Pyridine -4- bases) -1- methyl indols reaction obtain N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5-
[[4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides：
Because the chlorine reactivity of 2- in pyrimidine ring is relatively low, therefore acid is preferably used as activation of catalyst pyrimidine ring,
So that the nucleophilic substitution of aniline can be carried out, preferred acid is methanesulfonic acid, p-methyl benzenesulfonic acid, p-methyl benzenesulfonic acid monohydrate
In one or more.Preferable reaction temperature is 50~65 DEG C, and the reaction time is 3~8h.
The preferred alcohols solvent of reaction dissolvent, more preferably one kind from 2- amylalcohols, n-butanol, normal propyl alcohol, isobutanol or several
Kind.
Above-mentioned overall reaction route is as follows:
The invention also discloses three important intermediates in AZD9291 building-up processes, the fluoro- 2- methoxyl groups -5- nitros of 4-
Anilino- t-butyl formate, 4- (N, N, N '-trimethyl ethylenediamine base) -2- methoxyl group -5- nitrobenzene amido t-butyl formates and
2- methoxyl groups -4-N, N, N '-trimethyl ethylenediamine base -5- acrylamido aniline, structure is as follows：
The inventive method advantage：
(1) this route higher, total recovery 65.4% that often walks yield.Greatly improved compared to more former route yield, and
The reaction condition of novel synthesis is gentle, and post processing is simple, environmentally friendly；Step (5) reaction temperature is 50~65 DEG C, relatively
In 100~115 DEG C of the reaction of original route similar step, the temperature needed for reducing reaction has saved cost.
(2) using the method reduction nitro of palladium carbon catalytic hydrogenating reduction at normal temperatures in step (3) of the present invention, it is to avoid original
The method reduced using iron ammonium in route, avoids numerous and diverse operation of spent ion exchange resin post processing, increased yield, while
The high temperature requirement of reaction is reduced, cost is saved, is conducive to industrialized production.
Specific embodiment
Following embodiments are used to that the present invention to be explained further, but do not limit the scope of the invention.
Embodiment 1：The preparation of the fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of compound 4-
By the fluoro- 2- methoxyl groups -5- nitroanilines of 500mg (2.69mmol) 4-, 586.24mg (2.69mmol Boc acid anhydrides and
10ml acetonitriles are added in single port bottle, are warming up to 55 DEG C of reaction 6h, and vacuum rotary steam falls acetonitrile, add 5ml ethyl acetate dissolving body
System, is slowly added to 1ml petroleum ethers and separates out solid under stirring, filtering obtains yellow solid 639mg, yield 84%.
Embodiment 2：Compound 4- (N, N, N '-trimethyl ethylenediamine base) -2- methoxyl group -5- tertiary the fourths of nitrobenzene amidocarbonic acid
The preparation of ester
Under nitrogen/argon gas shielded, by 200mg (0.698mmol) 4- tertiary fourths of fluoro- 2- methoxyl groups -5- nitrobenzene amidocarbonic acids
Ester, 78.47mg (0.768mmol) N, N, N '-trimethyl ethylenediamines, 117.27mg (0.907mmol) DIPEA
And 10mlN, N- methylacetamide are added in 50ml single-necked flasks, 45 DEG C are warming up to, stirring reaction 2h is down to room temperature, added
40ml water, is extracted twice with 20ml dichloromethane, merges organic layer, uses saturated common salt water washing, is dried, and suction filtration is spin-dried for dichloro
Methane obtains 252mg bright orange solids, yield 98%.
Embodiment 3：Compound 2- (N, N, N '-trimethyl ethylenediamine base) -4- methoxyl group -5- t-butyl carbamate aniline
Preparation
Under nitrogen/argon gas shielded, by 500mg (1.3mmol) 4- (N, N, N '-trimethyl ethylenediamine base) -2- methoxyl groups -5-
Nitrobenzene amido t-butyl formate, 2.5mg palladium carbons, 50ml methyl alcohol is added in the single-necked flask of 100ml, and system is put with hydrogen
Change three times, stirring reaction 2h, one layer of diatomite of cushioning on filter paper, system filtering, are spin-dried for mother liquor at room temperature, obtain sepia oil
Shape thing 422.4mg, yield 96%.
Embodiment 4:Compound 2- methoxyl groups -4-N, N, N '-trimethyl ethylenediamine base -5- acrylamido aniline preparation
Under nitrogen/argon gas shielded, by 500mg (1.48mmol) 2- (N, N, N '-trimethyl ethylenediamine base) -4- methoxyl groups -
It is dissolved in 15ml Isosorbide-5-Nitraes-dioxane under 5- t-butyl carbamate aniline ice baths, is slowly added dropwise 147.08mg
The mixed solution of (1.63mmol) acryloyl chloride and 5ml Isosorbide-5-Nitraes-dioxane, control temperature is at 0~10 DEG C, and completion of dropping is follow-up
, be warmed to room temperature for temperature afterwards by continuous stirring 10min, and to 4ml 4N aqueous hydrochloric acid solutions are added in system, stirring 10h is after completion of the reaction
PH 7~9 is adjusted with saturated aqueous solution of sodium bicarbonate, is extracted with 20ml dichloromethane, saturated common salt water washing organic layer, dried, taken out
Filter, vacuum rotary steam falls dichloromethane, obtains the greyish white solid 384.5mg of foam-like, yield 89%.1H NMR(CDCl3-d6,
400MHz), 2.29 (br s, 8H), 2.67 (s, 1H), 2.89 (t, 2H, J=4.0Hz ,-CH2-), 3.78 (s, 2H), 3.83 (s,
3H), 2.89 (t, 1H, J=16.0Hz ,-CH=), 6.39 (d, J=2.4Hz, 2H ,=CH2), 6.68 (s, 1H), 7.98 (s,
1H), 10.03 (s, 1H)；13CNMR (100MHz, CDCl3)δ(ppm)：44.15,45.15,55.82,57.21,105.15,
107.14,125.86,129.96,132.31,132.36,133.89,143.59,163.39.MS(ES+)m/e(M+)293.2。
Embodiment 5：N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- methyl -
1H- indol-3-yls) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides preparation method
Under nitrogen/argon gas shielded, to addition 100mg (0.41mmol) 3- (2- chlorine pyrimidine-4-yl) -1- first in single-necked flask
Base indoles, 125.98mg (0.43mmol) 2- methoxyl groups -4-N, N, N '-trimethyl ethylenediamine base -5- acrylamido aniline,
76.32mg (0.44mmol) p-methyl benzenesulfonic acid and 5ml isobutanols, at 55 DEG C, stirring reaction 5h has solid to separate out to reaction temperature,
Suction filtration after room temperature is down to, filter cake is collected, filter cake is dissolved in 30ml water, neutrality is adjusted to saturated sodium bicarbonate aqueous solution, use 10ml
Dichloromethane is extracted twice, and merges organic layer, dries, and suction filtration, vacuum rotary steam falls dichloromethane and obtains faint yellow solid
190.5mg, yield 93%.1H NMR(CDCl3-d6, 400MHz), 2.30 (br s, 8H), 2.72 (s, 1H), 2.92 (t, 2H, J
=5.2Hz), 3.90 (s, 3H), 4.02 (s, 3H), 5.73 (t, 1H, J=6.0Hz), 6.47 (d, 2H, J=14.0Hz), 6.81
(s, 1H), 7.22 (d, 2H, J=5.2Hz), 7.27-7.32 (m, 2H), 7.41-7.43 (m, 1H), 7.75 (s, 1H), 8.08 (d,
1H, J=8.8Hz), 8.40 (d, 1H, J=5.2Hz), 9.12 (s, 1H), 9.87 (s, 1H), 10.19 (s, 1H).MS(ES+)m/
e(M+)500.3。
Claims (9)
1. a kind of antineoplastic N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- first
Base -1H- indol-3-yls) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that including as follows
Step：
（1）The fluoro- 2- methoxyl groups -5- nitroanilines of 4- obtain the fluoro- 2- methoxyl groups -5- nitrobenzene amidos of 4- after being protected through Boc acid anhydrides
T-butyl formate；
（2）Step（1）The fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of resulting 4- and N, N, N '-trimethyl second two
Amine reaction obtains compound 4-（N, N, N '-trimethyl ethylenediamine base）- 2- methoxyl group -5- nitrobenzene amido t-butyl formates；
（3）Step（2）Resulting 4-（N, N, N '-trimethyl ethylenediamine base）- 2- methoxyl group -5- tertiary the fourths of nitrobenzene amidocarbonic acid
Ester obtains compound 2- through reduction reaction（N, N, N '-trimethyl ethylenediamine base）- 4- methoxyl group -5- t-butyl carbamate benzene
Amine；
（4）Step（3）Resulting 2-（N, N, N '-trimethyl ethylenediamine base）- 4- methoxyl group -5- t-butyl carbamate aniline
Compound 2- methoxyl group -4- N, N, N are obtained with Boc protection groups are taken off after acryloyl chloride reaction '-trimethyl ethylenediamine base -5- propylene
Amide groups aniline；
（5）Step（4）Resulting 2- methoxyl group -4- N, N, N '-trimethyl ethylenediamine base -5- acrylamidos aniline and 3-
（2- chlorine pyrimidine-4-yls）The reaction of -1- methyl indols obtains N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxies
Base -5- [[4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides.
2. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（1）
The carrying out reacted using catalyst, the catalyst is DMAP or pyridine.
3. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（1）
Middle reaction dissolvent is one or more in dichloromethane, acetonitrile, 1,2- dichloroethanes, toluene.
4. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（2）
The middle fluoro- 2- methoxyl groups -5- nitrobenzene amido t-butyl formates of 4- and N, N, N '-trimethyl ethylenediamine carries out instead in the basic conditions
Should.
5. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（2）
Middle reaction dissolvent is N,N-dimethylformamide, dimethyl sulfoxide (DMSO), DMAC N,N' dimethyl acetamide, HMPA, 1,3-
One or more in dimethyl-2-imidazolinone.
6. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（3）
Described in reduction reaction be that using palladium carbon catalytic hydrogenating reduction, the consumption of the palladium carbon is 4-（N, N, N '-trimethyl ethylenediamine
Base）The 2% ~ 10% of -2- methoxyl group -5- nitrobenzene amido t-butyl formate weight.
7. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（4）
Middle 2-（N, N, N '-trimethyl ethylenediamine base）- 4- methoxyl groups -5- t-butyl carbamates aniline is molten with acryloyl chloride reaction
Carried out in one or more in agent tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, 2- methylfurans, 1,3- dioxolanes, take off Boc protections
Base is to carry out in acid condition.
8. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（5）
Reacted using catalyst, the catalyst is p-methyl benzenesulfonic acid, p-methyl benzenesulfonic acid monohydrate or methanesulfonic acid.
9. N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- according to claim 1
Methyl-1H-indole -3- bases) -2- pyrimidine radicals] amino] phenyl] -2- acrylamides synthetic method, it is characterised in that step（5）
Reaction dissolvent be one or more in 2- amylalcohols, n-butanol, isobutanol.
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| CN108129342A (en) * | 2016-11-30 | 2018-06-08 | 浙江九洲药物科技有限公司 | It is a kind of difficult to understand uncommon for Buddhist nun's intermediate and preparation method thereof |
| CN106883216B (en) * | 2017-04-06 | 2020-03-13 | 张家港威胜生物医药有限公司 | Preparation method of oxitinib |
| WO2018207120A1 (en) * | 2017-05-11 | 2018-11-15 | Aurobindo Pharma Limited | A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline |
| CN108218839A (en) * | 2018-03-20 | 2018-06-29 | 上药康丽（常州）药业有限公司 | A kind of preparation method of antitumor drug AZD9291 |
| CN111057073A (en) * | 2019-12-26 | 2020-04-24 | 浙江工业大学 | 4-indole-2-arylamino pyrimidine compound and application thereof in inflammation treatment |
| CN112341346B (en) * | 2020-10-30 | 2024-03-08 | 烟台舜康生物科技有限公司 | Synthesis method of Orientinib intermediate |
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