CN105503835B - A kind of novel quinazoline quinoline derivant LU1510 and its preparation method and application - Google Patents
A kind of novel quinazoline quinoline derivant LU1510 and its preparation method and application Download PDFInfo
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of novel quinazoline quinoline derivant LU1510 and preparation method thereof, its chemical name is 4 amine of N 4 [(4 dimethylamino phenyl) methoxyl group] phenyl 7 methoxyl group 6 [(1 pyrroles, 2 base) ethoxy] quinazoline.Quinazoline derivant and its pharmaceutically acceptable salt, the solvate and hydrate of the present invention has outstanding antitumor In vitro and in vivo activity to MCF 7, SK BR 3, MDA MB 468, U 87MG, has preferable application prospect on antitumor drug is prepared.
Description
Technical field
The invention belongs to biomedicine field, more particularly to a kind of novel quinazoline quinoline derivant LU1510 and its preparation side
Method and application.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, in the past 20 years, China's tumor mortality
Rate rises 29.42%.In the middle prime of life crowd of 35 to 59 years old, tumour, which has arranged, to be occupied first of all kinds of causes of the death.It data show：I
State's tumor incidence is about 2,00/,100,000 people, more than about 2,200,000 people of annual new cases, is controlling more than about 6,000,000 people of patient.It is swollen
The treatment method of knurl has operative treatment, radiotherapy and chemotherapy.At present, chemotherapy is still the master of clinical treatment tumour
Want means.Seeking antitumor medicine is one of hot spot of new drug research.In recent years, 4- amino-quinazoline compounds are because having
Excellent bioactivity, enjoys the extensive concern of people, becomes biological educational circles and hot spot that region of chemistry scholars study.They are right
EGF receptor or pdgf receptor tyrosine kinase produce good inhibiting effect, show with anti-lung cancer, stomach cancer, colon cancer, breast
The effects such as the effect of gland cancer, gallbladder cancer and prostate cancer etc., antibacterial, AntiHIV1 RT activity, anti-inflammatory, treatment diabetes, such as Gefitinib, strategic point
Lip river is for marketed drugs such as Buddhist nun, xylene monosulfonic acid Lapatinibs.Inventor's discovery, N-4- [(4- dimethylamino phenyls) methoxyl group] benzene
Base -7- methoxyl groups -6- [(1- pyrroles -2- bases) ethoxy] quinazoline -4- amine has certain antitumor activity, and inventor proposes and N-
4- [(4- dimethylamino phenyls) methoxyl group] phenyl -7- methoxyl groups -6- [(1- pyrroles -2- bases) ethoxy] quinazoline -4- amine or
The pharmaceutically acceptable salt of person's compound, solvate either prodrug or stereoisomer or dynamic isomer
Or the relevant invention of metabolin.
The content of the invention
Goal of the invention：To solve problems of the prior art, the present invention provides a kind of novel quinazoline quinoline derivant
LU1510, its chemical name are N-4- [(4- dimethylamino phenyls) methoxyl group] phenyl -7- methoxyl groups -6- [(1- pyrroles -2- bases)
Ethoxy] quinazoline -4- amine, it has suppression to tetra- plants of tumor cell proliferations of MCF-7, SK-BR-3, MDA-MB-468, U-87MG
System activity.
Technical solution：To realize above-mentioned technical purpose, the present invention provides a kind of novel quinazoline quinoline derivant LU1510, its
Chemical name is N-4- [(4- dimethylamino phenyls) methoxyl group] phenyl -7- methoxyl groups -6- [(1- pyrroles -2- bases) ethoxy] quinoline
Oxazoline -4- amine, its structural formula are as follows：
Present invention further proposes the preparation method of above-mentioned novel quinazoline quinoline derivant LU1510, include the following steps：
S1：Under nitrogen protection, pyrroles is dissolved in tetrahydrofuran, EtMgBr diethyl ether solutions is slowly added dropwise under ice bath, stir
Mix 30 minutes~2 it is small when, when 0~60 DEG C of reaction solution stirring 30 minutes~2 is small, 0~60 DEG C adds methyl bromoacetate and stirs 30 points
When clock~2 are small, compound (1), i.e. 2- (1- pyrroles -2- bases) acetic acid esters are generated；
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, is added portionwise while stirring under ice bath
LiAlH4More than 30 minutes, obtain reduzate compound (2), i.e. 2- (1- pyrroles -2- bases) ethanol；
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrochysene
Furans, is added portionwise DTAD while stirring under ice bath, when reaction 6 is small more than, generate compound (3), the i.e. chloro- 7- methoxies of 4-
Base -6- [2- (1- pyrroles -2- bases) ethoxy] quinazoline；
S4：4- dimethylaminobenzaldehydes are dissolved in tetrahydrofuran, 0~25 DEG C is added portionwise sodium borohydride, stirring reaction 4~
12 it is small when, generate compound (4), i.e. 4- dimethylaminos phenmethylol；
S5：By compound (4), dissolved with DMF, add NaH, when 25~100 DEG C of stirrings 1~6 are small, 0~25 DEG C adds in batches
Enter the fluoro- 4- nitrobenzenes generation compounds (5) of 1-, i.e. N, N- dimethyl -4- (4- nitre phenyl methyl) aniline；
S6：Compound (5) is dissolved in tetrahydrofuran, Raney's nickel is added portionwise, is passed through hydrogen, 25~60 DEG C of stirring reactions 4
~12 it is small when, generate compound (6), i.e. 4- [(4- dimethylaminos) phenyl] aminoanisole；
S7：By compound (3) with n-Butanol soluble, compound (6) is added, when 25~100 DEG C of stirrings 1~6 are small, generationization
Compound (7), i.e. N-4- [(4- dimethylamino phenyls) methoxyl group] phenyl -7- methoxyl groups -6- [(1- pyrroles -2- bases) ethoxy] quinoline
Oxazoline -4- amine.
Preferably, in step S1, the concentration of EtMgBr diethyl ether solutions is 3M, and drop speed is 5~10ml/min, EtMgBr second
Ether, methyl bromoacetate, tetrahydrofuran, the amount ratio of pyrroles are 100~500mL：20~50g：250~1000ml：20~50g.
In step S2, LiAlH4Dosage be per g of compound (1) add 0.25~2g.
In step S3, the DTAD points of 3~6 batches of additions, when interval 2~4 is small/time, wherein, the chloro- 7- methoxyl groups quinolines of 4-
Oxazoline -6- alcohol, PPh3, DTAD, compound (2) mole dosage ratio be 1: 1: 1: 0.8~1.4.
In step S4,3~6 batches of additions of the sodium borohydride point, when interval 2~4 is small/time, 4- dimethylaminobenzaldehydes,
The mole dosage ratio of sodium borohydride is 1: 0.6~2.4.
In step S5, points of 3~6 batches additions of the NaH are spaced 20~40 minutes/time, the fluoro- 4- nitrobenzenes of NaH, 1- with
The mole dosage ratio of compound (4) is 1: 0.5~1.5: 0.5~1.5.
In step S6, the dosage of Raney's nickel be per g of compound (5) 0.2~1.5.
In step S7, compound (3), the mole dosage ratio of compound (6) are 1: 0.8~1.2.
Present invention further proposes application of the above-mentioned novel quinazoline quinoline derivant in antitumor agent is prepared.
The present invention proposes a kind of pharmaceutical composition at the same time, and said composition includes the compound described in the claims 1
And pharmaceutically acceptable carrier.
Closer, the present invention proposes above-claimed cpd, or above-mentioned pharmaceutical composition is in medicament is prepared
Purposes.
Meanwhile can pharmaceutically connect the invention also provides above-mentioned novel quinazoline quinoline derivant LU1510 or the compound
The salt received, solvate either prodrug or stereoisomer or dynamic isomer or metabolin prepare it is antitumor
Application in agent.
Finally, the present invention proposes the pharmaceutically acceptable of above-mentioned novel quinazoline quinoline derivant LU1510 or the compound
Salt, either prodrug or stereoisomer or dynamic isomer or metabolin and one or more resist solvate
Cancer medicament, which is incorporated in prepare, to be used to treat the purposes on the medicine of tumour.
Beneficial effect：Its suppression is evaluated the invention discloses a kind of novel quinazoline quinoline derivant LU1510, and using mtt assay
Tetra- plants of proliferative activity o f tumors of MCF-7, SK-BR-3, MDA-MB-468, U-87MG, calculate and suppress the increasing of these four tumour cells
The IC grown50Value, the results showed that prepared novel quinazoline quinoline derivant LU1510 is inhibited to above-mentioned tumour cell, can
It is used to prepare anti-tumor agent.
Brief description of the drawings
Fig. 1 is the synthetic route chart of quinazoline derivant, wherein：I) methyl bromoacetate, EtMgBr, THF；Ii) THF,
LiAlH4；Iii) the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3, DTAD, THF；iv)NaBH4, THF；v)1-fluoro-4-
Nitrobenzene, NaH, DMF, vi) Raney's nickel, THF, H2, vii) and n-BuOH.
Embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares 2- (1- pyrroles -2- bases) acetic acid esters (compound 1).
500mL tetrahydrofurans are placed in four neck round-bottom flasks of nitrogen protection of 2000mL, add 50g pyrroles.Ice bath
Under 266.8mL 3M EtMgBr diethyl ether solutions be slowly added dropwise and stir 30min, drop speed is 5ml/min.Reaction solution stirs at room temperature
1 it is small when, be added dropwise 45.7g methyl bromoacetates under ice bath, reaction solution be stirred at room temperature 1 it is small when.It is whole to add 500mL of 1N HCl
Only react.Reaction solution is extracted with ethyl acetate 3 times, combined ethyl acetate layer, and saturated sodium-chloride water solution is washed 3 times.Separate merging
Ethyl acetate layer, in 250mL triangular flasks add anhydrous sodium sulfate drying 6 it is small when, be filtered under diminished pressure.Filtrate decompression is concentrated into
It is dry, 19g (yield 46%) compound 1 is obtained through column chromatography, is brown oil.
Embodiment 2 prepares 2- (1- pyrroles -2- bases) ethanol (compound 2).
19g 2- (1- pyrroles -2- bases) acetic acid esters (compound 1) is dissolved in 200mL tetrahydrofurans, is placed in the nitrogen of 500mL
In four neck round-bottom flasks of gas shielded, 5.6g LiAlH are added portionwise under ice bath4, stir 30min.Added into reaction solution
5.6mL water, 15%NaOH 16.8mL, are stirred at room temperature 10min, terminate reaction.Anhydrous sodium sulfate is added in 250mL triangular flasks
When drying 6 is small, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and is obtained 10g (yield 66%) compound 2 through column chromatography, is brown oil
Shape.
The compound 2 of preparation is carried out1H-NMR standards are as a result as follows：
1H-NMR：(300MHz, DMSO-d6, ppm)：δ 8.52 (brs, 1H), 6.73-6.71 (m, 1H), 6.19-6.14 (m,
1H), 6.01-6.00 (m, 1H), 3.87-3.83 (t, J=5.7Hz, 2H), 2.88-2.84 (t, J=5.7Hz, 2H).
Embodiment 3 prepares 4- chloro- 7- methoxyl groups -6- [2- (1- pyrroles -2- bases) ethoxy] quinazoline (compound 3).
By the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 12.6g 4-, 6g 2- (1- pyrroles -2- bases) ethanol (compound 2),
17.1g PPh3150mL tetrahydrofurans are dissolved in, are placed in the three neck round bottom of 250mL nitrogen protection, (are divided in batches under ice bath
4 batches, every batch of interval 2h) 15g DTAD are added, it is stirred overnight at room temperature.Reaction mixture filters out solid residue, filtrate decompression
It is concentrated to dryness.Obtained residue obtains 8.8g (yield 54%) compound 3 with through column chromatography, is colourless powder.
Embodiment 4 prepares 4- dimethylaminos phenmethylol (compound 4).
By 10g 4- dimethylaminobenzaldehydes, 100mL tetrahydrofurans are dissolved in, are placed in 250mL three-neck flasks, ice bath stirs
Mix down and add 4.6g sodium borohydrides in batches (point 4 batches, every batch of interval 2h), be stirred overnight at room temperature.Add 30mL methanol and terminate reaction.
Reaction solution is concentrated under reduced pressure into dry, obtains 8g (yield 79%) compound 4 through column chromatography, is pale yellowish oil.
Embodiment 5 prepares N, N- dimethyl -4- (4- nitre phenyl methyl) aniline (compound 5)
8g 4- dimethylaminos phenmethylols (compound 4) are placed in the three-neck flask of 250mL, it is molten to add 70mL DMF
Solution, (point 4 batches, every batch of interval 30min) adds 4gNaH in batches under ice bath, be stirred at room temperature 1 it is small when.(divide in batches under reaction solution ice bath
4 batches, every batch of interval 2h) the fluoro- 4- nitrobenzenes of 7.5g 1- are added, it is stirred overnight at room temperature, adds 300mL frozen water and terminate reaction.Acetic acid
Ethyl ester extracts 3 times, merges organic layer, is washed 3 times with saturated nacl aqueous solution, separate organic layer, added in 250mL triangular flasks
When anhydrous sodium sulfate drying 6 is small, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 11g (yield 76%) compound is obtained through column chromatography
5, it is yellow powder.
Embodiment 6 prepares 4- [(4- dimethylaminos) phenyl] aminoanisole (compound 6)
By 11g N, N- dimethyl -4- (4- nitre phenyl methyl) aniline (compound 5), is dissolved in 120mL tetrahydrofurans, puts
In 250mL round-bottomed flasks, 2g Raney's nickels (dividing 4 batches, every batch of interval 2h) are added portionwise, is passed through hydrogen, is stirred overnight at room temperature.Instead
Liquid is answered to be filtered under diminished pressure, filtrate is concentrated to dryness, and obtains 8g (yield 82%) compound 6 through column chromatography, is colourless powder.
Embodiment 7 prepares 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminobenzene
Base amino methyl phenylacetate (compound 7)
By the chloro- 7- methoxyl groups -6- of 1.5g4- [2- (1- pyrroles -2- bases) ethoxy] quinazoline (compound 3), 1.2g4-
[(4- dimethylaminos) phenyl] aminoanisole (compound 6), is dissolved in 30mL n-butanols, is placed in 100mL three neck round bottom
In, when 60 DEG C of oil bath stirrings 1 are small.Ice bath is cooled to room temperature, and reaction solution adds 100mL water to dilute, and pH is adjusted with aqueous sodium carbonate
To 9, ethyl acetate extracts 3 times, merges organic layer, and saturated sodium-chloride water solution is washed 2 times.Organic layer adds in 250mL triangular flasks
Enter anhydrous sodium sulfate drying 6 it is small when, be filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 0.718g (yield 14%) is obtained through column chromatography
Compound 7, is buff powder.
The compound 7 of preparation is carried out ESI-MS,1H-NMR standards are as a result as follows：
ESI-MS(m/z)：510[M+H]+；1H-NMR (300MHz, DMSO-d6, ppm)：δ 10.71 (s, 1H), 9.46 (s,
1H), 8.38 (s, 1H), 7.84 (s, 1H), 7.58-7.55 (d, J=8.7Hz, 2H), 7.29-7.26 (d, J=8.4Hz, 2H),
7.17 (s, 1H), 7.02-6.99 (d, J=8.7Hz, 2H), 674-6.71 (d, J=8.4Hz, 2H), 6.66 (s, 1H), 5.94
(s, 2H), 4.96 (s, 2H), 4.30-4.25 (t, J=7.4Hz, 2H), 3.94 (s, 3H), 3.14-3.09 (t, J=7.2Hz,
2H), 2.90 (s, 6H).
8 compound of experimental example, 7 anti-tumour cell proliferative activity is evaluated.
(1) given the test agent：
The compound 7 of the present invention is configured to required concentration with the culture medium containing 0.1%DMSO.
(2) cell line：
MCF-7 (human breast cancer cell, ATCC：HTB-22), SK-BR-3 (human breast cancer cell, ATCC：HTB-30)、U-
87MG (human brain astrocytes' blastoma, ATCC：HTB-14), MDA-MB-468 (human breast cancer cell, ATCC：HTB-132)4
Strain tumour cell is purchased from Unite States Standard type culture collection institute (ATCC).
(3) key instrument and material
Ultra-pure water instrument：MILLIPORE Direct-Q 3；
High-pressure sterilizing pot：HVE-50, Hirayama company；
Digital display thermostat water bath：HH-4, Guo Hua Electrical Appliances Co., Ltd；
Super-clean bench：VS-1300-U clean benches, SuZhou Antai Air Tech Co., Ltd.；
Cell incubation case：HF151UVCO2 incubators, Shanghai power Shengong department；
Refrigerated centrifuge：Anting Scientific Instrument Factory, Shanghai
Microplate reader：ELx800, Biotek company
Oscillator plate：ZD-9556, Taicang science and education equipment factory；
96 porocyte culture plates, 25cm2Blake bottle：Corning Costar companies；
2mL cryopreservation tubes：Corning Costar companies；
(4) main agents
RPMI-1640 culture mediums：Gibco companies；
DMEM culture mediums：Gibco companies；
L-15 culture mediums：Gibco companies；
MEM culture mediums：Gibco companies；
PBS buffer：Gibco companies；
Hyclone：Gibco companies；
0.25% trypsin solution：Hyclone companies；
MTT (four tetrazolium bromides)：Sigma companies, are dissolved in PBS solution, and the solution of 5mg/mL is made, makes after filtration sterilization
With being kept in dark place；
Adriamycin (ADR)：Beijing Hua Feng United Technologies Corp.s.
DMSO：Dimethyl sub-maple, Sigma companies；
(5) test method
MCF-7 cells select DMEM culture mediums, and U-87MG cells select MEM culture mediums, and MDA-MB-468 cells select L-
15 culture mediums, other cells select RPMI-1640 culture mediums.Hyclone and 80UmL in culture medium containing 10% fire extinguishing-1
Penicillin and 0.08mgmL-1Streptomysin.
By MCF-7, SK-BR-3, MDA-MB-468, U-87MG cell of growth conditions well, in exponential phase by 1
×104The density of a/mL is inoculated in 96 orifice plates, per 100 μ l of hole.It is placed in 37 DEG C, 5%CO2Wait to paste when culture 12 is small in incubator
Wall.Dosing cell hole is added the compound 7 for being dissolved in culture medium of to be measured, sterilized processing by default concentration gradient, per hole 200
μ l, blanc cell hole add isometric culture medium, and control cell hole is added by default concentration gradient is dissolved in culture in equal volume
The adriamycin (ADR) of base, parallel 6 hole.In 37 DEG C, 5%CO2After when culture 48 is small in incubator, 10 μ l concentration are added per hole is
The MTT solution of 5mg/mL, continues to be placed in 37 DEG C, 5%CO2When culture 4 is small in incubator.It is careful to suction out supernatant, added per hole
150 μ l DMSO dissolving purple powders (first a ceremonial jade-ladle, used in libation), Oscillating Flat makes precipitation all dissolve for 10 minutes, in being measured in microplate reader
O.D. it is worth (absorbance), wavelength 570nm.
According to formula, " relative survival rate=(D drug containing-D blank)/(D control-D blank) × 100% " calculates each sample
The inhibiting rate of sample under product concentration to tumour cell.
Test it is parallel be repeated 3 times, with inhibiting rate to compound concentration map, calculate the compounds of this invention 7 IC50(half
Effective inhibition concentration) value.Positive control medicine is used as using adriamycin (ADR) at the same time.
(6) experimental result
1 compound 7LU1510 anti-tumour cell proliferative activities (IC of table50±SDμM)
| Compound | MCF-7 | SK-BR-3 | U-87MG | MDA-MB-468 |
| ADR | 3.98±0.07 | 4.65±0.02 | 82.47±7.15 | 2.45±0.31 |
| Compound 7 | 54.69±3.79 | 23.73±4.03 | 59.35±5.77 | 10.26±1.08 |
As shown in table 1, the test result of 7 anti-tumour cell proliferative activity of compound is given, the results showed that prepared
Novel quinazoline quinoline derivant is inhibited to above-mentioned tumour cell, available for preparing anti-tumor agent.
Claims (7)
1. a kind of preparation method of quinazoline derivant LU1510, it is characterised in that its chemical structural formula is：
It is prepared via a method which to obtain：
S1：Under nitrogen protection, pyrroles is dissolved in tetrahydrofuran, EtMgBr diethyl ether solutions, stirring 30 is slowly added dropwise under ice bath
When minute~2 are small, when 0~60 DEG C of stirring 30 minutes~2 of reaction solution is small, 0~60 DEG C adds methyl bromoacetate stirring 30 minutes~2
Hour, generation compound (1), i.e.,
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, LiAlH is added portionwise while stirring under ice bath4, stir
Mix more than 30 minutes, obtain reduzate compound (2), i.e.,
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrofuran,
Be added portionwise DTAD while stirring under ice bath, when reaction 6 is small more than, generate compound (3), i.e.,
S4：4- dimethylaminobenzaldehydes are dissolved in tetrahydrofuran, 0~25 DEG C is added portionwise sodium borohydride, and stirring reaction 4~12 is small
When, compound (4) is generated, i.e.,
S5：By compound (4), dissolved with DMF, add NaH, when 25~100 DEG C of stirrings 1~6 are small, 0~25 DEG C is added portionwise 1-
Fluoro- 4- nitrobenzenes generation compound (5), i.e.,
S6：Compound (5) is dissolved in tetrahydrofuran, Raney's nickel is added portionwise, is passed through hydrogen, 25~60 DEG C of stirring reactions 4~12
Hour, generation compound (6), i.e.,
S7：By compound (3) with n-Butanol soluble, compound (6) is added, when 25~100 DEG C of stirrings 1~6 are small, generates compound
(7), i.e.,
2. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S1,
The concentration of EtMgBr diethyl ether solutions is 3M, and drop speed is 5~10ml/min, EtMgBr ether, methyl bromoacetate, tetrahydrofuran, pyrrole
The amount ratio coughed up is 100~500mL：20~50g：250~1000ml：20~50g；In step S2, LiAlH4Dosage be every
G of compound (1) adds 0.25~2g.
3. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S3, institute
The DTAD stated points of 3~6 batches of additions, when interval 2~4 is small/time, wherein, the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3、DTAD、
The mole dosage ratio of compound (2) is 1:1:1:0.8~1.4.
4. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S4, institute
3~6 batches of additions of the sodium borohydride stated point, when interval 2~4 is small/time, 4- dimethylaminobenzaldehydes, the mole dosage of sodium borohydride
Than for 1:0.6~2.4.
5. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S5, institute
The NaH stated points of 3~6 batches of additions, are spaced 20~40 minutes/time, the fluoro- 4- nitrobenzenes of NaH, 1- and the mole dosage of compound (4)
Than for 1:0.5~1.5:0.5~1.5.
6. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S6, thunder
The dosage of Buddhist nun's nickel is per g of compound (5) 0.2~1.5.
7. the preparation method of quinazoline derivant LU1510 according to claim 1, it is characterised in that in step S7, change
Compound (3), the mole dosage ratio of compound (6) are 1:0.8~1.2.
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| US20090143399A1 (en) * | 2003-10-14 | 2009-06-04 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
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| CN1391562A (en) * | 1999-09-21 | 2003-01-15 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as pharmaceuticals |
| CN1993349A (en) * | 2004-06-04 | 2007-07-04 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as ERBB receptor tyrosine kinases |
| CN102532042A (en) * | 2010-12-30 | 2012-07-04 | 上海医药工业研究院 | Aryl urea compound as well as intermediate and application thereof |
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| CN105503835A (en) | 2016-04-20 |
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