CN105481835B - A kind of quinazoline derivant LU1508 and its preparation method and application - Google Patents
A kind of quinazoline derivant LU1508 and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of novel quinazoline quinoline derivant LU1508 and preparation method thereof, chemical name is 4 { 4 [(7 methoxyl group) 6 (1 pyrroles, 2 base) ethoxy] quinazoline, 4 base } aminophenyiamino methylphenols.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 118MG, HCT116, U 87MG, has preferable application prospect on preparing antitumor drug.
Description
Technical field
The invention belongs to biomedicine fields, more particularly to a kind of novel quinazoline quinoline derivant LU1508 and its preparation side
Method and application.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease seriously threatening human health, in the past 20 years, China's tumor mortality
Rate rises 29.42%.In 35 to 59 years old middle prime of life crowds, 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 about 6,000,000 people of patient or more.It is swollen
The therapy of tumor has operative treatment, radiotherapy and chemotherapy.Currently, 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 receives the extensive concern of people, becomes biological educational circles and hot spot that region of chemistry scholars study.They are right
EGF receptors or pdgf receptor tyrosine kinase generate good inhibiting effect, show with anti-lung cancer, gastric cancer, colon cancer,
Effect of breast cancer, gallbladder cancer and prostate cancer etc., antibacterial, AntiHIV1 RT activity is anti-inflammatory, treat diabetes the effects that, as Gefitinib,
The marketed drugs such as Tarceva, xylene monosulfonic acid Lapatinib.Inventor's discovery, 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -
2- yls) ethoxy] quinazoline -4- bases } aminophenyiamino methylphenol has certain antitumor activity, and inventor proposes and 4-
{ 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminophenyiamino methylphenol or the change
Close the pharmaceutically acceptable salt of object, solvate either prodrug or stereoisomer or tautomer or generation
Thank to the relevant invention of object.
Invention content
Goal of the invention：To solve problems of the prior art, the present invention provides a kind of novel quinazoline quinoline derivant
LU1508, chemical name are 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminobenzene
Base amino methyl phenol, to six plants of MCF-7, SK-BR-3, MDA-MB-468, U-118 MG, HCT116, U-87 MG tumours
Cell Proliferation has inhibitory activity.
Technical solution：To realize the above-mentioned technical purpose, the present invention provides a kind of novel quinazoline quinoline derivant LU1508,
Its chemical name is 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminophenyiamino first
Base phenol, structural formula are as follows：
Present invention further proposes the preparation methods of above-mentioned novel quinazoline quinoline derivant LU1508, 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
It mixes 30 minutes~2 hours, 0~60 DEG C of reaction solution stirs 30 minutes~2 hours, and 0~60 DEG C is added methyl bromoacetate and stirs 30 points
Clock~2 hour generate compound (1), i.e. 2- (1- pyrroles -2- bases) acetic acid esters；
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, is added portionwise while stirring under ice bath
LiAlH430 minutes or more, obtain reduzate compound (2), i.e. 2- (1- pyrroles -2- bases) ethyl alcohol；
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrochysene
DTAD is added portionwise in furans while stirring under ice bath, react 6 hours or more, generate compound (3), the i.e. chloro- 7- methoxies of 4-
Base -6- [2- (1- pyrroles -2- bases) ethoxy] quinazoline；
S4：Under nitrogen protection, 4- hydroxymethylphenols, triethylamine are dissolved with ethyl acetate, 0~25 DEG C of dropwise addition acetyl
Chlorine is stirred to react 4~12 hours, generates compound (4), i.e. 4- methylols phenylacetate；
S5：Under nitrogen protection, with ether dissolution carbon tetrabromide is added, 0~25 DEG C is added portionwise in compound (4)
Ph3P, 25~100 DEG C are stirred 3~12 hours, and compound (5), i.e. 4- bromomethyls phenylacetate are generated；
S6：Compound (5), benzene-Isosorbide-5-Nitrae-diamines and potassium carbonate are dissolved in tetrahydrofuran, 60~120 DEG C are stirred to react 1~6
Hour, generate compound (6), i.e. 4- [(4- aminophenyls) amino] Methyl.alpha.-toluate.
S7：By compound (3) with n-Butanol soluble, compound (6) is added, trifluoroacetic acid, 25~100 DEG C of stirrings 1 are added dropwise
~6 hours, generate compound (7), i.e. 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } ammonia
Base phenvlaminomethvl phenylacetate；
S8：Compound (7) is dissolved in tetrahydrofuran, ammonium hydroxide is added, 25~100 DEG C are stirred to react 4~12 hours, generationization
Close object (8), i.e. 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminophenyiamino methyl
Phenol.
Preferably, in step S1, a concentration of 3M of EtMgBr diethyl ether solutions, drop speed is 5~10ml/min, EtMgBr second
Ether, methyl bromoacetate, tetrahydrofuran, pyrroles amount ratio be 100~500mL: 20~50g: 250~1000ml: 20~50g.
In step S2, LiAlH4Dosage be per g of compound (1) be added 0.25~2g.
In step S3, the DTAD points of 3~6 batches of additions are spaced 2~4 hours/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, the mole dosage ratio of 4- hydroxymethylphenols, triethylamine and chloroacetic chloride is 1: 1: 0.6~1.4.
In step S5, Ph3P, carbon tetrabromide and the mole dosage ratio of compound (4) are 1: 1: 0.6~1.4.
In step S6, the mole dosage ratio of benzene-Isosorbide-5-Nitrae-diamines, potassium carbonate and compound (5) is 1: 1: 0.4~2.5.
In step S7, the mole dosage ratio of compound (3), compound (6) and trifluoroacetic acid is 1: 1: 0.01~1.0.
In step S8, the dosage of ammonium hydroxide is that 5~20ml of ammonium hydroxide is added in every 1 g of compound (7).
Present invention further proposes application of the above-mentioned novel quinazoline quinoline derivant in preparing antitumor agent.
The present invention proposes a kind of pharmaceutical composition simultaneously, and the composition includes the novel quinazoline quinoline derivant and pharmaceutically
Acceptable carrier.
Closer, the present invention proposes above compound or above-mentioned pharmaceutical composition in preparing medicament
Purposes.
Meanwhile can pharmaceutically connect the invention also provides above-mentioned novel quinazoline quinoline derivant LU1508 or the compound
The salt received, solvate either prodrug or stereoisomer or tautomer or metabolin prepare it is antitumor
Application in agent.
Finally, the present invention proposes the pharmaceutically acceptable of above-mentioned novel quinazoline quinoline derivant LU1508 or the compound
Salt, solvate either prodrug or stereoisomer or tautomer or metabolin with it is one or more anti-
Cancer medicament is incorporated in the purposes prepared on the drug for treating tumour.
Advantageous effect：The invention discloses a kind of novel quinazoline quinoline derivant LU1508, and evaluate its inhibition using mtt assay
Six plants of MCF-7, SK-BR-3, MDA-MB-468, U-118 MG, HCT116, U-87 MG proliferative activity o f tumors calculate and inhibit
The IC of this six kinds of tumor cell proliferations50Value, the results showed that prepared novel quinazoline quinoline derivant LU1508 is thin to above-mentioned tumour
Born of the same parents are inhibited, can be used for preparing anti-tumor agent.
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)Et3N, chloroacetic chloride EA；v) CBr4,
Ph3P, Et2O；Vi) benzene-Isosorbide-5-Nitrae-diamines, K2CO3, THF；Vii) n-BuOH, TFA；Viii) THF, NH3·H2O
Specific implementation mode
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 the nitrogen protection of 2000mL, 50g pyrroles is added.Ice bath
Under (drop speed be 5ml/min) 266.8mL 3M EtMgBr diethyl ether solutions be slowly added dropwise and stir 30min.Reaction solution stirs at room temperature
It mixes 1 hour, 45.7g methyl bromoacetates is added dropwise under ice bath, reaction solution is stirred for 1 hour at room temperature.500mL of 1N HCl are added
Terminate reaction.Reaction solution is extracted with ethyl acetate 3 times, combined ethyl acetate layer, and saturated sodium-chloride water solution is washed 3 times.Separate conjunction
And ethyl acetate layer, in 250mL triangular flasks be added anhydrous sodium sulfate dry 6 hours, be filtered under diminished pressure.Filtrate decompression concentrates
To doing, 19g (yield 46%) compound 1 is obtained through column chromatography, is brown oil.
Embodiment 2 prepares 2- (1- pyrroles -2- bases) ethyl alcohol (compound 2).
19g 2- (1- pyrroles -2- bases) acetic acid esters (compound 1) is dissolved in 200mL tetrahydrofurans, is placed in 500 mL's
In four neck round-bottom flasks of nitrogen protection, 5.6g LiAlH are added in (in four batches, every batch of interval 10min) in batches under ice bath4, stirring
30min.5.6mL water is added into reaction solution, 10min is stirred at room temperature in 15%NaOH 16.8mL, terminates reaction.In 250mL tri-
Anhydrous sodium sulfate is added in the bottle of angle to dry 6 hours, is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 10g (yields are obtained through column chromatography
66%) compound 2 are brown oil.
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 12.6g4-, 6g 2- (1- pyrroles -2- bases) ethyl alcohol (compound 2),
17.1gPPh3150mL tetrahydrofurans are dissolved in, are placed in the three neck round bottom of 250mL nitrogen protections, (divide 3 in batches under ice bath
Batch, every batch of interval 2h) 15gDTAD is added, it is stirred overnight at room temperature.Reaction mixture filters out solid residue, and filtrate decompression is dense
It is reduced to dry.Obtained residue obtains 8.8g (yield 54%) compound 3 with through column chromatography, is colourless powder.
Embodiment 4 prepares 4- methylols phenylacetate (compound 4).
By 15g 4- hydroxymethylphenols and 16.8mL triethylamines, it is dissolved in 200mL ethyl acetate, is placed in 500 mL nitrogen guarantor
In the three-neck flask of shield, 9.4g chloroacetic chlorides are added dropwise under ice bath stirring, are stirred overnight at room temperature.Reaction solution is filtered under diminished pressure, and filtrate is through column
Chromatography obtains 12g (yield 60%) compound 4, is colorless oil.
The compound 4 of preparation is carried out1H-NMR standards are as a result as follows：
1H-NMR (300MHz, CD3Cl-d6, ppm)：δ 7.42-7.40 (d, J=8.4Hz, 2H), 7.12-7.09 (d, J=
8.4Hz, 2H), 4.72 (s, 2H), 2.33 (s, 3H)
Embodiment 5 prepares 4- bromomethyls phenylacetate (compound 5)
11.2g 4- methylols phenylacetates (compound 4) are dissolved in 200mL ether, the nitrogen protection of 500mL is placed in
Three-neck flask in, 26.9g carbon tetrabromides are added, 21.2gPh is added in (point 4 batches, every batch of interval 1h) in batches under ice bath3P, room
Temperature stirring 4 hours.Reaction solution is diluted with 200mL ethyl acetate, is filtered under diminished pressure, and filtrate is washed 3 times with saturated nacl aqueous solution, point
Go out organic layer and anhydrous sodium sulfate drying 6 hours is added in 250mL triangular flasks, is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, through column
Chromatography obtains 10g (yield 65%) compound 5, is colourless powder.
The compound 5 of preparation is carried out1H-NMR standards are as a result as follows：
1H-NMR (300MHz, CD3Cl-d6, ppm)：δ 7.44-7.41 (d, J=8.4Hz, 2H), 7.10-7.08 (d, J=
8.4Hz, 2H), 4.51 (s, 2H), 2.32 (s, 3H)
Embodiment 6 prepares 4- [(4- aminophenyls) amino] Methyl.alpha.-toluate (compound 6)
By 9g 4- bromomethyls phenylacetates (compound 5), 8.5g benzene-Isosorbide-5-Nitrae-diamines, 10.8g potassium carbonate is dissolved in
200mL tetrahydrofurans are placed in 500mL three neck round bottom, and 60 DEG C of oil baths are stirred 1 hour.Ice bath is cooled to room temperature, reaction solution
200mL ethyl acetate is added to dilute, saturated sodium-chloride water solution is washed 2 times.Anhydrous sodium sulfate is added in 250mL triangular flasks in organic layer
It is 6 hours dry, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 3.5g (yield 35%) compound 6 is obtained through column chromatography, is yellow
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)
The chloro- 7- methoxyl groups -6- of 2.5g 4- [2- (1- pyrroles -2- bases) methylol] quinazoline (compound 3) is dissolved in
It in 80mL n-butanols, is placed in the round-bottomed flask of 250mL, 2.1g 4- [(4- aminophenyls) amino] Methyl.alpha.-toluate is added
(compound 6), is added dropwise 0.01mL trifluoroacetic acids, and 75 DEG C of oil baths are stirred 2 hours.Ice bath is cooled to room temperature, and sodium carbonate liquor is added dropwise
PH to 9 is adjusted, reaction solution is extracted with ethyl acetate 2 times, merges organic layer, and saturated sodium-chloride water solution is washed 2 times.Separate organic layer
Anhydrous sodium sulfate is added in 250mL triangular flasks to dry 6 hours, is filtered under diminished pressure, filtrate is concentrated to dryness, and 2.2g is obtained through column chromatography
(yield 51%) compound 7 is brown ceramic powder.
Embodiment 8 prepares 4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminobenzene
Base amino methyl phenol (compound 8)
By 2.2g4- { 4- [(7- methoxyl groups) -6- (1- pyrroles -2- bases) ethoxy] quinazoline -4- bases } aminophenyiamino
Methyl.alpha.-toluate (compound 7) is dissolved in 30mL tetrahydrofurans, and 15mL NH are added3·H2O is placed in 100mL round-bottomed flasks
In, it is stirred overnight at room temperature.Reaction solution adds 50mL water to dilute, and is extracted with ethyl acetate 3 times, merges organic layer, saturated sodium-chloride water
Solution is washed 4 times.Anhydrous sodium sulfate is added in 250mL triangular flasks and dries 6 hours for organic layer, is filtered under diminished pressure.Filtrate decompression concentrates
To doing, 1.147g (yield 57%) compound 8 is obtained through column chromatography, is brown ceramic powder.
To the compound 8 of preparation carry out ESI-MS,1H-NMR standards are as a result as follows：
ESI-MS(m/z)：482[M+H]+；1H-NMR (300MHz, DMSO-d6, ppm)：δ 10.70 (s, 1H), 9.25 (s,
1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.28-7.26 (d, J=8.4Hz, 2H), 7.18-7.15 (d, J=8.4Hz, 2H),
7.13 (s, 1H), 6.72-6.69 (d, J=8.4Hz, 2H), 6.49 (s, 1H), 6.60-6.57 (d, J=8.7Hz, 2H),
6.03-5.93 (t, J=5.4Hz, 1H), 5.93 (s, 2H), 4.27-4.22 (t, J=5.1Hz, 1H), 4.14-4.12 (d, J=
5.4Hz, 1H), 3.92 (s, 3H), 3.12-3.07 (t, J=7.5Hz, 2H)
9 compound of experimental example, 8 anti-tumour cell proliferative activity is evaluated.
(1) given the test agent：
The compound of the present invention 8 is configured to required concentration with the culture medium containing 0.1%DMSO.
(2) cell strain：
MCF-7 (human breast cancer cell, ATCC：HTB-22), SK-BR-3 (human breast cancer cell, ATCC：HTB-30)、
HCT116 (human colon cancer cell, ATCC：CCL-247), U-118 MG (human brain astrocytes' blastoma, ATCC：HTB-15)、
U-87 MG (human brain astrocytes' blastoma, ATCC：HTB-14), MDA-MB-468 (human breast cancer cell, ATCC：HTB-
132) 6 plants of tumour cells are 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, 25cm2Culture bottle：Corning Costar companies；
2mL cryopreservation tubes：Corning Costar companies；
(4) main agents
RPMI-1640 culture mediums：Gibco companies；
DMEM culture mediums：Gibco companies；
McCoy ' s 5A culture mediums：Gibco companies；
L-15 culture mediums：Gibco companies；
MEM culture mediums：Gibco companies；
PBS buffer solution：Gibco companies；
Fetal calf serum：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, U-118 MG cells select DMEM culture mediums, U-87MG cells to select MEM culture mediums, MDA-MB-468 thin
Born of the same parents select L-15 culture mediums, 116 cells of HCT that McCoy ' s 5A culture mediums, other cells is selected to select RPMI-1640 culture mediums.
Contain the fetal calf serum and 80UmL of 10% fire extinguishing in culture medium-1Penicillin and 0.08mgmL-1Streptomysin.
By growth conditions the good, MCF-7 in exponential phase, SK-BR-3, MDA-MB-468, U-118 MG,
HCT116, U-87 MG cells press 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%CO2Training
Support case in cultivate wait within 12 hours it is adherent.Dosing cell hole is dissolved in training by what preset concentration gradient was added to be measured, sterilized processing
The compound 8 for supporting base, per 200 μ l of hole, isometric culture medium is added in blanc cell hole, and control cell hole is by preset concentration ladder
The adriamycin (ADR) for being dissolved in culture medium in equal volume, parallel 6 hole is added in degree.In 37 DEG C, 5%CO2It is cultivated 48 hours in incubator
Afterwards, the MTT solution of 10 a concentration of 5mg/mL of μ l is added per hole, continues to be placed in 37 DEG C, 5%CO2It is cultivated 4 hours in incubator.It is small
Supernatant is sucked out in the heart, and 150 μ l DMSO dissolving purple powders (first a ceremonial jade-ladle, used in libation) are added per hole, and Oscillating Flat makes precipitation whole for 10 minutes
Dissolving, in measurement O.D. values (absorbance), wavelength 570nm in microplate reader.
Each sample is calculated according to formula " relative survival rate=(D drug containing-D blank)/(D control-D blank) × 100% "
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 8 IC50(half
Effective inhibition concentration) value.Positive control medicine is used as using adriamycin (ADR) simultaneously.
(6) experimental result
1 compound 8LU1508 anti-tumour cell proliferative activities (IC of table50±SDμM)
| Compound | MCF-7 | SK-BR-3 | HCT 116 | U-118 MG | U-87 MG | MDA-MB-468 |
| ADR | 3.98±0.07 | 4.65±0.02 | 26.57±0.12 | 13.49±1.75 | 82.47±7.15 | 2.45±0.31 |
| Compound 8 | 40.68±1.81 | 27.26±4.16 | 68.02±2.72 | 50.59±3.40 | 92.58±7.67 | 24.49±2.89 |
As shown in table 1, the test result of 8 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, can be used for preparing anti-tumor agent.
Claims (8)
1. a kind of preparation method of quinazoline derivant LU1508, chemical structural formula are：
It is characterised in that it includes following steps：
S1：Under nitrogen protection, pyrroles is dissolved in tetrahydrofuran, EtMgBr diethyl ether solutions, stirring 30 is slowly added dropwise under ice bath
Minute~2 hours, 0~60 DEG C of reaction solution stirs 30 minutes~2 hours, and 0~60 DEG C is added methyl bromoacetate stirring 30 minutes~2
Hour, compound (1) is generated, i.e.,
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, LiAlH is added portionwise while stirring under ice bath4 30
Minute or more, reduzate compound (2) is obtained, i.e.,
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrofuran, in ice
DTAD is added portionwise under bath while stirring, react 6 hours or more, compound (3) is generated, i.e.,
S4：Under nitrogen protection, 4- hydroxymethylphenols, triethylamine are dissolved with ethyl acetate, 0~25 DEG C of dropwise addition chloroacetic chloride stirs
It mixes reaction 4~12 hours, generates compound (4), i.e.,
S5：Under nitrogen protection, with ether dissolution carbon tetrabromide is added, 0~25 DEG C is added portionwise Ph in compound (4)3P, 25
~100 DEG C are stirred 3~12 hours, generate compound (5), i.e.,
S6：Compound (5), benzene-Isosorbide-5-Nitrae-diamines and potassium carbonate are dissolved in tetrahydrofuran, 60~120 DEG C are stirred to react 1~6 hour,
Compound (6) is generated, i.e.,
S7：By compound (3) with n-Butanol soluble, compound (6) is added, trifluoroacetic acid is added dropwise, 25~100 DEG C of stirrings 1~6 are small
When, compound (7) is generated, i.e.,
S8：Compound (7) is dissolved in tetrahydrofuran, ammonium hydroxide is added, 25~100 DEG C are stirred to react 4~12 hours, generate compound
(8), i.e.,
2. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S1,
A concentration of 3M of EtMgBr diethyl ether solutions, drop speed are 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
0.25~2g is added in g of compound (1).
3. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S3, institute
The DTAD stated points of 3~6 batches of additions, are spaced 2~4 hours/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 LU1508 according to claim 1, which is characterized in that in step S4,4-
The mole dosage ratio of hydroxymethylphenol, triethylamine and chloroacetic chloride is 1:1:0.6~1.4.
5. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S5,
Ph3P, carbon tetrabromide and the mole dosage ratio of compound (4) are 1:1:0.6~1.4.
6. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S6, benzene-
The mole dosage ratio of 1,4- diamines, potassium carbonate and compound (5) is 1:1:0.4~2.5.
7. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S7, change
The mole dosage ratio for closing object (3), compound (6) and trifluoroacetic acid is 1:1:0.01~1.0.
8. the preparation method of quinazoline derivant LU1508 according to claim 1, which is characterized in that in step S8, ammonia
The dosage of water is that 5~20ml of ammonium hydroxide is added in every 1 g of compound (7).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510875195.9A CN105481835B (en) | 2015-12-03 | 2015-12-03 | A kind of quinazoline derivant LU1508 and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510875195.9A CN105481835B (en) | 2015-12-03 | 2015-12-03 | A kind of quinazoline derivant LU1508 and its preparation method and application |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| US20090143399A1 (en) * | 2003-10-14 | 2009-06-04 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
| CN102686581A (en) * | 2009-12-21 | 2012-09-19 | 张强 | Novel quinazoline derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391562A (en) * | 1999-09-21 | 2003-01-15 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as pharmaceuticals |
| US20090143399A1 (en) * | 2003-10-14 | 2009-06-04 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
| CN102686581A (en) * | 2009-12-21 | 2012-09-19 | 张强 | Novel quinazoline derivatives |
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