CN108623565A - A kind of preparation method of compound - Google Patents
A kind of preparation method of compound Download PDFInfo
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- CN108623565A CN108623565A CN201710176619.1A CN201710176619A CN108623565A CN 108623565 A CN108623565 A CN 108623565A CN 201710176619 A CN201710176619 A CN 201710176619A CN 108623565 A CN108623565 A CN 108623565A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The present invention provides a kind of synthesis technologies of compound, and specifically, the present invention provides a kind of methods by preparation of compounds of formula Compound I, wherein the definition of each group is as noted in the discussion.The route of the present invention have the characteristics that can industrialized production, yield is high, product is easily separated, the compound that the present invention synthesizes is multiple target point tyrosine protein kinase inhibitor, with good antitumor activity.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, in particular it relates to the synthesis technology of quinolines.
Background technology
Protein tyrosine kinase (PTK) is a kind of protein with protein tyrosine kinase activity, it can be catalyzed on ATP
Phosphoric acid gene be transferred on many protein-tyrosine residues related with cell activities, bring it about phosphorylation.Albumen
Tyrosine kinase signal access participate in normal cell adjusting, signal, transmission and development, also with the proliferation of tumour cell, differentiation,
Migration is closely related with apoptosis.
Activation occurs in many development of cancer and is given birth to so as to cause blood vessel by vascular endothelial growth factor receptor VEGFR
At.Vascular endothelial growth factor-A (VEGF-A), as the key members of angiogenesis, by combining VEGFR-1 and VERFR-2
It plays a role.Vascular endothelial growth factor receptor further activates network downstream signaling pathway, including phosphatidylinositols -3- to swash
Enzyme/protein kinase B signal path.It finds that VEGF and VEGFR is over-expressed in tumor patient by immunohistochemical experiment, prompts
Vascular endothelial growth factor receptor activation plays a significant role in tumour fast-growth.
Angiogenesis plays a significant role in terms of growth, development, breeding and the wound of biology are cured mouth, primary tumo(u)r
Growth and transfer also rely on angiogenesis, and newborn tumour needs more blood vessels to meet the needs of own metabolism and proliferation,
And it is spread to other histoorgans by blood circulation.Angiogenesis is the key factor of tumour growth, and only tumour does not provide
Nutrition and oxygen, while being the access that tumour cell enters system circulation and transfer.A variety of angiogenesis of tumor cell secretion
It connects each other and regulates and controls between the factor.And in the numerous factors of the formation with regulating and controlling effect to new vessels, blood vessel endothelium
Growth factor (Vascular endothelial growth factor, VEGF) be induction of vascular generate principal element it
One, it is to act on one of most strong, highest positivity regulatory factor of specificity, it and corresponding vascular endothelial growth factor receptor
After (VEGF receplor, VEGFR) is combined, the proliferation by specific signal transduction pathway stimulating endothelial cell and migration, from
And promote the formation of new vessels.
VEGF is also referred to as vasopermeable factor, be a kind of cell powerful and that varied organisms function can be generated because
Son is in a kind of glycoprotein that 1989 are isolated and purified out by Ferrarra in Niu Chuiti folliculus sternzellen culture solutions
One member of platelet derived growth factor (Platelet derived growth factor, PDGF) family, molecular weight
For 34~45KD, sequence is highly conserved, is distributed widely in the groups such as brain, kidney, spleen, pancreas and the bone in humans and animals body
In knitting, expression is adjusted by cell factor, extracellular factor, anoxic, P53 genes.VEGFR is combined generation one with its ligand VEGF
Serial physiology and biochemical process, it is final that new vessels is promoted to generate.In normal blood vessels, angiogenesis factor and angiogenesis suppression
The factor processed remains the level for comparing balance, and in the growth course of tumour, and the high expression of VEGFR and VEGF destroys this
Balance, promotes tumor neovasculature formation.
C-Met, also known as MET or HGFR are a kind of by MET proto-oncogenes (being primarily present in stem cell, progenitor cells) coding
Protein product, be hepatocyte growth factor transmembrane receptor, have tyrosine kinase activity.It is thin that c-Met is mainly expressed in epithelium
Born of the same parents play in embryonic development and wound healing and focus on also seen in endothelial cell, liver cell, nerve cell and hematopoietic cell
It acts on.Hepatocyte growth factor (hepatocyte growth factor, HGF) be the c-Met that is secreted by interstitial cell by
The unique ligand of body.
C-Met receptors play an important role during the signal transduction of the metabolism of cell, differentiation and natural death of cerebral cells,
With ligand binding, 5 bars Signal Transduction Pathways of downstream can be activated, such as RAS/RAF, phosphatidylinositol3 3 kinase (PI3K), signal transduction
With transcription activator (STAT), Notch and Beta-catenin, promote the biology such as cell mitogen, form generation anti-
It answers, to participate in embryonic development, tissue damage reparation, liver regeneration and the invasion and transfer of tumour.
Hepatocyte growth factor (HGF) is also known as dispersion factor, is the ligand of tyrosine-kinase enzyme variants c-Met, and conduct
A kind of fibroblastic derivative factor that epithelial cell can be induced to disperse, all having rush to many epithelial cells has silk point
It splits, the effect that inducing morphological changes.In addition, HGF can stimulate vascular endothelial growth factor, can also raise and extracellular base
The expression of the relevant molecule of matter proteolysis and its receptor.In order to generate effect (biological effect), HGF must be with its receptor c-
Met, that is, receptor tyrosine kinase is combined.The specific membrane receptor of HGF is the expression product of Immunohistochemistry, the assignment of genes gene mapping
In Chromosome 7q31, size class 110kb contains 21 exons.It includes many regulation and control such as AP1, AP2, NF2JB, SP1 that it, which starts domain,
Sequence.
HGF is with after the specific binding of c-Met receptor proteins, and induction C-Met receptor protein occurred conformations change, activated receptor
Tyrosine protein kinase (PTK) in intracellular protein kinase domain, this is the primary ring of HGF/c-Met signal transduction pathways
Section.In most of tumour cell, close to the tyrosine residue of 4 phosphorylation sites of intracellular region autophosphorylation occurs for c-Met,
Then phosphatidase (PLC γ), Phosphoinositide-3 kinase (PI3K), Ras albumen, S γ C are activated by a series of phosphorylation reaction
The tyrosine phosphorylation of the albumen such as albumen, adaptor protein Gabl and growth factor receptor binding protein precursor 2 (G γ b2).Through waterfall type
Phosphorylation reaction, signal is amplified step by step, is finally transferred to endonuclear transcription mechanism, to adjust the increasing of tumour cell
It grows, migrate and invasive ability.
HGF and c-Met adjusts in many human cancers and promotes the growth of tumour, angiogenesis, invasion and transfer.c-
Met expression activation is by increasing anoxic caused by factor-1 α (HIF-1 α) hypoxia inducible and leading to the invasion of hypoxic tumor.
The expression that HIF-1 α reduce c-Met can be caused blood vessel to trim and trigger by VEGF inhibitor, to migrating, invasive tumour cell
There is selectivity with by metastasis tendency diffusion.
In conclusion quinolines noval chemical compound according to the present invention needs a kind of synthesis work of suitable industrialized production
Skill, product purity is high, and the tyrosine protein kinase inhibitor with multiple target point, their main function is by inhibiting junket ammonia
Pka acid is active and plays its effect.Certainly, it is also not excluded for this kind of compound and inhibits other sharp with the relevant albumen of disease
The possibility of enzyme.
Invention content
The object of the present invention is to provide a kind of synthesis technologies of suitable industrialized production, keep product purity high, have more targets
The tyrosine protein kinase inhibitor of point.
The first aspect of the present invention provides a kind of preparation method of type I compound (2):
(2) II compound of formula and sodium hydroxide, sodium carbonate, sodium bicarbonate, lithium hydroxide, potassium carbonate, sodium bicarbonate are used, or
A combination thereof etc. and other alkali well known by persons skilled in the art reaction, obtain type I compound.
Wherein:R1Selected from hydrogen, OH, NH2;R2It is C selected from ROH, RNH, wherein R1-C4Alkyl, halogenated C1-C4Alkyl;Ar is
Aryl or heteroaryl, and can be by halogen, C1-C4Alkyl, halogenated C1-C4Alkyl, C1-C4Alkoxy or halogenated C1-C4Alkoxy takes
Generation;Y is 0,1,2;X is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, grass
Acid, p-methyl benzenesulfonic acid etc. and other acid well known by persons skilled in the art;Z be 0,1,2H2O。
In another preferred example, in the step (2), the reaction temperature is 0 DEG C~50 DEG C, the reaction time 1~
12 hours.
In another preferred example, in the step (2), the reaction carries out in atent solvent, the inertia
Solvent be selected from benzene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile,
Ethyl acetate, absolute ethyl alcohol, or combinations thereof.
In another preferred example, in the step (2), the molar ratio of the type I compound and all kinds of acid is 1/
0.1~1/20.
In another preferred example, the method also optionally includes step (1):
It is reacted with compound A with III compound of formula, obtains II compound of formula:
Wherein, R2It is same as above with Ar.
In another preferred example, in the step (1), the reaction temperature is 0 DEG C~50 DEG C, the reaction time 1~
12 hours.
In another preferred example, in the step (1), the reaction carries out in atent solvent, the inertia
Solvent be selected from benzene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile,
Ethyl acetate, absolute ethyl alcohol, or combinations thereof.
In another preferred example, in the step (1), the reaction can carry out in the presence of with or without alkali;It is described
Alkali be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, or combinations thereof.
In another preferred example, in the step (1), II compound of the formula and the molar ratio of compound A are
1/0.1~1/100.
Beneficial effect of the present invention
Specific implementation mode
By comparing the research of synthetic route, finally it is determined that from III compound of formula be starting material prepare compound, obtains
The synthetic method of quinolines is arrived.The advantages that synthetic method is suitble to industrialized production, product purity is high, and have
There is antitumor activity.Compound obtained by this method, using hydrogen spectrum, Mass Spectrometric Identification.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.
Embodiment 1:
Synthesis step:
Step (1) is reacted:
500g cyclopropane -1,1- dicarboxylic acids { the fluoro- 4- of 3- [6- methoxyl groups -7- (piperidin-4-yl methoxies are added in a kettle
Base)-quinoline -4- oxygroups]-phenyl }-amide benzamide dihydrochloride and n,N-Dimethylformamide 2000ml, after stirring dissolved clarification
The temperature of reaction system is down to 0 DEG C, adds potassium carbonate 1500g, is reacted at room temperature 2 hours;The temperature of reaction system is down to 0
DEG C, ethyl chloroacetate 1250g is added, reacts at room temperature 2 hours;The temperature of reaction system is down to 0 DEG C, the ice water of 8000ml is delayed
Slow addition has a large amount of solids to be precipitated, and stirs 1 hour, until whole precipitations, filter, be washed with water 3 times;The nothing that filter cake is measured with 2 times again
Water-ethanol is beaten twice, and filtering, filter cake sets 40-70 DEG C of drying 4~8 hours;430g intermediates 1 are obtained, are in pale yellow powder.It receives
Rate:80%.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ6.69(1H),δ7.24(1H),δ7.18
(1H),δ8.0(1-NH),δ3.73(3H),δ8.0(1-NH),δ0.90(2H),δ0.90(2H),δ7.64(1H),δ7.24(1H),
δ7.00(1H),δ7.24(1H),δ7.64(1H),δ3.90(2H),δ2.00(1H),δ1.46(2H),δ2.24(2H),δ2.24
(2H),δ1.46(2H),δ3.32(2H),δ4.12(2H),δ1.30(3H)
Step (2) is reacted:
420g intermediates 1 are added in a kettle, the ethyl alcohol of 8 times of amounts is added, the temperature of system is down to 0 DEG C, 2 times are measured
Lithium hydroxide be added to reaction system, react at room temperature 4-5 hours;Reaction system is down to 0 DEG C, with hydrochloric acid tune pH to 7;In room
The lower revolving of temperature, is added a small amount of tetrahydrofuran and continues to rotate;Stop revolving and be slowly added to dichloromethane, stirring occurs a large amount of
Solid is precipitated, and filters, and filter cake is washed with water 3 times, and filter cake sets 40-70 DEG C of drying 4~8 hours;Obtain 300g compounds.Yield 70%,
M.p.214.0-216.2 DEG C of fusing point
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.52(2H),δ2.09(3H),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.64(1H),δ7.24(1H),δ0.90(2H),δ0.90
(2H)
m/z:640.27
Embodiment 2:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),,δ3.9(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.30(2H),δ11.0(1-OH),δ6.69(1H),
δ7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.52(1H),δ7.04(1H),δ7.04(1H),δ7.52
(1H),δ0.90(2H),δ0.90(2H),δ2.35(3H)
m/z:656.26
Embodiment 3:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.25(2H),δ6.0(2-NH),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.64(1H),δ7.24(1H),δ7.00(1H),δ7.04
(1H),δ7.24(1H),δ7.64(1H),δ0.90(2H),δ0.90(2H)
m/z:641.26
Embodiment 4:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.25(2H),δ6.0(2-NH),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.52(1H),δ7.04(1H),δ7.04(1H),δ7.52
(1H),δ0.90(2H),δ0.90(2H),δ2.35(3H)
m/z:655.28
Embodiment 5:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.25(2H),δ6.0(2-NH),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.62(1H),δ6.95(1H),δ6.95(1H),δ7.62
(1H),δ0.90(2H),δ0.90(2H)
m/z:659.26
Embodiment 6:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.25(2H),δ6.0(2-NH),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.53(1H),δ6.75(1H),δ7.53(1H),δ0.90
(2H),δ0.90(2H),δ3.73(3H)
m/z:671.28
Embodiment 7:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.30(2H),δ11.0(1-OH),δ6.69(1H),
δ7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.62(1H),δ6.95(1H),δ6.95(1H),δ7.62
(1H),δ0.90(2H),δ0.90(2H)
m/z:660.24
Embodiment 8:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.52(2H),δ2.09(2H),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.53(1H),δ6.75(1H),δ6.75(1H),δ7.53
(1H),δ0.90(2H),δ0.90(2H),δ3.73(3H)
m/z:670.28
Embodiment 9:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.30(2H),δ11.0(1-OH),δ6.69(1H),
δ7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.59(1H),δ7.10(1H),δ7.10(1H),δ7.59
(1H),δ0.90(2H),δ0.90(2H),δ2.59(2H),δ1.24(3H)
m/z:670.28
Embodiment 10:
Synthetic method is with reference to embodiment 1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.29(1H),δ7.32(1H),δ8.55(1H),δ6.47(1H),δ3.73(3H),δ3.90(2H),δ2.00
(1H),δ1.46(2H),δ2.24(2H),δ2.24(2H),δ1.46(2H),δ3.25(2H),δ6.0(2-NH),δ6.69(1H),δ
7.24(1H),δ7.18(1H),δ8.0(1-NH),δ8.0(1-NH),δ7.59(1H),δ7.10(1H),δ7.10(1H),δ7.59
(1H),δ0.90(2H),δ0.90(2H),δ2.59(2H),δ1.24(3H)
m/z:669.30
Embodiment 11:Tyrosine kinase activity inhibits body outer screening test
It studies compound to inhibit tyrosine kinase activity, uses IC50It indicates.
Experimental method:
Enzyme reaction substrate Poly (Glu, Tyr)4:120 μ g/ml are diluted to the PBS of no potassium ion, coated elisa plate sets 37
DEG C reaction 12-16 hours, discard liquid in hole;T-PBS board-washings three times, 10 minutes every time;The dry ELISA Plate in 37 DEG C of baking ovens;
Being coated with addition given the test agent in ELISA Plate hole, (given the test agent is first configured to the storing solution of 10-2M with DMSO, is stored after packing
In -20 DEG C, it is diluted to required concentration with reaction solution buffer solution before use, is added in experimental port, makes it in 100 μ l reaction systems
Reach corresponding final concentration);ATP and tested tyrosine kinase (the diluted ATP solution of addition reaction buffer, addition is added
With the diluted tested tyrosine kinase of reaction buffer);Reaction system total volume is 100ul.Simultaneously set up negative control hole and
Without enzyme control wells.Reaction system is placed in wet box, 37 DEG C of shaking tables are protected from light 1 hour, after reaction T-PBS board-washings three
It is secondary;Antibody is added, 37 DEG C of shaking tables react 30 minutes, and T-PBS board-washings are three times;The sheep anti mouse of horseradish peroxidase-labeled is added
IgG, 37 DEG C of shaking tables react 30 minutes, and T-PBS board-washings are three times;OPD developing solutions are added, room temperature is protected from light 1-10 minutes;It is added
2M H2SO450 μ l stopped reactions, with wavelengthtunable decline orifice plate microplate reader survey AB490Value.
Table 1 inhibits IC to tyrosine kinase activity50(nM)
Note:(1. A) 30nM or smaller;
2.(B)>30nM to 100nM;
3.(C)>100nM
Embodiment 12:Cell proliferation test
The proliferation inhibition activity for studying compound on intracellular, uses IC50It indicates.
Experimental method:Exponential phase cell removes the culture solution in culture bottle, PBS rinses cell one time, pancreatin digestion
It is collected by centrifugation, is resuspended with the culture medium containing 10% fetal calf serum, counts and be adjusted to suitable concentration.96 holes are added in cell suspension
Plate, per hole 100ul, compound is configured to 20mM solution with DMSO, compound solution and taxol (liquid storage 0.2mM) is used DMSO
Gradient dilution (10 concentration), the compound solution and paclitaxel solution for taking 5ul gradient dilutions good respectively are added to 495ul and contain
In the culture medium of 10%FBS, it is configured to testing compound solution.100ul testing compound solutions are taken to be added to 96 orifice plate corresponding apertures
In, carbon dioxide cell incubator culture 72 hours.Culture medium is removed, XTT working solutions 150ul is added per hole, carbon dioxide is trained
It supports and is placed 2 hours in case, microwell plate vibrates 5min, and microplate reader 450nm reads light absorption value.
The proliferation inhibition activity IC of 2 cell of table50(μM)
Note:1.(A)≤10μM;
2.(B)>10μM;
The above is only a preferred embodiment of the present invention, for those skilled in the art, exist
Without departing from the principles of the invention, several improvements and modifications can also be made, these improvements and modifications also should be regarded as this hair
Bright protection domain;Those skilled in the art can make various modifications or changes to the present invention, and such equivalent forms are equally fallen within
The scope of the appended claims of the present application.
Claims (3)
1. providing a kind of preparation method of formula (I) compound:
Type I compound is obtained by the reaction with II compound of formula;
Wherein:R1Selected from hydrogen, OH, NH2;R2It is C selected from ROH, RNH, wherein R1-C4Alkyl, halogenated C1-C4Alkyl;Ar be aryl or
Heteroaryl, and can be by halogen, C1-C4Alkyl, halogenated C1-C4Alkyl, C1-C4Alkoxy or halogenated C1-C4Alkoxy replaces;Y is
0、1、2;X is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, right
Toluenesulfonic acid etc. and other acid well known by persons skilled in the art;Z be 0,1,2H2O;The reaction temperature is 0 DEG C~50
DEG C, 1~12 hour reaction time;
The reaction carries out in atent solvent, and the atent solvent is selected from benzene, dichloromethane, chloroform, tetrahydrochysene furan
Mutter, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, ethyl acetate, absolute ethyl alcohol, or combinations thereof;
The reaction can carry out in the presence of with or without alkali;The alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, hydrogen
Lithia, potassium carbonate, sodium bicarbonate, or combinations thereof;
The molar ratio of the type I compound and acid is 1/0.1~1/20.
2. the method as described in claim 1, which is characterized in that the method also optionally includes step:
It is reacted with compound A with III compound of formula, obtains II compound of formula:
Wherein, R2It is C selected from ROH, RNH, wherein R1-C4Alkyl, halogenated C1-C4Alkyl;Ar is the same as described in claim 1;
The reaction temperature is 0 DEG C~50 DEG C, 1~12 hour reaction time;
The reaction carries out in atent solvent, and the atent solvent is selected from benzene, dichloromethane, chloroform, tetrahydrochysene furan
Mutter, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, ethyl acetate, absolute ethyl alcohol, or combinations thereof;
The reaction can carry out in the presence of with or without alkali;The alkali be selected from potassium carbonate, sodium carbonate, sodium bicarbonate or its
Combination;
The molar ratio of II compound of the formula and compound A are 1/0.1~1/100.
3. quinolines or combinations thereof object made from the method as described in claim 1 is the tyrosine egg for having multiple target point
White kinase inhibitor has good antitumor activity.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710176619.1A CN108623565A (en) | 2017-03-23 | 2017-03-23 | A kind of preparation method of compound |
PCT/CN2017/081677 WO2018170997A1 (en) | 2017-03-23 | 2017-04-24 | Method for preparing compound |
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WO2013040801A1 (en) * | 2011-09-19 | 2013-03-28 | 广州盈升生物科技有限公司 | Hydroxamic acid compound containing quinolyl and preparation method thereof, and pharmaceutical composition containing this compound and use thereof |
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WO2013040801A1 (en) * | 2011-09-19 | 2013-03-28 | 广州盈升生物科技有限公司 | Hydroxamic acid compound containing quinolyl and preparation method thereof, and pharmaceutical composition containing this compound and use thereof |
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