CN106986895A - Quinazoline ditosylate salt Mutiple Targets antitumoral compounds and its preparation method and application - Google Patents
Quinazoline ditosylate salt Mutiple Targets antitumoral compounds and its preparation method and application Download PDFInfo
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- CN106986895A CN106986895A CN201710304468.3A CN201710304468A CN106986895A CN 106986895 A CN106986895 A CN 106986895A CN 201710304468 A CN201710304468 A CN 201710304468A CN 106986895 A CN106986895 A CN 106986895A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 51
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- KVSLPQXJQYNHIK-UHFFFAOYSA-N c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O Chemical compound c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O KVSLPQXJQYNHIK-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 13
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 35
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 30
- -1 substituted-phenyl Chemical group 0.000 claims description 27
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 26
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
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- SRHDVFDLYAGCRL-UHFFFAOYSA-N ethyl 2-[[bis(2-chloroethyl)amino-[(2-ethoxy-2-oxoethyl)amino]phosphoryl]amino]acetate Chemical compound CCOC(=O)CNP(=O)(N(CCCl)CCCl)NCC(=O)OCC SRHDVFDLYAGCRL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 1
- LVBXOHCSIIQPRK-UHFFFAOYSA-N quinoline thionyl dichloride Chemical compound N1=CC=CC2=CC=CC=C12.S(=O)(Cl)Cl LVBXOHCSIIQPRK-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides a kind of quinazoline ditosylate salt Mutiple Targets antitumoral compounds as shown in chemical formula (I) and preparation method thereof, more particularly to EGFR, HER 2 and DNA Mutiple Targets antitumoral compounds, also provides its preparation method and the application in antineoplastic.Research shows that the compounds of this invention has significant antitumor activity, and metabolic stability is obviously improved relative to reference substance EMB 3.
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to EGFR, HER-2 and DNA Mutiple Targets antitumoral compounds and its preparation
Method, and its application in treatment tumour.
Background technology
The generation of tumour and the complicated biological process that development is that multifactor effect, a polygenes are participated in, single medicine
The treatment method of the single target spot of thing often has the problem of unsatisfactory curative effect, toxic side effect drug resistance occur greatly and easily.Mesh
Before, the treated with combined medication frequently with a variety of different mechanism of action is passed through in clinical treatment, the problem of to overcome above-mentioned.According to this
One clinical experience, scientist has designed and synthesized many small-molecule drugs with multiple target effect mechanism, pharmacological evaluation
Prove, this thinking is feasible.
EGFR micromolecular inhibitors are the antineoplastics listed in recent years, and therapeutic effect is notable, but in clinical practice
In, due to such medicine because whole act on can constantly produce variation during ATP-binding site, thus use, and then produce
Raw drug resistance, reduces curative effect of medication.Moreover, many cells express EGFR and HER-2 acceptors simultaneously so that EGFR inhibitor
Therapeutic effect substantially reduce.This requires design and effective to mutation receptor while act on EGFR and HER-2
New inhibitor.
Endoxan is a kind of DNA alkylating agents antineoplastics applied for many years, but serious toxic side effect limitation
Application clinically.Although having there is scientist to combine EGFR micromolecular inhibitors and DNA alkylating agents to devise
A series of pair of target drug molecule, but the antitumor activity of this kind of compound is general.
According to the theory of Mutiple Targets drug design, and this experimental group is for many years about Cyclophosphamide quaternary ammonium salt derivant
Research foundation, the precursor structure of EGFR/HER-2 inhibitor is combined with Glyciphosphoramide by suitable linking arm, is designed and is closed
Into the 4- fragrant amino quinazoline phosphamide nitrogen mustards inhibitor of a class EMB-3, the existing EGFR/HER-2 acceptors suppression of the compound
System activity, there is DNA alkanisations again, and without the obvious toxic side effect of discovery, but in vivo studies proves that its accretion rate is fast,
Half-life in vivo is short.To improve the metabolic stability of such compound, we are according to the principle design of skeleton transition and synthesize
A series of EGFR/HER-2/DNA damage Mutiple Targets compounds of cyclic structures, it is desirable to increase such compound in vivo steady
It is qualitative, increase Antitumor Activity of Drugs, reduce the dosage of medicine.
The content of the invention
Mutiple Targets compound is damaged the invention provides a kind of EGFR/HER-2/DNA of cyclic structure, the compound has
Structure as shown in chemical formula (I)：
Wherein, R1Selected from hydrogen, lower alkoxy；It preferably is selected from hydrogen, methoxy or ethoxy.
R2Selected from substituted or unsubstituted phenyl, the substituted phenyl refers to phenyl by one or more halogens, C1-C4
Alkynyl, low alkyl group, lower alkoxy or alkoxy aryl substitution；It preferably is selected from the chloro- 4- fluorine of 3- bromines, 3-, 3- acetenyls or 3- chlorine
- 4- (3- fluorine benzyloxy), 3- trifluoromethyls, 3- benzyloxies.
R3Selected from hydrogen, cyano group；It preferably is selected from hydrogen.
A is O or NH；
It is defined in the present invention：
" low alkyl group " can be C1-C6 alkyl or substituted alkyl, for example, methyl, ethyl, propyl group, isopropyl
Base, cyclopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclobutyl etc., when for substituted alkyl, substituent can be example
Such as halogen or substituted-phenyl.
" lower alkoxy " can be C1-C6 alkoxies or substituted alkoxy, for example, methoxyl group, ethyoxyl,
Isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, just oneself
Epoxide, dissident's epoxide etc., when for substituted alkoxy, substituent can be such as halogen or substituted-phenyl.
" alkoxy aryl " can be such as benzyl epoxide or rudimentary substituted benzyl epoxide, the rudimentary substituent
One or more halogens, amino or C1-C4 alkyl on phenyl ring, C1-C4 alkoxies etc. can be provided at.
" halogen " is chlorine, fluorine or bromine.
The compound of the present invention may include, but be not limited to following preferred compound, and its structure is as shown in the table：
Present invention also offers the preparation method of the Mutiple Targets compound shown in chemical formula (I)：
Wherein, when A is O and R1For hydrogen, R2、R3The synthetic route one of compound when being defined such as afore mentioned chemical formula (I)
It is as follows：
Synthetic route one：
Reagent conditions and reaction：a)Et3N, reacts at room temperature；b)HCONH2, 160 DEG C；c)Ac2O, 100 DEG C；d)SOCl2, return
Stream；
E) substituted aniline, i-PrOH, Et3N, backflow；f)NH3OH, CH3OH, room temperature reaction；G) 3, DIAD, PPh3,
CH2Cl2.
Dichlor-phosphoryl mustargen obtains 2- (double (2- chloroethyls) amino) -5- hydroxyls with the reaction of 3- amino -1,2- dihydroxypropane
Methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides.
5- hydroxyl -2- aminobenzoic acids obtain 4,6- dihydroxy quinazolines with formamide high temperature cyclization；Then 6-OH is selected
Property acetylation, obtains 6- acetoxyl group -4- hydroxyquinazolines, then be reacted to 6- acetoxyl group -4- chloroquine azoles with thionyl chloride
Quinoline, it is not purified that 4- substitution phenylamino -6- acetoxyl group quinazolines are directly obtained with substituted aniline reaction, then in ammoniacal liquor/first
Deacetylation obtains 4- substituted anilinic -6- hydroxyquinazolines in alcohol system；It is last different in triphenylphosphine, azoformic acid two
Under the conditions of propyl ester, with 2- (double (2- chloroethyls) amino) -5- methylols -1,3, the reaction of 2- oxynitride phosphor heterocycle pentane -2- oxides
Obtain the compound shown in the formula (I) of part.
Wherein, when A is O and R1For methoxyl group, R2、R3The synthesis road of compound when being defined such as afore mentioned chemical formula (I)
Line two is as follows：
Synthetic route two：
Reagent and reaction condition：a)SOCl2, DMF (cat.), backflow；b)NH4OH, Methanol, room temperature reaction；C) 3,
PPh3, DTAD, DCM, room temperature reaction；D) substituted aniline, DMF, 90 DEG C
7- methoxyl group -4- hydroxyquinazoline -6- alcohol acetic esters flow back in thionyl chloride obtains 7- methoxyl group -4- chloroquine azoles
Quinoline -6- alcohol acetic esters, the not purified deacetylation in ammonia hydroxide/methanol system obtains 6- hydroxyl -7- methoxyl group -4- chloroquine azoles
Quinoline；Then under the conditions of triphenylphosphine, azoformic acid di-t-butyl ester, with 2- (double (2- chloroethyls) amino) -5- hydroxyl first
Base -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides reaction obtains double (2- chloroethyls) amino -5- (the chloro- 7- methoxyl groups of 4-) of 2-
Quinazoline methyl ether -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides；Finally heating response is obtained in DMF with substituted aniline
Compound shown in the formula (I) of part.
Wherein, when A is NH and R1For hydrogen, R2、R3The synthetic route three of compound when being defined such as afore mentioned chemical formula (I)
It is as follows：
Synthetic route three：
Reagent and reaction condition：a)HCONH2, 160 DEG C；b)SOCl2, DMF；c)CH3OH, NH4OH, substituted aniline, room temperature
Reaction；
d)(NH2CH2)2CHOH, Cul, t-BuONa, DMF, backflow；e)Cl2PON(CH2CH2Cl)2, Et3N, i-PrOH, 80
℃
2- amino -5- iodo-benzoic acids add after excessive formamide cyclization under high temperature and obtain the iodo- 4- hydroxyquinazolines of 6-, then with
Thionyl chloride backflow obtains the chloro- 6- iodine quinazolines of 4-, then not purified that the iodo- 4- virtues of 6- are directly obtained with substituted aniline reaction
Amido quinazoline intermediate.Then under argon gas protection, using DMF as solvent, the CuI Ullmann reactions being catalyzed and 2- hydroxyls are passed through
The reaction of base -1,3- diaminopropanes obtains intermediate 1- amino -3- ((4- substituted anilinics quinazoline) 6- amino) propane diols,
The compound shown in the formula (I) of part is finally obtained with phosphinylidyne dichloro mustargen cyclization.
Present invention also offers the Mutiple Targets compound shown in chemical formula (I) in the application of anti-tumor aspect, research display
It has significant antitumor activity.
Embodiment
The present invention is further described in detail with reference to embodiment, the embodiment provided is only for explaining
The bright present invention, the scope being not intended to be limiting of the invention.
Embodiment 1：Double (2- chloroethyls) amino -5- (6- (4- (the 3- bromobenzenes amido) quinazoline) oxygen) methyl isophthalic acids of 2- are prepared,
3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a1)
1st, 2- (double (2- chloroethyls) amino) -5- methylols -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides (3) is synthesized
3- amidos -1,2-PD (5.54g, 60.8mmo1) is dissolved in 100mL isopropanols, adds dichlor-phosphoryl mustargen
(15.7 g, 60.8mmol) and triethylamine (12.3g, 121.6mmol), is stirred at room temperature 24 hours.After reaction terminates, suction filtration, filter
Liquid extracts three times (150mL × 3) after being evaporated with ethyl acetate and water, is washed after merging organic layer with saturated nacl aqueous solution three times,
Plus concentrated after anhydrous sodium sulfate drying, dodge post separation (dichloromethane:Methanol=40:1) 9.08g Off-white solids, are obtained, are produced
Rate 54%.Mp:98℃.
1H NMR(400MHz,CDCl3)δ4.53(m,1H),3.84(d,1H),3.63(m,6H),3.44(m,6H),3.32
(d, 1H)
13C NMR(101MHz,CDCl3)δ78.71,63.56,49.09,43.07,42.24.
31P NMR(162MHz,CDCl3)δ30.37.
2nd, synthesis 4,6- dihydroxy quinazoline (5)
5- hydroxyl -2- aminobenzoic acids (45.00g, 150mmol) are added in 200mL formamides, 1h is reacted at 150 DEG C,
Produce a large amount of solids.After cooling, add water suction filtration, drying, obtains light coffee color metallic luster scale sample solid 21.25g, yield
86%.Mp>300℃
1H NMR(400MHz,DMSO)δ12.02(s,1H),10.05(s,1H),7.90(s,1H),7.61–7.49(m,
1H), 7.42 (s, 1H), 7.25 (d, J=7.8Hz, 1H)
13C NMR(101MHz,DMSO)δ161.04,156.58,142.66,142.37,129.29,124.12,109.19.
3rd, synthesis 4- hydroxyl -6- acetoxyl groups quinazolines (6)
4,6- dihydroxy quinazoline (23.50g, 145mmol) and 30mL pyridines are added in 220mL acetic anhydrides, 100 DEG C
Lower reaction 2h.After cooling, pour into trash ice, separate out a large amount of solids, suction filtration, drying obtains light tan solid 30.00g, yield
84%.Mp:130-132℃
4th, 4- (3- bromoanilinos) -6- acetoxyl groups quinazoline (8) is synthesized
Compound 6- acetoxyl group -4- hydroxyquinazolines (15.00g, 60mmol) and DMF (10mL) are added to 80mL bis-
In chlorine sulfoxide, 5h is answered in backflow.Decompression boils off thionyl chloride, then the chlorination for taking away residual is rotated with ethyl acetate (100mL × 3)
Sulfoxide, obtains yellow solid.Addition 100mL isopropanols, 3- bromanilines (12.00g, 70mmol) and triethylamine (9.00 g,
90mmol), flow back at 80 DEG C 6h.Cooling, suction filtration is washed with isopropanol, water and ether successively, is dried, is obtained faint yellow solid,
15.30g, yield 71%.Mp:238-239℃
1H NMR(300MHz,DMSO-d6):δ 2.40 (s, 3H), 7.44-7.54 (m, 2H), 7.78 (d, J=7.5Hz,
1H), 7.93-8.09(m,3H),8.67(s,1H),8.99(s,1H),11.39(s,1H).
5th, 4- (3- bromoanilinos) -6- hydroxyquinazolines (9) are synthesized
4- (3- bromoanilinos) -6- acetoxyl groups quinazoline (15.00g, 40mmol) and concentrated ammonia liquor 50mL are added to 150mL
In methanol, room temperature reaction is stayed overnight.Concentration, add water suction filtration, drying, obtains Tan solid 12.10g, yield 95%.Mp>300 ℃.
1H NMR(400MHz,DMSO)δ10.10(s,1H),9.58(s,1H),8.51(s,1H),8.27(s,1H),7.93
(d, J=7.7Hz, 1H), 7.79 (s, 1H), 7.70 (d, J=8.9Hz, 1H), 7.45 (d, J=8.6Hz, 1H), 7.33 (t, J
=7.9Hz, 1H), 7.26 (d, J=7.6Hz, 1H)
6th, double (2- chloroethyls) amino -5- (6- (4- (3- bromobenzenes amido) quinazoline) oxygen) methyl isophthalic acids, 3,2- oxygen of synthesis 2-
Nitrogen phospholane -2- oxides (numbering：10a1)
2- (double (2- chloroethyls) amino) -5- methylols -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides (1.00g,
3.6mmol) it is suspended in 6mL dichloromethane, is stirred at 0 DEG C with triphenylphosphine (1.04g, 4mmol).DIAD is slowly added dropwise, it is molten
Liquid is in faint yellow clarification, reacts 1h at 0 DEG C.Add 4- (3- bromoanilinos) -6- hydroxyquinazolines (0.40g, 1mmol), reaction
Overnight, solution is changed into brown clarification from yellow green muddiness.After reaction terminates, system adds methylene chloride and water extraction, anhydrous slufuric acid
Sodium is concentrated after standing, and dodges post (dichloromethane:Methanol=60:1) weak yellow foam shape solid 372mg, yield 18%, are obtained. Mp：
84-87℃。
1H NMR(400MHz,CDCl3)δ9.57(s,1H),8.62(s,1H),8.15(s,1H),7.97(m,2H),7.67
(m, 2H),7.30(s,1H),7.20(s,2H),4.87(s,1H),4.66–4.50(m,1H),4.19(m,1H),3.85–3.54
(m,6H), 3.39(m,5H).
13C NMR(101MHz,CDCl3)δ157.55,157.10,152.38,144.21,140.62,129.95,
128.38,126.72, 125.49,124.69,122.15,120.58,115.83,103.59,77.24,71.19,48.74(d,
), J=5.0Hz 43.74 (d, J=9 Hz), 42.13.
31P NMR(162MHz,CDCl3)δ29.25.
HRMS(ESI+)m/z calcd for C21H24BrCl2N5O3P(M+H)+574.01717,found 574.01751.
Embodiment 2：Prepare double (2- chloroethyls) amino -5- of 2- (6- (4- (3 '-chloro- 4 '-(3 "-fluorine benzyloxy) phenylamino)
Quinazoline) oxygen) methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a2)
1st, synthesis 6- hydroxyl -7- methoxyl group -4- chloro-quinazolines (13)
7- methoxyl group -4- hydroxyquinazoline -6- alcohol acetic esters (4.68g, 20mmol) and DMF (0.4mL) are added to 25mL
In thionyl chloride, flow back 5 hours.Decompression boils off thionyl chloride, then is rotated with chloroform (10mL × 3) and toluene (10mL × 2)
The thionyl chloride of residual is taken away, 7- methoxyl group -4- chloro-quinazoline -6- alcohol acetic esters are obtained.It is not purified, add it to dense ammonia
In methanol (70mL) solution of water (35mL), it is stirred at room temperature 3 hours, suction filtration, filter cake is washed with ether obtains 6- hydroxyl -7- methoxies
Base -4- chloro-quinazolines, pale white solid 3.61g, yield 84.6%.
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.79(s,1H),7.39(s,1H),7.37(s,1H),
4.01 (s,3H).
13C NMR(101MHz,DMSO-d6)δ157.64,157.03,151.78,150.34,148.24,119.37,
107.43, 105.73,56.84.
2nd, double (2- chloroethyls) amino -5- (6- (the chloro- 7- methoxyquinazoline hydrochlorides of 4-) oxygen) methyl isophthalic acids, 3,2- oxygen nitrogen of synthesis 2-
Phospholane -2- oxides (14)
By 6- hydroxyl -7- methoxyl group -4- chloro-quinazolines (211mg, 1.0mmol), 2- (double (2- chloroethyls) amino) -5- hydroxyls
Methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (333mg, 1.2mmol), triphenylphosphine (341mg, 1.3mmol) adds
Enter into anhydrous methylene chloride (15mL), argon gas protection.It is stirred at room temperature down and DTAD (300mg, 1.3mmol) is slowly added dropwise, number
Minute is stirred at room temperature 12 hours after dripping off, and reaction solution directly mixes sample, dodges post separation (dichloromethane：Ethyl acetate=1:1 → bis-
Chloromethanes：Ethyl acetate：Methanol=40:40:1) white solid 397mg, yield 84.5% are obtained.
1H NMR(400MHz,DMSO-d6) δ 8.86 (s, 1H), 7.42 (s, 2H), 5.12 (d, J=16.0Hz, 1H), 4.88
(m, 1H), 4.33 (d, J=5.3Hz, 2H), 4.02 (s, 3H), 3.70 (m, 4H), 3.51 (m, 1H), 3.33 (dd, J=13.0,
4.9Hz, 4H)
13C NMR(101MHz,DMSO-d6)δ158.53,157.08,152.79,150.52,149.10,118.89,
107.54, 104.14,75.78,70.97,57.06,48.70,43.55,42.89.
3rd, double (2- chloroethyls) amino -5- of synthesis 2- (6- (4- (3 '-chloro- 4 '-(3 "-fluorine benzyloxy) phenylamino) quinoline azoles
Quinoline) oxygen) methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a2)
By double (2- chloroethyls) amino -5- (the chloro- 7- methoxyl groups of the 4-) quinazoline methyl ether -1,3,2- oxynitride phosphor Polymorphs of 2-
Alkane -2- oxides (170mg, 0.362mmol), the chloro- 4- of 3- (3- fluorine benzyloxy) aniline (109mg, 0.434mmol) is added to
In DMF (5mL), 100 DEG C are stirred 10 hours, and reaction is cooled down after terminating, and add ethyl acetate (10mL), suction filtration, filter cake is used a large amount of
Ethyl acetate is washed.Sample is directly mixed after filtrate is evaporated, post separation (dichloromethane is dodged：Ethyl acetate=1:1 → dichloromethane：
Ethyl acetate：Methanol=40:40:1) yellow solid 42mg, yield 16.9%, Mp are obtained:108-110℃
1H NMR(400MHz,DMSO-d6) δ 9.53 (s, 1H), 8.46 (s, 1H), 7.99 (d, J=2.5Hz, 1H), 7.93
(s, 1H), 7.74 (d, J=9.0Hz, 1H), 7.47 (dd, J=12.0,4.3Hz, 1H), 7.35-7.15 (m, 5H), 5.24 (s,
3H), 4.90 (d, J=5.8Hz, 1H), 4.32 (d, J=44.4Hz, 2H), 3.94 (s, 3H), 3.68 (d, J=6.9Hz, 4H),
(s, the 1H) of 3.55 (d, J=13.4Hz, 1H), 3.37 (s, 1H), 3.31 (s, 1H), 3.25 (s, 1H), 3.03
13C NMR(101MHz,DMSO-d6)δ164.71,163.89,161.49,156.82,154.78,153.54,
149.83, 148.20,147.57,140.25,134.19,131.03,130.97,124.17,123.79,122.33,
121.59,115.24,115.04, 114.90,114.61,114.39,109.15,108.03,76.03,71.25,70.01,
56.38,48.66,46.20,42.86.
31P NMR(162MHz,DMSO-d6)δ29.92.
HRMS:m/z calcd.for C29H31Cl3FN5O5P[M+H]+684.110693；found 684.11057.
Embodiment 3：Prepare double (2- chloroethyls) amino -5- (6- (4- (the chloro- 4- fluoroanilinos of the 3-) quinazoline) oxygen) first of 2-
Base -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a3)
Synthetic method is with compound 10a2.Faint yellow solid, is denoted as 10a3, yield 22.6%, Mp:112-114℃
1H NMR(400MHz,CDCl3) δ 9.37 (s, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 8.12 (d, J=6.7Hz,
1H), 7.96-7.85 (m, 1H), 7.21 (s, 1H), 7.10 (t, J=8.9Hz, 1H), 4.97 (dt, J=17.1,8.7Hz,
1H), 4.72 (dd, J=13.2,9.4Hz, 1H), 4.32 (dd, J=13.3,2.4Hz, 1H), 4.00 (s, 3H), 3.73 (dd, J
=17.2,8.7Hz, 1H), 3.58 (t, J=6.5Hz, 4H), 3.40 (d, J=43.0Hz, 5H), 3.19 (d, J=15.9Hz,
1H).
13C NMR(101MHz,CDCl3)δ157.00,154.85,153.79–153.59(m),152.91,148.52,
(d, J=1.7Hz), 136.60,123.26 121.07 (d, J=4.1Hz), 120.43 (d, J=18.3Hz), 116.25,
116.03,109.45,107.28,106.01 (s), 77.31, (d, J=21.1Hz), 72.34,56.21,48.74 (d, J=
5.1Hz), 43.32 (d, J=9.6Hz), 42.01.
31P NMR(162MHz,CDCl3)δ29.93.
HRMS:m/z calcd.for C22H25Cl3FN5O4P[M+H]+578.068829；found 578.06898.
Embodiment 4：Double (2- chloroethyls) amino -5- (6- (4- (3- bromoanilinos) quinazoline) oxygen) methyl isophthalic acids of 2- are prepared,
3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a4)
Synthetic method is with compound 10a2.Faint yellow solid, is denoted as 10a4, yield 7.5%, Mp:117-119℃
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.63(s,1H),8.16(s,1H),8.11(s,1H),7.99
(d, J=7.4Hz, 1H), 7.19 (dd, J=13.6,5.5Hz, 3H), 4.91 (s, 1H), 4.71-4.56 (m, 1H), 4.25 (d,
J=12.9Hz, 1H), 3.95 (s, 3H), 3.65 (dd, J=17.2,8.7Hz, 1H), 3.60-3.51 (m, 4H), 3.43 (d, J
=12.3Hz, 4H), 3.36 (s, 2H)
13C NMR(101MHz,CDCl3)δ156.96,154.74,153.74,148.38,147.53,141.35,
129.95, 125.99,124.01,122.17,119.89,109.59,107.47,105.81,77.26,72.14,56.17,
48.72 (d, J=5.1Hz), 43.38 (d, J=9.5Hz), 42.16.
31P NMR(162MHz,CDCl3)δ29.01.
HRMS:m/z calcd.for C22H26BrCl2N5O4P[M+H]+604.027735；found 604.02691.
Embodiment 5：Prepare double (2- chloroethyls) amino -5- (6- (4- (3- ethynylanilinos) quinazoline) oxygen) first of 2-
Base -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10a5)
Synthetic method is with compound 10a2.Tan solid, is denoted as 10a5, yield 19.9%, Mp:113-115℃
1H NMR(400MHz,CDCl3) δ 9.30 (s, 1H), 8.64 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=6.2Hz,
2H), 7.30 (t, J=8.2Hz, 1H), 7.19 (d, J=7.1Hz, 2H), 4.93 (dt, J=16.2,8.0Hz, 1H), 4.67
(dd, J=13.0,9.2Hz, 1H), 4.26 (d, J=13.0Hz, 1H), 3.97 (s, 3H), 3.67 (q, J=8.8Hz, 1H),
(s, the 1H) of 3.56 (t, J=5.8Hz, 4H), 3.50-3.27 (m, 6H), 3.06
13C NMR(101MHz,CDCl3)δ157.08,154.60,154.00,148.30,147.75,140.00,
128.74, 126.91,124.69,122.27,122.06,109.67,107.65,105.83,83.89,77.32,76.90,
(72.24,56.19,48.75 d, J=5.1Hz), 43.34 (d, J=9.5Hz), 42.24.
31P NMR(162MHz,CDCl3)δ28.87.
HRMS:m/z calcd.for C24H27Cl2N5O4P[M+H]+550.117223；found 550.11609.
Embodiment 6：Prepare the iodo- 4- of intermediate 6- (halo phenylamino) quinazoline (numbering：17b-17g)；
1st, 6- iodo- 4- (3- bromoanilinos) quinazoline (17b) is synthesized
The iodo- 4- hydroxyquinazolines (2.72g, 10mmol) of 6- and DMF (0.2mL) are added in 24mL thionyl chlorides, flowed back
5h.Decompression boils off thionyl chloride, then the thionyl chloride for taking away residual is rotated with ethyl acetate (100mL × 3), obtains yellow and consolidates
The chloro- 6- iodine quinazolines of body 4-.Addition 20mL isopropanols, 3- bromanilines (2.06g, 12mmol) and triethylamine (1.00g,
10mmol), 80 DEG C of backflow 6h.Cooling, suction filtration, the filtrate continuation that adds diethyl ether separates out solid, obtained solid massive laundering and again
Secondary suction filtration, drying, obtains light yellow solid 3.61g, yield 84.6%, Mp：197–199℃.
1H NMR(400MHz,DMSO-d6) δ 10.90 (s, 1H), 9.22 (s, 1H), 8.84 (s, 1H), 8.23 (dd, J=
8.2,3.4Hz, 1H), 8.13 (s, 1H), 7.85 (dd, J=8.2,3.4Hz, 1H), 7.64 (d, J=8.7Hz, 1H), 7.40
(t, J=9.0 Hz, 1H)
13C NMR(101MHz,DMSO-d6)δ157.84,152.05,143.47,141.3,138.94,132.65,
130.52, 128.31,126.16,123.9,122.6,121.12,115.6,93.69.
Embodiment 7：Prepare 6- iodo- 4- (the chloro- 4- fluoroanilinos of 3-) quinazoline (17c)
Synthetic method is with compound 17b.White solid, is denoted as 17c, yellow solid, yield 95.1%, Mp:162–165
℃。
1H NMR(400MHz,DMSO-d6) δ 10.77 (s, 1H), 9.15 (s, 1H), 8.80 (s, 1H), 8.22 (d, J=
8.7Hz, 1H), 8.15 (dd, J=6.7,2.3Hz, 1H), 7.84 (dd, J=8.2,3.4Hz, 1H), 7.64 (d, J=8.7Hz,
1H), 7.49 (t, J=9.0Hz, 1H)
13C NMR(101MHz,DMSO-d6)δ156.18,154.52,152.11,150.02,147.86,143.16,
137.78 (d, J=2.9Hz), 129.2,124.3,123.24,122.17 (d, J=6.6Hz), 119.14 (d, J=
18.3Hz), 117.01 (d, J=7.4 Hz), 116.76,101.28.
Embodiment 8：Prepare 6- iodo- 4- (3- 3-ethynylphenylaminos) quinazoline (numbering：17d)
Synthetic method is with compound 17b.Light yellow solid, is denoted as 17d, yield 80.0%, Mp:185-186℃.
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.01(s,1H),8.67(s,1H),8.24–8.02(m,
2H), 7.95 (d, J=8.0Hz, 1H), 7.58 (d, J=8.7Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.26 (d, J=
7.5Hz,1H), 4.21(s,1H).
13C NMR(101MHz,DMSO-d6)δ156.85,155.17,149.30,141.90,139.76,131.92,
130.28, 129.40,127.39,125.41,123.14,122.28,117.37,92.15,83.91,81.08.
Embodiment 9：Prepare 6- iodo- 4- (3 '-chloro- 4 '-(3 "-fluorine benzyloxy) phenylamino) quinazoline (numbering：17e)
Synthetic method is with compound 17b.Off-white powder, is denoted as 17e, yield 93.0%, Mp:221–224℃.
1H NMR(400MHz,DMSO-d6) δ 9.84 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.10 (d, J=
8.6Hz, 1H), 8.05 (s, 1H), 7.77 (d, J=8.8Hz, 1H), 7.56 (d, J=8.7Hz, 1H), 7.48 (dd, J=
13.9,7.8Hz, 1H), 7.38-7.24 (m, 3H), 7.19 (t, J=8.5Hz, 1H), 5.26 (s, 2H)
13C NMR(101MHz,DMSO-d6)δ163.65,161.23,156.53,155.03,149.98,148.97,
(d, J=7.7Hz), 141.52,139.87 133.23,131.59,130.77 (d, J=8.0Hz), 130.01,124.16,
(123.53,122.30,121.30,117.05,114.92 d, J=20.8Hz), 114.42 (d, J=13.6Hz), 114.14,
91.74,69.63.
Embodiment 10：Prepare 6- iodo- 4- (3- benzotrifluorides amino) quinazoline (numbering：17f)
Synthetic method is with compound 17b.Light gray solid, is denoted as 17f, yield 78.2%, Mp:149-151℃.
1H NMR(400MHz,DMSO-d6) δ 11.84 (s, 1H), 9.42 (s, 1H), 9.01 (s, 1H), 8.39 (dd, J=
8.7,1.6Hz, 1H), 8.20 (s, 1H), 8.13 (d, J=8.2Hz, 1H), 7.80 (d, J=8.7Hz, 1H), 7.78-7.64
(m,2H).
13C NMR(101MHz,DMSO-d6)δ158.50,151.46,144.14,139.23,137.70,132.98,
(129.98,129.53,129.21,128.13,125.27,122.73 d, J=8.2Hz), 122.32,120.79 (d, J=
9Hz),115.39,94.23.
Embodiment 11：Prepare 6- iodo- 4- (3 '-benzyloxy) phenylaminos quinazoline (numbering：17g)
Synthetic method is with compound 17b.Light yellow solid, is denoted as 17g, yield 89.7%, Mp:175–176℃.
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.65(s,1H),8.20–8.04(m,1H),7.71(s,
1H), 7.58 (d, J=8.7Hz, 1H), 7.53-7.39 (m, 5H), 7.36 (d, J=7.2Hz, 1H), 7.32 (t, J=8.1Hz,
1H), 6.82 (dd, J=8.1,1.8Hz, 1H), 5.14 (s, 2H)
13C NMR(101MHz,DMSO-d6)δ158.89,156.77,155.21,149.34,141.84,140.47,
137.51, 131.85,130.21,129.70,128.91,128.30,128.14,117.44,115.03,110.48,
109.38,92.02,69.74.
Embodiment 12：Prepare 2- (double (2- chloroethyls)) amino -5- (6- (4- (3- bromoanilinos) quinazoline) amino) first
Base -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10b)
By the iodo- 4- of 6- (3- bromanilines) quinazoline (5mmol, 2.13g), 2- hydroxyls -1,3- propane diamine (10mmol,
Dry there-necked flask 0.92g) is added with catalyst CuI (4%, 0.04g) with sodium tert-butoxide (5mmol, 0.48g), argon gas is protected
Shield, injection 12mL DMF.80 DEG C of constant temperature back flow reaction 4h.Filtering, adds 50mL distilled water, and filtrate is extracted with ethyl acetate 3
It is secondary, each 50mL.Merging filtrate, anhydrous Na2SO4Concentrated after drying.Crude product yellowish-brown oily liquids is obtained, without isolation directly
For next step reaction.By yellowish-brown oily liquids crude product obtained in the previous step, triethylamine (0.36mL, 5mmol) adds 10mL
Isopropanol stirs 1min.Phosphinylidyne dichloro mustargen (1.30g, 5mmol) is added into system again, 12h is stirred at room temperature.Plus distilled water
50mL, is extracted with ethyl acetate 3 times, each 50mL.Merging filtrate, after drying, with silica gel column chromatography (dichloromethane：Methanol=
50: 1 → 20: 1) separate.Obtain glassy yellow foaming solid 0.170g, two step gross production rates 11.8%, Mp:85–87℃.
1H NMR(400MHz,CDCl3)δ9.57(s,1H),8.62(s,1H),8.15(s,1H),7.97(m,2H),7.67
(m, 2H),7.30(s,1H),7.20(s,2H),4.87(m,1H),457(m,1H),4.17(m,1H),3.41-3.59(m,
6H), 3.32-3.37(m,5H).
13C NMR(101MHz,CDCl3)δ157.55,157.10,152.38,144.21,140.62,129.95,
128.38,126.72, 125.49,124.69,122.15,120.58,115.83,103.59,48.77,48.72,43.78,
43.69,42.13.
31P NMR(162MHz,CDCl3)δ29.25.
HRMS(ESI+)m/z calcd for C21H25BrCl2N6O2P(M+H)+573.03316,found 573.03318.
Embodiment 13：Prepare 2- (double (2- chloroethyls)) amino -5- (6- (4- (the chloro- 4- fluoroanilinos of 3-) quinazoline) ammonia
Base) methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10c)
Synthetic method is with compound 10b.Yellow foamy solid, is denoted as 10c, yield 8.67%, Mp:112–117℃.
1H NMR(400MHz,DMSO-d6) δ 9.88 (s, 1H), 8.44 (s, 1H), 8.24 (dd, J=6.8,2.5Hz, 1H),
7.96 (ddd, J=8.9,4.2,2.8Hz, 1H), 7.57 (d, J=9.0Hz, 1H), 7.48 (d, J=2.0Hz, 1H), 7.43 (t,
J=9.1Hz, 1H), 7.35 (dd, J=9.0,2.1Hz, 1H), 6.65 (t, J=6.0Hz, 1H), 4.67 (dt, J=8.7,
6.1Hz, 1H), 3.71-3.61 (m, 4H), 3.55 (dd, J=14.0,7.0Hz, 2H), 3.48-3.41 (m, 1H), 3.38-
3.29 (m, 4H), 3.24 (d, J=10.9Hz, 2H)
13C NMR(101MHz,DMSO-d6)δ156.07,154.34,149.13,147.75,141.06,136.85,
127.28,124.30,123.21,122.12,118.76 (d, J=18.4Hz), 116.52,116.24 (d, J=12.1Hz),
97.11,77.68,54.86,48.17,44.46 (d, J=9.4Hz), 42.28.
31P NMR(162MHz,CDCl3)δ29.21.
HRMS(ESI+)m/z calcd for C21H23Cl3FN6O2P(M+H)+547.03316,found 547.02883.
Embodiment 14：Prepare 2- (double (2- chloroethyls)) amino -5- (6- (4- (3- 3-ethynylphenylaminos) quinazoline) amino)
Methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10d)
Synthetic method is with compound 10b.Pale yellow foam solid, is denoted as 10d, yield 11.43%, Mp:93–97℃.
1H NMR(400MHz,DMSO-d6) δ 9.48 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.99 (d, J=
8.0Hz, 1H), 7.58 (s, 2H), 7.28 (dd, J=9.1,6.6Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 7.05 (d, J=
8.3Hz, 1H), 4.85 (s, 1H), 4.63-4.46 (m, 1H), 3.63 (d, J=10.8Hz, 2H), 3.51 (dd, J=14.5,
7.9Hz, 5H), 3.36 (dd, J=11.9,6.2Hz, 2H), 3.30-3.15 (m, 4H), 3.08 (s, 1H)
13C NMR(101MHz,DMSO-d6)δ157.08,150.69,146.89,142.58,139.77,130.94,
128.77 (d, J=11.5Hz), 127.91,127.23,125.18,123.80,122.59,122.25,116.79,99.19,
83.83,79.48,49.41,48.82,44.46 (d, J=9.5Hz), 42.26.
31P NMR(162MHz,CDCl3)δ29.34.
HRMS(ESI+)m/z calcd for C23H26Cl2N6O2P(M+H)+519.12264,found 519.12247
Embodiment 15：Prepare 2- (double (2- chloroethyls)) amino -5- (6- (4- (3 '-chloro- 4 '-(3 "-fluorine benzyloxy) phenylaminos
Base) quinazoline) amino) methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10e)
Synthetic method is with compound 10b.Pale yellow foam solid.It is denoted as 10e, yield 14.9%, Mp:125–130℃.
1H NMR(400MHz,CDCl3) δ 9.29 (s, 1H), 8.41 (s, 1H), 7.93 (d, J=2.4Hz, 1H), 7.71
(dd, J=8.9,2.4Hz, 1H), 7.27-7.19 (m, 1H), 7.14-7.08 (m, 2H), 6.97-6.87 (m, 2H), 6.81 (d,
J=9.0Hz, 1H), 4.99 (s, 2H), 4.63 (s, 1H), 4.57-4.41 (m, 1H), 3.62-3.47 (m, 3H), 3.43 (t, J
=6.6Hz, 4H), 3.34-3.07 (m, 6H)
13C NMR(101MHz,CDCl3)δ164.18,161.73,157.04,151.09,150.05,146.74,
(d, J=7.4Hz), 143.05,139.31 134.10,130.14 (d, J=8.1Hz), 128.24,123.85,122.99,
122.54 (d, J=2.9 Hz), 121.46,116.76,114.80 (d, J=21.1Hz), 114.47,113.98 (d, J=
22.2Hz), 99.28,79.50,70.46,62.50,49.54,48.80 (d, J=4.9Hz), 44.41,42.14,30.11.
31P NMR(162MHz,CDCl3)δ29.66.
HRMS(ESI+)m/z calcd for C28H30Cl3N6O3P(M+H)+653.11611,found 653.11449.
Embodiment 16：Prepare double (2- chloroethyls) amino -5- (6- (4- (3 '-benzotrifluoride amino) quinazoline) amino) of 2-
Methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10f)
Synthetic method is with compound 10b.Pale yellow foam solid.It is denoted as 10f, yield 14.9%, Mp:95–97℃.
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.50(s,1H),7.74(s,1H),7.54(s,2H),7.50–
7.37 (m, 4H), 7.37-7.26 (m, 4H), 7.24-7.19 (m, 1H), 6.99 (d, J=7.0Hz, 1H), 6.69 (d, J=
7.3Hz, 1H), 5.02 (s, 2H), 4.76 (s, 1H), 4.43 (s, 1H), 3.76 (d, J=14.0Hz, 1H), 3.52 (s, 2H),
(m, the 3H) of 3.44 (s, 4H), 3.30 (s, 4H), 3.22 (d, J=14.6Hz, 2H), 3.15-2.99
13C NMR(101MHz,CDCl3)δ148.4,128.99,125.66,124.97,120.38,119.01,98.86,
(79.45,48.94,48.81 d, J=5.0Hz), 44.71 (d, J=9.6Hz), 42.07.
HRMS(ESI+)m/z calcd for C22H25Cl2N 6O2P(M+H)+563.11611,found 563.11449.
Embodiment 17：Prepare 2- (double (2- chloroethyls)) amino -5- (6- (4- (3 '-benzyloxy) phenylaminos quinazoline) ammonia
Base) methyl isophthalic acid, 3,2- oxynitride phosphor heterocycle pentane -2- oxides (numbering：10g)
Synthetic method is with compound 10b.Pale yellow foam solid.It is denoted as 10g, yield 15.9%, Mp：89–92℃.
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.50(s,1H),7.74(s,4H),7.54(s,5H),7.50–
7.37 (m, 4H), 7.31 (m, 4H), 7.24-7.18 (m, 1H), 6.99 (d, J=7.0Hz, 1H), 6.69 (d, J=7.3Hz,
1H), 5.02 (s, 2H), 4.76 (s, 1H), 4.43 (s, 1H), 3.76 (d, J=14.0Hz, 1H), 3.52 (s, 2H), 3.44 (s,
4H), 3.30 (s, 4H), 3.22 (d, J=14.6Hz, 2H), 3.18-2.98 (m, 3H)
13C NMR(101MHz,CDCl3)δ161.56,158.07,155.99,152.61,149.51,145.47,
(138.99,135.79,128.50,127.52,126.98,126.59,122.38,115.54 d, J=4.4Hz), 114.27,
109.41,108.65, 98.14,69.04,47.34,41.12,35.48,28.67.
31P NMR(162MHz,CDCl3)δ28.87
HRMS(ESI+)m/z calcd for C28H32Cl2N6O3P(M+H)+601.16451,found 601.16485.
Embodiment 18：The antitumor activity test of the compounds of this invention
Experimental example 1：The influence bred to SKBr-3, MDA-MB-468, Calu-3 and H522 cell
In vitro culture human breast cancer cell SKBr-3, MDA-MB-468 and lung carcinoma cell H522, Calu-3, cell growth is extremely
After exponential phase, cell is collected, 1000rpm centrifugation 5min abandon supernatant, appropriate culture medium suspends, adjustment cell concentration is extremely
3.5~4.5 × 104/ml.By cell suspension inoculation into 96 porocyte culture plates, per the μ l of hole 100, cell culture incubator (37 is placed
DEG C, 5%CO2) in after culture 24h, medication group adds the μ l of medicine 100 of cell culture medium per hole, every kind of medicine set three it is multiple
Hole, negative control group is culture medium containing 0.5%DMSO.Cultivated in incubator after 72h, the 5mg/ml μ l of MTT 20 added per hole,
Put 37 DEG C of placement 3h.150 μ l DMSO are added per hole, in 37 DEG C of shaking table vibration 5min, in 492nm detection absorbances (OD).Fortune
IC is calculated with the statistical softwares of Prism Graphpad 5.050Value.
Part of compounds shown in chemical formula (I) has good antitumor activity to aforementioned four tumor cell line, its
IC50Value the results are shown in Table 1：
IC of the compound of table 1. to four tumor cell lines50It is worth (unit：μM)
Experimental example 2：To EGFR and HER-2 Receptor Binding Assays
To confirm that such compound is inhibited to EFGR and HER-2 acceptors, the part shown in the chemical formula (I) of selection
Compound is probe, has carried out Receptor Binding Assay.As shown in table 2：
IC of the compound of table 2. to EGFR and HER-250It is worth (unit：nM)
| Kinase | 10a2 | 10a3 | 10a4 | 10a5 | 10e | EMB-3 | Staurosporine |
| EGFR | 4.61 | 0.26 | 0.27 | 0.24 | 18.38 | 7.4 | 33.00 |
| HER-2 | 0.94 | 29.49 | 11.82 | 111.95 | 2.35 | 82 | 44.42 |
Embodiment 19：The internal metabolic stability test of the compounds of this invention
Compound 10b and 10e drug metabolism situations in SD rat bodies are as shown in table 3：
Drug metabolism situation is tested in table 3 compound cjb-11 and cjb-41 SD rat bodies
| Compound | Administering mode | t1/2(hr) | AUClast(hr*ng/mL) | AUCInf(hr*ng/mL) | CL(mL/min/kg) |
| 10b | IV | 1.17±0.06 | 761±91 | 765±92 | 22.0±2.7 |
| 10e | IV | 1.49±0.02 | 959±177 | 969±177 | 17.6±3.6 |
| EMB-3 | IV | 0.52±0.023 | 659±84 | 661±85 | 75.7±8.5 |
After transforming EMB-3 linking arm as cyclic structure and maintaining the carbon chain lengths of 3 carbon atoms in linking arm,
Compound 10b and 10e half-life period have respectively reached 1.17 hours and 1.49 hours, are 2.25 times of EMB-3 half-life period respectively
With 2.87 times, it was demonstrated that its metabolic stability is obviously improved.
Claims (8)
1. a class Mutiple Targets antitumoral compounds, the compound has the structure as shown in chemical formula (I)：
Wherein, R1Selected from hydrogen, lower alkoxy；
R2Selected from substituted or unsubstituted phenyl, the substituted phenyl refer to phenyl by one or more halogens, C1-C4 alkynyls,
Low alkyl group, lower alkoxy or alkoxy aryl substitution；
R3Selected from hydrogen, cyano group；
A is O or NH.
2. compound according to claim 1, wherein low alkyl group are C1-C6 alkyl or substituted alkyl, the substitution
Alkyl can be such as halogen or substituted-phenyl.
3. compound according to claim 1, wherein lower alkoxy are C1-C6 alkoxies or substituted alkoxy, institute
It can be such as halogen or substituted-phenyl to state substituted alkoxy.
4. compound according to claim 1, wherein alkoxy aryl are benzyl epoxide or rudimentary substituted benzyl epoxide,
The rudimentary substituent refers to one or more halogens, the alkyl of amino or 1-3 carbon, alkoxy on phenyl ring etc..
5. compound according to claim 1, wherein halogen are chlorine, fluorine or bromine.
6. compound according to claim 1, wherein R1Selected from hydrogen, methoxy or ethoxy；R2Selected from 3- bromines, the chloro- 4- of 3-
Fluorine, 3- acetenyls or the chloro- 4- of 3- (3- fluorine benzyloxy), 3- trifluoromethyls, 3- benzyloxies；R3Selected from hydrogen.
7. the preparation method of any one of the claim 1-6 compounds, this method comprises the following steps：
Wherein, when A is O and R1For hydrogen, R2、R3The following institute of synthetic route one of compound when being defined such as afore mentioned chemical formula (I)
Show：
Synthetic route one：
Reagent conditions and reaction：a)Et3N, reacts at room temperature；b)HCONH2, 160 DEG C；c)Ac2O, 100 DEG C；d)SOCl2, backflow；
E) substituted aniline, i-PrOH, Et3N, backflow；f)NH3OH, CH3OH, room temperature reaction；G) 3, DIAD, PPh3, CH2Cl2.
The reaction of dichlor-phosphoryl mustargen and 3- amino -1,2- dihydroxypropane obtain 2- (double (2- chloroethyls) amino) -5- methylols -
1,3,2- oxynitride phosphor heterocycle pentane -2- oxides.
5- hydroxyl -2- aminobenzoic acids obtain 4,6- dihydroxy quinazolines with formamide high temperature cyclization；Then by the selective second of 6-OH
It is acylated, 6- acetoxyl group -4- hydroxyquinazolines are obtained, then 6- acetoxyl group -4- chloro-quinazolines are reacted to thionyl chloride, no
It is purified that 4- substitution phenylamino -6- acetoxyl group quinazolines are directly obtained with substituted aniline reaction, then in ammonia hydroxide/methanol system
Middle deacetylation obtains 4- substituted anilinic -6- hydroxyquinazolines；Finally in triphenylphosphine, diisopropyl azodiformate condition
Under, with 2- (double (2- chloroethyls) amino) -5- methylols -1,3, the reaction of 2- oxynitride phosphor heterocycle pentane -2- oxides obtains part
Compound shown in formula (I).
Wherein, when A is O and R1For methoxyl group, R2、R3The synthetic route two of compound when being defined such as afore mentioned chemical formula (I) is such as
Shown in lower：
Synthetic route two：
Reagent and reaction condition：a)SOCl2, DMF (cat.), backflow；b)NH4OH, Methanol, room temperature reaction；C) 3, PPh3,
DTAD, DCM, room temperature reaction；D) substituted aniline, DMF, 90 DEG C
7- methoxyl group -4- hydroxyquinazoline -6- alcohol acetic esters flowed back in thionyl chloride obtain 7- methoxyl group -4- chloro-quinazolines -
6- alcohol acetic esters, the not purified deacetylation in ammonia hydroxide/methanol system obtains 6- hydroxyl -7- methoxyl group -4- chloro-quinazolines；So
Afterwards under the conditions of triphenylphosphine, azoformic acid di-t-butyl ester, and 2- (double (2- chloroethyls) amino) -5- methylols -1,3,
The reaction of 2- oxynitride phosphor heterocycle pentane -2- oxides obtains double (2- chloroethyls) amino -5- (the chloro- 7- methoxyl groups of 4-) the quinazoline first of 2-
Base ether -1,3,2- oxynitride phosphor heterocycle pentane -2- oxides；Finally heating response obtains part formula (I) in DMF with substituted aniline
Shown compound.
Wherein, when A is NH and R1For hydrogen, R2、R3The synthetic route three of compound when being defined such as afore mentioned chemical formula (I) is as follows
It is shown：
Synthetic route three：
Reagent and reaction condition：a)HCONH2, 160 DEG C；b)SOCl2, DMF；c)CH3OH, NH4OH, substituted aniline, room temperature reaction；
d)
(NH2CH2)2CHOH, Cul, t-BuONa, DMF, backflow；e)Cl2PON(CH2CH2Cl)2, Et3N, i-PrOH, 80 DEG C of
2- amino -5- iodo-benzoic acids add after excessive formamide cyclization under high temperature and obtain the iodo- 4- hydroxyquinazolines of 6-, then with chlorination
Sulfoxide backflow obtains the chloro- 6- iodine quinazolines of 4-, then not purified directly to obtain the iodo- 4- aryl amines quinolines of 6- with substituted aniline reaction
Oxazoline intermediate.Then under argon gas protection, using DMF as solvent, the CuI Ullmann reactions being catalyzed and 2- hydroxyls -1,3- are passed through
Diaminopropanes reaction obtains intermediate 1- amino -3- ((4- substituted anilinics quinazoline) 6- amino) propane diols, finally and phosphorus
Acyl dichloro mustargen cyclization obtains the compound shown in the formula (I) of part.
8. compound or compound made from according to preparation method as described in claim 7 exist as described in claim any one of 1-6
Prepare the application in antineoplastic.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4387060A (en) * | 1979-11-08 | 1983-06-07 | Bayer Aktiengesellschaft | 2-Thi-1,3,2-oxazaphospholanes |
| CN102718801A (en) * | 2011-03-30 | 2012-10-10 | 北京大学 | A method for preparing derivative of cyclophosphamide quaternary ammonium salt |
| CN102850397A (en) * | 2011-06-29 | 2013-01-02 | 北京大学 | Multi-target antitumor compounds and preparation method and application thereof |
| CN103102345A (en) * | 2011-11-14 | 2013-05-15 | 广东东阳光药业有限公司 | Aminoquinazoline derivative, salts thereof and application method |
-
2017
- 2017-05-03 CN CN201710304468.3A patent/CN106986895A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4387060A (en) * | 1979-11-08 | 1983-06-07 | Bayer Aktiengesellschaft | 2-Thi-1,3,2-oxazaphospholanes |
| CN102718801A (en) * | 2011-03-30 | 2012-10-10 | 北京大学 | A method for preparing derivative of cyclophosphamide quaternary ammonium salt |
| CN102850397A (en) * | 2011-06-29 | 2013-01-02 | 北京大学 | Multi-target antitumor compounds and preparation method and application thereof |
| CN103102345A (en) * | 2011-11-14 | 2013-05-15 | 广东东阳光药业有限公司 | Aminoquinazoline derivative, salts thereof and application method |
Non-Patent Citations (2)
| Title |
|---|
| SONGWEN LIN ET AL.: "Design, synthesis and biological evaluation of quinazoline-phosphoramidate mustard conjugates as anticancer drugs", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 宋维良等: "抗肿瘤药物的研究III.含氨基酸的氮芥磷酰胺衍生物的合成", 《药学学报》 * |
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