CN102617463A - Quinoline derivative and quinazoline derivative and preparation method thereof - Google Patents
Quinoline derivative and quinazoline derivative and preparation method thereof Download PDFInfo
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- CN102617463A CN102617463A CN2012100467861A CN201210046786A CN102617463A CN 102617463 A CN102617463 A CN 102617463A CN 2012100467861 A CN2012100467861 A CN 2012100467861A CN 201210046786 A CN201210046786 A CN 201210046786A CN 102617463 A CN102617463 A CN 102617463A
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Abstract
The invention discloses a quinoline derivative and a quinazoline derivative, molecular structural formulas are shown in (I) and (II), wherein R1 and R2 are same and both are five to six-member unsaturated carbon rings, five to six-member unsaturated substitution carbon rings, five to six-member unsaturated heterocyclic rings or five to six-member unsaturated substitution heterocyclic rings. The five to six-member unsaturated heterocyclic rings contain one or more nitrogen, oxygen or sulfur atoms. A compound (I) and a compound (II) are prepared with 4- hydroxyl-3 methoxy acetophenone (I-i) and 4-hydroxyl-3 methoxy methyl benzoate (II-I) serving as starting materials and obtained through a series of reactions. The quinoline derivative and the quinazoline derivative are compounds with brand-novel structures and have potential receptor tyrosine kinase inhibition activity; the preparation steps are formed by optimization combination of mature processes, the reaction is stable, and the reproducibility is good.
Description
Technical field
The invention belongs to the organic synthesis field, relate to quinoline and preparation method thereof and quinazoline derivative and preparation method thereof.
Background technology
Tyrosylprotein kinase is a kind of specifically with some the tyrosine residues phosphorylation on the protein substrate, thereby regulates the enzyme of its function.Tyrosylprotein kinase can be divided three classes: 1. receptor tyrosine kinase, be the single transmembrane protein, in vertebrates, found 50 surplus kind; 2. cytoplasmic tyrosine kinase is like Src family, Tec family, ZAP70, family, JAK family etc.; Tyrosylprotein kinase such as Abl and Wee in 3. examining (Robinson, Oncogene, 2000,19,5548-5557).
Receptor tyrosine kinase (receptor protein tyro sine kinases, extracellular region RPTKs) is the binding partner structural domain, part is solubility or membrane-bound polypeptide or protein hormone, comprises Regular Insulin and multiple growth factor.Born of the same parents' inner segment is the catalytic site of LCK, and has the autophosphorylation site.
Part (like EGF) outside born of the same parents with receptors bind and cause conformational change; Cause receptor dimerizationization (dimerization) to form homology or heterodimer; Phosphorylation born of the same parents inner segment tyrosine residues each other in dimer, the protein tyrosine kinase activity of activated receptor itself.This receptoroid mainly contains EGFR (EGF-R ELISA), PDGFR (platelet-derived growth factor receptors), FGFR (bfgf receptor); VEGFR (Shi Aixin, Fu Dexing, Chinese medicine magazines such as (vascular endothelial cell production factor acceptors); 2008,14,1001-1005).
With these acceptors as the oncotherapy target spot, for the tumour medicine of development of new provide maybe, receptor tyrosine kinase inhibitors is exactly to suppress the phosphorylation of Tyrosylprotein kinase; Thereby the signal conduction in blocking-up downstream has the therapeutical agent (Faivre S, the Delbaldo C that suppress tumour production effect; J ClinOncol; 2006,24,25-35).
Once Ni Ka ltd patent: reported series of quinazoline verivate or its pharmaceutical salts among the PCT/GB 97/00344, the pharmaceutical composition of its verivate is used for receptor tyrosine kinase inhibitors character, treatment proliferative disease such as cancer aspect.Hengrui Pharmaceutical Co., Ltd., Shanghai's patent: application number: 200910045382.9; In reported a kind of new quinazoline compounds with and tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt and meta-bolites and metabolic precursor thereof or prodrug, as kinases inhibitor.Mitsubishi Pharmaceutical Corp's patent: WO02/066445 has reported series of quinazoline verivate or its pharmacy acceptable salt, hydrate or solvolyte, optically active body or raceme or non-enantiomer mixture, has the protein kinase inhibiting activity of good tyrosine-specific.
By patent EP0520722, EP0566226, WO95/15758; WO95/19169; WO96/09294, WO96/15118 etc. are known, and part has the substituent quinazoline derivant of aniline to have receptor tyrosine kinase inhibition activity at the 4-bit strip; Analyze from EP0602851 and WO95/23141, some has the substituent quinazoline derivant of heteroaryl amino and also has receptor tyrosine kinase inhibition activity in the 4-position.Quinoline and quinazoline derivant have been put down in writing among the patent WO97/17329 with antitumous effect.
Summary of the invention
First technical problem to be solved by this invention is: provide a kind of and have the potential receptor tyrosine kinase and suppress active quinoline.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: quinoline, and (I) is as follows for its general structure:
Wherein: R1 is 5～6 yuan of unsaturated carbocyclics, 5～6 yuan of unsaturated replacement carbocyclic rings, 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles; Said 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles contain one or more N, O or S atom.
Said quinoline, its preferred structure formula is following, but is not limited to these structural formulas:
Second technical problem to be solved by this invention is: the preparation method that a kind of quinoline is provided.
For solving second technical problem, the technical scheme that the present invention adopts is: a kind of preparation method of quinoline, and its preparation process is:
With 4-hydroxyl-3 methoxyacetophenone (I-i) is starting raw material; Protective reaction on the process, nitrated, reduction, cyclization, chloro, go protection, Mitsunobu reaction to obtain 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii), compound (I-viii) and compound N H
2-R
1Reaction obtains target general formula compound (I).
The 3rd technical problem to be solved by this invention is: provide a kind of new potential receptor tyrosine kinase that has equally to suppress active quinazoline derivant.
For solving the 3rd technical problem, the technical scheme that the present invention adopted is: quinazoline derivant, its molecular structural formula (II) as follows:
Wherein: R
2Be 5～6 yuan of unsaturated carbocyclics, 5～6 yuan of unsaturated replacement carbocyclic rings, 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles; Said 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles contain one or more N, O or S atom.
Said quinazoline derivant (II), its preferred structure formula is following, but is not limited to these structural formulas:
The 4th technical problem to be solved by this invention is: the preparation method that a kind of quinazoline derivant is provided.
For solving the 4th technical problem, the technical scheme that the present invention adopted is: the preparation method of quinazoline derivant (II), and its preparation process is:
With 4-hydroxyl-3 methoxyl methyl benzoate (II-i) is starting raw material; Protection on the process, nitrated, reduction, cyclization, replace, go to protect, replace, go acidylate, chlorination reaction to get 4-chloro-6-methoxyl group-7-(3-piperidines propoxy-) quinazoline (II-x), compound (II-x) and compound N H
2-R
2Reaction obtains general formula compound (II).
Beneficial effect of the present invention: quinoline provided by the invention and quinazoline derivant, be brand-new structural compounds, have the potential receptor tyrosine kinase and suppress active; Their preparation process is that sophisticated process optimization is combined, stable reaction, favorable reproducibility.
Specific embodiment
Below in conjunction with embodiment the present invention is further specified.
The structure of compound is to confirm through nucleus magnetic resonance (NMR) or liquid phase and mass spectrum logotype appearance (LCMS, Agilent 1100).
1H NMR displacement (δ) provides with 1,000,000/(ppm) unit.Measuring solvent is deuterochloroform (CDCl
3) or deuterium for dimethyl alum (DMSO-d
6), in be designated as TMS (TMS), chemical shift is with 10
-6(ppm) action provides for unit.
Embodiment 1:
The preparation of 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii):
1) with 4-hydroxyl-3 methoxyacetophenone (I-i) (40g, 240mmol), bromobenzene (31.4ml, 260mmol) and salt of wormwood (99.6g, 360mmol) mixing solutions drops among the DMF (800mL), is heated to 40 ℃ of (12-18h) reactions of spending the night.Reaction solution is cooled to room temperature, and recrystallization in ice bath filters, and the washing final vacuum is dry, obtains 1-(4-benzyloxy-3 methoxyphenyl) ketone (I-ii) (61g, 99%).
2) with midbody 1-(4-benzyloxy-3 methoxyphenyl) ketone (I-ii) (5.0g; 19.5mmol) be dissolved in the 75ml methylene dichloride; Temperature of reaction is controlled at 0 ± 2 ℃, keeps this temperature, stirs to drip nitric acid (1.5mL down; The 90Wt.% mass concentration) and the vitriol oil (1.8mL, 96.2Wt.% mass concentration) mixing acid; Behind 0 ℃ of stirring reaction 1h, drip nitric acid (0.5mL, 90Wt.% mass concentration), reaction solution stirs 20min; Reaction solution is added in the methylene dichloride (25mL), pour into (60mL) in the water,, dry after the merging organic phase with the dried over sodium sulfate final vacuum with the saturated potassium hydrogen carbonate aqueous solution (60mL * 2) flushing twice; The residuum that drying is crossed adds in DMF (3mL) and ether (70mL) mixed solution; Being stirred to solid separates out fully; Filter the back with ether flushing in a small amount, obtain yellow solid 1-(4-benzyloxy)-5-methoxyl group-2-nitro benzophenone (I-iii) (3.6g, yield 61%) after the drying;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, CDCl
3), δ (ppm): 7.64 (s, 1H), 7.42-7.35 (m, 5H), 6.76 (s, 1H), 5.21 (s, 2H), 3.93 (s, 3H), 2.48 (s, 3H).
3) with iron powder (477mmol, 27g) drop into ammonium acetate (500mmol, 31g); 1-(4-benzyloxy)-5-methoxyl group-2-nitro benzophenone (I-iii) (120mmol; 36g), in the mixing solutions of toluene (500mL) and water, back flow reaction is spent the night (12-18h) up to the reaction end; Through washing with ETHYLE ACETATE behind the diatomite filtration; Organic phase water and saturated sodium-chloride water solution flushing, dried over sodium sulfate gets 1-(the amino 4-benzyloxy of 2--5-methoxyl group) benzophenone (I-iv), yield 90%;
1H NMR (Bruker ARX-400 nuclear magnetic resonance spectrometer, CDCl
3), δ (ppm): 7.408-7.298 (m, 5H), 7.130 (s, IH), 6.155 (br, 2H), 6.104 (s, 1H), 5.134 (s, 2H), 3.834 (s, 3H), 2.507 (s, 3H).
4) 1-(the amino 4-benzyloxy of 2--5-methoxyl group) benzophenone (I-iv) (108mmol 29.3g) adds among the DME (dme) (700mL), mixing solutions drop into sodium methylate (432mmol, 23.35g) in; Mixture stirs 30min, adds ethyl formate (540mmol, 44mL) stirring reaction spend the night (be generally 12-18h, as react incomplete need and add sodium methylate, reaction is monitored with LC/MS); Reaction finishes back water (40mL) dilution, and with the hydrochloric acid neutralization, with the sedimentation and filtration after washing, vacuum-drying obtains 7-benzyloxy-6-methoxy quinoline-4-alcohol (I-v) (22g, yield 72%).
1H NMR (Bruker ARX-400 nuclear magnetic resonance spectrometer, CDCl
3), δ (ppm): 10.7 (br, 1H), 7.703 (s, 1H), 7.493-7.461 (t, 1H); 7.431-7.413 (br d, 2H), 7.372-7.333 (s, 2H), 7.296-7.283 (d, 1H), 6.839 (s; 1H), 6.212-6.193 (d, 1H), 5.212 (s, 2H), 3.965 (s, 3H).
5) POCl3 (300mL) add 7-benzyloxy-6-methoxy quinoline-4-alcohol (I-v) (40g, 140mmol), mixing solutions reflux 2h; Reaction mixture is poured in the mixture of ice and yellow soda ash, added solid sodium bicarbonate again pH value of solution is adjusted to 8, at room temperature stirring reaction 12-18h; Filter the washing after drying and get light brown solid 7-benzyloxy-4-chloro-6-methoxy quinoline (I-vi) (40.2g, 95%);
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.61 (s, 1H), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H).
6) with 7-benzyloxy-4-chloro-6-methoxy quinoline (I-vi) (6.8g, 20mmol) drop into TFA (trifluoroacetic acid, 80mL) in, reflux 5.5h; Revolve steaming (heating in water bath; The decompression of conventional vacuum water pump) removes volatile matter; Resistates and mixing solutions are adjusted to neutrality through saturated sodium bicarbonate solution in the water layer, after the filtration washing, wash with ether; Drying obtains 4-chloro-7-hydroxyl-6-methoxy quinoline (I-vii) (4.1g, yield 98%) under the vacuum condition.
7) with the azo diethyl ester (1.20mL, 76mmol) slowly drop to triphenylphosphine (20g, 76mmol); 4-chloro-7-hydroxyl-6-methoxy quinoline (I-vii) (10g, 47mmol), 3-morpholine-1-propyl alcohol (7.5g; 52mmol), in the mixing solutions of methylene dichloride (500mL), solvent mixture at room temperature stirs 4h; The column chromatography purification after drying obtains 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii) (10.5g, yield 66%);
1HNMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H).
Embodiment 2:
The preparation of (3-chloro-4 fluorophenyls)-[6-methoxyl group-7-(3-morpholine-4-base-propoxy-)-quinolyl-4]-ammonia (I-a):
With 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii) (33.68g, 0.1mol) with 3-chloro-4-fluoroaniline (14.50g, 0.1mol) and DMF (250mL) mixing post-heating to the 1h that refluxes, revolve to steam and remove unnecessary solvent; Add toluene concentrating under reduced pressure, triplicate in the residuum; Add Virahol (100mL) in the residuum again, stirring at room 1h, suction filtration; Filter cake add to 3-chloro-4-fluoroaniline (7.25g, in aqueous isopropanol 0.05mol) (150mL), reflux 3h, TLC (thin-layer chromatography) detection reaction is complete; Be cooled to room temperature, evaporated under reduced pressure adds entry (200mL) in the light yellow solid of gained; Be heated to 60 ℃, transfer to pH=9.5～10.0, cooling back crystallization, filtration with saturated sodium hydroxide solution; The filter cake column chromatography purification gets white solid (38.29g, yield 86%);
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H); 7.38 (s, 1H), 7.16-7.14 (d, 1H), 6.85-6.84 (d, 1H), 6.67 (s; 1H), 6.54-6.53 (s, 1H), 4.21 (m, 2H), 3.97 (s, 3H); 3.58-3.56 (m, 2H), 2.50-2.30 (m, 6H), 1.97-1.95 (m, 2H).
Embodiment 3:
The preparation of [6-methoxyl group-7-(3-morpholine-1-base-propoxy-)-quinolyl-4]-(2-methyl-pyrimidine-5-yl)-ammonia (I-b):
(16.84g 0.05mol) is dissolved in 150mL N, in the dinethylformamide with 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii); Add 2-methyl-5-aminopyrimidine (5.73g; 0.0053mol) and triethylamine 11g (0.1mol), be heated to 80 ℃, stir 4h; Be cooled to room temperature, it is slowly poured in the 100mL water, stir 10min; Suction filtration, it is in 80% the aqueous ethanolic solution that filter cake is added the 15mL volume(tric)fraction, is heated to 80 ℃; Stir 5min, slow again Dropwise 5 mL water is cooled to room temperature; Suction filtration, column chromatography gets white solid 16.58g behind the filtration cakes torrefaction, yield 81%;
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.60 (d, 1H), 8.38 (s, 2H), 7.55 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 6.67 (s, 1H), 4.21 (m, 2H), 3.97 (s, 3H), 3.58 (m, 2H), 2.53 (s, 3H), 2.50-2.30 (m, 6H), 1.97-1.95 (m, 2H).
Embodiment 4
The preparation of (2,4-dimethyl--pyrimidine-5-yl)-[6-methoxyl group-7-(3-morpholine-4-base-propoxy-)-quinolyl-4]-ammonia (I-c):
(33.61g, 0.1mol) with 2, (13.55g 1.1mol) and Virahol (300mL), joins in the reactor drum of 500mL, at N 4-dimethyl--5-aminopyrimidine with 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii)
2Protection is stirring at room 1h down, and post-heating is cooled to room temperature to back flow reaction 8h, separates out solid, suction filtration, and the filter cake activated carbon decolorizing adds ammoniacal liquor (20mL), stirring at room 6h, methylene dichloride (150mL) extraction, saturated common salt water washing, anhydrous Na
2SO
4Drying is revolved dried solvent, and column chromatography obtains white solid (33.46g, yield 79%);
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.62 (d, 1H), 8.41 (s, 1H), 7.56 (d, 1H), 7.45 (s, 1H); 7.38 (s, 1H), 6.57 (s, 1H), 4.21 (m, 2H), 3.97 (s, 3H), 3.58 (m; 2H), 2.55 (s, 3H), 2.53 (s, 3H), 2.50-2.30 (m, 6H), 1.97-1.95 (m, 2H).
Embodiment 5
The preparation of (2-chloromethyl-pyrimidine-4-yl)-[6-methoxyl group-7-(3-morpholine-4-base-propoxy-)-quinolyl-4]-ammonia (I-d):
(33.68g 0.1mol) is dissolved in the ethanol (150mL), drips to be dissolved with 2-chloromethyl-4-aminopyrimidine (14.36g, ethanolic soln 100mL 0.1mol), heating reflux reaction 12h under stirring with 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii); Be evaporated to driedly, add entry (60mL) in the residuum, be cooled to 0 ℃, add frozen water (60mL), continue to stir 30min, filter, filter cake is with frozen water (50mL) washing, and column chromatography purification gets white crystals shape solid 39.5g, yield 89%;
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.61 (d, 1H), 7.96 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H); 7.38 (s, 1H), 6.87 (s, 1H), 6.93 (d, 1H), 4.33 (s, 2H), 4.21 (m; 2H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97-1.95 (m, 2H).
Embodiment 6
The preparation of 5-[6-methoxyl group-7-(3-morpholine-4-base-propoxy-)-quinolyl-4-ammonia]-Nicotine nitrile (I-e):
With 3-cyanic acid-5-EL-970 (11.91g 0.1mol) is dissolved in the 50mL methyl alcohol, slowly drop to 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii) (33.68g, 0.1mol), at N
2Protection joins in the acetonitrile (120mL) down, is stirred to complete dissolving, stirring reaction spend the night (12-18h) under refluxing; Reaction solution revolves to steam removes acetonitrile, adds entry (50mL) in the residuum, and extract for three times with ETHYLE ACETATE (150mL * 3) the full back of dissolving, and merges organic phase; Anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated into dried; Add normal hexane (120mL) in the residuum, stirring and crystallizing is filtered; The filter cake column chromatography purification gets off-white color solid 33.56g, yield 80%;
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.93 (s, 1H), 8.61 (d, 1H), 8.47 (s, 1H), 8.03 (s, 1H); 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 6.61 (s, 1H), 4.21 (m; 2H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97-1.95 (m, 2H).
Embodiment 7
The preparation of 3-[6-methoxyl group-7-(3-morpholine-4-base-propoxy-)-quinolyl-4-ammonia]-4-methyl-thiophene-2-carboxylic acid methyl esters (I-f):
(33.68g 0.1mol) is suspended in the 300mL anhydrous acetonitrile, adds CDI (N, N '-carbonyl dimidazoles with 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii); 19.45g), in 35 ℃ of reaction 3h, add 3-amino-4-thiotolene-2-methyl-formiate (17.97g successively; 0.105mol), triethylamine (110mL, 0.1mol), in 60 ℃ the reaction 24h; Separate out a large amount of safran solids, be cooled to 10 ℃, filter; 0～5 ℃ of acetonitrile washing gets safran solid 42.45g, yield 90% behind the column chromatography purification of bullion oven dry back;
1H NMR (Bruker AV-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.60 (d, 1H), 7.56 (d, 1H), 7.50 (s, 1H), 7.45 (s, 1H); 7.38 (s, 1H), 6.37 (s, 1H), 4.21 (m, 2H), 3.97 (s, 3H), 3.87 (s; 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 2.25 (s, 3H), 1.97-1.95 (m, 2H).
Embodiment 8
(II-x) preparation of 4-chloro-6-methoxyl group-7-(3-piperidines propoxy-) quinazoline:
A) with 4-hydroxyl-3 methoxyl methyl benzoate (II-i) (7.29g, 40mmol) be dissolved in DMF (25mL), salt of wormwood (8.29g, 60mmol), (5.26mL is in mixing solutions 44mmol) for bromotoluene; Mixture heating up to 100 ℃, stirring reaction 3h; Be cooled to room temperature, add water, this product detects product with ethyl acetate extraction to TLC and disappears, and merges organic phase, water and saturated sodium-chloride water solution washing; Through anhydrous sodium sulfate drying, remove solvent and get 4-benzyloxy-3-methoxyl methyl benzoate (II-ii), need not to be further purified next step reaction of direct input.
B) nitric acid (45mL, 0.963mol) and the mixture of acetic acid (45mL) be placed in the ice bath, stir and to drip step a) gained 4-benzyloxy-3-methoxyl methyl benzoate (II-ii) down and be dissolved in 200mL acetic acid (10.3g, the solution that 50mmol) forms; Reaction mixture stirs 20min at-10 ℃; Add frozen water (250mL) in the mixture; And pass through to add aqueous sodium hydroxide solution (mass concentration 40Wt.%) and regulate pH to no longer increase of deposition, filter, clean with clear water; The dry gray solid 4-benzyloxy-5-methoxyl group-2-nitrobenzoic acid methyl esters (II-iii) (30g, 98%) that gets; LCMS (Agilent 1100): 318 [M+1]
+
C) 4-benzyloxy-5-methoxyl group-2-nitrobenzoic acid methyl esters (II-iii) (4g; 12.6mmol) drop into and be furnished with whisking appliance, TM, reflux exchanger; In the 20mL reactor drum of hydrogen formation apparatus; Add platinum sulfuration carbon dust (0.2g), dme (20mL), said mixture reacts 7h under the stirring at normal temperature in hydrogen atmosphere; After reaction is accomplished, reaction mixture was placed 10 days, filtered, the reaction mixture underpressure distillation obtains light brown solid 2-amino-4-benzyloxy-5-methoxyl methyl benzoate (II-iv) (3.17g, 87%);
1H NMR (Bruker ARX-400 nuclear magnetic resonance spectrometer, CDCl
3), δ (ppm): 7.31-7.41 (m, 6H), 6.15 (s, 1H), 5.37 (brs, 2H), 5.09 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H).
D) with 2-amino-4-benzyloxy-5-methoxyl methyl benzoate (II-iv) (5.09g, 17.7mmol) with the methane amide methyl esters at 190 ℃ of reaction 5h, with the mixture cooling, pour into and add sodium-chlor in the water and wash after reaction finishes; Throw out is filtered, washing, drying under reduced pressure obtains brown brown solid 7-benzyloxy-6-methoxyl group-3,4-dihydroquinazoline-4-ketone (II-v) (4g, 80%);
1H NMR (Bruker ARX-400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 12.10 (br s, 1H), 7.98 (s, 1H), 7.51-7.33 (m, 5H), 7.23 (s, 1H), 5.26 (s, 2H), 3.88 (s, 3H);
E) sodium hydride (1.44g, 60Wt.% 36mmol) add 7-benzyloxy-6-methoxyl group-3 in batches in 20min, 4-dihydroquinazoline-4-ketone (II-v) (8.46g, 30mmol) at N, in dinethylformamide (70mL) solution, mixture stirs 1.5h; (5.65g 37.5mmol) splashes into mixture and at room temperature stirs 2h the chlorine trimethylacetic acid; With ETHYLE ACETATE (100mL) diluted mixture thing, add in the aqueous hydrochloric acid (4mL) of frozen water (400mL) and 2mol/L; Separate organic layer, water layer is used ethyl acetate extraction, and organic layer is with salt solution cleaning, drying (sal epsom) back evaporate to dryness; Solid grinds with ether and sherwood oil mixing, filters, and collects solid and dry 7-benzyloxy-6-methoxyl group-3-pivalyl-3, the 4-dihydroquinazoline-4-ketone (II-vi) (10g, yield 84%) of getting under vacuum condition;
1H?NMR(Bruker?AV400，DMSO-d
6)，δ(ppm)：8.34(s，1H)，7.51(s，1H)，7.49(d，2H)，7.47(t，2H)，7.35(m，1H)，7.27(s，1H)，5.9(s，2H)，5.3(s，2H)，3.89(s，3H)，1.11(s，9H)。
F) with 7-benzyloxy-6-methoxyl group-3-pivalyl-3; 4-dihydro-chinazoline (II-vi) (7g; 17.7mmol) drop in the mixed solution of ETHYLE ACETATE (250mL), DMF (50mL), methyl alcohol (50mL), acetic acid (0.7mL); Add 10Wt.% palladium carbon catalyst (700mg), normal pressure is stirring reaction 40min under hydrogen atmosphere; Solvent is removed in filtration catalizer, underpressure distillation, the ether flushing, and residue is collected, and filters, and vacuum-drying obtains 7-hydroxyl-6-methoxyl group-3-pivalyl-3,4-dihydro-chinazoline (II-vii) (4.36g, yield 80%);
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.5 (s, 1H), 7.48 (s, 1H), 7.0 (s, 1H), 5.89 (s, 2H), 3.89 (s, 3H), 1.11 (s, 9H).
G) with 7-hydroxyl-6-methoxyl group-3-pivalyl-3,4-dihydro-chinazoline (II-vii) (2g 6.5mmol) is dissolved among the DMF (16mL), drop into salt of wormwood (1.26g, 9.1mmol), 1-(3-chloropropyl) piperidines (1.26g, 7.8mmol); 90 ℃ of stirring reaction 1.5h under argon shield; Filter out unnecessary salt of wormwood, underpressure distillation is revolved and is done DMF, oily matter under vacuum condition, spend the night (12-18h); Get the 2.8g product: 6-methoxyl group-7-(3-piperidines propoxy-)-3-pivalyl-3,4-dihydro-chinazoline (II-viii);
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.40 (s1, H), 7.50 (s, 1H), 7.15 (s, 1H), 5.95 (s, 2H), 4.20 (t, 2H), 3.90 (s, 3H), 2.40 (m, 2H), 2.35 (m, 4H), 1.95 (m, 2H), 1.50 (m, 4H), 1.40 (m, 2H), 1.10 (s, 9H);
H) with 6-methoxyl group-7-(3-piperidines propoxy-)-3-pivalyl-3, (2.35g 5.45mmol) drops in the methyl alcohol (50mL) 4-dihydro-chinazoline (II-viii), stirred overnight under the room temperature (12-18h) reaction; Volatile matter is removed under vacuum state, and residue grinds with ether, filters; Carry out column chromatography purification with ether ether/methylene dichloride (volume ratio is 1/1); Vacuum-drying obtains 6-methoxyl group-7-(3-piperidines propoxy-)-3,4-dihydro-chinazoline (II-ix) (1.65g, yield 95%);
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 7.9 (s, 1H), 7.44 (s, 1H), 7.11 (s, 1H), 4.15 (t, 2H), 3.9 (s, 3H), 2.4 (t, 2H), 2.35 (br s, 4H), 1.85-1.95 (m, 2H), 1.4-1.55 (m, 4H), 1.3-1.4 (m, 2H).
I) with 6-methoxyl group-7-(3-piperidines propoxy-)-3, and 4-dihydro-chinazoline (II-ix) (1.5g, 4.7mmol) adding is mixed with in the THIONYL CHLORIDE 97 (15mL) of DMF (1.5mL) reflux 3h; After the cooling, volatile matter is removed under vacuum state; Extracted in toluene is regulated pH=10 with 6 times of normal 20Wt.% aqueous sodium hydroxide solutions of raw material then, and branch vibration layer merges organic layer, and with the saturated sodium-chloride water solution flushing, dried over mgso is revolved to steam to remove and desolvated; Residue gets 4-chloro-6-methoxyl group-7-(3-piperidines propoxy-) quinazoline (II-x) (1.21g, yield 76%) through column chromatography purification;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.9 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 4.29 (t, 2H), 4.0 (s, 3H), 2.45 (t, 2H), 2.4 (br s, 4H), 1.9-2.05 (m, 2H), 1.5-1.6 (m, 4H), 1.35-1.45 (m, 2H).
Embodiment 9
The preparation of (3-chloro-4 fluorophenyls)-[6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-yl]-ammonia (II-a):
With 4-chloro-6-methoxyl group-7-(3-piperidines-1-propoxy-) quinazoline (II-x) (33.78g; 0.1mol) and 3-chloro-4-fluoroaniline (15.23g, 0.105mol) input methylene dichloride (300mL) solution, 5 ℃ of ice-water bath cooling controlled temperature; Back flow reaction 12h is evaporated to dried; Water (30mL) solution that adds sodium hydroxide (4.5g), refluxing and stirring, cooling is filtered, and filter cake gets white crystal 36.65g, yield 82% with water washing, column chromatography purification;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.93 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.10 (d; 1H), 6.93 (s, 1H), 6.71 (d, 1H), 6.60 (s, 1H); 4.29 (t, 2H), 4.01 (s, 3H), 2.45 (t, 2H), 2.4 (br s; 4H), and 2.06-1.95 (m, 2H), 1.5-1.6 (m, 4H), 1.45-1.35 (m, 2H).
Embodiment 10
The preparation of [6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-yl]-(2-methyl-pyrimidine-5-yl)-ammonia (II-b):
(33.78g 0.1mol) is dissolved among the DMF, and (11.46g 0.105mol) and triethylamine 11g (0.1mol), is heated to 80 ℃, stirs 4h to add 2-methyl-5-aminopyrimidine with 4-chloro-6-methoxyl group-7-(3-piperidines-1-propoxy-) quinazoline (II-x); Be cooled to room temperature, it is slowly poured in the 100mL water, stir 10min, suction filtration, the solid column chromatography obtains the 32g product, yield 78%;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.92 (s, 1H), 8.42 (s, 2H), 7.46 (s, 1H), 7.41 (s, 1H); 6.77 (s, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 2.49 (s, 3H), 2.45 (t; 2H), 2.4 (br s, 4H), 2.05-1.95 (m, 2H), 1.5-1.6 (m, 4H), 1.45-1.35 (m, 2H).
Embodiment 11
The preparation of (2,4-dimethyl--piperidines-5-yl)-[6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-yl]-ammonia (II-c):
With 4-chloro-6-methoxyl group-7-(3-piperidines-1-propoxy-) quinazoline (II-x) (33.78g, 0.1mol) with 2,4-dimethyl--5-aminopyrimidine (13.55g; 1.1mol) add 250mL1, in the 2-ethylene dichloride, add Virahol back flow reaction 19h; Filter; Filter cake is with 1, and the 2-ethylene dichloride washs, anhydrous Na
2SO
4Drying, underpressure distillation gets colourless transparent liquid, behind the curing column chromatography, gets white crystal 36.08%, yield 85%;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.91 (s, 1H), 8.44 (s, 1H), 7.46 (s, 1H), 7.41 (s; 1H), 6.87 (s, 1H), 4.29 (t, 2H), 4.01 (s, 3H); 2.45 (t, 2H), 2.43 (s, 3H), 2.40 (br s, 4H), 2.33 (s; 3H), and 2.05-1.93 (m, 2H), 1.61-1.53 (m, 4H), 1.45-1.35 (m, 2H).
Embodiment 12
The preparation of (2-chloromethyl-pyrimidine-4-yl)-[6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-yl]-ammonia (II-d):
(33.78g 0.1mol) is dissolved in the Virahol (260mL), and (14.36g 0.1mol), stirs heating reflux reaction 12h down to drip 2-chloromethyl-4-aminopyrimidine with 4-chloro-6-methoxyl group-7-(3-piperidines-1-propoxy-) quinazoline (II-x); Be evaporated to driedly, add entry (60mL) in the residuum, be cooled to 0 ℃, add frozen water (60mL), continue to stir 30min, filter, filter cake is with frozen water (50mL) washing, and reduced pressure at room temperature gets white crystals shape solid 39.6g, yield 88% behind the column chromatography;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.92 (s, 1H), 7.95 (d, 1H), 6.63 (d, 1H), 7.46 (s; 1H), 7.41 (s, 1H), 6.44 (s, 1H), 4.31 (d, 2H); 4.29 (t, 2H), 4.00 (s, 3H), 2.45 (t, 2H), 2.4 (br s; 4H), and 1.9-2.05 (m, 2H), 1.65-1.56 (m, 4H), 1.45-1.36 (m, 2H).
Embodiment 13
The preparation of 5-[6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-base-ammonia]-Nicotine nitrile (II-e):
3-cyanic acid-5-EL-970 is dissolved (11.91g, 0.1mol) in methyl alcohol, slowly drop to 4-chloro-6-methoxyl group-7-(3-piperidines-1-propoxy-) quinazoline (II-x) (33.78g, 0.1mol), the stirring reaction that refluxes down spend the night (12-18h); Reaction solution removes acetonitrile under reduced pressure, adds entry (50mL) in the residuum, and extract for three times with ETHYLE ACETATE (100mL * 3) the full back of dissolving, and merges organic layer; Anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated into dried; Add normal hexane (120mL) in the residuum, stirring and crystallizing is filtered; The filter cake drying under reduced pressure gets off-white color solid 31.54g, yield 75% behind the column chromatography;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.93 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 8.32 (s; 1H), 7.46 (s, 1H), 7.41 (s, 1H), 6.25 (s, 1H); 4.29 (t, 2H), 4.00 (s, 3H), 2.45 (t, 2H), 2.4 (br s; 4H), and 1.9-2.05 (m, 2H), 1.65-1.56 (m, 4H), 1.45-1.36 (m, 2H).
Embodiment 14
The preparation of 3-[6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-4a, 8a-dihydro-chinazoline-4-base-ammonia]-4-methyl-thiophene-2-carboxylic acid methyl esters (II-f):
With 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (II-x) (33.78g, 0.1mol) (17.97g 0.105mol) is dissolved in dry DMF, is warming up to back flow reaction 2h with 3-amino-4-thiotolene-2-methyl-formiate; TCL analyze to confirm reaction end, and reaction finishes, cool to room temperature slowly, and reaction solution is poured in the water, uses the 250mL ethyl acetate extraction, organic layer water, saturated sodium-chloride water washing, anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets oily liquids, column chromatography, vacuum-drying gets white solid 43g, yield 91%;
1H NMR (Bruker AV400 nuclear magnetic resonance spectrometer, DMSO-d
6), δ (ppm): 8.92 (s, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.41 (s; 1H), 6.59 (s, 1H), 4.29 (t, 2H), 4.00 (s, 3H); 3.93 (s, 3H), 3.37 (s, 3H), 2.45 (t, 2H), 2.4 (br s; 4H), and 1.9-2.05 (m, 2H), 1.65-1.56 (m, 4H), 1.45-1.36 (m, 2H).
Claims (6)
1. quinoline, its molecular structural formula (I) be as follows:
Wherein: R
1Be 5～6 yuan of unsaturated carbocyclics, 5～6 yuan of unsaturated replacement carbocyclic rings, 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles; Said 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles contain one or more N, O or S atom.
2. according to the said quinoline of claim 1, preferred structure is:
3. the preparation method of claim 1 or 2 said quinolines, its preparation process is:
With 4-hydroxyl-3 methoxyacetophenone (I-i) is starting raw material; Through last protective reaction, nitrated, reduction, cyclization, chloro, go protection, Mitsunobu react 4-chloro-6-methoxyl group-7-(3-morpholine propoxy-) quinoline (I-viii), compound (I-viii) and compound N H
2-R
1Reaction obtains target general formula compound (I).
4. quinazoline derivant, its molecular structural formula (II) be as follows:
Wherein: R
2Be 5～6 yuan of unsaturated carbocyclics, 5～6 yuan of unsaturated replacement carbocyclic rings, 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles; Said 5～6 membered unsaturated heterocycles or 5～6 yuan of unsaturated substituted heterocycles contain one or more N, O or S atom.
5. according to the said quinazoline derivant of claim 4, its preferred structure formula is:
6. the preparation method of claim 4 or 5 said quinazoline derivants, its preparation process is:
With 4-hydroxyl-3 methoxyl methyl benzoate (II-i) is starting raw material; Through last protective reaction, nitrated, reduction, cyclization, replace, go to protect, replace, go acidylate, chlorination reaction to get 4-chloro-6-methoxyl group-7-(3-piperidines propoxy-) quinazoline (II-x), compound (II-x) and compound N H
2-R
2Reaction obtains general formula compound (II).
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| US10421754B2 (en) * | 2014-08-11 | 2019-09-24 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Quinazoline derivative |
| AU2015303724B2 (en) * | 2014-08-11 | 2020-03-12 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Quinazoline derivative |
| CN106660970B (en) * | 2014-08-11 | 2020-07-10 | 石药集团中奇制药技术（石家庄）有限公司 | Quinazoline derivatives |
| US10774079B2 (en) | 2014-08-11 | 2020-09-15 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Quinazoline derivative |
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