CN105669566A - Preparation method of pharmaceutical intermediate N-arylquinazolinyl-amine compounds - Google Patents
Preparation method of pharmaceutical intermediate N-arylquinazolinyl-amine compounds Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
Abstract
The invention discloses a preparation method of pharmaceutical intermediate N-arylquinazolinyl-amine compounds, belonging to the field of pharmaceutical synthesis. The method comprises the following steps: carrying out nitrification and reduction on the initial raw material 3-bromobenzaldehyde, cyclizing with cyanamide, and carrying out coupling and substitution to obtain the N-arylquinazolinyl-amine compounds. Compared with the existing route, the preparation method disclosed by the invention has the characteristics of accessible raw materials, higher yield of the whole reaction route, mild reaction conditions, lower production cost and the like, is simple to operate, and is very suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, the preparation method relating to a kind of pharmaceutical intermediate compound, specifically as the preparation method of the N-aryl-quinazoline-2-amines of medicine intermediate.
Background technology
Hepatocarcinoma (HepatocellularcarcinomaHCC) is accompanied by several genes and the complicated and diversified malignant tumor of epigenetics change. The whole world nearly 1,250,000 people every year die from hepatocarcinoma, wherein have about 45% to occur in China. China is the district occurred frequently of hepatocarcinoma in the world, and trend occurred frequently is very severe. The mortality rate of Jin20Nian Lai China hepatocarcinoma adds 41.7%. Fibroblast growth factor receptor 4 (FibroblastgrowthfactorreceptorFGFR4) can start hepatic carcinoma growth, particularly cause stable and structural activation when its high expressed or by gene alteration, finally cause propagation and the growth of tumor cell. BLU9931 is relative to FGFR family and other kinases, it is shown that height optionally suppresses FGFR4, is the novel irreversible inhibitors of kinases of one targeting FGFR4. BLU9931 demonstrates the anti-tumor activity of brilliance in the Mice Body that hepatocarcinoma xenogenesis suppresses.
At organic chemistry and medicinal chemistry art, N-aryl-quinazoline-2-amines has important effect and status, itself it is generally of certain pharmaceutically active, and it is usually used to the multiple compound with pharmaceutically active of synthesis, for instance antineoplastic FGFR-4 kinase inhibitor drug, PDK1 kinase inhibitor drug etc.
Just because of N-aryl-quinazoline-2-amines important function in the field such as organic synthesis, pharmaceutical chemistry, its synthesis has been carried out substantial amounts of research by people, and achieves a lot of novel synthetic route and method, the route of synthesis of this compounds abundant.
WO2014/011900 discloses with 2-amino-5-bromobenzoic acid for raw material, through reduction, oxidation, cyclization, replaces, coupling, and coupling six step obtains the quinazoline amines that important intermediate aryl replaces. There is technical process potential safety hazard big (needing low temperature borane reduction, phosphorus oxychloride high temperature reflux) in this route, experiment condition harshness cannot amplify the shortcoming such as (coupling reaction needs microwave condition), yield low (yield of coupling reaction only has 38%). It addition, this route has related to two step coupling reactions, improve the cost of raw material and the difficulty of post processing, do not meet the theory of Green Chemistry.Therefore, it is necessary to explore the preparation method more optimized.
Summary of the invention
It is an object of the invention to for above-mentioned the deficiencies in the prior art, it is provided that the preparation method of a kind of N-aryl-quinazoline-2-amines.
The method is with 3-bromobenzaldehyde for initiation material, prepares this compound through five step reactions. The structure of this compound is as follows:
It is an object of the invention to realize in the following manner: the preparation method of a kind of N-aryl-quinazoline-2-amines, it is characterized in 3-bromobenzaldehyde for initiation material, by nitrated, reduction, cyclization with cyanamide, coupling, replaces five steps and obtains important intermediate N-aryl-quinazoline-2-amines. Course of reaction is as follows:
Specifically, said method comprises the following steps:
A, with 3-bromobenzaldehyde (Compound II per) for initiation material, obtain the bromo-2-nitrobenzaldehyde of 5-(Compound II per I) through nitrated;
B, 5-bromo-2-nitrobenzaldehyde (Compound II per I) obtain 2-amino-5-bromobenzaldehyde (compound IV) through reduction;
C, 2-amino-5-bromobenzaldehyde (compound IV) and cyanamide cyclization obtain 6-bromine quinazoline-2-amine (compound V);
D, 6-bromine quinazoline-2-amine (compound V) and the coupling under palladium catalyst effect of 3,5-dimethoxyphenylboronic obtain 6-(3,5-Dimethoxyphenyl) quinazoline-2-amine (compound VI);
E, 6-(3,5-Dimethoxyphenyl) quinazoline-2-amine (compound VI) obtains N-aryl-quinazoline-2-amine (compound I) through o-fluoronitrobenzene and the replacement of polysubstituted derivant thereof.
Described step a, particularly as follows: Compound II per and nitric acid or sodium nitrate are in solvent sulphuric acid, reacts at 0-40 DEG C, and the mol ratio obtaining Compound II per I, Compound II per and nitric acid or sodium nitrate after 1-12 hour is 1:1.0-1.5; Sulfuric acid concentration is 70-98%;
Described step b is particularly as follows: Compound II per I is in etoh solvent, and with iron powder/hydrochloric acid, hydrated ferric oxide ./hydrazine hydrate or Reduction with Stannous Chloride, at 40-80 DEG C, reaction 2-12h obtains the mol ratio of compound IV, Compound II per I and reducing agent is 1:0.1-0.5;
Described step c is particularly as follows: compound IV and cyanamide are at solvent N, dinethylformamide, N, in N-dimethyl acetylamide, dimethyl sulfoxide or N-Methyl pyrrolidone, at 60-200 DEG C, reaction 2-12h obtains the mol ratio of compound V, compound IV and cyanamide is 1:1.2-3.0;
Described step d is particularly as follows: compound V and 3, 5-dimethoxyphenylboronic is at solvent ethylene glycol dimethyl ether, 1, 4-dioxane, in isopropanol or ethanol, add palladium catalyst carbon, [1, double, two (diphenylphosphino) ferrocene of 1'-] palladium chloride or tetrakis triphenylphosphine palladium, add inorganic base potassium carbonate, sodium carbonate or cesium carbonate, react at 60-100 DEG C, 18-24h obtains compound VI, compound V and 3, the mol ratio of 5-dimethoxyphenylboronic is 1:1.1-1.5, the mol ratio of compound V and palladium catalyst is 1:0.05-0.5, the mol ratio of compound V and inorganic base is 1:1.5-2.5,
Described step e is particularly as follows: make compound VI at solvent N, with o-fluoronitrobenzene and polysubstituted derivatives reaction thereof in dinethylformamide or oxolane, add NaH and do alkali, react 18-24h under 0 DEG C-room temperature and obtain compound I, the mol ratio of compound VI and o-fluoronitrobenzene and polysubstituted derivant thereof is 1:1.1-1.5, and the mol ratio of compound VI and NaH is 1:1.1-1.5.
Compared with prior art, the preparation method raw material of the present invention is easy to get, and whole reaction scheme productivity is higher, and reaction condition is gentle, and simple to operate, production cost is relatively low, is especially suitable for industrialized production.
Detailed description of the invention
With specific embodiment, the preparation method of the N-aryl-quinazoline-2-amines of the present invention is described in detail below.
Embodiment 1
The synthesis of 1.1 Compound II per I
When ice-water bath, the sulphuric acid (5.4mol) that 289ml mass fraction is 98% is added in tri-mouthfuls of round-bottomed flasks of 1L, it is stirred for price modification and is slowly added dropwise 64ml Compound II per (0.54mol), finish, it is down to after 10 DEG C until system temperature and slowly drips, to system, the nitric acid (0.59mol) that 27ml mass fraction is 65%, finish TLC monitoring, react 4 hours substrate reactions complete, reaction system is poured slowly in 2L frozen water, sucking filtration, filter cake washes with water, it is washed till filtrate no acidic, it is white solid 91g that solid normal hexane and re-crystallizing in ethyl acetate obtain Compound II per I, yield 73.1%.
1HNMR (400MHz, CDCl3) δ 10.41 (s, 1H), 8.06 (d, J=2.1Hz, 1H), 8.03 (d, J=8.6Hz, 1H), 7.88 (dd, J=8.6,2.1Hz, 1H).
13CNMR(101MHz,CDCl3)δ186.74,136.51,132.65,129.57,126.13。
Embodiment 2
The synthesis of 1.2 compound IV
90g Compound II per I (0.39mmol) is joined in 1L round-bottomed flask, add 300ml dehydrated alcohol to system, add 32g reduced iron powder (0.58mol) under stirring condition, add 0.1MHCl200ml to system, oil bath is heated to 80 DEG C, reacting 4 hours, substrate reactions is complete, and rotation is evaporated off part ethanol, solid precipitates out, sucking filtration, solid with methylene chloride pull an oar Compound II per I is pale yellow powder 71g, productivity 92%. HPLC analyzes and shows purity 97%, it is not necessary to separates purification further and is directly used in next step reaction.
Embodiment 3
The preparation of 1.3 compound V
70g compound IV (0.35mmol) is joined in 500ml beaker, it is sequentially added into 250ml ether, 25ml mass fraction be 37% hydrochloric acid stir 5 minutes, sucking filtration, solid joins in 500ml round-bottomed flask, add 29g cyanamide (0.70mol), add 60mlN, dinethylformamide, oil bath is heated to 80 DEG C, TLC monitors, after reacting 12 hours, substrate reactions is complete, cooling reaction system, add 300ml water, sucking filtration, solid ethyl acetate and normal hexane recrystallization obtain product, sucking filtration obtains compound V pale yellow powder 56g, yield 72%.m.p.270-272 DEG C, ESI-MSm/z:223.87,225.89 [M+H, M+2H]+.
1HNMR (400MHz, DMSO) δ: 9.09 (s, 1H), 8.05 (d, J=2.1Hz, 1H), 7.77 (dd, J=9.0,2.3Hz, 1H), 7.36 (d, J=9.0Hz, 1H), 6.99 (s, 2H).
13CNMR(101MHz,DMSO)δ:161.64,160.99,150.60,136.75,129.81,126.86,120.51,113.20。
Embodiment 4
The preparation of 1.4 compound VI
By compound V2.00g (8.9mmol); 3; 5-dimethoxyphenylboronic 2.44g (13.4mmol); 10% palladium/carbon 475mg (0.45mmol) and potassium carbonate 2.47g (17.9mmol) is in 250mL round-bottomed flask; make solvent with 60mL glycol dimethyl ether and 10mL water, heat under nitrogen protection to 80 DEG C of reactions 3 hours. Reactant liquor is filtered by kieselguhr, and filtrate concentration obtains crude product. Adding as far as possible few hot ethyl acetate to dissolve, be then rapidly added a large amount of cold diethyl ether and quickly cool down, precipitating out a large amount of flaxen solid, it is yellow solid 2.01g that filtering and washing obtains compound VI, yield 80.1%.m.p.210-212 DEG C; ESI-MSm/z:281.96, [M+H]+.
1HNMR (400MHz, DMSO) δ: 9.16 (s, 1H), 8.12 (d, J=2.0Hz, 1H), 8.03 (dd, J=8.8,2.0Hz, 1H), 7.48 (d, J=8.8Hz, 1H), 6.89 (s, 2H), 6.88 (d, J=1.9Hz, 2H), 6.52 (d, J=2.0Hz, 1H), 3.83 (s, 6H).
13CNMR(101MHz,DMSO)δ:162.68,160.91,151.42,141.43,133.34,133.05,125.42,124.91,119.48,104.58,99.19,55.26。
Embodiment 5
The preparation of 1.5 compound VII
Take NaH (60%) 570mg (14.22mmol) under nitrogen protection, add oxolane (THF) 20mL heavily steamed, cool down 15 points minutes under ice bath;Take 2g compound VI to be dissolved in the 50mL THF heavily steamed, be added dropwise in above-mentioned system at 0 DEG C, dropwise rear room temperature stirring reaction 2 hours; System ice bath again is cooled to 0 DEG C, separately takes 1.32g (8.5mmol) 2-fluorin-3-nitrotoluene and is dissolved in the 20mL THF heavily steamed, is slowly added dropwise in system, reinforced complete, removes ice bath, makes system slowly rise to room temperature, continues stirring reaction overnight. Adding 50mL shrend to go out reaction, system is extracted with ethyl acetate (30mL × 3). Merging organic layer, with saturated common salt water washing 3 times, organic facies anhydrous sodium sulfate dries, and filters, the thick product of concentration. Obtaining compound VII with ethyl acetate and petroleum ether recrystallization again is red solid 2.58g, yield 87.2%.m.p.125-127 DEG C; ESI-MSm/z:417.11, [M+H]+.
1HNMR (400MHz, DMSO) δ: 9.56 (s, 1H), 9.29 (s, 1H), 8.23 (d, J=1.9Hz, 1H), 8.10 (dd, J=8.8,1.8Hz, 1H), 7.81 (d, J=7.5Hz, 1H), 7.66 (d, J=7.4Hz, 1H), 7.47 (d, J=8.5Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 6.90 (d, J=2.1Hz, 2H), 6.53 (t, J=2.1Hz, 1H), 3.83 (s, 6H), 2.38 (s, 3H).
13CNMR(101MHz,DMSO)δ:162.86,160.95,157.48,146.14,141.16,137.12,134.97,134.82,133.62,130.91,125.50,125.46,125.42,122.45,120.53,104.73,99.46,55.30,18.13。
Claims (6)
1. a preparation method for N-aryl-quinazoline-2-amines, this compound has the structure shown in formula I:
In formula, R is monosubstituted or polysubstituted aromatic ring structure, what it is characterized in that this compound is prepared by with 3-bromobenzaldehyde for initiation material, obtains intermediate N aryl-quinazoline-2-amines by nitrated, reduction and the cyclization of cyanamide, coupling, replacement five step; Specifically comprise the following steps that
A, with 3-bromobenzaldehyde and Compound II per for initiation material, obtain the bromo-2-nitrobenzaldehyde of 5-and Compound II per I through nitrated;
B, Compound II per I obtain 2-amino-5-bromobenzaldehyde and compound IV through reduction;
C, compound IV and cyanamide cyclization obtain 6-bromine quinazoline-2-amine and compound V;
D, compound V and the coupling under palladium catalyst effect of 3,5-dimethoxyphenylboronic obtain 6-(3,5-Dimethoxyphenyl) quinazoline-2-amine and compound VI;
E, compound VI obtain N-aryl-quinazoline-2-amine and compound I through o-fluoronitrobenzene and the replacement of polysubstituted derivant thereof.
2. preparation method according to claim 1, it is characterized in that described step a particularly as follows: Compound II per and nitric acid or sodium nitrate are in solvent sulphuric acid, react at 0-40 DEG C, Compound II per I is obtained after 1-12 hour, the mol ratio of Compound II per and nitric acid or sodium nitrate is 1:1.0-1.5, and sulfuric acid concentration is 70-98%.
3. preparation method according to claim 1, it is characterized in that described step b particularly as follows: Compound II per I is in etoh solvent, with iron powder/hydrochloric acid, hydrated ferric oxide ./hydrazine hydrate or Reduction with Stannous Chloride, at 40-80 DEG C, reaction 2-12h obtains the mol ratio of compound IV, Compound II per I and reducing agent is 1:0.1-0.5.
4. preparation method according to claim 1, it is characterized in that described step c particularly as follows: compound IV and cyanamide are at solvent N, dinethylformamide, N, in N-dimethyl acetylamide, dimethyl sulfoxide or N-Methyl pyrrolidone, at 60-200 DEG C, reaction 2-12h obtains the mol ratio of compound V, compound IV and cyanamide is 1:1.2-3.0.
5. preparation method according to claim 1, it is characterized in that described step d particularly as follows: compound V and 3, 5-dimethoxyphenylboronic is at solvent ethylene glycol dimethyl ether, 1, 4-dioxane, in isopropanol or ethanol, add palladium catalyst carbon, [1, double, two (diphenylphosphino) ferrocene of 1'-] palladium chloride or tetrakis triphenylphosphine palladium, add inorganic base potassium carbonate, sodium carbonate or cesium carbonate, react at 60-100 DEG C, 18-24h obtains compound VI, compound V and 3, the mol ratio of 5-dimethoxyphenylboronic is 1:1.1-1.5, the mol ratio of compound V and palladium catalyst is 1:0.05-0.5, the mol ratio of compound V and inorganic base is 1:1.5-2.5.
6. preparation method according to claim 1, it is characterized in that described step e particularly as follows: make compound VI at solvent N, with o-fluoronitrobenzene and polysubstituted derivatives reaction thereof in dinethylformamide or oxolane, add NaH and do alkali, react 18-24h under 0 DEG C-room temperature and obtain compound I, the mol ratio of compound VI and o-fluoronitrobenzene and polysubstituted derivant thereof is 1:1.1-1.5, and the mol ratio of compound VI and NaH is 1:1.1-1.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112920228A (en) * | 2021-02-01 | 2021-06-08 | 衡阳师范学院 | Aromatic ring bridged ferrocene and diphenylamine compound as well as preparation method and application thereof |
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| JP2008007490A (en) * | 2006-06-30 | 2008-01-17 | Canon Inc | Condensed heterocyclic compound and organic light-emitting element |
| CN104540809A (en) * | 2012-07-11 | 2015-04-22 | 蓝印药品公司 | Inhibitors of the fibroblast growth factor receptor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112920228A (en) * | 2021-02-01 | 2021-06-08 | 衡阳师范学院 | Aromatic ring bridged ferrocene and diphenylamine compound as well as preparation method and application thereof |
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