CN1049498A - 2,4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant is synthetic - Google Patents
2,4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant is synthetic Download PDFInfo
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- CN1049498A CN1049498A CN 89106578 CN89106578A CN1049498A CN 1049498 A CN1049498 A CN 1049498A CN 89106578 CN89106578 CN 89106578 CN 89106578 A CN89106578 A CN 89106578A CN 1049498 A CN1049498 A CN 1049498A
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- replacement
- diamino
- quinazoline
- benzyl amino
- quinazoline derivant
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Abstract
The invention belongs to and have 2 of antitumor, antimalarial and effect such as antibiotic, 4-diamino-5-replacements-6-(N-replacement benzyl amino) quinazoline derivant synthetic method.The present invention has introduced with 5-and has replaced 2; 4; 6-triamino quinazoline and substituted aroma aldehyde are that raw material is through condensation and reduction Synthetic 2; 4-diamino-5-replacement-6-benzyl amido quinazoline derivatives carries out formylation, nitrosification and the Synthetic 2 that methylates then respectively, the method for 4-diamino-5-replacement-6-(N-replacement benzyl amino) quinazoline derivant; important intermediate 5-fluoro-2; 4,6-triamino quinazoline is made with reduction through nitrated by 2-fluoro-6-aminobenzonitrile and cyanamide cyclization again.
Description
The invention belongs to 2 of antitumor, antimalarial and anti-microbial effect, 4-diamino-5-replacement-6-(N-replaces benzyl amino) the quinazoline derivant synthetic method.
2, it is dihydrofolate reductase inhibitor that 4-diamino-6-replaces the benzyl amido quinazoline derivatives, have antitumor, antimalarial and anti-microbial effect, on the amino of 6 side chains, introduce methyl and obviously improve its antitumor action, as SIPI759(CN 86 100512 A; Acta Pharmaceutica Sinica 1989,24: 99), but curative effect is still not very good.
The amino of 5 of this ring and 6 side chains plays a crucial role to its metabolism as can be seen from the structure of known six tetrahydrofolate coenzymes.That the present invention is intended to seek is antitumor, the synthetic method of antimalarial and the stronger new compound of anti-microbial effect.The present invention implements by following steps: introduce alkyl or halogen for 5 at the quinazoline ring; on the amino of 6 side chains, introduce formyl radical, nitroso-group or methyl synthetic a series of 2; 4-diamino-5-replacement-6-(N-replacement benzyl amino) synthetic method of quinazoline derivant (I～IV), its structural formula is as follows:
Wherein R is C
1～C
4Alkyl, halogen, alkoxyl group etc.
X is the halogen of different positions, C
1～C
4Alkyl, alkoxyl group etc.
Ⅰ
1（SIPI 1060） R＝Cl X＝H
Ⅰ
2（SIPI 1305） R＝Cl X＝3-Cl
Ⅰ
3（SIPI 1306） R＝F X＝4-F
Ⅱ
1（SIPI 1300） R＝Cl X＝H
Ⅱ
2（SIPI 1065） R＝CH
3X＝3，4-OCH
2O-
Ⅲ
1（SIPI 1055） R＝CH
3X＝4-Cl
Ⅲ
2（SIPI 1058） R＝CH
3X＝4-F
Ⅳ
1（SIPI 1070） R＝CH
3X＝4-Cl
Ⅳ
2（SIPI 1071） R＝CH
3X＝4-F
Ⅳ
3（SIPI 1086） R＝CH
3X＝2-Cl
Synthetic method is as follows:
5-is replaced-2,4, and 6-triamino quinazoline and various substituted benzaldehyde condensation make corresponding various Xi Fushi alkali, again with sodium borohydride or make catalyzer with platinum oxide and lead to hydrogen reduction and make 2,4-diamino-5-replacement-6-benzyl amino-quinazoline compound (I).I and formic acid reaction make 2,4-diamino-5-replacement-6-(N-formyl radical-replacement benzyl amino) quinazoline compounds (II); I and Sodium Nitrite react in acetic acid and make 2,4-diamino-5-replacement-6-(N-nitroso-group-replacement benzyl amino) quinazoline compounds (III); I and sodium borohydride and formaldehyde reaction or II make 2,4-diamino-5-replacement-6-(N-methyl-replacement benzyl amino with potassium boron hydrogen and aluminum trichloride (anhydrous) or with the Li-Al hydrogen reduction) quinazoline compounds (IV) row reaction formula as follows:
Important intermediate 5-fluoro-2,4, the preparation of 6-triamino quinazoline is to be that raw material and cyanamide and pyridine hydrochloride make 2 110～130 ℃ of cyclizations with 2-fluoro-6-aminobenzonitrile, 4-diamino-5-fluquinconazole quinoline, use nitric acid and sulfuric acid mixed acid nitrification then, in hydrochloric acid, reduce and get with tin protochloride again, as follows the row reaction formula:
Example one
2,4-diamino-5-chloro-6-(3-benzyl chloride amino) quinazoline (I
2) preparation
Get 5-chloro-2,4,6-triamino quinazoline 3.8g(0.018 mole), m chlorobenzaldehyde 3.8g(0.027 mole) and ethanol 40ml, mix and refluxed 8～10 hours, boil off part ethanol, cooling, filtration drying gets 2,4-diamino-5-chloro-6-(3-chlorobenzene methene amido) quinazoline 4.98g.Put it in the reaction flask, add ethanol 60ml, under the backflow situation, add sodium borohydride 2.29g(0.061 mole slowly), finish the back and refluxed 3～6 hours, cooling is filtered, washing, the dry crude product that gets, get yellow needle 4g with the Diluted Alcohol recrystallization, yield 80%, 209～210 ℃ of fusing points.
Ultimate analysis: C
15H
13Cl
2N
5Calculated value %C53.90, H3.93, N20.96, Cl21.21; Experimental value % C53.60, H3.91, N20.63, Cl21.45
Example two
2,4-diamino-5-methyl-6-benzyl amido quinazoline (I
4) preparation
Get 5-methyl-2,4,6-triamino quinazoline acetate 2.2g(0.009 mole), phenyl aldehyde 1.4g(0.013 mole), add dehydrated alcohol 60ml and refluxed 4～6 hours, cooling, filter 2,4-diamino-5-methyl-6-(Ben Yajiaji amino) quinazoline acetate 2.1g.This salt is put reaction flask, add ethylene glycol monomethyl ether 210ml and a little platinum oxide, stirred 24 hours at 40～60 ℃ of logical hydrogen, filter, the filtrate evaporate to dryness with the alkalization of 2N caustic lye of soda, extracts with tetrahydrofuran (THF) and ethyl acetate mixture then, washing, anhydrous sodium sulfate drying, evaporate to dryness gets yellow particle shape crystallization 0.9g with ethyl alcohol recrystallization, yield 52%, 190～191 ℃ of fusing points.
Ultimate analysis: C
16H
17N
5Calculated value %C68.82, H6.09, N25.09; Experimental value %C69.30, H6.22, N25.09
Example three
2,4-diamino-5-chloro-6-(N-formyl benzyl amino) quinazoline (II
1) preparation
Get 2,4-diamino-5-chloro-6-benzyl amido quinazoline 1g(0.0033 mole) adds formic acid 20ml, reflux 2～4 hours, evaporated under reduced pressure, be dissolved in water, ammoniacal liquor alkalization, solid crude product, spent glycol methyl ether-alcohol-water mixed solution crystallization gets yellow powder 0.65g, yield 59.3%, 216～217 ℃ of fusing points.
Ultimate analysis: C
16H
14ClN
5O calculated value % C58.63, H4.30, N21.36, Cl10.82; Experimental value %C58.48, H4.33, Cl10.75
Example four
2,4-diamino-5-methyl-6-(N-formyl radical-3,4-dioxy methyne benzyl amino) quinazoline (II
2) preparation
Get 2,4-diamino-5-methyl-6-(3,4-dioxy methyne benzyl amino) quinazoline 0.93g(0.0029 mole), add formic acid 6.3ml and stir, splash into aceticanhydride 2.1ml at 15～20 ℃, continue to stir 1 hour,, filter with the ammoniacal liquor alkalization, spent glycol methyl ether recrystallization, get white powder 0.4g, yield 39.2%, 220～222 ℃ of fusing points.
Ultimate analysis: C
18H
17N
5O
3Calculated value %C59.07, H5.85, N16.39; Experimental value %C58.76, H5.57, N15.97
Example five
2,4-diamino-5-methyl-6-(N-nitroso-group-4-chloro-benzyl amino) quinazoline (III
1) preparation
Get 2,4-diamino-5-methyl-6-(4-chloro-benzyl amino) quinazoline 1g(0.0032 mole) is dissolved among the 50% acetic acid 25ml, ice-cold to about 0 ℃, add Sodium Nitrite 0.24g(0.0033 mole) solution formed with water 2.5ml, stirring reaction 3～6 hours, ammoniacal liquor alkalization, filter, get blush powder 0.8g with ethyl alcohol recrystallization, yield 72.7%, 214～215 ℃ of fusing points
Ultimate analysis: C
16H
15ClN
6O calculated value % C56.06, H4.38, N24.53, Cl10.36; Experimental value %C56.03, H4.32, N24.41, Cl10.09
Example six
2,4-diamino-5-methyl-6-(N-methyl-4-chloro-benzyl amino) quinazoline (IV
1) the vitriol preparation
Get 2,4-diamino-5-methyl-6-(4-benzyl chloride amino) quinazoline 0.8g(0.0026 mole), the suspension that sodium borohydride 0.6g and tetrahydrofuran (THF) 18ml form splashes into 37% formaldehyde 0.75ml at 25～30 ℃, in the mixed solution that dilute sulphuric acid and tetrahydrofuran (THF) 18ml form, stirred 18～24 hours, boil off solvent, washing, add alcohol reflux again and get buff powder 0.41g, yield 48%, fusing point＞300 ℃
Ultimate analysis: C
17H
18ClN
5H
2SO
4Calculated value % N16.45, Cl8.34; Experimental value % N16.03, Cl7.98
Example seven
2,4-diamino-5-methyl-6-(N-methyl-4-fluoro-benzyl amino) quinazoline (IV
2) preparation
Get 2; 4-diamino-5-methyl-6-(N-formyl radical-4-fluoro-benzyl amino) quinazoline 1g(0.003 mole) and anhydrous tetrahydro furan 40ml put in the reaction flask; under agitation add Li-Al hydrogen 0.45g(0.012 mole), under nitrogen gas stream, refluxed 3～6 hours, add water a little; extract with tetrahydrofuran (THF) and ethyl acetate mixed solution; anhydrous sodium sulfate drying, evaporate to dryness separates (developping agent: methyl alcohol: acetone=3: 1) get yellow powder 0.15g with flaggy; yield 15.8%, 265～267 ℃ of fusing points
Ultimate analysis: C
17H
18FN
5Calculated value % C65.59, H5.79, N22.51; Experimental value % C65.82, H5.61, N22.51
Example eight
2,4-diamino-5-methyl-6-(N-methyl-4-chloro-benzyl amino) quinazoline (IV
1) preparation
Get aluminum trichloride (anhydrous) 30g, tetrahydrofuran (THF) 500ml puts in the reaction flask, adds potassium boron hydrogen 12g, stirring at room 2 hours, drips tetrahydrofuran (THF), collects distilled tetrahydrofuran (THF) reduced liquid (noting anhydrous) more than 90 ℃.With 2; 4-diamino-5-methyl-6-(N-formyl radical-4-chloro-benzyl amino) quinazoline 1g(0.0029 mole) joins among the above-mentioned tetrahydrofuran (THF) reduced liquid 750ml; reflux and stirred 1 hour, drip 10% hydrochloric acid and make the reaction solution clarification, alkalize with caustic lye of soda again; ethyl acetate extraction; wash neutrality with saturated nacl aqueous solution, anhydrous sodium sulfate drying boils off solvent, gets 0.25g with ethyl alcohol recrystallization; yield 26.3%, 223～225 ℃ of fusing points
Ultimate analysis: C
17H
18ClN
5Calculated value % C62.29, H5.50, N21.37, Cl10.84; Experimental value % C62.09, H5.50, N20.92, Cl10.84
Example nine
5-fluoro-2,4, the preparation of 6-triamino quinazoline
Get 2-amino-6-fluorine benzonitrile 15.5g(0.114 mole), cyanamide 10.32g(0.245 mole) and pyridine hydrochloride 62g mix, frit reaction is 1 hour in 110～130 ℃ of oil baths, and is cold slightly, adds alcohol reflux for a moment, be as cold as room temperature, filter, get 5-fluoro-2 with the ammoniacal liquor recrystallization, 4-diamino quinazoline white, needle-shaped crystals 15g, yield 73.8%, 249.5～251.5 ℃ of fusing points
With 5-fluoro-2,4-diamino quinazoline 15g(0.085 mole) joins in the mixed solution of nitrosonitric acid 30ml and vitriol oil 30ml in batches, room temperature reaction 16～20 hours, with the ammoniacal liquor alkalization, filter washing, the dry 5-fluoro-2 that gets, 4-diamino-6-nitro-quinazoline yellow crystal 17.8g, yield 94.7%, fusing point＞360 ℃
Get hydrochloric acid 267ml and Glacial acetic acid 80ml stirs, add tin protochloride (Sncl
22H
2O) 57g(0.25 mole), add above-mentioned itrated compound 17.8g(0.08 mole at 15～25 ℃ in batches), add the back stirring at room 18～20 hours, filter, filter cake is dissolved in the frozen water, and alkalization is filtered, washing, the water recrystallization gets 5-fluoro-2,4,6-triamino quinazoline light brown crystallization 8.4g, yield 43.5%, 212～214 ℃ of fusing points
Ultimate analysis: C
8H
8FN
5Calculated value %C49.73, H4.18, N36.25, F9.83; Experimental value % C50.11, H4.22, N35.87F9.46
Claims (5)
1, a kind of have 2 of antitumor, antimalarial and an anti-microbial effect, the synthetic method of 4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant, it is characterized in that 5-is replaced-2,4,6-triamino quinazoline and various substituted benzaldehyde condensation make corresponding various Xi Fushi alkali, be reduced into 2,4-diamino-5-replacement-6-benzyl amino-quinazoline compound (I) with sodium borohydride or contact hydride process subsequently.I carries out formylation, nitrosification respectively and methylates making 2,4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant II, III and IV.
2, by described the sort of 2 of antitumor, antimalarial and the anti-microbial effect that have of claim 1; 4-diamino-5-replacement-6-(N-replacement benzyl amino) synthetic method of quinazoline derivant; it is characterized in that I and formic acid reaction are made 2,4-diamino-5-replacement-6-(N-formyl radical-replacement benzyl amino) quinazoline derivant (II).
3, by described the sort of 2 of antitumor, antimalarial and the anti-microbial effect that have of claim 1,4-diamino-5-replacement-6-(N-replacement benzyl amino) synthetic method of quinazoline derivant, it is characterized in that I and Sodium Nitrite reacted in acetic acid and make 2,4-diamino-5-replacement-6-(N-nitroso-group-replacement benzyl amino) quinazoline derivant (III).
4, by described the sort of 2 of antitumor, antimalarial and the anti-microbial effect that have of claim 1,4-diamino-5-replacement-6-(N-replacement benzyl amino) synthetic method of quinazoline derivant, it is characterized in that making 2,4-diamino-5-replacement-6-(N-methyl-replacement benzyl amino with methods such as potassium boron hydrogen and aluminum chloride or Li-Al hydrogen reduction with I and sodium borohydride and formaldehyde reaction or with II) quinazoline derivant (IV).
5, by described the sort of 2 of antitumor, antimalarial and the anti-microbial effect that have of claim 1,4-diamino-5-replacement-6-(N-replacement benzyl amino) synthetic method of quinazoline derivant, it is characterized in that with 2-fluoro-6-aminobenzonitrile be raw material, with cyanamide and pyridine hydrochloride, become 2 110～130 ℃ of cyclizations, 4-diamino-5-fluquinconazole quinoline, again with nitric acid and sulfuric acid mixed acid nitrification, reduce in hydrochloric acid with tin protochloride then and make important intermediate 5-fluoro-2,4,6-triamino quinazoline.
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|---|---|---|---|
| CN 89106578 CN1049498A (en) | 1989-08-16 | 1989-08-16 | 2,4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant is synthetic |
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| CN 89106578 CN1049498A (en) | 1989-08-16 | 1989-08-16 | 2,4-diamino-5-replacement-6-(N-replaces benzyl amino) quinazoline derivant is synthetic |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102918051A (en) * | 2010-03-16 | 2013-02-06 | 诺马德卡谟·加林多塞维利亚 | N6-(methylferrocene) quinazoline-2, 4, 6-triamine (H2) and derivatives thereof, and prodrugs for use as antibacterial, antiparasitic, antiprotozoal and antileishmanial agents |
| CN103215752A (en) * | 2012-01-19 | 2013-07-24 | 佛山市南海必得福无纺布有限公司 | Long-acting anti-acarid, mildew-proof and anti-bacterial PP (Polypropylene) non-woven fabric and preparation method thereof |
| CN104496914A (en) * | 2014-12-31 | 2015-04-08 | 西北大学 | Synthesis method of 2-aryl-substituted quinazoline compounds |
| CN110698417A (en) * | 2018-07-09 | 2020-01-17 | 新发药业有限公司 | Preparation method of 6-substituent furyl-4-substituted amino quinazoline derivative and key intermediate thereof |
-
1989
- 1989-08-16 CN CN 89106578 patent/CN1049498A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102918051A (en) * | 2010-03-16 | 2013-02-06 | 诺马德卡谟·加林多塞维利亚 | N6-(methylferrocene) quinazoline-2, 4, 6-triamine (H2) and derivatives thereof, and prodrugs for use as antibacterial, antiparasitic, antiprotozoal and antileishmanial agents |
| CN102918051B (en) * | 2010-03-16 | 2015-09-09 | 诺马德卡谟·加林多塞维利亚 | N6-(methyl ferrocene) quinazoline-2,4,6-triamine (H2) and its derivative, and the prodrug being used as antiseptic-germicide, antiparasitic, protozoacide and anti-Leishmania agent |
| CN103215752A (en) * | 2012-01-19 | 2013-07-24 | 佛山市南海必得福无纺布有限公司 | Long-acting anti-acarid, mildew-proof and anti-bacterial PP (Polypropylene) non-woven fabric and preparation method thereof |
| CN103215752B (en) * | 2012-01-19 | 2016-12-14 | 佛山市南海必得福无纺布有限公司 | A kind of long-acting anti-demodicid mite, mildew-resistant, antibacterial PP non-woven fabrics and preparation method thereof |
| CN104496914A (en) * | 2014-12-31 | 2015-04-08 | 西北大学 | Synthesis method of 2-aryl-substituted quinazoline compounds |
| CN110698417A (en) * | 2018-07-09 | 2020-01-17 | 新发药业有限公司 | Preparation method of 6-substituent furyl-4-substituted amino quinazoline derivative and key intermediate thereof |
| CN110698417B (en) * | 2018-07-09 | 2020-11-20 | 新发药业有限公司 | Preparation method of 6-substituent furyl-4-substituted amino quinazoline derivative and key intermediate thereof |
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