CN102816164A

CN102816164A - A method for synthesizing 7-amino-2,3-dihydropyrimidin[4,5-d]pyrimidin-4(1H)-one

Info

Publication number: CN102816164A
Application number: CN2012103199959A
Authority: CN
Inventors: 李加荣; 陈姝; 史大昕; 张奇
Original assignee: Beijing Institute of Technology BIT
Current assignee: Beijing Institute of Technology BIT
Priority date: 2012-08-31
Filing date: 2012-08-31
Publication date: 2012-12-12

Abstract

The invention relates to a method for producing 7-amino-2, 3-dihydropyrimidine [4,5-d ] by reacting guanidine, 2-ethoxymethylenepropionitrile and carbonyl compounds]Pyrimidin-4(1H) -one (7-amino-2, 3-dihydropyrimido [4,5-d ]]Synthesis method of pyrimidin-4(1H) -one) heterocyclic compound, and reaction general formulaAs shown in the figure, in the formula: wherein R is₁，R₂Is H, alkyl, aryl or heteroaryl, or R₁、R₂Together with the carbon atom to which they are attached form a 3-to 7-membered cycloalkyl group. The catalyst for the reaction is anhydrous zinc chloride, anhydrous aluminum trichloride Lewis acid, or hydrochloric acid, sulfuric acid protonic acid or sodium hydroxide, sodium methoxide, sodium ethoxide or tert-butyl alcohol potassium base catalyst. Carrying out conventional heating for reaction; the purification adopts recrystallization or column chromatography separation means. The invention has the advantages of easily obtained raw materials, simple process and mild reaction conditions; wide reaction application range, and can synthesize various 7-amino-2, 3-dihydropyrimidines [4,5-d ] by using different substrates]Pyrimidine-4 (1H) -ketone heterocyclic compounds.

Description

A kind of synthetic 7-amino-2, the method for 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone

(1) technical field

The present invention relates to a kind of via guanidine, 2-oxyethyl group methylene radical the third two eyeball and carbonyl compound prepared in reaction 7-amino-2; 3-dihydro-pyrimidin [4; 5-d] pyrimidine-4 (1H)-ketone (7-amino-2; The compound method of 3-dihydropyrimido [4,5-d] pyrimidin-4 (1H)-one) heterogeneous ring compound.

(2) background technology

7-is amino-2,3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone fused ring compound be one type have a good physiologically active contain the polynitrogen heterocycle compound.For example, compd A [2-aminopyrimidine [4,5-d] pyrimidines-4 (8H)-ketone] is one type of dihydro reductase inhibitor, to associated conditions have potential medicinal curative effect (Eur.J.Med.Chem., 2003,38:719-728.); Compd B [7-

aminopyrimidine [4; 5-d] and pyrimidine-2,4 (1H, 3H)-diketone] be one type of tyrosine kinase inhibitor; Fringing-type cancer of the stomach there is therapeutic action (Bioorg.Med.Chem.Lett.; 2006,16:1950-1953.): Compound C can be used as the biological base pairing of T and A in the dna double chain, at biomedicine field important Research Significance (J.Am.Chem.Soc. is arranged; 2011,133:6926-6929).

Known 7-amino-2, the compound method of 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone compound is less, and similar heterocyclic compound method mainly contains:

(1) under the catalysis of sodium hydroxide, reacts Synthetic 2-phenyl pyrimidine [4,5-d] pyrimidines-4 (3H)-ketone (reactions step is following) (Syn.Commun., 2006,36:2963-2973 with 4-amino-5-pyrimidine nitrile and aromatic aldehyde; ), the needed 4-amino of this method-5-pyrimidine nitrile needs three-step reaction just can synthesize, and severe reaction conditions, long reaction time, and post-processing step is loaded down with trivial details.

(2) with 2,3-di-amino-pyrimidine-4 (3H)-ketone and methane amide 150 degrees centigrade down reaction obtained in 16 hours 2-aminopyrimidine [4,5-d] pyrimidines-4 (3H)-ketone (reactions step is following) (Eur.J.Med.Chem., 2003,38:719-728).

(3) by amino-5 pyrimidine nitriles of 2 substituted 4-through synthetic 7 substituted Mi Dingbings [4,5-d] pyrimidine of two steps-4-alcohol (reactions step is following) (J.Am.Chem.Soc.1960,82:5711-5718).This method productive rate is lower.

In sum, known 7-amino-2, in the compound method of 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone compound, or temperature is higher or the reaction times is long or midbody costs an arm and a leg, and is difficult to preparation.These deficiencies have been brought inconvenience to the synthetic especially suitability for industrialized production of this compounds.

(3) summary of the invention

For overcoming above-mentioned existing in prior technology problem, the invention provides a kind of synthetic 7-amino-2, the novel method of 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone fused ring compound, raw material of the present invention is easy to get, and technology is simple, and reaction conditions is gentle; The reactive applications scope is wide, the synthetic multiple 7-amino-2 of available different substrates, 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone heterogeneous ring compound.

Technical scheme of the present invention is: guanidine, and 2-oxyethyl group methylene radical the third two eyeballs and carbonyl compound reaction, it is amino-2 to generate 7-, 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone heterogeneous ring compound, reaction expression is:

R wherein ₁, R ₂Be substituting group alkyl, aryl or heteroaryl, perhaps R ₁, R ₂Form 3 yuan to 7 yuan naphthenic base with the carbon atom that is connected.Wherein, the C of the preferred straight or branched of alkyl _1-6Alkyl, more preferably methyl, ethyl, propyl group, butyl, amyl group, hexyl; The C of the preferred straight or branched of alkoxyl group _1-6Alkoxyl group, more preferably methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy; The preferred C of aryl _6-10Aryl, more preferably phenyl, tolyl, ethylbenzene base; Heteroaryl is preferably 5 to 10 yuan of heteroaryls that comprise 1 to 3 Sauerstoffatom or nitrogen-atoms, more preferably pyridine, pyrimidine, pyrrole Lip river, pyrans.Employed catalyzer is a kind of in Louis's acids, proton acids or the bases; Wherein more excellent is, but is not limited to: Zinc Chloride Anhydrous, aluminum trichloride (anhydrous), cupric chloride, cuprous chloride, hydrochloric acid, sulfuric acid, pyridine, piperidines, salt of wormwood, sodium hydroxide (potassium), sodium alkoxide (potassium).The addition sequence of 2-oxyethyl group methylene radical the third two eyeballs, carbonyl compound and catalyzer can exchange arbitrarily.

The preparation process is:

(1) reinforced

With mol ratio is that guanidine, 2-oxyethyl group methylene radical the third two eyeballs and the carbonyl compound mixture of 1:1:1 ~ 1:1:100 adds in the reaction vessel, adds consumption and be 1 ~ 5002-oxyethyl group methylene radical, the third two eyeball solvents doubly as reaction medium.Reaction medium does, but is not limited to benzene,toluene,xylene, DMSO 99.8MIN., N, dinethylformamide, N, N-DEF, THF and halogenated hydrocarbon polar solvent a kind of; Be liquid carbonyl compound down for normal temperature, except using aforesaid reaction medium, self also can be used as reaction medium.Add consumption then and be the catalyzer of 0.1 ~ 50 times in 2-oxyethyl group methylene radical the third two eyeballs.Employed catalyzer is a kind of in Louis's acids, proton acids or the bases; Wherein more excellent is, but is not limited to: Zinc Chloride Anhydrous, aluminum trichloride (anhydrous), cupric chloride, cuprous chloride, hydrochloric acid, sulfuric acid, pyridine, piperidines, salt of wormwood, sodium hydroxide (potassium), sodium alkoxide (potassium).The addition sequence of guanidine, 2-oxyethyl group methylene radical the third two eyeballs, carbonyl compound, reaction medium and catalyzer can exchange arbitrarily.

(2) reaction

In the conventional heating unit, make reactant under the temperature of reaction of 30 minutes post-heating to 200 of room temperature reaction ℃ the stirring reaction several seconds to several hours, with thin-layer chromatography monitoring reaction process.The developping agent of thin-layer chromatography is methyl alcohol, both mixed solutions of methylene dichloride.

(3) reaction solution aftertreatment

Cooled reaction solution is scattered in 5 times of dispersion medium below the volume of reaction solution, and dispersion medium does, but is not limited to water, ethanol, methyl alcohol, sherwood oil, methyl alcohol, perhaps wherein in both mixed solutions.Filter, will filtrate and use ETHYLE ACETATE, or a kind of organic solvent extraction in the methylene dichloride, chloroform, ether 2-5 time, the merging organic phase.Filter cake is used methyl alcohol, the perhaps a kind of organic solvent extracting in ethanol, acetone, THF, ETHYLE ACETATE, the acetonitrile, the organic phase after the extracting is mixed with the organic phase that above extraction obtains.Then with mixed liquid with but after being not limited to a kind of drying in SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate, anhydrous magnesium sulfate, the Calcium Chloride Powder Anhydrous siccative, rotation steams solvent, obtains solid mixture.

(4) product purification

Crude product for step 3 carries out recrystallization or column chromatography purification, and obtaining productive rate is the pure target compound of 1-99%.Recrystallization solvent can be, but be not limited to water, methyl alcohol, ethanol, Virahol, acetone, acetonitrile, THF, dioxane, ETHYLE ACETATE, methylene dichloride, benzene, toluene.Adopt silicagel column or alumina column during column chromatography, developping agent does, but is not limited to ethyl acetate/petroleum ether (1:1 ~ 1:5, volume ratio), methyl alcohol/chloroform (1:5 ~ 1:50, volume ratio), methylene dichloride, acetone.

The invention has the advantages that: raw material is easy to get, and technology is simple, and the reaction times is short, and reaction conditions is gentle.Have wide range of applications the various 7-amino-2 of available different substrate one-step synthesis, 3-dihydro-pyrimidin [4,5-d] pyrimidines-4 (1H)-ketone.

(4) embodiment:

Embodiment 1

In the there-necked flask of 25ml, add 10ml ethanol and be dissolved with the 2mmol guanidine behind alkali reaction, stir adding 2mmol 2-Ethoxy methylene malononitrile 99 down, the 8mmol pimelinketone adds the 0.6mmol sodium methylate again; With mixed solution stirring reaction 6h, after reaction is accomplished, reaction solution is put into refrigerator and cooled freeze and spend the night, separate out solid; After the filtration, use recrystallizing methanol, obtain 7'-amino-1'H-spiral shell [hexanaphthene-1,2'-pyrimidine [4; 5-d] pyrimidine]-4' (3'H)-ketone (I), yield 80%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and ketopentamethylene is:

The spectral data of product (I) is: ESI-MS:232 [M-H]; IR (KBr): 3315,3180,2935,2851,1662,1609,1472,1446,1421cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.181 (s, 1H, NH-CO), 7.791 (s, 1H, Pyrimidine-H), 7.731 (s, 1H, C-NH), 6.640 (s, 2H, Pyrimidine-NH2), 1.647 (m, 8H, C-H), 1.291 (m, C-H). ¹³(100MHz, DMSO): δ 164.8,162.2,161.1,156.7,97.6,67.7,24.5,20.6. for C NMR

Embodiment 2

Replace pimelinketone with suberone, other is with embodiment 1.Target compound (II), yield 80%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and suberone is:

The spectral data of product (II) is: ESI-MS:248 [M+H]; IR (KBr): 3413,3339,3173,2933,2845,1659,1624,1600,1473,1408cm ^-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.180 (s, 1H, NH-CO), 7.877 (s, 1H, Pyrimidine-H), 7.869 (s, 1H, C-NH), 6.618 (s, 2H, Pyrimidine-NH ₂), 1.868 (m, 4H, CH), 1.502 (s, 8H, CH). ¹³(100MHz, DMSO): δ 164.8,162.0,160.9,156.6,97.5,71.8,42.0,29.4,20.8. for C NMR

Embodiment 3

Replace pimelinketone with acetone, other is with embodiment 1, target compound (III), yield 91%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and acetone is:

The spectral data of product (III) is: ESI-MS:216 [M+Na]; IR (KBr): 3464,3229,3148,2943,1663,1615,1482,1455,1418cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.182 (s, 1H, NH-CO), 7.774 (s, 1H, Pyrimidine-H), 7.749 (s, 1H, C-NH), 6.681 (s, 2H, Pyrimi dine-NH2), 1.371 (s, 6H, CH). ¹³(100MHz, DMSO): δ 164.8,162.0,161.0,156.7,97.1,66.6,29.8. for C NMR

Embodiment 4

Replace pimelinketone with butanone, other is with embodiment 1, target compound (IV), yield 90%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and butanone is:

The spectral data of product (IV) is: ESI-MS:206 [M-H]; IR (KBr): 3228,2969,1648,1611,1447cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.135 (s, 1H, NH-CO), 7.671 (s, 2H, Pyrimidine-H/C-NH), 6.600 (s, 2H, Pyrimidine-NH2), 1.599 (m, 2H, CH), 1.329 (s, 3H, CH), 0.815 (t, 3H, J=6.8, CH). ¹³(100MHz, DMSO): δ 164.7,162.1,161.2,156.4,96.9,69.2,34.6,29.0,7.9. for C NMR

Embodiment 5

Replace pimelinketone with 2 pentanone, other is with embodiment 1, target compound (V), yield 92%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and 2 pentanone is:

The spectral data of product (V) is: ESI-MS:220 [M-H]; IR (KBr): 3336,3225,3142,2962,1678,1608,1574,1474,1415cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.139 (s, 1H, NH-CO), 7.693 (s, 2H, Pyrimidine-H/C-NH), 6.625 (s, 2H; Pyrimidine-NH2), 1.573 (m, 2H, CH), 1.334 (s, 3H, CH), 1.288 (t, 2H; J=8, CH), 0.839 (t, 3H, J=7.2, CH) .13CNMR (100MHz, DMSO): δ 164.8,162.0; 161.1,156.4,96.9,68.9,44.6,29.3,16.4,13.9.

Embodiment 6

Replace pimelinketone with propione, other is with embodiment 1, target compound (VI), yield 90%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and propione is:

The spectral data of product (VI) is: ESI-MS:244 [M+Na]; IR (KBr): 3156,2970,2936,1671,1600,1477,1419cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.107 (s, 1H, NH-CO), 7.566 (s, 1H, Pyrimidine-H), 7.518 (s, 1H, C-NH), 6.574 (s, 2H, Pyrimidine-NH2), 1.566 (m, 4H, CH), 0.814 (t, 6H, J=7.2, CH). ¹³(100MHz, DMSO): δ 165.2,162.3,161.6,156.1,96.6,79.2,72.1,34.2,7.5. for C NMR

Embodiment 7

Replace pimelinketone with the 3-espeleton, other is with embodiment 1, target compound (VII), yield 82%, Mp>300 ℃.The reaction formula of 2-amino-3-cyanopyridine and 3-espeleton is:

The spectral data of product (VII) is: ESI-MS:244 [M+Na]; IR (KBr): 3416,3173,2970,1657,1605,1566,1482,1414cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.121 (s, 1H, NH-CO), 7.747 (s, 1H, Pyrimidine-H), 7.713 (s, 1H, C-NH), 6.580 (s, 2H, Pyrimidine-NH2), 1.821 (m, 1H, CH), 1.524 (s, 3H, CH), 0.834 (m, 6H, CH). ¹³(100MHz, DMSO): δ 164.7,161.8,161.0,156.2,97.1,71.3,38.9,25.9,16.6. for C NMR

Embodiment 8

Replace pimelinketone with benzyl acetone, other is with embodiment 1, target compound (VIII), yield 89%, Mp>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and benzyl acetone is:

The POP data of product (VIII) are: ESI-MS:282 [M-H]; IR (KBr): 3416,3174,2929,1638,1602,1472,1407cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.187 (s, 1H, NH-CO), 7.812 (s, 2H, Pyrimidine-H/C-NH); 7.264 (t, 2H, J=7.6, Ph-H), 7.177 (t, 3H, J=2; Ph-H), 6.653 (s, 2H, Pyrimidine-NH2), 2.612 (t, 2H, J=8.4; CH), 1.905 (m, 2H, CH), 1.388 (s, 3H, CH). ¹³(100MHz, DMSO): δ 164.8,162.1,161.2,156.6,141.7,128.3,128.2,125.7,96.8,79.2,68.8,43.6,29.7,29.6. for C NMR

Embodiment 9

Replace pimelinketone with methyl phenyl ketone, recrystallization solvent select for use methanol (1:1, v:v), other obtains target compound (IX), yield 75%, Mp with embodiment 1>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and methyl phenyl ketone is:

The spectral data of product (IX) is: ESI-MS:254 [M-H]; IR (KBr): 3453,3329,1665,1577,1444cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.399 (s, 1H, NH-CO), 8.338 (s, 1H, Pyrimidine-H); 7.939 (s, 1H, Pyrimidine-NH), 7.274 (d, 2H, J=8, Ph-H); 7.139 (t, 2H, J=8, Ph-H), 7.044 (t, 1H, J=6.4; Ph-H), 6.541 (s, 2H, Pyrimidine-NH2), 1.462 (s, 3H, CH). ¹³(100MHz, DMSO): δ 164.7,162.9,161.6,157.0,147.2,128.1,127.3,124.8,98.3,69.6,30.1. for CNMR

Embodiment 10

Replace pimelinketone with phenyl aldehyde, other obtains target compound (X), yield 70%, Mp with embodiment 2>300 ℃.The reaction formula of guanidine, 2-Ethoxy methylene malononitrile 99 and phenyl aldehyde is:

The spectral data of product (X) is: ESI-MS:264 [M+Na]; IR (KBr): 3464,3299,3090,2938,1673,1643,1606,1565,1475,1420cm-1; ¹H NMR (400MHz, DMSO): δ (ppm) 8.206 (s, 2H, NH-CO/Pyrimidine-H), 8.160 (s, 1H, C-NH), 7.376 (m, 5H, Ph-H), 6.776 (s, 2H, Pyrimidine-NH2), 5.726 (s, 1H, N-CH). ¹³(100MHz, DMSO): δ 164.8,162.2,161.5,156.9,142.5,128.5,128.3,126.0,98.0,64.9. for C NMR

Claims

1. A method for synthesizing 7-amino-2,3-dihydropyrimidine [4,5-d] pyrimidin-4 (1H)-ketone heterocyclic compounds, characterized in that: with guanidine, 2-ethoxy Methylene malononitrile reacts with carbonyl compounds to generate 7-amino-2,3-dihydropyrimidin[4,5-d]pyrimidin-4(1H)-one heterocyclic compounds, and the general reaction formula is:

R ₁ and R ₂ are H, alkyl, aryl or heteroaryl, or R ₁ and R ₂ form a 3- to 7-membered cycloalkyl group together with the connected carbon atoms.

2. a method for synthesizing 7-amino-2,3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound as claimed in claim 1, wherein the alkyl group is selected from linear or Branched C _1-6 alkyl, alkoxy selected from straight or branched C _1-6 alkoxy, aryl selected from C _6-10 aryl, heteroaryl selected from 1 to 3 A 5- to 10-membered heteroaryl group of an oxygen atom or a nitrogen atom.

3. a kind of method for synthesizing 7-amino-2,3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound as claimed in claim 1, wherein alkyl is selected from methyl, Ethyl, propyl, butyl, pentyl or hexyl; alkoxy is selected from methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

4. a kind of method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidin-4-(3H)-one compound as claimed in claim 1, aryl is selected from phenyl, tolyl or ethylphenyl; heteroaryl selected from pyridine, pyrimidine, pyrrole, pyran.

5. a method for synthesizing 7-amino-2,3-dihydropyrimidin[4,5-d]pyrimidin-4(1H)-one compound as claimed in claim 1, characterized in that: the reaction medium is benzene , toluene, xylene, nitrobenzene, chlorobenzene, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-diethylformamide, tetrahydrofuran or halogenated hydrocarbons; for room temperature The liquid carbonyl compound, in addition to using the aforementioned reaction medium, itself can also be used as a reaction medium.

6. a method for synthesizing 7-amino-2,3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound as claimed in claim 1, characterized in that: reactant 1, The ratio of the amount of substances in 2 and 3 is 1:1:1~1:1:100.

7. a kind of method for synthesizing 7-amino-2,3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound as claimed in claim 1, it is characterized in that: the catalyst of reaction is Anhydrous zinc chloride, anhydrous aluminum trichloride, cuprous chloride, cupric chloride Lewis acids, or hydrochloric acid, sulfuric acid, phosphoprotic acid or pyridine, piperidine, potassium carbonate, sodium hydroxide, potassium hydroxide , Sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide base catalyst.

8. a kind of method for synthesizing 7-amino-2,3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound as claimed in claim 1, is characterized in that: the consumption of Lewis catalyst 1 to 1.5 times the amount of substance in reactant 1; the amount of protonic acid or base catalyst is 1% to 100% of the amount of substance in reactant 1.

9. a kind of synthetic 7-amino-2 as claimed in claim 1, the method for 3-dihydropyrimidin [4,5-d] pyrimidin-4 (1H)-one compound, it is characterized in that: described reaction Normal pressure heating is adopted, and the reaction time is 6 to 10 hours.

10. A method of synthesizing 7-amino-2,3-dihydropyrimidin[4,5-d]pyrimidin-4(1H)-one compound as claimed in claim 1, characterized in that the product is separated and purified The method is: cooling the reaction liquid, filtering to obtain the crude product; recrystallization or column chromatography purification of the crude product, the recrystallization solvent is water, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, Ethyl acetate, dichloromethane, benzene or toluene; silica gel column or alumina column is used for column chromatography, and the eluent is ethyl acetate/petroleum ether with a volume ratio of 1:1~1:5, and a volume ratio of 1 :5~1:50 methanol/chloroform, dichloromethane or acetone.