CN103172636B - Pyridine-quinazolinone compound and preparation method thereof - Google Patents
Pyridine-quinazolinone compound and preparation method thereof Download PDFInfo
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- IMRWILPUOVGIMU-UHFFFAOYSA-N Brc1ncccc1 Chemical compound Brc1ncccc1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- TXDUTHBFYKGSAH-UHFFFAOYSA-N CN(C1N2CCc3c1[nH]c1c3cccc1)c(cccc1)c1C2=O Chemical compound CN(C1N2CCc3c1[nH]c1c3cccc1)c(cccc1)c1C2=O TXDUTHBFYKGSAH-UHFFFAOYSA-N 0.000 description 1
- MONJTOUXCWKOFS-UHFFFAOYSA-N O=C1N(C=CC=C2)C2=Nc2c1cccc2 Chemical compound O=C1N(C=CC=C2)C2=Nc2c1cccc2 MONJTOUXCWKOFS-UHFFFAOYSA-N 0.000 description 1
- ACVGWSKVRYFWRP-UHFFFAOYSA-N O=C1N(CCc2c3[nH]c4ccccc24)C3=Nc2c1cccc2 Chemical compound O=C1N(CCc2c3[nH]c4ccccc24)C3=Nc2c1cccc2 ACVGWSKVRYFWRP-UHFFFAOYSA-N 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a pyridino-quinazolinone compound and a preparation method thereof. The structural formula of the compound is shown in the specification, wherein R1=-Ome or H; and R2=-H, -Me, -Ph, -CO2Et, or-Br. The substituted pyridino-quinazolinone compound disclosed by the invention is an important pharmaceutical molecular active skeleton and organically synthesized intermediate, and plays an important role in pharmaceutical chemistry. According to the method, raw materials are available, the reaction yield is high, and the applicable scope of a substrate is wide. Conventional solvents are used in reaction, the operation is simple, the conditions are mild, the reaction is environment-friendly, and the reaction yield is up to 95%, and therefore, the pyridine-quinazolinone compound and the preparation method thereof disclosed by the invention are extremely suitable for industrial production.
Description
Technical field
The present invention relates to a kind of Pyridine-quinazolinocompound compound and preparation method thereof.
Background technology
Nitrogen heterocyclic ring is a kind of very common pharmacophoric group in drug research field, is one of important goal of current small-molecule drug research and development.In recent years, in the brand medicine that global sales comes out at the top, mostly there is nitrogen heterocyclic ring skeleton.The physiologically active such as antibacterial, antitumor that nitrogen-containing heterocycle compound has, and its significance in basic theory and applied research, make to synthesize this compounds and research its chemistry and biological nature, become a heat subject of organic chemistry and association area.And 11
h-pyrido [2,1-
b] quinazoline-11-ketone is exactly a class in nitrogen heterocyclic ring, they are widely used in field of medicaments.This compounds all demonstrates excellent biological activity, see following documents in anti-inflammatory, antianaphylaxis, anticonvulsion, anticancer and tranquilizing soporific, hypotensive, cytoprotective etc.:
[1] (a) Schwender, C. F.; Sunday, B. R.; Herzig, D. J.
J. Med. Chem. 1979,
22, 114. (b) Aziz, M. A. A.; Daboun, H. A.; Gawad, S. M. A.
J. Prakt. Chem. 1990,
332, 610。
[2] Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D.
J. Med. Chem. 1990,
33, 161。
[3] Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang, G. J.; Hamel, E.
J. Med. Chem. 1990,
33, 1721。
[4] Buyuktimkin, S.
Pharmazie 1986,
40, 393。
[5] (a) Yen, M. H.; Sheu, J. R.; Peng, I. H.; Lee, Y. M.; Chern, J. W.
J. Pharm. Pharmacol. 1996,
48, 90。
(b) Matzkies, F.; Stechert, R.; Rauber, G.; Matzkies, F., Jr.; Drescher, U.
Arzneim.-Forsch. 1989,
39, 1171。
[6] Boehringer Ingelheim Int.
Patent:Ger. Offen. DE 390639, 1989。
Some important natural alkaloids also contain pyrido quinazolinone skeleton, as evodiamine.Evodiamine belongs to indoles alkaloid, is considered to the main pharmacodynamics composition of evodia alkaloid, have that easing pain and diminishing inflammation, antihypertensive diuretic, contraction segmental bronchus, regulate body temperature, fat-reducing, expelling parasite are antibacterial, central excitation, the effect such as antitumor, see following documents:
[7] Chu, J. H.
Sci. Rec. (China) 1951,
4, 279;
Chem. Abstr. 1952,
46, 11589b。
[8] Dou Changgui.
chinese medicinal materials 2003,
26, 295.
[9] Li Yuanjian.
chinese Pharmacological Bulletin 2003,
19, 1084.
[10] Wu Lijun.
china's combination of Chinese tradiational and Western medicine magazine 2004,
24, 169.
Because this type of structural compounds has excellent pharmacologically active, thus cause the great interest of biological medicine researchist.Derivative research based on quianzolinones becomes focus.Therefore, develop the efficient pyridine synthesis of a kind of energy and the novel method of quianzolinones, have great importance.It not only can provide important synthetic intermediate for pyrido quinazolinone analog derivative, and the Pyridine-quinazolinocompound compound of simultaneously synthesizing itself also can for physiologically active screening.
At present, the pyridine synthesis reported in document the method for quinazolinone mainly contains following several:
(1) aniline reaction that replaces of dichloropyridine and ester group.But this kind of reaction, owing to being subject to the restriction of substrate source, the suitability of substrate has difficulties, and yield is very low.
(2) 2-bromopyridine and anthranilic acid are under salt of wormwood, copper powder effect, obtain pyrido quinazolinone.But this reaction conditions is harsher, need higher temperature of reaction.
(3) PA and 0-chloro-benzoic acid pyridine synthesis quinazolinone under copper sulfate, salt of wormwood, microwave catalysis.But this synthetic method has certain reaction limitation, is unfavorable for suitability for industrialized production.
(4) with PA and adjacent bromo benzyl bromo for raw material, pyridine synthesis under cuprous iodide, cesium carbonate, part effect quinazolinone.But the reaction reagent of this synthetic method is expensive, raw material not easily obtains, and is confined to minority substrate, limit its application in organic synthesis and chemical industry.
In sum, the method preparing Pyridine-quinazolinocompound compound has a lot, but the raw material of these reactions is difficult to obtain, and needs the synthesis step through more complicated; Reaction raw materials limitation in some reaction is comparatively large, and reaction yield is lower, and reaction reagent costliness and reaction conditions are comparatively harsh etc.
Summary of the invention
An object of the present invention is to provide a kind of Pyridine-quinazolinocompound compound.
Two of object of the present invention is the preparation method providing this compound.
For achieving the above object, the reaction mechanism that the inventive method adopts is:
Wherein: R
1=-OMe ,-H;
R
2= -H，-Me，-Ph，-CO
2Et，-Br。
According to above-mentioned reaction mechanism, present invention employs following technical scheme:
A kind of Pyridine-quinazolinocompound compound, is characterized in that the structural formula of this compound is:
Wherein: R
1=OMe, H;
R
2= H，
o-Me，
m-Me，
p-Ph，
m-Ph，
o-CO
2Et，
m-Br，
p-Me.
A kind of method preparing the Pyridine-quinazolinocompound compound of above-mentioned replacement, it is characterized in that the method has following steps: by replace picolinamide and Potassium ethanoate, additive is by 1:(2.0 ~ 5.0): the mol ratio of (1.0 ~ 5.0) is dissolved in N, in dinethylformamide, and add the cuprous iodide and 1 of catalyst levels, 10-phenanthroline, 90 ~ 100
oat C temperature, stirring reaction disappears to reaction raw materials; Filter, obtain crude product except after desolventizing; This crude product is purified, namely obtains the corresponding Pyridine-quinazolinocompound compound replaced; The structural formula of the picolinamide of described replacement is:
; Described additive is: quaternary ammonium compound.
Above-mentioned quaternary ammonium compound is: tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, tetrabutylammonium acetate ammonium or tetramethyl ammonium chloride.
The Pyridine-quinazolinocompound compound of the replacement that the present invention relates to is active skeleton and the organic synthesis intermediate of the important drug molecule of a class, occupies an important position in pharmaceutical chemistry.
The inventive method raw material is easy to get, and reaction yield is high, wide application range of substrates.Use Conventional solvents in reaction, simple to operate, mild condition, reaction environmental protection, reaction yield reaches as high as 95%, is very applicable to industrial production.
Embodiment
Embodiment one: 11
h-pyrido [2,1-
b] quinazoline-11-ketone
11
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 14.6 grams of 2-(2-bromophenyl)-
n-(pyridine-2-base) ethanamide, 2.7 gram of 1,10-phenanthroline, 1.3 grams of cuprous iodides, 20 grams of Potassium ethanoates, 20 grams of tetrabutylammonium chlorides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(pyridine-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying, obtains 9.3 gram 11 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 95%.Fusing point: 208-210 DEG C.
-1 1698, 1641, 1527, 1456, 764.
1 H NMR (CDCl 3 , 500 MHz): δ 8.86 (d,
J = 7.0 Hz,1H), 8.43 (d,
J = 8.0 Hz,1H), 7.84-7.76 (m, 2H), 7.50-7.48 (m, 3H), 6.86-6.83 (m, 1H).
13 C NMR (CDCl 3 , 125 MHz):δ 159.0, 148.6, 147.7, 135.1, 134.1, 127.3, 126.9, 126.7, 126.3, 125.2, 116.3, 112.5.
LC-MS (ESI) m/z:197 [M
+H].
Raw material 2-(2-bromophenyl)-
nthe synthesis of-(pyridine-2-base) ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 10.5 grams of PAs, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 24.3 grams of 2-(2-bromophenyl)-
n-(pyridine-2-base) ethanamide, productive rate is 90%.Fusing point: 116-118 DEG C.
-1 3250, 2913, 1681, 1577, 1533, 1462, 1294, 741.
1 H NMR (CDCl 3 , 500 MHz): δ8.23-8.21 (m, 2H), 8.16 (br ,1H), 7.70-7.67 (m, 1H),7.61 (d,
J = 8.0 Hz,1H), 7.40 (dd,
J= 7.5, 1.5 Hz, 1H), 7.33 (t,
J = 7.5 Hz,1H), 7.19 (td,
J= 7.5, 1.5 Hz, 1H), 7.03-7.01 (m, 1H), 3.91 (s, 2H).
13 C NMR (CDCl 3 , 125 MHz):δ168.4, 151.2, 147.3, 138.7, 134.0, 133.2, 131.8, 129.4, 128.1, 125.1, 120.0, 114.3, 45.0.
LC-MS (ESI) m/z:293 [M
+H (
81Br)], 291 [M
+H (
79Br)].
HRMS:m/z calcd for C
13H
12BrN
2O [M
+H]
+ 291.0128; Found: 291.0131.
Embodiment two: 6-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone
6-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 15.3 grams of 2-(2-bromophenyl)-
n-(3-picoline-2-base) ethanamide, 2.9 gram of 1,10-phenanthroline, 1.6 grams of cuprous iodides, 15 grams of Potassium ethanoates, 22 grams of Tetrabutyl amonium bromides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(3-picoline-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 9.1 grams of 6-methyl isophthalic acids 1 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 87%.Fusing point: 128-130 DEG C.
-1 1699, 1641, 1530, 1456, 764.
1 H NMR (CDCl 3 , 500 MHz):δ 8.78 (d,
J = 7.5 Hz,1H), 8.42 (d,
J = 8.0 Hz,1H), 7.84-7.81 (m, 2H), 7.47-7.43 (m, 1H), 7.35 (d,
J = 8.5 Hz,1H), 6.76 (t,
J = 7.0 Hz,1H), 2.58 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ 159.4, 148.0, 147.5, 134.9, 134.4, 132.5, 127.3, 127.2, 125.2, 124.9, 116.0, 112.2, 18.7.
LC-MS (ESI) m/z: 211 [M
+H].
Raw material 2-(2-bromophenyl)-
nthe synthesis of-(3-picoline-2-base) ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 12.1 grams of 2-amino-3-picolines, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 22.7 grams of 2-(2-bromophenyl)-
n-(3-picoline-2-base) ethanamide, productive rate is 80%.Fusing point: 116-118 DEG C.
-1 3239, 2927, 2851, 1660, 1576, 1524, 1450, 1338, 1261, 747.
1 H NMR (CDCl 3 , 500 MHz): δ8.19 (d,
J = 3.5 Hz,1H), 7.60-7.54 (m, 2H), 7.41 (dd,
J= 7.5, 1.5 Hz, 1H), 7.30 (td,
J= 7.5, 1.0 Hz, 1H), 7.16 (td,
J= 7.5, 1.5 Hz, 1H), 7.08 (dd,
J= 7.5, 0.5 Hz, 1H), 3.98 (s, 2H), 2.26 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ168.7, 157.3, 149.6, 145.4, 140.0, 134.8, 133.0, 132.0, 129.1, 127.9, 125.2, 121.7, 44.0, 18.3.
LC-MS (ESI) m/z:307 [M
+H (
81Br)], 305 [M
+H (
79Br)].
HRMS:m/z calcd for C
14H
14BrN
2O [M
+H]
+ 305.0284; Found: 305.0289.
Embodiment three: 11-oxygen-11
h-pyrido [2,1-
b] quinazoline-6-carboxylic acid, ethyl ester
11-oxygen-11
h-pyrido [2,1-
b] quinazoline-6-carboxylic acid, ethyl ester adopts following step: in 250 milliliters of round-bottomed flasks, 1. add 18.2 grams of 2-(2-(2-bromophenyl) acetamido) Nikithan, 2.9 gram 1,10-phenanthroline, 1.6 grams of cuprous iodides, 15 grams of Potassium ethanoates, 22 grams of tetrabutylammonium iodides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.Follow the tracks of reaction by thin-layer chromatography method, disappear to reaction raw materials 2-(2-(2-bromophenyl) acetamido) Nikithan; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 7.4 grams of 11-oxygen-11 to crude product
h-pyrido [2,1-
b] quinazoline-6-carboxylic acid, ethyl ester, productive rate is 55%.Fusing point: 118-120 DEG C.
-1 1724, 1700, 1536, 1287, 763.
1 H NMR (CDCl 3 , 500 MHz):δ 8.97 (dd,
J= 7.5, 1.0 Hz, 1H), 8.43 (d,
J = 9.0 Hz,1H), 7.86-7.85 (m, 3H), 7.52-7.49 (m, 1H), 6.87 (t,
J = 7.0 Hz,1H), 4.51 (q,
J = 7.0 Hz,2H), 1.46 (t,
J = 7.0 Hz,3H).
13 C NMR (CDCl 3 , 125 MHz):δ 165.1, 158.8, 147.9, 144.5, 135.6, 135.3, 129.4, 129.4, 127.8, 127.2, 126.0, 116.4, 111.0, 62.1, 14.3.
LC-MS (ESI) m/z: 269 [M
+H].
HRMS: m/z calcd for C
15H
13N
2O
3[M
+H]269.0921; Found: 269.0925.
The synthesis of raw material 2-(2-(2-bromophenyl) acetamido) Nikithan adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 18.5 grams of 2-aminonicotinate, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying, obtain 20.5 grams of 2-(2-(2-bromophenyl) acetamido) Nikithan, productive rate is 61% to crude product.Fusing point: 116-118 DEG C.
-1 3245, 2929, 2850, 1667, 1585, 1496, 1294, 1239, 739.
1 H NMR (CDCl 3 , 500 MHz): δ10.90 (s,1H), 8.55 (dd,
J= 5.0, 2.0 Hz, 1H), 8.07 (dd,
J= 8.0, 2.0 Hz, 1H), 7.61 (dd,
J= 8.0, 1.0 Hz, 1H), 7.42 (dd,
J= 7.5, 1.5 Hz, 1H), 7.36 (td,
J= 7.5, 1.0 Hz, 1H), 7.30 (dd,
J= 7.5, 5.0 Hz, 1H), 7.22 (td,
J= 8.0, 2.0 Hz, 1H), 4.14 (q,
J= 7.0 Hz, 2H), 3.95 (s, 2H), 1.21 (t,
J= 7.0 Hz, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ169.1, 166.4, 151.4, 149.1, 139.4, 135.6, 132.7, 132.6, 129.4, 128.1, 125.1, 120.4, 120.2, 61.2, 43.2, 14.5.
LC-MS (ESI) m/z:365 [M
+H (
81Br)], 363 [M
+H (
79Br)].
HRMS:m/z calcd for C
16H
16BrN
2O
3[M
+H]
+ 363.0339; Found: 363.0349.
Embodiment four: 7-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone
7-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 15.3 grams of 2-(2-bromophenyl)-
n-(4-picoline-2-base) ethanamide, 2.9 gram of 1,10-phenanthroline, 1.6 grams of cuprous iodides, 23 grams of Potassium ethanoates, 22 grams of 4-butyl ammonium hydrogen sulfates, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(4-picoline-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 8.3 grams of 7-methyl isophthalic acids 1 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 79%.Fusing point: 150-152 DEG C.
-1 1702, 1652, 1530, 1456, 767.
1 H NMR (CDCl 3 , 500 MHz): δ 8.81 (d,
J = 7.5 Hz,1H), 8.42 (d,
J = 8.0 Hz,1H), 7.84-7.82 (m,2H), 7.47-7.43 (m,2H), 6.77 (d,
J = 7.0 Hz,1H), 2.44 (s,3H).
13 C NMR (CDCl 3 , 125 MHz):δ 158.8, 147.7, 146.6, 135.2, 127.4, 127.4, 126.3, 126.1, 124.9, 123.3, 115.8, 115.8, 18.3.
LC-MS (ESI) m/z: 211 [M
+H].
Raw material 2-(2-bromophenyl)-
nthe synthesis of-(4-picoline-2-base) ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 12.1 grams of 2-AMINO-4-PICOLINEs, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 19.8 grams of 2-(2-bromophenyl)-
n-(4-picoline-2-base) ethanamide, productive rate is 70%.Fusing point: 118-120 DEG C.
-1 3247, 2923, 2850, 1689, 1577, 1541, 1416, 1331, 744.
1 H NMR (CDCl 3 , 500 MHz): δ8.44 (br, 1H), 8.09-8.08 (m, 2H), 7.60 (dd,
J= 8.0, 1.5 Hz, 1H), 7.39 (dd,
J= 7.5, 1.5 Hz, 1H), 7.32 (td,
J= 7.5, 1.0 Hz, 1H), 7.18 (td,
J= 8.0, 1.5 Hz, 1H), 6.87-6.86 (m,1H), 3.90 (s, 2H), 2.35 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ168.5, 151.6, 150.2, 147.1, 134.3, 133.1, 131.8, 129.3, 128.0, 125.1, 121.1, 115.0, 44.8, 21.4.
LC-MS (ESI) m/z:307 [M
+H (
81Br)], 305 [M
+H (
79Br)].
HRMS:m/z calcd for C
14H
14BrN
2O [M
+H]
+ 305.0284; Found: 305.0280.
Embodiment five: 7-phenyl-11
h-pyrido [2,1-
b] quinazoline-11-ketone
7-phenyl-11
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 18.4 grams of 2-(2-bromophenyl)-
n-(4-phenylpyridine-2-base) ethanamide, 2.9 gram of 1,10-phenanthroline, 1.6 grams of cuprous iodides, 15 grams of Potassium ethanoates, 22 grams of tetrabutylammonium acetate ammoniums, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(4-phenylpyridine-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 11.2 grams of 7-phenyl-11 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 82%.Fusing point: 146-148 DEG C.
-1 1689, 1647, 1531, 1454, 757, 689.
1 H NMR (CDCl 3 , 500 MHz): δ 8.88 (d,
J = 7.5 Hz,1H), 8.40 (d,
J = 8.0 Hz,1H), 7.82-7.69 (m, 5H), 7.50-7.41 (m,4H), 7.13 (d,
J = 7.5 Hz,1H).
13 C NMR (CDCl 3 , 125 MHz):δ 158.8, 148.8, 147.9, 146.2, 136.3, 135.2, 130.0, 129.3, 127.4, 126.9, 126.8, 126.7, 125.1, 121.8, 116.1, 112.3.
LC-MS (ESI) m/z: 273 [M
+H].
HRMS:m/z calcd for C
18H
13N
2O [M
+H] 273.1022; Found: 273.1035.
Raw material 2-(2-bromophenyl)-N-(4-phenylpyridine-2-Ji) synthesis of ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 15.8 grams of 4-phenylpyridine-2-amine, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product column chromatography (sherwood oil: ethyl acetate=5: 1) purifying obtains 30 grams of 2-(2-bromophenyls)-N-(4-phenylpyridine-2-Ji) ethanamide, productive rate is 88%.Fusing point: 142-144 DEG C.
-1 3251, 2929, 1692, 1559, 1408, 1223, 763, 746.
1 H NMR (CDCl 3 , 500 MHz): δ8.85 (br,1H), 8.58 (s,1H), 8.31 (d,
J = 5.0 Hz,1H), 7.70 (d,
J = 6.5 Hz,2H), 7.63 (d,
J = 8.0 Hz,1H), 7.48-7.43 (m,4H), 7.35 (t,
J = 7.5 Hz,1H), 7.31-7.29 (m,1H), , 7.21 (t,
J = 7.0 Hz,1H), 3.97 (s, 2H).
13 C NMR (CDCl 3 , 125 MHz):δ168.6, 152.0, 151.2, 147.7, 137.9, 134.1, 133.2, 131.9, 129.4, 129.3, 129.0, 128.1, 127.2, 125.1, 118.1, 112.1, 45.0.
LC-MS (ESI) m/z:369 [M
+H (
81Br)], 367 [M
+H (
79Br)].
HRMS:m/z calcd for C
19H
16BrN
2O [M
+H]
+ 367.0441; Found: 367.0447.
Embodiment six: 8-phenyl-11
h-pyrido [2,1-
b] quinazoline-11-ketone
8-phenyl-11
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 18.4 grams of 2-(2-bromophenyl)-
n-(5-phenylpyridine-2-base) ethanamide, 2.9 gram of 1,10-phenanthroline, 1.7 grams of cuprous iodides, 20 grams of Potassium ethanoates, 18 grams of tetramethyl ammonium chlorides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(5-phenylpyridine-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 11.7 grams of 8-phenyl-11 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 86%.Fusing point: 148-150 DEG C.
-1 1686, 1552, 1532, 1457, 778, 766.
1 H NMR (CDCl 3 , 500 MHz):δ 9.05 (s,1H), 8.44 (d,
J = 8.0 Hz,1H), 7.83-7.77 (m, 3H), 7.62 (d,
J = 7.0 Hz,2H), 7.57 (d,
J = 9.5 Hz,1H), 7.49-7.44 (m, 3H), 7.40 (d,
J = 7.0 Hz,1H).
13 C NMR (CDCl 3 , 125 MHz):δ 158.9, 148.3, 146.8, 135.8, 135.1, 134.7, 129.3, 128.5, 127.4, 126.9, 126.6, 126.4, 126.4, 125.3, 123.4, 116.2.
LC-MS (ESI) m/z:273 [M
+H].
HRMS:m/z calcd for C
18H
13N
2O [M
+]273.1022; Found: 273.1020.
Raw material 2-(2-bromophenyl)-N-(5-phenylpyridine-2-base) synthesis of ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 15.8 grams of 5-phenylpyridine-2-amine, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product column chromatography (sherwood oil: ethyl acetate=5: 1) purifying obtains 27.8 grams of 2-(2-bromophenyls)-N-(5-phenylpyridine-2-base) ethanamide, productive rate is 81%.Fusing point: 138-140 DEG C.
-1 3256, 2925, 1692, 1586, 1523, 1469, 768, 741.
1 H NMR (CDCl 3 , 500 MHz): δ8.45 (d,
J = 2.5 Hz,1H), 8.43 (br,1H), 8.33 (d,
J = 8.5 Hz,1H), 7.94 (dd,
J= 8.5, 2.5 Hz, 1H), 7.63 (dd,
J= 8.0, 1.0 Hz, 1H), 7.54-7.34 (m,7H), 7.21 (td,
J= 7.5, 1.5 Hz, 1H), 3.96 (s, 2H).
13 C NMR (CDCl 3 , 125 MHz):δ168.4, 150.5, 145.7, 137.3, 137.0, 134.1, 133.2, 133.1, 131.8, 129.4, 129.1, 128.1, 127.9, 126.8, 125.1, 114.2, 45.0.
LC-MS (ESI) m/z:369 [M
+H (
81Br)], 367 [M
+H (
79Br)].
HRMS:m/z calcd for C
19H
16BrN
2O [M
+H]
+ 367.0441; Found: 367.0442.
Embodiment seven: 2-methoxyl group-11
h-pyrido [2,1-
b] quinazoline-11-ketone
2-methoxyl group-11
h-pyrido [2,1-
b] preparation of quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 16.1 grams of 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(pyridine-2-base) ethanamide, 3.0 gram of 1,10-phenanthroline, 1.8 grams of cuprous iodides, 16 grams of Potassium ethanoates, 18 grams of tetramethyl ammonium chlorides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(pyridine-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 9.9 grams of 2-methoxyl groups-11 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 88%.Fusing point: 158-160 DEG C.
-1 1694, 1642, 1545, 1482, 1375, 1022, 762.
1 H NMR (CDCl 3 , 500 MHz):δ 8.86 (d,
J = 7.0 Hz,1H), 7.75-7.72 (m, 2H), 7.54-7.46 (m, 3H), 6.88-6.85 (m, 1H), 3.94 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz): δ 158.5, 157.4, 146.0, 143.2, 133.3, 128.3, 127.0, 126.4, 126.0, 116.7, 112.8, 105.2, 55.9.
LC-MS (ESI) m/z: 227 [M
+H].
Raw material 2-(the bromo-5-p-methoxy-phenyl of 2-)-
nthe synthesis of-(pyridine-2-base) ethanamide adopts following step: in 250 milliliters of round-bottomed flasks, 1. add 22.8 grams of bromo-5-methoxyphenylacetic acids of 2-, 23 grams of dicyclohexylcarbodiimide, 10.5 grams of PAs, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 23.5 grams of 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(pyridine-2-base) ethanamide, productive rate is 79%.Fusing point: 136-138 DEG C.
-1 246, 2934, 2851, 1690, 1582, 1533, 1437, 1309, 1245, 1014, 776.
1 H NMR (CDCl 3 , 500 MHz): δ8.70 (br,1H), 8.28 (d,
J = 8.5 Hz,1H), 8.22 (dd,
J= 5.0, 1.0 Hz, 1H), 7.78-7.74 (m, 1H), 7.48 (d,
J = 9.0 Hz,1H), 7.08-7.06 (m, 1H), 6.95 (d,
J = 3.0 Hz,1H), 6.75 (dd,
J= 9.0, 3.0 Hz, 1H), 3.90 (s, 2H), 3.80 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ168.3, 159.3, 151.2, 147.3, 138.8, 134.8, 133.8, 120.0, 117.3, 115.3, 115.3, 114.3, 55.5, 45.2.
LC-MS (ESI) m/z:323 [M
+H (
81Br)], 321 [M
+H (
79Br)].
HRMS:m/z calcd for C
14H
14BrN
2O
2[M
+H]
+ 321.0233; Found: 321.0242.
Embodiment eight: 2-methoxyl group-6-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone
2-methoxyl group-6-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 16.8 grams of 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(3-picoline-2-base) ethanamide, 3.0 gram of 1,10-phenanthroline, 1.8 grams of cuprous iodides, 24.5 grams of Potassium ethanoates, 28 grams of 4-butyl ammonium hydrogen sulfates, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(3-picoline-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 8.4 grams of 2-methoxyl group-6-methyl isophthalic acids 1 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 70%.Fusing point: 132-134 DEG C.
-1 1682, 1640, 1521, 1486, 1383, 1028, 762.
1 H NMR (CDCl 3 , 500 MHz):δ 8.80 (d,
J = 7.5 Hz,1H), 7.81 (d,
J = 8.5 Hz,1H), 7.74 (d,
J = 2.5 Hz,1H), 7.48-7.86 (m, 1H) , 7.33 (d,
J = 6.0 Hz,1H), 6.78 (t,
J = 7.0 Hz,1H), 3.96 (s, 3H), 2.60 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz): δ 159.1, 157.2, 145.9, 143.3, 134.5, 131.0, 129.2, 126.5, 124.6, 116.5, 112.7, 104.9, 55.8, 18.6.
LC-MS (ESI)
m/z:
241 [M
+H].
HRMS:m/z calcd for C
14H
12N
2O
2[M
+]240.0899; Found: 240.0900.
Raw material 2-(the bromo-5-p-methoxy-phenyl of 2-)-
nthe synthesis of-(3-picoline-2-base) ethanamide adopts following step: in 250 milliliters of round-bottomed flasks, 1. add 22.8 grams of bromo-5-methoxyphenylacetic acids of 2-, 23 grams of dicyclohexylcarbodiimide, 12.1 grams of 2-amino-3-picolines, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 23.3 grams of 2-(the bromo-5-p-methoxy-phenyl of 2-)-
n-(3-picoline-2-base) ethanamide, productive rate is 75%.Fusing point: 164-166 DEG C.
-1 3326, 2930, 2851, 1664, 1575, 1528, 1449, 1338, 1245, 1088, 802.
1 H NMR (CDCl 3 , 500 MHz): δ8.47 (br,1H), 8.18 (d,
J = 4.0 Hz,1H), 7.53 (d,
J = 7.5 Hz,1H), 7.45 (d,
J = 9.0 Hz,1H), 7.07 (dd,
J= 7.5, 5.0 Hz, 1H), 6.95 (d,
J = 3.0 Hz,1H), 6.71 (dd,
J= 9.0, 3.0 Hz, 1H), 3.91 (s, 2H), 3.75 (s, 3H), 2.25 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ168.5, 159.2, 157.0, 149.3, 145.4, 140.1, 135.5, 133.6, 121.8, 117.3, 115.4, 115.2, 55.5, 44.5, 18.2.
LC-MS (ESI) m/z:337 [M
+H (
81Br)], 335 [M
+H (
79Br)].
HRMS:m/z calcd for C
15H
16BrN
2O
2[M
+H]
+ 335.0390; Found: 335.0401.
Embodiment nine: 7-bromo-11H-pyrido [2,1-b] quinazoline-11-ketone
7-bromo-11
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 18.5 grams of 2-(2-bromophenyl)-
n-(4-bromopyridine-2-base) ethanamide, 3.0 gram of 1,10-phenanthroline, 1.8 grams of cuprous iodides, 24.5 grams of Potassium ethanoates, 25 grams of tetrabutylammonium acetate ammoniums, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(4-bromopyridine-2-base) ethanamide disappears; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 7.8 grams of 7-bromo-11 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 57%.Fusing point: 174-176 DEG C.
-1 1687, 1625, 1546, 1466, 762.
1 H NMR (CDCl 3 , 500 MHz):8.66 (d,
J = 7.5 Hz,1H), 8.37 (dd,
J= 8.0, 1.5 Hz, 1H), 7.83-7.80 (m, 1H), 7.72 (d,
J = 8.0 Hz,1H), 7.66 (d,
J = 3.0 Hz,1H), 7.48-7.44 (m,1H), 6.88 (dd,
J= 7.5, 2.0 Hz, 1H).
13 C NMR (CDCl 3 , 125 MHz): δ 158.6, 148.4, 146.9, 135.4, 129.8, 127.8, 127.4, 127.2, 127.0, 125.7, 116.6, 116.3.
LC-MS (ESI) m/z:277 [M
+H (
81Br)], 275 [M
+H (
79Br)].
HRMS:m/z calcd for C
12H
8BrN
2O [M
+H]274.9815; Found: 274.9818.
Raw material 2-(2-bromophenyl)-
nthe synthesis of-(4-bromopyridine-2-base) ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 19.3 grams of 2-amino-4-bromopyridines, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 20.6 grams of 2-(2-bromophenyl)-
n-(4-bromopyridine-2-base) ethanamide, productive rate is 60%.Fusing point: 168-170 DEG C.
-1 3235, 2913, 1694, 1575, 1397, 1250, 739.
1 H NMR (DMSO
, 500 MHz): δ11.04 (s, 1H), 8.31 (s, 1H), 8.25 (d,
J = 5.5 Hz,1H), 7.61 (d,
J = 8.0 Hz,1H), 7.42 (d,
J = 7.0 Hz,1H), 7.37-7.34 (m, 2H), 7.22 (t,
J = 7.0 Hz,1H), 3.96 (s, 2H).
13 C NMR (DMSO
, 125 MHz):δ169.8, 153.4, 149.8, 135.7, 133.6, 132.8, 132.7, 129.4, 128.1, 125.1, 122.8, 116.3, 43.5.
LC-MS (ESI) m/z:373 [M
+H (
81Br) (
81Br)], 371 [M
+H (
81Br)(
79Br)], 369 [M
+H (
79Br)(
79Br)].
HRMS:m/z calcd for C
13H
11Br
2N
2O [M
+H]
+ 368.9233; Found: 368.9237.
Embodiment ten: 8-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone
8-methyl isophthalic acid 1
h-pyrido [2,1-
b] quinazoline-11-ketone adopts following step: 1. add in 250 milliliters of round-bottomed flasks 15.3 grams of 2-(2-bromophenyl)-
n-(5-picoline-2-base) ethanamide, 3.0 gram of 1,10-phenanthroline, 1.8 grams of cuprous iodides, 24.5 grams of Potassium ethanoates, 25 grams of tetrabutylammonium chlorides, 200 milliliters of DMF, are heated to 90 ~ 100 DEG C.With thin-layer chromatography method follow the tracks of reaction, to reaction raw materials 2-(2-bromophenyl)-
n-(5-picoline-2-base) ethanamide disappears; 2. after reaction terminates, after system diatomite filtration, with Rotary Evaporators except desolventizing obtains crude product; 3. with column chromatography, (sherwood oil: ethyl acetate=5: 1) purifying obtains 8.5 grams of 8-methyl isophthalic acids 1 to crude product
h-pyrido [2,1-
b] quinazoline-11-ketone, productive rate is 81%.Fusing point: 148-150 DEG C.
-1 1683, 1648, 1547, 1530, 1458, 769.
1 H NMR (CDCl 3 , 500 MHz):δ 8.69 (s,1H), 8.44 (d,
J = 8.5 Hz,1H), 7.85-7.80 (m, 2H), 7.54 (d,
J = 9.5 Hz,1H), 7.48-7.42 (m,2H), 2.37 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz): δ 158.6, 147.8, 146.9, 138.1, 135.1, 127.4, 126.3, 125.3, 125.2, 123.7, 122.8, 116.0, 18.3.
LC-MS (ESI) m/z:211 [M
+H].
Raw material 2-(2-bromophenyl)-
nthe synthesis of-(5-picoline-2-base) ethanamide adopts following step: 1. in 250 milliliters of round-bottomed flasks, add 20 grams of 2-bromo-acids, 23 grams of dicyclohexylcarbodiimide, 12.1 grams of 2-amino-5-picolines, 200 milliliters of methylene dichloride, stirring at room temperature 24 hours; 2., after reaction terminates, crude product is obtained by removing desolventizing with Rotary Evaporators after system diatomite filtration; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 18.7 grams of 2-(2-bromophenyl)-
n-(5-picoline-2-base) ethanamide, productive rate is 66%.Fusing point: 98-100 DEG C.
-1 3243, 2919, 2850, 1688, 1591, 1520, 1474, 1300, 739.
1 H NMR (CDCl 3 , 500 MHz): δ8.59 (br, 1H), 8.17 (d,
J = 8.5 Hz,1H), 8.05 (d,
J = 1.5 Hz,1H),7.62 (dd,
J= 8.0, 1.0 Hz, 1H), 7.56 (dd,
J= 8.5, 2.0 Hz, 1H), 7.42 (dd,
J= 8.0, 2.0 Hz, 1H), 7.35 (td,
J= 8.5, 1.0 Hz, 1H), 7.20 (td,
J= 7.5, 1.5 Hz, 1H), 3.93 (s, 2H), 2.30 (s, 3H).
13 C NMR (CDCl 3 , 125 MHz):δ168.2, 157.1, 149.2, 147.3, 139.2, 134.3, 133.1, 131.8, 129.3, 128.0, 125.1, 113.9, 44.9, 17.8.
LC-MS (ESI) m/z:307 [M
+H (
81Br)], 305 [M
+H (
79Br)].
HRMS:m/z calcd for C
14H
14BrN
2O [M
+H]
+ 305.0284; Found: 305.0296。
Claims (2)
1. a preparation method for Pyridine-quinazolinocompound compound, the structural formula of this compound is:
Wherein: R
1=-OMe, H;
R
2=-H ,-Me ,-Ph ,-CO
2et ,-Br; It is characterized in that the method has following steps: by replace picolinamide and Potassium ethanoate, additive is by 1:(2.0 ~ 5.0): the mol ratio of (1.0 ~ 5.0) is dissolved in N, in dinethylformamide, and add cuprous iodide and 1, the 10-phenanthroline of catalyst levels, 90 ~ 100
oat C temperature, stirring reaction disappears to reaction raw materials; Filter, obtain crude product except after desolventizing; This crude product is purified, namely obtains the corresponding Pyridine-quinazolinocompound compound replaced; The structural formula of the picolinamide of described replacement is:
; Described additive is: quaternary ammonium compound.
2. method according to claim 1, is characterized in that described quaternary ammonium compound is: tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, tetrabutylammonium acetate ammonium or tetramethyl ammonium chloride.
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| A novel approach for the one-pot synthesis of linear and angular fused quinazolinones;Arindam Maity et al.,;《Tetrahedron Letters》;20110409;第52卷;第3034页Scheme1 * |
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