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Method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one

A dihydropyridine, 3-d technology, applied in organic chemistry and other directions, can solve the problems of cumbersome steps, long time-consuming, long reaction time, etc., and achieve the effects of mild reaction conditions, wide application range and short reaction time.

Inactive Publication Date: 2011-07-20
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] (4) Prepared from N-(benzyloxycarbonyl)glycyl chloride and 2-amino-3-cyanopyridine through multi-step reaction (US Pat.US20070275987A1). Toxic substances such as hydrobromic acid
[0011] In summary, in the known synthetic methods of 2,3-dihydropyrido[2,3-d]pyrimidin-4-(3H)-one compounds, either the temperature is higher, or the reaction time is longer, or Intermediates are expensive and difficult to prepare
These deficiencies have brought a lot of inconvenience to the synthesis of this type of compound, especially industrialized production

Method used

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  • Method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one
  • Method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one
  • Method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one

Examples

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Effect test

example example 1

[0027] Add 2ml of dried cyclohexanone into a 25ml three-necked flask, add 2mmol of 2-amino-3-cyanopyridine while stirring, then add 0.6mmol of sodium methoxide, stir the mixture for 1 hour, after the reaction is completed, the reaction solution Put it in the refrigerator to freeze overnight, and the solid precipitated out. After filtration, it was recrystallized with ethanol:THF (1:1, v:v) to obtain 1'H-spiro[cyclopentane-1,2'-pyrido[2, 3-d]pyrimidine]-4'(3'H)-one (I), yield 63%, Mp 265°C. The reaction formula of 2-amino-3-cyanopyridine and cyclopentanone is:

[0028]

[0029] The spectral data of product (I) is: 1 H NMR (400MHz, DMSO-d 6 )δ H : 1.67-1.83 (8H, d, C 4 h 8 ), 6.65-6.69 (1H, m, J=12Hz, Pyridine-H), 7.61 (1H, s, NH), 7.85-7.88 (1H, d, J=7.2Hz, Pyridine-H), 8.127 (1H, s, Pyridine-H), 8.305 (1H, s, NH) 13 C NMR (100MHz, DMSO-d 6 )δ C : 22.47(4C), 77.09, 109.47, 113.78, 136.02, 153.09, 158.03, 163.22; IR(KBr): 3271, 3168, 2922, 1644, 1600, 1420cm -1;ESI-...

Embodiment 2

[0031] Replace cyclopentanone with cyclohexanone, other with embodiment 1. The target compound (II) was obtained with a yield of 95%, Mp 263°C. The reaction formula of 2-amino-3-cyanopyridine and cyclohexanone is:

[0032]

[0033] The spectral data of product (Ⅱ) is: 1 H NMR (400MHz, CDCl 3 )δ H : 1.01 (3H, t, J=14.8Hz, CH 3 ), 1.55 (2H, s, CH 2 ), 1.81 (3H, m, J=22H, CH 3 ), 5.438 (1H, S, NH), 6.150 (1H, s, NH), 6.75 (1H, m, J=12.4Hz, Pyridine-H), 8.10 (1H, m, J=8.8Hz, Pyridine-H ), 8.17 (1H, d, J=4.0Hz, Pyridine-H); 13 C NMR (100MHz, CDCl 3 )δ C : 21.334(2C), 23.947, 38.120(2C), 67.814, 109.029, 114.386, 136.474, 152.693, 155.982, 162.826; IR(KBr): 3221, 3172, 2927, 1675, 1607, 1437cm -1 ;ESI-MS m / z: [M+H] + 218.1, [M+Na] + 240.1; Anal. Calcd. for C 12 h 15 N 3 O: C, 66.34; H, 6.96; N, 19.34; found C, 65.75; H 7.07; N 19.08.

Embodiment 3

[0035] Cycloheptanone was used instead of cyclohexanone, and the others were the same as in Example 2 to obtain the target compound (Ⅲ) with a yield of 67%, Mp 272°C. The reaction formula of 2-amino-3-cyanopyridine and cycloheptanone is:

[0036]

[0037] The spectral data of product (Ⅲ) is: 1 H NMR (400MHz, DMSO-d 6 )δ H : 1.50 (8H, s, CH 2 ), 1.90 (4H, d, J=7.6Hz, CH 2 ), 6.65 (1H, m, J = 12Hz, Pyridine-H), 7.60 (1H, S, NH), 7.84 (1H, t, J = 7.2Hz, Pyridine-H), 8.12 (1H, t, J = 4.4Hz, Pyridine-H) 8.26 (1H, s, NH); 13 C NMR (100MHz, DMSO-d 6 )δ C : 21.27(2C), 29.84(2C), 42.10(2C), 72.27, 109.23, 113.60, 135.82, 153.19, 157.34, 162.79; IR(KBr): 3220, 3170, 2924, 1667, 1608, 1444cm -1 ;ESI-MS m / z: [M+H] + 232.1, [M+Na] + 254.2; Anal. Calcd. for C 13 h 17 N 3 O: C, 67.51; H, 7.41; N, 18.17; found C, 67.40; H, 6.44; N, 17.91

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Abstract

The invention provides a method for synthesizing 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one heterocyclic compounds and the general equation of reaction is shown in the figure, wherein R belongs to the substituent group and can be F, Cl, Br, I, NO2, NO, CN, alkyl, alkoxy, amino or other groups, the number and position of the substituent group are not limited; and R1 and R2 represent H, alkyl, aryl or heteroaryl, or R1, R2 and the connected carbon atoms form C3-7 cycloalkyl. The reaction catalyst belongs to Lewis acids such as anhydrous zinc chloride and anhydrous aluminium choride, or protonic acids such as hydrochloric acid and sulfuric acid, or alkaline catalysts such as sodium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide. The reaction can be promoted through conventional heating or microwave treatment; and recrystallization or column chromatography is adopted for purification. The method has common raw material, simple process and mild reaction conditions; and the reaction has wide application range and can be adopted to synthesize various 2,3-dihydropyrido[2,3-d]pyrimidine-4-(3H)-one heterocyclic compounds by using different substrates.

Description

(1) Technical field [0001] The present invention relates to a method for preparing 2,3-dihydropyrido[2,3-d]pyrimidin-4-(3H)-one (2 , 3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one) synthetic method of heterocyclic compound. (2) Background technology [0002] 2,3-Dihydropyrido[2,3-d]pyrimidin-4-(3H)-one condensed ring compounds are a kind of polynitrogen-containing heterocyclic compounds with good physiological activity. For example, compound A [2-(pyridin-3-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one)] is a potent diuretic (Arzneim.- Forsch.1993,43:1322-1326; J.Med.Chem.1982,25:98-102.); Compound B [5,7-dimethyl-2-(3,4,5-trimethoxyphenyl )-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one] and its analogs have strong antibacterial activity (Eur.J.Med.Chem., 2009, 44: 1369-1376; Indian J.Heterocycl.Chem., 1995, 4:211-214): Compound C (AMG 487) is a CXCR3 antagonist (Bioorg.Med.Chem.Lett.2009, 19:5114-5118; Arch.Pharm.Chem.Life Sci.2007, 340:281-291; Bioorg.Med.Chem.Lett.2007, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10C07D471/04
Inventor 李加荣杨留攀史大昕张奇
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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