9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds as well as preparation method and application thereof

An azabicycle and compound technology, which can be used in organic chemistry, X-ray contrast agent preparation, preparations for in vivo tests, etc., can solve problems such as early diagnosis and discovery of unfavorable tumors, and achieve high product yield and high affinity. The effect of sex, simple equipment

Active Publication Date: 2018-11-02
CHINA JILIANG UNIV
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  • Abstract
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Problems solved by technology

Most organic X-ray contrast agents are non-targeted contrast agents, which have no tissue-organ distribution specificity, which is not conduci

Method used

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  • 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds as well as preparation method and application thereof
  • 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds as well as preparation method and application thereof
  • 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、9

[0034] Example 1, 9-aza[6'-(2,4,6)-triiodophenylacetamide-α-amino]hexylamino-9-azabicyclo[3.3.1]nonane-3α-alkyl The synthetic method of phenyl carbamate compound, carries out following steps successively:

[0035] 1), take aniline (1.74g, 0.018mol) and dissolve in 68mL distilled water to obtain aniline aqueous solution;

[0036] Another NaCl (3.9g, 0.067mol) was dissolved in 14mL of distilled water, and ICl (10g, 0.062mol) was weighed and slowly added to the NaCl aqueous solution under stirring (the purpose of slow addition was to keep the temperature not higher than 30°C), to obtain mixed solution;

[0037] Add 2 / 3 of the mixed solution dropwise to the aniline aqueous solution under stirring (the purpose of the dropwise addition is to keep the temperature not higher than 80°C); add the remaining 1 / 3 of the mixed solution dropwise (the purpose of the dropwise addition is to make the temperature not higher than 90°C ), stirred and reacted for 3 hours, naturally cooled to room...

Embodiment 2

[0049] In Example 2, the raw material aniline in Example 1 was changed to 5-aminoisophthalic acid, and the molar weight remained unchanged, and the rest were identical to steps 1) to 3) of Example 1.

[0050] Its step 1), step 2) corresponding reaction formula is:

[0051]

[0052] The name of the product (S2) obtained in step 1) is: 3,5-dicarboxy(2,4,6)triiodoaniline;

[0053] The name of the product obtained in step 2) is: chloroacetyl 3,5-dicarboxy(2,4,6)triiodoaniline.

[0054] The final product is 9-aza[6'-(2,4,6)-triiodoisophthaloacetamide-α-amino]hexylamino-9-azabicyclo[3.3.1]nonane-3α- Alkyl phenyl carbamate, brown solid, yield 87%, m.p.112°C; 1 H NMR (500MHz, CDCl3) δ10.21(d, 2H), 8.16(d, J=5.3Hz, 3H), 7.26(s, 2H), 6.75(s, 2H), 5.55(s, 1H), 3.82 (d,J=18.0Hz,3H),3.59(s,2H),3.42(s,2H),3.15–2.93(m,2H),2.83(d,J=64.7Hz,3H),2.43–2.13( m,3H),1.93(s,4H),1.71(d,J=5.5Hz,4H),1.63–1.33(m,8H);Elementalanal.For C 33 h 41 o 8 N 4 I 3 (%), calculated: C, 39.52; H, 4.09; N...

Embodiment 3

[0059] The product (S2)3,5-dicarboxy (2,4,6)triiodoaniline (10g, 0.018mol) obtained in step 1) of Example 2 was dissolved in 40mL ethyl acetate, and 60mL SOCl2( 8.6g, 0.072mol) was slowly added dropwise (the purpose of dropping is to control the temperature not to exceed 10°C), after the dropwise addition was completed, the temperature was raised to 80°C, and the reaction was refluxed for 20 hours, and about half of the volume of the solvent was evaporated, left to stand for 2 hours, and filtered , and dried (dried at 85° C. until the water content ≤ 1.5%) to obtain a brownish-brown powdery compound (S3).

[0060] The above brownish brown powdery solid compound (10g, 16.8mmol) was dissolved in 10mL DMAc, mixed with 3-amino-1,2-propanediol (3.8g, 41.8mmol) and triethylamine (5.1g, 50.5mmol), iced React in the bath for 30 minutes, raise the temperature to 50°C, and react for 3 hours. Cool to room temperature, add 10 mL of water, adjust the pH to 5 with 10% hydrochloric acid, ev...

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Abstract

The invention discloses 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds. A preparation method of the compound comprises steps as follows: 9-nitrogen(6'-amino)hexylamine-9-9-aza-bicyclo[3.3.1] nonane-3 alpha-alkylamidophenyl formate and a chloroacetyl triiodoaniline derivative are mixed in an organic solvent in the mole ratio being 1:(1.0-1.5) and subjected to a reaction at the room temperature under the catalytic action of cesium hydroxide for 20-30 h, and a product, namely, the 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds, is obtained. The invention also discloses an application of the 9-aza-bicyclo[3.3.1] nonane coupled iodine-rich compounds as a contrast medium for early diagnosis of breast cancer.

Description

technical field [0001] The invention belongs to the technical field of 9-azabicyclo[3.3.1]nonane coupling iodine-rich compounds. The full name of 9-azabicyclo[3.3.1]nonane coupling iodine-rich compounds is: 9-nitrogen [6'-(2,4,6)-triiodophenylacetamide-α-amino]hexylamino-9-azabicyclo[3.3.1]nonane-3α-alkylcarbamate phenyl ester compound. Background technique [0002] Imaging based on the X-ray principle is a widely used medical diagnostic method, and most diagnostic imaging today is based on this principle. Due to the large atomic number of iodine atoms, the ability to block X-rays is relatively strong. Therefore, organic iodine compounds are currently commonly used clinical X-ray contrast agents. Most organic X-ray contrast agents are non-targeted contrast agents, which have no tissue-organ distribution specificity, which is not conducive to early diagnosis and detection of tumors. Therefore, research on targeted contrast agents has gradually increased in recent years. The...

Claims

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Application Information

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IPC IPC(8): C07D471/08A61K49/04
CPCA61K49/0438C07D471/08
Inventor 吴志平白雪燕吴雨琦
Owner CHINA JILIANG UNIV
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