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Preparation method of cycleanine

A technology of cyclamenine and tetraaza heterocycle is applied in the field of preparation of cyclamenine, can solve the problems of reduced reaction yield, complicated post-processing, high production and application cost, and achieves the effect of high yield

Pending Publication Date: 2022-05-06
SHANGHAI LINKCHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in the above-mentioned reactions, without exception, ring-closing reactions are involved, and most of the raw materials for these ring-closing reactions contain diamines, dicarboxylic acids and other compounds that are easily self-condensed or intermolecularly condensed, which leads to various reactions in the reaction substrate. Intermolecular or intramolecular condensation reaction, thus reducing the reaction yield
[0005] In addition, the above-mentioned Weisman method and glyoxal method will form a carbon skeleton between four nitrogen atoms during the synthesis process, and finally remove the carbon skeleton by reduction, which will lead to low atom utilization and complicated post-processing , not enough environmental protection and a series of problems, the cost of production and application in industry is too high

Method used

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  • Preparation method of cycleanine
  • Preparation method of cycleanine
  • Preparation method of cycleanine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation method of compound 1g

[0039] This embodiment provides a preparation method of compound 1g, the reaction equation is:

[0040]

[0041] Including the following reaction steps:

[0042] Step 1, step 1, 50g compound 5 (480mmol, 1eq) was dissolved in 200mL tetrahydrofuran to obtain a tetrahydrofuran solution of compound 5, and the tetrahydrofuran solution of compound 5 was added dropwise to 2.88L of 1mol / L borane in tetrahydrofuran solution, Stir the reaction at room temperature for 1 h, add dropwise 1.44L 5mol / L sodium hydroxide aqueous solution and 652g 30% hydrogen peroxide (5.76mol, 12eq) successively, stir the reaction for 6h, let stand, separate, take the organic phase, wash with saturated sodium carbonate aqueous solution ( 500mL×2), the organic phase was taken, concentrated under reduced pressure, and subjected to column chromatography to obtain 52.5g of compound 4 with a yield of 62.1%;

[0043] Step 2, dissolve 50g of compound 4 (283.8mmol, ...

Embodiment 8

[0050] Screening of Reaction Conditions in the Preparation Method of Compound 1

[0051] This example screens the specific reaction conditions used in step 3 of Example 1.

[0052] When adopting Lewis acid, reaction condition is as follows (hereinafter referred to as reaction condition A for short):

[0053] 20g of compound 3 (118.9mmol, 1eq), 49.5g of hydroxylamine hydrochloride (713.4mmol, 6eq) and 70.2g of sodium acetate (856.1mmol, 7.2eq) were dissolved in 150mL of ethanol, stirred for 1h, 100mL of DMF was added, and about 70mL of ethanol was added, then 100mL of DMF was added, and all remaining ethanol was distilled off, 120.4g of triethylamine (1.19mol, 10eq), Lewis acid, 1.45g of DMAP (11.9mmol, 0.1eq) were added successively, and the reaction was stirred for 3h, and 100mL of diethylamine was added Dilute with methyl chloride, wash with water (200mL×3), wash with saturated aqueous sodium chloride solution (200mL×1), combine the organic phases, dry over anhydrous sodium...

Embodiment 3

[0062] The preparation method of trigonine

[0063] The present embodiment provides a kind of preparation method of trigonine, and the reaction equation is as follows:

[0064]

[0065] Including the following reaction steps:

[0066] 20g of compound 1g (87.6mmol, 1eq, prepared by the method provided in Example 1) was dissolved in 120mL of tetrahydrofuran, and 182mL of 2.5mol / L lithium aluminum hydride in tetrahydrofuran was added dropwise under an ice-water bath. After the addition was completed, 68 Reflux reaction at ℃ for 8 hours. After the reaction, quench the reaction by adding 200mL 2mol / L aqueous sodium hydroxide solution in an ice-water bath, filter off the solid, extract with 200mL dichloromethane, combine the organic phases, and wash once with 200mL saturated brine. Dry over sodium sulfate, concentrate under reduced pressure, and perform flash column chromatography to obtain 11.0 g of compound 2 with a yield of 72.8%.

[0067] Compound 2 is characterized by:

...

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Abstract

The invention provides a preparation method of cycleanine, and belongs to the field of organic synthesis. The invention provides a preparation method of cycleanine, which comprises the following reaction steps: a 1, 4, 7, 10-tetraazacyclododecane derivative is contacted with a carbonyl reducing agent to obtain cycleanine, the 1, 4, 7, 10-tetraazacyclododecane derivative is a compound with at least one carbon atom on the ring of 1, 4, 7, 10-tetraazacyclododecane being oxo, and the carbonyl reducing agent is a compound with at least one carbon atom on the ring of 1, 4, 7, 10-tetraazacyclododecane being oxo. The carbonyl reducing agent is lithium aluminum hydride, sodium borohydride or potassium borohydride. According to the technical scheme, the invention provides a brand-new cycleanine synthesis route which does not involve a ring-closing reaction and has high yield.

Description

technical field [0001] The present invention relates to the field of organic synthesis, in particular to a preparation method of trigonine. Background technique [0002] Trigonine (1,4,7,10-tetraazacyclododecane) is a very important intermediate in the synthesis of diagnostic reagents and therapeutic drugs. The compound has a wide range of uses, such as being used for removing stones in the human body and inhibiting the loss caused by myocardial ischemia and reperfusion. In addition, in the manufacture of contrast agents for medical imaging technologies such as nuclear magnetic resonance imaging, X-ray CT, and ultrasound imaging, as well as radiotherapy drugs for malignant tumors, terpene and its derivatives have shown extremely important application values. As a precursor of a macrocyclic chelating agent for synthesizing metal ions, trigonine can form stable complexes with various metal ions, especially the complexes formed with classical paramagnetic metal ions gadolinium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02
CPCC07D257/02
Inventor 陆茜匡逸张唐志
Owner SHANGHAI LINKCHEM TECH CO LTD
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