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A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine

A synthesis method and naphthyridine technology are applied in the field of synthesis of pharmaceutical intermediates, which can solve the problems of explosion, high environmental hazard, strong toxicity of azide and the like, and achieve the effect of mild reaction conditions

Active Publication Date: 2019-08-13
CHEMSHUTTLE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This intermediate is a class of important intermediates for the research of new anti-tumor and anti-leukemia drugs. The existing document WO2008149163A2 reports the specific preparation scheme of this compound. The method uses 1,6-naphthyridine-2-carboxylic acid as a raw material to obtain it through hydrogenation reduction 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, then Boc protected the amino group, then rearranged by Curtis, and finally deprotected to obtain 5,6,7,8-tetrahydro-1 , 6-naphthyridine-2-amine, this method uses azide in the Curtis rearrangement, which has the danger of explosion, and azide has strong toxicity and is more harmful to the environment

Method used

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  • A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine
  • A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine
  • A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine

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Embodiment 1

[0022] A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine, said method comprising the steps of:

[0023] (1) In a 250mL single-necked bottle, dissolve 20.0g of 2-chloro-5,6,7,8-tetrahydronaphthyridine and 14.0g of triethylamine in 50mL of dichloromethane, and stir the solution in an ice-salt bath Cool and add 27.2g Boc dropwise 2 O, after the dropwise addition, react at room temperature for 1 hour, add 50 mL of dichloromethane to dilute, wash twice with 1 mol / L dilute hydrochloric acid, once with saturated sodium bicarbonate and once with saturated brine, and dry the organic phase with anhydrous magnesium sulfate , filtered, and the filtrate was spin-dried to obtain 30.9g of a light yellow substance, namely 2-chloro-6-tert-butoxycarbonyl-5,7,8-trihydro-1,6-naphthyridine, yield 97%, LCMS ( ESI):m / z 269(M+H) + ,169(M-100) + .

[0024] (2) Weigh 7.0 g of 2-chloro-6-tert-butoxycarbonyl-5,7,8-trihydro-1,6-naphthyridine prepared in step (1) into a 250 mL sing...

Embodiment 2

[0027] A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine, said method comprising the steps of:

[0028] (1) In a 250 mL single-necked bottle, add 5.0 g of 2-bromo-5,6,7,8-tetrahydronaphthyridine, 6.5 g of potassium carbonate, 5.9 g of benzyl chloride and 50 mL of acetonitrile in sequence. Heat to reflux to react overnight, filter after the reaction is complete, spin the filtrate to remove the solvent and pass through the column, rinse with EA:PE=1:20-1:10 to obtain 6.3g of white solid, namely 2-bromo-6-benzyl-5, 7,8-Trihydro-1,6-naphthyridine, yield 89%, LCMS (ESI): m / z 303, 305 (M+H) + .

[0029] (2) Weigh 5.0 g of 2-bromo-6-benzyl-5,7,8-trihydro-1,6-naphthyridine prepared in step (1) into a 100 mL single-necked bottle, add 50 mL of DMF and stir to dissolve, Then add 3.7g benzyl carbamate, 3.7g Xantphos, 6.8g K 2 CO 3 , and 3.5g tetrakistriphenylphosphine palladium, the reaction mixture was heated to 120°C for 4h under the protection of nitrogen, then...

Embodiment 3

[0032] A method for synthesizing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine, said method comprising the steps of:

[0033] (1) In a 250mL single-necked bottle, dissolve 10.0g of 2-chloro-5,6,7,8-tetrahydronaphthyridine and 9.2g of DIEA in 50mL of THF, cool to -10~-5°C, and add 11.1 g benzyl chloroformate, react at room temperature for 2h after the dropwise addition. After the reaction is complete, dilute with 200 mL of water, extract three times with 200 mL of ethyl acetate, wash the organic phase with 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin the filtrate to Dry to obtain 16.3g of light yellow substance, namely 2-chloro-6-benzyloxycarbonyl-5,7,8-trihydro-1,6-naphthyridine, yield 91%, LCMS (ESI): m / z 303,305(M+H) + .

[0034] (2) Weigh 3.0 g of 2-chloro-6-benzyloxycarbonyl-5,7,8-trihydro-1,6-naphthyridine prepared in step (1) into a 100 mL stuffy tank, add 50 mL THF and stir t...

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Abstract

The invention discloses a synthesis method of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine. The synthesis method comprises the specific steps: (1) carrying out amino protection reaction on 2-halo-5,6,7,8-tetrahydro-1,6-naphthyridine to prepare 6-site-protected 2-halo-5,7,8-trihydro-1,6-naphthyridine; (2) carrying out palladium-catalyzed coupling reaction on the 6-site-protected 2-halo-5,7,8-trihydro-1,6-naphthyridine and carbamate under basic conditionsto prepare double-site-protected 5,7,8-trihydro-1,6-naphthyridine-2-amine; (3) carrying out deprotection reaction on the double-site-protected 5,7,8-trihydro-1,6-naphthyridine-2-amine to prepare 5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine. In the whole technical process, only conventional reagents are used, the use of azides with high toxicity and environmental hazards is avoided, reaction conditions are mild and the method is safer and more environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method of using 2-halo-5,6,7,8-tetrahydro-1,6-naphthyridine as a raw material through amino protection reaction, coupling reaction, The process of the deprotection reaction, the method for preparing 5,6,7,8-tetrahydro-1,6-naphthyridine-2 amine. Background technique [0002] 5,6,7,8-tetrahydro-1,6-naphthyridine-2amine is the main core structure of AMG925, a dual inhibitor of cyclin-dependent kinase 4 and FMS-like tyrosine kinase 3. This intermediate is a class of important intermediates for the research of new anti-tumor and anti-leukemia drugs. The existing document WO2008149163A2 reports the specific preparation scheme of this compound. The method uses 1,6-naphthyridine-2-carboxylic acid as a raw material to obtain it through hydrogenation reduction 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid, then Boc protected the amino group, th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCY02P20/55
Inventor 苟远诚
Owner CHEMSHUTTLE
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