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A kind of preparation method of pisalom intermediate

A technology for pisalom and intermediates, which is applied in the field of preparation of amine phosphate binder pisalom intermediates, can solve the problems of unsuitability for industrial production, high toxicity of acrylonitrile, unfavorable labor protection and the like, and achieves good industrial performance. Prospect, less three wastes, easy to operate

Active Publication Date: 2017-04-05
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the route is short, this method needs to use the highly toxic substance acrylonitrile. Because acrylonitrile is highly toxic and easy to volatilize, there is a relatively large safety hazard, which is not conducive to labor protection. At the same time, the yield is low and it is not suitable for industrial production. , and its reaction equation is as follows:

Method used

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  • A kind of preparation method of pisalom intermediate
  • A kind of preparation method of pisalom intermediate
  • A kind of preparation method of pisalom intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Synthesis of N,N,N,N-tetrakis(3-aminopropyl)-1,4-butanediamine

[0025] Add 500g of allyl bromide, 300g of sodium azide and 7L of tetrahydrofuran into a 10L autoclave, seal it, and react at 35°C for 10h. After the reaction is complete, lower the temperature to 0°C, add 92g of 1,4-butanediamine, seal it, and react at 50°C for 20h. After the reaction is complete, add 20g of 10% Pd-C, pass through 2MPa hydrogen pressure, and react at 25°C for 24h. After the reaction is complete, suction filtration, the filtrate is precipitated under reduced pressure, and the residue is distilled under reduced pressure to obtain 258g of colorless liquid, with a yield of 79%. .

[0026] The purity by HPLC was 99.1%. HRMS(ESI+,m / z)(M+H) + = 317.54.

[0027] 13 C-NMR (400MHz,D 2 O): δ=53.3(N CH 2 CH 2 CH 2 CH 2 N),51.2(N CH 2 CH 2 CH 2 NH 2 ), 39.6 (CH 2 NH 2 ),28.8(CH 2 CH 2 NH 2 ), 23.9 (N CH 2 CH 2 CH 2 CH 2 N);

[0028] 'H-NMR (200MHz, CDCl 3 ,):δ=2.70(t...

Embodiment 2

[0029] Example 2: Synthesis of N,N,N,N-tetrakis(3-aminopropyl)-1,4-butanediamine

[0030] Add 500g of allyl bromide, 300g of sodium azide and 7L of methanol into a 10L autoclave, seal it, and react at 35°C for 10h. After the reaction is complete, lower the temperature to 0°C, add 92g of 1,4-butanediamine, seal it, and react at 50°C for 20h. After the reaction is complete, add 20g of 10% Pd-C, introduce a hydrogen pressure of 2MPa, and react at 25°C for 24h. After the reaction is complete, suction filtration, the filtrate is precipitated under reduced pressure, and the residue is distilled under reduced pressure to obtain 230g of colorless liquid, with a yield of 70%. .

[0031] The purity by HPLC was 99.0%. HRMS(ESI+,m / z)(M+H) + = 317.54.

Embodiment 3

[0032] Example 3: Synthesis of N,N,N,N-tetrakis(3-aminopropyl)-1,4-butanediamine

[0033] Add 500g of allyl bromide, 270g of sodium azide and 7L of tetrahydrofuran into a 10L autoclave, seal it, and react at 30°C for 13h. After the reaction is complete, lower the temperature to 0°C, add 92g of 1,4-butanediamine, seal it, and react at 50°C for 20h. After the reaction is complete, add 20g of 10% Pd-C, introduce 2MPa hydrogen pressure, and react at 25°C for 24h. After the reaction is complete, suction filtration, the filtrate is precipitated under reduced pressure, and the residue is distilled under reduced pressure to obtain 245g of colorless liquid, with a yield of 75%. .

[0034] The purity by HPLC was 99.2%. HRMS(ESI+,m / z)(M+H) + = 317.54.

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Abstract

The invention discloses a bixalomer intermediate preparing method. Allyl bromide is used as a raw material, 3-nitrine-1-propylene is obtained under the effect of sodium azide, the 3-nitrine-1-propylene and 1,4-butanediamine performs addition reaction to obtain N,N,N,N-quadri(3-azide propyl)-1,4-butanediamine, and then hydrogenation reaction is performed to obtain N,N,N,N-quadri(3-amino propyl)-1,4-butanediamine. The raw materials adopted by the method are cheap and easy to obtain, a one-pot method is adopted to perform reaction, operation is simple and convenient, the yield is high, the purity of a product is higher, the purity, detected by HPLC, of quadri-amino propyl-1,4-butanediamine is above 99%, waste gas, waste water and industrial residues produced by the adopted preparation process are little, and therefore, the bixalomer intermediate preparing method has very good industrial prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an amine phosphate binding agent pisalom intermediate. Background technique [0002] Bixalomer (bixalomer) is a kind of amine phosphate binding agent, was applied for listing in Japan in June, 2012 by Astellas Pharma company, trade name KIKLIN, is a kind of medicine for the treatment of hyperphosphatemia of chronic kidney disease dialysis, its Inhibits phosphate absorption by reducing serum inorganic phosphorus concentration in the gastrointestinal tract. A multicenter non-inferiority study showed that pisalom had a similar effect on lowering serum phosphorus as sevelamer hydrochloride, but did not increase the risk of metabolic acidosis in patients. [0003] The currently reported synthesis routes of pisalom generally have disadvantages such as difficult purification or harsh reaction conditions. For example, E.M.M.de Brabander-van den Ber...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/14C07C209/42
Inventor 包金远徐峰蒋玉伟施路
Owner NANJING HUAWE MEDICINE TECH DEV