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Preparation method for Talaporfin and intermediate thereof

A technology of taraporfin and its compounds, which is applied in the field of preparation of taraporfin and its intermediates, can solve problems such as difficult storage, unstable intermediates, and difficulties in industrial production, and achieves non-dangerous steps, improved selectivity, The effect of reducing the possibility of racemization

Inactive Publication Date: 2013-04-10
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can effectively control the content of isomers and impurities, but the intermediates are unstable and difficult to store, which brings difficulties to industrial production

Method used

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  • Preparation method for Talaporfin and intermediate thereof
  • Preparation method for Talaporfin and intermediate thereof
  • Preparation method for Talaporfin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] (1) Preparation of chlorin e6 monoaspartic acid-4-tert-butyl ester:

[0025] 30g of chlorin e6 was suspended in dichloromethane, 9.6g of EDC and 2.4g of p-dimethylaminopyridine were added, and the reaction was carried out at room temperature. TLC detected that the reaction of the raw materials was basically completed, and 11.4g of L-aspartic acid-4-tert. Butyl ester, TLC detection intermediate acid anhydride reaction is completed, stop reaction, medium pressure preparative chromatographic separation (separation condition: 80mm × 400mm stainless steel column, 300-400 purpose silica gel, dichloromethane: methanol: glacial acetic acid is 25: 1: 0.1 is eluent), collect the target spots, evaporate the solvent to dryness to obtain 25.9 g of chlorin e6 monoaspartate-4-tert-butyl ester, with a yield of 67.1%. By HPLC analysis, the purity was 99.09%.

[0026] MS: 768.6 (M+1) + , 790.6(M+Na) + .

[0027] 1 HNMR: (DMSO, 600M): 9.79(1H,S), 9.73(1H,S), 9.16(1H,S), 8.32(1H,m), 8...

Embodiment 2

[0034] (1) Preparation of chlorin e6 monoaspartic acid-4-tert-butyl ester:

[0035] Suspend 30g of chlorin e6 in chloroform, add 10.4g of DCC and 2.4g of p-dimethylaminopyridine, react at -20°C, TLC detects that the reaction of the raw materials is basically completed, add 7.6g of L-aspartic acid-4 -tert-butyl ester, the completion of the reaction of the intermediate acid anhydride monitored by TLC, the reaction was stopped, and the medium pressure preparative chromatographic separation (separation conditions: 80mm × 400mm stainless steel column, 300-400 mesh silica gel, dichloromethane: methanol: glacial acetic acid was 25: 1: 0.1 is the eluent), collect the target points, evaporate the solvent to obtain 27.1 g of chlorin e6 monoaspartate-4-tert-butyl ester, and the yield is 70.2%. By HPLC analysis, the purity was 99.04%.

[0036] MS: 768.6 (M+1) + , 790.6(M+Na) + .

[0037] 1 HNMR: (DMSO, 600M): 9.79(1H,S), 9.73(1H,S), 9.16(1H,S), 8.32(1H,m), 8.10(1H,dd), 6.48(1H,dd), ...

Embodiment 3

[0045] (1) Preparation of chlorin e6 monoaspartic acid-4-trimethylsilyl ester:

[0046] 3g of chlorin e6 was suspended in dichloromethane, 1.36g of EDC and 0.24g of p-dimethylaminopyridine were added, and the reaction was carried out at 80 °C. Trimethylsilyl ester, TLC monitoring intermediate acid anhydride reaction is completed, stop reaction, medium pressure preparative chromatographic separation (separation conditions: 40mm × 400mm stainless steel column, 300-400 mesh silica gel, dichloromethane: methanol: glacial acetic acid is 25: 1: 0.1 is the eluent), collect the target points, evaporate the solvent to obtain chlorin e6 monoaspartic acid-4-trimethylsilyl ester 2.5 g, the yield is 63.3%, and the purity is 99.08%.

[0047] MS: 785.4 (M+1) + , 817.5(M+Na) + .

[0048] (2) Preparation of talaporfin:

[0049] Dissolve 20 g of chlorin e6 monoaspartate-4-tert-butyl ester in 2000 ml of 1 mol / L trifluoroacetic acid methanol solution at room temperature, and react at 0° C. un...

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Abstract

The invention belongs to the field of medical chemistry and particularly relates to a preparation method for Talaporfin and an intermediate thereof. The Talaporfin is obtained by taking a compound chlorins e6 mono aspartic acid-4-ester as a key intermediate and hydrolyzing the chlorins e6 mono aspartic acid-4-ester. The preparation method for the Talaporfin and the intermediate thereof has the advantages that the product purity is improved; the operation is simplified; requirements on equipment are lowered; and industrial production is easy.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation method of talaporfin and an intermediate thereof. Background technique [0002] Talaporphin sodium, its chemical name is chlorphene e6 monoaspartic acid amide tetrasodium salt, and its chemical structural formula is as follows: [0003] [0004] The product is used as a photosensitizer in medicine, and is an excellent photosensitizer for photodynamic therapy to treat tumors. It was launched in Japan in 2004. So far, there are few reports on the synthesis of talaporfin. Patent US4675338 discloses the preparation method of talaporfin. Chlorin e6 is reacted with di-tert-butyl L-aspartate under the action of a condensing agent. , directly hydrolyzed without separation, and then separated by high-performance liquid phase preparation to obtain the final product. The method has fewer steps and is simple to operate. However, the two carboxyl groups of L-aspartic aci...

Claims

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Application Information

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IPC IPC(8): C07D487/22
Inventor 杨绍波李燕葛铭经侯贺增范传文张明会
Owner QILU PHARMA
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