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Synthesis and application of pasireotide pentapeptide intermediate

A technology of pasireotide pentapeptide and retinide pentapeptide is applied in the application field of preparing pasireotide, can solve the problems of difficult detection of reaction, high cost, unsuitability for large-scale production and the like, and achieves rapid reaction and high efficiency. Complete, easy-to-monitor, and easy-to-scale results

Active Publication Date: 2016-12-07
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem solved by the present invention is to provide a liquid-phase synthesis method of pasiiretide pentapeptide intermediate, and then realize the liquid-phase synthesis of pasiiretide, and solve the problem that the current solid-phase synthesis method is costly, the reaction is difficult to detect, and the Suitable for large-scale production and other issues

Method used

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  • Synthesis and application of pasireotide pentapeptide intermediate
  • Synthesis and application of pasireotide pentapeptide intermediate
  • Synthesis and application of pasireotide pentapeptide intermediate

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0060] Preparation Example 1 N-Benzyloxycarbonyl-D-tryptophan-(N-hydroxyl)succinimide ester (a)

[0061]

[0062] N-Benzyloxycarbonyl-D-tryptophan (7.0 g, 20.7 mmol) and N-hydroxysuccinimide (2.4 g, 20.7 mmol) were added to anhydrous THF (80 ml), and stirred at room temperature. The temperature was controlled at about 5°C, and a THF (20ml) solution of DCC (4.3g, 20.9mmol) was slowly added dropwise. Stir at room temperature for 24h, filter several times, and concentrate the filtrate to dryness under reduced pressure. The obtained yellow oil was recrystallized from isopropanol to obtain 7.6 g of off-white solid with a yield of 84.6%. 1 HNMR (400MHz, DMSO) δ10.94 (s, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.56 (d, J = 7.9Hz, 1H), 7.31 (ddd, J = 24.4, 17.1, 8.5 Hz,5H),7.09(t,J=7.2Hz,1H),7.00(t,J=7.2Hz,1H),4.99(q,J=12.6Hz,2H),4.72-4.59(m,1H), 3.35(dd,J=14.6,4.7Hz,1H),3.17(dd,J=14.6,9.9Hz,1H),2.80(d,J=31.4Hz,4H)

preparation example 2

[0063] Preparation Example 2 N-(9-fluorenylmethoxycarbonyl)phenylglycine-(N-hydroxyl)succinimide ester (b)

[0064]

[0065] N-(9-fluorenylmethoxycarbonyl)phenylglycine (10 g, 26.8 mmol) and N-hydroxysuccinimide (3.1 g, 26.8 mmol) were added to anhydrous THF (100 ml), and stirred at room temperature. Control the temperature at about 5°C, slowly drop into a solution of DCC (5.6g, 27.1mmol) in THF (20ml), and stir at room temperature for 24h. After several times of filtration, the filtrate was concentrated to dryness under reduced pressure, and ethyl acetate was added for recrystallization to obtain 11.2 g of white solid with a yield of 89.2%. 1 H NMR (400MHz, CDCl3) δ7.76(d, J=7.3Hz, 2H), 7.64-7.53(m, 2H), 7.40(t, J=7.4Hz, 2H), 7.31(t, J=7.4Hz ,2H),5.79(s,1H),4.54(m,J=8.1Hz,1H),4.45-4.40(m,1H),4.39-4.23(m,1H),2.81(s,4H)

preparation example 3

[0066] Preparation Example 3 N-tert-butoxycarbonyl-O-benzyl-tyrosine-(N-hydroxy)succinimide ester (c)

[0067]

[0068] Add N-tert-butoxycarbonyl-O-benzyl-tyrosine (7.4g, 19.9mmol) and N-hydroxysuccinimide (2.3g, 19.9mmol) to anhydrous THF (80ml), stir at room temperature . Control the temperature at about 5°C, slowly drop into a solution of DCC (4.1g, 20.1mmol) in THF (20ml), and stir at room temperature for 5h. After several times of filtration, the filtrate was concentrated to dryness under reduced pressure, and ethyl acetate was added for recrystallization to obtain 8.5 g of white solid with a yield of 91.0%. 1 H NMR (400MHz, CDCl3) δ7.47-7.29 (m, 4H), 7.20 (d, J = 8.1Hz, 2H), 6.93 (d, J = 8.1Hz, 2H), 5.04 (s, 2H), 4.89 (d,J=12.6Hz,1H),3.31-3.06(m,2H),2.85(s,4H),1.42(s,9H)

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Abstract

The invention discloses a liquid synthetic method of pasireotide pentapeptide intermediate, i.e., a preparation method of H-Phg-D-Trp-Lys(Boc)-Tyr(Bzl)-Phe-OR. By using the liquid linker peptide synthetic method, reaction is easy to detect, the cost is lower than that of a solid synthetic method, and the method is more suitable for large-scale industrial production. The liquid synthetic method includes the main synthetic steps of linking carbobenzoxy-protected D-tryptophan and 9-fluorenylmethoxycarbonyl-protected phenylglycine one by one to Alpha-N terminals of lysine to obtain a tripeptide fragment in 3+2 mode through BSA protected lysine and N-hydroxysuccinimide ester method; condensing ester-protected phenylalanine and t-butyloxycarboryl-protected O-benzyl-tyrosine to obtain a dipeptide fragment through N-hydroxysuccinimide ester method; condensing the tripeptide and dipeptide through TBTU method to obtain the target product, pasireotide pentapeptide intermediate.

Description

technical field [0001] The invention relates to a liquid-phase synthesis method of a pasiiretide pentapeptide intermediate, and the application of the key intermediate in the preparation of pasiiretide. Background technique [0002] Pasiiretide was developed by Novartis. It was approved for marketing by the European Commission in April 2012, and was approved by the US FDA in December of the same year. Its structure is shown in (II) below. It is an injectable ring Hexapeptide somatostatin analogues, which exert their pharmacological activity by binding to somatostatin receptors (ssts), are the first to treat adult patients with Cushing's disease who are inoperable or have failed surgical treatment. Orphan drug for the treatment of Cushing's disease. [0003] [0004] At present, the synthesis of pasiiretide mostly adopts solid-phase synthesis method, for example, according to the standard Fmoc / tBu strategy, using SASRIN Resin as the starting resin, solid-phase condensatio...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/02
CPCC07K7/06Y02P20/55
Inventor 冯文华陈淼
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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