The method for preparing bivalirudin

A technology of bivalirudin and definition, applied in the field of preparation of bivalirudin, can solve the problems of difficult removal of impurities, unsuitable for large-scale preparation of bivalirudin, etc., and achieves the effect of easy industrial-scale production

Active Publication Date: 2011-11-30
POLYPEPTIDE LAB HLDG PPL AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A disadvantage of this strategy is the substantial formation of D-Tyr 19 -- Bivalirudin
This impurity is difficult to remove, thus requiring additional labor, cost, and lost yield to obtain a purified product
In addition, the amount of purified bivalirudin obtained in the examples of WO 2007 / 033383 is only in the range of grams, which indicates that this method is not suitable for large-scale preparation of bivalirudin with good purity

Method used

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  • The method for preparing bivalirudin
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Examples

Experimental program
Comparison scheme
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Embodiment 1

[0469] Embodiment 1: Preparation of H-Asn-Gly 10 -OBzl TFA

[0470] To a mixture of TFA (90 L), toluene (388 L) and THF (45 L) was added Boc-Asn-Gly-OBzl (90.20 kg; Hexagon Labs Inc., USA) at 20°C. To the resulting mixture was slowly added TFA (198 L) at < 22°C. The reaction was allowed to complete at 20°C. The completion of the cleavage was monitored by HPLC.

[0471] Then, THF was added slowly, and the reaction mixture was evaporated in vacuo. Triazeotropic distillation was performed using a mixture of toluene and THF. Get H-Asn-Gly 10 -OBzl·TFA, as an oily residue, diluted with ethyl acetate. The resulting solution was used directly in the next chemical step (see Example 3). Yield: 100%. Purity (HPLC): 99.3%.

Embodiment 2

[0472] Embodiment 2: Preparation of Boc-Gly 5 -Gly-Gly-Gly-OH TEA (SEQ ID NO 10)

[0473] to Boc-Gly at 20°C 5 -Gly-Gly-Gly-OEt (SEQ ID NO 10) [98.11 kg; Bonora et al., Gazzetta Chimica Italiana 1980, 110, 503-510, analogously prepared from Boc-Gly-Gly-OH (Senn Chemicals, Switzerland) and H -Gly-Gly-OEt·HCl (Senn Chemicals, Switzerland)] to a suspension in a mixture of acetone (78.44 L) and processed water (491 L) was slowly added TEA (73.1 L). The reaction was allowed to complete at 20°C. The completion of the saponification reaction was monitored by HPLC.

Embodiment 3

[0475] Embodiment 3: Preparation of Boc-Gly 5 -Gly-Gly-Gly-Asn-Gly 10 -OBzl(SEQ ID NO 5)

[0476] Adjustment of H-Asn-Gly with TEA at 0 °C 10 - pH of OBzl·TFA (573 L, see Example 1) in ethyl acetate to 6-6.5. Boc-Gly prepared according to Example 2 5 - A solution of Gly-Gly-Gly-OH (SEQ ID NO 10) was cooled to 0°C and added to the above solution, followed by HOBt (28.52 kg) and EDC·HCl (69.81 kg). The pH was adjusted to 6-6.5 with TEA (121 L) at 0°C. The reaction mixture was allowed to warm to room temperature.

[0477] After the coupling reaction was complete (after about 10 h; as indicated by HPLC), NaCl was added to the reaction mixture. The resulting suspension was cooled and filtered to give a solid residue, washed several times with aqueous NaCl and then cooled. The resulting solid was dried in vacuo to give 130.15 kg (100%) of Boc-Gly 5 -Gly-Gly-Gly-Asn-Gly 10 -- OBzl (SEQ ID NO 5), 97.9% pure (HPLC).

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Abstract

The present invention relates to a process for the production of bivalirudin, a 20-mer peptide of formula H-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-Asp-Phe-Glu-Glu-lle15-Pro-Glu-Glu-Tyr-Leu20-OH (I) via a convergent five-fragment synthesis, and to several peptide intermediates thereof.

Description

technical field [0001] The present invention relates to a novel convergent synthesis of bivalirudin, which is a 20-mer peptide having the formula [0002] H-D-Phe 1 -Pro-Arg-Pro-Gly 5 -Gly-Gly-Gly-Asn-Gly 10 -Asp-Phe-Glu--Glu-Ile 15 -Pro-Glu-Glu-Tyr-Leu 20 -OH (I) [0003] The present invention also relates to some protected peptides as intermediates in the synthesis of bivalirudin. Background technique [0004] Proteolytic processing mediated by thrombin is key to the control of blood coagulation. Hirudin is a potential clinical thrombin peptide inhibitor, which consists of 65 amino acids. But there are also shorter peptide fragments that have been shown to be effective against thrombosis, a life-threatening condition. [0005] US 5,196,404 discloses bivalirudin, one of these shorter polypeptides, and is a potent thrombin inhibitor. Bivalirudin is also known as Hirulog-8, BG-8967, Efludan, or and has the amino acid sequence given in Formula I. [0006] WO 98 / 5...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/10C07K14/815
CPCC07K14/815C07K5/1016C07K1/06C07K5/10C07K7/00Y02P20/55C07K7/06C07K7/08
Inventor 杰弗里·苏门卢西亚诺·弗尼
Owner POLYPEPTIDE LAB HLDG PPL AB
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