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Method for synthesizing Etelcalcetide

A liquid-phase synthesis and l-cys technology, applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problem of easy removal of guanidinium groups, difficult purification, and inability to obtain ideal yield and purity of final products and other problems, to avoid low conversion rate, less impurities, and facilitate large-scale production

Inactive Publication Date: 2017-07-07
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, Etelcalcetide needs to carry out the oxidation reaction of intermolecular sulfhydryl groups. If the reaction is carried out according to the conventional disulfide bond construction method, the final product with ideal yield and purity will not be obtained.
In addition, if the compound is synthesized by ordinary solid-phase synthesis method, the guanidine group is relatively easy to remove to form degradation impurities, and the purification is extremely difficult.

Method used

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  • Method for synthesizing Etelcalcetide
  • Method for synthesizing Etelcalcetide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Fmoc-D-Arg(Pbf)-NH 2 Synthesis

[0044] 1. The inventive method

[0045] Fmoc-D-Arg(Pbf)-OH (130g, 200mmol) was added to 1000ml of dichloromethane, cooled in an ice-water bath to below 10°C, added isopropyl chloroformate (27g, 220mmol, 1.1equ.), stirred After 5 minutes, DIPEA (31 g, 242 mmol, 1.21 equ.) was slowly added dropwise, and the resulting mixture was stirred while keeping the system temperature below 10° C., and the reaction was monitored by TLC until the raw material point disappeared.

[0046] 200 milliliters of ammonia water was slowly added to the above reaction solution, keeping the reaction temperature below 20° C., continued to stir for 2 hours, separated the liquid, washed the DCM layer twice, dried over anhydrous sodium sulfate, and obtained 115 g of a white solid after removing the solvent (yield 88.5%), and the HPLC purity was 95.2%.

[0047] 2. Comparison method

[0048] Fmoc-D-Arg(Pbf)-OH (130g, 200mmol) was added to 1000ml of dichlo...

Embodiment 2

[0051] Example 2: Fmoc-D-Ala-D-Arg(Pbf)-NH 2 Synthesis

[0052] Fmoc-D-Ala-OH (4.67g, 15mmol) was added to 100ml of dichloromethane, stirred for 10 minutes, cooled to below 10°C in an ice-water bath, and isopropyl chloroformate (2.0g, 16.5mmol, 1.1 equ.), after stirring for 5 minutes, slowly added DIPEA (2.33g, 18.1mmol, 1.21equ.), the resulting mixture kept the temperature of the system below 10°C, stirred, and TLC monitored the reaction until the raw material point disappeared.

[0053] Fmoc-D-Arg(Pbf)-NH 2 Remove Fmoc protecting group, H-D-Arg(Pbf)-NH 2 (7.0g, 16.5mmol) was dissolved by adding dichloromethane (50ml), and then added to the above reaction solution, keeping the temperature of the system below 10°C and continuing to stir for 10 hours until the starting point disappeared (TLC).

[0054] The reaction mixture solution was washed once with saturated sodium bicarbonate solution, washed twice with water, dried over anhydrous sodium sulfate, and 11.1 g of a white s...

Embodiment 3

[0061] Example 3: Fmoc-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-NH 2 Synthesis

[0062] Fmoc-D-Ala-R-Arg(Pbf)-NH 2 (8.9g 12mmol) was added in dichloromethane (200 milliliters), after stirring for 5 minutes, piperidine (5.1g, 60mmol) was added dropwise, and the reaction solution continued to stir until Fmoc-D-Ala-R-Arg(Pbf)- NH 2 Completely gone (TLC). Wash with dilute hydrochloric acid until the dichloromethane solution is neutral, separate the layers, dry the dichloromethane solution, and remove the solvent to obtain the oil H-D-Ala-D-Arg(Pbf)-NH 2 (5.3g, yield 85.8%), the oil was treated with ethyl acetate / n-hexane to obtain pure product.

[0063] Fmoc-D-Arg(Pbf)-OH (6.5g, 10mmol) was added to 100ml of N,N-dimethylformamide, cooled in an ice-water bath to below 10°C, and isopropyl chloroformate (1.34g, 11mmol, 1.1equ.), after stirring for 5 minutes, slowly added DIPEA (1.56g, 12.1mmol, 1.21equ.), the resulting mixture kept the system temperature below 10°C, stirred, and TLC monitore...

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Abstract

The invention relates to the field of medicine synthesis, and discloses a method for synthesizing Etelcalcetide. The method comprises the following steps: performing liquid-phase synthesis so as to obtain straight-chain heptapeptide which is subjected to acetylization at an N end and is subjected to amidation at a C end on the amino acid sequence of SEQ ID NO:1; performing NCS (Chlorosuccinimide) chlorination on L-Cys, and substituting chlorine on the sulfydryl, and generating L-Cys (SCl); performing coupling reaction on the straight-chain heptapeptide and L-Cys (SCl) to generate disulfide, thereby obtaining Etelcalcetide. As the Etelcalcetide is synthesized by using a whole liquid-phase method, relatively small amounts of reagents and solvents are used when being compared with those of a solid-phase method, the synthesis is green and environmental-friendly, no expensive resin is used, and thus the cost is lowered. Meanwhile, as NCS which is cheap and easy to obtain and cysteine are adopted to form an active intermediate to construct the disulfide bond, the defects that a conventional method is low in conversion rate and low in purity are avoided, and large-scale production of the Etelcalcetide can be facilitated.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a method for synthesizing Etelcalcetide. Background technique [0002] Secondary hyperparathyroidism (SHPT, referred to as secondary hyperparathyroidism), refers to chronic renal insufficiency, intestinal malabsorption syndrome, Fanconi syndrome and renal tubular acidosis, vitamin D deficiency or resistance, and pregnancy , breast-feeding, etc., the parathyroid glands are stimulated by hypocalcemia, hypomagnesemia or hyperphosphatemia for a long time to secrete excessive parathyroid hormone (PTH) to increase blood calcium, blood magnesium and reduce blood phosphorus. Chronic compensatory clinical presentation, long-standing parathyroid hyperplasia eventually leads to the formation of functionally autonomous adenomas. [0003] Etelcalcetide is a novel calcimimetic agent developed by Kai Pharmaceuticals, Inc., which can inhibit the secretion of parathyroid hormone (PTH). Seconda...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/02
CPCC07K1/02C07K1/06C07K7/06
Inventor 刘飞孟伍柯瑾宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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