51 results about "Eptifibatide" patented technology

The invention relates, interalia, to the field of purification of peptides, notably cyclic or non-cyclic peptides their analogs or derivatives thereof. More particularly, the invention relates to a simplified and optimized purification process of cyclic peptides from a composition comprising the said peptide and at least one related impurity by chromatographic procedures enabling high yields, selectivity and purity of the desired end product. The improved process is particularly useful for the preparation of eptifibatide, exenatide, atosiban, nesiritide and their respective derivatives and analogs. The polypeptides are prepared in high purity of at least about 96 %, and preferably at least about 99 %.

The invention relates to the field of preparation of polypeptides and particularly relates to a preparation method of eptifibatide. The preparation method comprises the following steps of: preparing a fine peptide solution of the eptifibatide; and performing rotary evaporation on the fine peptide solution of the eptifibatide to get a fine peptide concentrated solution of the eptifibatide, and freeze-drying to obtain eptifibatide, wherein the concentration of the fine peptide concentrated solution of the eptifibatide is 15-30mg / mL; and the temperature of rotary evaporation is 25 DEG C-35 DEG C. The preparation method of the fine peptide solution of the eptifibatide comprises the following steps of: coupling Cys with resin to get Cys-resin; and gradually coupling the Cys-resin with Pro, Trp, Asp, Gly, Har and Mpr to get a peptide with the sequence as shown in SEQ (sequence) ID (identity) NO: 1, and further performing oxidation, cracking, purification and salt transfer to get the fine peptide solution of the eptifibatide. By adopting the preparation method provided by the invention, the production of dimer impurities in the eptifibatide can be greatly reduced, and organic residues of acetonitrile and the like can be in line with the related standard in Chinese Pharmacopoeia.

The invention relates to a liquid-phase synthesis method of eptifibatide as a polypeptide medicament and belongs to the technical field of synthesis of polypeptides. According to the technical scheme, the liquid-phase synthesis method comprises the following steps: (1) synthesizing a peptide fragment Mpa(R1)-Lys(R2)-Gly-OH; (2) synthesizing a peptide fragment H-Asp(R3)-Trp-Pro-Cys(R4)-NH2; (3) condensing the peptide fragment Mpa(R1)-Lys(R2)-Gly-OH and the peptide fragment H-Asp(R3)-Trp-Pro-Cys(R4)-NH2 to obtain a linear peptide Mpa(R1)-Lys(R2)-Gly-Asp(R3)-Trp-Pro-Cys(R4)-NH2; (4) cyclizing the linear peptide Mpa(R1)-Lys(R2)-Gly-Asp(R3)-Trp-Pr-Cys(R4)-NH2 to form an intramolecular disulfide bond to obtain a side chain protected cyclopeptide; (5) removing a side chain protecting group of the cyclopeptide; and (6) converting a side chain amino group of the cyclopeptide Lys into a guanidine group to obtain the eptifibatide. According to the liquid-phase synthesis method of the eptifibatide, an initiating raw material, namely an Fmoc-Har-OH special amino acid derivative is avoided, a condition and method for converting the amino group of the cyclopeptide into the guanidine group are established, and a raw material reagent is low in cost and easily obtained, so that the product cost is effectively reduced and the production benefit is remarkably increased.

The invention discloses a method for preparing Eptifibatide with a solid phase method, which comprises the following steps of: 1) selecting Sieber resin to remove Fmoc, and obtaining H2N-Sieber resin; 2) adopting Fmoc / tBu solid phase method to couple and synthesize linear peptide Eptifibatide-Sieber resin with full protective lateral chains in sequence; 3) conducting solid phase oxidation to the resin, and obtaining oxidant peptide Eptifibatide-Sieber resin with full protective lateral chains; 4) cutting the resin and removing the lateral chain protection, and obtaining crude product of Eptifibatide; and 5) conducting separation and purification, and breeze drying by a freeze dryer, and obtaining refined Eptifibatide peptide. The technology is characterized by simple operation, easy post treatment, less investment of raw material, low cost, high yield and the like, and has considerable economical and practical value and wide application prospect in the field of polypeptide drug design and synthesis simultaneously.

The invention discloses a preparation method for eptifibatide. The method includes the steps of sequentially coupling and connecting Fmoc-protected amino acid and a protected amino acid tripeptide section with Fmoc-Cys(Trt) resin as a coupling resin carrier, splitting eptifibatide resin through a split agent, oxidizing reduced type eptifibatide in an acetonitrile aqueous solution, conducting condensation after oxidation, and conducting purification, salt transfer and freeze drying on crude eptifibatide product concentrated liquor to obtain a fine eptifibatide product. By means of the preparation method, production cost can be effectively reduced, yield is increased, and the content of impurities in the finished product is reduced.

The invention relates to a new technique for purifying and preparing eptifibatide. At present, the eptifibatide is separated, purified and produced by adopting opposite phase high pressure liquid chromatography. However, mass production is not easy to realize, and the equipment are expensive. Separation and purification are carried out by the method by applying two solvent systems which are not dissolved in each other and make epicyclic motion at high speed in a chromatographic column tube; the processing steps comprises: a. synthetic crude product of the eptifibatide is dissolved by solvent; b. the dissolved crude product of the eptifibatide is separated and purified by high-speed centrifugation separation chromatography (FCPC), and is tested by a uv detector from the distance of 230nm, so that target peak is collected by subsection; c. the collected cut fraction is tested by HPLC, wherein, the cut fraction with the purity higher than 98% is bended to be treated by the next step, and the cut fraction with the purity lower than 98% is recycled and purified again; d. ion exchange is carried out on the cut fraction with qualified purity to remove trifluoroacetic acid (TFA), and then the cut fraction is transformed into acetic acid eptifibatide. The new technique has no irreversible adsorption and the advantages of no loss of sample, no pollution, high speed and high efficiency, and is suitable for mass production.

An Eptifibatide preparation method with product purity of more than 99.5%, the method comprising: using a solid phase polypeptide synthesis method to prepare eptifibatide resin, conducting acidolysis on the Eptifibatide resin to obtain a crude Eptifibatide linear peptide product, oxidizing to obtain a crude Eptifibatide product, purifying and exchanging salt to obtain an Eptifibatide finished product; the method using the solid phase polypeptide synthesis method to prepare the eptifibatide resin is: using a solid phase coupling synthesis method to sequentially splice a corresponding protective amino acid or a segment in the following sequence onto amino resin, and obtaining the Eptifibatide resin: X—Y-Trp(R1)-Pro-Cys(R2)-amino resin, wherein R1 is Boc or H, R2 is Trt or Acm, X is Mpr(R2)-Harg(R3), R3 is Pbf or H, and Y is Gly-Asp(OtBu).

The invention discloses an eptifibatide synthesis method. Fluorenylmethoxycarbonyl aminomethyl resin is used as a carrier, the method comprises amino acid condensation reactions from Step 1 to Step 7, resin connected with 7 amino acids is cut and linear thiohydracrylic acid-homoarginine-glycine-aspartic acid-tryptophan-proline-cysteine-NH2 is obtained in Step 8, a ring is formed under the catalysis of 2,2'-dipyridyl disulfide in Step 9, and eptifibatide is obtained. Further, the condensation reactions and deprotection reactions are conducted at 60-80 DEG C. The method has the characteristics of high yield, few byproduct and simplicity in separation and purification, and compared with the prior art, the method has the advantages that a lot of time is saved and the method is applicable to pilot production and industrial production.

The invention belongs to the field of pharmaceutical preparations, and relates to an eptifibatide lyophilized powder injection formula and preparation thereof. The eptifibatide lyophilized powder injection is composed of eptifibatide and pharmaceutically acceptable auxiliary materials, contains a given amount of citric acid, excipient, acidity regulator and water for injection, and is prepared by preparing the drug and the auxiliary materials into a solution by the water for injection, and performing a lyophilizing process (the water for injection is removed in the process). The eptifibatide lyophilized powder injection provided by the invention solves the problems of high viscosity, long lyophilizing process and poor rehydration of a high dose of polypeptide drug solution, and provides convenience for clinical medication.

The preparation process of solid phase polypeptide synthesized eptifibatide includes the following steps: (1) connecting amino acids one by one with Rink Amide resin, Rink Amide MBHA resin or Rink Amide AM resin as initial material, and Fmoc protected amino aids as monomer, with the last peptide chain being S-benzyl mercapto propionic acid Map(SBzl); (2) adding peptide cutting agent (TFA / HBr / HAc / TIS / EDT) to cut peptide; (3) precipitating and collecting coarse reductant eptifibatide product in ether solvent; (4) dissolving coarse reductant eptifibatide product in water, regulating pH value with ammonia water to 7.5-10.0, introducing air for oxidation, and collecting coarse eptifibatide product; and (5) separating and purifying the coarse product in C18 column to obtain the target product. The present invention has high yield, and is suitable for industrial production.

The present invention provides, inter alia, convergent processes for preparing eptifibatide that involve coupling a 2-6 eptifibatide fragment to an activated cysteinamide residue to form a 2-7 eptifibatide fragment, attaching a mercaptopropionic acid residue to the 2-7 eptifibatide fragment through disulfide bond formation, coupling the peptide intramolecularly, and removing the protecting group, to form eptifibatide. The invention further provides products produced by the described processes, novel compounds that can be used as synthetic intermediates for the preparation of eptifibatide, and novel compounds that are structurally similar to eptifibatide.