Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
A technology of bivalirudin and resin, which is applied in the field of polypeptide drug preparation, can solve problems such as difficult complete purification, reduced product purity, and inability to effectively improve the total yield of the product, and achieves warm reaction conditions, simple reaction operation, and wide application Effects on value and application prospects
Active Publication Date: 2011-12-21
CHENGDU SHENGNUO BIOTEC CO LTD
View PDF14 Cites 36 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
Problems solved by technology
[0013] The structure of bivalirudin contains a Gly-Gly-Gly-Gly fragment. In the process of sequentially inserting Fmoc-Gly in the solid phase method, due to the characteristics of Gly itself, the following impurities are produced in the product: [+1Gly]-bivalirudin Ludin, [+2Gly]-bivalirudin, [-1Gly]-bivalirudin, [-2Gly]-bivalirudin, and these impurities are similar to the polarity of bivalirudin itself, so in the purification When it is difficult to completely purify it, the total yield of the product cannot be effectively improved, and the purity of the product is reduced, which affects the safety of the drug
[0014] None of the above patents can solve the problem of increase and decrease of Gly in the structure of bivalirudin. In order to solve the above problems, Israel NOVETIDE Company WO2010117725 patent uses Fmoc-Gly-Gly-OH as raw material to insert Gly-Gly- Gly-Gly fragments, but only resolve [+1Gly]-bivalirudin and [-1Gly]-bivalirudin impurities, but not [+2Gly]-bivalirudin and [-2Gly]- Production of bivalirudin
Method used
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
Smart Image
Examples
Experimental program
Comparison scheme
Effect test
Embodiment 1
[0058] The preparation of embodiment 1Fmoc-Leu-Wang resin
[0059] Take wang resin 500g (substitution value 1.0mmol / g), swell with 5L N,N-dimethylamide (DMF) for 30 minutes, add Fmoc-Leu-OH 353g (1.0mol), stir for 30 minutes and then add 155ml DIC (1.0mol), 135gHOBt (1.0mol), 6.1g (0.05mol) DMAP, stirred and reacted at room temperature for 18 hours, and after filtration, the resin was washed 3 times with DMF, dichloromethane (DCM), methanol, and dried under reduced pressure to obtain Fmoc-Leu-Waug resin 651g, esterification yield 95.6%.
[0061] Take the above Fmoc-Leu-Wang resin, swell with 5L 20% piperidine (PIP) / NN-dimethylamide (DMF) solution for 10 minutes, add 5L 20% PIP / DMF solution after filtration, and stir at room temperature for 25 After filtering, the resin was washed three times with DMF, DCM and methanol, and dried under reduced pressure to obtain the preparation of H-Leu-Wang resin.
Embodiment 3
[0062] The preparation of embodiment 3Fmoc-Leu-2-Cl-Trt resin
[0063] Take 500g of 2-Cl-Trt-Cl resin (substitution value 1.0mmol / g), swell with 5LN, N-dimethylamide (DMF) for 30 minutes, add 353g (1.0mol) of Fmoc-Leu-OH, and stir Add 260ml DIEA (1.5mol) after 30 minutes, stir at room temperature for 3 hours, filter and wash the resin 3 times with DMF, DCM, methanol, and dry under reduced pressure to obtain 655g of Fmoc-Leu-2-Cl-Trt resin, esterification Yield 98.1%.
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
PUM
Property
Measurement
Unit
specific rotation
aaaaa
aaaaa
Login to view more
Abstract
The invention belongs to the technical field of polypeptide medicament preparation methods, and in particular relates to a preparation method for bivalirudin. The preparation method for the bivalirudin comprises solid phase polypeptide synthesis for preparing bivalirudin resin, acid hydrolysis of the bivalirudin resin to obtain a crude bivalirudin product, and purification of the crude bivalirudin product to obtain a purified bivalirudin product, wherein the solid phase polypeptide synthesis for preparing the bivalirudin resin comprises the following steps of: sequentially connecting corresponding Fmoc- protected amino acids in the following sequences to Fmoc-Leu-carrier resin by a solid phase coupling synthesis method: R1-D-Phe-Pro-Arg(Pbf)-Pro-X-Asn(R2)-Gly-Asp(OtBu)-, Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)- and Tyr(tBu)-Leu-resin, and thus obtaining the bivalirudin resin; and when the X fragment is connected, only one times of solid phase coupling synthesis reaction is used, and the corresponding Fmoc- protected amino acid is Fmoc-Gly-Gly-Gly-Gly-OH. The purity of the bivalirudin is more than 99.5 percent, and the single impurity is less than 0.2 percent.
Description
technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a preparation method of bivalirudin. Background technique [0002] Bivalirudin is a direct thrombin inhibitor (DTI), consisting of 20 amino acid residues. Direct thrombin inhibitors (DTI) are a group of polypeptides that directly inhibit thrombin activity without the participation of cofactors. They not only have anticoagulant function, but also inhibit platelet aggregation. Compared with other anticoagulant drugs, its pharmacological action and pharmacokinetic characteristics are superior, especially in cardiovascular diseases. [0003] Bivalirudin is a hirudin derivative (fragment), an artificially synthesized polypeptide containing 20 amino acid residues. It is mainly composed of two parts, one part is a short peptide chain at the amino terminal (N-terminal), containing a phenylalanine-proline-arginine-proline sequence, which can specifically bin...
Claims
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.
Login to view more