CN109879938B - Preparation method of ganirelix acetate - Google Patents
Preparation method of ganirelix acetate Download PDFInfo
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Abstract
The application relates to the field of medicine synthesis, and relates to a preparation method of ganirelix acetate, which comprises the steps of carrying out salt conversion on ganirelix crude peptide by utilizing a chromatography method and then purifying to obtain ganirelix acetate, wherein only an acetic acid aqueous solution and an acetic acid acetonitrile solution system are adopted as eluent in the whole process, the purity of the obtained ganirelix acetate reaches 99.82%, the maximum single impurity content is only 0.04%, no trifluoroacetic acid residue exists completely, no extra ions are introduced in the process, and the operation is simple and suitable for industrial production.
Description
Technical Field
The application relates to the field of drug synthesis, in particular to a preparation method of ganirelix acetate.
Background
Ganirelix acetate (Ganirelix Acetate), a decapeptide compound, is a gonadotrophin releasing hormone (GNRH) antagonist for the treatment of fertility disorders, and has the structural formula:
the size of the ganirelix acetate preparation is smaller and is 0.25mg/0.5ml, the yield is not required to be large, but a large amount of impurities are easy to generate in the ganirelix acetate preparation process, particularly the isomer impurities with quite similar structures are difficult to remove, and the purification process is difficult, so that the maximum single impurity is controlled at a very low level and the overall purity is difficult to improve.
The preparation method of ganirelix acetate disclosed in the prior art generally comprises the steps of obtaining ganirelix resin through one-by-one extension coupling by a solid phase synthesis method, obtaining ganirelix crude peptide through acid (such as trifluoroacetic acid) cleavage, and then purifying and converting salt to obtain ganirelix acetate. For example, CN107056894a discloses that ganirelix crude peptide is purified to produce ganirelix acetate with a purity of 99.7% by salt transfer (purified mobile phase: 0.1% tfa/aqueous solution-0.1% tfa/acetonitrile solution, salt transfer mobile phase: 1% acetic acid/aqueous solution-acetonitrile) with a maximum single impurity of less than 0.1%. CN102993274a discloses that the ganirelix crude peptide is purified in mobile phase with different concentration by a salt transfer step (purification mobile phase: sodium perchlorate solution (pH adjusted with phosphoric acid) -acetonitrile, salt transfer mobile phase: acetic acid solution-acetonitrile) to obtain a product with the highest purity of 99.73%, and single impurity is less than 0.1%, and the method uses sodium perchlorate solution which is not suitable for use in industrial mass production process, and many problems occur when the perchlorate system is introduced into industry for purification: firstly, sodium perchlorate is unstable and is inflammable and explosive and toxic, secondly, the mobile phase needs phosphoric acid to adjust the pH value, filtering and other operations, and after purification, the sodium ions, phosphate ions and perchlorate ions are needed to be desalted, and the subsequent treatment procedures are added, so that the inspection requirement on finished products is also improved, and the method is not suitable for industrial mass production.
Disclosure of Invention
In one aspect, the present application provides a method for preparing ganirelix acetate, comprising the following steps:
1) The method comprises the steps of (1) treating ganirelix crude peptide by a chromatographic method to obtain ganirelix acetate, wherein a stationary phase used by the chromatographic method is alkylsilane bonded silica gel, and a mobile phase used by the chromatographic method consists of a mixed system of a mobile phase A and a mobile phase B, and the elution mode is gradient elution;
2) Purifying the ganirelix acetate obtained in the step 1) by a chromatographic method, wherein a stationary phase used by the chromatographic method is alkylsilane bonded silica gel, and a mobile phase used by the chromatographic method consists of a mixed system of a mobile phase C and a mobile phase D, and the elution mode is gradient elution;
wherein the mobile phase A in the step 1) is a mixed solvent of acetic acid and water, and the volume ratio of the acetic acid to the water is 1.0-5.0:100, preferably 1.2-4.0:100, more preferably 1.5-3:100, further preferably 1.5-2.0:100, and most preferably 2.0:100;
wherein the mobile phase B of the step 1) is a mixed solvent of acetic acid and acetonitrile, and the volume ratio of the acetic acid to the acetonitrile is 1.0-5.0:100, preferably 1.2-4.0:100, more preferably 1.5-3:100, further preferably 1.5-2.0:100, and most preferably 2.0:100;
wherein the mobile phase C in the step 2) is a mixed solvent of acetic acid and water, and the volume ratio of the acetic acid to the water is 1.0-4.0:100, preferably 1.1-3.5:100, more preferably 1.2-3.0:100, further preferably 1.3-2.0:100, and most preferably 1.5:100;
wherein the mobile phase D in the step 2) is a mixed solvent of acetic acid and acetonitrile, and the volume ratio of the acetic acid to the acetonitrile is 1.0-4.0:100, preferably 1.1-3.5:100, more preferably 1.2-3.0:100, further preferably 1.3-2.0:100, and most preferably 1.5:100.
In some embodiments of the present application, the ganirelix crude peptide is a trifluoroacetic acid-containing ganirelix crude peptide.
In some embodiments of the present application, the crude ganirelix peptide is obtained by cleavage of a ganirelix peptide resin with trifluoroacetic acid.
In some embodiments of the present application, the ganirelix peptide resin is prepared by Fmoc solid phase synthesis using an amino resin as a solid phase carrier.
In some embodiments of the present application, the alkylsilane-bonded silica gel in step 1) is an octaalkylsilane-bonded silica gel or an octadecylsilane-bonded silica gel, preferably an octadecylsilane-bonded silica gel.
In some embodiments of the present application, the volume ratio of mobile phase a to mobile phase B during the gradient elution of step 1) varies from 95:5 to 20:80.
It will be appreciated that the volume ratio of mobile phase a to mobile phase B varies from 95:5 to 20:80, meaning that the volume percentage of mobile phase a in the mobile phase is progressively reduced in the variation.
In some embodiments of the present application, the eluting of step 1) is performed by a sequence of steps comprising:
i) Eluting by using a mobile phase composed of a mixed system of a mobile phase A and a mobile phase B, wherein the volume ratio of the mobile phase A to the mobile phase B is 95:5;
ii) eluting with a mobile phase comprising a mixed system of mobile phase A and mobile phase B, wherein the volume ratio of mobile phase A to mobile phase B is 80:20.
In some embodiments of the present application, the flow rate of the mobile phase in step 1), step i) or step ii) is 2.0L/min.
In some embodiments of the present application, the elution time of step i) is 400 to 1000 minutes, preferably 500 to 800 minutes, most preferably 600 minutes.
In some embodiments of the present application, the ganirelix crude peptide of step 1) is chromatographically processed to yield ganirelix acetate in the form of a ganirelix crude peptide solution prepared by dissolving the ganirelix crude peptide in a mixed solvent of water and acetic acid.
In some embodiments of the present application, the volumetric ratio of acetic acid to water in the ganirelix crude peptide solution is 0.2 to 3:1, preferably 0.5 to 2:1, more preferably 1:1.
In some embodiments of the present application, the ratio of the volume of the mixed solvent to the mass of the ganirelix crude peptide in terms of mL and g is 1 to 50:1, preferably 2 to 20:1, more preferably 3 to 10:1, and most preferably 6.4:1.
In some embodiments of the present application, step 1) comprises loading the crude ganirelix peptide solution into a chromatographic column prior to elution, wherein the flow rate of the solution at loading can be selected as desired, e.g., the flow rate of the solution at loading is 0.2L/min.
In some embodiments of the present application, the ganirelix crude peptide solution is filtered through a 0.45 μm filter membrane; specifically, the ganirelix crude peptide solution was filtered through a 0.45 μm filter before loading onto a chromatographic column.
In some embodiments of the present application, step 1) comprises a step of equilibration of the chromatographic column prior to elution, the equilibration using a mobile phase consisting of a mixed system of mobile phase a and mobile phase B, wherein the volume ratio of mobile phase a to mobile phase B is 95:5; specifically, the step 1) of balancing the chromatographic column before elution means that the chromatographic column is balanced before loading the ganirelix crude peptide solution into the chromatographic column; specifically, the flow rate of the mobile phase at equilibrium may be selected as desired, for example, the flow rate of the mobile phase at equilibrium is 2.0L/min.
In some embodiments of the present application, the elution time of step i) is 20 to 100 minutes, preferably 30 to 60 minutes, most preferably 50 minutes.
In some embodiments of the present application, the step 1) further comprises a step of concentrating the resulting eluent comprising ganirelix acetate; the concentration may be performed under reduced pressure, for example, the vacuum degree at reduced pressure may be-0.10 to-0.06 Mpa; the concentration can be carried out at a proper temperature according to the requirement, for example, the temperature during concentration is 37.5+/-2.5 ℃; the concentrating step may be concentrating the eluent comprising ganirelix acetate to less than 25% of the original weight.
In some embodiments of the present application, the alkylsilane-bonded silica gel in step 2) is an octaalkylsilane-bonded silica gel or an octadecylsilane-bonded silica gel, preferably an octadecylsilane-bonded silica gel.
In some embodiments of the present application, the volume ratio of mobile phase C to mobile phase D during the gradient elution of step 2) varies from 85:15 to 65:35.
It will be appreciated that the volume ratio of mobile phase C to mobile phase D varies from 85:15 to 65:35, meaning that the volume percentage of mobile phase C in mobile phase is progressively reduced in the variation.
In some embodiments of the present application, the elution mode of step 2) is performed by the sequence of the following steps:
a) Eluting by using a mobile phase composed of a mixed system of a mobile phase C and a mobile phase D, wherein the volume ratio of the mobile phase C to the mobile phase D is 85:15;
b) Eluting by using a mobile phase composed of a mixed system of a mobile phase C and a mobile phase D, wherein the volume ratio of the mobile phase C to the mobile phase D is 75:25;
c) Elution was performed using a mobile phase consisting of a mixed system of mobile phase C and mobile phase D, wherein the volume ratio of mobile phase C to mobile phase D was 65:35.
In some embodiments of the present application, the flow rate of the mobile phase in step 2), step a), step b) or step c) is 2.0L/min.
In some embodiments of the present application, the elution time of step a) is 10 to 60 minutes, preferably 20 to 30 minutes, most preferably 25 minutes.
In some embodiments of the present application, the elution time of step b) is 10 to 120 minutes, preferably 30 to 60 minutes, most preferably 45 minutes.
In some embodiments of the present application, the elution time of step c) is 10 to 120 minutes, preferably 30 to 60 minutes, most preferably 40 minutes.
In some embodiments of the present application, the elution mode of step 2) is as follows:
in some embodiments of the present application, step 2) comprises loading the ganirelix acetate solution obtained in step 1) into a chromatographic column prior to elution, wherein the flow rate of the solution at loading can be selected as desired, e.g. the flow rate of the solution at loading is 0.5L/min.
In some embodiments of the present application, step 2) comprises a step of equilibration of the chromatographic column prior to elution, the equilibration using a mobile phase consisting of a mixed system of mobile phase C and mobile phase D, wherein the volume ratio of mobile phase C to mobile phase D is 95:5; specifically, the step 1) of balancing the chromatographic column before elution means that the chromatographic column is balanced before loading the ganirelix crude peptide solution into the chromatographic column; specifically, the flow rate of the mobile phase at equilibrium may be selected as desired, for example, the flow rate of the mobile phase at equilibrium is 2.0L/min.
In some embodiments of the present application, the elution time of step i) is 10 to 120 minutes, preferably 30 to 80 minutes, most preferably 50 minutes.
In some embodiments of the present application, the step 2) further comprises a step of concentrating the resulting eluent comprising ganirelix acetate; the concentration may be performed under reduced pressure, for example, the vacuum degree at reduced pressure may be-0.10 to-0.06 Mpa; the concentration can be carried out at a proper temperature according to the requirement, for example, the temperature during concentration is 37.5+/-2.5 ℃; the concentrating step may be concentrating the eluent comprising ganirelix acetate to less than 85% of the original weight.
In some embodiments of the present application, the step 2) further comprises a step of lyophilizing the resulting eluent comprising ganirelix acetate; specifically, the step of lyophilization is performed after concentrating the resulting eluent comprising ganirelix acetate.
In some embodiments of the present application, the single impurity content of ganirelix acetate obtained in step 2) is not more than 0.05%, preferably not more than 0.04%; in some embodiments of the present application, the single impurity content of ganirelix acetate obtained in step 2) is 0.04%.
In some embodiments of the present application, the purity of ganirelix acetate obtained in step 2) is not less than 99.8%, preferably not less than 99.82%; in some embodiments of the present application, the ganirelix acetate obtained in step 2) has a purity of 99.82%.
In some embodiments of the present application, the ganirelix acetate obtained in step 2) does not contain trifluoroacetic acid.
In another aspect, it is an object of the present application to provide a pharmaceutical composition comprising ganirelix acetate, wherein the single impurity content of the composition is not more than 0.05%, and the content of ganirelix acetate is not less than 99.8%.
In some embodiments of the present application, the ganirelix acetate of the composition is prepared by a method of preparing ganirelix acetate as previously described.
In some embodiments of the present application, the composition further comprises a pharmaceutically acceptable excipient.
In some embodiments of the present application, the single impurity content of the composition is no greater than 0.04%, and in some embodiments of the present application, the single impurity content of the composition is 0.04%.
In some embodiments of the present application, the composition does not contain trifluoroacetic acid.
In some embodiments of the present application, the composition has a ganirelix acetate content of not less than 99.82%, and in some embodiments of the present application, the composition has a ganirelix acetate content of 99.82%.
In a further aspect, the object of the present application is to provide the use of a pharmaceutical composition comprising ganirelix acetate as described above for the preparation of a medicament for the treatment and/or prevention of gonadotropin releasing hormone mediated disorders selected from disorders related to fertility disorders. In a further aspect, the object of the present application is to provide a method for the treatment or prophylaxis of a gonadotropin releasing hormone mediated disorder selected from the group consisting of disorders associated with fertility, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a pharmaceutical composition of ganirelix acetate as described hereinbefore.
The term "pharmaceutically acceptable adjuvant" refers to any agent or carrier or medium capable of delivering an effective amount of the active substance of the present application, which does not interfere with the biological activity of the active substance and which does not have toxic or side effects to the host or patient. Representative carriers include water, oils, and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancing agents, transdermal enhancers, and the like. Their agents are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, disease state, or condition, (ii) reduces, ameliorates, or eliminates one or more symptoms of the particular disease, disease state, or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, disease state, or condition described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state or condition, and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.
Compared with the prior art, the method has the advantages that the ganirelix crude peptide is subjected to salt conversion and then purified by adopting the chromatography to obtain ganirelix acetate, the whole process only adopts an acetic acid aqueous solution and acetic acid acetonitrile solution system as an eluent, the purity of the obtained ganirelix acetate reaches 99.82%, the maximum single impurity content is only 0.04%, no trifluoroacetic acid residue exists completely, no extra ions are introduced in the process, and the method is simple to operate and suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
The crude ganirelix peptide for trans-salification can be prepared by prior art methods, for example using an amino resin, solid phase synthesis using the corresponding Fmoc-AA to give a ganirelix peptide resin which is cleaved by TFA to give a solid crude ganirelix peptide. Fmoc-AA, fluorenylmethoxycarbonyl protected amino acid; TFA: trifluoroacetic acid.
V/V in the present application means a volume ratio, for example, 2% (V/V) of an aqueous acetic acid solution means a volume ratio of acetic acid to water in the aqueous acetic acid solution of 2:100, and further, as in mobile phase A: mobile phase b=95:5 (V/V) means that the mobile phase consists of a mixed system of mobile phase a and mobile phase B, wherein the volume ratio of mobile phase a and mobile phase B is 95:5.
Purity was measured using HPLC conditions: the column was packed with octadecylsilane chemically bonded silica (Thermo Scientific Acclaim, C18 (4.6X105 mm,5 um)) as a filler, as measured by high performance liquid chromatography (2015, china Pharmacopeia, general rule 0512).
EXAMPLE 1 preparation of ganirelix acetate solution
Mobile phase a:2% (V/V) aqueous acetic acid.
Mobile phase B:2% (V/V) acetonitrile acetate solution.
Chromatographic column: and the built-in reverse phase octadecylsilane chemically bonded silica is used as a filler.
Column balance: the flow rate was set at 2.0L/min, mobile phase A was selected to equilibrate for 50 minutes with mobile phase B=95:5 (V/V), and after equilibration was completed, the vessel was ready for use.
400mL of purified water and 400mL of glacial acetic acid are added into a beaker, after stirring uniformly, 125g of solid ganirelix crude peptide (obtained by cleavage of ganirelix resin by trifluoroacetic acid, HPLC purity 92.95%) is added, after ultrasonic dissolution, the mixture is filtered through a 0.45 μm filter membrane, the filtrate is collected, and after column equilibration, the flow rate is set to be 200mL/min for loading.
After the sample loading is finished, the detection wavelength is set to be 280nm, and the flow rate is 2.0L/min. Mobile phase a: mobile phase b=95:5 (V/V) for 600 minutes.
After the transformation is finished, the mobile phase A is used continuously: mobile phase b=20:80 (V/V) elution of the sample and collection of the eluent containing ganirelix acetate.
Transferring the collected eluent into a rotary evaporator, controlling the water bath temperature at 37.5+/-2.5 ℃ and the vacuum degree at-0.10 to-0.06 MPa, and concentrating under reduced pressure to less than 1/4 of the weight before concentration to obtain the ganirelix acetate solution.
Example 2 preparation of ganirelix acetate concentrate
Mobile phase a:1.5% (V/V) aqueous acetic acid.
Mobile phase B:1.5% (V/V) acetonitrile acetate solution.
Chromatographic column: and the built-in reverse phase octadecylsilane chemically bonded silica is used as a filler.
Column balance: the flow rate was set at 2.0L/min and mobile phase A, mobile phase B=85:15 (V/V) was chosen for 50 minutes and after the equilibration was completed, it was ready for use.
After column equilibration, the flow rate was set at 500mL/min and the ganirelix acetate solution prepared in example 1 was loaded.
After loading, the detection wavelength was set to 280nm, and the elution procedure was set according to the following table parameters:
monitoring and collecting target peak fraction eluent, transferring the eluent into a rotary evaporator, controlling the water bath temperature at 37.5+/-2.5 ℃ and the vacuum degree at-0.10 to-0.06 MPa, concentrating under reduced pressure to less than 0.85 times of the weight before concentration to obtain ganirelix acetate purified liquid, and freeze-drying the purified liquid to obtain 61.25g of ganirelix acetate refined product (HPLC purity is 99.82%, single impurity is 0.04% at maximum, and trifluoroacetic acid is completely free from residues).
Claims (5)
1. A method for preparing ganirelix acetate, comprising the following steps:
1) The method comprises the steps of (1) treating ganirelix crude peptide by a chromatographic method to obtain ganirelix acetate, wherein a stationary phase used by the chromatographic method is octadecylsilane chemically bonded silica gel, and a mobile phase used by the chromatographic method consists of a mixed system of a mobile phase A and a mobile phase B, and the elution mode is gradient elution; the volume ratio of mobile phase a to mobile phase B varies from 95:5 to 20:80; the flow rate of the mobile phase in the step 1) is 2.0L/min;
the step 1) comprises the step of balancing the chromatographic column before elution, wherein the balanced mobile phase consists of a mixed system of a mobile phase A and a mobile phase B, and the volume ratio of the mobile phase A to the mobile phase B is 95:5;
the ganirelix crude peptide of the step 1) is processed by chromatography in the form of a ganirelix crude peptide solution to obtain ganirelix acetate, wherein the ganirelix crude peptide solution is prepared by dissolving the ganirelix crude peptide in a mixed solvent of water and acetic acid, and the volume ratio of the acetic acid to the water is 1:1; in the ganirelix crude peptide solution, the ratio of the volume of the mixed solvent to the mass of the ganirelix crude peptide is 3-10:1 according to the ratio relationship of mL and g as units;
the step 1) is to load a ganirelix crude peptide solution into a chromatographic column before elution, and the flow rate of the solution is 0.2L/min during loading;
in the step 1), the ganirelix crude peptide solution is filtered through a 0.45 μm filter membrane before being loaded on a chromatographic column;
the elution mode of the step 1) is carried out by the sequence of the following steps:
i) Eluting by using a mobile phase composed of a mixed system of a mobile phase A and a mobile phase B, wherein the volume ratio of the mobile phase A to the mobile phase B is 95:5; the elution time of step i) is 600 minutes;
ii) eluting with a mobile phase comprising a mixed system of mobile phase A and mobile phase B, wherein the volume ratio of mobile phase A to mobile phase B is 20:80;
2) Purifying the ganirelix acetate obtained in the step 1) by a chromatographic method, wherein a stationary phase used by the chromatographic method is octadecylsilane chemically bonded silica, and a mobile phase used by the chromatographic method consists of a mixed system of a mobile phase C and a mobile phase D, and the elution mode is gradient elution; the volume ratio of mobile phase C to mobile phase D varies from 85:15 to 65:35; the flow rate of the mobile phase in the step 2) is 2.0L/min;
the step 2) comprises the step of balancing the chromatographic column before elution, wherein the balanced mobile phase consists of a mixed system of a mobile phase C and a mobile phase D, and the volume ratio of the mobile phase C to the mobile phase D is 95:5;
the step 2) is to load the ganirelix acetate solution obtained in the step 1) into a chromatographic column before elution, and the flow rate of the solution during loading is 0.5L/min;
the elution mode of the step 2) is shown in the following table:
wherein the mobile phase A of the step 1) is a mixed solvent of acetic acid and water, and the volume ratio of the acetic acid to the water is 2.0:100;
wherein the mobile phase B of the step 1) is a mixed solvent of acetic acid and acetonitrile, and the volume ratio of the acetic acid to the acetonitrile is 2.0:100;
wherein the mobile phase C in the step 2) is a mixed solvent of acetic acid and water, and the volume ratio of the acetic acid to the water is 1.5:100;
wherein the mobile phase D of the step 2) is a mixed solvent of acetic acid and acetonitrile, the volume ratio of the acetic acid to the acetonitrile is 1.5:100, and the ganirelix crude peptide is a ganirelix crude peptide containing trifluoroacetic acid; the ganirelix crude peptide is obtained by cracking ganirelix peptide resin by trifluoroacetic acid;
the single impurity content of the ganirelix acetate obtained in the step 2) is not more than 0.04%, the content of the ganirelix acetate is not less than 99.8%, and the obtained ganirelix acetate does not contain trifluoroacetic acid.
2. The process according to claim 1, wherein the ratio of the volume of the mixed solvent to the mass of the ganirelix crude peptide in terms of mL and g is 6.4:1 in the ganirelix crude peptide solution of step 1).
3. The method of claim 1, wherein the step 2) further comprises the step of lyophilizing the resulting eluent containing ganirelix acetate.
4. A method of preparation according to claim 3, wherein the step of lyophilizing is performed after concentrating the resulting eluent comprising ganirelix acetate.
5. The process of claim 1, wherein the ganirelix acetate obtained in step 2) has a single impurity content of 0.04%.
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| CN102584945A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Preparation method for ganirelix acetate |
| CN102993274A (en) * | 2012-11-30 | 2013-03-27 | 深圳翰宇药业股份有限公司 | Purification method of ganirelix acetate |
| EP3156413A1 (en) * | 2013-06-18 | 2017-04-19 | Hybio Pharmaceutical Co., Ltd | Ganirelix precursor and method for preparing ganirelix acetate by using anirelix precursor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102584945A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Preparation method for ganirelix acetate |
| CN102993274A (en) * | 2012-11-30 | 2013-03-27 | 深圳翰宇药业股份有限公司 | Purification method of ganirelix acetate |
| EP3156413A1 (en) * | 2013-06-18 | 2017-04-19 | Hybio Pharmaceutical Co., Ltd | Ganirelix precursor and method for preparing ganirelix acetate by using anirelix precursor |
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