+

WO2018177055A1 - Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y - Google Patents

Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y Download PDF

Info

Publication number
WO2018177055A1
WO2018177055A1 PCT/CN2018/077229 CN2018077229W WO2018177055A1 WO 2018177055 A1 WO2018177055 A1 WO 2018177055A1 CN 2018077229 W CN2018077229 W CN 2018077229W WO 2018177055 A1 WO2018177055 A1 WO 2018177055A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carboxylic acid
acid derivative
hydrophilic polymer
substituted
Prior art date
Application number
PCT/CN2018/077229
Other languages
English (en)
Chinese (zh)
Inventor
陈晓萌
林美娜
张如军
赵宣
Original Assignee
北京键凯科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201710915311.4A external-priority patent/CN108659227B/zh
Application filed by 北京键凯科技股份有限公司 filed Critical 北京键凯科技股份有限公司
Priority to EP18775559.0A priority Critical patent/EP3604388B1/fr
Publication of WO2018177055A1 publication Critical patent/WO2018177055A1/fr
Priority to US16/588,620 priority patent/US11359089B2/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment

Definitions

  • the invention relates to the technical field of polymers, in particular to a method for preparing a Y-branched hydrophilic polymer carboxylic acid derivative, in particular to a high-purity high molecular weight Y-branched polyethylene glycol carboxylic acid derivative. Preparation.
  • PEG Polyethylene glycol
  • Y-type polyethylene glycol is a widely used polyethylene glycol, which can significantly reduce the loss of activity of modified drugs, especially in improving the clinical application of protein and peptide drugs. It prevents the antibody from approaching the protein drug, thereby greatly increasing the circulating half-life of the protein drug in the body while greatly reducing its immunogenicity in vivo.
  • the terminal group of the Y-type PEG when the terminal group of the Y-type PEG is a carboxyl group, it can react with an amino group, a hydroxyl group or a thiol group on a modified drug or other compound to form a covalent bond to realize a modified linkage, and is a commonly used Y-type PEG derivative.
  • the preparation method thereof is as described in the patent CN1243779C.
  • the adsorption strength of the above three compounds on the column is ranked as mPEG- Cm, mPEG-gly, Y-cm.
  • the above preparation reaction product includes the target product Y-cm and the unreacted reactants mPEG-gly and mPEG-cm.
  • mPEG-gly greatly interferes with the separation, so that the purity of the target product is The yield is lowered.
  • the yield of the Y-type PEG product is low, only 50%, the product separation is difficult, and the cost is high, which is not favorable for industrial amplification.
  • the present invention provides a process for the preparation of a Y-branched hydrophilic polymeric carboxylic acid derivative.
  • the method includes the following reaction:
  • P a and P b are the same or different hydrophilic polymer residues
  • X 1 and X 3 are a linking group independently selected from: -(CH 2 ) i -, a combination of one or more of -(CH 2 ) i O-, -(CH 2 ) i S- and -(CH 2 ) i CO-, i is an integer from 0 to 10,
  • X 2 is a linking group, chosen from :-( CH 2) r -, - (CH 2) r O -, - (CH 2) r S- , and a combination of one or more of the following, r is an integer from 0 to 10,
  • F is a terminal group selected from: substituted or unsubstituted C 1-6 alkyl, C 1-6 substituted or unsubstituted alkoxy group,
  • R 1 and R 2 are independently selected from: -H, C 1-6 substituted or unsubstituted alkyl, C 1-6 substituted or unsubstituted alkoxy, C 3-6 substituted or unsubstituted cycloalkyl And a C 4-10 substituted or unsubstituted alkylene cycloalkyl group,
  • R 3 is selected from the group consisting of: -H, a C 1-6 substituted or unsubstituted alkyl group, a C 6-10 substituted or unsubstituted aralkyl group, and a C 4-10 substituted or unsubstituted heterocycloalkyl group,
  • the above preparation method is more suitable for preparing a higher molecular weight Y-branched hydrophilic polymer carboxylic acid derivative, and the reaction yield and product purity are higher, and separation is easier.
  • the Y-branched hydrophilic polymer carboxylic acid derivative may have a molecular weight of 15 to 50 KDa (specifically 15, 16, 16, 20, 22, 24, 26, 28) , 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50 KDa).
  • the anhydride is an organic acid anhydride.
  • the organic acid anhydride is selected from the group consisting of: di-tert-butyl dicarbonate (Boc anhydride), acetic anhydride, propionic anhydride, isobutyric anhydride, butyric anhydride, benzoic anhydride, and phthalic anhydride. One or more of them.
  • the anhydride is a Boc anhydride.
  • the anhydride and reactant The molar ratio of the added amount is 0.01-10:1 (specifically, 0.01:1, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1) , 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2.0:1, 3.0:1, 4.0:1, 5.0:1, 6.0:1, 7.0 : 1, 8.0: 1, 9.0: 1 or 10.0: 1).
  • the reaction time after addition of the anhydride is from 0.1 to 24 hours (specifically 0.1, 1, 2, 3, 4, 5, 10, 15, 20 or 24 hours).
  • the separating and purifying step comprises the step of separating and purifying using ion exchange chromatography.
  • the P a and P b are independently selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polytetrahydrofuran, polypropylene oxide, polybutylene oxide, polyoxygen A residue of a copolymer of one or more of a heterocyclic butane and a polypropylene morpholine.
  • the P a and/or P b are polyethylene glycol residues.
  • the P a is a polyethylene glycol residue having a structure of R a —O—(CH 2 CH 2 O) m —, and R a is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, m is an integer from 170 to 565.
  • said R a is selected from: H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and benzyl.
  • said R a is H or methyl.
  • the P a is a methoxypolyethylene glycol residue having the structure CH 3 O-(CH 2 CH 2 O) m -, and m is an integer from 170 to 565.
  • the P a may have a molecular weight of 7.5 to 25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) , 20, 21, 22, 23, 24 or 25KDa).
  • the P b is a polyethylene glycol residue having a structure of R b —O—(CH 2 CH 2 O) n —, and R b is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, n being an integer from 170 to 565.
  • the R b is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.
  • said R b is H or methyl.
  • the molecular weight of P b may be 7.5-25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24 or 25KDa).
  • the m and n are equal integers.
  • the Y-branched hydrophilic polymeric carboxylic acid derivative is a Y-branched polyethylene glycol carboxylic acid derivative.
  • the X 1 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 -, - CH (CH 3) -, - CH 2 CH (CH 3) -, - CH 2 CH 2 CH (CH 3) -, - CH 2 CH 2 CH (CH 3) -, - CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) i O- And a combination of one or more of -(CH 2 ) i CO-, i is an integer from 0 to 5 (eg, 0, 1, 2, 3, 4 or 5).
  • said X 1 is -CH 2 CH 2 -.
  • the X 3 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, - CH (CH 3) -, - CH 2 CH (CH 3) -, - CH 2 CH 2 CH (CH 3) -, - CH 2 CH 2 CH (CH 3) -, - CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) i O- And a combination of one or more of -(CH 2 ) i CO-, i is an integer from 0 to 5 (eg, 0, 1, 2, 3, 4 or 5).
  • said X 3 is -CH 2 -.
  • the X 2 is
  • the R 3 is selected from the group consisting of: -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 SCH 3 -, -CH 2 OH, -CH 2 SH, -CH(OH)CH 3 , -CH 2 COOH and -CH 2 CH 2 COOH.
  • the X 2 is -CH 2 - or -CH(CH 3 )-.
  • the F is selected from the group consisting of: methoxy, ethoxy,
  • the F is
  • reaction of the preparation method is:
  • Another aspect of the present invention provides a Y-branched hydrophilic polymer carboxylic acid derivative prepared by the above method, which has the following structure:
  • P a , P b , X 1 , X 2 and X 3 have the above definitions of the present invention.
  • the carboxylic acid derivative has a molecular weight of 15-50 KDa (specifically 15, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50KDa).
  • the P a and P b are independently selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polytetrahydrofuran, polypropylene oxide, polybutylene oxide, polyoxygen A residue of a copolymer of one or more of a heterocyclic butane and a polypropylene morpholine.
  • the P a and/or P b are polyethylene glycol residues.
  • the P a is a polyethylene glycol residue having a structure of R a —O—(CH 2 CH 2 O) m —, and R a is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, m is an integer from 170 to 565.
  • said R a is selected from: H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and benzyl.
  • said R a is H or methyl.
  • the P a is a methoxypolyethylene glycol residue having the structure CH 3 O-(CH 2 CH 2 O) m -, and m is an integer from 170 to 565.
  • the P a has a molecular weight of 7.5 to 25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25KDa).
  • the P b is a polyethylene glycol residue having a structure of R b —O—(CH 2 CH 2 O) n —, and R b is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, n being an integer from 170 to 565.
  • the R b is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.
  • said R b is H or methyl.
  • the P b is a methoxypolyethylene glycol residue having the structure CH 3 O-(CH 2 CH 2 O) n -, n being an integer from 170 to 565.
  • the molecular weight of P b may be 7.5-25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24 or 25KDa).
  • the Y-branched hydrophilic polymer carboxylic acid derivative is a Y-branched polyethylene glycol carboxylic acid derivative having the following structure:
  • the X 1 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) i O- and - i CO- combination of one or more of (2 CH), i is an integer (e.g., 3, 4 or 5) 0-5.
  • said X 1 is -CH 2 CH 2 -.
  • the X 3 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - , -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) i O- And a combination of one or more of -(CH 2 ) i CO-, i is an integer from 0 to 5 (eg, 0, 1, 2, 3, 4 or 5).
  • said X 3 is -CH 2 -.
  • the X 2 is
  • the carboxylic acid derivative has the structure:
  • the R 3 is selected from the group consisting of: -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 SCH 3 -, -CH 2 OH, -CH 2 SH, -CH(OH)CH 3 , -CH 2 COOH and -CH 2 CH 2 COOH.
  • said R 3 is -H or -CH 3 .
  • the m and n are equal integers.
  • Another aspect of the present invention also provides a Y-branched hydrophilic polymer derivative derived from the above carboxylic acid, which has the following structure:
  • X 4 is a linking group selected from the group consisting of: -(CH 2 ) j -, -(CH 2 ) j O-, -(CH 2 ) j S-, -(CH 2 ) j CO-, -(CH 2 ) a combination of one or more of j NH-, -(CH 2 ) j CONH- and -(CH 2 ) j NHCO-, j is an integer from 0 to 10,
  • Q is a terminal group selected from: C 1-6 alkoxy, hydroxy, amino, carboxy, thiol, ester, keto, aldehyde, o-dithiopyridyl, azide, hydrazide, alkynyl , silyl, maleimide and succinimide groups.
  • the derivative may have a molecular weight of 15-50 KDa (specifically 15, 16, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50 KDa).
  • the P a and P b are independently selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polytetrahydrofuran, polypropylene oxide, polybutylene oxide, polyoxygen A residue of a copolymer of one or more of a heterocyclic butane and a polypropylene morpholine.
  • the P a and/or P b are polyethylene glycol residues.
  • the P a is a polyethylene glycol residue having a structure of R a —O—(CH 2 CH 2 O) m —, and R a is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, m is an integer from 170 to 565.
  • said R a is selected from: H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and benzyl.
  • said R a is H or methyl.
  • the P a is a methoxypolyethylene glycol residue having the structure CH 3 O-(CH 2 CH 2 O) m -, and m is an integer from 170 to 565.
  • the P a has a molecular weight of 7.5 to 25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25KDa).
  • the P b is a polyethylene glycol residue having a structure of R b —O—(CH 2 CH 2 O) n —, and R b is selected from the group consisting of: H, C 1- 6 alkyl, C 3-6 cycloalkyl and C 6-10 cycloalkyl, n being an integer from 170 to 565.
  • the R b is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.
  • said R b is H or methyl.
  • the molecular weight of P b may be 7.5-25 KDa (specifically, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24 or 25KDa).
  • the Y-branched hydrophilic polymer derivative is a Y-branched polyethylene glycol derivative having the following structure:
  • the X 4 is selected from: a single bond, -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -(CH 2 ) j CO-, -(CH 2 ) j NH-, -(CH 2 ) j CONH- and -(CH 2 ) j NHCO-
  • j is an integer from 0 to 5 (eg, 0, 1, 2, 3, 4, or 5).
  • the X 4 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 NH -, - CH 2 CH 2 CH 2 NH -, - CH 2 CONH -, - CH 2 CH 2 CONH- , and combinations -CH 2 CH 2 CH 2 CONH- of one or more.
  • the Q is selected from the group consisting of: -OH, -SH, -NH 2 , -COOH, -CHO, And -N 3 .
  • the Y-branched hydrophilic polymer derivative has the following structure:
  • the R 3 is selected from the group consisting of: -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 SCH 3 -, -CH 2 OH, -CH 2 SH, -CH(OH)CH 3 , -CH 2 COOH and -CH 2 CH 2 COOH.
  • said R 3 is -H or -CH 3 .
  • the m and n are equal integers.
  • Another aspect of the present invention provides a process for producing the above Y-branched hydrophilic polymer derivative, which comprises the steps of the preparation method of the above Y-branched hydrophilic polymer carboxylic acid derivative.
  • Another aspect of the present invention provides a use of the above Y-branched hydrophilic polymer carboxylic acid derivative, Y-branched hydrophilic polymer derivative in a modified drug.
  • Another aspect of the present invention provides a combination of the above Y-branched hydrophilic polymer carboxylic acid derivative, Y-branched hydrophilic polymer derivative and a drug of the present invention.
  • the drug is selected from the group consisting of amino acids, polypeptides, proteins, sugars, organic acids, alkaloids, flavonoids, terpenoids, terpenoids, phenylpropanoid phenols, steroids, and steroids. drug.
  • Another aspect of the present invention provides a method for producing the above-mentioned Y-branched hydrophilic polymer carboxylic acid derivative of the present invention, in the pharmaceutical composition for preparing the above-mentioned Y-branched hydrophilic polymer carboxylic acid derivative application.
  • Another aspect of the present invention provides a method for preparing the above-mentioned Y-branched hydrophilic polymer carboxylic acid derivative of the present invention, in the preparation of the above Y-branched hydrophilic polymer derivative, and a pharmaceutical combination thereof .
  • Another aspect of the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above combination of the invention and, optionally, a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the present invention provides a Y-branched hydrophilic polymer carboxylic acid derivative, a Y-branched polyethylene glycol derivative, and a pharmaceutical conjugate thereof and a pharmaceutical composition thereof, in the preparation of a therapeutic disease The application of the drug.
  • the preparation method of the Y-branched hydrophilic polymer carboxylic acid derivative (especially the high-purity high molecular weight Y-branched polyethylene glycol carboxylic acid derivative) provided by the invention has simple preparation steps but the product after the reaction The separation is easy, the separation cost is low, the product purity and the yield are high, and the preparation of other derivatives based on the preparation of the carboxylic acid derivative and the drug combination thereof is facilitated, which is advantageous for industrial amplification and commercial application.
  • the prepared Y-branched hydrophilic polymer carboxylic acid derivative (especially the high molecular weight Y-branched polyethylene glycol carboxylic acid derivative) has high purity and high commercial value, especially in the preparation of prevention and/or Or the application of drugs for the treatment of diseases.
  • Figure 1 is a GFC chromatogram of the crude product before column separation provided in Example 1 of the present invention.
  • Example 2 is a chromatogram of a collection starting point GFC provided in Example 1 of the present invention.
  • Fig. 3 is a view showing a peak point GFC chromatogram provided in Example 1 of the present invention.
  • Example 4 is a GFC chromatogram of the post-column product provided in Example 1 of the present invention.
  • Fig. 5 is a GFC chromatogram of the crude product before column separation according to Example 2 of the present invention.
  • Figure 6 is a chromatogram of the collection starting point GFC provided in Example 2 of the present invention.
  • Fig. 7 is a view showing a peak point GFC chromatogram provided in Example 2 of the present invention.
  • Figure 8 is a GFC chromatogram of the post-column product provided in Example 2 of the present invention.
  • Figure 9 is a GFC chromatogram of the pre-column crude product provided in Example 3 of the present invention.
  • Figure 10 is a chromatogram of the collection starting point GFC provided in Example 3 of the present invention.
  • Figure 11 is a view showing a peak point GFC chromatogram provided in Example 3 of the present invention.
  • Figure 12 is a GFC chromatogram of the post-column product provided in Example 3 of the present invention.
  • Figure 13 is a GFC chromatogram of the crude product before column separation according to Example 4 of the present invention.
  • Figure 14 is a chromatogram of the collection starting point GFC provided in Example 4 of the present invention.
  • Figure 15 is a view showing a peak point GFC chromatogram provided in Example 4 of the present invention.
  • Figure 16 is a GFC chromatogram of the post-column product provided in Example 4 of the present invention.
  • Figure 17 is a GFC chromatogram of the pre-column crude product provided in Example 5 of the present invention.
  • Figure 18 is a chromatogram of the collection starting point GFC provided in Example 5 of the present invention.
  • Fig. 19 is a view showing a peak point GFC chromatogram provided in Example 5 of the present invention.
  • Figure 20 is a GFC chromatogram of the post-column product provided in Example 5 of the present invention.
  • Alkyl refers to a hydrocarbon chain radical that is linear or branched and free of unsaturated bonds, and which is attached to the rest of the molecule by a single bond.
  • the C1-C6 alkyl group means an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, iso Amyl, neopentyl, tert-amyl, n-hexyl, isohexyl and the like.
  • alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl” radical such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. .
  • cycloalkylalkyl such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.
  • an aryl group it is correspondingly an "aralkyl” radical such as benzyl, benzhydryl or phenethyl.
  • heterocyclic group it is correspondingly a "heterocyclylalkyl” radical.
  • alkoxy means a substituent formed by substituting a hydrogen in a hydroxy group with an alkyl group
  • alkoxy group of C1-C6 means an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group or an ethoxy group. , propoxy, butoxy, and the like.
  • Cycloalkyl means an alicyclic hydrocarbon such as containing from 1 to 4 monocyclic and/or fused rings containing from 3 to 18 carbon atoms, preferably from 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl or Adamantyl and the like
  • the C3-C6 cycloalkyl group in the present invention means a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • a “substituted” group as used in the present invention refers to a group substituted at one or more of the available sites by one or more suitable groups, specifically, for example, a substituted alkyl group, which refers to an alkyl group.
  • One or more hydrogens are substituted by one or more suitable groups such as an alkyl group (e.g., a C1-6 alkyl group, particularly a C1-3 alkyl group such as a methyl group, an ethyl group).
  • alkoxy such as C1-6 alkoxy, especially C1-3 alkoxy, such as methoxy, ethoxy or propoxy
  • alkenyl such as An alkenyl group of C1-6, especially an alkenyl group of C1-3, such as a vinyl group, an alkynyl group (such as an alkynyl group of C1-6, especially an alkynyl group of C1-3, such as a propynyl group), a cycloalkyl group (such as a cycloalkyl group of C3-6, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), an aryl group (such as an aryl group of C6-12, especially a phenyl group), an aryloxy group (such as benzene) An oxy), an alkylaryl group (such as a benzyl group), a heterocyclic group (such as a heterocycl
  • some specific groups and chemical structures involved in the present invention correspond to the following: hydroxyl group, -OH; amino group, -NH 2 ; carboxyl group, Sulfhydryl, -SH; ester group, (wherein Q 1 may be an alkyl group, an aryl group or a heterocyclic group such as methyl, ethyl, n-propyl, t-butyl, maleimide, succinimidyl, Ketone, (wherein Q 2 may be substituted or unsubstituted alkyl, aryl, heterocyclic, such as substituted or unsubstituted methyl, ethyl, n-propyl, Ethyl, -CHO; o-dithiopyridyl, Azido group, Acyl hydrazino, Alkynyl, Silyl group, (wherein Q 3 may be the same or different alkyl or alkoxy group, such as methyl, ethyl, propyl
  • the definition of the linking group refers to the group two linking groups listed in the above chemical bond formed by the engagement of the connection, for example - (CH 2) j - and -
  • the combination of (CH 2 ) j NHCO- may be -(CH 2 ) j NHCO(CH 2 ) j -; specifically, the combination of -CH 2 - and -CH 2 CH 2 NHCO- may be -CH 2 CH 2 NHCOCH 2 -, -CH 2 CH 2 CH 2 NHCO-.
  • the "combination” is used to define the chemical structure of the linking group, and does not involve the preparation steps, combination order, and the like of the linking group.
  • the Y-branched polyethylene glycol-acetic acid having a molecular weight of 20,000 was prepared by the synthesis method of Example 5 of Patent CN1243779C: 10 g of polyethylene glycol monomethyl ether-aminoacetic acid (mPEG-Gly) having a molecular weight of 10,000 and a molecular weight of 10 g 10000 of polyethylene glycol monomethyl ether-carboxyacetate succinimide ester (mPEG-OCH 2 CO-NHS) was dissolved in 200 ml of dichloromethane, 0.11 ml of triethylamine was added to the solution, and the reaction was carried out overnight at room temperature.
  • mPEG-Gly polyethylene glycol monomethyl ether-aminoacetic acid
  • mPEG-OCH 2 CO-NHS polyethylene glycol monomethyl ether-carboxyacetate succinimide ester
  • the solvent was concentrated, the residue was added diethyl ether, and the precipitate was collected by filtration, dried in vacuo, purified by ion-exchange chromatography column, and monitored by GFC, and collected at a peak height of the target product exceeding 5 mv, and collected at less than 5 mv.
  • Step of reacting mPEG-Gly with mPEG-OCH 2 CO-NHS Referring to Example 2, after reacting at room temperature overnight, BOC anhydride was added, the reaction was carried out for 3 h, the solvent was concentrated by rotary evaporation, the residue was added diethyl ether, and the precipitate was collected by filtration, dried under vacuum, and ion exchange Column purification, GFC monitoring, starting with the peak height of the target product exceeding 5 mv, and collecting at less than 5 mv.
  • the Y-branched polyethylene glycol-acetic acid having a molecular weight of 44,000 was prepared by the synthesis method of Example 5 of Patent CN1243779C: 10g of polyethylene glycol monomethyl ether-aminoacetic acid (mPEG-Gly) having a molecular weight of 22000 and a molecular weight of 10g 22000 of polyethylene glycol monomethyl ether-carboxyacetate succinimide ester (mPEG-OCH 2 CO-NHS) was dissolved in 200 ml of dichloromethane, 0.23 ml of triethylamine was added to the solution, and the reaction was carried out overnight at room temperature.
  • mPEG-Gly polyethylene glycol monomethyl ether-aminoacetic acid
  • mPEG-OCH 2 CO-NHS polyethylene glycol monomethyl ether-carboxyacetate succinimide ester
  • the solvent was concentrated, the residue was added diethyl ether, and the precipitate was collected by filtration, dried in vacuo, purified by ion-exchange chromatography column, and monitored by GFC, and collected at a peak height of the target product exceeding 5 mv, and collected at less than 5 mv.
  • Step of reacting mPEG-Gly with mPEG-OCH 2 CO-NHS Referring to Example 4, after reacting at room temperature overnight, adding BOC anhydride, reacting for 3 hours, concentrating the solvent by rotary evaporation, adding the residue to diethyl ether, collecting the precipitate by filtration, vacuum drying, ion exchange Column purification, GFC monitoring, starting with the peak height of the target product exceeding 5 mv, and collecting at less than 5 mv.
  • the effect of the prior art on product purification will gradually increase with increasing molecular weight, and the method of the present invention can significantly improve purification yield and product purity for high molecular weight products.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Polyethers (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en Y, en particulier un procédé de préparation d'un dérivé d'acide carboxylique de polyéthylène glycol ramifié en Y présentant une pureté élevée et un poids moléculaire élevé. Les étapes de préparation sont simples, le produit après réaction est facile à séparer, le coût de séparation est faible, la pureté et le rendement du produit sont élevés, ce qui facilite la préparation ultérieure d'autres dérivés et de conjugués médicamenteux sur la base de la préparation du dérivé d'acide carboxylique, tout en étant avantageux pour une amplification industrielle et des applications commerciales. Le produit dérivé d'acide carboxylique de polymère hydrophile ramifié en Y préparé (en particulier le dérivé d'acide carboxylique de polyéthylène glycol ramifié en Y présentant un poids moléculaire élevé) présente une grande pureté et une valeur d'application commerciale élevée, et est notamment utilisé dans la préparation de médicaments pour la prévention et/ou le traitement de maladies.
PCT/CN2018/077229 2017-03-30 2018-02-26 Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y WO2018177055A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP18775559.0A EP3604388B1 (fr) 2017-03-30 2018-02-26 Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y
US16/588,620 US11359089B2 (en) 2017-03-30 2019-09-30 Method for preparing Y-branched hydrophilic polymer carboxylic acid derivative

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710202947.4 2017-03-30
CN201710202947 2017-03-30
CN201710915311.4 2017-09-29
CN201710915311.4A CN108659227B (zh) 2017-03-30 2017-09-29 一种y型分支的亲水性聚合物羧酸衍生物的制备方法

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/588,620 Continuation US11359089B2 (en) 2017-03-30 2019-09-30 Method for preparing Y-branched hydrophilic polymer carboxylic acid derivative

Publications (1)

Publication Number Publication Date
WO2018177055A1 true WO2018177055A1 (fr) 2018-10-04

Family

ID=63674149

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/077229 WO2018177055A1 (fr) 2017-03-30 2018-02-26 Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y

Country Status (1)

Country Link
WO (1) WO2018177055A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2304976A1 (fr) * 1997-11-05 1999-05-14 J. Milton Harris Administration de molecules conjuguees a du polyethylene glycol a partir d'hydrogels degradables
CN1556828A (zh) * 2002-03-13 2004-12-22 ƽ 具有y形分支的亲水性聚合物衍生物、其制备方法、与药物分子的结合物以及包含该结合物的药物组合物
CN1706865A (zh) * 2004-06-11 2005-12-14 北京键凯科技有限公司 多叉分支的聚乙二醇－氨基酸寡肽及其活性衍生物和药物结合物
CN101029131A (zh) * 2007-03-16 2007-09-05 中国人民解放军国防科学技术大学 一种分枝型聚乙二醇及其制备方法
CN101259284A (zh) * 2008-04-15 2008-09-10 华东师范大学 一种基于树形聚合物肝靶向抗癌纳米前药系统、制备及用途
CN104530415A (zh) * 2014-10-01 2015-04-22 厦门赛诺邦格生物科技有限公司 一种异官能化y型聚乙二醇衍生物、制备方法及其生物相关物质

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2304976A1 (fr) * 1997-11-05 1999-05-14 J. Milton Harris Administration de molecules conjuguees a du polyethylene glycol a partir d'hydrogels degradables
CN1556828A (zh) * 2002-03-13 2004-12-22 ƽ 具有y形分支的亲水性聚合物衍生物、其制备方法、与药物分子的结合物以及包含该结合物的药物组合物
CN1243779C (zh) 2002-03-13 2006-03-01 北京键凯科技有限公司 具有y形分支的亲水性聚合物衍生物、其制备方法、与药物分子的结合物以及包含该结合物的药物组合物
CN1706865A (zh) * 2004-06-11 2005-12-14 北京键凯科技有限公司 多叉分支的聚乙二醇－氨基酸寡肽及其活性衍生物和药物结合物
CN101029131A (zh) * 2007-03-16 2007-09-05 中国人民解放军国防科学技术大学 一种分枝型聚乙二醇及其制备方法
CN101259284A (zh) * 2008-04-15 2008-09-10 华东师范大学 一种基于树形聚合物肝靶向抗癌纳米前药系统、制备及用途
CN104530415A (zh) * 2014-10-01 2015-04-22 厦门赛诺邦格生物科技有限公司 一种异官能化y型聚乙二醇衍生物、制备方法及其生物相关物质

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3604388A4 *

Similar Documents

Publication Publication Date Title
US10385165B2 (en) N-maleimidyl polymer derivatives
JP6505659B2 (ja) リファキシミン複合体
CN1069099C (zh) 阿霉素的二聚物和三聚物
CN104559213B (zh) 一种聚三亚甲基碳酸酯与聚乙二醇改进聚肽膜亲水性与柔顺性的方法
WO2003076490A1 (fr) Derive polymere hydrophile a ramification de type y et procede de preparation d'un composite medical contenant le compose precite
US20040225097A1 (en) Novel preparation method of peg-maleimide derivatives
WO1997006202A1 (fr) Polymere sequence pourvu de groupes fonctionnels aux deux extremites
US10836869B1 (en) Polymer excipients for drug delivery applications
JP2002506087A (ja) 近位の反応性基を持つポリ（エチレングリコール）誘導体
JPWO2006088248A1 (ja) ポリオキシアルキレン誘導体
US11286344B2 (en) Polymer excipients for drug delivery applications
CN101108895B (zh) 聚乙二醇乙醛衍生物及其与药物的结合物
US11359089B2 (en) Method for preparing Y-branched hydrophilic polymer carboxylic acid derivative
JP2019510126A (ja) マルチアームポリエチレングリコール及びその活性誘導体
CN105566663B (zh) 一种用聚对二氧环己酮与p(cpp-sa)-聚乙二醇改进聚乙烯醇膜耐水性及柔顺性的方法
JP5371067B2 (ja) 高純度のポリエチレングリコールアルデヒド誘導体の製造方法
WO2008052428A1 (fr) Procédé de preparation et conjugué avec molécule médicinale correspondante
WO2018177055A1 (fr) Procédé de préparation d'un dérivé d'acide carboxylique de polymère hydrophile ramifié en y
CN105542480B (zh) 一种用聚己内酯与p(cpp‑sa)‑聚乙二醇改进聚乙烯醇膜耐水性及柔顺性的方法
CN103483583B (zh) 一种ε-聚赖氨酸的制备方法
US7550628B2 (en) Process for preparing phenolic acid salts of gabapentin
CN101220084A (zh) 聚乙二醇修饰的三价铁亚血红素短肽化合物及制备方法
CN101020062A (zh) 亲水性聚乙二醇支载熊果酸系列新药及其制备方法
CN107303393B (zh) 丙泊酚聚乙二醇缀合前药的制备与应用
CN111035623A (zh) 一种ido1多肽纳米抑制剂及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18775559

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018775559

Country of ref document: EP

Effective date: 20191030

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载