CN114479059B - Propionaldehyde functionalized polyethylene glycol derivative and preparation method thereof - Google Patents
Propionaldehyde functionalized polyethylene glycol derivative and preparation method thereof Download PDFInfo
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- CN114479059B CN114479059B CN202210186703.2A CN202210186703A CN114479059B CN 114479059 B CN114479059 B CN 114479059B CN 202210186703 A CN202210186703 A CN 202210186703A CN 114479059 B CN114479059 B CN 114479059B
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- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 63
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 63
- 150000002334 glycols Chemical class 0.000 title claims abstract description 60
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000007800 oxidant agent Substances 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 230000001590 oxidative effect Effects 0.000 claims abstract description 29
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 253
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 24
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 15
- 229940035437 1,3-propanediol Drugs 0.000 claims description 15
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000012312 sodium hydride Substances 0.000 claims description 14
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 238000006804 Parikh-Doering oxidation reaction Methods 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 27
- 238000003786 synthesis reaction Methods 0.000 abstract description 27
- 229920000642 polymer Polymers 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 153
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 47
- 239000002904 solvent Substances 0.000 description 45
- 239000012153 distilled water Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 29
- 229910052739 hydrogen Inorganic materials 0.000 description 27
- 239000001257 hydrogen Substances 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 25
- 238000005227 gel permeation chromatography Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000004611 spectroscopical analysis Methods 0.000 description 23
- 239000012265 solid product Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 238000000605 extraction Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- DXWRNRRBDAQWDB-UHFFFAOYSA-N 3-chloro-1,1-dimethoxypropane Chemical compound COC(OC)CCCl DXWRNRRBDAQWDB-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- GNHMRTZZNHZDDM-UHFFFAOYSA-N 3-chloropropionitrile Chemical compound ClCCC#N GNHMRTZZNHZDDM-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 108010027737 peginterferon beta-1a Proteins 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 229940007060 plegridy Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/3311—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing a hydroxy group
- C08G65/3312—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing a hydroxy group acyclic
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
-
- 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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
Abstract
The invention provides a polyethylene glycol derivative functionalized by propionaldehyde and a preparation method thereof, and relates to the field of polymer synthesis chemistry. The structural general formula of the propionaldehyde functionalized polyethylene glycol derivative is shown as a formula I. The invention also provides a preparation method of the propionaldehyde functionalized polyethylene glycol derivative, which comprises the following steps: dissolving 1, 3-propylene glycol in an organic solvent, adding alkali for reaction, and then adding a polyethylene glycol derivative modified by a leaving group for reaction to obtain a propanol functionalized polyethylene glycol derivative; dissolving the obtained propanol functionalized polyethylene glycol derivative in an organic solvent, and adding an oxidant for reaction to obtain the propanal functionalized polyethylene glycol derivative. The nuclear magnetic purity of the prepared propionaldehyde functionalized polyethylene glycol derivative is more than 99 percent, and the preparation method is simple and efficient.
Description
Technical Field
The invention relates to the field of polymer synthesis chemistry, in particular to a polyethylene glycol derivative functionalized by propionaldehyde and a preparation method thereof.
Background
Polyethylene glycol is a nonionic water-soluble polymer, has excellent biocompatibility, is a polymer with the lowest protein and cell absorption level in the polymer known so far, and is widely applied to the fields of medicines, foods, cosmetics and the like. Particularly in the field of medicine, the preparation method has important application in improving the solubility, immunogenicity and stability of the medicine, prolonging the half life of the medicine and improving the curative effect.
The polyethylene glycol derivative functionalized by the propionaldehyde can modify small molecules or biological macromolecules with amino groups through reductive amination reaction, is an important reagent for pegylation, and is particularly applied to the synthesis of drugs on the market such as Neulosta and Plegridy. At present, the preparation of the polyethylene glycol derivative functionalized by the propionaldehyde mainly adopts a method of directly replacing 3-chloro-1, 1-dimethoxy propane by the polyethylene glycol derivative and then deprotecting. The method requires the addition of a large excess of 3-chloro-1, 1-dimethoxypropane (generally 50 equivalents) during the substitution process, but the reaction is still not guaranteed to be complete, high-purity products are difficult to obtain, and high efficiency, green and economical efficiency are lacking. Therefore, it is important to develop a simple, efficient, green and economical preparation method capable of obtaining high-purity propionaldehyde functionalized polyethylene glycol derivatives.
Disclosure of Invention
The invention aims to solve the problems that the existing preparation method of the polyethylene glycol derivative functionalized by propionaldehyde is difficult to obtain a high-purity product and lacks high efficiency, green and economical efficiency, and provides the polyethylene glycol derivative functionalized by propionaldehyde and the preparation method thereof.
The invention firstly provides a propionaldehyde functionalized polyethylene glycol derivative, the structural general formula of which is shown as the formula I:
in the formula I, n is any integer from 1 to 2000, and x is one of 1,2,3,4,6 and 8;
in the formula I, R is selected from any one of the following substituent groups according to the difference of x:
preferably, the structural formula of the propionaldehyde functionalized polyethylene glycol derivative is as follows:
the invention also provides a preparation method of the propionaldehyde functionalized polyethylene glycol derivative, which comprises the following steps:
step one: dissolving 1, 3-propylene glycol in an organic solvent, adding alkali for reaction, then adding a polyethylene glycol derivative modified by a leaving group, and reacting at 25-80 ℃ for 2-24 hours to obtain a propanol functionalized polyethylene glycol derivative;
step two: dissolving the obtained propanol functionalized polyethylene glycol derivative in an organic solvent, adding an oxidant, and reacting for 2-24 hours at the temperature of-78-80 ℃ to obtain the propanal functionalized polyethylene glycol derivative.
Preferably, the base in the first step is selected from one or more of triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, sodium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide.
Preferably, the reaction temperature of the alkali added in the first step is room temperature, and the reaction time is 1-3 h.
Preferably, in the first step, the molar ratio of the 1, 3-propanediol to the polyethylene glycol derivative modified by the leaving group is 1:1-10:1.
Preferably, the leaving group modified polyethylene glycol derivative has the following structural formula:
wherein n is any integer from 1 to 2000, R 1 Is one or more of Cl, br, I, OMs and OTs; x is one of 1,2,3,4,6 and 8, and R is selected from any one of the following substituent groups according to the difference of x:
preferably, the oxidant in the second step is one or more selected from the group consisting of an agar reagent, a Cro3.2Py oxidant, a PDC oxidant, a PCC oxidant, a dess-Martin oxidant, an IBX oxidant, a Swern oxidant, a Pfitzner-Moffatt oxidant, an align-Goldman oxidant and a Parikh-Doering oxidant.
Preferably, the reaction solvent in the second step is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, N '-dimethylformamide, N' -dimethylacetamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, tertiary butanol and acetone.
Preferably, in the second step, the molar ratio of the propanol-functionalized polyethylene glycol derivative to the oxidant is 1:1-1:5.
The beneficial effects of the invention are that
The invention provides a propionaldehyde functionalized polyethylene glycol derivative and a preparation method thereof, wherein the structural general formula of the derivative is shown in formula I. The nuclear magnetic purity of the polyethylene glycol derivative functionalized by the propionaldehyde is more than 99%, the preparation method is simple and efficient, the problem that the existing method lacks high efficiency, green and economy is solved, and the method has important significance for promoting development of polyethylene glycol reagents and research and development and production of polyethylene glycol modified medicines.
Drawings
FIG. 1 shows a nuclear magnetic resonance spectrum of 5k mPEG-POH prepared in example 12 of the present invention 1 HNMR)；
FIG. 2 shows a nuclear magnetic resonance spectrum of 5k mPEG-Ald prepared in example 12 of the present invention 1 H NMR)；
FIG. 3 is a Gel Permeation Chromatogram (GPC) of 5k mPEG-Ald prepared in example 12 of the present invention;
Detailed Description
The invention firstly provides a propionaldehyde functionalized polyethylene glycol derivative, the structural general formula of which is shown as the formula I:
in the formula I, n is any integer from 1 to 2000, and x is one of 1,2,3,4,6 and 8;
in the formula I, R is selected from any one of the following substituent groups according to the difference of x:
preferably, the structural formula of the propionaldehyde functionalized polyethylene glycol derivative is as follows:
the invention also provides a preparation method of the propionaldehyde functionalized polyethylene glycol derivative, which comprises the following steps:
step one: dissolving 1, 3-propylene glycol in an organic solvent, adding alkali for reaction, wherein the reaction temperature is preferably room temperature, the reaction time is preferably 1-3 hours, adding a polyethylene glycol derivative modified by a leaving group, reacting for 2-24 hours at 25-80 ℃, preferably concentrating the reaction liquid, adding distilled water and dichloromethane for extraction, combining organic phases, drying anhydrous magnesium sulfate, filtering and evaporating to dryness, performing column chromatography or settling in diethyl ether, and collecting the polyethylene glycol derivative modified by propanol; the synthetic route of the step is as follows:
the organic solvent is preferably selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, N '-dimethylformamide, N' -dimethylacetamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, tertiary butanol or acetone, and the base is preferably selected from one or more of triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), sodium hydroxide, potassium hydroxide, lithium hydroxide, tertiary butanol potassium, sodium hydride, potassium hydride, sodium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide;
the molar ratio of the 1, 3-propanediol to the leaving group modified polyethylene glycol derivative is preferably 1:1-10:1, and the molar ratio of the 1, 3-propanediol to the base is preferably 1:1-1:5.
The structural formula of the leaving group modified polyethylene glycol derivative is preferably as follows:
wherein n is any integer from 1 to 2000, R 1 Is one or more of Cl, br, I, OMs and OTs; x is one of 1,2,3,4,6 and 8, and R is selected from any one of the following substituent groups according to the difference of x:
step two: dissolving the obtained propanol-modified polyethylene glycol derivative in an organic solvent, adding an oxidant, reacting for 2-24 hours at the temperature of-78-80 ℃, preferably concentrating the reaction liquid, adding distilled water, extracting with dichloromethane, combining organic phases, drying with anhydrous magnesium sulfate, filtering, evaporating to dryness, performing column chromatography or settling in diethyl ether, and collecting the polyethylene glycol derivative to obtain the propanal functionalized polyethylene glycol derivative. The molar ratio of the propanol functionalized polyethylene glycol derivative to the oxidant in the second step is preferably 1:1-1:5, and the synthetic route of the second step is as follows:
the oxidant is preferably selected from Jones reagent and CrO 3 2Py oxidizer, PDC oxidizer, PCC oxidizer, dess-Martin oxidizer, IBX oxidizer, swern oxidizer, pfitzner-Moffatt oxidizer, albright-Goldman oxygenOne or more of a chemosing agent and a Parikh-Doering oxidizing agent. The reaction solvent is preferably selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, N '-dimethylformamide, N' -dimethylacetamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, tertiary butanol and acetone.
The invention is described in further detail below with reference to the specific examples, which refer to the synthesis of starting leaving group modified polyethylene glycol derivatives in examples 1 to 11. The synthesis of representative high purity propionaldehyde functionalized polyethylene glycol derivatives is detailed in examples 12-22.
Example 1
Synthesis of 5k mPEG-OMs
50g of 5k mPEG-OH was dissolved in 200mL of dichloromethane, 4.2mL of triethylamine was added thereto, 50mL of a dichloromethane solution of methanesulfonyl chloride (1.5 mL) was slowly added dropwise thereto at zero temperature, and the reaction was gradually allowed to proceed to room temperature for 24 hours. 100ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 5k mPEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 2
Synthesis of 5k MsO-PEG-OMs
50g of 5k mPEG-OH was dissolved in 200mL of dichloromethane, 9mL of triethylamine was added thereto, 50mL of a dichloromethane solution of methanesulfonyl chloride (3 mL) was slowly added dropwise at zero temperature, and the reaction was gradually allowed to proceed to room temperature for 24 hours. 100ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 5kMsO-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 3
Synthesis of 2k BnO-PEG-OMs
50g of 2k BnO-PEG-OH was dissolved in 200mL of methylene chloride, 11mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (3.9 mL) was slowly added dropwise at zero temperature, and the reaction was gradually allowed to proceed to room temperature for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k BnO-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 4
Synthesis of 2k AATert-PEG-OMs
50g of 2k BnO-PEG-OH was dissolved in 200mL of t-butanol, 4.2g of potassium t-butoxide was added, the reaction was carried out at room temperature for 1 hour, 8mL of t-butyl bromoacetate was slowly added, and the reaction was carried out at 50℃for 24 hours. 200ml of distilled water was added thereto, and t-butanol was distilled off. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k AATert-PEG-OBn was obtained as a white solid by settling in diethyl ether.
30g of 2k BnO-PEG-Tert was dissolved in 200mL of methanol, 3g of Pd/C was added and reacted at room temperature under hydrogen for 24 hours, the Pd/C was filtered off with celite, the filtrate was concentrated and settled in diethyl ether to give the white solid product 2kAATert-PEG-OH.
20g of 2k of Tert-PEG-OH was dissolved in 100mL of methylene chloride, 4.5mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (1.6 mL) was slowly added dropwise at zero degree, and the reaction was gradually allowed to stand at room temperature for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k AATert-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 5
Synthesis of 2k PATET-PEG-OMs
50g of 2k BnO-PEG-OH was dissolved in 200mL of t-butanol, 4.2g of potassium t-butoxide was added, the reaction was carried out at room temperature for 1 hour, 7.5mL of t-butyl acrylate was slowly added, and the reaction was carried out at room temperature for 24 hours. 200ml of distilled water was added thereto, and t-butanol was distilled off. 200ml of distilled water was added, extracted 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether to give 2k PATET-PEG-OBn as a white solid.
30g of 2k PATET-PEG-OBn is dissolved in 200mL of methanol, 3g of Pd/C is added, the reaction is carried out for 24 hours at room temperature under the condition of hydrogen, the Pd/C is filtered out by diatomite, the filtrate is concentrated, and the white solid product 2k PATET-PEG-OH is obtained after settling in diethyl ether.
20g of 2k PATET-PEG-OH was dissolved in 100mL of methylene chloride, 4.5mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (1.6 mL) was slowly added dropwise at zero degree, and the mixture was gradually warmed to room temperature to react for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2 kPATET-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 6
Synthesis of 2k N3-PEG-OMs
20g of 2k BnO-PEG-OMs were dissolved in 200mL of ethanol, 1.95g of sodium azide was added, and the mixture was heated under reflux for 24 hours. Ethanol was distilled off, 200ml of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2kN3-PEG-OBn was obtained as a white solid by settling in diethyl ether.
10g of 2k N3-PEG-OBn was dissolved in 50mL of trifluoroacetic acid and heated to 100℃for 24 hours. And (3) removing trifluoroacetic acid by evaporation, adding saturated sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, drying with anhydrous magnesium sulfate, removing solvent by evaporation, and settling in diethyl ether to obtain a white solid product 2kN3-PEG-OH.
10g of 2k N3-PEG-OH was dissolved in 100mL of methylene chloride, 2.5mL of triethylamine was added thereto, and 50mL of methylene chloride solution of methanesulfonyl chloride (1.0 mL) was slowly added dropwise thereto at zero degree, and the mixture was gradually warmed to room temperature and reacted for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2kN3-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 7
Synthesis of 5k Alkyne-PEG-OMs
50g of 5k BnO-PEG-OH was dissolved in 200mL of t-butanol, 2.3g of potassium t-butoxide was added, the reaction was carried out at room temperature for 1 hour, 2.4mL of 3-bromopropyne was slowly added, and the temperature was raised to 50℃for 24 hours. 200ml of distilled water was added thereto, and t-butanol was distilled off. 200ml of distilled water was added, extracted 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether to give a white solid, 5k Alkyne-PEG-OBn.
30g of 5k Alkyne-PEG-OBn was dissolved in 50mL of trifluoroacetic acid and heated to 100℃for 24 hours. And (3) removing trifluoroacetic acid by evaporation, adding saturated sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, drying with anhydrous magnesium sulfate, removing solvent by evaporation, and settling in diethyl ether to obtain a white solid product, namely 5k Alkyne-PEG-OH.
20g of 5k Alkyne-PEG-OH was dissolved in 100mL of methylene chloride, 1.7mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (1.0 mL) was slowly added dropwise at zero temperature, and the mixture was gradually warmed to room temperature and reacted for 24 hours. 200ml of distilled water was added, extracted 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 5k Alkyne-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 8
Synthesis of 5kBocNH-PEG-OMs
50g of 5k BnO-PEG-OMs were dissolved in 200mL of t-butanol, 300mL of 40% aqueous ammonia was added and reacted at room temperature for 3 days. The reaction liquid is extracted for 3 times by dichloromethane, dried by anhydrous magnesium sulfate, the solvent is distilled off, and the white solid product 5kNH2-PEG-OBn is obtained by settling in diethyl ether.
30g of 5k NH2-PEG-OBn was dissolved in 100mL of methylene chloride, 1.7mL of triethylamine was added thereto, and 1.3g of di-t-butyl dicarbonate was further added thereto, and the mixture was reacted at room temperature for 6 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether to give a white solid, 5kBocNH-PEG-OBn.
30g of 5k BocNH-PEG-OBn was dissolved in 100mL of methanol, 3g of Pd/C was added and reacted at room temperature under hydrogen for 24 hours, the Pd/C was filtered off with celite, the filtrate was concentrated and settled in diethyl ether to give the white solid product 5k BocNH-PEG-OH.
20g of 5k BocNH-PEG-OH was dissolved in 100mL of methylene chloride, 1.7mL of triethylamine was added thereto, and 50mL of methylene chloride solution of methanesulfonyl chloride (1.0 mL) was slowly added dropwise thereto at zero degree, and the mixture was gradually warmed to room temperature and reacted for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 5k BocNH-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 9
Synthesis of 2k Hy-PEG-OMs
30g of 2k BnO-PEG-Tert was dissolved in 200mL of ethanol, 20mL of hydrazine hydrate was added, and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, 200ml of distilled water was added, extracted 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k Hy-PEG-OBn was obtained as a white solid by settling in diethyl ether.
20g of 2k Hy-PEG-OBn is dissolved in 100mL of methanol, 2g of Pd/C is added, the reaction is carried out for 24 hours at room temperature under the condition of hydrogen, the Pd/C is filtered out by diatomite, the filtrate is concentrated, and the white solid product 2kHy-PEG-OH is obtained after settling in diethyl ether.
20g of 2k Hy-PEG-OH was dissolved in 100mL of methylene chloride, 4.2mL of triethylamine was added thereto, and 50mL of methylene chloride solution of methanesulfonyl chloride (1.8 mL) was slowly added dropwise thereto at zero degree, and the mixture was gradually warmed to room temperature and reacted for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether to give 2k Hy-PEG-OMs as a white solid.
Example 10
Synthesis of 2k CN-PEG-OMs
50g of 2k BnO-PEG-OH was dissolved in 200mL of t-butanol, 5.6g of potassium t-butoxide was added, the reaction was carried out at room temperature for 1 hour, 4mL of 3-chloropropionitrile was slowly added, and the temperature was raised to 50℃for 24 hours. 200ml of distilled water was added thereto, and t-butanol was distilled off. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k CN-PEG-OBn was obtained as a white solid by settling in diethyl ether.
30g of 2k CN-PEG-OBn was dissolved in 50mL of trifluoroacetic acid and heated to 100℃for 24 hours. And (3) removing trifluoroacetic acid by evaporation, adding saturated sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, drying with anhydrous magnesium sulfate, removing solvent by evaporation, and settling in diethyl ether to obtain a white solid product 2k CN-PEG-OH.
20g of 2k CN-PEG-OH was dissolved in 100mL of methylene chloride, 4.2mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (1.8 mL) was slowly added dropwise at zero temperature, and the reaction was gradually allowed to proceed to room temperature for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 2k CN-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 11
Synthesis of 10k4-Arm-PEG-OMs
20g of 10k 4-Arm-PEG-OH was dissolved in 100mL of methylene chloride, 3.5mL of triethylamine was added thereto, 50mL of methylene chloride solution of methanesulfonyl chloride (1.3 mL) was slowly added dropwise at zero degree, and the mixture was gradually warmed to room temperature to react for 24 hours. 200ml of distilled water was added, extracted 3 times with dichloromethane, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product 10k4-Arm-PEG-OMs was obtained as a white solid by settling in diethyl ether.
Example 12
Synthesis of 5k mPEG-Ald
1.5mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 0.8g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 20g of 5k mPEG-OMs prepared in example 1 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 5k mPEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.1H NMR is shown in FIG. 1.
5g of 5k mPEG-POH is dissolved in 20mL of dichloromethane, 0.85g of DMP oxidant is added, the reaction is carried out for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, the dichloromethane is extracted for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 5k mPEG-Ald were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.1H NMR is shown in FIG. 2.GPC chart is shown in FIG. 3.
Example 13
Synthesis of 5k Ald-PEG-Ald
2mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 0.64g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 20g of 5kMsO-PEG-OMs prepared in example 2 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 5k POH-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.
10g of 5k POH-PEG-POH is dissolved in 20mL of dichloromethane, 0.9g of DMP oxidant is added, the reaction is carried out for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 5k Ald-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.
Example 14
Synthesis of 2k BnO-PEG-Ald
3.62mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 2g of sodium hydride was added, stirred at room temperature for 1 hour, 20g of 2KBnO-PEG-OMs prepared in example 3 was added to react for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, anhydrous magnesium sulfate was dried, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 2k BnO-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.
5g of 2k BnO-PEG-POH is dissolved in 50mL of methylene chloride, 2.1g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, methylene chloride is extracted for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k BnO-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >99%, nuclear magnetic purity >99%.
Example 15
Synthesis of 2k AATert-PEG-Ald
1.82mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 1g of sodium hydride was added, stirred at room temperature for 1 hour, 10g of 2k AATert-PEG-OMs prepared in example 4 was added to react for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, anhydrous magnesium sulfate was dried, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 2k AATert-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
5g of 2k AATert-PEG-POH is dissolved in 50mL of methylene chloride, 2.2g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, methylene chloride is extracted for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k AATert-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
Example 16
Synthesis of 2k PATET-PEG-Ald and 2k PA-PEG-Ald
2mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 1g of sodium hydride was added, stirred at room temperature for 1 hour, 10g of 2k PATERT-PEG-OMs prepared in example 5 was added to react for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was settled in diethyl ether to obtain a white solid. The structure and purity of 2k PATET-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
5g of 2k PATET-PEG-POH is dissolved in 50mL of dichloromethane, 2.2g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k PATET-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
2g of 2k PATET-PEG-Ald was dissolved in 20mL of trifluoroacetic acid and reacted at room temperature for 24 hours. Trifluoroacetic acid is distilled off, 100ml of distilled water is added, dichloromethane extraction is carried out for 3 times, anhydrous magnesium sulfate is dried, solvent is distilled off, and white solid product 2kPA-PEG-Ald is obtained after settling in diethyl ether. Gel permeation chromatography purity >99%. The structure and purity of 2k PA-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
Example 17
Synthesis of 2k N3-PEG-Ald
2mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 1g of sodium hydride was added, stirred at room temperature for 1 hour, 10g of 2kN3-PEG-OMs prepared in example 6 was added to react for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was settled in diethyl ether to obtain a white solid. The structure and purity of 2kN3-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
5g of 2kN3-PEG-POH is dissolved in 50mL of dichloromethane, 2.2g of DMP oxidant is added, the reaction is carried out for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k N3-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
Example 18
Synthesis of 5k Alkyne-PEG-Ald
1.5mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 1.6g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 20g of 5k Alkyne-PEG-OMs prepared in example 7 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, anhydrous magnesium sulfate was dried, the solvent was distilled off, and the mixture was settled in diethyl ether to obtain a white solid product. The structure and purity of 5k Alkyne-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
5g of 5k Alkyne-PEG-POH is dissolved in 50mL of methylene dichloride, 2g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, methylene dichloride is extracted for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 5k Alkyne-PEG-Ald were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
Example 19
Synthesis of 5k BocNH-PEG-Ald
1.5mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 0.8g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 20g of 5KBOCNH-PEG-OMs prepared in example 8 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, anhydrous magnesium sulfate was dried, the solvent was distilled off, and the mixture was settled in diethyl ether to obtain a white solid product. The structure and purity of 5k BocNH-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
10g of 5k BocNH-PEG-POH is dissolved in 50mL of dichloromethane, 1.6g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 5kBocNH-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
Example 20
Synthesis of 2k Hy-PEG-Ald
3.6mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 2g of sodium hydride was added and stirred at room temperature for 1 hour, 20g of 2k Hy-PEG-OMs prepared in example 9 was added and reacted for 24 hours, 100mL of distilled water was added and extracted 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 2k Hy-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
5g of 2k Hy-PEG-POH is dissolved in 50mL of dichloromethane, 2.2g of DMP oxidant is added, the reaction is carried out for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k Hy-PEG-Ald were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >98% and nuclear magnetic purity >99%.
Example 21
Synthesis of 2k CN-PEG-Ald
1.8mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 1.0g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 10g of 2k CN-PEG-OMs prepared in example 10 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. The structure and purity of 2k CN-PEG-POH were characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
5g of 2k CN-PEG-POH is dissolved in 50mL of dichloromethane, 2.12g of DMP oxidant is added, the reaction is carried out for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. The structure and purity of 2k CN-PEG-Ald was characterized by Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy (1H NMR). GPC purity >97% and nuclear magnetic purity >99%.
Example 22
Synthesis of 10k4-Arm-PEG-Ald
2mL of 1, 3-propanediol was dissolved in 100mL of N, N-dimethylformamide, 0.64g of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, 20g of 10k4-Arm-PEG-OMs prepared in example 11 was added and reacted for 24 hours, 100mL of distilled water was added, extraction was performed 3 times with methylene chloride, anhydrous magnesium sulfate was dried, the solvent was distilled off, and the product was precipitated in diethyl ether as a white solid. By Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy 1 H NMR) characterizes the structure and purity of 5k 10k 4-Arm-PEG-POH. GPC purity>98%, nuclear magnetic purity>99％。
5g of 10k 4-Arm-PEG-POH is dissolved in 50mL of dichloromethane, 0.43g of DMP oxidant is added for reaction for 24 hours at room temperature, the reaction solution is concentrated, 50mL of saturated sodium bicarbonate aqueous solution is added, dichloromethane is used for extraction for 3 times, anhydrous magnesium sulfate is dried, the solvent is distilled off, and the white solid product is obtained by settling in diethyl ether. By Gel Permeation Chromatography (GPC) and 400MHz nuclear magnetic resonance hydrogen spectroscopy 1 H NMR) characterizes the structure and purity of 10k 4-Arm-PEG-alds. GPC purity>98%, nuclear magnetic purity>99％。
Claims (9)
1. A process for the preparation of a propionaldehyde functionalized polyethylene glycol derivative, comprising:
step one: dissolving 1, 3-propylene glycol in an organic solvent, adding alkali for reaction, then adding a polyethylene glycol derivative modified by a leaving group, and reacting at 25-80 ℃ for 2-24 hours to obtain a propanol functionalized polyethylene glycol derivative;
step two: dissolving the obtained propanol functionalized polyethylene glycol derivative in an organic solvent, adding an oxidant, and reacting for 2-24 hours at the temperature of-78-80 ℃ to obtain a propionaldehyde functionalized polyethylene glycol derivative;
the structural general formula of the propionaldehyde functionalized polyethylene glycol derivative is shown in formula I:
in the formula I, n is any integer from 1 to 2000, and x is one of 1,2,3,4,6 and 8;
in the formula I, R is selected from any one of the following substituent groups according to the difference of x:
2. the method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the structural formula of said propionaldehyde functionalized polyethylene glycol derivative is as follows:
3. the method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the base in the first step is selected from one or more of triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, sodium, lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hexamethyldisilazide.
4. The method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the reaction temperature of adding alkali in the first step is room temperature, and the reaction time is 1-3 h.
5. The method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the molar ratio of 1, 3-propanediol to leaving group modified polyethylene glycol derivative in step one is 1:1-10:1.
6. The method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the leaving group modified polyethylene glycol derivative has the following structural formula:
wherein n is any integer from 1 to 2000, R 1 Is one or more of Cl, br, I, OMs and OTs; x is one of 1,2,3,4,6 and 8, and R is selected from any one of the following substituent groups according to the difference of x:
7. the method for preparing a propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the oxidizing agent in the second step is one or more selected from the group consisting of a agains reagent, a cro3.2py oxidizing agent, a PDC oxidizing agent, a PCC oxidizing agent, a dess-martin oxidizing agent, an IBX oxidizing agent, a Swern oxidizing agent, a Pfitzner-Moffatt oxidizing agent, an align-Goldman oxidizing agent, and a Parikh-Doering oxidizing agent.
8. The method for preparing the propionaldehyde functionalized polyethylene glycol derivative according to claim 1, wherein the reaction solvent in the second step is one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, N '-dimethylformamide, N' -dimethylacetamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, tert-butanol and acetone.
9. The method for preparing a polyethylene glycol derivative functionalized with propionaldehyde according to claim 1, wherein the molar ratio of the polyethylene glycol derivative functionalized with propanol to the oxidant in the second step is 1:1-1:5.
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| US5252714A (en) * | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
| EP1591467A1 (en) * | 2002-09-09 | 2005-11-02 | Nektar Therapeutics Al, Corporation | Conjugate between a polyethylene glycol having a terminal alkanal group and a human growth hormone |
| CN101108895A (en) * | 2006-07-19 | 2008-01-23 | 北京键凯科技有限公司 | Polyglycol ethanal derivant and combo of medicament and the same |
| CN104927044A (en) * | 2015-06-15 | 2015-09-23 | 浙江医药高等专科学校 | Preparation method of high-purity polyethylene glycol aldehyde derivative |
| CN107189054A (en) * | 2017-06-02 | 2017-09-22 | 温州大学 | A kind of polyethylene glycol containing acetal bonds, derivative and its synthetic method |
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| US20040249119A1 (en) * | 2003-06-05 | 2004-12-09 | Fox Martin Edward | Novel mPEG propionaldehyde precursor |
| KR100967833B1 (en) * | 2008-05-20 | 2010-07-05 | 아이디비켐(주) | A method for preparing high-purity polyethyleneglycol aldehyde derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5252714A (en) * | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
| EP1591467A1 (en) * | 2002-09-09 | 2005-11-02 | Nektar Therapeutics Al, Corporation | Conjugate between a polyethylene glycol having a terminal alkanal group and a human growth hormone |
| CN101108895A (en) * | 2006-07-19 | 2008-01-23 | 北京键凯科技有限公司 | Polyglycol ethanal derivant and combo of medicament and the same |
| CN104927044A (en) * | 2015-06-15 | 2015-09-23 | 浙江医药高等专科学校 | Preparation method of high-purity polyethylene glycol aldehyde derivative |
| CN107189054A (en) * | 2017-06-02 | 2017-09-22 | 温州大学 | A kind of polyethylene glycol containing acetal bonds, derivative and its synthetic method |
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