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Branched hetero-polyethylene glycol and intermediate

A technology of polyethylene glycol and intermediates, applied in the field of branched chain isopolyethylene glycol compounds, to achieve the effect of inhibiting the reduction of physiological activity

Active Publication Date: 2013-03-20
NOF CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, in the case of considering a substance having a drug at one end and a directional molecule bonded to it at the other end, a polyethylene glycol-bonded substance, when multiple bonding of the drug is obtained, increased transport efficiency becomes possible

Method used

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  • Branched hetero-polyethylene glycol and intermediate
  • Branched hetero-polyethylene glycol and intermediate
  • Branched hetero-polyethylene glycol and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0119] Add 18.2 g (0.1 mol) of 3-benzyloxy-1,2-propanediol, 150 g of anhydrous toluene, 0.9 g (39 mmol: 26 %) sodium metal, and the whole was stirred at room temperature under nitrogen gas until the sodium metal was dissolved. The solution was charged into a 5 L autoclave, and after replacing the inside of the system with nitrogen, the temperature was raised to 100°C. After adding thereto 1,982 g (45 mol) of ethylene oxide at 100 to 130° C. and a pressure of 1 MPa or less, the reaction was further continued for 2 hours. After removing unreacted ethylene oxide gas under reduced pressure, the whole was cooled to 60°C, and the pH was adjusted to 7.5 using 85% phosphoric acid aqueous solution to obtain the following compound (a1).

[0120] 1 H-NMR; δ(ppm):

[0121] 3.40-3.90(1785H,m,HO( CH 2 CH 2 O) n - CH 2 ,HO( CH 2 CH 2 O) n - CH , CH 2 O-CH 2 Ph),4.54(2H,s,- CH 2 Ph),7.27-7.38(5H,m,-CH 2 Ph )

[0122] GPC analysis:

[0123] Number average molecular we...

Embodiment 2）

[0127] Into a 3 L four-necked flask equipped with a thermometer, a nitrogen gas inlet tube, a stirrer, a Dean-stark tube and a cooling tube, 372 g (18.6 mmol) of the above compound (a1) and 1,860 g of toluene were charged. The whole was heated under reflux and water was removed as an azeotrope. After cooling to room temperature, 6.02 g (59.5 mmol) of triethylamine and 5.54 g (48.4 mmol) of methanesulfonyl chloride were added thereto, and allowed to react at 40° C. for 3 hours. Subsequently, a solution of 85.6 g (465 mmol) of 3,3-diethoxy-1-propanol in toluene (256.8 g) containing 2.58 g (112 mmol) of sodium dissolved therein was added thereto, followed by reaction at 70°C for 5 Hour. After the reaction solution was filtered, the filtrate was transferred to a 10 L stainless steel tank, and crystallization was performed by adding 1.488 g of ethyl acetate, 1,488 g of ethanol, and 2,976 g of hexane. After the precipitated crystals were filtered to remove the solvent, the crystal...

Embodiment 3）

[0135] 50 g of the above-mentioned compound (a2) and 25 g of 5% palladium-carbon (50% hydrated product) were charged in a 1 L four-necked flask equipped with a thermometer, a nitrogen inlet tube, a stirrer and a cooling tube. After replacing with nitrogen, 400 g of methanol and 67 g of cyclohexene were added thereto, the temperature was raised, and gentle reflux was performed at 52 to 55° C. to carry out a reaction for 2 hours. After cooling the reaction solution to room temperature, palladium-carbon was filtered off, and the filtrate was concentrated. To the concentrate, 400 g of toluene and 200 g of hexane were added, and crystallization was performed. The resulting crystals were collected by filtration and dried to obtain the following compound (a3).

[0136] 1 H-NMR; δ(ppm):

[0137] 1.16-1.24(12H,t,( CH 3 CH 2 O) 2 -CHCH 2 CH 2 -),1.85-1.95(4H,q,(CH 3 CH 2 O) 2 -CH CH 2 CH 2 -),3.40-3.90(1673H,m,-( CH 2 CH 2 O) n - CH 2 ,-( CH 2 CH 2 O) n - CH ...

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Abstract

Provided is a branched hetero-polyethylene glycol compound that includes two types of functional groups capable of reacting with various biofunctional substances, and in which one of said functional groups is provided in plurality. The disclosed branched hetero-polyethylene glycol is represented by formula [1]. (In the formula, X and Y each represent an atomic group containing at least a functional group that reacts with and forms a covalent bond with a functional group in a biofunctional molecule; the functional group in the atomic group (X) is different from the functional group in the atomic group (Y); s represents the number of polyethylene glycol chains and is an integer of 2 to 8; n is the average number of moles added to each polyethylene glycol chain and satisfies 20=n=2000; and E represents a branched linker moiety that has a binding valence of s to the polyethylene glycol chains and that has a binding valence of 1 to the functional group (Y).)

Description

technical field [0001] The present invention relates to branched chain isopolyethylene glycols. More specifically, the present invention relates to branched isopolyethylene glycol compounds, which are used in the modification of biofunctional molecules, drugs or drug carriers in drug delivery systems, materials and devices for diagnosis, and the like. Background technique [0002] Polyethylene glycol itself exhibits low toxicity and antigenicity, and has excellent solubility in water and many organic solvents. Therefore, terminally activated polyethylene glycol compounds introducing reactive functional groups in the terminal have been widely used to provide various functions, such as providing concealment of drugs and drug carriers in vivo and dissolving them in drug delivery systems, As well as improving the biocompatibility of the material surface. Among these compounds, so-called heterobifunctional polyethylene glycols having functional groups with different reactivity ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/32A61K47/48
CPCA61K47/48A61K47/48215C08G65/2612C08G65/32C08G65/3255C08G65/3312C08G65/33337C08G65/33341C08G65/3344C08L2203/02A61K47/60Y02P20/55A61K47/50C08L71/00
Inventor 山本裕二吉冈宏树真锅文朗
Owner NOF CORP
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