CN1392148A - 5-benzyloxymethyl-1,4-dioxane-2-one and its preparing method and use - Google Patents

Abstract

5-benzyloxymethyl-1,4-dioxane-2-one, its structural formula is (see the formula on the right), the present invention provides 5-benzyloxymethyl-1,4-dioxane-2 The preparation method of -ketone: take 5-hydroxymethyl-1,4-dioxane-2-one and benzyl chloride as raw materials to prepare 5-benzyloxy Methyl-1,4-dioxane-2-one. The obtained compound monomer is used to prepare functionalized biodegradable polydioxanone and biodegradable copolymers, which can improve the physical, chemical and biological properties of corresponding polymers. As an intermediate, it is used to prepare functionalized cyclic p-dioxanone and polydioxanone, and is used to prepare cyclic intermediates containing drugs or biologically active substances, so as to prepare polymer drug controlled release systems.

Description

5-benzyloxymethyl-1,4-dioxane-2-one and its preparation method and use

technical field

The invention relates to 5-benzyloxymethyl-1,4-dioxane-2-one and its preparation method and application, belonging to the field of organic chemistry.

Background technique

Ring-opening polymerization is one of the important polymer synthesis methods. Common synthetic biodegradable polymers such as polyesters, polyamino acids, polycarbonates, polyphosphates, and polydioxanone are generally prepared by ring-opening polymerization. In order to further develop biodegradable polymers, one of the important approaches is to design and synthesize cyclic monomers with novel structures.

Among biodegradable aliphatic polyester materials, polydioxanone (PDON) can be safely used in vivo because it has neither acute inflammation nor toxic side effects after implantation. And because of its lower glass transition temperature (-16°C) and better flexibility, it is clinically used as a surgical suture as a better biomedical material. However, since PDON has about 55% crystallinity, which affects its hydrophilicity to a certain extent, and makes its degradation time 6 months, we introduce side chain hydroxyl groups on its main chain in order to improve its hydrophilicity. thereby accelerating its degradation rate. The significance of this work lies in: ① the hydrophilicity/hydrophobicity of the polymer can be changed by controlling the ratio of the introduced functional groups; ② the degradation rate of the polymer can be changed by the introduction of side chain functional groups, and the to control the degradation rate; ③ Various drugs can be bonded to the side chain functional groups to form a drug controlled release system.

Contents of the invention

The object of the present invention is to provide a new six-membered ring-p-dioxanone monomer containing functional groups: 5-benzyloxymethyl-1,4-dioxan-2-one and its preparation method and applications, by changing the functional groups on the cyclic monomers, the physical, chemical and biological properties of the corresponding polymers can be changed, and drugs can be introduced into the monomers or polymers through the functional groups, thus further expanding the biodegradable poly The application fields of oxyhexanone and its copolymers have laid a good foundation.

The technical measures taken for realizing the above-mentioned purpose of the present invention:

5-benzyloxymethyl-1,4-dioxane-2-one, its structural formula is:

The invention provides a preparation method of 5-benzyloxymethyl-1,4-dioxane-2-one: using 5-hydroxymethyl-1,4-dioxane-2-one and benzyl chloride as The raw materials are refluxed in the presence of sodium hydride or sodium hydroxide or sodium metal to prepare 5-benzyloxymethyl-1,4-dioxane-2-one.

The above-mentioned 5-hydroxymethyl-1,4-dioxane-2-ketone can be obtained by the prior art; it can also be obtained by the following method: 5-hydroxyl-1,3-benzylidene glycerol and ethyl bromoacetate Reaction at 45-65°C in the presence of metallic sodium or sodium hydride, followed by hydrolysis twice under alkaline conditions and acidic conditions, followed by vacuum distillation to obtain 5-hydroxymethyl-1,4-dioxane-2-one, and then Using 5-hydroxymethyl-1,4-dioxane-2-one and benzyl chloride as raw materials to react in the presence of sodium hydride to prepare 5-benzyloxymethyl-1,4-dioxane-2- ketone.

The molecular weight of 5-benzyloxymethyl-1,4-dioxane-2-one is 222, determined by mass spectrometer (MS); its structure is determined by infrared spectrum (FT-IR), proton nuclear magnetic resonance spectrum ( ¹ HNMR) , confirmed by carbon-13 nuclear magnetic resonance spectrum ( ¹³ CNMR).

Adopt the beneficial effect that the present invention reaches:

The present invention uses 5-hydroxymethyl-1,4-dioxan-2-one in the prior art as a raw material for the first time to design and synthesize a six-membered ring-p-dioxanone monomer with a novel structure. That is, 5-benzyloxymethyl-1,4-dioxane-2-one. The structure of the compound was confirmed by infrared spectrum (FT-IR), proton nuclear magnetic resonance spectrum ( ¹ HNMR) and carbon-13 nuclear magnetic resonance spectrum ( ¹³ CNMR). The synthesized cyclic monomers can be used for ring-opening polymerization, and by changing the functional groups on the cyclic monomers, the physical, chemical and biological properties of the corresponding polymers can be changed, and drugs can be introduced into monomers or polymers through functional groups, Thus laying a good foundation for further expanding the application field of biodegradable polydioxanone and its copolymer.

The 5-benzyloxymethyl-1,4-dioxan-2-ketone prepared by the present invention also has the following purposes: 1. It is used to prepare novel functionalized biodegradable polydioxanone monomers, The physical, chemical and biological properties of the corresponding polymers can be improved. 2. The monomer used to prepare biodegradable copolymers can be combined with other cyclic monomers, such as 1,4-dioxane-2-one, lactide, glycolide, ε-caprolactone, Ring-opening copolymerization of trimethylene carbonate and cyclic phosphate, etc., to expand the types and uses of polydioxanone. Adjustable physical, chemical and biological properties can be obtained by controlling the distribution ratio of the components in the copolymer. 3. Intermediates for preparing functionalized cyclic p-dioxanone and polydioxanone, further improving the physical, chemical and biological properties of polydioxanone. 4. It is used to prepare cyclic intermediates containing drugs or biologically active substances, so as to prepare polymer drug controlled release systems.

Detailed ways

The present invention can directly use 5-hydroxymethyl-1,4-dioxane-2-one and benzyl chloride as raw materials to react to prepare 5-benzyloxymethyl-1,4-dioxane-2-one . 5-benzyloxymethyl-1,4-dioxane-2-one can also be prepared according to the following reaction formula:

Embodiment one:

5-hydroxyl-1, the preparation of 3-dioxane (compound 1): in the mixed solution of 522g benzaldehyde (4.92mol) and 451g glycerol (4.90mol), the concentrated sulfuric acid of catalyst amount is added dropwise, at room temperature stirring reaction After 4 hours, the reaction system was decompressed with a water pump and heated slightly (40-45° C.) to remove the water produced by the reaction until the reactant turned into a pale yellow clear solution. It was cooled to room temperature, stirred for 1 h, 500 mL of anhydrous diethyl ether was added to the reaction solution, washed with 10% sodium carbonate solution (150 mL×2) and 150 mL of saturated brine respectively, the organic layer was dried with anhydrous sodium sulfate, and added Diluted with 500 mL of anhydrous ether, put the solution in the refrigerator overnight to obtain white needle-like crystals, recrystallized twice with anhydrous ether to obtain 423 g of the product (yield 48%), m.p.82-83°C.

Embodiment two:

Preparation of 5-hydroxymethyl-1,4-dioxane-2-one: 30g (0.167mol) compound 5-hydroxyl-1,3-dioxane 1 was dissolved in 300mL anhydrous toluene, and 3.91g (0.17mol) sodium metal, under the protection of _N , the reaction mixture was slightly refluxed until the sodium metal reacted completely, the reaction solution was cooled to room temperature, and under stirring, slowly added dropwise 41g (0.245mol) ethyl bromoacetate. After stirring at room temperature for 3 h, add 500 mL of toluene to dilute the reaction solution and pour it into 150 mL of ice water. The organic layer is dried with anhydrous Na ₂ SO ₄ . Colored oil, crystallized compound 2 can be obtained after standing. Dissolve 30.5g (0.115mol) of compound 2 in 200mL of ethanol, then add 200mL of 1M NaOH in ethanol, and stir at room temperature for 2h. After removing the solvent, the residue was dissolved in water and acidified to pH=3 with concentrated hydrochloric acid. After stirring at room temperature for 3 h, the reaction solution was washed with a small amount of dichloromethane to remove unreacted raw materials. After removing water, distill under reduced pressure, collect the fraction at 150-160°C/1mmHg, and redistill this fraction (bp128-132°C/0.07mmHg) to obtain a colorless oily substance 3(5-hydroxymethyl-1, 4-dioxan-2-one, 8.54 g, 48% yield).

Embodiment three:

The preparation of 5-benzyloxymethyl-1,4-dioxane-2-ketone: the compound 3 (5-hydroxymethyl-1,4-dioxane-2-ketone of 10g (0.076mol) ) was dissolved in 150mL of anhydrous 1,4-dioxane, 3.64g (0.152mol) of sodium hydride and 12.7g (0.1mol) of benzyl chloride were added to this solution, the reaction mixture was refluxed for 12h and cooled and filtered, and the filtrate After concentration, the residue was distilled under reduced pressure to obtain 7.60 g of compound 4 (bp 177-180° C./2 mmHg), with a yield of 45%. FTIR (cm ^-1 ): 1745, 1378, 1109, 742, 690; ¹ H NMR (CDCl ₃ , ppm): δ3.60-3.75 (m, 1H, -COO-CH ₂ -CH-), 3.80-3.90 (m, 2H, -COO-CH ₂ -CH-), 4.38 (s, 2H, -OCO-CH ₂ -O-), 4.40~4.50 (m, 2H, -CH ₂ -O-CH ₂ Ph), 4.70 (s, 2H, -CH ₂ -O-CH ₂ Ph), 7.15-7.20 (m, 5H, -C ₆ H ₅ ); MS (m/z): 222 (M ⁺ ).

The same product can also be obtained by replacing sodium hydride with sodium hydroxide or metal sodium in the above reaction.

Embodiment four:

Synthesis of copolymers of 5-benzyloxymethyl-1,4-dioxan-2-one and 1,4-dioxan-2-one: metered 5-benzyloxymethyl-1,4 -dioxane-2-ketone and 1,4-dioxane-2-ketone and initiator solution are added in the dry glass polymerization tube, and the system is repeatedly evacuated and filled with _N Process 4 times, with Remove the solvent, then seal the tube under reduced pressure, put it in a constant temperature oil bath to polymerize for a period of time, and take it out. The obtained polymer is dissolved with a small amount of chloroform, precipitated with a large amount of methanol, filtered, and dried to constant temperature. Heavy.

Claims (4)

1,5-benzyloxymethyl-1, the 4-dioxane-2-ketone, its structural formula is:

2, the described 5-benzyloxymethyl-1 of claim 1, the preparation method of 4-dioxane-2-ketone, it is characterized in that: with 5-methylol-1,4-dioxane-2-ketone and benzyl chlorine are that raw material back flow reaction in the presence of sodium hydride or sodium hydroxide or sodium Metal 99.5 makes 5-benzyloxymethyl-1, the 4-dioxane-2-ketone.

3, preparation method according to claim 2, it is characterized in that: with 5-hydroxyl-1,3-benzal glycerine and ethyl bromoacetate be 45～65 ℃ of reactions in the presence of sodium Metal 99.5 or sodium hydride, underpressure distillation makes 5-methylol-1 after alkaline condition and twice hydrolysis of acidic conditions again, the 4-dioxane-2-ketone, again with 5-methylol-1,4-dioxane-2-ketone and benzyl chlorine are that raw material reacts in the presence of sodium hydride and makes 5-benzyloxymethyl-1, the 4-dioxane-2-ketone.

4, the described 5-benzyloxymethyl-1 of claim 1, the 4-dioxane-2-ketone is used to prepare functionalization biodegradable poly P-Dioxane ketone, biodegradable copolymer, is used to prepare functionalization ring-type P-Dioxane ketone and poly-P-Dioxane ketone, is used to prepare the cyclic intermediate that contains medicine or biologically active substance as intermediate.