CN115959986A - Preparation method of methoxypolyethylene glycol acetic acid and propionic acid - Google Patents

Abstract

The invention provides a preparation method of methoxypolyethylene glycol acetic acid and propionic acid, which synthesizes a target compound through one-step reaction and obtains a high-purity product after simple post-treatment. The method has the advantages of short operation steps, simple purification method, no need of column chromatography, low cost, mild reaction conditions and suitability for amplification.

Description

Preparation method of methoxypolyethylene glycol acetic acid and propionic acid

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of methoxypolyethylene glycol acetic acid and propionic acid

Background

Polyethylene glycol (PEG) is the most commonly used polymer in biopharmaceuticals, and can improve drug solubility and stability, reduce immunogenicity, and prolong drug half-life. Polyethylene glycols on an industrial scale are obtained by anionic polymerization of ethylene oxide, which are complex mixtures of polymers of different lengths. Heterogeneous polyethylene glycol may cause a series of problems in its application, such as difficulty in purification and characterization of the resulting PEG-drug conjugate, limitation of drug quality control methods, difference in therapeutic effect due to lot-to-lot variation, and the like. The monodisperse polyethylene glycol has a certain polymerization degree, and the molecular weight and the structure are determined, so that the defect of heterogeneous polyethylene glycol is overcome, but how to efficiently prepare the monodisperse polyethylene glycol with small molecular weight and the derivatives thereof is still the next more complicated problem. The existing available synthesis line generally has the problems of large raw material consumption, long synthesis steps, low reaction yield, difficult purification and the like.

The polyethylene glycol molecule contains two active end groups (hydroxyl groups), and if one of the hydroxyl groups is sealed by a methoxy group and the hydroxyl group at the other end is modified by a carboxymethyl or carboxyethyl group, the methoxy polyethylene glycol acetic acid (mPEGn-CH) is obtained ₂ COOH) or methoxypolyethyleneglycol propanoic acid (mPEGn-CH) ₂ CH ₂ COOH), they are a useful class of organic synthetic intermediates for polyethylene glycols. Wherein the active carboxyl group can be condensed with amino group, or derivatized, converted into alcohol, aldehyde, ester, etc., and then reacted with a suitable reactive group.

The literature reports (US 2019161468, EP3127900, US 9301951) that the preparation method of methoxypolyethylene glycol acetic acid comprises two synthetic steps: 1) Deprotonating raw material mPEGn-OH with a strong base such as NaH to undergo nucleophilic substitution with tert-butyl bromoacetate; 2) The tert-butyl ester is removed under acidic conditions. The preparation method of methoxypolyethylene glycol propionic acid also comprises two steps (CN 109096128): 1) Deprotonating raw material mPEGN-OH by using strong base such as sodium block, and carrying out Michelal addition reaction with tert-butyl acrylate; 2) The tert-butyl ester is removed under acidic conditions.

The disadvantages of both methods are: 1) Strong base such as NaH or sodium blocks are needed, the chemical reaction activity is high, the material can spontaneously combust in humid air and is a dangerous chemical product easy to explode, or tert-butyl ester potassium is used, and the cost is high; 2) The obtained intermediate tert-butyl ester can enter the next step generally through column chromatography purification, and the production cost is high; 3) The yield of the two steps is lower.

Disclosure of Invention

Definition of

Unless otherwise indicated, the terms used in the specification and claims are defined as follows:

"PEG" refers to polyethylene glycol and also includes homologs or derivatives thereof, such as polypropylene glycol, polybutylene glycol, copolymers of ethylene glycol and propylene glycol, and the like.

"halo" means substituted by "halogen" and includes chloro, bromo, iodo, or the like.

"base" refers to a compound that, when reacted with another compound, deprotonates the compound. Bases suitable for use in the present application include, but are not limited to, organic bases, alkali or alkaline earth metal hydroxides, alkali metal salts, and the like. Common bases include, but are not limited to, nitrogen-containing heterocycles and amines, such as pyridine, imidazole, benzimidazole, triethylamine, N-methylmorpholine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU), sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium and potassium alkoxides (including but not limited to sodium and potassium tert-butoxide, sodium 1-propoxide, potassium 1-propoxide, sodium and potassium 2-propoxide, sodium and potassium ethoxide, sodium and potassium methoxide, and the like), sodium amide (NaNH H-R-H) ₂ ) Potassium amide (KNH) ₂ ) Sodium hydride, potassium hydride, and the like.

"ambient conditions" refers to conditions under which tests are conducted in a standard laboratory, such as 1atm, air, ambient temperature of 18 to 28 ℃, relative humidity of 30-80%. Unless otherwise indicated, the reactions in the present application are all carried out under ambient conditions.

"treating" or "reacting" refers to the addition of one chemical species (commonly referred to as a reagent or reactant) or the mixing of two or more species under appropriate conditions to produce the desired product. It should be noted that the reaction that produces the desired product may not necessarily result directly from the combination of two or more reagents that were initially added, i.e., one or more intermediates that lead to the formation of the desired product may be produced in the mixture.

"crystallization" and "recrystallization" are used interchangeably and refer to the process of obtaining a particular, stable polymorphic or crystalline form of a compound from the compound dissolved or suspended in a solvent system. The crystallization can be carried out by using a solvent and an antisolvent.

The invention provides a preparation method of methoxypolyethylene glycol acetic acid and propionic acid (formula I), namely, a target compound is synthesized through one-step reaction, and a high-purity product is obtained through simple post-treatment. The method has the advantages of short operation steps, simple purification method, no need of column chromatography, low cost, mild reaction conditions and suitability for amplification.

The method comprises the following operation steps: 1) Dissolving monomethoxy polyethylene glycol in an organic solvent; 2) Adding a proper amount of alkali under a proper temperature condition; 3) Adding a proper amount of halogenated acetyl ester or acrylic ester under a proper temperature condition, and stirring for a certain time under the proper temperature condition; 4) Diluting the reaction solution with water, layering the mixture, and adjusting the pH value of the aqueous phase; 5) The aqueous phase is extracted with a suitable organic solvent, the combined extracts are washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.

In one embodiment, the organic solvent in step 1) is one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dichloromethane, toluene, dioxane, methanol and ethanol. Preferred organic solvents are tetrahydrofuran, dioxane or toluene.

In one embodiment, the reaction temperature in step 2) is from-45 to 50 ℃. The preferred reaction temperature is-10-5 ℃.

In one embodiment, the base in step 2) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium carbonate, sodium hydride, and potassium hydride. Preferred bases are inorganic bases such as sodium hydroxide or potassium hydroxide.

Further, the inorganic base used in step 2) is 5 to 80% aqueous sodium hydroxide or potassium hydroxide, preferably 20 to 60% aqueous sodium hydroxide or potassium hydroxide, and more preferably 40 to 50% aqueous sodium hydroxide or potassium hydroxide.

In one embodiment, the molar ratio of base to monomethoxypolyethylene glycol in step 2) is 1:1-100:1, preferably 5:1-50:1, more preferably 10:1-40:1, more preferably 20:1-30:1.

in one embodiment, the haloacetyl ester added in step 3) is one of tert-butyl chloroacetate, tert-butyl bromoacetate, methyl chloroacetate, methyl bromoacetate, ethyl chloroacetate, ethyl bromoacetate, preferably methyl bromoacetate, ethyl bromoacetate or tert-butyl bromoacetate; the acrylate is methyl acrylate, ethyl acrylate or tert-butyl acrylate.

Further, the molar ratio of the halogenated acetyl ester or the acrylic ester and the monomethoxy polyethylene glycol added in the step 3) is 1:1-10:1, preferably 1:1-5:1, more preferably 1:1-3:1.

further, the haloacetyl ester or acrylate in step 3) is added at-20-30 ℃ and then stirred at-20-30 ℃, preferably at-10-15 ℃ and then stirred at 10-30 ℃.

Further, the reaction stirring time in step 3) is 30 minutes to 96 hours, preferably 16 to 24 hours, and more preferably 2 to 8 hours.

In one embodiment, when step 2) or step 3) is performed, a phase transfer catalyst such as benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, or the like may be added.

In one embodiment, the aqueous phase after separation in step 4) is adjusted to acidic pH with sulfuric acid, nitric acid, hydrochloric acid or phosphoric acid, preferably pH 1 to 6.5, more preferably 2 to 4.

In one embodiment, the extraction solvent in step 5) is dichloromethane, ethyl acetate or isopropyl acetate.

The preparation method in the application of the invention has the following process route:

wherein n =1-100.

Compared with the prior art, the invention has the advantages that:

1) The two-step reaction operation is optimized to a one-step reaction.

2) The purification process is simple, and column chromatography purification is not required.

3) Can obtain uniform, stable and high-purity product.

4) The process does not involve the use of dangerous chemicals, and is green and environment-friendly.

5) Low requirement on equipment and simple operation.

Drawings

FIG. 1 shows methoxy hepta-polyethylene glycol acetic acid as the product of example 2 ¹ H-NMR spectrum.

FIG. 2 shows methoxy octa-polyethylene glycol acetic acid as the product of example 3 ¹ H-NMR spectrum.

FIG. 3 shows the methoxy nonapolyethylene glycol acetic acid product of example 4 ¹ H-NMR spectrum.

FIG. 4 is a representation of methoxy hexapolyethylene glycol propionic acid product of example 8 ¹ H-NMR spectrum.

FIG. 5 shows methoxy heptapolyethylene glycol propionic acid as the product of example 9 ¹ H-NMR spectrum.

FIG. 6 shows methoxy octapolyethylene glycol propionic acid as the product of example 10 ¹ H-NMR spectrum.

FIG. 7 shows methoxypolyethyleneglycol propionic acid as the product of example 12 ¹ H-NMR spectrum.

Detailed description of the preferred embodiment

Example 1

14.2g of hexaethyleneglycol monomethyl ether was dissolved in 150mL of toluene, stirred and dissolved, cooled to 0 ℃ in an ice bath, and 127g of a 50% aqueous solution of sodium hydroxide was added thereto, and the temperature of the reaction mixture was controlled so as not to exceed 10 ℃, cooled to 5 ℃, and 37.4g of t-butyl bromoacetate was added dropwise. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. The reaction solution was analyzed by LC-MS, showing no remaining raw material, the reaction was stopped, water (200 mL) was added to quench the reaction, stirring was carried out, and the aqueous phase was separated after standing for separation. Adjusting the pH value of the water phase to 2-3 by concentrated hydrochloric acid, extracting with dichloromethane (3X 0.2L), mixing the extractive solutions, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating,the desired product, methoxyhexapolyethylene glycol acetic acid (17 g, 100% yield), was obtained. ESI-MS m/z: C ₁₅ H ₃₀ O ₉ [M+H] ⁺ Theoretical 355.19, found 355.19.

Example 2

23.8g of heptaethyleneglycol monomethyl ether was dissolved in 300mL of toluene, stirred and dissolved, and then cooled to 0 ℃ in an ice bath, 185g of a 50% aqueous solution of sodium hydroxide was added thereto, and the temperature of the reaction mixture was controlled not to exceed 10 ℃ and cooled to 5 ℃, and 54.6g of t-butyl bromoacetate was added dropwise. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. And (3) analyzing the reaction liquid by LC-MS (liquid chromatography-mass spectrometry) to show that no raw material remains, stopping the reaction, adding water to quench the reaction, stirring, standing for layering, and separating out a water phase. Adjusting the pH value of the water phase to 2-3 by concentrated hydrochloric acid, extracting the water phase for three times by dichloromethane, combining extract liquor, washing the extract liquor by saturated salt water once, drying the extract liquor by anhydrous sodium sulfate, filtering and concentrating to obtain a target product, namely methoxy hepta-polyethylene glycol acetic acid (25.2 g, the yield is 90%). ¹ H NMR(400MHz，DMSO)δ4.01(s，2H)，3.60–3.55(m，2H)，3.55–3.47(m，24H)，3.44–3.40(m，2H)，3.24(s，3H)。ESI-MS m/z：C ₁₇ H ₃₄ O ₁₀ [M+H] ⁺ : calcd 399.22, found 399.25.

Example 3

384.5g of octaethylene glycol monomethyl ether was dissolved in 3L of toluene, mechanically stirred, cooled in an ice bath to 0 ℃ and 2.6kg of 50% aqueous sodium hydroxide solution was added thereto while controlling the temperature of the reaction solution not to exceed 10 ℃, cooled to 5 ℃, 780g of t-butyl bromoacetate was added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the mixture was stirred for 16 hours. The reaction solution was analyzed by LC-MS to show that no raw material remained, and the reaction was stopped, and 5L of water was added to quench the reaction. Stirring vigorously, standing for layering, and separating out water phase. The aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 4L), the combined extracts were washed once with saturated brine (3L), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy octapolyethylene glycol acetic acid (403 g, 91% yield). ¹ H NMR(400MHz，DMSO)δ4.01(s，2H)，3.61–3.55(m，3H)，3.55–3.45(m，28H)，3.44–3.40(m，2H)，3.24(s，3H)。ESI-MS m/z：C ₁₉ H ₃₈ O ₁₁ [M+H] ⁺ : calcd 443.24, found 443.31.

Example 4

428.5g of nonaethylene glycol monomethyl ether is dissolved in 3L of toluene, mechanically stirred for 30min, cooled to 0 ℃ in ice bath, 2kg of 50% sodium hydroxide aqueous solution is added, cooled to 5 ℃, 780g of tert-butyl bromoacetate is added dropwise, and the temperature of the reaction system is controlled below 15 ℃. After the dropwise addition, the temperature was naturally raised to room temperature (23 ℃), the reaction was stopped by stirring for 6 hours, and 5L of water was added to quench the reaction. The reaction solution was vigorously stirred, and after standing and layering, the aqueous phase was separated. The aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 4L), the combined extracts were washed once with saturated brine (1L), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxynonapolyethylene glycol acetic acid (500 g, 100% yield). ¹ H NMR(400MHz，DMSO)δ4.01(s，2H)，3.58(dd，J＝5.8，3.0Hz，3H)，3.56–3.45(m，32H)，3.42(dd，J＝5.9，3.5Hz，2H)，3.24(s，3H)。ESI-MS m/z：C ₂₁ H ₄₂ O ₁₂ [M+H] ⁺ : calcd 487.27, found 487.35.

Example 5

11.5g of octaethyleneglycol monomethyl ether was dissolved in 100mL of dichloromethane, magnetically stirred until dissolved, and 60g of a 50% aqueous solution of sodium hydroxide was added thereto, followed by dropwise addition of 23.4g of t-butyl bromoacetate. After the addition, the reaction was carried out at room temperature (23 ℃ C.) overnight. The reaction solution was analyzed by LC-MS, which showed that substantially no starting material remained, and the reaction was stopped. The reaction was quenched by the addition of 500mL of water. The reaction solution was stirred vigorously, allowed to stand for stratification and the aqueous phase was separated. The aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 300 mL), the combined extracts were washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy octapolyethylene glycol acetic acid (13 g, 100% yield). ESI-MS m/z: c ₁₉ H ₃₈ O ₁₁ [M+H] ⁺ : calcd 443.24, found 443.31.

Example 6

115g of octaethylene glycol monomethyl ether was dissolved in 1L of toluene, mechanically stirred, cooled to 10 ℃ and 1kg of a 30% aqueous sodium hydroxide solution was added thereto while controlling the temperature of the reaction solution not to exceed 10 ℃, cooled to 5 ℃, 234g of t-butyl bromoacetate and 10g of tetrabutylammonium hydrogen sulfate were added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the mixture was stirred for 48 hours. LC-MS analysis of the reaction solution showed that a small amount of the starting material remained, and the reaction was stopped, and 0.5L of water was added to quench the reaction. The reaction solution was vigorously stirred, and after standing and layering, the aqueous phase was separated. The aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 1L), the combined extracts were washed once with saturated brine (0.2L), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy octapolyethylene glycol acetic acid (133 g, 100% yield). ESI-MS m/z: c ₁₉ H ₃₈ O ₁₁ [M+H] ⁺ : calcd 443.24, found 443.31.

Example 7

1.15g of octaethyleneglycol monomethyl ether was dissolved in 10mL of toluene, magnetically stirred, cooled to 10 ℃ and 10g of a 30% aqueous solution of sodium hydroxide was added thereto while controlling the temperature of the reaction solution not to exceed 10 ℃, cooled to 5 ℃, 2.34g of t-butyl bromoacetate and 0.1g of tetrabutylammonium chloride were added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the mixture was stirred for 48 hours. LC-MS analysis of the reaction solution showed that a small amount of starting material remained, and the reaction was stopped, and 10mL of water was added to quench the reaction. The reaction solution was stirred vigorously, allowed to stand for stratification and the aqueous phase was separated. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 10 mL), the combined extracts were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy octapolyethylene glycol acetic acid (1.2 g, 85.2% yield). ESI-MS m/z: c ₁₉ H ₃₈ O ₁₁ [M+H] ⁺ : calcd 443.24, found 443.31.

Example 8

Dissolving 3.41g of hexaethyleneglycol monomethyl ether in 20mL of toluene, magnetically stirring for 30min, cooling to 0 ℃ in an ice salt bath, and adding 20g of 50% hydrogen hydroxideSubsequently, the temperature of the aqueous sodium solution was further lowered to 5 ℃ and 5.13g of t-butyl acrylate was added dropwise thereto while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. Adding 50mL of water to quench and react, stirring the reaction solution vigorously, standing for layering, and separating out a water phase. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 20 mL), the combined extracts were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy hexapolyethylene glycol propionic acid (2.9 g, 79% yield). ¹ H NMR(400MHz,DMSO)δ3.60(t,J＝6.3Hz,2H),3.53–3.48(m,24H),3.43(dd,J＝5.9,3.5Hz,2H),3.24(s,3H),2.44(t,J＝6.4Hz,2H)。ESI-MS m/z:C ₁₆ H ₃₂ O ₉ [M+H] ⁺ Theoretical 369.42, found 369.17.

Example 9

3.41g of heptaethylene glycol monomethyl ether was dissolved in 20mL of toluene, and the mixture was magnetically stirred for 30min, cooled to 0 ℃ in an ice salt bath, 20g of a 50% aqueous sodium hydroxide solution was added, and then, when the temperature was further reduced to 5 ℃, 5.13g of t-butyl acrylate was added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. Adding 50mL of water to quench and react, stirring the reaction solution vigorously, standing for layering, and separating out a water phase. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 20 mL), the combined extracts were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxypolyethyleneglycol propionic acid (3.6 g, 86% yield). ¹ H NMR(400MHz,DMSO)δ12.14(bs,1H)，3.60(t,J＝6.4Hz,1H),3.55–3.45(m,28H),3.43(dd,J＝5.9,3.6Hz,2H),3.24(s,3H),2.43(t,J＝6.4Hz,2H)。ESI-MS m/z:C ₁₈ H ₃₆ O ₁₀ [M+H] ⁺ Theoretical 413.48, found 413.19.

Example 10

Dissolving 3.84g of octaethylene glycol monomethyl ether in 20mL of toluene, magnetically stirring for 30min, cooling to 0 ℃ in an ice salt bath, adding 20g of 50% sodium hydroxide aqueous solution, continuously cooling to 5 ℃, dropwise adding 5.13g of tert-butyl acrylate, and controlling the reaction systemThe temperature of (2) is 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. Adding 50mL of water to quench and react, stirring the reaction solution vigorously, standing for layering, and separating out a water phase. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 20 mL), the combined extracts were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy octapolyethylene glycol propionic acid (4.2 g, 92% yield). ¹ H NMR(400MHz,DMSO)δ12.13(bs,1H)，3.60(t,J＝6.4Hz,2H),3.55–3.45(m,32H),3.43(dd,J＝5.9,3.5Hz,2H),3.24(s,3H),2.44(t,J＝6.4Hz,2H)。ESI-MS m/z:C ₂₀ H ₄₀ O ₁₁ [M+H] ⁺ Theoretical 457.53, found 457.24.

Example 11

4.28g of nonaethylene glycol monomethyl ether was dissolved in 20mL of toluene, and the mixture was magnetically stirred for 30min, cooled to 0 ℃ in an ice salt bath, 20g of a 50% aqueous sodium hydroxide solution was added, and then, when the temperature was further reduced to 5 ℃, 5.13g of t-butyl acrylate was added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. Adding 50mL of water to quench and react, stirring the reaction solution vigorously, standing for layering, and separating out a water phase. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, then extracted with dichloromethane (2X 20 mL), the combined extracts were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxy nonapolyethylene glycol propionic acid (4.2 g, 84% yield). ESI-MS m/z: C ₂₂ H ₄₄ O ₁₂ [M+H] ⁺ Theoretical 501.58, found 501.58.

Example 12

4.73g of decaethylene glycol monomethyl ether was dissolved in 20mL of toluene, and the mixture was magnetically stirred for 30min, cooled to 0 ℃ in an ice salt bath, 20g of a 50% aqueous sodium hydroxide solution was added, and then, when the temperature was further reduced to 5 ℃, 5.13g of t-butyl acrylate was added dropwise while controlling the temperature of the reaction system to 15 ℃ or lower. After the addition, the temperature was naturally raised to room temperature (23 ℃ C.), and the reaction was stirred overnight. Adding 50mL of water to quench and react, stirring the reaction solution vigorously, standing for layering, and separating out a water phase. Adjusting the pH value of the water phase to 2-3 by concentrated hydrochloric acid, and then using IIMethyl chloride extraction (2X 20 mL), combined extracts, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product, methoxypolyethyleneglycol propionic acid (5.0 g, 92% yield). ¹ H NMR(400MHz,DMSO)δ12.12(bs,1H),3.60(t,J＝6.4Hz,2H),3.55–3.45(m,40H),3.43(dd,J＝5.9,3.5Hz,2H),3.24(s,3H),2.44(t,J＝6.4Hz,2H)。ESI-MS m/z:C ₂₄ H ₄₈ O ₁₃ [M+H] ⁺ Theoretical 545.64, found 545.29.

Claims (15)

1. A method for preparing methoxypolyethylene glycol acetic acid and propionic acid (formula I),

characterized in that the method comprises the following operating steps: 1) Dissolving monomethoxy polyethylene glycol in an organic solvent; 2) Adding a proper amount of alkali solution under a proper temperature condition; 3) Adding a proper amount of halogenated acetyl ester or acrylic ester under a proper temperature condition, and stirring for a certain time under the proper temperature condition; 4) Diluting the reaction solution with water, layering the mixture, and adjusting the pH value of the aqueous phase; 5) The aqueous phase is extracted with a suitable organic solvent, the combined extracts are washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.

2. The method according to claim 1, wherein the organic solvent in step 1) is one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dichloromethane, toluene, dioxane, methanol and ethanol, preferably tetrahydrofuran, dioxane or toluene.

3. The process according to claim 1, wherein the reaction temperature in step 2) is-45 to 50 ℃, preferably-10-5 ℃.

4. The preparation method according to claim 1, wherein the base in step 2) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride and potassium hydride, preferably sodium hydroxide or potassium hydroxide.

5. Sodium or potassium hydroxide according to claim 6, characterized in that it is added as a 5-80%, preferably 20-60% or more preferably 40-50% aqueous solution.

6. The method according to claim 1, wherein the molar ratio of the alkali solution to the monomethoxypolyethylene glycol in the step 2) is 1:1-100:1, preferably 5:1-50:1, or more preferably 20:1-30:1.

7. the preparation method according to claim 1, wherein the haloacetyl ester in step 3) is one of t-butyl chloroacetate, t-butyl bromoacetate, methyl chloroacetate, methyl bromoacetate, ethyl chloroacetate and ethyl bromoacetate, preferably methyl bromoacetate, ethyl bromoacetate or t-butyl bromoacetate; the acrylate is methyl acrylate, ethyl acrylate or tert-butyl acrylate.

8. The method of claim 1, wherein the molar ratio of the haloacetyl ester or acrylate and the monomethoxypolyethylene glycol added in step 3) is 1:1-10:1, preferably 1:1-5:1, more preferably 1:1-3:1.

9. the method according to claim 1, wherein the temperature of the addition of the haloacetyl ester or acrylate in step 3) is-20 to 30 ℃, the stirring temperature is-20 to 30 ℃, preferably-10 to 15 ℃ and the stirring temperature is 10 to 30 ℃.

10. The reaction of claim 1 with stirring time of 30 minutes to 96 hours, preferably 16 to 24 hours, more preferably 2 to 8 hours.

11. The method according to claim 1, wherein a phase transfer catalyst is added when step 2) or step 3) is performed.

12. The phase transfer catalyst of claim 21, selected from benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, and the like.

13. The process according to claim 1, wherein the aqueous phase after separation in step 4) is adjusted to a pH of 1 to 6.5, preferably a pH of 2 to 4, with sulfuric acid, nitric acid, hydrochloric acid or phosphoric acid.

14. The method according to claim 1, wherein the extraction solvent in step 5) is dichloromethane, ethyl acetate or isopropyl acetate.

15. The organic solvent according to claim 2, preferably: tetrahydrofuran, dioxane or toluene.

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