Synthesis method of 2-(2-(2-bromoethyoxyl) ethyoxyl) ethanol

Abstract

The invention discloses a synthesis method of 2-(2-(2-bromoethyoxyl) ethyoxyl) ethanol, which comprises the following step: by taking a compound 2-chloroethoxy-2-ethyoxyl diethanol as a raw material, under the action of zinc bromide, obtaining a target compound 2-(2-(2-bromoethyoxyl) ethyoxyl) ethanol. Zinc bromide adopted in the process serves as a bromine source and has the effect of Lewis acid, chlorine leaving groups are activated, and the reaction is completed efficiently. Finally, the preparation of the compound 2-(2-(2-bromoethyoxyl) ethyoxyl) ethanol through short steps, simple operation, low cost and relatively mild reaction conditions is realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol. BACKGROUND

[0002] The compound 2-(2-(2-bromoethoxy)ethoxy)ethanol is a polyethylene glycol (PEG) derivative containing a bromine substituent, which has a structure similar to triethylene glycol and is mainly used as an organic synthesis intermediate or functional material in multiple fields. Based on the analysis of similar compounds, its main uses include: On the one hand, it can be used as an organic synthesis intermediate, which is often used to construct complex molecules, such as precursors of drugs or functional materials, and other functional groups are introduced through nucleophilic substitution reactions of bromine atoms. Similar chloro derivatives (such as 2-[2-(2-chloroethoxy)ethoxy]ethanol) are widely used in the synthesis of pharmaceutical intermediates or special chemicals; on the other hand, as a PEG compound, 2-(2-(2-bromoethoxy)ethoxy)ethanol can be used to synthesize protein degradation targeting chimera (PROTAC) molecules, similar to the use of short-chain bromo-PEG derivatives (such as 2-(2-bromoethoxy)ethanol) in cancer research, which promotes the degradation of target proteins by connecting target protein ligands and E3 ubiquitin ligase ligands; in addition, 2-(2-(2-bromoethoxy)ethoxy)ethanol can be used as a high-boiling solvent, and its polyether structure makes it suitable for the ink, dye, resin and coating industries, providing good solubility and leveling as a solvent, similar to the application examples of similar compounds 2-(2-methoxyethoxy)ethanol.

[0003] In the prior art, triethylene glycol is generally used as a raw material to react with carbon tetrabromide under the action of triphenylphosphine to prepare the compound 2-(2-(2-bromoethoxy)ethoxy)ethanol. Although the yield of this method can reach more than 80%, carbon tetrabromide used in this method is a highly toxic chemical with high risk. Therefore, it is of great significance to develop a new synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol. The synthesis method has the advantages of low cost, short steps, easy operation, relatively mild reaction conditions, low safety hazards, and high yield.

[0005] The technical scheme of the present application is as follows: A synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol, which is carried out according to the following flowchart: .

[0006] Further, specifically comprising the following steps: (1) Compound 1, i.e. 2-chloroethoxy-2-ethoxydiethanol, is dissolved in an organic solvent I, then zinc bromide is added, and the temperature is raised to 80-150 DEG C, and stirring is carried out for 8-20 h.

[0007] (2) After the reaction is completed, the reaction liquid is treated, and the target compound 2, i.e. 2-(2-(2-bromoethoxy)ethoxy)ethanol, is obtained.

[0008] Further, in step (1), the organic solvent I includes at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0009] Further, in step (1), the mass-volume ratio g / mL of compound 1 to the organic solvent I is 1:5-40.

[0010] Further, in step (1), the molar ratio of compound 1 to zinc bromide is 1:1-5.

[0011] Further, in step (2), after the reaction is completed, the reaction liquid is cooled to room temperature, and then added to water, extracted with an organic solvent II, the organic phases are combined, washed, dried, filtered, and rotary evaporated to obtain the target compound 2, i.e. 2-(2-(2-bromoethoxy)ethoxy)ethanol.

[0012] Further, in step (2), the organic solvent II is selected from any one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0013] Further, in step (1), the organic solvent I is N,N-dimethylformamide.

[0014] Further, in step (1), the temperature is raised to 110 DEG C.

[0015] Further, in step (1), stirring is carried out for 12 h.

[0016] The present application has the beneficial technical effects that: The present application provides a synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol, which uses compound 2-chloroethoxy-2-ethoxydiethanol as a raw material, and obtains target compound 2-(2-(2-bromoethoxy)ethoxy)ethanol under the action of zinc bromide. In this process, zinc bromide is used as a bromine source to provide bromide ions (Br - ), which participate in nucleophilic substitution reaction. Zinc bromide has significant advantages as a bromine source in this reaction, mainly including efficient bromide ion supply and Lewis acid activation, specifically: zinc bromide is easily dissociated into Zn2+ and Br - ion, Br - directly attacks the chloro carbon (-CH2-Cl) as a strong nucleophile, realizes fast chloro-bromo exchange; Zn 2+ coordinates with the chlorine atom as a Lewis acid, weakens the bond energy of C-Cl bond, reduces the removal energy barrier of leaving group (Cl - ), so that the reaction is efficiently completed under mild conditions. Finally, a compound 2-(2-(2-bromoethoxy)ethoxy)ethanol preparation method with short steps, simple operation, low cost, mild reaction conditions and suitable for large-scale production is obtained. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 NMR spectrum of 2-(2-(2-bromoethoxy)ethoxy)ethanol prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0018] The present application will be described in detail below in combination with the drawings and examples.

[0019] Example 1

[0020] A synthesis method of 2-(2-(2-bromoethoxy)ethoxy)ethanol, comprising the following steps: (1) Compound 1, i.e. 2-chloroethoxy-2-ethoxydiethanol (200.00 g, 1.19 mol, 1.00 eq), is dissolved in N,N-dimethylformamide (2.0 L), then zinc bromide (534.20 g, 2.37 mol, 2.00 eq) is added, and the temperature is raised to 110℃, and the reaction is stirred for 12 h.

[0021] (2) After the reaction is completed, the reaction liquid is cooled to room temperature, and added to water (3.0 L), extracted with ethyl acetate twice (1.5 L x 2), the organic phases are combined, the organic phase is washed with water twice (2.0 L x 2), saturated brine twice (2.0 L x 2), then dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the target compound 2, i.e. 2-(2-(2-bromoethoxy)ethoxy)ethanol (weight 250.00 g, purity 98%, yield 97%).

[0022] The NMR spectrum of the obtained compound 2 (2-(2-(2-bromoethoxy)ethoxy)ethanol) is shown in Figure 1 The characterization data are as follows: 1H NMR (400 MHz, cdcl3) δ 3.82 (t, J = 6.2 Hz, 2H), 3.77 - 3.71 (m, 2H), 3.69 (s, 4H), 3.65 - 3.58 (m, 2H), 3.48 (t, J = 6.2 Hz, 2H), 2.19 (s, 1H). Example 2-3 The synthesis method of Example 2-3 is basically the same as that of Example 1, except that the molar amount of zinc bromide in Example 2-3 step (1) is 1.19 mol, 5.93 mol, respectively, and the remaining contents are unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Example 2-3 is shown in Table 1.

[0023] Example 4-6 The synthesis method of Example 4-6 is basically the same as that of Example 1, except that N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile are used instead of N,N-dimethylformamide in Example 4-6 step (1), respectively, and the remaining contents are unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Example 4-6 is shown in Table 1.

[0024] Example 7-9 The synthesis method of Example 7-9 is basically the same as that of Example 1, except that the stirring reaction temperature in Example 7-9 step (1) is 80°C, 100°C, and 150°C, respectively, and the remaining contents are unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Example 7-9 is shown in Table 1.

[0025] Example 10-11 The synthesis method of Example 10-11 is basically the same as that of Example 1, except that the stirring reaction time in Example 10-11 step (1) is 8h and 20h, respectively, and the remaining contents are unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Example 10-11 is shown in Table 1.

[0026] Comparative Example 1 The synthesis method of Comparative Example 1 is basically the same as that of Example 1, except that toluene is used instead of N,N-dimethylformamide in Comparative Example 1 step (1), and the remaining contents are unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Comparative Example 1 is shown in Table 1.

[0027] Comparative Example 2 The synthesis method of Comparative Example 1 is basically the same as that of Example 1, except that copper bromide is used to replace zinc bromide in Example 1 in step (1) of Comparative Example 1. The rest remains unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Comparative Example 2 is shown in Table 1.

[0028] Comparative Example 3 The synthesis method of Comparative Example 1 is basically the same as that of Example 1, except that sodium bromide is used to replace zinc bromide in Example 1 in step (1) of Comparative Example 1. The rest remains unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Comparative Example 3 is shown in Table 1.

[0029] Comparative Example 4 The synthesis method of Comparative Example 1 is basically the same as that of Example 1. The only difference is that in step (1) of Comparative Example 1, 4.74 mol sodium bromide and 120℃ are used instead of 2.37 mol zinc bromide and 110℃ in Example 1. The rest remains unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Comparative Example 4 is shown in Table 1.

[0030] Comparative Example 5 The synthesis method of Comparative Example 1 is basically the same as that of Example 1. The only difference is that potassium bromide is used to replace zinc bromide in Example 1 in step (1) of Comparative Example 1. The rest remains unchanged. The yield of 2-(2-(2-bromoethoxy)ethoxy)ethanol in Comparative Example 5 is shown in Table 1.

[0031] Table 1 Synthesis conditions and yield results of 2-(2-(2-bromoethoxy)ethoxy)ethanol for each example

[0032] As can be seen from the results in Table 1, and from the results of Examples 1-3, when the molar ratio of the starting material 2-chloroethoxy-2-ethoxydiethanol to zinc bromide is 1.0:1.0~5.0, the yield of the target compound 2-(2-(2-bromoethoxy)ethoxy)ethanol is relatively high. Among them, the product yields are basically the same when the molar ratio of 2-chloroethoxy-2-ethoxydiethanol to zinc bromide is 1.0:2.0 and 1.0:5.0.

[0033] In Examples 1 and 4-6, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile were used as solvents for the reaction, respectively. The reaction proceeded smoothly, and the yield of the target compound 2-(2-(2-bromoethoxy)ethoxy)ethanol was relatively high. Among them, the reaction with N,N-dimethylformamide as solvent yielded the highest yield. In Comparative Example 1, toluene was used as solvent, and the yield of the target compound was low.

[0034] As can be seen from the results of Example 1 and Examples 7-9, the reaction effect is substantially optimal when the reaction is performed at a temperature condition of 110°C.

[0035] As can be seen from the results of Example 1 and Examples 10-11, the reaction effect is substantially optimal when the reaction is performed for 12 h.

[0036] As can be seen from the results of Example 1 and Comparative Examples 2-5, the reaction effect is poor when the bromine source is replaced by copper bromide (CuBr2), sodium bromide (NaBr), or potassium bromide (KBr).

[0037] The above merely describes preferred embodiments of the present application, and the present application is not limited to the above examples. It can be understood that other improvements and changes directly derived or thought of by those skilled in the art without departing from the spirit and concept of the present application shall be considered to be within the protection scope of the present application.

Claims

1. A method for the synthesis of 2-(2-(2-bromoethoxy)ethoxy)ethanol, characterized in that, The synthetic method is carried out according to the following flow chart: 。 2. The synthetic method according to claim 1, characterized in that, Specifically comprising the following steps: (1) Compound 1, i.e. 2-chloroethoxy-2-ethoxydiethanol, is dissolved in an organic solvent I, zinc bromide is added, and the temperature is raised to 80-150 DEG C, and stirring is carried out for 8-20 h; (2) After the reaction is completed, the reaction liquid is subjected to post-treatment, and the target compound 2, i.e. 2-(2-(2-bromoethoxy)ethoxy)ethanol, is obtained.

3. The method of synthesis of claim 2, wherein, In the step (1), The organic solvent I comprises at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

4. The method of synthesis of claim 2, wherein, In the step (1), The mass-volume ratio g / mL of the compound 1 to the organic solvent I is 1:5-40.

5. The method of synthesis of claim 2, wherein, In the step (1), The molar ratio of the compound 1 to zinc bromide is 1:1-5.

6. The method of synthesis of claim 2, wherein, In the step (2), The post-treatment is that, after the reaction is completed, the reaction liquid is cooled to room temperature, and is added to water, extracted with an organic solvent II, the organic phases are combined, the organic phase is washed with water, saturated brine, and then is subjected to drying, filtration, and rotary evaporation to obtain the target compound 2, i.e. 2-(2-(2-bromoethoxy)ethoxy)ethanol.

7. The method of synthesis of claim 6, wherein, In the step (2), The organic solvent II is selected from any one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

8. The method of synthesis of claim 2, wherein, In the step (1), the organic solvent I is N,N-dimethylformamide.

9. The method of synthesis of claim 2, wherein, In the step (1), the temperature is raised to 110 DEG C.

10. The method of synthesis of claim 2, wherein, In the step (1), the stirring is carried out for 12 h.

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