CN114213283B - Method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one-pot method - Google Patents
Method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one-pot method Download PDFInfo
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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
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- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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Abstract
The invention discloses a method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by a one-pot method, and belongs to the technical field of synthesis. The method specifically comprises the steps of taking diglycolamine as a raw material, adopting di-tert-butyl dicarbonate to carry out amino protection, adding ethyl bromoacetate to carry out etherification reaction, and then carrying out the procedures of hydrolysis, deprotection, fomc-based amino protection and crystallization to prepare [2- [1- (Fmoc-amino) ethoxy ] acetic acid by a one-pot method; wherein the solvent used in the etherification reaction is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether. The purity of the product prepared by the method is more than 99%, the method has the characteristics of high yield, simple and convenient operation, lower production cost and the like, and the problems of complex preparation method, low yield and environmental protection of the existing method for preparing the [2- [1- (Fmoc-amino) ethoxy ] acetic acid can be effectively solved.
Description
Technical Field
The invention belongs to the technical field of synthesis, and relates to a method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by a one-pot method.
Background
The [2- [1- (Fmoc-amino) ethoxy ] acetic acid is a key intermediate compound for synthesizing an anti-AIDS drug, namely, ilabolt and a diabetes therapeutic drug, namely, the sorulon, and the modified PEG and the homolog thereof can be simultaneously applied to drug development, for example, protein drugs, peptide compounds, liposomes, micromolecular drugs and the like can be modified through coupling reaction. The modified compounds tend to have the following advantages: 1. a longer half-life; 2. lower maximum blood concentration; 3. the fluctuation of the blood concentration is small; 4. less enzymatic degradation; 5. less immunogenic and antigenic; 6. less toxic; 7. better solubility; 8. the frequency of administration is reduced; 9. the compliance of patients is improved, the quality of life is improved, and the treatment cost is reduced; 10. the liposome has stronger passive targeting effect on tumors, and the like. In addition, the modified PEG can be used for purifying and analyzing biomacromolecules and cells, and can be used as a novel drug material or a drug carrier after modifying saccharides.
In the synthesis of [2- [1- (Fmoc-amino) ethoxy ] acetic acid, the earliest literature report in 2002, the report route uses diglycolamine as a starting material, amino groups are protected by Boc and Cbz, etherification reaction uses tetrahydrofuran as a solvent and carries out etherification reaction with tert-butyl bromoacetate or ethyl bromoacetate under the action of sodium hydride or potassium tert-butoxide, then post-treatment is carried out, hydrolysis and deprotection groups are carried out, and finally Fmoc extraction, concentration and crystallization are carried out to obtain the product. However, since the hydrolysis process can be performed after the etherification reaction is completed and the extraction and concentration operation is performed, the operation process is excessively complicated, the production cost is increased, and the final yield is low due to poor impurity removal effect of the crystallization method.
CN110078644A, month 8 and 2 of 2019, discloses a preparation method of [2- [1- (Fmoc-amino) ethoxy ] acetic acid, wherein phthalic anhydride is used as amino for protection, the obtained intermediate is subjected to etherification reaction with halogenated acetic acid or halogenated acetate, deprotection or deprotection and hydrolysis are carried out, and the obtained product is reacted with Fomc-based amino protection reagent and then purified, so that [2- [1- (Fmoc-amino) ethoxy ] acetic acid is obtained. Although the method can obtain higher yield, the reaction temperature of phthalic anhydride and diglycolamine is higher, the safety risk is increased, the whole reaction and extraction steps are more, the solvent after solvent extraction is a mixed solvent which cannot be recovered, the green chemistry is not met, the crystallization process is too complicated, and the yield is low.
Thus, in view of the problems in the prior art, the present invention has studied a novel process for the preparation of [2- [1- (Fmoc-amino) ethoxy ] acetic acid.
Disclosure of Invention
The invention aims to solve the technical problems that the existing method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid is complex, low in product yield and not environment-friendly.
The technical scheme adopted for solving the technical problems is as follows: the one-pot method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid comprises the steps of taking diglycolamine as a raw material, adopting di-tert-butyl dicarbonate to carry out amino protection, adding ethyl bromoacetate to carry out etherification reaction, and then carrying out hydrolysis, deprotection and Fomc-based amino protection and crystallization to prepare the [2- [1- (Fmoc-amino) ethoxy ] acetic acid; wherein the solvent used in the etherification reaction is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether.
The amino protection by adopting the di-tert-butyl dicarbonate is as follows: in the presence of an alkaline reagent, diglycolamine and di-tert-butyl dicarbonate are added into a solvent to react to obtain an intermediate to be etherified
Wherein, the di-glycol amine and the di-tert-butyl dicarbonate are respectively 1mol, 1 to 1.5mol, 1 to 4mol of the di-glycol amine and the alkaline reagent.
Further, the above diglycolamine to alkaline reagent=1 mol:1-1.5 mol, diglycolamine to solvent (V/V) =1:0.5-2.
Further, the basic reagent is triethylamine; the solvent is any one of ethanol, methanol, acetonitrile and dichloromethane.
Further, the reaction temperature is controlled to be 10-50 ℃ and the reaction time is controlled to be 2-24h.
The etherification reaction by adding ethyl bromoacetate is as follows: uniformly mixing an intermediate to be etherified with a solvent, adding an alkaline reagent, stirring at a low temperature for reaction, adding a mixture of ethyl bromoacetate and the solvent at a low temperature, and naturally heating for reaction to obtain the etherified intermediate
Wherein, the intermediate to be etherified is bromoethyl acetate=1mol:1.1-2 mol; intermediate to be etherified: alkaline reagent = 1 mol: 1.1-2mol; the solvent is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether.
Further, the solvent mixed with the intermediate to be etherified is the intermediate to be etherified (V/V) =4-10:1; solvent mixed with ethyl bromoacetate to be etherified intermediate (V/V) =0.8-2:1.
Further, the alkaline agent is sodium hydride and/or potassium tert-butoxide.
Furthermore, the reaction is carried out under the protection of nitrogen, the alkaline solvent is added in batches, and the low temperature is less than 5 ℃.
The hydrolysis process comprises the following steps: directly adding sodium hydroxide and/or potassium hydroxide solution into the etherified intermediate for hydrolysis, standing and separating liquid to obtain a hydrolyzed intermediate
Wherein, the intermediate to be etherified, sodium hydroxide and/or potassium hydroxide=1mol:1.1-2mol.
Further, the solubility of the sodium hydroxide and/or potassium hydroxide solution is 1-3mol/L.
Further, standing and layering after the hydrolysis reaction, and separating liquid to obtain an organic phase and a water phase, wherein the water phase is a hydrolyzed intermediate; the organic phase is concentrated by rotary evaporation to obtain a solvent, and the solvent is recycled after being recovered.
The deprotection is to add hydrochloric acid into the intermediate after hydrolysis for deprotection to obtain a deprotection reaction solution
Wherein, the intermediate to be etherified is hydrochloric acid=1 mol:2-4 mol.
Further, the solubility of the hydrochloric acid solution was 12mol/L.
The Fomc amino protection is as follows: regulating pH of the deprotection reaction liquid to 8-10, and adding solvent and Fomc-based amino protecting reagent for reaction
Wherein, the intermediate to be etherified is Fomc amino protecting reagent=1:0.5-2 mol; the Fomc-based amino protecting reagent was Fmoc-OSu (Fmoc N-hydroxysuccinimide este, fluorenylmethoxycarbonyl succinimide) and/or Fmoc-Cl (9-Fluorenylmethyl Chloroformate, fluorenylmethoxycarbonyl chloride).
Further, the reaction is carried out by adjusting the pH with at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Further, the intermediate to be etherified is Fomc-based amino protecting reagent=1 mol:0.6-1 mol; intermediate to be etherified: solvent (V/V) =1:3-6; the solvent is water and ethanol, and the volume ratio of the water to the ethanol is 1:1.
The crystallization process comprises the following steps: and (3) concentrating the reaction solution after Fomc amino protection under reduced pressure to remove ethanol, regulating the pH to 2-3 with hydrochloric acid or sulfuric acid, adding seed crystals for crystallization, and filtering and drying the precipitated solid to obtain pure [2- [1- (Fmoc-amino) ethoxy ] acetic acid.
Further, the seed crystal is [2- [1- (Fmoc-amino) ethoxy ] acetic acid seed crystal.
All the reactions above were monitored by TLC for completion.
The purity of the [2- [1- (Fmoc-amino) ethoxy ] acetic acid prepared by the method is more than 99 percent.
The beneficial effects of the invention are as follows: in the prior art, solvents such as tetrahydrofuran, acetonitrile and the like which are mutually soluble with water are adopted in the etherification reaction step, quenching, extraction, concentration and other operations are required to be carried out in the post-reaction treatment, the next reaction is carried out, and the concentrated solution is a mixed solution and cannot be recycled. The etherification reaction step of the invention adopts 2-methyltetrahydrofuran or cyclopentyl methyl ether as a reaction solvent, the hydrolysis reaction can be carried out by directly adding alkali after the reaction is finished, the hydrolysis reaction is directly carried out by standing for layering, an organic phase takes away impurities, the organic phase can be concentrated to recover the 2-methyltetrahydrofuran and the cyclopentyl methyl ether, the cost is greatly saved, the amino deprotection reaction is directly carried out after the water phase is subjected to acid adjustment, and the reaction operation is simple.
In the prior art, after Fmoc reaction is finished, a large amount of solvent is needed to extract and concentrate the product from water, and then recrystallization is carried out. After the Fmoc reaction is finished, most of ethanol is concentrated, the pH is adjusted to 2-3, and then seed crystals are added for crystallization, so that the high-purity [2- [1- (Fmoc-amino) ethoxy ] acetic acid can be obtained.
According to the invention, the one-pot method is adopted to prepare the [2- [1- (Fmoc-amino) ethoxy ] acetic acid, and reactants are continuously subjected to multi-step reaction in one reactor, so that the reaction efficiency is improved, the energy is saved, and the environment is protected; the purity of the prepared product is more than 99 percent, the yield is high, and the operation is simple and convenient; meanwhile, the solvent can be recycled after extraction, the production cost is low, the environment-friendly chemical is met, and the method is suitable for industrial production.
Detailed Description
The technical scheme of the invention can be implemented in the following way.
The one-pot method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid comprises the steps of taking diglycolamine as a raw material, adopting di-tert-butyl dicarbonate to carry out amino protection, adding ethyl bromoacetate to carry out etherification reaction, and then carrying out hydrolysis, deprotection and Fomc-based amino protection and crystallization to prepare the [2- [1- (Fmoc-amino) ethoxy ] acetic acid; wherein the solvent used in the etherification reaction is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether.
The method for preparing the [2- [1- (Fmoc-amino) ethoxy ] acetic acid by the one-pot method specifically comprises the following steps of:
a. performing amino protection on diglycolamine by using di-tert-butyl dicarbonate, and concentrating to obtain an amino-protected intermediate to be etherified;
b. c, carrying out etherification reaction on the intermediate to be etherified obtained in the step a and ethyl bromoacetate to obtain an etherified intermediate;
c. adding the etherified intermediate obtained in the step b into a solution for hydrolysis reaction to obtain a hydrolyzed intermediate;
d. c, adding hydrochloric acid into the hydrolyzed intermediate obtained in the step c for deprotection;
e. and d, carrying out amino protection reaction on the product of the step d and a Fomc amino protection reagent, and crystallizing to obtain [2- [1- (Fmoc-amino) ethoxy ] acetic acid.
In the step a, di-tert-butyl dicarbonate is used for protecting the amino group of diglycolamine, namely diglycolamine and di-tert-butyl dicarbonate are added into a solvent to react in the presence of an alkaline reagent to obtain an intermediate to be etherified, wherein the ratio of the diglycolamine to the di-tert-butyl dicarbonate is 1mol to 1-1.5mol, and the ratio of the diglycolamine to the alkaline reagent is 1mol to 1-4mol; preferably, diglycolamine: alkaline agent = 1 mol:1-1.5 mol.
In order to ensure that the experiment can be performed, it is therefore preferred that the above diglycolamine: solvent (V/V) =1:0.5-2; more preferably, the basic reagent is triethylamine; the solvent is any one of ethanol, methanol, acetonitrile and dichloromethane; controlling the reaction temperature to be 10-50 ℃ and the reaction time to be 2-24h.
In the step b, ethyl bromoacetate is added for etherification reaction, and the steps are as follows: uniformly mixing an intermediate to be etherified with a solvent, adding an alkaline reagent, stirring at a low temperature for reaction, then adding a mixture of ethyl bromoacetate and the solvent at a low temperature, and naturally heating for reaction to obtain the etherified intermediate; wherein, the intermediate to be etherified is bromoethyl acetate=1mol:1.1-2 mol; intermediate to be etherified: alkaline reagent = 1 mol: 1.1-2mol; the solvent is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether.
Preferably, the solvent mixed with the intermediate to be etherified is the intermediate to be etherified (V/V) =4-10:1; solvent mixed with ethyl bromoacetate to be etherified intermediate (V/V) =0.8-2:1; more preferably, the alkaline agent is sodium hydride and/or potassium tert-butoxide; the reaction is carried out under the protection of nitrogen, the alkaline solvent is added in batches, and the low temperature is less than 5 ℃.
In the step c, the hydrolysis reaction is as follows: directly adding sodium hydroxide and/or potassium hydroxide solution into the etherified intermediate for hydrolysis, standing and separating liquid to obtain a hydrolyzed intermediate; wherein, the intermediate to be etherified, sodium hydroxide and/or potassium hydroxide=1mol:1.1-2mol.
Preferably, the solubility of the sodium hydroxide and/or potassium hydroxide solution is 1-3mol/L.
In order to reduce the production cost and meet the green chemical requirements, the hydrolysis reaction is preferably followed by standing and layering, and separating to obtain an organic phase and a water phase, wherein the water phase is a hydrolyzed intermediate; the organic phase is concentrated by rotary evaporation to obtain a solvent, and the solvent is recycled after being recovered.
In the step d, the intermediate to be etherified is hydrochloric acid=1 mol:2-4 mol; preferably, the solubility of the hydrochloric acid solution is 12mol/L.
In the step e, fomc amino protection is to adjust the pH value of the product in the deprotection process to 8-10, and then solvent and Fomc amino protection reagent are added for reaction; wherein, the intermediate to be etherified is Fomc amino protecting reagent=1mol:0.6-1mol; the Fomc-based amino protecting reagent was Fmoc-OSu (Fmoc N-hydroxysuccinimide este, fluorenylmethoxycarbonyl succinimide) and/or Fmoc-Cl (9-Fluorenylmethyl Chloroformate, fluorenylmethoxycarbonyl chloride).
Preferably, the reaction is carried out by adjusting the pH by at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; more preferably, the above intermediate to be etherified: solvent (V/V) =1:3-6; the solvent is water and ethanol, and the volume ratio of the water to the ethanol is 1:1.
In the step e, the crystallization step is as follows: concentrating the Fomc amino protected product under reduced pressure to remove ethanol, adjusting pH to 2-3 with hydrochloric acid or sulfuric acid, adding seed crystal for crystallization, filtering and drying the precipitated solid to obtain pure [2- [1- (Fmoc-amino) ethoxy ] acetic acid.
Preferably, the seed crystal is [2- [1- (Fmoc-amino) ethoxy ] acetic acid seed crystal.
Since the etherified intermediate is not quantifiable, all the reagents of the invention are added in amounts calculated on the intermediate to be etherified. In order to ensure that the reaction is sufficient, it is therefore preferred that all of the reactions described above be monitored by TLC for completion.
The purity of the [2- [1- (Fmoc-amino) ethoxy ] acetic acid prepared by the method is more than 99 percent.
The technical scheme and effect of the present invention will be further described by practical examples.
Examples
Example 1
One pot method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid comprises the following specific experimental steps:
a. 13g of diglycolamine and 13.7g of triethylamine are sequentially added into a 200mL three-port bottle, uniformly mixed, then 28.4g of di-tert-butyl dicarbonate is dissolved by 10g of methanol, then the mixture is dripped into the three-port bottle, the dripping is reacted for 3 hours at 20-30 ℃, TLC (thin layer chromatography) is monitored until the raw materials disappear, and the mixture is concentrated to dryness under reduced pressure, so that 24.9g of intermediate to be etherified is obtained, and the yield is 98.1%;
b. under the protection of nitrogen, adding 125g of 2-methyltetrahydrofuran into the intermediate to be etherified obtained in the step a, stirring, controlling the temperature to be less than 5 ℃, adding 7.3g of NaH in batches, stirring and reacting for 2 hours, then dropwise adding a mixture of 30.5g of ethyl bromoacetate and 25g of 2-methyltetrahydrofuran, naturally heating and reacting overnight after dropwise adding, monitoring by sampling TLC, and obtaining the etherified intermediate after the reaction is finished;
c. slowly adding 90mL of 2mol/L sodium hydroxide aqueous solution, stirring for reaction at normal temperature after adding, sampling TLC monitoring after 1 hour, standing for 10min for layering and separating liquid after hydrolysis, and performing rotary evaporation on an organic phase to obtain 2-methyltetrahydrofuran, recovering 2-methyltetrahydrofuran, wherein the aqueous phase is an intermediate after hydrolysis, and adding the aqueous phase into a reaction kettle again for further reaction;
d. adding 42.5g of concentrated hydrochloric acid into the reaction kettle for deprotection, and sampling TLC after 2 hours of reaction to monitor the completion of the reaction;
e. adding sodium bicarbonate solid to adjust the pH of the product in the step d to be about 9, adding 100mL of water and 100mL of ethanol, adding 30.8g of Fmoc-osu in batches, performing TLC monitoring after the reaction is performed for 6 hours, and performing reaction after the reaction is finished; concentrating under reduced pressure to remove most ethanol, adjusting pH to 3 with hydrochloric acid, adding seed crystal for crystallization, crystallizing for 2 hr, filtering, and drying to obtain 28.6g white solid (2- [1- (Fmoc-amino) ethoxy ] acetic acid).
And (3) result detection: the purity of the obtained [2- [1- (Fmoc-amino) ethoxy ] acetic acid is 99.5 percent, and the yield is 60 percent
Example 2
One pot method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid comprises the following specific experimental steps:
a. 17.9g of diglycolamine and 18.9g of triethylamine are sequentially added into a 200mL three-port bottle, uniformly mixed, then 39.2g of di-tert-butyl dicarbonate is dissolved by 14g of methanol, then the mixture is dropwise added into the three-port bottle, the mixture is reacted for 3 hours at the temperature of 30-40 ℃, TLC (thin layer chromatography) is monitored until the raw materials disappear, and the mixture is concentrated to dryness under reduced pressure, so that 34.9g of intermediate to be etherified is obtained, and the yield is 99.9%;
b. under the protection of nitrogen, 180g of cyclopentyl methyl ether is added into the intermediate to be etherified obtained in the step a, stirring is carried out, the temperature is controlled to be less than 5 ℃, 28g of potassium tert-butoxide is added in batches, stirring is carried out for 2 hours, then 43g of mixture of ethyl bromoacetate and 35g of cyclopentyl methyl ether is added dropwise, natural heating reaction is carried out overnight after the dropwise, sampling TLC monitoring is carried out, and the etherified intermediate is obtained after the reaction is finished;
c. slowly adding 170mL of 2mol/L sodium hydroxide aqueous solution, stirring after adding, reacting at normal temperature, monitoring by sampling TLC after 5 hours, standing for 10 minutes for layering and separating liquid after hydrolysis, rotationally steaming an organic phase to obtain cyclopentyl methyl ether, recovering the cyclopentyl methyl ether, adding the aqueous phase as a hydrolyzed intermediate into a reaction kettle again, and carrying out the next reaction;
d. adding 60g of concentrated hydrochloric acid into the reaction kettle for deprotection, and sampling TLC after 2 hours of reaction to monitor the completion of the reaction;
e. adding sodium bicarbonate solid to adjust the pH of the product in the step d to be about 9, adding 140mL of water and 140mL of ethanol, adding 42.5g of Fmoc-osu in batches, performing TLC monitoring after the reaction is performed for 6 hours, and after the reaction is finished; concentrating under reduced pressure to remove most ethanol, adjusting pH to 2 with hydrochloric acid, adding seed crystal for crystallization, crystallizing for 2 hr, filtering, and drying to obtain 41.6g white solid (2- [1- (Fmoc-amino) ethoxy ] acetic acid).
And (3) result detection: the purity of the obtained [2- [1- (Fmoc-amino) ethoxy ] acetic acid was 99.6%, and the yield was 63.2%.
Claims (7)
1. A method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by a one-pot method is characterized in that: diglycolamine is used as a raw material, di-tert-butyl dicarbonate is adopted to carry out amino protection, ethyl bromoacetate is added to carry out etherification reaction, and then the steps of hydrolysis, deprotection, fmoc-amino protection and crystallization are carried out, so that [2- [1- (Fmoc-amino) ethoxy ] acetic acid is prepared by a one-pot method; wherein the solvent used in the etherification reaction is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether;
the etherification reaction by adding ethyl bromoacetate is as follows: uniformly mixing an intermediate to be etherified with a solvent, adding an alkaline reagent, stirring at a low temperature for reaction, adding a mixture of ethyl bromoacetate and the solvent at a low temperature, and naturally heating for reaction to obtain the etherified intermediate
Wherein, the intermediate to be etherified and the alkaline reagent are in a ratio of 1mol to 1.1-2mol; intermediate to be etherified: ethyl bromoacetate=1 mol:1.1-2 mol; the solvent is at least one of 2-methyltetrahydrofuran and cyclopentyl methyl ether; adding sodium hydride and/or potassium tert-butoxide as alkaline reagents in the etherification reaction step by ethyl bromoacetate;
the hydrolysis process comprises the following steps: directly adding sodium hydroxide and/or potassium hydroxide solution into the etherified intermediate for hydrolysis, standing and separating liquid to obtain a hydrolyzed intermediate
Wherein, the intermediate to be etherified is sodium hydroxide and/or potassium hydroxide=1mol:1.1-2mol;
the crystallization is that after the reaction liquid after Fmoc amino protection is decompressed and concentrated to remove ethanol, hydrochloric acid or sulfuric acid is used for adjusting the pH value to 2-3, seed crystals are added for crystallization, and the precipitated solid is filtered and dried to obtain pure [2- [1- (Fmoc-amino) ethoxy ] acetic acid.
2. A one-pot process according to claim 1 wherein [2- [1- (Fmoc-amino) ethoxy ] is prepared]Ethoxy group]A process for the production of acetic acid, characterized by: the amino protection of the di-tert-butyl dicarbonate is carried out by adopting di-tert-butyl dicarbonate: in the presence of an alkaline reagent, diglycolamine and di-tert-butyl dicarbonate are added into a solvent to react to obtain an intermediate to be etherified
Wherein, the di-glycol amine and the di-tert-butyl dicarbonate are respectively 1mol, 1 to 1.5mol, 1 to 4mol of the di-glycol amine and the alkaline reagent.
3. The method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one pot method according to claim 2, wherein: the method comprises the steps of adopting di-tert-butyl dicarbonate to carry out amino protection on the di-tert-butyl dicarbonate, wherein an alkaline reagent is triethylamine; the solvent is any one of ethanol, methanol, acetonitrile and dichloromethane.
4. The method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one pot method according to claim 1, wherein: standing for layering after hydrolysis reaction, separating liquid to obtain an organic phase and a water phase, wherein the water phase is a hydrolyzed intermediate, concentrating the organic phase by rotary evaporation to obtain a solvent, and recycling the solvent.
5. A one-pot process according to claim 1 wherein [2- [1- (Fmoc-amino) ethoxy ] is prepared]Ethoxy group]A process for the production of acetic acid, characterized by: the deprotection is as follows: adding hydrochloric acid into the hydrolyzed intermediate for deprotection to obtain a deprotection reaction solution
Wherein, the intermediate to be etherified is hydrochloric acid=1 mol:2-4 mol. />
6. A one-pot process according to claim 1 wherein [2- [1- (Fmoc-amino) ethoxy ] is prepared]Ethoxy group]A process for the production of acetic acid, characterized by: the Fmoc-based amino protection is as follows: adjusting the pH of the deprotection reaction liquid to 8-10, and then adding solvent and Fmoc-amino protecting reagent for reaction
Wherein the intermediate to be etherified is Fmoc-amino protecting reagent=1 mol:0.5-2 mol, and the Fmoc-amino protecting reagent is Fmoc-OSu and/or Fmoc-Cl.
7. The method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one-pot method according to claim 6, wherein: at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate is used for adjusting the pH in the Fmoc amino protection step.
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