CN113480453B - Synthesis method of NH2-PEG5-NHBoc - Google Patents

Synthesis method of NH2-PEG5-NHBoc Download PDF

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CN113480453B
CN113480453B CN202110907276.8A CN202110907276A CN113480453B CN 113480453 B CN113480453 B CN 113480453B CN 202110907276 A CN202110907276 A CN 202110907276A CN 113480453 B CN113480453 B CN 113480453B
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CN113480453A (en
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刘天柱
罗宇
王子安
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Suzhou Highfine Biotech Co Ltd
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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Abstract

The invention provides a synthetic method of NH2-PEG5-NHBoc, wherein the NH2-PEG5-NHBoc represents [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, and the synthetic method comprises the following steps: the method comprises the following steps of S1, taking 2- [2- (trityl-amino) -ethoxy ] -ethanol and (2- (2- (2- (benzyloxy) -ethoxy) -ethyl-4-p-toluene sulfonate as starting materials, carrying out substitution reaction to generate a first intermediate product, S2, carrying out catalytic hydrogenation on the first intermediate product and hydrogen, and then carrying out nucleophilic substitution reaction on the first intermediate product and Boc anhydride to generate a second intermediate product, S3, carrying out nucleophilic substitution reaction on the second intermediate product and p-toluenesulfonyl chloride to generate a third intermediate product, S4, carrying out nucleophilic substitution reaction on the third intermediate product and sodium azide to generate a fourth intermediate product, and S5, carrying out reduction reaction on the fourth intermediate product and hydrogen to generate the NH2-PEG5-NHBoc.

Description

Synthesis method of NH2-PEG5-NHBoc
Technical Field
The invention relates to the technical field of synthesis of antibody-conjugated drugs (ADC), in particular to a synthesis method of NH2-PEG5-NHBoc.
Background
Research on antibody-conjugated drugs (ADCs) can be traced back to 1980s, but the first antibody-conjugated drug (developed under the trade name Mylotarg, pfizer) was not approved by the FDA for treating acute myelocytic leukemia until 2000, but due to limitations in conjugation technology, targeting, effectiveness, etc., the complete antibody-conjugated drug is unstable in blood, resulting in the generation of lethal toxicity, which was withdrawn from the market in 2010. This makes the unknown study of ADC drugs even worse with a shadow.
However, takeda/SeattleGenetics developed a novel antibody conjugate drug brentuximabvedotin (SGN-35, trade name Adcetris) by an improvement over the original technology, using its own novel antibody conjugate technology, which was approved by the FDA for the treatment of hodgkin lymphoma and systemic anaplastic large cell lymphoma in 2011. The antibody conjugate drug made a breakthrough again in 2013, and Ado-trastuzumab (T-DM 1, trade name Kadcyla) developed by Genentech/immunolgen combination was approved by FDA for HER2 positive breast cancer, which is the first antibody conjugate drug against solid tumors. With the success of the development of these two drugs, ADC drugs again enter the field of research in the state of fire-heat.
Because of the advantages of clear target, mature technology, good selectivity and the like, the research on antibody drug conjugates is expected to continue to be a research hotspot in the anticancer field in the next few years. To keep pace with the development of new drugs in the world, domestic and especially those powerful pharmaceutical companies inevitably add to the development trend of ADCs.
Among them, NH2-PEG5-NHBoc, namely [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, is one of important raw materials for synthesizing ADC drugs, and plays an important role in the development of antibody coupling drugs.
However, there is only one of the current synthetic methods for [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester (ref: journal of the American Chemical Society,2013, vol.135, p.12684-12689, minerals, 2013, vol.18, p.11639-11657), and this synthetic method requires starting from the expensive raw material, pentaethylene glycol, and then it is converted into the product in multiple steps with an overall yield of only 42%. The method has high production cost and is difficult to realize industrial production.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for synthesizing NH2-PEG5-NHBoc, i.e., [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tert-butyl carbamate, with a short synthetic route, simple operation, low cost, and high yield.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method of synthesizing NH2-PEG5-NHBoc according to an embodiment of the present invention, said NH2-PEG5-NHBoc representing [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, comprising the steps of:
step S1, starting with 2- [2- (trityl-amino) -ethoxy ] -ethanol and (2- (2- (2- (benzyloxy) -ethoxy) -ethyl-4-p-toluenesulfonate, a substitution reaction occurs to produce a first intermediate product which is [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine;
step S2, subjecting the first intermediate product to catalytic hydrogenation with hydrogen, followed by nucleophilic substitution reaction with Boc anhydride to produce a second intermediate product, which is [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester;
step S3, carrying out nucleophilic substitution reaction on the second intermediate product and p-toluenesulfonyl chloride to generate a third intermediate product, wherein the third intermediate product is p-toluenesulfonic acid 2- (2- {2- [2- (2-tert-butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ester;
step S4, carrying out nucleophilic substitution reaction on the third intermediate product and sodium azide to generate a fourth intermediate product, wherein the fourth intermediate product is [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tert-butyl carbamate;
and S5, carrying out reduction reaction on the fourth intermediate product and hydrogen to generate the [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tert-butyl carbamate.
According to some embodiments of the present invention, in the step S1, the substitution reaction occurs in a first solvent under the action of a first base, wherein the first solvent is N, N-dimethylacetamide, N-dimethylformamide, or a mixture thereof, the first base is sodium hydride, the reaction temperature is 0 to 20 ℃, and the reaction time is 6 to 10 hours.
According to some embodiments of the invention, said step S2 comprises:
step S21, carrying out catalytic hydrogenation on the first intermediate product and hydrogen in a second solvent and concentrated hydrochloric acid under the action of a catalyst;
and S22, adding Boc anhydride into the solution after the catalytic hydrogenation reaction is finished so as to perform nucleophilic substitution reaction to generate the second intermediate product.
Further, in the step S21, the catalyst is 10% Pd/C, the molar ratio of the concentrated hydrochloric acid to the first intermediate product is 2.7.
Further, in the step S22, after the catalytic hydrogenation reaction is completed, suction filtration is performed and the pH of the filtrate is adjusted to 6 to 8, and thereafter Boc anhydride is added to the filtrate to generate the nucleophilic substitution reaction.
Further, in step S22, the first intermediate product: the Boc anhydride molar ratio is 1.1, the reaction temperature is 40-60 ℃, and the reaction time is 4-8 hours.
According to some embodiments of the present invention, in step S3, the second intermediate product and p-toluenesulfonyl chloride are subjected to nucleophilic substitution reaction under the action of a second base in a third solvent, wherein the third solvent is dichloromethane, the second base is triethylamine, pyridine, or a mixture thereof, the reaction temperature is 0 to 5 ℃, and the reaction time is 6 to 10 hours.
According to some embodiments of the present invention, in step S4, the nucleophilic substitution reaction between the third intermediate product and the sodium azide is performed in a fourth solvent, wherein the fourth solvent is N, N-dimethylformamide, the molar ratio of the sodium azide to the third intermediate product is 1.1, the reaction temperature is 50 to 80 ℃, and the reaction time is 5 to 8 hours.
According to some embodiments of the present invention, in the step S5, the fourth intermediate product is subjected to a reduction reaction with hydrogen gas under the action of a catalyst 10% Pd/C in a fifth solvent, wherein the fifth solvent is methanol, ethanol, or a mixture thereof, the mass ratio of the catalyst 10% Pd/C to the fourth intermediate product is 0.1.
According to some embodiments of the present invention, after the first intermediate product, the second intermediate product, the third intermediate product, and the fourth intermediate product are obtained by the reaction, the first intermediate product, the second intermediate product, the third intermediate product, and the fourth intermediate product are respectively subjected to suction filtration, filter cake washing, drying, and solvent evaporation to purify, and the purified first intermediate product, second intermediate product, third intermediate product, and fourth intermediate product are used for the next reaction.
The technical scheme of the invention at least has one of the following beneficial effects:
1. according to the synthesis method provided by the embodiment of the invention, the simple compound I and the compound II are used as starting materials, and the compound VII, namely [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, is obtained through substitution reaction, catalytic hydrogenation, nucleophilic substitution for 3 times and reduction reaction, so that the synthesis route is simple and short, the operation is simple and convenient, the yield is high, and the total yield can reach 70%;
2. according to the synthesis method disclosed by the embodiment of the invention, the use of expensive reagents is not involved, so that the cost is reduced;
3. the synthesis method provided by the embodiment of the invention is simple and convenient to operate, and the conditions are easy to control.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
First, a method of synthesizing [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester according to an embodiment of the present invention will be described.
The synthetic route of the synthetic method is shown as the following formula:
Figure GDA0004058953710000051
specifically, the synthesis method comprises the following steps:
the method comprises the following steps:
step S1, starting with 2- [2- (trityl-amino) -ethoxy ] -ethanol (formula I, shown above, which is sometimes referred to hereinafter as Compound I) and (2- (2- (2- (benzyloxy) -ethoxy) -ethyl-4-p-toluenesulfonate (formula II, shown above, which is sometimes referred to hereinafter as Compound II), a substitution reaction takes place to form a first intermediate product (formula III, shown above, which is sometimes referred to hereinafter as Compound III), which is [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine.
Among them, compound I can be synthesized, for example, by the method described in Journal of the American Chemical Society,2015, vol.137, p.2996-3003, and Compound II can be synthesized, for example, by the method described in Journal of Organic Chemistry,2006, vol.71, #26, p.9884-9886. The methods have the advantages of simple synthesis process, high yield and low production cost.
Preferably, in step S1, the substitution reaction occurs in a first solvent under the action of a first base, wherein the first solvent is N, N-dimethylacetamide, N-dimethylformamide, or a mixture thereof, the first base is sodium hydride, the reaction temperature is 0 to 20 ℃, and the reaction time is 6 to 10 hours. Under the above conditions, the yield can be improved, and the reaction conditions are simple and easy to operate.
Step S2, catalytically hydrogenating the first intermediate product with hydrogen, followed by nucleophilic substitution reaction with Boc anhydride to form a second intermediate product (shown as IV in the above formula, which is sometimes referred to as compound IV below) which is [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester.
That is, after the first intermediate (compound III) described above is obtained, it is first subjected to catalytic hydrogenation to remove the protecting groups on both sides of compound III, followed by nucleophilic substitution reaction with Boc anhydride to produce the second intermediate (compound IV).
According to some embodiments of the invention, said step S2 comprises:
step S21, catalytically hydrogenating the first intermediate product and hydrogen in a second solvent and concentrated hydrochloric acid (i.e. 36% hydrochloric acid) under the action of a catalyst.
Specifically, in step S21, the catalyst is 10% Pd/C, the molar ratio of the concentrated hydrochloric acid to the first intermediate product is 2.7.
Under the condition, the catalytic hydrogenation is more favorably carried out completely, and the protecting groups on both sides can be more completely removed.
And S22, adding Boc anhydride into the solution after the catalytic hydrogenation reaction is finished so as to generate nucleophilic substitution reaction and generate the second intermediate product.
Further, in the step S22, after the catalytic hydrogenation reaction is completed, suction filtration is performed and the pH of the filtrate is adjusted to 6 to 8, and thereafter Boc anhydride is added to the filtrate to cause the nucleophilic substitution reaction. That is, after the catalytic hydrogenation reaction is completed, first, suction filtration is performed to remove insoluble substances, thereafter, the pH of the filtrate is adjusted to be neutral, for example, sodium carbonate, sodium bicarbonate solution may be used to adjust the pH, etc., and finally, boc anhydride is added to the filtrate to cause the nucleophilic substitution reaction. Is beneficial to improving the yield and reducing unnecessary by-products.
Further, in step S22, the first intermediate product: the Boc anhydride molar ratio is 1.1, the reaction temperature is 40-60 ℃, and the reaction time is 4-8 hours. Under the condition, the full implementation of nucleophilic substitution reaction is facilitated, and the reaction condition is simple and easy to operate.
And step S3, carrying out nucleophilic substitution reaction on the second intermediate product and p-toluenesulfonyl chloride to generate a third intermediate product (the chemical formula of which is shown as V in the formula, and the third intermediate product is sometimes referred to as compound V) which is p-toluenesulfonic acid 2- (2- {2- [2- (2-tert-butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ester.
That is, compound IV and p-toluenesulfonyl chloride are subjected to nucleophilic substitution reaction to produce compound V.
Preferably, in step S3, in a third solvent, under the action of a second base, the second intermediate product and p-toluenesulfonyl chloride undergo a nucleophilic substitution reaction, where the third solvent is dichloromethane, the second base is triethylamine, pyridine, or a mixture thereof, the reaction temperature is 0 to 5 ℃, and the reaction time is 6 to 10 hours.
And S4, carrying out nucleophilic substitution reaction on the third intermediate product and sodium azide to generate a fourth intermediate product (the chemical formula of which is shown as VI in the formula, and the fourth intermediate product is sometimes referred to as compound VI below), wherein the fourth intermediate product is [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester.
That is, compound V is subjected to nucleophilic substitution reaction with sodium azide to produce compound VI.
Preferably, the third intermediate product and the sodium azide are subjected to nucleophilic substitution reaction in a fourth solvent, wherein the fourth solvent is N, N-dimethylformamide, the molar ratio of the sodium azide to the third intermediate product is 1.1.
And (S5) carrying out reduction reaction on the fourth intermediate product and hydrogen to generate the [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester (the chemical formula of which is shown as VII in the formula, and the compound is sometimes referred to as compound VII below).
That is, compound VI is subjected to a reduction reaction with hydrogen to produce compound VII.
Preferably, in the step S5, the fourth intermediate product and hydrogen gas are subjected to a reduction reaction in a fifth solvent under the action of a catalyst 10% Pd/C, the fifth solvent is methanol, ethanol, or a mixture thereof, the mass ratio of the catalyst 10% Pd/C to the fourth intermediate product is 0.1.
According to some embodiments of the present invention, after the first intermediate product, the second intermediate product, the third intermediate product, and the fourth intermediate product are obtained from the above reaction, suction filtration, cake washing, drying, solvent evaporation for purification are respectively performed, and the purified first intermediate product, second intermediate product, third intermediate product, and fourth intermediate product are used for the next reaction. Therefore, the method is not only beneficial to improving the yield, but also beneficial to reducing by-products and simplifying the purification of the target compound VII.
Hereinafter, the synthesis method according to the present invention is described in further detail by specific examples.
Example 1
1.1 Synthesis of Compound III, i.e., [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine
320mL of N, N-dimethylacetamide, 64.51g of the compound I and 73.34g of the compound II are put into a 500mL single-neck flask, the mixture is cooled to an ice-water bath under an argon protection system and stirred, 7.44g of sodium hydride (60%) is added, the internal temperature is controlled to be 0-5 ℃, the reaction is carried out for 10 hours, and the progress of the reaction is monitored by TLC. After the reaction was completed, 1.2L of an aqueous ammonium chloride solution was added to the system, the product was extracted 2 times with 600mL of ethyl acetate, and the combined organic phases were washed 2 times with 600mL of an aqueous ammonium chloride solution. The organic phase was dried and the solvent evaporated to dryness to give 100.1g of compound III with a yield of 94.2%.
1H NMR(CDCl3,400MHz):δ＝7.1-7.5(m,20H),4.63(s,2H),3.6-3.7(m,16H),3.5(t,J＝4Hz,2H),2.35(t,J＝4Hz,2H),2.0(s,1H).
1.2 Synthesis of Compound IV, [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
75.6g of the compound III obtained above, 36.5g of concentrated hydrochloric acid (36%) and 7.56g of Pd/C as a catalyst were charged in a 2L single-neck flask, and the system was replaced with hydrogen gas 4 to 5 times, heated to 50 ℃ and stirred to react for 10 hours. TLC monitored the progress of the reaction. And cooling and filtering after the reaction is finished, adding sodium carbonate into the filtrate to adjust the pH value to be neutral, filtering, adding 31.8g of Boc anhydride and 300mL of water into the filtrate, heating to 50 ℃, stirring, generating gas, and reacting for 5 hours. TLC monitored the progress of the reaction. After the reaction, suction filtration is carried out, a filter cake is washed by ethanol, the filter cake and the filtrate are combined and evaporated to dryness, the acetonitrile is carried to dryness, 500mL of dichloromethane dissolved product is added, the solid is removed by suction filtration, the filtrate is evaporated to dryness, and 38.6g of compound IV is obtained, and the yield is 86.3%.
1.3 Synthesis of Compound V, i.e., 2- (2- {2- [2- (2-tert-Butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl p-toluenesulfonate
38.6g of the compound IV obtained above, 500mL of methylene chloride, 0.81g of 4-dimethylaminopyridine (5%) and 17.41g of triethylamine were put into a 1L single-neck flask and stirred in an ice-water bath. 27.81g of p-toluenesulfonyl chloride was added in portions, and the mixture was reacted in an ice water bath for 9 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, 250mL of 1mol/L hydrochloric acid is added for washing, then the obtained product is washed to be neutral by using clear water, the dichloromethane is evaporated after the obtained product is dried by anhydrous sodium sulfate, and the obtained product is passed through a chromatographic column to obtain 51.8g of a compound V, wherein the yield is 92.4%.
1H NMR(CDCl3,400MHz):δ＝7.8(d,J＝8Hz,2H),7.3(d,J＝8Hz,2H),5.0(s,1H),4.2(s,2H),3.3-3.6(m,18H),2.4(s,3H),1.4(s,9H).
1.4 Synthesis of Compound VI, i.e., [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
A1L single-neck flask was charged with 155.4mL of compound V, N, N-dimethylformamide, and 8.83g of sodium azide, heated to 75 deg.C, stirred, and protected with nitrogen. The reaction was run for 8 hours and the progress of the reaction was monitored by TLC. After the reaction, the reaction product is cooled to room temperature, the reaction product is filtered, 450mL of water is added into the filtrate, 250mL of ethyl acetate is used for extracting a water layer twice, 300mL of saturated sodium bicarbonate solution is used for washing ethyl acetate three times, the ethyl acetate is dried, filtered, the ethyl acetate is evaporated to dryness, and acetonitrile is carried out for three times. 36.6g of compound VI are obtained with a yield of 96%.1H NMR (CDCl3, 400MHz): delta =5.0 (s, 1H), 3.3-3.7 (m, 16H), 3.15-3.3 (m, 4H), 1.3 (s, 9H).
1.5 Synthesis of Compound VII, i.e. [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
15g of compound VI,1.5g of 10% Pd/C as a catalyst and 150mL of ethanol are added into a 500mL single-neck bottle, the system is replaced by hydrogen for 4 to 5 times, and the mixture is stirred at room temperature and reacted for 10 hours. TLC monitored the progress of the reaction. After the reaction, the reaction solution is filtered, the solvent and water are evaporated, dichloromethane is added to dissolve the product, the filtration is carried out, and dichloromethane is evaporated to dryness to obtain 12.8g of a compound VII with the yield of 92%.
1H NMR(CDCl3,400MHz):δ＝5.35(s,1H),4.7(s,3H),5.0(s,1H),3.5-3.7(m,16H),3.3-3.6(m,18H),3.75(s,2H),2.95(s,2H),1.35(s,9H).
Example 2
2.1 Synthesis of Compound III, i.e., [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine
250mL of N, N-dimethylacetamide, 64.51g of the compound I and 73.34g of the compound II were put into a 500mL single-neck flask, and the mixture was stirred in an ice-water bath under an argon atmosphere, 6.2g of sodium hydride (60%) was added, the reaction was carried out for 8 hours while controlling the internal temperature at 0 to 5 ℃, and the progress of the reaction was monitored by TLC. After the reaction was completed, 1.2L of an aqueous ammonium chloride solution was added to the system, the product was extracted 2 times with 600mL of ethyl acetate, and the combined organic phases were washed 2 times with 600mL of an aqueous ammonium chloride solution. The organic phase was dried and the solvent evaporated to dryness to give 75.6g of compound III with 71% yield.
1H NMR(CDCl3,400MHz):δ＝7.1-7.5(m,20H),4.63(s,2H),3.6-3.7(m,16H),3.5(t,J＝4Hz,2H),2.35(t,J＝4Hz,2H),2.0(s,1H).
2.2 Synthesis of Compound IV, i.e., [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
75.6g of the compound III, 36.5g of concentrated hydrochloric acid (36%) and 800mL of ethanol as a solvent and 7.6g of 10% Pd/C as a catalyst were placed in a 2L single-neck flask, and the system was replaced with hydrogen for 4 to 5 times, heated to 40 ℃ and stirred to react for 7 hours. TLC monitored the progress of the reaction. And cooling and filtering after the reaction is finished, adding sodium carbonate into the filtrate to adjust the pH value to be neutral, filtering, adding 31.8g of Boc anhydride and 300mL of water into the filtrate, heating to 40 ℃, stirring, generating gas, and reacting for 3 hours. TLC monitored the progress of the reaction. And after the reaction is finished, performing suction filtration, washing a filter cake by using ethanol, combining the filter cake with the filtrate, evaporating to dryness, drying an acetonitrile belt, adding 500mL of dichloromethane dissolved product, performing suction filtration to remove solids, and evaporating the filtrate to dryness to obtain 32.5g of a compound IV with the yield of 72.5%.
2.3 Synthesis of Compound V, i.e., 2- (2- {2- [2- (2-tert-Butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl p-toluenesulfonate
A1L single-necked flask was charged with 38.6g of Compound IV,500mL of methylene chloride, 0.81g of 4-dimethylaminopyridine (5%) and 8.4g of pyridine, and the mixture was stirred in an ice-water bath. 27.81g of p-toluenesulfonyl chloride was added in portions, and reacted in an ice water bath for 6 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, 250mL of 1mol/L hydrochloric acid is added for washing, then the obtained product is washed to be neutral by using clear water, the dichloromethane is evaporated after the obtained product is dried by anhydrous sodium sulfate, and the obtained product is passed through a chromatographic column to obtain 45.7g of a compound V, wherein the yield is 81.6%.
1H NMR(CDCl3,400MHz):δ＝7.8(d,J＝8Hz,2H),7.3(d,J＝8Hz,2H),5.0(s,1H),4.2(s,2H),3.3-3.6(m,18H),2.4(s,3H),1.4(s,9H).
2.4 Synthesis of Compound VI, i.e., [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
A1L single-neck flask was charged with 155.4mL of compound V, N, N-dimethylformamide, and 8.83g of sodium azide, heated to 50 ℃ and stirred under nitrogen. The reaction was run for 8 hours and the progress of the reaction was monitored by TLC. After the reaction is finished, cooling to room temperature, performing suction filtration, adding 450mL of water into the filtrate, extracting the water layer twice by using 250mL of ethyl acetate, washing the ethyl acetate three times by using 300mL of saturated sodium bicarbonate solution, drying the ethyl acetate, filtering, evaporating the ethyl acetate to dryness, and drying the acetonitrile for three times. 33.9g of compound VI are obtained with a yield of 89%.
1H NMR(CDCl3,400MHz):δ＝5.0(s,1H),3.3-3.7(m,16H),3.15-3.3(m,4H),1.3(s,9H).
2.5 Synthesis of Compound VII, i.e., [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
In a 500mL single-neck flask, 15g of compound VI,1.5g of 10% Pd/C as a catalyst and 150mL of ethanol were added, and the system was replaced with hydrogen for 4 to 5 times, stirred at room temperature, and reacted for 6 hours. TLC monitored the progress of the reaction. After the reaction, suction filtration was performed, the solvent and water were evaporated, a dichloromethane-dissolved product was added, suction filtration was performed, and dichloromethane was evaporated to dryness to obtain 11.1g of compound VII, with a yield of 79.5%.
1H NMR(CDCl3,400MHz):δ＝5.35(s,1H),4.7(s,3H),5.0(s,1H),3.5-3.7(m,16H),3.3-3.6(m,18H),3.75(s,2H),2.95(s,2H),1.35(s,9H).
Example 3
3.1 Synthesis of Compound III, i.e., [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine
320mL of N, N-dimethylformamide, 64.51g of the compound I and 73.34g of the compound II are put into a 500mL single-neck flask, the mixture is cooled to an ice-water bath under an argon protection system, stirred, added with 7.44g of sodium hydride (60%), reacted for 6 hours at an internal temperature of 15-20 ℃ and monitored by TLC for the progress of the reaction. After the reaction was completed, 1.2L of aqueous ammonium chloride solution was added to the system, the product was extracted 2 times with 600mL of ethyl acetate, and the organic phases were combined and washed 2 times with 600mL of aqueous ammonium chloride solution. The organic phase was dried and the solvent evaporated to dryness to give 91.8g of compound III in 86.3% yield.
1H NMR(CDCl3,400MHz):δ＝7.1-7.5(m,20H),4.63(s,2H),3.6-3.7(m,16H),3.5(t,J＝4Hz,2H),2.35(t,J＝4Hz,2H),2.0(s,1H).
3.2 Synthesis of Compound IV, [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
75.6g of the compound III, 36.5g of concentrated hydrochloric acid (36%) and 800mL of methanol as a solvent and 7.6g of 10% Pd/C as a catalyst were charged into a 2L single-neck flask, and the system was replaced with hydrogen for 4 to 5 times, heated to 50 ℃ and stirred to react for 10 hours. TLC monitored the progress of the reaction. And cooling and filtering after the reaction is finished, adding sodium carbonate into the filtrate to adjust the pH value to be neutral, filtering, adding 31.8g of Boc anhydride and 300mL of water into the filtrate, heating to 50 ℃, stirring, generating gas, and reacting for 5 hours. TLC monitored the progress of the reaction. After the reaction, the mixture is filtered, a filter cake is washed by ethanol, the filter cake and the filtrate are combined and evaporated to dryness, acetonitrile is carried away to dryness, 500mL of dichloromethane is added to dissolve the product, the solid is removed by suction filtration, the filtrate is evaporated to dryness, and 36.1g of compound IV is obtained, wherein the yield is 80.4%.
3.3 Synthesis of Compound V, i.e., 2- (2- {2- [2- (2-tert-Butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl p-toluenesulfonate
A1L one-neck flask was charged with 38.6g of Compound IV,500mL of methylene chloride, 0.81g of 4-dimethylaminopyridine (5%), and 17.41g of triethylamine, and the mixture was stirred in an ice-water bath. 27.81g of p-toluenesulfonyl chloride was added in portions, and reacted at room temperature for 9 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, 250mL of 1mol/L hydrochloric acid is added for washing, then the obtained product is washed to be neutral by using clear water, the dichloromethane is evaporated after the obtained product is dried by anhydrous sodium sulfate, and the obtained product is passed through a chromatographic column to obtain 35.8g of a compound V, wherein the yield is 63.8%.
1H NMR(CDCl3,400MHz):δ＝7.8(d,2J＝8Hz,H),7.3(d,J＝8Hz,2H),5.0(s,1H),4.2(s,2H),3.3-3.6(m,18H),2.4(s,3H),1.4(s,9H).
3.4 Synthesis of Compound VI, i.e., [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
A1L single-neck flask was charged with 155.4mL of compound V, N, N-dimethylformamide, and 8.83g of sodium azide, heated to 75 deg.C, stirred, and protected with nitrogen. The reaction was run for 5 hours and the progress of the reaction was monitored by TLC. After the reaction, the reaction product is cooled to room temperature, the reaction product is filtered, 450mL of water is added into the filtrate, 250mL of ethyl acetate is used for extracting a water layer twice, 300mL of saturated sodium bicarbonate solution is used for washing ethyl acetate three times, the ethyl acetate is dried, filtered, the ethyl acetate is evaporated to dryness, and acetonitrile is carried out for three times. 30.6g of compound VI are obtained with a yield of 80.3%.
1H NMR(CDCl3,400MHz):δ＝5.0(s,1H),3.3-3.7(m,16H),3.15-3.3(m,4H),1.3(s,9H).
3.5 Synthesis of Compound VII, i.e., [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester
15g of compound VI,1.5g of 10% Pd/C as a catalyst and 150mL of methanol are added into a 500mL single-neck flask, the system is replaced by hydrogen for 4 to 5 times, and the mixture is stirred at room temperature and reacted for 10 hours. TLC monitored the progress of the reaction. After the reaction, the reaction solution was filtered, the solvent and water were evaporated, the dichloromethane-dissolved product was added, filtered, and the dichloromethane was evaporated to dryness to obtain 12.1g of compound VII with a yield of 87%.
1H NMR(CDCl3,400MHz):δ＝5.35(s,1H),4.7(s,3H),5.0(s,1H),3.5-3.7(m,16H),3.3-3.6(m,18H),3.75(s,2H),2.95(s,2H),1.35(s,9H).
As can be seen from the above-described specific embodiments,
1. according to the synthesis method provided by the embodiment of the invention, a simple compound I and a simple compound II are adopted as starting raw materials, and a compound VII, namely [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, is obtained through substitution reaction, catalytic hydrogenation, nucleophilic substitution for 3 times and reduction reaction, so that the synthesis method is simple and short in synthesis route, simple and convenient to operate, high in yield, and far higher than that of the existing method, and the total yield can be up to 70%;
2. according to the synthesis method disclosed by the embodiment of the invention, the use of expensive reagents is not involved, so that the cost is reduced;
3. the synthesis method provided by the embodiment of the invention is simple and convenient to operate, and the conditions are easy to control.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (10)

1. A method of synthesizing NH2-PEG5-NHBoc, said NH2-PEG5-NHBoc representing [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester, comprising the steps of:
step S1, starting with 2- [2- (trityl-amino) -ethoxy ] -ethanol and (2- (2- (2- (benzyloxy) -ethoxy) -ethyl-4-p-toluenesulfonate, a substitution reaction occurs to produce a first intermediate product which is [2- (2- {2- [2- (2-benzyloxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tritylamine;
step S2, subjecting the first intermediate product to catalytic hydrogenation with hydrogen, followed by nucleophilic substitution reaction with Boc anhydride to produce a second intermediate product, which is [2- (2- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -carbamic acid tert-butyl ester;
step S3, carrying out nucleophilic substitution reaction on the second intermediate product and p-toluenesulfonyl chloride to generate a third intermediate product, wherein the third intermediate product is p-toluenesulfonic acid 2- (2- {2- [2- (2-tert-butoxycarbonylamino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ester;
step S4, carrying out nucleophilic substitution reaction on the third intermediate product and sodium azide to generate a fourth intermediate product, wherein the fourth intermediate product is [2- (2- {2- [2- (2-azido-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tert-butyl carbamate;
and S5, carrying out reduction reaction on the fourth intermediate product and hydrogen to generate the [2- (2- {2- [2- (2-amino-ethoxy) -ethoxy ] -ethoxy } -ethoxy) -ethyl ] -tert-butyl carbamate.
2. The method according to claim 1, wherein the substitution reaction is performed in a first solvent under the action of a first base in step S1, wherein the first solvent is N, N-dimethylacetamide, N-dimethylformamide, or a mixture thereof, the first base is sodium hydride, the reaction temperature is 0 to 20 ℃, and the reaction time is 6 to 10 hours.
3. The method according to claim 1, wherein the step S2 comprises:
step S21, carrying out catalytic hydrogenation on the first intermediate product and hydrogen in a second solvent and concentrated hydrochloric acid under the action of a catalyst;
and S22, adding Boc anhydride into the solution after the catalytic hydrogenation reaction is finished so as to perform nucleophilic substitution reaction to generate the second intermediate product.
4. The method according to claim 3, wherein in the step S21, the catalyst is 10% Pd/C, the molar ratio of the concentrated hydrochloric acid to the first intermediate product is 2.7.
5. The method of claim 3, wherein in the step S22, after the catalytic hydrogenation reaction is completed, suction filtration is performed and the pH value of the filtrate is adjusted to 6-8, and thereafter Boc anhydride is added to the filtrate to perform the nucleophilic substitution reaction.
6. The method of claim 5, wherein in step S22, the first intermediate product: the Boc anhydride molar ratio is 1.1, the reaction temperature is 40-60 ℃, and the reaction time is 4-8 hours.
7. The method according to claim 1, wherein in step S3, the second intermediate product and p-toluenesulfonyl chloride are subjected to nucleophilic substitution reaction under the action of a second base in a third solvent, wherein the third solvent is dichloromethane, the second base is triethylamine, pyridine or a mixture thereof, the reaction temperature is 0 to 5 ℃, and the reaction time is 6 to 10 hours.
8. The method according to claim 1, wherein in step S4, the third intermediate product and the sodium azide are subjected to nucleophilic substitution reaction in a fourth solvent, wherein the fourth solvent is N, N-dimethylformamide, the molar ratio of the sodium azide to the third intermediate product is 1.1.
9. The method according to claim 1, wherein in step S5, the fourth intermediate product is subjected to a reduction reaction with hydrogen gas in a fifth solvent by the action of a catalyst 10% pd/C, wherein the fifth solvent is methanol, ethanol, or a mixture thereof, wherein the mass ratio of the pd/C to the fourth intermediate product is 0.1.
10. The method according to claim 1, wherein after the first intermediate product, the second intermediate product, the third intermediate product and the fourth intermediate product are obtained through the reaction, the first intermediate product, the second intermediate product, the third intermediate product and the fourth intermediate product are respectively subjected to suction filtration, filter cake washing, drying and solvent evaporation to purify the first intermediate product, the second intermediate product, the third intermediate product and the fourth intermediate product, which are purified, are used for the next reaction.
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