A method for synthesizing N,N-bis(2-oxoethyl)benzyl carbamate
By using diethanolamine as a starting material and employing nucleophilic substitution of benzyl chloroformate and a TEMPO/sodium hypochlorite oxidation system, the problems of high raw material cost and safety risks in existing technologies have been solved, achieving efficient and low-cost synthesis of N,N-bis(2-oxoethyl)carbamate, which is suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- FUJIAN KAIXIN PHARM CO LTD
- Filing Date
- 2026-02-25
- Publication Date
- 2026-06-02
AI Technical Summary
In the existing synthesis process of N,N-bis(2-oxoethyl)carbamate, the starting material 2,5-dihydropyrrole-1-carboxylic acid benzyl ester has high procurement costs and poor supply stability. Precious metal catalysts such as potassium osmium tetroxide are expensive and pose safety and environmental risks, which limits their industrial application.
Using diethanolamine as the starting material, N-benzyloxycarbonyl diethanolamine is generated through the nucleophilic substitution reaction of benzyl chloroformate. Then, N,N-bis(2-oxoethyl)carbamate is prepared by oxidation reaction using a TEMPO/sodium hypochlorite oxidation system. The use of bulk chemical reagents reduces costs and is suitable for industrial production.
It reduces raw material costs, increases yield, simplifies synthesis routes, is suitable for large-scale industrial production, and avoids resource dependence and safety risks associated with precious metal catalysts.
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Figure CN122127250A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, and particularly relates to a method for synthesizing N,N-bis(2-oxoethyl)carbamate. Background Technology
[0002] N,N-bis(2-oxoethyl)carbamate, a bifunctional intermediate possessing both benzyloxycarbonyl and dialdehyde groups, is a key building block in the synthesis of antitumor and antiviral drugs. Its dialdehyde group can construct the piperazine ring, the core of the drug molecule, through condensation reactions. Simultaneously, the benzyloxycarbonyl group, as a classic protecting group for amino groups, allows this intermediate to be used in the synthesis of peptide and nucleic acid monomers and polypeptide chains, achieving selective protection and deprotection of amino groups. Due to its "bifunctional adaptability," the development of its synthetic process has attracted the attention of chemists.
[0003] Chinese patent CN115397821A discloses a method for preparing N,N-bis(2-oxoethyl)carbamate benzyl ester. This method uses benzyl 2,5-dihydropyrrole-1-carboxylate as the starting material and obtains the target product through a two-step "hydroxylation-oxidation" reaction. Two implementation methods are provided for the first step, the hydroxylation reaction: Implementation method one uses a combination of tripotassium hexafluoroferrate, potassium carbonate, methanesulfonamide, and potassium osmium tetroxide as reagents; Implementation method two uses N-methylmorpholine-N-oxide as the oxidant and osmium tetroxide as the catalyst. Both methods achieve the conversion of the starting material to benzyl 3,4-dihydroxypyrrole-1-carboxylate. In the second step, benzyl 3,4-dihydroxypyrrole-1-carboxylate is further oxidized with sodium periodate to obtain N,N-bis(2-oxoethyl)carbamate benzyl ester.
[0004]
[0005] Chinese patent CN115916776A reports a one-step oxidation process, which also uses 2,5,-dihydropyrrole-1-carboxylate as the starting material, sodium periodate as the oxidant, 2,6-dimethylpyridine as the base, and potassium osmium tetroxide dihydrate (VI) as the catalyst to directly produce N,N-bis(2-oxoethyl)carboxylate through the hydroxyl oxidation reaction of the pyrrole ring.
[0006]
[0007] However, the existing methods described above have significant drawbacks: the starting material, benzyl 2,5-dihydropyrrole-1-carboxylate, is a custom-made reagent, resulting in high procurement costs and poor supply stability; if it is prepared in-house, it requires multiple additional synthetic steps, which are cumbersome and result in significant losses, further increasing the overall production cost. Furthermore, the potassium osmium tetroxide used in the process is a precious metal catalyst, which is expensive, and osmium tetroxide is a highly toxic reagent, posing serious safety and environmental risks, further limiting its industrial-scale application. Summary of the Invention
[0008] The present invention addresses the problems existing in the prior art by providing a method for synthesizing N,N-bis(2-oxoethyl)carbamate. The method is rationally designed, uses readily available diethanolamine as the starting material, reduces raw material costs, and achieves a high yield, making it easy to scale up for industrial production.
[0009] To achieve the above objectives, the technical solution adopted in this invention is: a method for synthesizing N,N-bis(2-oxoethyl)carbamate, using diethanolamine as a raw material, through a nucleophilic substitution reaction with benzyl chloroformate to obtain N-benzyloxycarbonyl diethanolamine, and then oxidizing N-benzyloxycarbonyl diethanolamine to obtain N,N-biscarbamate, the reaction equation of which is as follows: .
[0010] Furthermore, in the step of synthesizing compound III from compound II, compound II reacts with benzyl chloroformate under the action of an alkali to obtain compound III. In the step of synthesizing compound I from compound III, compound III reacts under the action of a TEMPO / sodium hypochlorite oxidation system to generate compound I.
[0011] Furthermore, in the step of synthesizing compound III from compound II, compound II and the base are placed in an aprotic polar solvent and stirred evenly. After cooling to 0~10℃, benzyl chloroformate is added dropwise. After the addition is complete, the mixture is moved to room temperature to continue the reaction to obtain compound III.
[0012] Furthermore, in the step of synthesizing compound III from compound II, the base is one or more of potassium carbonate, potassium bicarbonate, and cesium carbonate.
[0013] Furthermore, in the step of synthesizing compound III from compound II, the aprotic polar solvent is one of acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
[0014] Furthermore, in the step of synthesizing compound III from compound II, the molar ratio of compound II: benzyl chloroformate: base is 1:1~1.2:1.5~2.
[0015] Furthermore, in the step of synthesizing compound I from compound III, the TEMPO / sodium hypochlorite oxidation system consists of a catalyst, an oxidant, a co-catalyst, and a buffer. The catalyst is TEMPO, the oxidant is sodium hypochlorite, the co-catalyst is one of sodium bromide, potassium bromide, lithium bromide, and lithium chloride, and the buffer is one of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
[0016] Furthermore, in the step of synthesizing compound I from compound III, the reaction uses water and dichloromethane as solvents.
[0017] Furthermore, in the step of synthesizing compound I from compound III, the molar ratio of compound III: catalyst: oxidant: co-catalyst: buffer is 1:0.03~0.04:2.1~2.2:0.3~0.4:0.25~0.3.
[0018] Compared with existing technologies, the present invention has the following advantages: The present invention is rationally designed, using readily available diethanolamine as the starting material, and efficiently prepares the target product through a two-step reaction of amino protection and oxidation. The synthetic route is simple and controllable. The second step oxidation reaction adopts a TEMPO / hypochlorite oxidation system, and the reagents used are all bulk chemical reagents that are readily available and inexpensive. Compared with the precious metal catalysts used in existing technologies, it can significantly reduce the raw material cost of the reaction and avoid the resource dependence and high cost problems caused by precious metal catalysts, making it more suitable for the cost control requirements of industrial production. At the same time, the first step reaction adopts mature and stable process conditions, combined with a mild selective oxidation system. The overall route has the characteristics of readily available raw materials, low cost, and high efficiency, making it suitable for large-scale industrial production. Attached Figure Description
[0019] Figure 1 This is LCMS graph a of compound III; Figure 2 This is LCMS image b of compound III; Figure 3 This is LCMS diagram a for compound I; Figure 4 This is LCMS image b for compound I; Figure 5 It is compound I. 1 HNMR image. Detailed Implementation
[0020] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.
[0021] The abbreviations for the reaction reagents mentioned in the instructions are as follows: TEMPO: Tetramethylpiperidine oxide.
[0022] This invention discloses a method for synthesizing N,N-bis(2-oxoethyl)carbamate benzyl ester. Using diethanolamine (compound II) as a starting material, N-benzyloxycarbonyl diethanolamine (compound III) is obtained through a nucleophilic substitution reaction with benzyl chloroformate. The N-benzyloxycarbonyl diethanolamine (compound III) is then oxidized to yield N,N-bis(2-oxoethyl)carbamate benzyl ester (compound I). The reaction equations are as follows: .
[0023] Specifically, in the step of synthesizing compound III from compound II, compound II reacts with benzyl chloroformate in an aprotic polar solvent under the action of a base via a nucleophilic substitution reaction to obtain compound III.
[0024] Specifically, in the step of synthesizing compound I from compound III, compound III is oxidized to compound I under the action of the TEMPO / sodium hypochlorite oxidation system.
[0025] Specifically, in the step of synthesizing compound III from compound II, compound II and the base are placed in an aprotic polar solvent and stirred evenly. After cooling to 0~10℃, benzyl chloroformate is added dropwise. After the addition is complete, the mixture is moved to room temperature to continue the reaction to obtain compound III.
[0026] Specifically, in the step of synthesizing compound III from compound II, the base is one or more of potassium carbonate, potassium bicarbonate, and cesium carbonate.
[0027] Specifically, in the step of synthesizing compound III from compound II, the aprotic polar solvent is one of acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
[0028] Specifically, in the step of synthesizing compound III from compound II, the molar ratio of compound II: benzyl chloroformate: base is 1:1~1.2:1.5~2.
[0029] Specifically, in the step of synthesizing compound I from compound III, the TEMPO / sodium hypochlorite oxidation system consists of a catalyst, an oxidant, a co-catalyst, and a buffer. The catalyst is TEMPO, the oxidant is sodium hypochlorite, the co-catalyst is one of sodium bromide, potassium bromide, lithium bromide, and lithium chloride, and the buffer is one of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
[0030] Specifically, in the step of synthesizing compound I from compound III, the reaction uses water and dichloromethane as solvents.
[0031] Specifically, in the step of synthesizing compound I from compound III, the molar ratio of compound III: catalyst: oxidant: co-catalyst: buffer is 1:0.03~0.04:2.1~2.2:0.3~0.4:0.25~0.3. Example
[0032] Synthesis of N-benzyloxycarbonyl diethanolamine (compound III): The reaction equation is as follows:
[0033] The specific steps are as follows: Diethanolamine (compound II) (500 g, 4.76 mol), potassium carbonate (1314.4 g, 9.51 mol), and acetonitrile (3000 mL) were added sequentially to a three-necked flask. The mixture was stirred and cooled to 10 °C. Benzyl chloroformate (812 g, 4.76 mol) was slowly added dropwise. After the addition was complete, the reaction system was naturally warmed to room temperature, and the reaction was continued to be stirred for 3 hours. The reaction was terminated when the starting material disappeared on the TLC plate. The reaction solution was filtered, and the filter cake was washed with acetonitrile (500 mL). The filtrate was evaporated to dryness, and water (1500 mL) was added. The aqueous phase was extracted with dichloromethane (1000 mL × 3). The organic phases were combined and washed with saturated brine (1000 mL). The mixture was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1071.7 g of compound III, with a yield of 94.1%. LCMS data: Figure 1 The main peak at 214 nm with a retention time of 0.44 min accounts for 82.25% of the area, which is the product peak of compound III. Figure 2 The results show that M+Na(262.1) and MW(239.1). Example
[0034] Synthesis of N,N-bis(2-oxoethyl)carbamate (compound I): The reaction equation is as follows:
[0035] The specific steps are as follows: Add N-benzyloxycarbonyl diethanolamine (compound III) (1 kg, 4.18 mol), potassium bromide (149.9 g, 1.26 mol), TEMPO (20 g, 0.128 mol), sodium bicarbonate (100 g, 1.19 mol), water (1.5 L), and dichloromethane (5 L) to a three-necked flask, stir and cool to 0°C, slowly add 5.5% sodium hypochlorite (11.9 kg), and react at this temperature for 1 h after the addition is complete. The reaction is stopped when the reactants have completely reacted under LC control. At 25 °C, 5 L of 8% potassium dihydrogen phosphate aqueous solution was added to the reaction solution. After stirring for 30 min, the mixture was separated. The aqueous phase was extracted once with dichloromethane (3 L). The organic phases were combined, washed with saturated brine (3 L), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude, pale yellow oily substance. The crude product was mixed with 2.5 L of dichloromethane and 1.5 kg of silica gel, and subjected to column chromatography (ethyl acetate:petroleum ether = 1:20) to give 939.1 g of compound I, with a yield of 95.5%. LCMS data: Figure 3 The main peak at 214 nm with a retention time of 2.43 min has an area ratio of 100%, which is the product peak of compound I; Figure 4 The results show that M+Na(258.0), MW(235). 1HNMR (400 MHz, DMSO) δ7.39-7.33(m, 5H), 5.12(s, 2H), 4.44-4.41(m, 2H), 4.26-4.19(m, 2H), 3.63-3.59(m, 2H).
[0036] This invention uses diethanolamine as a raw material to obtain N,N-bis(2-oxoethyl)carbamate via amino protection and oxidation reaction, providing a new synthetic route for key building blocks in the synthesis of antitumor and antiviral drugs. The process selection is reasonable, the raw materials are simple and readily available, the operation and post-processing are convenient, and it is easy to scale up for industrial production.
[0037] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.
Claims
1. A method for synthesizing N,N-bis(2-oxoethyl)carbamate, characterized in that: Using diethanolamine as a starting material, N-benzyloxycarbonyl diethanolamine is obtained through a nucleophilic substitution reaction with benzyl chloroformate. The N-benzyloxycarbonyl diethanolamine is then oxidized to give N,N-dicarbamate benzyl ester. The reaction equation is as follows: Among them, reactant II is diethanolamine, reactant III is N-benzyloxycarbonyl diethanolamine, and reactant I is N,N-dicarbamate benzyl ester.
2. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 1, characterized in that: In the step of synthesizing compound III from compound II, compound II reacts with benzyl chloroformate under the action of a base to obtain compound III. In the step of synthesizing compound I from compound III, compound III reacts under the action of a TEMPO / sodium hypochlorite oxidation system to generate compound I.
3. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 1, characterized in that: In the step of synthesizing compound III from compound II, compound II and the base are placed in an aprotic polar solvent and stirred until homogeneous. After cooling to 0-10°C, benzyl chloroformate is added dropwise. After the addition is complete, the mixture is moved to room temperature and the reaction continues to yield compound III.
4. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 3, characterized in that: In the step of synthesizing compound III from compound II, the base is one or more of potassium carbonate, potassium bicarbonate, and cesium carbonate.
5. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 3, characterized in that: In the step of synthesizing compound III from compound II, the aprotic polar solvent is one of acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
6. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 1, characterized in that: In the step of synthesizing compound III from compound II, the molar ratio of compound II: benzyl chloroformate: base is 1:1~1.2:1.5~2.
7. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 1, characterized in that: In the step of synthesizing compound I from compound III, the TEMPO / sodium hypochlorite oxidation system consists of a catalyst, an oxidant, a co-catalyst, and a buffer. The catalyst is TEMPO, the oxidant is sodium hypochlorite, the co-catalyst is one of sodium bromide, potassium bromide, lithium bromide, and lithium chloride, and the buffer is one of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
8. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 1, characterized in that: In the step of synthesizing compound I from compound III, the reaction uses water and dichloromethane as solvents.
9. The method for synthesizing N,N-bis(2-oxoethyl)carbamate according to claim 7, characterized in that: In the step of synthesizing compound I from compound III, the molar ratio of compound III: catalyst: oxidant: co-catalyst: buffer is 1:0.03~0.04:2.1~2.2:0.3~0.4:0.25~0.3.