Synthesis method of 1-(t-butyloxycarbonyl)-3-ethoxyazetidine-3-carboxylic acid

Abstract

The invention discloses a synthesis method of 1-(t-butyloxycarboryl)-3-ethoxy azetidine-3-carboxylic acid, and the synthesis route is as follows: the invention discloses a preparation method of 1-(t-butyloxycarboryl)-3-ethoxy azetidine-3-carboxylic acid, which comprises the following steps: by taking 3-oxo azetidine-1-carboxylic acid tert-butyl ester as a raw material, reacting at the temperature of 60-80 DEG C for 2-4 hours, and then adding a catalyst, thereby obtaining the 1-(t-butyloxycarboryl)-3-ethoxy azetidine-3-carboxylic acid. Under an alkaline condition, chloroform and ethanol are mediated, so that a keto carbonyl group of the 3-oxo-azetidine-1-carboxylic acid tert-butyl ester is converted into an ethyoxyl carboxylic acid group, and the target compound 1-(t-butyloxycarbonyl)-3-ethyoxyl azetidine-3-carboxylic acid is obtained. The synthesis method is low in cost, mild in reaction condition, low in potential safety hazard, ideal in yield and simple and efficient in operation, and a potential route is provided for large-scale production of the compound 1-(t-butyloxycarbonyl)-3-ethoxyazetidine-3-carboxylic acid.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid. Background Technology

[0002] Compound 1-(tert-Butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid is an azacyclobutane derivative whose structure includes a tert-butoxycarbonyl (Boc) protecting group and a carboxyl functional group, making it commonly used as an intermediate or protecting group in organic synthesis. Based on the applications of similar compounds, this substance may primarily be used in the field of peptide synthesis to introduce specific functional groups or protect amino groups, thereby playing a key role in drug development or biomaterial preparation.

[0003] In addition, nitrogen-containing heterocyclic butanes can be used as biochemical reagents in life science research to synthesize complex molecules or drug precursors; their Boc protecting groups can enhance stability and reaction selectivity, making them suitable for high-throughput synthesis experiments.

[0004] In existing technologies, there are reports of synthesizing compound 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid by reacting 3-ethoxyazacyclobutane-3-carboxylic acid with di-tert-butyl dicarbonate. However, the high price of compound 3-ethoxyazacyclobutane-3-carboxylic acid makes this preparation method costly. Therefore, further research on the preparation method of compound 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid is of certain significance. Summary of the Invention

[0005] To address the aforementioned problems in existing technologies, this invention provides a method for synthesizing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid. The entire synthesis process of this invention is low-cost, simple, convenient to operate, operates under mild reaction conditions, has low safety risks, and achieves ideal yields.

[0006] The technical solution of the present invention is as follows: The first objective of this invention is to provide a method for synthesizing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid, wherein the method involves a conversion reaction of the ketone carbonyl group by chloroform and ethanol under strongly alkaline conditions, ultimately transforming the ketone group (C=O) of compound 1 (tert-butyl 3-oxazacyclobutane-1-carboxylic acid) into the ethoxycarboxylic acid group (-C(OEt)COOH) of compound 2 (1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid).

[0007] The synthetic route of the synthetic method is as follows: .

[0008] Specifically, the steps include the following: (1) Add the alkali to chloroform, add water for the first time, stir at 15℃~40℃ for 20~50 minutes, cool down to 5℃~15℃, slowly add compound 1, namely 3-oxoazonicyclic butane-1-carboxylic acid tert-butyl ester, let it rise naturally to room temperature, stir for 3~6 hours, then add ethanol, stir at 15℃~40℃ for 8~16 hours, then add water for the second time, heat up to 70~120℃ and stir for 8~16 hours; (2) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 2, namely 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid.

[0009] Furthermore, in step (1), the alkali is selected from either potassium hydroxide or sodium hydroxide; Further, in step (1), the molar ratio of compound 1 to the base is 1:2.0~4.0; Further, in step (1), the mass-to-volume ratio of compound 1 to chloroform is 1:5~20 (g / mL); Further, in step (1), the mass-to-volume ratio of compound 1 to ethanol (g / mL) is 1:0.8~3.0; Further, in step (1), the mass-to-volume ratio of compound 1 to the water added for the first time is 1:0.02~0.08 (g / mL); Further, in step (1), the mass-to-volume ratio of compound 1 to the water added a second time is 1:0.8~3.0 (g / mL); Further, in step (2), the post-processing is as follows: After the reaction was completed, the mixture was allowed to cool naturally to room temperature, allowed to stand and separate into layers, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 5-6 with an acidic aqueous solution under stirring. The mixture was then extracted with organic solvent I, and the organic phases were combined. The organic phases were dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain the target compound 2, namely 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid.

[0010] Further, in step (2), the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0011] Further, in step (2), the organic solvent I is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0012] Furthermore, in step (2), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0013] The beneficial technical effects of this invention are as follows: This invention provides a method for preparing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid. The synthetic method involves the conversion of the ketone carbonyl group by chloroform and ethanol under strongly alkaline conditions, ultimately transforming the ketone group (C=O) of compound 1 (tert-butyl 3-oxazacyclobutane-1-carboxylic acid) into the ethoxycarboxylic acid group (-C(OEt)COOH) of compound 2 (1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid). The core reaction types include: dichlorocarbene formation and nucleophilic addition—chloroform generates dichlorocarbene (:CCl2) under alkaline conditions, attacking the ketone carbonyl group; ethanol nucleophilic substitution—ethoxy ions substitute the chlorine atom of the dichloro adduct; alkaline hydrolysis—hydrolysis dechlorination forms the carboxylic acid functional group. This synthetic method for preparing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid has significant advantages: low cost, mild reaction conditions, low safety risks, ideal yield, and simple and efficient operation. Precise pH control, adjusting to a weakly acidic range of 5-6, effectively protects the acid-sensitive Boc group, ensuring full protonation of the carboxyl group while preventing the loss of the tert-butoxycarbonyl (Boc) protecting group caused by a strong acid environment. Ultimately, it provides a potential route for the large-scale production of 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid, and also provides a method and approach for the conversion of the ketone group (C=O) of aazacyclobutane derivatives into an ethoxycarboxylic acid group (-C(OEt)COOH). Attached Figure Description

[0014] Figure 1 This is a schematic diagram of the synthetic route for compound 2 of the present invention.

[0015] Figure 2 The above is the 1H NMR spectrum of compound 2 obtained in Example 1 of this invention. Detailed Implementation

[0016] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0017] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0018] Example 1

[0019] A synthetic method for 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid, the synthetic route is as follows:

[0020] The specific steps are as follows: (1) Add potassium hydroxide (163.86 g, 2.92 mol, 2.50 eq) to chloroform (2.0 L), then add water (10 mL), and stir at 25 °C for 30 minutes. Cool down to about 10 °C, and slowly add compound 1, namely tert-butyl 3-oxoazacyclobutane-1-carboxylic acid (200.00 g, 1.17 mol, 1.00 eq), and allow it to rise naturally to room temperature (25 °C), then stir for 4 hours. Add ethanol (200 mL), and stir at 25 °C for 12 hours. Then add water (200 mL), and heat to 80 °C and stir for 12 hours.

[0021] (2) After the reaction is complete, the mixture is allowed to cool naturally to room temperature, stand for separation, and the aqueous phase is collected. The pH of the aqueous phase is adjusted to 5-6 with 1M hydrochloric acid aqueous solution under stirring. The mixture is then extracted three times with ethyl acetate (300mL×3). The organic phases are combined and dried with anhydrous sodium sulfate. The mixture is concentrated under reduced pressure to obtain the crude product. The crude product is purified by slurrying with petroleum ether to obtain the target compound 2, namely 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid (off-white powder, weight 281.30g, purity 98%, yield 96%).

[0022] The proton NMR spectrum of the obtained compound 2 is as follows: Figure 2 As shown, the obtained characterization data are as follows: 1 H NMR (400 MHz, DMSO) δ 13.33 (s, 1H), 4.05 (s, 2H), 3.83 (d, J = 7.6Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.37 (d, J = 9.7 Hz, 9H), 1.14 (t, J = 7.0 Hz, 3H). Example 2

[0023] The reaction steps were basically the same as in Example 1, except that potassium hydroxide (163.86 g, 2.92 mol, 2.50 eq) was replaced with potassium hydroxide (131.09 g, 2.34 mol, 2.00 eq), with a yield of 92%.

[0024] Example 3

[0025] The reaction steps were basically the same as in Example 1, except that potassium hydroxide (163.86 g, 2.92 mol, 2.50 eq) was replaced with potassium hydroxide (196.64 g, 3.50 mol, 3.00 eq), with a yield of 96%.

[0026] Example 4

[0027] The reaction steps were basically the same as in Example 1, except that potassium hydroxide (163.86 g, 2.92 mol, 2.50 eq) was replaced with potassium hydroxide (262.18 g, 4.67 mol, 4.00 eq), with a yield of 91%.

[0028] Example 5

[0029] The reaction steps were basically the same as in Example 1, except that potassium hydroxide (163.86 g, 2.92 mol, 2.50 eq) was replaced with sodium hydroxide (121.49 g, 3.04 mol, 2.60 eq), with a yield of 95%.

[0030] As can be seen from Examples 1-4, when the molar ratio of compound 1 to potassium hydroxide is 1.0:(2.0~4.0), the yield of compound 2 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 1 to potassium hydroxide is 1.0:2.5 and 1.0:3.0, and the reaction effect is basically optimal.

[0031] As can be seen from Examples 1 and 5, the reaction proceeds smoothly when potassium hydroxide and sodium hydroxide are used as bases, respectively, and the yield of compound 2 is high, not less than 95%. Among them, the reaction yield is higher when potassium hydroxide is used as base.

[0032] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid, characterized in that, Using tert-butyl 3-oxoazacyclobutane-1-carboxylic acid as a raw material, the target compound 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid was obtained under alkaline conditions mediated by chloroform and ethanol.

2. The synthesis method according to claim 1, characterized in that, The synthetic route of the synthetic method is as follows: 。 3. The synthesis method according to claim 2, characterized in that, Specifically, the steps include the following: (1) Add the alkali to chloroform, add water for the first time, stir at 15℃~40℃ for 20~50 minutes, cool down to 5℃~15℃, slowly add compound 1, namely 3-oxoazonicyclic butane-1-carboxylic acid tert-butyl ester, let it rise naturally to room temperature, stir for 3~6 hours, then add ethanol, stir at 15℃~40℃ for 8~16 hours, then add water for the second time, heat up to 70~120℃ and stir for 8~16 hours; (2) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 2, namely 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid.

4. The synthesis method according to claim 3, characterized in that, In step (1), the alkali is selected from either potassium hydroxide or sodium hydroxide.

5. The synthesis method according to claim 3, characterized in that, In step (1), The molar ratio of compound 1 to the base is 1:2.0~4.

0.

6. The synthesis method according to claim 3, characterized in that, In step (1), The mass-to-volume ratio of compound 1 to chloroform (g / mL) is 1:5~20; The mass-to-volume ratio of compound 1 to ethanol (g / mL) is 1:0.8~3.0; The mass-to-volume ratio (g / mL) of compound 1 to the water added for the first time is 1:0.02~0.08; The mass-to-volume ratio (g / mL) of compound 1 to the second added water is 1:0.8~3.

0.

7. The synthesis method according to claim 3, characterized in that, In step (2), the post-processing is as follows: After the reaction was completed, the mixture was allowed to cool naturally to room temperature, allowed to stand and separate into layers, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 5-6 with an acidic aqueous solution under stirring. The mixture was then extracted with organic solvent I, and the organic phases were combined. The organic phases were dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain the target compound 2, namely 1-(tert-butoxycarbonyl)-3-ethoxyazacyclobutane-3-carboxylic acid.

8. The synthesis method according to claim 7, characterized in that, In step (2), the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

9. The synthesis method according to claim 7, characterized in that, In step (2), the organic solvent I is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

10. The synthesis method according to claim 7, characterized in that, In step (2), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

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