Preparation method of (1R, 2R)-aminocyclobutanol

Abstract

The invention discloses a synthesis method of (1R, 2R)-aminocyclobutanol, which comprises the following steps: carrying out nucleophilic addition reaction on an azodicarboxylic acid compound and cyclobutanone, reducing carbonyl of the product to construct a basic skeleton of amino alcohol, removing N-protecting group, and finally breaking hydrazine bond through hydrogenation reduction to obtain (1R, 2R)-aminocyclobutanol. The quaternary amino alcohol is prepared. The synthetic route starts from cyclobutanone and azodicarboxylic acid compounds, and the quaternary amino alcohol is finally synthesized through multi-step reaction. The route avoids using expensive reagents and catalysts, has simple steps and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a preparation method of (1R, 2R)-aminocyclobutanol. Background Art

[0002] Psoriasis is a complex, chronic inflammatory skin disease. TAK-279, a highly effective and selective TYK2 inhibitor, has demonstrated significant efficacy in regulating the JAK-STAT pathway and alleviating inflammatory responses, making it of great significance for the treatment of psoriasis. In the structure of TAK-279, 1,2-aminocyclobutanol is an important chiral building block. This type of β-tetraaminoalcohol structure is also present in many other pyrazolopyrimidine-containing TYK2 inhibitors. The structural formulas of TAK-279 and (1R,2R)-aminocyclobutanol are as follows:

[0003]

[0004] In 2023, Oleksandr O's team reported a [2+2] cycloaddition reaction between ketene dimethyl acetal and polymethyl acrylate to obtain 2,2-dimethoxycyclobutane-1-carboxylic acid methyl ester, which was then hydrolyzed to obtain 2,2-dimethoxycyclobutane-1-carboxylic acid, which was then reacted with ethyl chloroformate to obtain (2,2-dimethoxycyclobutyl)-tert-butyl carbamate. Toluenesulfonic acid was then added to obtain 2-tert-butyl carbamate cyclobutanone, which was then reduced with NaBH4 to obtain (2-hydroxycyclobutyl)carbamate tert-butyl. After post-treatment, the final product, trans-2-hydroxycyclobutane-1-ammonium chloride, was obtained. This route has high synthetic efficiency, but the synthesis steps are cumbersome and time-consuming, and the reagents used are expensive and highly toxic.

[0005] The reaction route is as follows:

[0006]

[0007] In 2023, the MASSE team in the United States reported a nine-step, six-stage synthesis route from cyclobutanone to 2-methoxycyclobutyl-1-amine. The overall yield of the synthetic route was 2%, demonstrating high optical purity. However, the method's complex steps, long reaction times, and high reagent costs limited its application in large-scale production. The synthetic route is as follows:

[0008]

[0009] In 2023, Robertsona's team developed a synthetic route for the synthesis of quaternary β-amino alcohols using microbial engineering enzymes. The key is to use P450 BM3Engineered enzymes achieve the hydroxylation of fatty alkanes. This synthetic route presents mild reaction conditions and a relatively novel design concept. However, the use of enzymes requires strict control of reaction conditions. This results in high production costs, a major obstacle to the widespread application of natural enzyme catalysts. The synthetic route is as follows:

[0010]

[0011] Most current synthetic routes for amino alcohols suffer from numerous shortcomings. They typically start from epoxy or nitrogen-containing compounds and often rely on expensive noble metal ligands or enzymes. This results in complex synthesis steps and high reagent costs. Furthermore, existing tetravalent amino alcohol synthesis routes are not suitable for large-scale production. These limitations make existing synthetic methods difficult to meet the needs of industrial production.

[0012] To address the above issues, the present invention proposes a new synthetic route: first, azodicarboxylates are used to introduce nitrogen atoms to construct an asymmetric CN bond. The key to this step lies in selecting a suitable catalyst and reaction conditions to ensure the efficient introduction of the nitrogen atom. Next, the carbonyl group is reduced to an alcohol. This step requires the selection of an efficient reducing agent to avoid the formation of by-products. Finally, the excess part is removed through a reduction reaction to obtain the final product, a tetraamino alcohol. Summary of the Invention

[0013] The technical solutions of the present invention are as follows:

[0014] The present invention provides a method for preparing (1R, 2R)-aminocyclobutanol as shown in formula d.

[0015]

[0016] In the formula a or b, R 1 is a C1-C10 alkyl group, R 2 is a C1-C10 alkyl group, wherein R 1 With R 2 same,

[0017] The preparation method is carried out according to the following steps:

[0018] (1) Dissolve the azodicarboxylic acid compound, cyclobutanone and catalyst in solvent a and heat at 0℃-45℃

[0019] (preferably 25° C.) for 10-20 hours, and after post-treatment a, obtain 2-[N,N-bis(oxycarbonyl)hydrazino]-1-cyclobutanone as shown in formula a; the azodicarboxylic acid compound is one or more of diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, or diisopropyl azodicarboxylate (preferably diethyl azodicarboxylate); and the catalyst is one or more of Cat.1, Cat.2, Cat.3, or Cat.4 (preferably Cat. 3);

[0020] The molar ratio of the catalyst, the azodicarboxylic acid compound, and the cyclobutanone is 0.05-0.3:1:1-2 (preferably 0.1:1:1.2) (benzoic acid may be added as an additive during specific implementation); the solvent a is one or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, 1-butyl-3-methylimidazolium hexafluorophosphate, or 1-butyl-3-methylimidazolium tetrafluoroborate;

[0021] (2) dissolving the 2-[N,N-bis(oxycarbonyl)hydrazinyl]-1-cyclobutanone as shown in formula a and a reducing agent in solvent b, and performing a hydrogenation reduction reaction at -78-0°C (preferably -55°C). After the reaction, the 2-[N,N-bis(oxycarbonyl)hydrazinyl]-1-cyclobutanol as shown in formula b is obtained by post-treatment b; the reducing agent is LiAIH4,

[0022] One or more of NaBH4, the molar ratio of 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanone as shown in formula a and the reducing agent is 1:1-3 (preferably 1:2); the solvent b is one or more of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1-butyl-3-methylimidazolium hexafluorophosphate or dichloromethane;

[0023] (3) The 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b and a removing agent are dissolved in a solvent c, reacted at 25-90°C (preferably 70°C) for 15-20 hours, and the resulting reaction solution is subjected to post-treatment c to obtain the 2-hydrazine-1-cyclobutanol as shown in formula c. The removing agent is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide or potassium carbonate, hydrogen chloride, hydrogen bromide and acetic acid solution, and the molar ratio of the 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b and potassium hydroxide is 1:1-3 (preferably 1:3); the solvent c is one or more of methanol, tetrahydrofuran, acetonitrile or N,N-dimethylformamide;

[0024] (4) dissolving the 2-hydrazine-1-cyclobutanol as shown in formula c and a reducing agent in anhydrous ethanol, reacting at 25-60° C. (preferably 50° C.) for 4-6 hours under a H2 atmosphere of 1-50 bar (preferably 50 bar), and then post-treating d to obtain (1R, 2R)-aminocyclobutanol as shown in formula d, wherein the reducing agent is Raney-Ni or palladium carbon (preferably palladium carbon), and the molar ratio of the 2-hydrazine-1-cyclobutanol as shown in formula c to the reducing agent is 1:0.05-1 (preferably 1:0.1);

[0025] Furthermore, in the step (1), the azodicarboxylic acid compound, cyclobutanone and the catalyst are dissolved in solvent a, and then benzoic acid is added, and the amount of the benzoic acid added is the same as the amount of the catalyst.

[0026] Furthermore, the solvent in step (1) is dichloromethane, and the volume of the dichloromethane is 0.5-3 mL / mmol based on the amount of cyclobutanone.

[0027] Furthermore, the solvent b in step (2) is tetrahydrofuran, and the volume of the tetrahydrofuran is 0.5-3 mL / mmol based on the amount of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone.

[0028] Furthermore, the removing agent in step (3) is methanol, and the volume of the methanol is 0.5-3 mL / mmol based on the amount of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanol.

[0029] Furthermore, the volume of anhydrous ethanol in step (4) is 0.5-3 mL / mmol based on the amount of 2-hydrazine-1-cyclobutanol.

[0030] Furthermore, the post-treatment a in step (1) is as follows: after the reaction is completed, ethyl acetate is added to extract to obtain an organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography to obtain an eluent containing 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone, and distilled under reduced pressure to obtain 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanone as shown in formula a.

[0031] Furthermore, the post-treatment b in step (2) is as follows: after the reaction is completed, water is added to quench the reaction, anhydrous sodium sulfate is added and filtered, and column chromatography separation (petroleum ether: ethyl acetate volume ratio = 1:1) is performed to obtain 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b

[0032] Furthermore, the post-treatment in step (3) is as follows: cooling, filtering and concentrating the reaction solution to obtain 2-hydrazine-1-cyclobutanol as shown in formula C.

[0033] Furthermore, the post-treatment d in step (4) is as follows: after reacting for 4-6 hours, filtering and distilling under reduced pressure to obtain a solid, adding concentrated hydrochloric acid, extracting with ethyl acetate, alkalizing the aqueous layer with sodium hydroxide, extracting with CH2Cl2, drying the organic layer with Na2SO4, adding a saturated HCl-Et2O solution, concentrating, and recrystallizing the residue (methanol / petroleum ether 60°C).

[0034] The (1R, 2R)-aminocyclobutanol shown in formula d is obtained.

[0035] Compared with the existing technology, the advantage of this synthetic route is that it avoids the use of expensive catalysts and reagents, simplifies the synthetic steps, and makes large-scale production possible. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is the H NMR spectrum of product a.

[0037] Figure 2 is the carbon NMR spectrum of product a.

[0038] Figure 3 is the H NMR spectrum of product b.

[0039] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of product d after adding an N-protecting group.

[0040] Figure 5 This is the mass spectrum of product c.

[0041] Figure 6 This is the mass spectrum of product d. DETAILED DESCRIPTION

[0042] The technical solution of the present invention will be further described below with reference to specific embodiments and in conjunction with the accompanying drawings, but the present invention is not limited thereto.

[0043] Example 1

[0044] Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone

[0045] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.3 (1.15 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 18.78 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 77% and a purity of 92% (HPLC).

[0046] Example 2 Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (Cat. 1)

[0047] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.1 (3.24 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 9.27 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 38% and a purity of 91% (HPLC).

[0048] Example 3 Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (Cat. 2 + benzoic acid)

[0049] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.2 (1.42 g, 0.01 mol, 0.08 eq.), and the additive benzoic acid (1.22 g, 0.01 mol, 0.08 eq.). Then, add 100 mL of dichloromethane and stir thoroughly. Then, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. The reaction was allowed to react until the color turned pale yellow, which took 20 hours. The dichloromethane was removed by vortexing, and the reaction mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was used to separate 8.78 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 36% and a purity of 92% (HPLC).

[0050] Example 4: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone (Cat. 3 + benzoic acid)

[0051] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.3 (1.5 g, 0.01 mol, 0.08 eq.), and benzoic acid (1.22 g, 0.01 mol, 0.08 eq.), then add 100 mL of dichloromethane and stir thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. React until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, and the reaction system is extracted with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 17.5 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 75% and a purity of 92% (HPLC).

[0052] Example 5: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone (Cat. 4)

[0053] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.4 (1.5 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 18.2 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 77% and a purity of 94% (HPLC).

[0054] Example 6: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone (Cat. 4)

[0055] Cyclobutanone (8.4g, 0.12mol, 1eq.), Cat.4 (1.3g, 0.01mol, 0.08eq.) were added to a 250mL flask, and then 100mL of dichloromethane was added and stirred evenly. Diethyl azodicarboxylate (17.4g, 0.1mol, 0.83eq.) was weighed and dissolved in 100mL of dichloromethane and added to the reaction system. The reaction was allowed to react until the reaction system turned light yellow, which took 20h. The dichloromethane in the reaction system was first removed by rotation, and then extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. 12.6g of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone was obtained by column chromatography separation with a yield of 52% and a purity of 94% (HPLC). Comparative Example 1 Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone (Cat.5)

[0056] Cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.5 (1.42 g, 0.01 mol, 0.08 eq.) were added to a 250 mL flask, followed by 100 mL of dichloromethane and stirred. Diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) was then weighed and dissolved in 100 mL of dichloromethane and added to the reaction system. Subsequent TLC spot plate observation and gas chromatography revealed no product formation. This suggests that Cat.5 is unsuitable as a catalyst for the current reaction system.

[0057]

[0058] Example 7: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone using tetrahydrofuran as solvent

[0059] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.4 (1.3 g, 0.01 mol, 0.08 eq.), and 100 mL of tetrahydrofuran (THF). Stir thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of THF and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The THF is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 7.6 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yield 35%, and purity 91% (HPLC).

[0060] Example 8: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone using acetonitrile as solvent

[0061] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.4 (1.3 g, 0.01 mol, 0.08 eq.), and 100 mL of acetonitrile, stirring thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of acetonitrile and add to the reaction system. React until the reaction system turns pale yellow, which takes 20 hours. Remove the acetonitrile by vortexing, then extract with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 11.4 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yield 49%, and purity 94% (HPLC).

[0062] Example 9: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone using N,N-dimethylformamide as solvent

[0063] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.4 (8.4 g, 0.12 mol, 1 eq.), and 100 mL of N,N-dimethylformamide, stirring thoroughly. Next, dissolve diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) in 100 mL of N,N-dimethylformamide and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The N,N-dimethylformamide is removed by vortexing, and the reaction system is extracted with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 11.5 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 40% and a purity of 91% (HPLC).

[0064] Example 10: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone using 1-butyl-3-methylimidazolium hexafluorophosphate as solvent

[0065] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.), Cat.4 (8.4 g, 0.12 mol, 1 eq.), and then add 100 mL of 1-butyl-3-methylimidazolium hexafluorophosphate and stir until uniform. Then, weigh diethyl azodicarboxylate (17.4 g, 0.1 mol, 0.83 eq.) and dissolve it in 100 mL of 1-butyl-3-methylimidazolium hexafluorophosphate. Add the mixture and react until the reaction system turns pale yellow, which takes 20 hours. The 1-butyl-3-methylimidazolium hexafluorophosphate is removed by vortexing, and the reaction mixture is extracted with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 16.5 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 69% and a purity of 95% (HPLC).

[0066] Example 11: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone using diethyl azodicarboxylate as a substrate

[0067] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.3 (1.15 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Next, dissolve diethyl azodicarboxylate (20.20 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. Allow to react until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 17.33 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 72% and a purity of 93% (HPLC).

[0068] Example 12 Preparation of 2-[N,N-bis(tert-butyloxycarbonyl)hydrazinyl]-1-cyclobutanone using di-tert-butyl azodicarboxylate as a substrate

[0069] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.3 (1.15 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Then, dissolve di-tert-butyl azodicarboxylate (23.02 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. React until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 15.94 g of 2-[N,N-bis(tert-butyloxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 68% and a purity of 94% (HPLC).

[0070] Example 13 Preparation of 2-[N,N-bis(benzyloxycarbonyl)hydrazinyl]-1-cyclobutanone using dibenzyl azodicarboxylate as a substrate

[0071] To a 250 mL flask, add cyclobutanone (8.4 g, 0.12 mol, 1 eq.) and Cat.3 (1.15 g, 0.01 mol, 0.08 eq.), followed by 100 mL of dichloromethane and stir thoroughly. Next, dissolve dibenzyl azodicarboxylate (29.82 g, 0.1 mol, 0.83 eq.) in 100 mL of dichloromethane and add to the reaction system. React until the reaction system turns pale yellow, which takes 20 hours. The dichloromethane is removed by vortexing, followed by extraction with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography is used to separate 16.84 g of 2-[N,N-bis(benzyloxycarbonyl)hydrazinyl]-1-cyclobutanone, yielding 68% and a purity of 94% (HPLC).

[0072] Example 14: Synthesis of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanol

[0073] 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, lithium aluminum hydride (9.108 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at -78°C. After 1.5 h of reaction, the reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was added with anhydrous sodium sulfate and filtered. Separation by column chromatography (petroleum ether:ethyl acetate, volume ratio = 1:1) afforded 25.18 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol, with a yield of 85% and a purity of 90%.

[0074] Example 15: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol by adding NaBH4 as a reducing agent

[0075] 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, NaBH4 (9.96 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at -55°C. After 1.5 h of reaction, the reaction was quenched by water and extracted with ethyl acetate. The organic phase was then added with anhydrous sodium sulfate and filtered. Column chromatography (petroleum ether:ethyl acetate, volume ratio = 1:1) yielded 12.09 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol, with a yield of 43% and a purity of 92%.

[0076] Comparative Example 2: Adding Al(i-Pr)3 as a reducing agent

[0077] 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, Al(i-Pr)3 (41.76 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at -55°C. After completion of the reaction, TLC analysis revealed no target product.

[0078] Example 16: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanol (reduction by adding lithium aluminum hydride at 0°C)

[0079] 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, lithium aluminum hydride (9.108 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at 0°C. After 1.5 h of reaction, the reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was added with anhydrous sodium sulfate and filtered. Separation by column chromatography (petroleum ether:ethyl acetate, volume ratio = 1:1) afforded 16.25 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol, with a yield of 55% and a purity of 92%.

[0080] Example 17: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (Reduction with Lithium Aluminum Hydride at -30°C) 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, lithium aluminum hydride (9.108 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at -30°C. After 1.5 h of reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was added with anhydrous sodium sulfate and filtered. Separation by column chromatography (petroleum ether:ethyl acetate, volume ratio = 1:1) yielded 23.64 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol, with a yield of 80% and a purity of 92%.

[0081] Example 18: Preparation of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (Reduction with Lithium Aluminum Hydride at -78°C) 1,2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanone (29.31 g, 0.12 mol, 1 eq.) prepared in Example 11 was added to a 250 mL flask, along with 100 mL of redistributed, dried tetrahydrofuran. Subsequently, lithium aluminum hydride (9.108 g, 0.24 mol, 2 eq.) was slowly added to the reaction system at -78°C. After 1.5 h of reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was added with anhydrous sodium sulfate and filtered. Separation by column chromatography (petroleum ether:ethyl acetate, volume ratio = 1:1) yielded 25.11 g of 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol, with a yield of 85% and a purity of 92%.

[0082] Example 19: Synthesis of 2-hydrazine-1-cyclobutanol (using KOH as a removing agent)

[0083] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and potassium hydroxide (2.52 g, 45 mmol, 3 eq.). 50 mL of methanol was added, and the temperature was raised to 70°C for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 35%.

[0084] Example 20: Synthesis of 2-hydrazine-1-cyclobutanol (using NaOH as a removing agent)

[0085] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and sodium hydroxide (1.8 g, 45 mmol, 3 eq.). 50 mL of methanol was added, and the mixture was heated to 70°C and allowed to react for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 48%.

[0086] Example 21: Synthesis of 2-hydrazine-1-cyclobutanol (using K2CO3 as a removing agent)

[0087] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and KCO (6.21 g, 45 mmol, 3 eq.). 50 mL of methanol was added, and the temperature was raised to 70°C for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 26%.

[0088] Example 22: Synthesis of 2-hydrazine-1-cyclobutanol (using LiOH as a removing agent)

[0089] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and LiOH (1.07 g, 45 mmol, 3 eq.). 50 mL of methanol was added, and the temperature was raised to 70°C for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 26%.

[0090] Example 23: Synthesis of 2-hydrazine-1-cyclobutanol (using HCl as a removing agent)

[0091] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and 30 mL of 20% HCl solution. The temperature was raised to 70°C and the reaction was allowed to react for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 58%.

[0092] Example 24: Synthesis of 2-hydrazine-1-cyclobutanol (using hydrogen bromide acetic acid solution as removing agent)

[0093] To a 50 mL flask was added 2-[N,N-bis(ethoxycarbonyl)hydrazinyl]-1-cyclobutanol (3.69 g, 15 mmol, 1 eq.) prepared in Example 18 and 30 mL of hydrogen bromide and acetic acid solution. The temperature was raised to 70°C and the reaction was allowed to react for 20 h. The reaction solution was cooled, filtered, and concentrated to yield 2-hydrazine-1-cyclobutanol. The reaction was monitored by gas chromatography, and the yield was calculated by area normalization to be 65%.

[0094] Example 25: Synthesis of (1R,2R)-aminocyclobutanol

[0095] To a reaction vessel was added the mixture of 2-hydrazine-1-cyclobutanol (5 mmol, 1 eq.) prepared in Example 24, followed by Raney-Ni (30 mg, 0.5 mmol, 10 mol%) and 15 mL of anhydrous ethanol. The atmosphere in the vessel was replaced with N2 and then with 50 bar of H2. After reacting at 50°C for 4 h, the vessel was opened, filtered, and the solvent removed by distillation under reduced pressure. Concentrated hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The aqueous layer was basified with sodium hydroxide and then extracted with CH2Cl2. The organic layer was dried (Na2SO4), treated with saturated HCl-Et2O solution, concentrated, and the residue was recrystallized (methanol / petroleum ether at 60°C) to yield 461 mg of the desired product, (1R,2R)-aminocyclobutanol, in a 75% yield with a purity of 85% (HPLC). The final product was purified and characterized by adding an N-protecting group.

[0096] Example 26: Synthesis of (1R,2R)-aminocyclobutanol

[0097] To a reaction vessel was added the mixture of 2-hydrazine-1-cyclobutanol (5 mmol, 1 eq.) prepared in Example 24, along with palladium-on-carbon catalyst (97.5 mg, 0.5 mmol, 10 mol%) and 15 mL of anhydrous ethanol. The atmosphere in the vessel was replaced with nitrogen and then with 50 bar of hydrogen. After reacting at 50°C for 4 hours, the vessel was opened, filtered, and the solvent removed by distillation under reduced pressure. Concentrated hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The aqueous layer was basified with sodium hydroxide and then extracted with CHCl. The organic layer was dried (NaSO), treated with saturated HCl-EtO solution, concentrated, and the residue was recrystallized (methanol / petroleum ether at 60°C) to yield 516 mg of the desired product, (1R,2R)-aminocyclobutanol, in an 84% yield and 86% purity (HPLC). The final product was purified and characterized by the addition of an N-protecting group.

Claims

1. A method for preparing (1R, 2R)-aminocyclobutanol as shown in formula d, It is characterized by: In the formula a or b, R 1 is a C1-C10 alkyl group, R 2 is a C1-C10 alkyl group, wherein R 1 With R 2 Similarly, the preparation method is carried out according to the following steps: (1) Dissolving an azodicarboxylic acid compound, cyclobutanone, and a catalyst in a solvent a, reacting at 0°C-45°C for 10-20h, and post-treating a to obtain 2-[N,N-bis(oxycarbonyl)hydrazinyl]-1-cyclobutanone as shown in formula a; the azodicarboxylic acid compound is one or more of diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, or diisopropyl azodicarboxylate; the catalyst is Cat.1, One or more of Cat.2, Cat.3 or Cat.4; the molar ratio of the catalyst, the azodicarboxylic acid compound and the cyclobutanone is 0.05-0.3:1:1-2; the solvent a is one or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, 1-butyl-3-methylimidazolium hexafluorophosphate or 1-butyl-3-methylimidazolium tetrafluoroborate; (2) dissolving the 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanone as shown in formula a and a reducing agent in solvent b, and performing a hydrogenation reduction reaction at -78-0°C. After the reaction, post-treating b to obtain 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b; the reducing agent is one or more of LiAIH4 and NaBH4, and the molar ratio of the 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanone as shown in formula a and the reducing agent is 1:1-3; the solvent b is one or more of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1-butyl-3-methylimidazolium hexafluorophosphate or dichloromethane; (3) dissolving the 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b and a removing agent in solvent c, reacting at 25-90° C. for 15-20 hours, and subjecting the resulting reaction solution to post-treatment c to obtain 2-hydrazine-1-cyclobutanol as shown in formula c. The removing agent is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, hydrogen chloride, and hydrogen bromide acetic acid solution, and the molar ratio of the 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b to potassium hydroxide is 1:1-3; the solvent c is one or more of methanol, tetrahydrofuran, acetonitrile, or N,N-dimethylformamide; (4) The 2-hydrazine-1-cyclobutanol as shown in formula c and a reducing agent are dissolved in anhydrous ethanol, reacted at 25-60° C. for 4-6 hours under a 1-50 bar H2 atmosphere, and then post-treated d to obtain (1R, 2R)-aminocyclobutanol as shown in formula d, wherein the reducing agent is Raney-Ni or palladium carbon, and the molar ratio of the 2-hydrazine-1-cyclobutanol as shown in formula c and the reducing agent is 1:0.05-1.

2. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein In the step (1), the azodicarboxylic acid compound, cyclobutanone and the catalyst are dissolved in solvent a, and then benzoic acid is added. The amount of the benzoic acid added is the same as the amount of the catalyst.

3. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The solvent in step (1) is dichloromethane, and the volume of the dichloromethane is 0.5-3 mL / mmol based on the amount of cyclobutanone.

4. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The solvent b in the step (2) is tetrahydrofuran, and the volume of the tetrahydrofuran is 0.5-3 mL / mmol based on the amount of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone.

5. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The removing agent in step (3) is methanol, and the volume of the methanol is 0.5-3 mL / mmol based on the amount of 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanol.

6. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The volume of anhydrous ethanol in the step (4) is 0.5-3 mL / mmol based on the amount of 2-hydrazine-1-cyclobutanol.

7. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The post-treatment a in step (1) is as follows: after the reaction is completed, ethyl acetate is added to extract to obtain an organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain an eluent containing 2-[N,N-bis(ethoxycarbonyl)hydrazine]-1-cyclobutanone, and distilled under reduced pressure to obtain 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanone as shown in formula a.

8. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The post-treatment b in step (2) is as follows: after the reaction is completed, water is added to quench the reaction, anhydrous sodium sulfate is added, the mixture is filtered, and column chromatography is performed to separate the mixture to obtain 2-[N,N-bis(oxycarbonyl)hydrazine]-1-cyclobutanol as shown in formula b.

9. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The post-treatment in step (3) is as follows: the reaction solution is cooled, filtered and concentrated to obtain 2-hydrazine-1-cyclobutanol as shown in formula C.

10. The method for preparing (1R, 2R)-aminocyclobutanol according to claim 1, wherein The post-treatment d in the step (4) is as follows: after reacting for 4-6 hours, filtering and distilling under reduced pressure to obtain a solid, adding concentrated hydrochloric acid, extracting with ethyl acetate, alkalizing the aqueous layer with sodium hydroxide, extracting with CH2Cl2, drying the organic layer with Na2SO4, adding a saturated HCl-Et2O solution, concentrating, and recrystallizing the residue to obtain (1R,2R)-aminocyclobutanol as shown in formula d.

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