1, 2, 3-isocarbon dialkyl-hydroxyl-amino trans-substituted cyclic compound and preparation method thereof

Abstract

The invention discloses a 1, 2, 3-carbon dialkyl-hydroxyl-amino trans-substituted cyclic compound and a preparation method thereof.The preparation method comprises the specific preparation steps that S1, under the alkaline condition, a compound 1 reacts with an alkoxycarbonylation reagent, and a compound 2 is generated; s2, reducing the compound 2 to obtain a compound 3; s3, carrying out protection reaction on hydroxyl of the compound 3 to obtain a hydroxyl-protected compound 4; s4, hydrolyzing the compound 4 in a methyl ester alkaline environment to obtain a compound 5; s5, carrying out Curis rearrangement on the compound 5 to obtain a compound 6; s6, under an acidic condition, removing a protecting group from a hydroxyl group of the compound 6 to obtain a compound 7; n in the synthetic route is equal to 1 or 2, and X is equal to C or O; r1 and R2 are C1-C5 alkyl groups. In the whole reaction route, raw materials and reagents are cheap and easy to obtain, no reagent dangerous to operate exists, the reaction condition is mild, the reaction yield is high, no harsh implementation condition exists, and the technical scheme is convenient to implement and suitable for process amplification.

Description

Technical Field

[0001] This invention relates to the field of compound preparation, specifically to a 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound and its preparation method. Background Technology

[0002] According to existing literature, 1,2,3-homocarbazide-hydroxy-amino substituted cyclic compounds are key intermediates for nucleoside antiviral drugs and carbohydrate-related drugs. The hydroxyl and amino substitutions in their structure are the core groups that realize drug activity. They can be used as the core skeleton or modification unit for drug / pesticide molecule design. Their flexible and varied structures, especially their well-defined stereoconfigurations, provide unique value and convenience for optimizing the structure of drug candidate molecules and improving drug efficacy, selectivity, drugability, and metabolic stability.

[0003] The following are existing literature reports on 1,2,3-homocarbazide-hydroxy-amino substituted cyclic compounds:

[0004] The literature Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, #24, pp. 5721-5726 and WO2012 / 125886 reports a 1,2,3-hydroxy-homocarbodimethyl-amino five-membered ring compound with the following structural formula:

[0005]

[0006] The structure of candidate compounds used for novel Janus kinase (JAK) inhibitors has been modified to achieve excellent target selectivity and target binding affinity.

[0007] References WO2022140472A1, US2018 / 44344, WO2021 / 254384, Journal of Medicinal Chemistry, 2021, vol.64, #13, pp.9056-9077 report a 1,1'-methylhydroxy-2-amino five-membered ring compound with the following structural formula:

[0008]

[0009] It has been used in drug screening and development of CDK degraders. WO2013 / 55577 also reports its use in drug screening and development of selective androgen receptor modulators.

[0010] According to document US2020 / 17461, 2-amino-4,4-dimethylcyclopentan-1-ol has the following structural formula:

[0011]

[0012] Screening and development of drugs already used to treat IKAROS family zinc finger protein 2 (IKZF2) dependent diseases.

[0013] WO2012125886A1 discloses a similar method for preparing 1,2,3-hydroxy-homocarbodialkyl-amino substituted cyclic compounds and monoalkyl-hydroxy-amino substituted cyclic compounds. However, it is not the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound disclosed in this invention. Moreover, its reaction steps are lengthy, the operation is cumbersome, the risk of side reactions is high, the industrial scale-up is difficult, and the yield loss is serious. Summary of the Invention

[0014] In order to overcome the deficiencies in the prior art, the present invention provides a method for preparing 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compounds with mild reaction conditions and high reaction yield.

[0015] This invention first provides a method for preparing 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compounds, the synthetic route being as follows:

[0016]

[0017] The specific preparation steps are as follows:

[0018] Under alkaline conditions (S1), compound 1 reacts with an alkoxycarbonylating agent to generate compound 2;

[0019] S2 reduces compound 2 to give compound 3;

[0020] S3 performs a protection reaction on the hydroxyl group of compound 3 to obtain hydroxyl-protected compound 4;

[0021] Compound 4 (S4) is hydrolyzed in an alkaline environment with methyl ester to give compound 5;

[0022] Compound S5 undergoes the Curtis rearrangement to yield compound 6;

[0023] Compound S6 is subjected to acidic conditions, during which the hydroxyl group of compound 6 is deprotected to yield compound 7;

[0024] In the synthetic route, n = 1 or 2, X = C or O; R1 and R2 are C1-C5 alkyl groups.

[0025] This invention also provides the following optimization scheme:

[0026] Preferably, step S1 specifically involves: adding an alkoxycarbonylating reagent and sodium hydride to a flask, then adding a mixture of compound 1 and methanol dropwise to the reaction solution; after the addition is complete, heating and stirring are performed; after the reaction is complete, the mixture is cooled, the reaction is quenched with methanol, and then acetic acid and water are added; the mixture is extracted with dichloromethane, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; after purification, compound 2 is obtained.

[0027] Preferably, step S2 is as follows: compound 2 is dissolved in methanol, acetic acid is added, and then sodium borohydride is added in batches and stirred for 10 minutes; the reaction is quenched with ammonium chloride aqueous solution, concentrated under reduced pressure to remove excess methanol, extracted with dichloromethane, the organic layer is separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; compound 3 is obtained after purification.

[0028] Preferably, step S3 specifically involves: dissolving compound 3 in dichloromethane, adding triethylamine and TBSOTf sequentially, and then heating and stirring until compound 3 is completely consumed. The mixture is then extracted with dichloromethane in an ice bath, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the purified compound 4 is obtained.

[0029] Preferably, step S4 is as follows: Compound 4 is dissolved in a methanol / tetrahydrofuran / water mixture, lithium hydroxide monohydrate is added, and the mixture is stirred until compound 4 is completely consumed; excess methanol and tetrahydrofuran are removed by vacuum concentration, the pH is adjusted to 1-2 with hydrochloric acid in an ice bath, ethyl acetate is added for extraction and separation, the mixture is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum; after purification, compound 5 is obtained.

[0030] Preferably, step S5 is as follows: compound 5 is dissolved in toluene, triethylamine is added and heated, and then diphenyl azidophosphate is added dropwise; after heating and stirring the reaction, water is added to quench the reaction until compound 5 is completely consumed; after cooling to room temperature, water is added, the mixture is extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the purified compound 6 is obtained.

[0031] Preferably, step S6 specifically involves: dissolving compound 6 in ethyl acetate, adding ethyl hydrochloride solution, stirring until compound 6 is completely consumed; concentrating under reduced pressure, adjusting the pH to 7-8 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure; after purification, compound 7 is obtained.

[0032] Preferably, the base in step S1 is one of sodium hydride, lithium diisopropylamino, sodium hexamethyldisilamino, potassium hexamethyldisilamino, or 1,8-diazabicycloundec-7-ene, and the amount used is 1 to 10 molar equivalents of the substrate; the alkoxycarbonylating agent can be one of dimethyl carbonate, diethyl carbonate, or diisopropyl carbonate; the solvent can be, but is not limited to, tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, or ethanol; the reaction temperature is from 0 to 100 degrees Celsius, more preferably from 25 to 80 degrees Celsius.

[0033] Preferably, in step S2, a reducing agent selected from sodium borohydride, lithium borohydride, lithium aluminum hydride, and borane is used for reduction. The amount used is 1-10 molar equivalents of the substrate; the solvent is selected from tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, and ethanol; the reaction temperature is 0 to 100 degrees Celsius, more preferably 0-20 degrees Celsius, and even more preferably 0 degrees Celsius.

[0034] Preferably, the protecting group in the protection reaction of step S3 is TBS (tert-butyldimethylsilyl ether), TBDPS (tert-butyldiphenylsilyl ether), TMS (trimethylsilyl ether), Bn (benzyl), substituted benzyl, methoxymethyl ether (MOM), or 2-(trimethylsilyl)ethoxymethyl ether (SEM), and the amount used is 1-10 molar equivalents of the substrate; the solvent is one of tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, or ethanol; the reaction temperature is 0 to 100 degrees Celsius, more preferably 0-25 degrees Celsius.

[0035] Preferably, the base in step S4 is one of sodium hydroxide, potassium hydroxide, or lithium hydroxide, and the amount used is 1-10 molar equivalents of the substrate; the solvent is one of water, methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, or n-hexane; the reaction temperature is 0 to 100 degrees Celsius, more preferably 30-60 degrees Celsius, and even more preferably 50 degrees Celsius.

[0036] Preferably, the reagent in step S5 is diphenyl azidophosphate (DPPA), used in an amount of 1-10 molar equivalents of the substrate; the organic base is one of triethylamine, diisopropylamine, and 1,8-diazabicycloundec-7-ene, used in an amount of 1-10 molar equivalents of the substrate; the solvent is one of methanol, ethanol, tert-butanol, benzyl alcohol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, and n-hexane; the reaction temperature is 0 to 100 degrees Celsius, more preferably 60-80 degrees Celsius, and even more preferably 70 degrees Celsius.

[0037] Preferably, in step S6, the acidic reagent is selected from one or more of formic acid, hydrofluoric acid, pyridine hydrogen fluoride, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid, and the amount used is 1-100 molar equivalents of the substrate; or a fluorine-containing reagent, such as tetrabutylammonium fluoride, potassium fluoride, sodium fluoride, ammonium fluoride, etc.; the solvent is selected from one of ethyl acetate, methanol, ethanol, tert-butanol, benzyl alcohol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, and n-hexane; the reaction temperature is 0 to 100 degrees Celsius, more preferably 20-30 degrees Celsius, and even more preferably 25 degrees Celsius.

[0038] The present invention also provides a 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound, which is prepared according to the above-described method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound.

[0039] The beneficial effects of this invention are:

[0040] This invention provides a method for preparing 1,2,3-homocarbazyl-hydroxy-amino trans-substituted cyclic compounds. It uses inexpensive and readily available cyclic carbonyl compounds as starting materials and proceeds through the following six steps: methoxycarbonylation, carbonyl reduction, TBS protection of the hydroxyl group, ester hydrolysis, Curtis rearrangement, and hydroxyl deprotection. The entire reaction route utilizes inexpensive and readily available starting materials and reagents, avoids handling hazardous reagents, employs mild reaction conditions, achieves high yields, and does not require stringent implementation conditions. The technical solution is easy to implement and suitable for process scale-up.

[0041] The target compound 7 of this invention is a type of nitrogen- and oxygen-containing synthetic building block compound, which has the following multiple uses:

[0042] 1. The target compound has both amino and hydroxyl groups in its structure, and its chemical properties are flexible and varied. Both nitrogen and oxygen atoms can be attached to various chemical groups.

[0043] 2. The target compound itself can act as a linking group, with nitrogen and oxygen atoms simultaneously linking two compound fragments.

[0044] 3. Target compounds and their derivatives can serve as core frameworks or modification units for existing drug / pesticide molecule design. By regulating lipophilicity and target binding affinity, constructing nitrogen-containing heterocycles or modifying active groups, biological activity and selectivity can be enhanced, and metabolic stability and drug-likeness can be optimized.

[0045] 4. In medicinal chemistry, precise regulation of molecular lipid solubility, water solubility, and charge distribution enhances the specific binding force with biological targets (enzymes, receptors, etc.), while optimizing metabolic stability and reducing toxic side effects, thus facilitating the efficient synthesis of innovative drugs such as antibacterial, antitumor, and anti-inflammatory drugs.

[0046] 5. In pesticide chemistry, it can enhance the activity against target pests, pathogens, or weeds, improve pesticide selectivity and environmental compatibility, reduce the impact on non-target organisms, provide convenient tools for the structural innovation of insecticides, fungicides, and herbicides, and significantly shorten the research and development cycle of new active molecules. Attached Figure Description

[0047] Figure 1 This is the nuclear magnetic resonance spectrum of compound 7 obtained in Example 1 of the present invention. Detailed Implementation

[0048] To enable those skilled in the art to better understand the technical solution of the invention, the invention will be further described in detail below with reference to specific embodiments.

[0049] The preparation method of the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound of this invention patent consists of the following 6 steps:

[0050]

[0051] More preferably, both R1 and R2 are methyl groups:

[0052]

[0053] In the synthetic route, n = 1 or 2, X = C or O; R1 and R2 are C1-C5 alkyl groups.

[0054] Step S1: Under alkaline conditions, compound 1 reacts with an alkoxycarbonylating agent to generate compound 2.

[0055] The base here can be, but is not limited to: sodium hydride, lithium diisopropylamino, sodium hexamethyldisilamino, potassium hexamethyldisilamino, 1,8-diazabicycloundec-7-ene, etc., in amounts of 1 to 10 molar equivalents of the substrate; the alkoxycarbonylating reagent can be one of dimethyl carbonate, diethyl carbonate, or diisopropyl carbonate; the solvent here can be, but is not limited to: tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, ethanol, etc.; the temperature is 0 to 100 degrees Celsius. This step involves alkoxycarbonylation of the α-position of the ketone carbonyl under alkaline conditions, resulting in high yields and few side reactions. Methoxycarbonylation is preferred, and the reagent used is an alkoxycarbonylating reagent.

[0056] Step S2: Reduce compound 2 to obtain compound 3. The reducing agent can be, but is not limited to, sodium borohydride, lithium borohydride, lithium aluminum hydride, borane, etc., in an amount of 1 to 10 molar equivalents of the substrate; the solvent can be, but is not limited to, tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, ethanol, etc.; the temperature is 0 to 100 degrees Celsius. This step reduces the ketone carbonyl group to an alcohol. Sodium borohydride is preferred as the reducing agent because it has stable reaction performance, high yield, few side reactions, and simple post-processing.

[0057] Step S3: The hydroxyl group of compound 3 is protected using a strategy to obtain compound 4 with hydroxyl protection. Here, PG (PG refers to the protecting group) can be, but is not limited to: TBS (tert-butyldimethylsilyl ether), TBDPS (tert-butyldiphenyl silyl ether), TMS (trimethylsilyl ether), Bn (benzyl), substituted benzyl, methoxymethyl ether (MOM), 2-(trimethylsilyl)ethoxymethyl ether (SEM), and the amount used is 1 to 10 molar equivalents of the substrate; the solvent can be, but is not limited to: tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, methanol, ethanol, etc.; the temperature is 0 to 100 degrees Celsius. This invention uses a suitable protecting group to avoid side reactions, improve yield, and facilitate purification and separation; TBS (tert-butyldimethyl silyl ether) is preferred as the protecting group.

[0058] Step S4: The methyl ester is hydrolyzed in an alkaline environment to yield compound 5. The alkaline agent can be, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., in amounts of 1 to 10 molar equivalents of the substrate; the solvent can be, but is not limited to, water, methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, etc.; the temperature is 0 to 100 degrees Celsius. This step involves ester hydrolysis under alkaline conditions. Lithium hydroxide is preferred in this invention due to its safe and stable reaction performance.

[0059] Step S5: Substrate carboxylic acid 5 undergoes the Curtis rearrangement to give compound 6. The main reagents are diphenyl azide phosphate (DPPA) in amounts of 1–10 molar equivalents of the substrate; organic bases (such as triethylamine, diisopropylamine, 1,8-diazabicycloundec-7-ene, etc.) in amounts of 1–10 molar equivalents of the substrate; solvents can be, but are not limited to: methanol, ethanol, tert-butanol, benzyl alcohol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, etc.; the temperature is 0 to 100 degrees Celsius. The Curtis rearrangement reaction yields a specific product and efficiently provides the target product.

[0060] Step S6: Under acidic conditions, the hydroxyl group is demained to yield compound 7. The acidic conditions can be, but are not limited to: formic acid, hydrofluoric acid, pyridine hydrogen fluoride, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc., in amounts of 1–100 molar equivalents of the substrate; or fluorine-containing reagents such as tetrabutylammonium fluoride, potassium fluoride, sodium fluoride, ammonium fluoride, etc.; the solvent can be, but is not limited to: ethyl acetate, methanol, ethanol, tert-butanol, benzyl alcohol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, n-hexane, etc.; the temperature is 0 to 100 degrees Celsius.

[0061] The above is a detailed description of the present invention. The following are embodiments of the present invention.

[0062] Example 1

[0063] The specific synthetic route of Example 1 is as follows:

[0064]

[0065] Where X = C, n = 1.

[0066] The specific preparation steps are as follows:

[0067] Step S1: Add the alkoxycarbonylating reagent (dimethyl carbonate, DMC, 550 mL) to the flask, then add sodium hydride (NaH, 23.5 g, 1.20 equivalents) at 25 °C. Next, add a mixture of compound 1 (55.0 g, 1.00 equivalents) and methanol (0.55 mL) dropwise to the reaction mixture. After the addition is complete, heat to 80 °C and stir for 6 hours. After the reaction is complete, thin-layer chromatography (TLC) analysis (petroleum ether / ethyl acetate = 40:1, Rf = 0.40) shows the formation of new spots. Cool to 0 °C, quench the reaction with methanol (19.3 mL), and then add acetic acid (38.5 mL) and water (500 mL). Extract with dichloromethane by liquid-liquid extraction, wash once with saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) yielded a purple liquid compound 2 with a mass of 49.9 g.

[0068] Step S2: Compound 2 (44.9 g, 1.00 equivalent) was dissolved in anhydrous methanol (450 mL), and acetic acid (15.84 g, 1.00 equivalent) was added at 0 °C. Then, sodium borohydride (29.94 g, 3.00 equivalent) was added in portions, and the mixture was stirred at 0 °C for 10 minutes. Thin-layer chromatography (TLC) analysis (petroleum ether / ethyl acetate = 5:1) confirmed that the starting material had been completely consumed. The reaction was quenched with 300 mL of ammonium chloride aqueous solution, concentrated under reduced pressure to remove excess methanol, extracted with dichloromethane, and the organic layer was separated. The organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to give compound 3a (pale yellow crystals, 19.9 g) and compound 3b (pale yellow oil, 17.7 g). The target product, compound 3, is compound 3b.

[0069] Step S3: Compound 3b (17.0 g, 1.00 equivalent) was dissolved in dichloromethane (170 mL). Triethylamine (TEA, 30.0 g, 3.00 equivalent) and TBSOTf (65.2 g, 2.50 equivalent) were added sequentially at 0 °C, followed by stirring at 25 °C for 3 hours. Thin-layer chromatography (TLC) analysis (petroleum ether / ethyl acetate = 40:1) confirmed that compound 3b was completely consumed. Water was added in an ice bath, and the mixture was extracted with dichloromethane, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 100:1) to give a yellow oily compound 4 (29.4 g).

[0070] Step S4: Compound 4 (28.0 g, 1.00 equivalent) was dissolved in a methanol / tetrahydrofuran / water mixture (14.0 mL / 14.0 mL / 14.0 mL), and lithium hydroxide monohydrate (41.0 g, 10.0 equivalent) was added. The mixture was stirred at 50 °C for 16 hours. Thin-layer chromatography (TLC) analysis (petroleum ether / ethyl acetate = 40:1) confirmed that starting material 4 had been completely consumed. The mixture was concentrated under reduced pressure to remove excess methanol and tetrahydrofuran. The pH was adjusted to 1-2 with 4M hydrochloric acid in an ice bath. Ethyl acetate was added for extraction and separation. The mixture was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1 → 20:1 → 0:1) to give a yellow oily compound 5 (19.9 g).

[0071] Step S5: Compound 5 (17.9 g, 1.00 equivalent) was dissolved in toluene (179 mL), and triethylamine (TEA, 7.31 g, 1.10 equivalent) was added. The mixture was heated to 70 °C, and then diphenyl azide phosphate (DPPA, 19.9 g, 1.10 equivalent) was added dropwise. After stirring at 70 °C for 2.5 hours, water was added to quench the reaction. Thin-layer chromatography (TLC) analysis (petroleum ether / ethyl acetate = 10:1) confirmed that starting material 5 had been completely consumed. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to give a yellow oily compound 6 (6.87 g).

[0072] Step S6: Compound 6 (6.44 g, 1.00 equivalent) was dissolved in ethyl acetate (20.0 mL), and a hydrogen chloride-ethyl acetate solution (100 mL, 9.8 M) was added. The mixture was stirred at 25 °C for 5 hours. Liquid chromatography-mass spectrometry (LCMS) confirmed that the starting material was completely consumed (m / z = 264). After concentration under reduced pressure, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 0% to 10%) to give a colorless oily compound 7 (2.90 g). Compound 7 was analyzed to obtain... Figure 1 The nuclear magnetic resonance (NMR) spectrum. Specific data are as follows:

[0073] ¹H NMR (400 MHz, DMSO-d⁶) δ=4.62–4.50 (br., ¹H), 3.50–3.20 (m, 2H), 2.98 (d, J=8.0 Hz, ¹H), 2.89–2.82 (m, ¹H), 1.83–1.74 (m, ¹H), 1.43–1.30 (m, 2H), 1.17–1.07 (m, 1H), 0.92 (s, 3H), 0.77 (s, 3H). Compound 7 was detected by LCMS, and the data obtained were: LCMS (ESI) m / z: 130.1 [M+H]⁺.

[0074] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound, characterized in that, The synthetic route is as follows: The specific preparation steps are as follows: Under alkaline conditions (S1), compound 1 reacts with an alkoxycarbonylating agent to generate compound 2; S2 reduces compound 2 to give compound 3; S3 performs a protection reaction on the hydroxyl group of compound 3 to obtain hydroxyl-protected compound 4; Compound 4 (S4) is hydrolyzed in an alkaline environment with methyl ester to give compound 5; Compound S5 undergoes the Curtis rearrangement to yield compound 6; Compound S6 is subjected to acidic conditions, during which the hydroxyl group of compound 6 is deprotected to yield compound 7; In the synthetic route, n = 1 or 2, X = C or O; R1 and R2 are C1-C5 alkyl groups.

2. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, Step S1 is as follows: Add the alkoxycarbonylating reagent and sodium hydride to the flask, then add the mixture of compound 1 and methanol dropwise to the reaction solution; after the addition is complete, heat and stir; after the reaction is complete, cool, quench the reaction with methanol, and then add acetic acid and water; extract, wash, dry, filter, concentrate under reduced pressure; finally, purify to obtain compound 2.

3. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, The S2 step is as follows: Dissolve compound 2 in methanol, add acetic acid, then add sodium borohydride in batches while stirring; quench the reaction with ammonium chloride aqueous solution, concentrate under reduced pressure to remove excess methanol, extract with dichloromethane, separate the organic layer, wash, dry and filter, and concentrate under reduced pressure. Compound 3 was obtained after purification.

4. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, Step S3 is as follows: Compound 3 is dissolved in dichloromethane, triethylamine and TBSOTf are added sequentially, and then the mixture is heated and stirred until compound 3 is completely consumed; ice bath extraction is performed, followed by washing, drying, filtration, and concentration under reduced pressure. Compound 4 was obtained after purification.

5. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, Step S4 is as follows: Dissolve compound 4 in a methanol / tetrahydrofuran / water mixture, add lithium hydroxide monohydrate, and stir until compound 4 is completely consumed; concentrate under reduced pressure to remove excess methanol and tetrahydrofuran, adjust the pH to 1-2 with hydrochloric acid in an ice bath, add ethyl acetate for extraction and separation, wash, dry and filter, and concentrate under reduced pressure. Compound 5 was obtained after purification.

6. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, Step S5 is as follows: Compound 5 is dissolved in toluene, triethylamine is added and heated, and then diphenyl azidophosphate is added dropwise; after heating and stirring the reaction, water is added to quench the reaction until compound 5 is completely consumed; after cooling to room temperature, water is added, and the mixture is extracted with ethyl acetate, washed, dried and filtered, and concentrated under reduced pressure; compound 6 is obtained after purification.

7. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, Step S6 is as follows: Dissolve compound 6 in ethyl acetate, add ethyl hydrochloride solution, and stir until compound 6 is completely consumed; after concentration under reduced pressure, adjust the pH to 7-8 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, wash, dry, filter, and concentrate under reduced pressure. Compound 7 was obtained after purification.

8. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, The base in step S1 is one or more of sodium hydride, lithium diisopropylamino, sodium hexamethyldisilamino, potassium hexamethyldisilamino, and 1,8-diazabicycloundec-7-ene.

9. The method for preparing the 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound according to claim 1, characterized in that, In step S2, one of the following reducing agents is used for reduction: sodium borohydride, lithium borohydride, lithium aluminum hydride, or borane.

10. A 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound, characterized in that, The 1,2,3-homocarbodialkyl-hydroxy-amino trans-substituted cyclic compound was prepared according to any one of claims 1-9.

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