Kinetic resolution method of terminal N-carbamate aziridine and chiral synthesis method of (S)-baclofen

Abstract

The invention discloses a kinetic resolution method of terminal N-carbamate aziridine and a chiral synthesis method of (S)-baclofen and (S)-sulconazole, and belongs to the technical field of chiral synthesis. The method comprises the step of obtaining one enantiomer product with a high ee (enantiomeric excess) value by adopting a terminal N-carbamate aziridine raceme as a reaction raw material under the action of a catalyst. The kinetic resolution method of the terminal N-carbamate aziridine has the advantages that the applicable aziridine substrate range is wide, the chiral recognition capability is high, and the method has a wide application prospect in the field of chiral resolution or chiral synthesis.

Description

Technical Field

[0001] The present invention belongs to the technical field of chiral synthesis, and more specifically, relates to a kinetic resolution method for terminal N-carbamate aziridines, and chiral synthesis methods for (S)-baclofen and (S)-sulconazole. Background Art

[0002] Optically active terminal aziridines have become important structural units in organic synthesis due to their high reactivity, inherent regioselectivity, and ability to transfer stereochemical information to subsequent products. A key factor in exploiting these properties is the choice of amino protecting group. This group not only regulates the reactivity and enantioselectivity during aziridine formation but also affects the flexibility of further transformation. Over the past few decades, researchers have been dedicated to developing catalytic asymmetric methods for synthesizing terminal aziridines with various protecting groups. Among them, N-sulfonyl aziridines can be efficiently obtained through the stereoselective addition of metal-catalyzed nitrene equivalents to alkenes. List achieved the kinetic resolution of N-acyl aziridines through an organocatalytic nucleophilic ring-opening reaction (Angew. Chem. Int. Ed. 2014, 53, 7063 - 7067), and Buchwald prepared N-alkyl aziridines through copper-catalyzed intramolecular hydroamination (J. Am. Chem. Soc. 2017, 139, 8428 - 8431).

[0003] Despite the success of these methods, the protecting groups involved have limited applications in multi-step syntheses. Analysis of the frequency of use of amino protecting groups in the synthesis of complex sequence molecules shows that carbamates (the carbamate family) are one of the most frequently used types of protecting groups. This stems from three key features: 1) Versatility, with various carbamates (such as Boc, Cbz, Fmoc, etc.) being widely favored in syntheses; 2) Excellent orthogonality, allowing for selective deprotection in complex sequences without disturbing other functional groups; 3) Mild protection / deprotection conditions. However, despite the widespread use of carbamate protecting groups in synthetic chemistry, the catalytic enantioselective synthesis of N-carbamate aziridines remains a major challenge, with limited synthetic methods currently available. The Lebel research group reported a method for the Cu(I)-BOX-catalyzed synthesis of N-Troc aziridination (Pure Appl. Chem. 2010, 82, 1827 - 1833), but it is limited to electron-deficient styrene substrates and moderate enantioselectivity. Recently, the Zhang research group achieved aziridination of styrene compounds with carbonyl azides using a Co(II)-porphyrin catalyst system, and the synthesized N-Troc aziridines had excellent enantioselectivity (Chem. 2021, 7, 1120–1134). However, this method is limited to the synthesis of a single carbamate (Troc), and its chlorine substituent enhances the reaction activity through non-covalent interactions. The chiral synthesis of aziridines containing different carbamates remains an unsolved problem. Summary of the Invention

[0004] 1. Problems to be Solved

[0005] Based on this, the object of the present invention is to at least partially solve the problem of the great difficulty in the enantioselective synthesis of terminal N-carbamate aziridines in the prior art. To address this problem, the first object of the present invention is to provide a kinetic resolution method for the enantiomers of terminal N-carbamate aziridines.

[0006] Based on the above kinetic resolution method, the second object of the present invention is to provide a chiral synthesis method for (S)-baclofen.

[0007] Based on the above kinetic resolution method, the third object of the present invention is to provide a chiral synthesis method for (S)-sulconazole.

[0008] 2. Technical Solutions

[0009] To solve the above problems, the technical solutions adopted in the present invention are as follows:

[0010]

Kinetic Resolution Method for Terminal N-Carbamate Aziridines

[0011] The first aspect of the present invention provides a kinetic resolution method for terminal N-carbamate aziridines, comprising the following reaction:

[0012] The reaction of obtaining a compound of general formula II from a compound of general formula I under the action of a catalyst;

[0013]

[0014]

[0015] wherein, R 1 is selected from R 3 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl or aryl;

[0016] R 2 is selected from substituted or unsubstituted aromatic groups, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0017] The catalyst is:

[0018]

[0019] C6.

[0020] In the kinetic resolution method for terminal N-carbamate aziridines of the present invention, the binuclear titanium catalyst C6 is used as the catalyst for kinetic resolution, which can achieve high regioselectivity and enantioselectivity. At the same time, the method of the present invention has a wide range of aziridine substrates, and terminal aziridines containing typical carbamate protecting groups can all be efficiently resolved to obtain products with high regioselectivity and enantioselectivity; further, in the present invention, resolution experiments of carbamate substrates with different steric hindrances and electronic properties are carried out, and all show high s factors, proving that the binuclear titanium catalyst C6 of the present invention has strong chiral recognition ability in the kinetic resolution of terminal N-carbamate aziridines; other chiral catalysts are also used in the present invention for the above reaction, but their enantioselectivities cannot reach the high selectivity of the binuclear titanium catalyst C6. The preparation steps of C6 are shown in the literature (Angew. Chem. Int. Ed. 2023, 62, e202309525. The preparation method is shown on page S16 of SI [Ti IV 2O preparation).

[0021] According to the kinetic resolution method for terminal N-carbamate aziridines according to any one of the first aspect of the present invention, R 3 is selected from substituted or unsubstituted C1-C40 alkyl, alkenyl, alkynyl or aryl, and the substitution is selected from one or more of alkyl substitution, alkoxy substitution, alkenyl substitution, alkynyl substitution, heterocyclic substitution, heteroaryl substitution, halogen atom substitution, fluorenyl substitution, heteroatom substitution.

[0022] The heteroatom substitution may be selected from one or more of N, S, O, and Si.

[0023] The heterocyclic substitution includes, for example, saturated or unsaturated heterocyclic substituents, etc.

[0024] The halogen atom substitution is, for example, F, Cl, Br, or I.

[0025] According to the kinetic resolution method of the terminal N-carbamate aziridine according to any one of the first aspects of the present invention, R 2 is selected from a substituted or unsubstituted aromatic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, and the substitution is selected from one or more of alkyl substitution, alkoxy substitution, alkenyl substitution, alkynyl substitution, aromatic group substitution, heterocyclic substitution, heteroaryl substitution, halogen atom substitution, fluorenyl substitution, siloxy substitution, haloalkane substitution, ester group substitution, and cyano substitution.

[0026] According to the kinetic resolution method of the terminal N-carbamate aziridine according to any one of the first aspects of the present invention, the R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, and Troc.

[0027] According to the kinetic resolution method of the terminal N-carbamate aziridine according to any one of the first aspects of the present invention, the R 2 is selected from a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

[0028] According to the kinetic resolution method of the terminal N-carbamate aziridine according to any one of the first aspects of the present invention, the reaction further includes a reducing agent and a hydrogen atom donor.

[0029] Preferably, the reducing agent is selected from one or more of zinc powder and manganese powder.

[0030] Preferably, the hydrogen atom donor is selected from one or more of H2O, D2O, or Bu3SnH.

[0031] It should be noted that in the present invention, it is found that not all hydrogen atom donors can obtain good enantioselectivity in the kinetic resolution of terminal N-carbamate aziridine. When the hydrogen atom donor is selected from one or more of H2O, D2O, or Bu3SnH, good enantioselectivity can be obtained.

[0032] The kinetic resolution method of terminal N-carbamate aziridine according to any one of the first aspects of the present invention, wherein the solvent is substituted or unsubstituted benzene; preferably, the substituted benzene is selected from toluene, xylene, and mesitylene.

[0033] The kinetic resolution method of terminal N-carbamate aziridine according to any one of the first aspects of the present invention, wherein the reaction further comprises an inorganic acid salt of an alkylamine; preferably, the inorganic acid salt of the alkylamine is selected from triethylamine hydrochloride, trimethylamine hydrochloride, tripropylamine hydrochloride, and diisopropylethylamine hydrochloride.

[0034]

Chiral Synthesis Method of (S)-Baclofen

[0035] As an example of the kinetic resolution method of terminal N-carbamate aziridine, the second aspect of the present invention provides a chiral synthesis method of (S)-baclofen, comprising the following reaction:

[0036] The reaction of obtaining a compound of general formula VIII from a compound of general formula VII under the action of a catalyst;

[0037]

[0038] Wherein, R 1 is selected from R 3 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl or aryl; preferably, R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc.

[0039] The catalyst is:

[0040]

[0041] C6.

[0042] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention further comprises the steps of preparing a compound of general formula IX from a compound of general formula VIII, and preparing (S)-baclofen from a compound of general formula IX.

[0043]

[0044] Wherein, R 4 is selected from substituted or unsubstituted C1-C40 alkyl. Preferably, it is substituted or unsubstituted C1-C6 alkyl.

[0045] According to the chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, R 4 is tBu.

[0046] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention further comprises the step of preparing a compound of general formula VII using a compound of general formula X;

[0047]

[0048] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, the synthesis method includes:

[0049] The step of preparing a compound of formula VII using formula X:

[0050]

[0051] The step of preparing a compound of formula VIII using a compound of formula VII:

[0052]

[0053] The step of preparing a compound of formula IX using a compound of formula VIII:

[0054]

[0055] The step of preparing (S)-baclofen using a compound of formula IX:

[0056]

[0057] wherein, R 1 is selected from R 3 is selected from substituted or unsubstituted C1-C40 alkyl, alkenyl, alkynyl or aryl; preferably, R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc;

[0058] R 4 is selected from substituted or unsubstituted C1-C40 alkyl. Preferably, it is substituted or unsubstituted C1-C6 alkyl. More preferably, R 4 is selected from tBu.

[0059] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, the reaction further comprises a reducing agent and a hydrogen atom donor;

[0060] The reducing agent is selected from one or more of zinc powder and manganese powder;

[0061] The hydrogen atom donor is selected from one or more of H2O, D2O or Bu3SnH.

[0062] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, wherein the solvent is a substituted or unsubstituted benzene; preferably, the substituted benzene is selected from toluene, xylene, and mesitylene.

[0063] The chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, wherein the reaction further comprises an inorganic acid salt of an alkylamine; preferably, the inorganic acid salt of an alkylamine is selected from triethylamine hydrochloride, trimethylamine hydrochloride, tripropylamine hydrochloride, and diisopropylethylamine hydrochloride.

[0064] In the reaction of the compound of general formula VII to obtain the compound of general formula VIII in the chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, the dosage of the catalyst is 0.05 - 0.5 equivalents. Further preferably 0.05 - 0.3 equivalents, more preferably 0.05 - 0.2 equivalents, and most preferably 0.1 - 0.2 equivalents. Here, the equivalent refers to the ratio of the number of moles of the added catalyst to the number of moles of the substrate.

[0065] In the reaction of the compound of general formula VII to obtain the compound of general formula VIII in the chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, the reaction duration is not less than 24 h. Further preferably 48 - 120 h, and most preferably 60 - 72 h.

[0066] In the reaction of the compound of general formula VII to obtain the compound of general formula VIII in the chiral synthesis method of (S)-baclofen according to any one of the second aspects of the present invention, the reaction temperature is -10 - 60 °C. Further preferably 10 - 40 °C, and most preferably 20 - 30 °C.

[0067]

Chiral synthesis method of (S)-sulconazole

[0068] As another example of the kinetic resolution method of terminal N-carbamate aziridine, the third aspect of the present invention provides a chiral synthesis method of (S)-sulconazole, comprising the following reaction:

[0069] The reaction of obtaining the compound of general formula IV from the compound of general formula III under the action of a catalyst;

[0070]

[0071] wherein, R 1 is selected from R 3 is selected from a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl; preferably, R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc;

[0072] The catalyst is:

[0073]

[0074] C6.

[0075] According to the chiral synthesis method of (S)-sulconazole described in any one of the third aspects of the present invention, it further comprises the step of preparing a compound of general formula V from a compound of general formula IV, and the step of preparing (S)-sulconazole from a compound of general formula V.

[0076]

[0077] According to the chiral synthesis method of (S)-sulconazole described in any one of the third aspects of the present invention, it further comprises the step of preparing a compound of general formula III from a compound of general formula VI;

[0078]

[0079] According to the chiral synthesis method of (S)-sulconazole described in any one of the third aspects of the present invention, the synthesis method includes:

[0080] The step of preparing a compound of formula III from a compound of formula VI:

[0081]

[0082] The step of preparing a compound of formula IV from a compound of formula III:

[0083]

[0084] The step of preparing a compound of formula V from a compound of formula IV:

[0085]

[0086] The step of preparing (S)-sulconazole from a compound of formula V:

[0087]

[0088] Wherein, R 1 is selected from R 3 is selected from substituted or unsubstituted C1-C40 alkyl, alkenyl, alkynyl or aryl; preferably, R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc.

[0089] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, the reaction further comprises a reducing agent and a hydrogen atom donor;

[0090] The reducing agent is selected from one or more of zinc powder and manganese powder;

[0091] The hydrogen atom donor is selected from one or more of H2O, D2O or Bu3SnH.

[0092] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, the solvent is substituted or unsubstituted benzene; preferably, the substituted benzene is selected from toluene, xylene and mesitylene.

[0093] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, the reaction further comprises an inorganic acid salt of alkylamine; preferably, the inorganic acid salt of alkylamine is selected from triethylamine hydrochloride, trimethylamine hydrochloride, tripropylamine hydrochloride and diisopropylethylamine hydrochloride.

[0094] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, in the reaction of the compound of general formula III to obtain the compound of general formula IV, the dosage of the catalyst is 0.05 - 0.5 equivalent. Further preferably 0.05 - 0.3 equivalent, more preferably 0.05 - 0.2 equivalent, and most preferably 0.1 - 0.2 equivalent. The equivalent here refers to the ratio of the number of moles of the catalyst added to the number of moles of the substrate.

[0095] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, in the reaction of the compound of general formula III to obtain the compound of general formula IV, the reaction duration is not less than 24 h. Further preferably 48 - 120 h, and most preferably 60 - 72 h.

[0096] The chiral synthesis method of (S)-sulconazole according to any one of the third aspects of the present invention, in the reaction of the compound of general formula III to obtain the compound of general formula IV, the reaction temperature is -10 - 60 °C. Further preferably 10 - 40 °C, and most preferably 20 - 30 °C.

[0097] 3. Beneficial effects

[0098] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0099] (1) The kinetic resolution method of terminal N-carbamate aziridines of the present invention uses a binuclear titanium catalyst C6 as the catalyst for kinetic resolution, which can achieve high regioselectivity and enantioselectivity. At the same time, the substrate scope of aziridines applicable to the method of the present invention is wide, and terminal aziridines containing typical carbamate protecting groups can be efficiently resolved to obtain products with high regioselectivity and enantioselectivity. Further, in the present invention, resolution experiments of carbamate substrates with different steric hindrances and electronic properties were carried out, and all showed high s-factors, proving that the binuclear titanium catalyst C6 of the present invention has strong chiral recognition ability in the kinetic resolution of terminal N-carbamate aziridines. It is worth noting that the kinetic resolution method of terminal N-carbamate aziridines of the present invention also has good tolerance to reduction-sensitive Troc groups, etc. Further, the reaction is compatible with acid-sensitive groups (silyl ethers, acetals) and reduction-sensitive groups (benzyl ethers, halogens). Further, different from the commonly used tin hydride as a hydrogen atom donor system, in the kinetic resolution method of the present invention, halogens such as fluorine, chlorine, and bromine are all completely retained, and heteroaromatic substrates (pyridine, thiophene) are also applicable to this system, which fully shows that the substrate scope of aziridines in the kinetic resolution method of the present invention is wide.

[0100] (2) The kinetic resolution method of terminal N-carbamate aziridines of the present invention can also handle complex systems. The diastereomeric mixture of aziridines conjugated with drug molecules and natural products can be efficiently resolved into single diastereomers (1ap-1av). Functional groups such as polysubstituted esters, electron-rich aromatics (1aq), amides (1ar, 1as), sulfonamides (1at), ketones (1au), and heteroaromatics (1av) all have good tolerance, proving the practicality of this method in the late-stage resolution of complex molecules.

[0101] (3) The kinetic resolution method of terminal N-carbamate aziridines of the present invention shows excellent practicality. In the examples, a gram-scale reaction was carried out with 1a as the substrate, and high enantioselectivity could still be maintained.

[0102] (4) When synthesizing the GABAB receptor agonist (S)-baclofen, traditional catalytic asymmetric synthesis requires a long 7-step route or relies on recrystallization to improve enantiomeric purity. The method of the present invention starts from the chiral 4-chlorophenyl aziridine 1y prepared from the corresponding imine, efficiently constructs a γ-amino acid intermediate through enol silyl ether addition, and then removes the Boc protecting group by TFA treatment and hydrolyzes the tert-butyl ester to complete the enantioselective synthesis of (S)-baclofen in an almost optically pure form. Compared with the prior art, the chiral synthesis method of (S)-baclofen of the present invention has significantly shortened steps.

[0103] (5) When synthesizing the antifungal drug (S)-sulconazole, traditional asymmetric synthesis methods rely on stoichiometric chiral auxiliaries to construct chiral centers or use toxic SnCl2 to reduce and generate amine intermediates required for imidazole, which limits the practicality and universality of the preparation methods. The present invention adopts a more green and sustainable strategy: generating racemic aziridine 1u through the Corey-Chaykovsky reaction of N-Boc-2,4-dichlorophenylimine, and converting the racemate into a highly optically pure chiral product through chiral synthesis (standard kinetic resolution (KR) reaction) using the C6 catalyst of the present invention; then treating with 4-chlorobenzyl mercaptan and BF3·Et2O to obtain 2-benzylthio-substituted phenethylamine with good yield and retention of enantioselectivity; finally, deprotecting with trifluoroacetic acid (TFA) and condensing with formaldehyde, glyoxal, and ammonia to form an imidazole ring to obtain (S)-sulconazole. Compared with the prior art, the chiral synthesis method of (S)-sulconazole in the present invention avoids the use of toxic SnCl2.

[0104] The abbreviated names and structures involved in this article are as follows:

[0105]

[0106] Description of the Drawings

[0107] Figure 1 It is a trend diagram of the reaction activity and stereoselectivity of kinetic resolution at different reaction times;

[0108] Figure 2 It is the 1H NMR spectrum of 1a prepared in Example 5;

[0109] Figure 3 It is the chiral high performance liquid chromatography of rac-1a prepared in Example 5;

[0110] Figure 4 It is the chiral high performance liquid chromatography of 1a prepared in Example 5;

[0111] Figure 5 It is the 1H NMR spectrum of (S)-sulconazole prepared in Example 54;

[0112] Figure 6 It is the chiral high performance liquid chromatography of (S)-sulconazole prepared in Example 54;

[0113] Figure 7 It is the chiral high performance liquid chromatography of (S)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)butanoate prepared in Example 55;

[0114] Figure 8 It is the 1H NMR spectrum of (S)-baclofen prepared in Example 55. Detailed implementation manners

[0115] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs; the term "and / or" as used herein includes any and all combinations of one or more of the related listed items.

[0116] For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not indicated, they are all conventional products that can be obtained through commercial purchase.

[0117] As used herein, the term "about" is used to provide flexibility and imprecision associated with a given term, measurement, or value. One of ordinary skill in the art can readily determine the degree of flexibility for a particular variable.

[0118] Concentrations, amounts, and other numerical data may be presented herein in a range format. It should be understood that such range formats are used merely for convenience and brevity and should be interpreted flexibly as including not only the explicitly recited numerical values as the limits of the range, but also all individual numerical values or sub-ranges subsumed within the stated range as if each numerical value and sub-range were explicitly recited.

[0119] The present invention will be further described below in conjunction with specific embodiments.

[0120] Preparation materials:

[0121] Sodium azide (NaN3), ammonium chloride (NH4Cl), triphenylphosphine (PPh3), 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), triethylamine hydrochloride (Et3N·HCl), zinc powder, toluene (Tol), deionized water (H2O), ethyl acetate (EtOAc), styrene oxide, di-tert-butyl dicarbonate, tributyltin hydride (nBu3SnH), tris(trimethylsilyl)silane ((TMS)3SiH), 1,4-cyclohexadiene, dihydropyridine, methyl thioglycolate, diethyl pyrocarbonate, benzyl chloroformate, allyl chloroformate, bis(trichloromethyl) carbonate, 1,4-dioxane, 9-fluorenylmethyl chloroformate, 2,2,2-trichloroethyl chloroformate, tert-butyl carbamate, tetrahydrofuran, sodium benzenesulfinate, 2,4-dichlorobenzaldehyde, trimethylsulfoxonium iodide, potassium tert-butoxide, anhydrous tert-butanol, 4-chlorobenzyl mercaptan, boron trifluoride diethyl ether complex, formaldehyde, glyoxal, p-chlorobenzaldehyde, cyclopentyl methyl ether, potassium hexamethyldisilazide, trimethylchlorosilane are all commercially available.

[0122] The chiral catalyst C6 was prepared by the method in the previously published paper of our research group (Angew. Chem. Int. Ed. 2023, 62, e202309525.).

[0123] The diisopropylethylamine hydrochloride was prepared by the following method: Diisopropylethylamine (5 mmol, 1 eq) and hydrochloric acid (5 mmol, 1 eq) were mixed and dissolved in acetone (30 mL), and after stirring for 30 min, a solid was precipitated. The solid was filtered through a sintered funnel, and the solid was washed 3 times with acetone (20 mL). The solid was added to a round-bottom flask, and toluene (10 mL × 3) was added. After rotary evaporation, diisopropylethylamine hydrochloride was obtained.

[0124] 2-(o-Tolyl)oxirane, 2-(m-Tolyl)oxirane, 2-(p-Tolyl)oxirane were prepared by the following method: Under nitrogen protection, trimethylsulfonium iodide (1.1 eq), sodium hydride (60% content, 1.1 eq) and freshly distilled dimethyl sulfoxide / tetrahydrofuran mixed solvent (volume ratio 1:1) were added to a pre-heated and dried Schlenk tube, and the system was maintained at 0 °C. After stirring at 0 °C for 2 h, a solution of aldehyde (1.0 eq, the aldehydes were o-phthalaldehyde, m-phthalaldehyde, p-phthalaldehyde respectively) in tetrahydrofuran was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature for 1 h, quenched with water, and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure (Note: Some epoxides have low boiling points, and the pressure needs to be controlled), and the obtained crude product was directly used for the next reaction without further purification (if necessary, it can be purified by flash column chromatography).

[0125] Instruments and methods:

[0126] Proton nuclear magnetic resonance ( 1 H NMR) chemical shifts were referenced to the residual signal of the undeuterated solvent as an internal standard (CHCl3, δ = 7.26 ppm) and were measured on a Bruker 400 MHz nuclear magnetic resonance spectrometer;

[0127] Chiral high performance liquid chromatography (chiral HPLC) analysis was performed using a Shimadzu high performance liquid chromatography.

[0128] All reactions involving air- or water-sensitive compounds were carried out under nitrogen protection using standard Schlenk and vacuum line techniques. All solvents used were purified by distillation over the designated desiccant and transferred under a nitrogen atmosphere: ethyl acetate (EtOAc, dried over CaH2), toluene (Tol, dried over sodium metal), 1,2-dimethoxyethane (DME, dried over CaH2), tetrahydrofuran (THF, dried over sodium metal).

[0129] The "yield" described in this article, that is, the "Yield" value, refers to the ratio of the amount of the product generated in the reaction to the theoretical maximum value.

[0130] The "ee value" described in this article refers to the enantiomeric excess value, specifically the percentage of the amount by which one isomer (such as R) in the enantiomeric mixture is more than the other isomer (such as S) in the total amount. The higher the ee value, the more the content of a certain enantiomer in the mixture and the higher the optical purity.

[0131] The "s value" described in this article refers to the selectivity factor, specifically in kinetic resolution, the ratio of the reaction rate of the chiral catalyst with one enantiomer to the reaction rate of the other enantiomer. The larger the s value, the stronger the selectivity of the chiral catalyst, and thus the more effective the kinetic resolution can be achieved.

[0132] General Procedure 1: Synthesis of Racemate

[0133]

[0134] (Note: In this formula, the R group on the benzene ring can be a different group from the R group on the ester group)

[0135] Under nitrogen protection, add the epoxy substrate (1.0 eq) and the methanol / water mixed solvent (the volume ratio of methanol to water is 1:3) to a preheated and dried Schlenk tube. Add sodium azide (NaN3, 2.0 eq) and ammonium chloride (NH4Cl, 2.0 eq) in sequence. After stirring and reacting at 60 °C for 6 hours, remove methanol under reduced pressure. Extract the remaining aqueous phase with diethyl ether, combine the organic phases and dry with anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain the crude azido alcohol.

[0136] Dissolve the crude azido alcohol in acetonitrile (CH3CN), add triphenylphosphine (PPh3, 1.0 eq), and heat and react at 60 °C for 12 hours. After the reaction is completed, concentrate the solvent under reduced pressure, add diethyl ether (30.0 mL), cool to -30 °C and filter out the precipitated triphenylphosphine oxide. The organic phase is dried by rotary evaporation to obtain the crude aziridine.

[0137] Under nitrogen protection, dissolve the free aziridine (1.0 eq), 4-dimethylaminopyridine (DMAP, 0.05 eq) and triethylamine (Et3N, 2.1 eq) in dichloromethane (CH2Cl2), and keep the temperature of the system at -78 °C. Dropwise add the dichloromethane solution of the protecting reagent (1.1 eq) to the above system and continue to stir at -78 °C for 2 hours.

[0138] The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate (MgSO4). After concentrating the solvent under reduced pressure, the crude product was purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent) to obtain racemic N-carbamate aziridine.

[0139] General Procedure 2: Preparation of single enantiomers from racemates

[0140] Under nitrogen protection, triethylamine hydrochloride (Et3N·HCl, 2.0 eq), zinc powder (Zn, 1.2 eq), chiral catalyst C6 (0.1 eq) and freshly distilled toluene (Tol, 3.0 mL) were successively added to a pre-heated and dried Schlenk tube. After stirring the mixture at 20 °C for 6 hours, deionized water (H2O, 8.0 eq) and the racemic N-carbamate aziridine prepared in General Procedure 1 (1.0 eq) were added. The reaction was continued to stir at 20 °C for 68 hours (the reaction progress was monitored by silica gel thin-layer chromatography pretreated with 5% triethylamine), and then the reaction was quenched with aqueous saturated sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was successively washed with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). After concentration under reduced pressure, the crude product was separated and purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent) to obtain single enantiomers.

[0141] Example 1: Preparation of 1a

[0142] (I) Preparation of rac-1a

[0143] Under nitrogen protection, styrene oxide (1.2 g, 10.0 mmol, 1.0 eq) and a methanol / water mixed solvent (volume ratio of methanol to water is 1:3) were added to a pre-heated and dried Schlenk tube. Sodium azide (1.3 g, 20.0 mmol, 2.0 eq) and ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq) were successively added, and the reaction was stirred at 60 °C for 6 hours, then methanol was removed under reduced pressure. The remaining aqueous phase was extracted with diethyl ether, the organic phases were combined and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude azido alcohol.

[0144] The crude azido alcohol was dissolved in acetonitrile, triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) was added, and the reaction was heated at 60 °C for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, diethyl ether (30.0 mL) was added, cooled to -30 °C and the precipitated triphenylphosphine oxide was filtered. The organic phase was dried by rotary evaporation to obtain the crude aziridine.

[0145] Under nitrogen protection, free aziridine (595.9 mg, 5.0 mmol, 1.0 eq), 4-dimethylaminopyridine (DMAP, 30.5 mg, 0.25 mmol, 0.05 eq) and triethylamine (1.1 g, 10.5 mmol, 2.1 eq) were dissolved in dichloromethane, and the temperature of the system was maintained at -78 °C. A dichloromethane solution of the protecting reagent di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, 1.1 eq) was added dropwise to the above system, and stirring was continued at -78 °C for 2 hours.

[0146] The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the solvent under reduced pressure, the crude product was purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent) to obtain tert-butyl 2-phenylaziridine-1-carboxylate (racemate, denoted as rac-1a).

[0147] (2) Effects of different hydrogen atom donors on the reaction in the preparation of 1a from rac-1a

[0148] This example was to test the effects of different hydrogen atom donors on the reaction activity and stereoselectivity. The specific procedure was as follows:

[0149]

[0150] Under nitrogen protection, triethylammonium hydrochloride (Et3N·HCl, 137.7 mg, 1.0 mmol, 2.0 eq), zinc powder (Zn, 39.2 mg, 0.6 mmol, 1.2 eq), chiral catalyst C6 (63.6 mg, 0.05 mmol, 0.1 eq) and freshly distilled toluene (Tol, 3.0 mL) were successively added to a preheated and dried Schlenk tube. After the mixture was stirred at 20 °C for 6 hours, a hydrogen atom donor (4.0 mmol, 8.0 eq) and tert-butyl 2-phenylaziridine-1-carboxylate (rac-1a, 0.5 mmol, 1.0 eq) prepared by the method in (1) were added. The reaction was continued to stir at 20 °C for several hours according to formula (1) (the time is shown in Table 1). Subsequently, the reaction was quenched with an aqueous solution of saturated sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was successively washed with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). The crude product obtained after concentration under reduced pressure was separated and purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent), and tert-butyl (R)-2-phenylaziridine-1-carboxylate (denoted as 1a) and tert-butyl phenethylcarbamate (denoted as 2a), both of which were yellow oils, were obtained respectively. The yields, ee values and s values of tert-butyl (R)-2-phenylaziridine-1-carboxylate and tert-butyl phenethylcarbamate obtained with different hydrogen atom donors were analyzed and calculated by 1H nuclear magnetic resonance spectroscopy ( 1 1H NMR), carbon-13 nuclear magnetic resonance spectroscopy ( 13 13C NMR), high-resolution mass spectrometry (HRMS) and chiral high-performance liquid chromatography, and the results are shown in Table 1.

[0151] Table 1 Reaction activities and stereoselectivities under different hydrogen atom donors

[0152]

[0153] As can be seen from Table 1, when H2O and tributyltin hydride (nBu3SnH) are used as hydrogen atom donors, the ee value of product 1a is 99%, and the s value is greater than 40, which is much higher than the ee values and s values of other hydrogen atom donors, and can effectively achieve the kinetic resolution and separation and purification of the R configuration.

[0154] Example 2: Influence of different solvents on the reaction in the preparation of 1a from rac-1a

[0155] This example was to test the influence of different solvents on the reaction activity and stereoselectivity. The specific process was as follows:

[0156]

[0157] All other steps are basically the same as those in step (ii) of Example 1, except that the hydrogen atom donor is deionized water, and the solvent toluene used in step (ii) is replaced with the other three solvents in Table 2.

[0158] The yields, ee values, and s values of tert-butyl (R)-2-phenylaziridine-1-carboxylate and tert-butyl phenethylcarbamate obtained with different solvents are shown in Table 2.

[0159] Table 2 Reaction activities and stereoselectivities under different solvents

[0160]

[0161] As can be seen from Table 2, not all solvents can achieve the kinetic resolution of the R configuration. Moreover, when the solvent is toluene, the kinetic resolution and separation and purification of the R configuration can be effectively achieved.

[0162] Example 3: Influence of different reaction times in the reaction of preparing 1a from rac-1a

[0163] This example is to test the changes in reaction activity and stereoselectivity with reaction time. The specific process is as follows:

[0164]

[0165] All other steps are basically the same as those in step (ii) of Example 1, except that the reaction time after adding the racemate is 3 - 168 h in Table 3. The yields, ee values of tert-butyl (R)-2-phenylaziridine-1-carboxylate and tert-butyl phenethylcarbamate, and the yield of 1a obtained at different reaction times are shown in Table 3 and Figure 1 as shown.

[0166] Table 3 Reaction activities and stereoselectivities under different reaction times

[0167]

[0168] From Table 3 and Figure 1 it can be seen that as the reaction time prolongs, the ee value of 1a gradually increases. When the reaction time reaches 50 h, the ee value reaches 97%. When the reaction time reaches 60 h, the ee value reaches 98%. When the reaction time reaches 80 h, the ee value reaches the highest 99% and tends to be stable. Considering comprehensively the ee value, yield, and kinetic resolution efficiency of 1a, in the reaction of this substrate, the reaction time should be controlled to be not less than 50 h.

[0169] Example 4

[0170] Under nitrogen protection, triethylamine hydrochloride (Et3N·HCl, 137.7 mg, 1.0 mmol, 2.0 eq), zinc powder (Zn, 65.4 mg, 1.0 mmol, 2.0 eq), chiral catalyst C6 (63.6 mg, 0.05 mmol, 0.1 eq) and freshly distilled toluene (Tol, 3.0 mL) were successively added to a preheated and dried Schlenk tube. After stirring the mixture at 35 °C for 6 hours, deionized water (H2O, 70 μL, 4.0 mmol, 8.0 eq) and the compound rac-1y (0.5 mmol, 1.0 eq) synthesized using General Procedure 1 were added. The reaction was continued by stirring at 35 °C for 68 hours (the reaction progress was monitored by silica gel thin-layer chromatography pretreated with 5% triethylamine), and then the reaction was quenched with saturated aqueous sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was washed successively with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). The crude product obtained after concentration under reduced pressure was separated and purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent), and 1y was obtained.

[0171] The yield of the obtained 1y was 47%, the ee value was 99%, and the s value was 80. This indicates that in the same reaction for preparing 1a, by adjusting the amount of the reducing agent and the reaction temperature, the effect of the kinetic resolution of the present invention remains basically unchanged.

[0172] Example 5: Preparation of 1a

[0173] (I) Preparation of rac-1a

[0174] According to General Procedure 1, styrene oxide (epoxy substrate, 1.2 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain a crude product of aziridine;

[0175] Aziridine (595.9 mg, 5.0 mmol, 1.0 eq), diethyl pyrocarbonate (protecting reagent, 1.2 g, 5.5 mmol, 1.1 eq), triethylamine (1.1 g, 10.5 mmol, 2.1 eq), and 4-dimethylaminopyridine (30.5 mg, 0.25 mmol, 0.05 eq) were reacted to obtain a white solid, namely racemic ethyl 2-phenylaziridine-1-carboxylate (denoted as rac-1a, 1.1 g, yield 94%, and its chiral high performance liquid chromatography is as Figure 3 shown).

[0176] (II) Preparation of 1a from rac-1a

[0177] According to General Procedure 2, ethyl (R)-2-phenylaziridine-1-carboxylate (1a, yield 46%, ee value 99%) was prepared using rac-1a obtained in Step (i) herein. Its nuclear magnetic resonance hydrogen spectrum ( 1 H NMR) is as Figure 2 shown, and its chiral high performance liquid chromatography is as Figure 4 shown), and ethyl phenethylcarbamate (2a, yield 54%).

[0178] Example 6: Preparation of 1b

[0179] (i) Preparation of rac-1b

[0180] According to General Procedure 1, styrene oxide (epoxy substrate, 1.4 g, 12.0 mmol, 1.0 eq), sodium azide (1.6 g, 24.0 mmol, 2.0 eq), ammonium chloride (1.3 g, 24.0 mmol, 2.0 eq), and triphenylphosphine (3.1 g, 12.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine;

[0181] The aziridine (715.1 mg, 6.0 mmol, 1.0 eq), diethyl pyrocarbonate (protecting reagent, 1.1 g, 6.6 mmol, 1.1 eq), triethylamine (1.3 g, 12.6 mmol, 2.1 eq), and 4-dimethylaminopyridine (DMAP, 36.6 mg, 0.3 mmol, 0.05 eq) were reacted to obtain a white solid, namely racemic ethyl-2-phenylaziridine-1-carboxylate (denoted as rac-1b, 0.7 g, yield 65%).

[0182] (ii) Preparation of 1b from rac-1b

[0183] According to General Procedure 2, ethyl (R)-2-phenylaziridine-1-carboxylate (denoted as 1b, yield 44%, ee value 99%) and ethyl phenethylcarbamate (denoted as 2b, yield 45%) were prepared using rac-1b obtained in Step (i) herein.

[0184] Example 7: Preparation of 1c

[0185] (i) Preparation of rac-1c

[0186] According to General Procedure 1, styrene oxide (epoxy substrate, 1.2 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine;

[0187] Aziridine (751.1 mg, 6.0 mmol, 1.0 eq), benzyl chloroformate (protecting reagent, 1.1 g, 6.6 mmol, 1.1 eq), triethylamine (1.3 g, 12.6 mmol, 2.1 eq), 4-dimethylaminopyridine (36.6 mg, 0.3 mmol, 0.05 eq) were reacted to obtain a colorless oil, namely racemic benzyl-2-phenylaziridine-1-carboxylate (denoted as rac-1c, 1.4 g, yield 92%).

[0188] (II) Preparation of 1c from rac-1c

[0189] According to General Procedure 2, (R)-benzyl-2-phenylaziridine-1-carboxylate (denoted as 1c, yield 43%, ee value 99%) and benzylphenethylcarbamate (denoted as 2c, yield 46%) were prepared using rac-1c obtained in Step (I).

[0190] Example 8: Preparation of 1d

[0191] (I) Preparation of rac-1d

[0192] According to General Procedure 1, styrene oxide (epoxy substrate, 1.2 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain crude aziridine;

[0193] Aziridine (595.9 mg, 5.0 mmol, 1.0 eq), allyl chloroformate (protecting reagent, 662.7 mg, 5.5 mmol, 1.1 eq), triethylamine (1.1 g, 10.5 mmol, 2.1 eq), 4-dimethylaminopyridine (30.5 mg, 0.25 mmol, 0.05 eq) were reacted to obtain a colorless oil, namely racemic allyl-2-phenylaziridine-1-carboxylate (denoted as rac-1d, 1.0 g, yield 95%).

[0194] (II) Preparation of 1d from rac-1d

[0195] According to General Procedure 2, (R)-allyl-2-phenylaziridine-1-carboxylate (denoted as 1d, yield 46%, ee value 98%) and allylphenethylcarbamate (denoted as 2d, yield 50%) were prepared using rac-1d obtained in Step (I).

[0196] Example 9: Preparation of 1e

[0197] (I) Preparation of rac-1e

[0198] Bis(trichloromethyl) carbonate (2.1 g, 7.0 mmol, 1.0 eq) and diethyl ether (20 mL) were added to a hot and dry Schlenk tube, and the mixture was cooled to -30 °C. A diethyl ether solution (10 mL) of 2-(trimethylsilyl)ethanol (2.5 g, 21.0 mmol, 3.0 eq) and pyridine (1.3 g, 16.8 mmol, 2.4 eq) was added dropwise over 1 hour. The reaction system was restored to room temperature and stirred for 9 hours. After the reaction was completed, the crude product 2-(trimethylsilyl)ethyl chloroformate was obtained by filtration through diatomaceous earth and removal of the solvent under reduced pressure.

[0199] According to General Procedure 1, styrene oxide (epoxy substrate, 1.2 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain the crude product aziridine.

[0200] Aziridine (715.1 mg, 6.0 mmol, 1.0 eq), 2-(trimethylsilyl)ethyl chloroformate (protecting reagent, 1.2 g, 6.6 mmol, 1.1 eq), triethylamine (1.3 g, 12.6 mmol, 2.1 eq), and 4-dimethylaminopyridine (36.6 mg, 0.3 mmol, 0.05 eq) were reacted to obtain a colorless oil, namely racemic 2-(trimethylsilyl)ethyl 2-phenylaziridine-1-carboxylate (denoted as rac-1e, 1.7 g, yield 92%).

[0201] (II) Preparation of 1e from rac-1e

[0202] According to General Procedure 2, (R)-2-(trimethylsilyl)ethyl 2-phenylaziridine-1-carboxylate (denoted as 1e, yield 46%, ee value 99%) and 2-(trimethylsilyl)ethyl phenethylcarbamate (denoted as 2e, yield 46%) were prepared using rac-1e obtained in step (I) of this procedure.

[0203] Example 10: Preparation of 1f

[0204] (I) Preparation of rac-1f

[0205] Under nitrogen protection, styrene oxide (1.2 g, 10.0 mmol, 1.0 eq) and a methanol / water mixed solvent (volume ratio of methanol to water is 1:3) were added to a preheated and dried Schlenk tube. Sodium azide (1.3 g, 20.0 mmol, 2.0 eq) and ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq) were added successively. After stirring at 60 °C for 6 hours, methanol was removed under reduced pressure. The remaining aqueous phase was extracted with diethyl ether, the organic phases were combined and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the crude azido alcohol.

[0206] The crude azido alcohol was dissolved in acetonitrile, and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) was added. The mixture was heated at 60 °C for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, diethyl ether (30.0 mL) was added, and the mixture was cooled to -30 °C and the precipitated triphenylphosphine oxide was filtered. The organic phase was dried by rotary evaporation to obtain the crude free aziridine.

[0207] Under nitrogen protection, the free aziridine (595.9 mg, 5.0 mmol, 1.0 eq) was dissolved in 1,4-dioxane. At room temperature, 9-fluorenylmethyl chloroformate (1.4 g, 5.5 mmol, 1.1 eq) and 10% aqueous sodium carbonate solution were added, and the mixture was stirred at 0 °C for 2 hours to form a mixture. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude product was purified by flash silica gel column chromatography (adding 1% diisopropylethylamine) to obtain a white solid, namely racemic (9H-fluoren-9-yl)methyl 2-phenylaziridine-1-carboxylate (denoted as rac-1f, 1.3 g, yield 74%).

[0208] (II) Preparation of 1f from rac-1f

[0209] Under nitrogen protection, diisopropylethylamine hydrochloride (iPr2NEt·HCl, 165.7 mg, 1.0 mmol, 2.0 eq), zinc powder (Zn, 39.2 mg, 0.6 mmol, 1.2 eq), chiral catalyst C6 (63.6 mg, 0.05 mmol, 0.1 eq) and freshly distilled toluene (Tol, 3.0 mL) were successively added to a preheated and dried Schlenk tube. After stirring the mixture at 20 °C for 6 hours, deionized water (H2O, 70 μL, 4.0 mmol, 8.0 eq) and racemic (9H-fluoren-9-yl)methyl 2-phenylaziridine-1-carboxylate (rac-1f, 0.5 mmol, 1.0 eq) were added. The reaction was continued by stirring at 20 °C for 68 hours (the reaction progress was monitored by silica gel thin-layer chromatography pretreated with 5% diisopropylethylamine), and then the reaction was quenched with saturated aqueous sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was successively washed with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). The crude product obtained after concentration under reduced pressure was separated and purified by flash column chromatography on silica gel (1% diisopropylethylamine was added to the eluent), and (R)-(9H-fluoren-9-yl)methyl 2-phenylaziridine-1-carboxylate (denoted as 1f, yield 47%, ee value 98%) and (9H-fluoren-9-yl)methyl phenethylcarbamate (denoted as 2f, yield 48%), both of which were yellow oils, were obtained respectively.

[0210] Example 11: Preparation of 1g

[0211] (I) Preparation of rac-1g

[0212] According to General Procedure 1, styrene oxide (epoxy substrate, 1.2 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine.

[0213] Aziridine (595.9 mg, 5.0 mmol, 1.0 eq), 2,2,2-trichloroethyl chloroformate (protecting reagent, 1.2 g, 5.5 mmol, 1.1 eq), triethylamine (1.1 g, 10.5 mmol, 2.1 eq), and 4-dimethylaminopyridine (30.5 mg, 0.25 mmol, 0.05 eq) were reacted to obtain a white solid, namely racemic 2,2,2-trichloroethyl 2-phenylaziridine-1-carboxylate (denoted as rac-1g, 1.3 g, yield 89%).

[0214] (II) Preparation of 1g from rac-1g

[0215] Under nitrogen protection, diisopropylethylamine hydrochloride (iPr2NEt·HCl, 165.7 mg, 1.0 mmol, 2.0 eq), zinc powder (Zn, 39.2 mg, 0.6 mmol, 1.2 eq), chiral catalyst C6 (63.6 mg, 0.05 mmol, 0.1 eq) and freshly distilled toluene (Tol, 3.0 mL) were successively added to a preheated and dried Schlenk tube. After stirring the mixture at 20 °C for 6 hours, deionized water (H2O, 70 μL, 4.0 mmol, 8.0 eq) and racemic 2,2,2-trichloroethyl 2-phenylaziridine-1-carboxylate (rac-1g, 0.5 mmol, 1.0 eq) were added. The reaction was continued by stirring at 20 °C for 68 hours (the reaction progress was monitored by silica gel thin-layer chromatography pretreated with 5% diisopropylethylamine), and then the reaction was quenched with saturated aqueous sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was washed successively with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). The crude product obtained after concentration under reduced pressure was separated and purified by flash column chromatography on silica gel (1% diisopropylethylamine was added to the eluent), and (R)-2,2,2-trichloroethyl 2-phenylaziridine-1-carboxylate (denoted as 1g, yield 42%, ee value 81%) and 2,2,2-trichloroethyl phenethylcarbamate (denoted as 2g, yield 31%), both of which were yellow oils, were obtained respectively.

[0216] Example 12: Preparation of 1h

[0217] (I) Preparation of rac-1h

[0218] According to General Procedure 1, 2-(o-tolyl)oxirane (epoxy substrate, 1.1 g, 8.0 mmol, 1.0 eq), sodium azide (1.1 g, 16.0 mmol, 2.0 eq), ammonium chloride (0.9 g, 16.0 mmol, 2.0 eq), and triphenylphosphine (2.1 g, 8.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine.

[0219] The aziridine (0.67 g, 5.0 mmol, 1.0 eq), di-tert-butyl dicarbonate (protecting reagent, 1.2 g, 5.5 mmol, 1.1 eq), triethylamine (1.1 g, 10.5 mmol, 2.1 eq), and 4-dimethylaminopyridine (30.5 mg, 0.25 mmol, 0.05 eq) were reacted to obtain a bright yellow oil, namely racemic tert-butyl 2-(o-tolyl)aziridine-1-carboxylate (denoted as rac-1h, 1.0 g, yield 87%).

[0220] (II) Preparation of 1h from rac-1h

[0221] According to General Procedure 2, (R)-tert-butyl 2-(o-tolyl)aziridine-1-carboxylate (denoted as 1h, yield 47%, ee value 99%) and tert-butyl (2-methylphenethyl)carbamate (denoted as 2h, yield 52%) were prepared using rac-1h obtained in Step (I) of this procedure.

[0222] Example 13: Preparation of 1i

[0223] (I) Preparation of rac-1i

[0224] According to General Procedure 1, 2-(m-tolyl)oxirane (epoxy substrate, 1.3 g, 10.0 mmol, 1.0 eq), sodium azide (1.3 g, 20.0 mmol, 2.0 eq), ammonium chloride (1.1 g, 20.0 mmol, 2.0 eq), and triphenylphosphine (2.6 g, 10.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine;

[0225] The aziridine (0.67 g, 5.0 mmol, 1.0 eq), di-tert-butyl dicarbonate (protecting reagent, 1.2 g, 5.5 mmol, 1.1 eq), triethylamine (1.1 g, 10.5 mmol, 2.1 eq), and 4-dimethylaminopyridine (30.5 mg, 0.25 mmol, 0.05 eq) were reacted to obtain a colorless oil, namely racemic tert-butyl 2-(m-tolyl)aziridine-1-carboxylate (denoted as rac-1i, 1.0 g, yield 85%).

[0226] (II) Preparation of 1i from rac-1i

[0227] According to General Procedure 2, (R)-tert-butyl 2-(m-tolyl)aziridine-1-carboxylate (denoted as 1i, yield 47%, ee value 99%) and tert-butyl (3-methylphenethyl)carbamate (denoted as 2i, yield 50%) were prepared using rac-1i obtained in Step (I) of this procedure.

[0228] Example 14: Preparation of 1j

[0229] (I) Preparation of rac-1j

[0230] According to General Procedure 1, 2-(p-tolyl)oxirane (epoxy substrate, 1.6 g, 12.0 mmol, 1.0 eq), sodium azide (1.6 g, 24.0 mmol, 2.0 eq), ammonium chloride (1.3 g, 24.0 mmol, 2.0 eq), and triphenylphosphine (3.1 g, 12.0 mmol, 1.0 eq) were reacted to obtain the crude aziridine;

[0231] Aziridine (1.1 g, 8.0 mmol, 1.0 eq), di-tert-butyl dicarbonate (protecting reagent, 1.9 g, 8.8 mmol, 1.1 eq), triethylamine (1.8 g, 16.8 mmol, 2.1 eq), and 4-dimethylaminopyridine (48.8 mg, 0.4 mmol, 0.05 eq) were reacted to obtain a colorless oil, namely racemic tert-butyl 2-(p-tolyl)aziridine-1-carboxylate (denoted as rac-1j, 1.4 g, yield 81%).

[0232] (II) Preparation of 1j from rac-1j

[0233] According to General Procedure 2, (R)-tert-butyl 2-(p-tolyl)aziridine-1-carboxylate (denoted as 1j, yield 46%, ee value 99%) and tert-butyl (4-methylphenethyl)carbamate (denoted as 2j, yield 51%) were prepared using rac-1j obtained in Step (I) of this procedure.

[0234] Examples 15 - 45

[0235] The racemate was prepared using the preparation method of General Procedure 1, and the enantiomers were prepared using the preparation method of General Procedure 2. The specific structures are shown in the following table.

[0236] Table 4 Product structures, yields, ee values, and s values of Examples 5 - 45

[0237]

[0238]

[0239]

[0240]

[0241]

[0242] Example 29*: The difference from General Procedure 2 is that the zinc powder is 2 eq and the reaction temperature is 35 °C.

[0243] Examples 46 - 52

[0244] The racemate was prepared using the preparation method of General Procedure 1, and the enantiomers were prepared using the preparation method of General Procedure 2. The specific structures are shown below. Among them, the racemate structure and the enantiomer structure are shown in the following figure, and the R groups are shown in the following table.

[0245]

[0246] Table 5 Product structures (R groups), yields, ee values, and s values of Examples 46 - 52

[0247]

[0248]

[0249] Example 53

[0250] This example is a gram-scale reaction of 1a, specifically as follows:

[0251]

[0252] Under nitrogen protection, triethylammonium hydrochloride (Et3N·HCl, 1.6 g, 12.0 mmol, 2.0 eq), zinc powder (Zn, 470.4 mg, 7.2 mmol, 1.2 eq), chiral catalyst C6 (763.2 mg, 0.6 mmol, 0.1 eq), and freshly distilled toluene (Tol, 35.0 mL) were successively added to a preheated and dried Schlenk tube. After stirring the mixture at 20 °C for 6 hours, deionized water (0.8 mL, 48.0 mmol, 8.0 eq) and tert-butyl 2-phenylaziridine-1-carboxylate (rac-1a, 1.3 g, 6.0 mmol, 1.0 eq) prepared in step (i) of Example 1 were added. The reaction was continued to stir at 20 °C for 72 h (the reaction progress was monitored by silica gel thin-layer chromatography pretreated with 5% triethylamine), and then the reaction was quenched with saturated aqueous sodium bicarbonate (NaHCO3), and the reaction product was extracted with ethyl acetate (EtOAc). The extracted reaction product was successively washed with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). The crude product obtained after concentration under reduced pressure was separated and purified by silica gel flash column chromatography (1% triethylamine was added to the eluent), and tert-butyl (R)-2-phenylaziridine-1-carboxylate (1a, 0.57 g, yield 44%, ee value 99%) and tert-butyl phenethylcarbamate (denoted as 2a), both of which were yellow oils, were obtained respectively.

[0253] This example proves that this kinetic resolution method not only has good resolution effect and yield at the microscale, but can still effectively resolve enantiomers at the gram-scale and maintain a good yield.

[0254] Example 54

[0255] This example is the synthetic route of (S)-sulconazole, and the specific process is as follows:

[0256]

[0257] To a preheated and dried Schlenk tube, a mixture of tert-butyl carbamate (BocNH2, 1.2 g, 10.0 mmol, 1.0 eq), 40 ml of a methanol / water mixed solvent (volume ratio of methanol to water is 1:3), sodium benzenesulfinate (3.3 g, 20.0 mmol, 2.0 eq), 2,4-dichlorobenzaldehyde (2.3 g, 13.0 mmol, 1.3 eq) and formic acid (1.2 g, 25.0 mmol, 2.5 eq) was added and stirred at room temperature for 72 hours, during which a precipitate formed. After the reaction was completed, the suspension was filtered through a sintered funnel, and the obtained solid was washed with water and dried on the funnel for 10 minutes. Subsequently, the solid was rinsed extensively with hexane to remove the excess benzaldehyde, and the obtained crude product was dried under vacuum overnight. The crude product was transferred to another preheated and dried Schlenk tube, potassium carbonate (K2CO3, 8.3 g, 60.0 mmol, 6.0 eq) and sodium sulfate were added and all were dissolved in tetrahydrofuran (THF, 0.17 M). The reaction mixture was heated to reflux overnight. After the reaction was completed, it was cooled to room temperature and filtered through an alternately laid layer of diatomaceous earth / sodium sulfate / diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated and dried under vacuum to obtain the final product tert-butyl-(2,4-dichlorophenyl)carbamate;

[0258] Under nitrogen protection, trimethylsulfoxonium iodide (Me3SOI, 1.9 g, 8.8 mmol, 1.1 eq), potassium tert-butoxide (tBuOK, 0.98 g, 8.8 mmol, 1.1 eq) and anhydrous tert-butanol (tBuOH, 30 ml) were added to a preheated and dried Schlenk tube. After stirring at 0 °C for 2 hours, a tert-butanol solution of tert-butyl-(2,4-dichlorophenyl)carbamate (2.2 g, 8.0 mmol, 1.0 eq) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature for 1 hour, quenched with water, and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent) to obtain racemic tert-butyl-2-(2,4-dichlorophenyl)aziridine-1-carboxylate (denoted as rac-1y, 1.72 g, yield 78%);

[0259] According to General Procedure 2, with the difference that 2 eq of zinc powder was used and the reaction temperature was 35 °C, (R)-tert-butyl-2-(2,4-dichlorophenyl)aziridine-1-carboxylate (denoted as 1y, 288.2 mg, yield 47%, ee value 99%) was prepared from the obtained rac-1y (576 mg, 2 mmol);

[0260] Under nitrogen protection, compound 1y (288.2 mg, 1.0 mmol, 99% ee) was dissolved in dichloromethane (2.0 mL), cooled to -78 °C, 4-chlorobenzyl mercaptan (190.4 mg, 1.2 mmol) and boron trifluoride diethyl ether complex (BF3·OEt2, 14.2 mg, 0.1 mmol) were added successively, and the mixture was stirred for 0.5 h. The reaction mixture was extracted with dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by flash column chromatography on silica gel (n-hexane:ethyl acetate = 20:1) to obtain a colorless oil, namely tert-butyl (S)-2-((4-chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethylcarbamate (358.2 mg, yield 81%, 98% ee).

[0261] tert-Butyl (S)-2-((4-chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethylcarbamate (222.5 mg, 0.5 mmol, 98% ee) was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (TFA, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude product.

[0262] Under nitrogen protection, the above crude product (69.3 mg, 0.2 mmol, 98% ee), formaldehyde (HCHO, 36 wt%, 33.3 mg, 0.4 mmol), glyoxal (40 wt%, 58.1 mg, 0.4 mmol), ammonium chloride (NH4Cl, 21.4 mg, 0.4 mmol) and methanol (MeOH, 3.0 mL) were added to a pre-dried Schlenk tube, and the mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the solvent was concentrated under reduced pressure, the pH was adjusted to 9 - 10 with saturated KOH solution, extracted with dichloromethane, the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by flash column chromatography on silica gel (dichloromethane:methanol = 50:1) to obtain a white solid. Namely (S)-Sulconazole (58.9 mg, yield 74%, 98% ee, the 1H NMR spectrum thereof is as Figure 5 shown, and the chiral high performance liquid chromatography thereof is as Figure 6 shown).

[0263] Example 55

[0264] This example is the synthetic route of (S)-Baclofen, and the specific process is as follows:

[0265]

[0266] To a pre-heated and dried Schlenk tube, a mixture of tert-butyl carbamate (BocNH2, 1.2 g, 10.0 mmol, 1.0 eq), 40 ml of a methanol / water mixed solvent (volume ratio of methanol to water is 1:3), sodium benzenesulfinate (3.3 g, 20.0 mmol, 2.0 eq), p-chlorobenzaldehyde (1.8 g, 13.0 mmol, 1.3 eq) and formic acid (1.2 g, 25.0 mmol, 2.5 eq) was added and stirred at room temperature for 36 hours, during which a precipitate formed. After the reaction was completed, the suspension was filtered through a sintered funnel, and the obtained solid was washed with water and dried on the funnel for 10 minutes. Subsequently, the solid was rinsed extensively with hexane to remove the excess benzaldehyde, and the obtained crude product was dried under vacuum overnight. The crude product was transferred to another pre-heated and dried Schlenk tube, potassium carbonate (K2CO3, 8.3 g, 60.0 mmol, 6.0 eq) and sodium sulfate were added and all were dissolved in tetrahydrofuran (THF, 0.17 M). The reaction mixture was heated to reflux overnight. After the reaction was completed, it was cooled to room temperature and filtered through an alternately laid layer of diatomaceous earth / sodium sulfate / diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated and dried under vacuum to obtain the final product tert-butyl (p-chlorophenyl) carbamate;

[0267] Under nitrogen protection, trimethylsulfoxonium iodide (Me3SOI, 1.9 g, 8.8 mmol, 1.1 eq), potassium tert-butoxide (0.98 g, 8.8 mmol, 1.1 eq) and anhydrous tert-butanol (30 ml) were added to a pre-heated and dried Schlenk tube. After stirring at 0 °C for 2 hours, a tert-butanol solution of tert-butyl (p-chlorophenyl) carbamate (1.9 g, 8.0 mmol, 1.0 eq) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature for 1 hour, quenched with water, and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was purified by flash column chromatography on silica gel (1% triethylamine was added to the eluent) to obtain racemic tert-butyl-2-(p-chlorophenyl)aziridine-1-carboxylate (denoted as rac-1u, 1.64 g, yield 82%);

[0268] According to General Procedure 2, (R)-tert-butyl-2-(p-chlorophenyl)aziridine-1-carboxylate (denoted as 1u, 253.1 mg, yield 44%, ee value 98%) was prepared using the rac-1u (506 mg, 2 mmol) obtained from the above procedure;

[0269] Under nitrogen protection, tert-butyl acetate (1.2 g, 10.0 mmol) was dissolved in cyclopentyl methyl ether (CPME, 20.0 mL), and the solution was cooled to 0 °C in an ice bath. Potassium hexamethyldisilazide (KHMDS, 0.5 M toluene solution, 12.0 mL, 11.0 mmol) was slowly added within 5 - 8 minutes, and the mixture was stirred at 0 °C for 30 minutes. Subsequently, trimethylchlorosilane (1.6 mL, 13.0 mmol) was added dropwise, and stirring was continued for 30 minutes. The reaction mixture was poured into a mixture of ice water and n-hexane, extracted with n-hexane, and the combined organic phases were dried over anhydrous magnesium sulfate. The crude product was purified by distillation to obtain ((1-(tert-butoxy)vinyl)oxy)trimethylsilane (1.22 g, yield 65%).

[0270] Under nitrogen protection, compound 1u (253.1 mg, 1.0 mmol, 99% ee) was dissolved in dichloromethane (DCM, 2.0 mL), cooled to -78 °C, and ((1-(tert-butoxy)vinyl)oxy)trimethylsilane (564.9 mg, 3.0 mmol) and boron trifluoride diethyl ether complex (BF3·Et2O, 170.3 mg, 1.2 mmol) were added. The mixture was stirred at low temperature for 0.5 hour. The reaction mixture was extracted with dichloromethane, the combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (n-hexane:ethyl acetate = 20:1) to obtain a colorless oil, namely tert-butyl (S)-4-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)butyrate (369.0 mg, yield 99%, ee value 98%, and its chiral high performance liquid chromatography is as shown in Figure 7 shown).

[0271] tert-Butyl (S)-4-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)butyrate (184.6 mg, 0.5 mmol, 98% ee) was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (TFA, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, and saturated KOH solution was added dropwise to adjust the pH to 6.5 - 7.0. After removing dichloromethane under reduced pressure, isopropanol (5.0 mL) was added until a solid precipitated at the bottom to obtain a white solid, namely (S)-baclofen (81.2 mg, yield 76%, specific rotation [α]D 22 = +17 (c = 1.1, CHCl3), and its 1H NMR spectrum is as shown in Figure 8 shown).

[0272] The above content is a schematic description of the present invention and its implementation manners. This description is not restrictive. What is shown in the embodiments is only one of the implementation manners of the present invention, and the actual implementation manners are not limited thereto. Therefore, if those of ordinary skill in the art are inspired by it and design, without creative efforts, implementation manners and embodiments similar to the technical solution without departing from the purpose of the present invention, they shall fall within the protection scope of the present invention.

Claims

1. A kinetic resolution method for terminal N-carbamate aziridines, characterized in that, Comprising the following reactions: The reaction of obtaining a compound of general formula II from a compound of general formula I under the action of a catalyst; wherein, R 1 is selected from R 3 a substituted or unsubstituted alkyl, alkenyl, alkynyl or aryl; R 2 selected from a substituted or unsubstituted aromatic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group; The catalyst is:

2. The kinetic resolution method of terminal N-carbamate aziridine according to claim 1, characterized in that R 3 selected from substituted or unsubstituted C1-C40 alkyl, alkenyl, alkynyl or aryl, and the substitution is selected from one or more of alkyl substitution, alkoxy substitution, alkenyl substitution, alkynyl substitution, heterocyclic substitution, heteroaryl substitution, halogen atom substitution, fluorene group substitution, and heteroatom substitution.

3. The kinetic resolution method of the terminal N-carbamate aziridine according to claim 1, characterized in that, R 2 selected from a substituted or unsubstituted aromatic group, a substituted or unsubstituted alkenyl group or a substituted or unsubstituted alkynyl group, wherein the substitution is selected from one or more of alkyl substitution, alkoxy substitution, alkenyl substitution, alkynyl substitution, aromatic group substitution, heterocyclic substitution, heteroaryl substitution, halogen atom substitution, fluorenyl substitution, siloxy substitution, haloalkane substitution, ester group substitution, and cyano substitution.

4. The kinetic resolution method of the terminal N-carbamate aziridine according to any one of claims 1 to 3, characterized in that, The R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc; The R 2 is selected from a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

5. The kinetic resolution method of the terminal N-carbamate aziridine according to any one of claims 1 to 3, characterized in that, The reaction further comprises a reducing agent and a hydrogen atom donor; The reducing agent is selected from one or more of zinc powder and manganese powder; The hydrogen atom donor is selected from one or more of H2O, D2O or Bu3SnH.

6. The kinetic resolution method of the terminal N-carbamate aziridine according to claim 5, characterized in that, The solvent is substituted or unsubstituted benzene; preferably, the substituted benzene is selected from toluene, xylene and mesitylene.

7. The kinetic resolution method of the terminal N-carbamate aziridine according to claim 5, characterized in that, The reaction further comprises an inorganic acid salt of alkylamine; preferably, the inorganic acid salt of alkylamine is selected from triethylamine hydrochloride, trimethylamine hydrochloride, tripropylamine hydrochloride and diisopropylethylamine hydrochloride.

8. A chiral synthesis method of (S)-baclofen, characterized in that, Comprising the following reactions: The reaction of obtaining a compound of general formula VIII from a compound of general formula VII under the action of a catalyst; Among them, R 1 is selected from R 3 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl or aryl; preferably, R 1 is selected from -COOEt, Boc, Cbz, Fmoc, Moc, Alloc, iNoc, Teoc, Troc; The catalyst is:

9. The chiral synthesis method of (S)-baclofen according to claim 8, characterized in that, It further comprises the step of preparing a compound of general formula IX from a compound of general formula VIII, and the step of preparing (S)-baclofen from a compound of general formula IX, Formula IX; Among them, R 4 is selected from substituted or unsubstituted C1-C40 alkyl groups.

10. The chiral synthesis method of (S)-baclofen according to claim 9, characterized in that, It further comprises the step of preparing a compound of general formula VII from a compound of general formula X;

Images