Chiral sulfonamide compounds, processes for their preparation and use

Abstract

The application provides a chiral sulfonamide compound and a preparation method and application thereof, relates to the field of compound synthesis, and a structural general formula of the chiral sulfonamide compound is shown as formula (1). The application discloses that sodium benzenesulfinate and amine are catalyzed by a catalyst quinine or quinidine to efficiently prepare a chiral sulfonamide compound and derivatives thereof, and the chiral sulfonamide compound and derivatives thereof have excellent yield, high enantioselectivity of up to 99%, and good application potential and research value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of compound synthesis, in particular to a chiral sulfonamide compound and a preparation method and application thereof. BACKGROUND

[0002] Due to the importance and wide application of chiral skeletons in various fields, the preparation of enantiomerically enriched S-stereogenic center compounds is a long-term goal of stereoselective synthesis. Especially the sulfonamide compounds containing sulfur chiral center, at present, are limited to further conversion (Nature Chem.202113, 327-334), and the synthesis catalyzed by small molecule chiral catalysts is very limited, therefore, the synthesis of chiral phenylsulfonamide and its derivatives has attracted great interest of scientists, and the development of efficient and highly stereoselective preparation method of chiral sulfonamide and its derivatives has extremely important application value. SUMMARY

[0003] In order to solve the above problems, the present application provides a chiral sulfonamide compound and a preparation method and application thereof, the present application designs and synthesizes a kind of novel structure, good substrate universality and high enantioselectivity chiral sulfonamide-containing compound and its derivative, and explores its use after further conversion. The present application is committed to the catalytic reaction of catalyst quinine, and a novel and efficient synthesis method of chiral sulfonamide-containing compound and its derivative is invented, which has the advantages of simple operation, good substrate universality, mild reaction conditions, excellent yield and stereoselectivity, etc.

[0004] In order to achieve the above purpose, the present application provides the following technical scheme:

[0005] The present application provides a chiral sulfonamide compound, the structure general formula of the chiral sulfonamide compound is shown as formula (1):

[0006]

[0007] Among them, the sulfur atom marked with * is a chiral S atom;

[0008] R 1 is tolyl, phenyl, ethylphenyl, biphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, tert-butyl, 4-methylphenyl or 4-methylphenyl;

[0009] R 2It can be hydrogen, phenyl, 4-methylphenyl, 4-isopropylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-tolyl, 2-chlorophenyl, 3-methylphenyl, 2-naphthalene, 2-fluoro-4-trifluoromethylphenyl, 2,4-dimethylphenyl, 2-chloro-4-methylphenyl, 2,4,6-trimethylphenyl, tert-butyl, triphenylmethyl, 1S,3S,5S,7S-adamantane-2-yl or N-diphenylmethyl.

[0010] The present invention also provides a method for preparing the chiral sulfinamide compound described in the above technical solution, comprising the following steps:

[0011] 1) Sulfonyl chloride is mixed with sodium sulfite, sodium bicarbonate and water and then heated to obtain a heat-treated product; water is removed from the heat-treated product to obtain a solid, and the solid is extracted with ethanol and filtered to obtain a filtrate;

[0012] The filtrate was concentrated under vacuum to obtain a solid. The solid was washed with ether and filtered. The obtained solid was dried under vacuum to obtain sodium benzenesulfonate.

[0013] 2) Dissolve the sodium benzenesulfinate obtained in step 1) with 2-chloro-6-nitrobenzoyl chloride or 2-bromo-6-nitrobenzoyl chloride or 2-methyl-6-nitrobenzoyl chloride 2(ethoxycarbonyl)-6-nitrobenzoyl chloride in chloroform and stir to obtain a mixed acid anhydride;

[0014] 3) The mixed anhydride obtained in step 2) is mixed with quinine, N,N-diisopropylethylamine and amine and stirred to obtain a chiral sulfinamide compound.

[0015] Preferably, in step 1), the volume ratio of the equivalent of sulfonyl chloride to the equivalent of sodium sulfite, the equivalent of sodium bicarbonate, and water is 1:2:2:10 ml.

[0016] The conditions for the heat treatment include: a temperature of 80°C and a time of 4–6 hours;

[0017] The vacuum drying time is 4 hours.

[0018] Preferably, in step 2), the molar ratio of sodium benzenesulfinate to the molar ratio of 2-chloro-6-nitrobenzoyl chloride and the volume ratio of chloroform is 0.11 mmol:0.1 mmol:1 ml.

[0019] The stirring conditions include: a temperature of 0°C and a time of 1 to 2 hours.

[0020] Preferably, in step 3), the molar ratio of the mixed anhydride to quinine and N,N-diisopropylethylamine, and the molar ratio of the amine is 0.1 mmol:0.02 mmol:0.13 mmol:0.14 mmol.

[0021] The stirring condition includes: temperature is 0℃, and time is 36-48h.

[0022] The application further provides a preparation method of the chiral sulfonamide compound.

[0023] I. Dissolving sodium p-toluenesulfinate and 2-chloro-6-nitrobenzoyl chloride in chloroform, and stirring to obtain mixed anhydride;

[0024] II. Stirring the mixed anhydride obtained in I with quinine, N,N-diisopropylethylamine and amine to obtain the chiral sulfonamide compound.

[0025] Preferably, the molar ratio of sodium p-toluenesulfinate to 2-chloro-6-nitrobenzoyl chloride to the volume of chloroform in step I is 0.11mmol:0.1mmol:1ml;

[0026] The stirring condition includes: temperature is 0℃, and time is 1-2h.

[0027] The molar ratio of the mixed anhydride to quinine, N,N-diisopropylethylamine and amine in II is 0.1mmol:0.02mmol:0.11mmol:0.1mmol;

[0028] The stirring condition includes: temperature is 0℃, and time is 2-3h.

[0029] The application further provides a method for preparing a chiral sulfonamide derivative by using the chiral sulfonamide compound.

[0030] Stirring the chiral sulfonamide compound, tetrahydrofuran, benzyl bromide and potassium hydroxide to obtain the chiral sulfonamide derivative;

[0031] Or

[0032] Stirring the chiral sulfonamide compound, iodosylbenzene and methanol to obtain the chiral sulfonamide derivative.

[0033] The application further provides a method for preparing a chiral sulfonamide derivative by using the chiral sulfonamide compound.

[0034] Stirring the chiral sulfonamide compound, benzaldehyde, dichloromethane and tetrahydropyrrole to obtain imine; and stirring the imine, tetrahydrofuran, alpha-bromoacetate and lithium bis(trimethylsilyl)amide to obtain the chiral sulfonamide derivative.

[0035] The application also provides application of the chiral sulfonamide compound in drug transfer.

[0036] The application has the following beneficial effects:

[0037] The application obtains an enantiomerically enriched S-stereocompound from easily available sulfite and amine through a simple quinine small molecule catalyst, and effectively solves the significant challenge of sulfonamidation by using a sterically hindered activating leaving group. Under the control of the catalyst, good stereoselectivity of S-N bond is achieved, and a wide range of chiral sulfonamides is prepared with high yield and excellent enantioselectivity. In addition, through efficient stereoselective sulfonamidation, a series of diversification of complex natural products and drug molecules can be easily realized, which greatly expands the scope and synthetic use of the current method. The developed catalyst-controlled enantioselective S-N bond formation method will open up a new way for the preparation of chiral sulfur stereocompounds and stimulate extensive research. DETAILED DESCRIPTION

[0038] The application provides a chiral sulfonamide compound, a structural general formula of the chiral sulfonamide compound is shown in formula (1):

[0039]

[0040] wherein, the sulfur atom marked with an asterisk is a chiral S atom;

[0041] R 1 is a tolyl group, a phenyl group, an ethylphenyl group, a biphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-iodophenyl group, a 4-nitrophenyl group, a 2-methoxyphenyl group, a 2,4,6-trimethylphenyl group, a tert-butyl group, a 4-methylphenyl group or a 4-methylphenyl group;

[0042] R 2 is hydrogen, a phenyl group, a 4-methylphenyl group, a 4-isopropylphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-trifluoromethylphenyl group, a 2-tolyl group, a 2-chlorophenyl group, a 3-methylphenyl group, a 2-naphthyl group, a 2-fluoro-4-trifluoromethylphenyl group, a 2,4-dimethylphenyl group, a 2-chloro-4-methylphenyl group, a 2,4,6-trimethylphenyl group, a tert-butyl group, a triphenylmethyl group, a 1S,3S,5S,7S-adamant-2-yl group or an N-diphenylmethyl group.

[0043] In the application, the chiral sulfonamide compound has any one of the following structures:

[0044]

[0045] The application also provides a preparation method of the chiral sulfonamide compound.

[0046] 1) heating treatment of the mixture of sulfonyl chloride, sodium sulfite, sodium bicarbonate and water to obtain a heating-treated product; removing water from the obtained heating-treated product to obtain a solid, and extracting the solid with ethanol to obtain a filtrate;

[0047] vacuum concentration of the filtrate to obtain a solid, washing the solid with diethyl ether, filtering, and vacuum drying the obtained solid to obtain sodium benzenesulfinate;

[0048]

[0049] 2) dissolving sodium benzenesulfinate obtained in step 1) with 2-chloro-6-nitrobenzoyl chloride or 2-bromo-6-nitrobenzoyl chloride or 2-methyl-6-nitrobenzoyl chloride or 2-(ethoxycarbonyl)-6-nitrobenzoyl chloride in chloroform, and stirring to obtain a mixed anhydride;

[0050] 3) stirring the mixed anhydride obtained in step 2) with quinine, N,N-diisopropylethylamine and amine to obtain a chiral sulfonamide compound.

[0051] In the present application, the equivalent ratio of the sulfonyl chloride, the equivalent of sodium sulfite, the equivalent of sodium bicarbonate and the volume of water is preferably 1:2:2:10 ml. In the present application, the conditions of the heating treatment preferably include a temperature of 80°C and a time of 4-6 h. In the present application, the time of the vacuum drying is preferably 4 h. In the present application, the molar ratio of the sodium benzenesulfinate, the 2-chloro-6-nitrobenzoyl chloride and the volume of chloroform is 0.11 mmol:0.1 mmol:1 ml; and the conditions of the stirring preferably include a temperature of 0°C and a time of 1-2 h. In the present application, the molar ratio of the mixed anhydride, the quinine, the N,N-diisopropylethylamine and the amine is 0.1 mmol:0.02 mmol:0.13 mmol:0.14 mmol; and the conditions of the stirring preferably include a temperature of 0°C and a time of 36-48 h.

[0052] In the present application, after the stirring of step 3), the obtained stirring product is added with saturated NaHCO3 solution to quench the reaction, dichloromethane is used for extraction, the mixture is vacuum concentrated, and the target compounds 8 and 9 are separated by column chromatography with eluent of polar petroleum ether: ethyl acetate = 5:1, and the corresponding yield is calculated after weighing. The structure of the target compounds is determined by nuclear magnetic resonance 1 H, 12 C and ESI, and the corresponding selectivity, optical activity and absolute configuration of the target compounds are determined by chiral HPLC, optical instrument and X-ray. 6 in the following structural formula is amine (HMDS is used for products 8a-8n).

[0053]

[0054] The application also provides the chiral sulfonamide compound in the above technical solution for use in drug transfer.

[0055]

[0056] Sulfonamides are special chiral precursors for a variety of stereoselective syntheses. Alkylated sulfonamides (S)-16 (structure above) are directly obtained under basic conditions. Through PhI=O oxidation, (S)-9e is easily converted into sulfonamide ester (R)-17, which is an extremely attractive skeleton in drug discovery. The prepared enantiomerically enriched sulfonamides can be easily used as chiral auxiliaries for stereoselective synthesis. For example, chiral nitrogen-containing heterocycle 18 is prepared in a two-step synthesis method with a yield of 91% and a d.r. of greater than 20:1. In addition, it is a great challenge to install it on a drug molecule through an enantioselective sulfonyl transfer reaction. In this regard, the application explores several aniline scaffold-containing drugs, such as benzocaine, procaine and tetracaine, to obtain their corresponding sulfonylated products (S)-19-21, proving the feasibility of drug diversification through catalyst-controlled stereoselective sulfonylation.

[0057] The application also provides a preparation method of the chiral sulfonamide compound in the above technical solution, comprising the following steps:

[0058] I. Dissolving sodium p-toluenesulfinate and 2-chloro-6-nitrobenzoyl chloride in chloroform and stirring to obtain a mixed anhydride;

[0059] II. Stirring the mixed anhydride obtained in I after mixing with quinine, N,N-diisopropylethylamine and amine to obtain a chiral sulfonamide compound.

[0060] In the application, the molar ratio of sodium p-toluenesulfinate to 2-chloro-6-nitrobenzoyl chloride and the volume ratio of chloroform in step I are preferably 0.11 mmol:0.1 mmol:1 ml; the stirring conditions are preferably that the temperature is 0℃ and the time is 1-2 h; the molar ratio of the mixed anhydride to quinine, N,N-diisopropylethylamine and amine is preferably 0.1 mmol:0.02 mmol:0.11 mmol:0.1 mmol; and the stirring conditions are preferably that the temperature is 0-25℃ and the time is 2-3 h.

[0061] The application also provides a method for preparing a chiral sulfonamide derivative by using the chiral sulfonamide compound in the above technical solution, comprising the following steps:

[0062] The chiral sulfonamide compound, tetrahydrofuran, benzyl bromide and potassium hydroxide are mixed and stirred to obtain a chiral sulfonamide derivative; or the chiral sulfonamide compound, iodosylbenzene and methanol are mixed and stirred to obtain a chiral sulfonamide derivative.

[0063] The chiral sulfonamide compound, tetrahydrofuran, benzyl bromide and potassium hydroxide are mixed and stirred to obtain a chiral sulfonamide derivative. In the present application, the mass of the chiral sulfonamide compound, the volume of tetrahydrofuran, the mass of benzyl bromide and the mass of potassium hydroxide are 18.8 mg: 1 ml: 17.1 mg: 8.4 mg. In the present application, the stirring temperature is 25-30℃, and the stirring time is 4 h.

[0064] The chiral sulfonamide compound, iodosylbenzene and methanol are mixed and stirred to obtain a chiral sulfonamide derivative. In the present application, the mass of the chiral sulfonamide compound, the mass of iodosylbenzene and the volume of methanol are 39.8 mg: 21.8 mg: 1 ml. In the present application, the stirring temperature is 25-30℃, and the stirring time is 40 h.

[0065] The present application also provides a method for preparing a chiral sulfonamide derivative by using the chiral sulfonamide compound according to the above technical solution, which comprises the following steps: mixing and stirring the chiral sulfonamide compound, benzaldehyde, dichloromethane and tetrahydropyrrole to obtain an imine; and mixing and stirring the imine, tetrahydrofuran, α-bromoacetate and lithium bis(trimethylsilyl)amide to obtain a chiral sulfonamide derivative.

[0066] In the present application, the mass of the chiral sulfonamide compound, the mass of benzaldehyde, the volume of dichloromethane, the mass of tetrahydropyrrole are 46.6 mg: 31.7 mg: 10 ml: 2.1 mg, and the stirring conditions preferably include a temperature of 60℃ and a time of 1 h. In the present application, the mass of the imine, the volume of tetrahydrofuran, the mass of α-bromoacetate and the volume of lithium bis(trimethylsilyl)amide are 24.3 mg: 2 ml: 24.5 mg: 130 μl, and the stirring conditions include a temperature of 78℃ and a time of 30 min.

[0067] In order to further illustrate the present application, the present application is described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0068] Example 1

[0069] Preparation of phenylsulfonamide:

[0070] (1) Dissolve sulfonyl chloride S1 (1.0 eq), sodium sulfite (2.0 eq) and sodium bicarbonate (2.0 eq) in 10.0 mL water, heat at 80 °C for 4-6 h. After cooling to room temperature, remove water under vacuum to get a solid residue. Extract with ethanol and filter, concentrate the filtrate, wash with 20.0 mL diethyl ether, filter to collect the solid, dry at 60 °C under vacuum for 4 h to get sodium benzenesulfinate 1.

[0071]

[0072] (2) Dissolve sodium benzenesulfinate 1 (0.11 mmol, 1.1 eq) with 2-chloro-6-nitrobenzoyl chloride 3d (0.1 mmol) in chloroform (1 mL), stir at 0 °C for 1-2 h to generate intermediate mixed anhydride, monitor the complete reaction of acyl chloride by TLC;

[0073] (3) Add catalyst quinine E (20% mmol, i.e. 0.02 mmol), N,N-diisopropylethylamine (0.13 mmol, 1.3 eq) and amine HMDS (0.14 mmol, 1.4 eq), continue stirring at 0 °C for 36-48 h, monitor the complete reaction by TLC spot test;

[0074] (4) Quench the reaction by adding saturated NaHCO3, extract with dichloromethane (3*10 mL), dry over anhydrous Na2SO4, filter, column chromatography (petroleum ether: ethyl acetate = 1:1) to isolate and purify the target compounds 8a-8n, further confirm the structure of the target compounds by nuclear magnetic resonance 1 H, 12 C and ESI, determine the corresponding selectivity and absolute configuration of the target compounds by chiral HPLC, polarimeter, X-ray.

[0075] Example 2

[0076] Preparation of N-arylbenzenesulfonamides

[0077] (1) Dissolve sodium p-toluenesulfinate 1b (0.11 mmol, 1.1 eq) with 2-chloro-6-nitrobenzoyl chloride 3d or 3e (0.1 mmol) in chloroform (1 mL), stir at 0 °C for 1-2 h to generate intermediate mixed anhydride, monitor the complete reaction of acyl chloride by TLC;

[0078] (2) Add catalyst quinine E (20% mmol, i.e. 0.02 mmol), N,N-diisopropylethylamine (0.11 mmol, 1.1 eq) and arylamine 6 (0.1 mmol, 1.0 eq), continue stirring at 0 °C for 2-3 h, monitor the complete reaction by TLC spot test;

[0079] (3) Add saturated NaHC03solution to quench the reaction, dichloromethane (3*10 mL) extraction, anhydrous Na2S04drying, filtration, column chromatography (petroleum ether: ethyl acetate = 5: 1) to separate and purify the target compound 8o-9g, and further determine the corresponding selectivity and absolute configuration of the target compound by nuclear magnetic resonance 1 H, 12 C and ESI to determine the structure of the target compound, and chiral HPLC, polarimeter, X-ray to determine the corresponding selectivity and absolute configuration of the target compound.

[0080] Example 3

[0081] Study on the synthesis of chiral sulfonamide derivatives:

[0082] (1) Preparation method of converting compound (S)-8b into (S)-16

[0083]

[0084] In a 10 mL vial equipped with magnetic stirring, 18.8 mg of (S)-8b was added, 1 mL of tetrahydrofuran was added to dissolve it, 17.1 mg of benzyl bromide and 8.4 mg of potassium hydroxide were added, and it was stirred at room temperature for 4 hours. TLC was used to monitor the completion of the reaction, saturated NH4Cl was added to quench it, and ethyl acetate was used for extraction, and anhydrous sodium sulfate was used for drying. The crude product was obtained by vacuum concentration, and column chromatography was used for separation, and the eluent was polar petroleum ether: ethyl acetate = 2: 1 to obtain the target compound (S)-16 with a yield of 92% and a corresponding selectivity of 96:4.

[0085] (2) Preparation method of converting compound (S)-9d into (R)-17

[0086]

[0087] In a 2 mL reaction tube equipped with magnetic stirring, 39.8 mg of (S)-9e was added, 21.8 mg of iodosylbenzene and 1.0 mL of methanol were added, and it was stirred at room temperature for 40 hours. TLC was used to monitor the completion of the reaction, vacuum concentration was used to obtain the crude product, column chromatography was used for separation, and the eluent was polar petroleum ether: ethyl acetate = 5: 1 to obtain the target compound (S)-17 with a yield of 72% and a corresponding selectivity of 87:13.

[0088] (3) Preparation method of converting compound (S)-9e into (R)-18

[0089]

[0090] In a 20 mL vial with magnetic stirring bar, 46.6 mg of (S)-8b and 31.7 mg of benzaldehyde were added sequentially, 10.0 mL of dichloromethane was added as solvent, 2.1 mg of tetrahydropryrrole was added, and the mixture was stirred at 60 °C for 1 hour. Concentration under reduced pressure gave a residue, which was dried without further purification. 24.3 mg of the imine prepared in the previous step and 2.0 mL of tetrahydrofuran were charged into a dry 10.0 mL round bottom flask, and the mixture was then cooled to -78 °C, followed by the addition of 24.5 mg of α-bromoacetate. 130.0 μL of lithium bis-trimethylsilylamide was added slowly dropwise into the mixture over 10 minutes, and after stirring at 78 °C for 30 minutes, 2.0 mL of water was added to the mixture, which was then allowed to warm to room temperature, extracted with EtOAc and dried over anhydrous MgSO4, and concentrated under reduced pressure to give a crude residue, which was separated by column chromatography with eluent polarity of petroleum ether: ethyl acetate = 5:1 to give the chiral nitrogen-containing heterocyclic product 18 in 92% yield and a corresponding selectivity of more than 20:1.

[0091] (4) Preparation of compounds (S)-19-21

[0092]

[0093] In a 10 mL vial with magnetic stirring bar, 19.6 mg of sodium p-toluenesulfinate 1b and 22 mg of 2-methyl-6-nitrobenzoyl chloride were added, 1.5 mL of chloroform was added as solvent, and the mixture was stirred at room temperature for 2 hours, which was monitored by TLC until the reaction was completed, followed by the sequential addition of 6.4 mg of quinine E, 14.2 mg of N,N-diisopropylethylamine and 16.5 mg of benzocaine or 23.6 mg of procaine or 26.4 mg of tetracaine, and the mixture was stirred at room temperature for 3 hours, followed by the addition of saturated sodium bicarbonate to quench the reaction, dichloromethane extraction, drying over anhydrous sodium sulfate, and concentration under reduced pressure to give a crude product, which was separated by column chromatography with eluent polarity of petroleum ether: ethyl acetate = 3:1 to give the target compounds (S)-19, (S)-20 and (S)-21 in 90%, 71% and 57% yields, respectively, and a corresponding selectivity of 94:6, 93:7 and 90:10, respectively.

[0094] The experimental characterization of the synthesized compounds is as follows:

[0095]

[0096] Substituent R 1 is tolyl, R 2 is H, the preparation is carried out according to the procedure and conditions of Example 1.

[0097] Pale yellow solid, 11.0 mg, 71% yield, melting point: 115.4-116.3 °C.

[0098] 1 H NMR (400 MHz, CDC13) δ 7.69 - 7.51 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.52 (s, 2H), 2.41 (s, 3H).

[0099] 13 C NMR (100 MHz, CDC13) δ 143.5, 141.5, 129.7, 125.5, 21.4 ppm.

[0100] HRMS (ESI, m / z): calculated for C7H9NOSNa + [M+Na] + : 178.0297, found: 207.0450.

[0101] [α] 25 D = +67.2 (c = 0.6 in CHCI3).

[0102] HPLC analysis: 98:2 e.r. (Chiralcel IA, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 6.0 min, Rt(minor) = 6.8 min.

[0103]

[0104] Substituent R 1 is phenyl, R 2 is H, the preparation methods and conditions are the same as Example 1;

[0105] Yellow solid, 8.8 mg, 62% yield, melting point: 109.8-110.7 °C;

[0106] 1 H NMR (400 MHz, CDC13) δ 7.82 - 7.62 (m, 2H), 7.53 - 7.42 (m, 3H), 4.62 (s, 2H).

[0107] 13 C NMR (100 MHz, CDC13) δ 146.5, 131.1, 129.0, 125.6 ppm.

[0108] HRMS (ESI, m / z): calculated for C6H7NOS Na + [M+Na] + : 164.0141, found: 164.0143.

[0109] [α] 25 D = +27.2 (c = 0.3 in CHCI3).

[0110] HPLC analysis: 94:6 e.r. (Chiralcel OD-H, 5:95 i-PrOH / n-Hexane, 0.8 mL / min), Rt(major) = 31.7 min, Rt(minor) = 34.1 min.

[0111]

[0112] Substituent R 1 is ethylphenyl, R 2 is H, prepared according to the procedure and conditions of Example 1;

[0113] Yellow solid, 11.3 mg, 67% yield, m.p. 118.4-118.9 °C.

[0114] 1 H NMR (400 MHz, CDCI3+ CD3OD) δ 7.58 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).

[0115] 13 C NMR (100 MHz, CDCI3) δ 147.9, 142.9, 128.5, 125.5, 28.7, 15.4 ppm.

[0116] HRMS (ESI, m / z): calculated for C8H 11 NOSNa + [M + Na] + : 192.0454, found: 192.0452.

[0117] [α] 25 D = -66.7 (c = 0.4 in CHCI3).

[0118] HPLC analysis: 98:2 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.3 min, Rt(major) = 6.9 min.

[0119]

[0120] Substituent R 1 is biphenyl, R 2 is H, prepared according to the procedures and conditions of Example 1;

[0121] Yellow solid powder, 13.5 mg, 62% yield, m.p.: 142.3-144.6 °C;

[0122] 1 H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.64-7.57 (m, 2H), 7.51-7.44 (m, 2H), 7.43-7.37 (m, 1H), 4.33 (s, 2H).

[0123] 13 C NMR (100 MHz, CD3OD) δ 148.4, 142.9, 138.6, 129.4, 129.3, 128.3, 127.7, 127.6 ppm.

[0124] HRMS (ESI, m / z): Calcd for C 11 H 12 O3Na + [M+Na] + : 207.0450, found: 207.0450.

[0125] [α] 25 D = -19.5 (c = 0.2 in CHCI3).

[0126] HPLC analysis: 97:3 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 8.5 min, Rt(major) = 13.7 min.

[0127]

[0128] Substituent R 1 is 4-methoxyphenyl, R 2 is H, prepared according to the procedures and conditions of Example 1;

[0129] Yellow solid powder, 11.8 mg, 69% yield, m.p.: 135.7-136.6 °C;

[0130] 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.14 (s, 2H), 3.80 (s, 3H).

[0131] 13 C NMR (100 MHz, DMSO-d6) δ 161.3, 140.0, 127.4, 114.4, 55.8 ppm.

[0132] HRMS (ESI, m / z): calculated for C7H9NO2SNa + [M+Na] + : 194.0246, found: 194.0246.

[0133] [α] 25 D = -47.2 (c = 0.4 in CHCI3).

[0134] HPLC analysis: 98:2 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 9.3 min, Rt(major) = 10.7 min.

[0135]

[0136] Substituent R 1 is 4-fluorophenyl, R 2 is H, prepared according to the procedure of Example 1 and stirred for 32 hours;

[0137] Yellow solid powder, 11.8 mg, 74% yield, melting point: 121.6-122.3 °C;

[0138] 1 H NMR (400 MHz, CDCI3+ DMSO-d6) δ 7.74 (m, 2H), 7.30-7.09 (m, 2H), 5.89 (d, J = 19.8 Hz, 2H).

[0139] 13 C NMR (100 MHz, CDCI3+ DMSO-d6) δ 163.9 (d, J = 249.0 Hz), 143.9 (d, J = 3.1 Hz), 128.2 (d, J = 8.8 Hz), 115.7 (d, J = 22.2 Hz) ppm.

[0140] 19F NMR (377 MHz, CDCI3+ DMSO-d6) δ -110.78 ppm.

[0141] HRMS (ESI, m / z): calculated for C6H6FNOSNa + [M+Na] + : 182.0046, found: 182.0046.

[0142] [α] 25 D = -27.3 (c = 0.3 in CHCI3).

[0143] HPLC analysis: 97:3 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.3 min, Rt(major) = 7.0 min.

[0144]

[0145] Substituent R 1 is 4-chlorophenyl, R 2 is H, prepared according to the procedure of Example 1 and stirred for 32 hours;

[0146] Yellow solid powder, 10.9 mg, 62% yield, melting point: 124.4-125.3 °C;

[0147] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.56 (m, 2H), 7.55 - 7.49 (m, 2H), 6.29 (s, 2H).

[0148] 13 C NMR (100 MHz, DMSO-d6) δ 147.1, 135.1, 128.7, 127.4 ppm.

[0149] HRMS (ESI, m / z): calculated for C6H6ClNOSNa + [M+Na] + : 197.9751, found: 197.9750.

[0150] [α] 25 D = -29.4 (c = 0.3 in CHCI3).

[0151] HPLC analysis: 95:5 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.4 min, Rt(major) = 7.7 min.

[0152]

[0153] Substituent R 1 was 4-bromophenyl, R 2 was H, prepared according to the procedures and conditions described in Example 1;

[0154] Yellow solid powder, 20.8 mg, 78% yield, m.p.: 139.4-139.9 °C;

[0155] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.25 (s, 2H).

[0156] 13 C NMR (100 MHz, DMSO-d6) δ 147.5, 131.5, 127.6, 123.9 ppm.

[0157] HRMS (ESI, m / z): calculated for C6H6BrNOSNa + [M+Na] + : 241.9246, found: 241.9244.

[0158] [α] 25 D = -31.0 (c = 0.2 in CHCI3).

[0159] HPLC analysis: 95:5 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.4 min, Rt(major) = 7.7 min.

[0160]

[0161] Substituent R 1 was 4-iodophenyl, R 2 was H, prepared according to the procedures and conditions described in Example 1;

[0162] Yellow solid powder, 20.8 mg, 78% yield, m.p.: 139.4-139.9 °C;

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 6.33 (s, 1 H).

[0164] 13 C NMR (100 MHz, DMSO-d6) δ 144.3, 136.0, 125.2, 96.1 ppm.

[0165] HRMS (ESI, m / z): calculated for C6H6INOSNa + [M+Na] + : 289.9107, found: 289.9108.

[0166] [α] 25 D = -7.8 (c = 0.2 in CHCI3).

[0167] HPLC analysis: 95:5 e.r. (Chiralcel IB, 20:80 i PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 7.8 min, Rt(major) = 10.5 min.

[0168]

[0169] Substituent R 1 is 4-nitrophenyl, R 2 is H, prepared according to the procedures and conditions of Example 1;

[0170] Yellow solid powder, 8.9 mg, 48% yield, m.p.: 142.7-143.8 °C;

[0171] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 8.8 Hz, 2 H), 6.53 (s, 2 H).

[0172] 13 C NMR (100 MHz, DMSO-d6) δ 154.9, 148.6, 127.0, 123.7 ppm.

[0173] HRMS (ESI, m / z): calculated for C6H6N2O3SNa + [M+Na]+ : 208.9991, found: 208.9999.

[0174] [α] 25 D = -19.5 (c = 0.2 in CHCI3).

[0175] HPLC analysis: 95:5 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 12.5 min, Rt(major) = 18.5 min.

[0176]

[0177] Substituent R 1 is 2-methoxyphenyl, R 2 is H, prepared according to the procedure of Example 1;

[0178] Yellow solid powder, 9.9 mg, 58% yield, m.p.: 127.4-129.3 °C;

[0179] 1 H NMR (400 MHz, CDCI3) δ 8.12-7.90 (m, 1H), 7.56-7.38 (m, 3H), 4.33 (s, 2H), 3.84 (s, 3H).

[0180] 13 C NMR (100 MHz, CDCI3) δ 157.5, 137.4, 131.9, 129.9, 120.4, 113.4, 56.7 ppm.

[0181] HRMS (ESI, m / z): calculated for C7H9NO2SNa + [M+Na] + : 194.0246, found: 194.0248.

[0182] [α] 25 D = -25.0 (c = 0.3 in CHCI3).

[0183] HPLC analysis: 98:2 e.r. (Chiralcel IB, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 9.3 min, Rt(major) = 10.7 min.

[0184]

[0185] Substituent R 1 is 2-methoxyphenyl, R 2 is H, prepared according to the procedures and conditions of Example 1;

[0186] Yellow solid powder, 12.6 mg, 66% yield, m.p.: 126.5-128.3 °C;

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 8.11-7.91 (m, 1H), 7.67-7.35 (m, 3H), 4.33 (s, 1H).

[0188] 13 C NMR (100 MHz, DMSO-d6) δ 145.9, 134.0, 132.7, 129.0, 128.9, 128.2, 127.9, 127.4, 125.4, 122.8 ppm.

[0189] HRMS (ESI, m / z): Calcd for C6H6ClNOSNa + [M+Na] + : 197.9751, found: 197.9750.

[0190] [α] 25 D = -41.2 (c = 0.3 in CHCI3).

[0191] HPLC analysis: 99:1 e.r. (Chiralcel OD-H, 15:85 i-PrOH / n-Hexane, 1 mL / min), Rt(major) = 14.1 min, Rt(minor) = 18.6 min.

[0192]

[0193] Substituent R 1 is 2,4,6-trimethylphenyl, R 2 is H, prepared according to the procedures and conditions of Example 1;

[0194] Yellow solid powder, 9.2 mg, 50% yield, m.p.: 116.4-117.2 °C;

[0195] 1H NMR (400 MHz, DMSO-d6) δ 6.81 (s, 2H), 5.99 (s, 2H), 2.44 (s, 6H), 2.17 (s, 3H).

[0196] 13 C NMR (100 MHz, DMSO-d6) δ 140.1, 139.0, 135.4, 130.1, 20.4, 18.8 ppm.

[0197] HRMS (ESI, m / z): calculated for C9H 13 NOSNa + [M+Na] + : 206.0610, found: 206.0610.

[0198] [α] 25 D = -37.3 (c = 0.3 in CHCI3).

[0199] HPLC analysis: 93:7 e.r. (Chiralcel IA, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 14.5 min, Rt(minor) = 15.8 min.

[0200]

[0201] Substituent R 1 is tert-butyl, R 2 is H, prepared according to the procedure and conditions of Example 1;

[0202] Yellow solid powder, 5.7 mg, 47% yield, melting point: 97.1-99.3 °C;

[0203] 1 H NMR (400 MHz, DMSO-d6) δ 5.21 (s, 2H), 1.00 (s, 9H).

[0204] 13 C NMR (100 MHz, DMSO-d6) δ 54.4, 22.7 ppm.

[0205] HRMS (ESI, m / z): calculated for C4H 11 NOSNa + [M+Na] + : 144.0454, found: 144.0456.

[0206] [α]25 D = -26.7 (c = 0.3 in CHCI3).

[0207] HPLC analysis: 94:6 e.r. (Chiralcel OJ-H, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.9 min, Rt(major) = 10.9 min.

[0208]

[0209] Substituent R 1 is 4-methylphenyl, R 2 is phenyl, prepared according to the procedure of Example 2 for 3 hours;

[0210] White solid, 17.1 mg, 74% yield, m.p. 110.4-111.3 °C;

[0211] 1 H NMR (400 MHz, CDCI3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.36-7.18 (m, 4H), 7.10-6.94 (m, 3H), 6.39 (s, 1H), 2.40 (s, 3H).

[0212] 13 C NMR (100 MHz, CDCI3) δ 142.0, 141.7, 140.8, 129.9, 129.6, 125.6, 123.7, 119.0, 21.5. ppm.

[0213] HRMS (ESI, m / z): calculated for C 13 H 13 NOSNa + [M + Na] + : m / z = 254.0610,

[0214] found: m / z = 254.0611.

[0215] [α] 25 D = -26.7 (c = 0.3 in CHCI3).

[0216] HPLC analysis: 94:6 e.r. (Chiralcel OJ-H, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 6.9 min, Rt(major) = 10.9 min.

[0217]

[0218] Substituent R 1 was 4-methylphenyl, R 2 was 4-methylphenyl, prepared according to the procedure of Example 2 for 3 hours;

[0219] White solid, 17.2 mg, 70% yield, m.p. 124.9-126.3 °C;

[0220] 1 H NMR (400 MHz, CDC13) δ 7.63 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.26 (s, 1H), 2.41 (s, 4H), 2.29 (s, 4H).

[0221] 13 C NMR (100 MHz, CDC13) δ 141.8, 141.8, 138.1, 133.4, 130.0, 129.8, 125.6, 119.7, 21.5, 20.8 ppm.

[0222] HRMS (ESI, m / z): calculated for C 14 H 15 NOSNa + [M + Na] + : m / z = 268.0767,

[0223] found: m / z = 268.0768.

[0224] [α] 25 D = -36.7 (c = 0.7 in CHCI3).

[0225] HPLC analysis: 95:5 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 11.6 min, Rt(minor) = 15.1 min.

[0226]

[0227] Substituent R 1 was 4-methylphenyl, R 2 was 4-isopropylphenyl, prepared according to the procedure of Example 2 for 3 hours;

[0228] White solid, 18.6 mg, 68% yield, m.p.: 130.9-132.3 °C;

[0229] 1 H NMR (400 MHz, CDC13) δ 7.64 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 1H), 6.31 (s, 1H), 2.95 - 2.77 (m, 1H), 2.42 (s, 3H), 1.22 (d, J = 7.0 Hz, 6H).

[0230] 13 C NMR (100 MHz, CDC13) δ 144.4, 141.8 (d, J = 2.2 Hz), 138.4, 129.8, 127.4, 125.6, 119.5, 33.6, 24.1, 21.5 ppm.

[0231] HRMS (ESI, m / z): calculated for C 16 H 19 ONSNa + [M+Na] + : 296.1080, found: 296.1082.

[0232] [α] 25 D = -41.8 (c = 0.5 in CHCI3).

[0233] HPLC analysis: 96:4 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 9.8

[0234] min, Rt(minor) = 14.5 min.

[0235]

[0236] Substituent R 1 is 4-methylphenyl, R 2 is 4-fluorophenyl, prepared according to the procedure of Example 2 for 2 hours;

[0237] White solid, 18.0 mg, 72% yield, m.p.: 137.4-138.3 °C;

[0238] 1H NMR (400 MHz, CDC13) δ 7.62 (d, J = 8.3 Hz, 2H), 7.34 - 7.26 (m, 2H), 7.07 - 7.01 (m, 2H), 6.99 - 6.91 (m, 2H), 6.27 (s, 1H), 2.42 (s, 3H).

[0239] 13 C NMR (100 MHz, CDC13) δ 159.7 (d, J = 242.8 Hz), 142.1, 141.3, 136.4 (d, J = 2.4 Hz), 129.9, 125.7, 121.9 (d, J = 8.0 Hz), 116.2 (d, J = 22.6 Hz), 21.5 ppm.

[0240] 19 F NMR (376 MHz, CDC13) δ -118.9 ppm.

[0241] HRMS (ESI, m / z): Calcd for C 13 H 12 FNOSNa + [M+Na] + : 272.0516, found: 272.0515.

[0242] [α] 25 D = -23.4 (c = 0.5 in CHCI3).

[0243] HPLC analysis: 95:5 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 10.1 min, Rt(minor) = 14.7 min.

[0244]

[0245] Substituent R 1 is 4-methylphenyl, R 2 is 4-chlorophenyl, prepared according to the procedure of Example 2 for 3 hours;

[0246] White solid, 22.3 mg, 84% yield, m.p.: 131.9-132.7 °C;

[0247] 1H NMR (400 MHz, CDC13) δ 7.59 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 2.41 (s, 3H).

[0248] 13 C NMR (100 MHz, CDC13) δ 142.1, 141.1, 139.4, 129.9, 129.5, 128.8, 125.6, 120.4, 21.5 ppm.

[0249] HRMS (ESI, m / z): calculated for C 13 H 12 ClNOSNa + [M+Na] + : 288.0226, found: 288.0220.

[0250] [α] 25 D = -13.0 (c = 0.2 in CHCI3).

[0251] HPLC analysis: 94:6 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 10.8 min, Rt(minor) = 15.1 min.

[0252]

[0253] Substituent R 1 is 4-methylphenyl, R 2 is 4-bromophenyl, prepared according to the procedure of Example 2 for 2 hours;

[0254] White solid, 24.5 mg, 79% yield, m.p.: 142.3-143.4 °C;

[0255] 1 H NMR (400 MHz, CDC13) δ 7.65 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 18.8, 8.4 Hz, 4H), 6.97 (d, J = 8.7 Hz, 2H), 6.04 (s, 1H), 2.43 (s, 3H).

[0256] 13C NMR (100 MHz, CDC13) δ 142.4, 141.3, 139.8, 132.6, 130.1, 125.5, 120.8, 116.5, 21.6 ppm.

[0257] HRMS (ESI, m / z): calculated for C 13 H 12 BrNOSNa + [M+Na] + : 331.9715, found: 331.9717.

[0258] [α] 25 D = -18.0 (c = 0.3 in CHCI3).

[0259] HPLC analysis: 95:5 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 9.9 min, Rt(minor) = 14.1 min.

[0260]

[0261] Substituent R 1 is 4-methylphenyl, R 2 is 4-trifluoromethylphenyl, prepared according to the procedure of Example 2 for 2 hours;

[0262] White solid, 20.4 mg, 68% yield, m.p.: 142.8-144.4 °C;

[0263] 1 H NMR (400 MHz, CDC13) 7.65 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.52 (s, 1H), 2.44 (s, 3H).

[0264] 13 C NMR (100 MHz, CDC13) δ 144.2, 142.6, 141.0, 130.2, 127.0 (d, J = 4.1 Hz), 125.5, 117.7, 21.6 ppm.

[0265] 19 F NMR (376 MHz, CDC13) δ -62.00 ppm.

[0266] HRMS (ESI, m / z): Calcd for C 14 H 12 F3NOSNa + [M+Na] + :322.0484, found: 322.0484.

[0267] [α] 25 D = -11.1 (c = 0.5 in CHCI3).

[0268] HPLC analysis: 94:6 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 8.2 min, Rt(minor) = 13.2 min.

[0269]

[0270] Substituent R 1 is 4-methylphenyl, R 2 is 2-tolyl, prepared according to the procedure of Example 2 for 3 hours;

[0271] White solid, 18.9 mg, 77% yield, m.p.: 101.4-103.5 °C;

[0272] 1 H NMR (400 MHz, CDCI3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.41-7.33 (m, 3H), 7.18 (ddd, J = 8.7, 7.1, 1.5 Hz, 2H), 7.02 (td, J = 7.4, 1.3 Hz, 1H), 5.88 (s, 1H), 2.44 (s, 3H), 2.24 (s, 3H).

[0273] 13 C NMR (100 MHz, CDCI3) δ 142.1, 142.0, 139.1, 131.0, 129.9, 128.5, 127.2, 125.6, 124.3, 120.1, 21.5, 18.0 ppm.

[0274] HRMS (ESI, m / z): Calcd for C 14 H 15 NOSNa + [M+Na] + :268.0767, found: 268.0768.

[0275] [α] 25 D = -7.2 (c = 0.7 in CHCI3).

[0276] HPLC analysis: 96:4 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 9.8 min, Rt(minor) = 13.1 min.

[0277]

[0278] Substituent R 1 is 4-methylphenyl, R 2 is 2-chlorophenyl, prepared according to the procedure of Example 2 for 2 hours;

[0279] White solid, 23.4 mg, 88% yield, m.p.: 174.2-176.4 °C;

[0280] 1 H NMR (400 MHz, CDCI3) 7.69 (d, J = 8.3 Hz, 1 H), 7.48 (dd, J = 8.1, 1.5 Hz, 1 H), 7.39-7.29 (m, 3H), 7.23-7.16 (m, 1 H), 7.00-6.92 (m, 1 H), 6.63 (s, 1 H), 2.42 (s, 3H).

[0281] 13 C NMR (100 MHz, Acetone-d6) δ 144.2, 137.7, 134.4, 130.0, 129.9, 128.1, 127.5, 127.3, 126.9, 125.2, 20.9 ppm.

[0282] HRMS (ESI, m / z): calculated for C 13 H 12 ClNOSNa + [M+Na] + : 288.0220, found: 288.0222.

[0283] [α] 25 D = -7.0 (c = 0.6 in CHCI3).

[0284] HPLC analysis: 99:1 e.r. (Chiralcel OD-H, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 4.9 min, Rt(minor) = 5.6 min.

[0285]

[0286] Substituent R 1 was 4-methylphenyl, R 2 was 3-methylphenyl, prepared according to the procedure of Example 2 for 3 hours;

[0287] White solid, 19.6 mg, 80% yield, m.p.: 154.2-155.3 °C;

[0288] 1 H NMR (400 MHz, CDC13) δ 7.65 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.87 (t, 2H), 6.18 (s, 1H), 2.43 (s, 3H), 2.30 (s, 3H).

[0289] 13 C NMR (100 MHz, CDC13) δ 142.0, 141.8, 140.8, 139.6, 129.9, 129.4, 125.6, 124.5, 119.5, 116.0, 21.5 ppm.

[0290] HRMS (ESI, m / z): calculated for C 14 H 15 NOSNa + [M+Na] + : 268.0767, found: 268.0727.

[0291] [α] 25 D = -21.4 (c = 0.6 in CHCI3).

[0292] HPLC analysis: 96:4 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 12.5 min, Rt(minor) = 16.6 min.

[0293]

[0294] Substituent R 1 was 4-methylphenyl, R 2 was 2-naphthalene, reaction time and conditions as in example 2 for 3 hours;

[0295] White solid, 25.9 mg, 92% yield, m.p. 125.4-125.9 °C.

[0296] 1 H NMR (400 MHz, CDC13) δ 7.79 - 7.64 (m, 5H), 7.51 (d, J = 2.3 Hz, 1H), 7.42 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.36 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.27 - 7.21 (m, 1H), 6.51 (s, 1H), 2.43 (s, 3H).

[0297] 13 C NMR (100 MHz, Acetone-d6) δ 142.3, 141.4, 139.8, 134.3, 130.0, 129.6, 129.1, 127.6, 126.8, 126.5, 125.6, 124.2, 119.5, 113.5, 20.4 ppm.

[0298] HRMS (ESI, m / z): calculated for C 17 H 15 NOSNa + [M+Na] + : 304.0767, found: 304.0768.

[0299] [α] 25 D = -9.4 (c = 0.4 in CHCI3).

[0300] HPLC analysis: 95:5 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 16.1 min, Rt(minor) = 22.7 min.

[0301]

[0302] Substituent R 1 was 4-methylphenyl, R 2 was 2-fluoro-4-trifluoromethylphenyl, reaction time and conditions as in example 2 for 2 hours;

[0303] White solid, 24.1 mg, 76% yield, m.p. 87.3-87.7 °C.

[0304] 1 H NMR (400 MHz, CDC13) δ 7.55 (d, J = 8.352 Hz, 2H), 7.34 - 7.18 (m, 4H), 7.03 (dd, J = 17.104, 7.958 Hz, 2H), 2.42 (s, 3H).

[0305] 13 C NMR (100 MHz, CDC13) δ 157.3 (d, J = 256.5 Hz), 144.8, 135.4, 132.9 (d, J = 3.1 Hz), 130.1, 127.5 (d, J = 8.5 Hz), 127.4, 123.4, 120.9 (d, J = 4.4 Hz), 119.3 (d, J = 13.4 Hz), 119.0 (d, J = 13.7 Hz), 118.2, 117.9, 21.7 ppm.

[0306] 19 F NMR (376 MHz, CDC13) δ -61.60, -61.64. ppm.

[0307] HRMS (ESI, m / z): calculated for C 14 H 11 F4NOSNa + [M+Na] + : 340.0390, found: 340.0390.

[0308] [α] 25 D = -13.9 (c = 0.9 in CHCI3).

[0309] HPLC analysis: 91 : 9 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 6.8 min, Rt(minor) = 8.9 min.

[0310]

[0311] Substituent R 1 is 4-methylphenyl, R 2 is 2,4-dimethylphenyl, prepared according to the procedure of Example 2 for 3 hours;

[0312] White solid, 20.0 mg, 77% yield, m.p.: 143.3-143.6 °C.

[0313] 1 H NMR (400 MHz, CDC13) δ 7.69 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 1.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 7.7, 1.7 Hz, 1H), 5.95 (s, 1H), 2.43 (s, 3H), 2.30 (s, 3H), 2.19 (s, 3H).

[0314] 13 C NMR (100 MHz, CDC13) δ 142.2, 141.9, 139.0, 137.0, 130.8, 129.9, 125.5, 125.3, 125.0, 120.6 (d, J = 2.1 Hz), 21.5, 21.1, 17.5 ppm.

[0315] HRMS (ESI, m / z): Calcd. for C 15 H 17 NOSNa + [M+Na] + : 282.0923, found: 282.0924.

[0316] [α] 25 D = -6.6 (c = 0.6 in CHCI3).

[0317] HPLC analysis: 95:5 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 8.2 min, Rt(minor) = 14.2 min.

[0318]

[0319] Substituent R 1 is 4-methylphenyl, R 2 is 2-chloro-4-methylphenyl, prepared according to the procedure of Example 2 for 2 hours;

[0320] White solid, 25.5 mg, 91% yield, m.p.: 98.0-100.0 °C.

[0321] 1H NMR (400 MHz, CDC13) δ 7.62 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 9.2 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.71 (dd, J = 8.3, 2.0 Hz, 1H), 6.49 (s, 1H), 2.36 (s, 3H), 2.24 (s, 3H).

[0322] 13 C NMR (100 MHz, CDC13) δ 144.2, 138.2, 136.1, 133.2, 129.7, 129.0, 127.4, 126.9, 123.2, 122.3, 21.6, 21.2 ppm.

[0323] HRMS (ESI, m / z): Calcd for C 14 H 14 ClNOSNa + [M+Na] + : 302.03776, found: 302.0376.

[0324] [α] 25 D = -15.9 (c = 0.5 in CHCI3).

[0325] HPLC analysis: 98:2 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 8.6 min, Rt(minor) = 16.6 min.

[0326]

[0327] Substituent R 1 is 4-methylphenyl, R 2 is 2,4,6-trimethylphenyl, prepared according to the procedure of Example 2 for 3 hours;

[0328] White solid, 21.1 mg, 77% yield, m.p.: 122.8-123.8 °C.

[0329] 1 H NMR (400 MHz, CDC13) 7.80 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.7 Hz, 1H), 6.91 (s, 2H), 5.52 (s, 1H), 2.45 (s, 3H), 2.39 (s, 6H), 2.28 (s, 3H).

[0330] 13 C NMR (100 MHz, CDC13) δ 143.4, 141.9, 135.9, 134.4, 133.9, 129.8, 129.6, 125.4, 21.5, 20.9, 19.2 ppm.

[0331] HRMS (ESI, m / z): calculated for C 16 H 19 NOSNa + [M+Na] + : 296.1080, found: 296.1080.

[0332] [α] 25 D = -8.5 (c = 0.7 in CHCI3).

[0333] HPLC analysis: 94:6 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 7.6 min, Rt(minor) = 10.1 min.

[0334]

[0335] Substituent R 1 is 4-methylphenyl, R 2 is tert-butyl, prepared according to the procedure of Example 2 reacting at -40 °C;

[0336] White solid, 11.4 mg, 54% yield, m.p. 85.0-85.5 °C.

[0337] 1 H NMR (400 MHz, CDC13) δ 7.56 (d, J = 8.3 Hz, 2H), 7.35-7.20 (m, 2H), 3.84 (s, 1H), 2.40 (s, 3H), 1.40 (s, 9H).

[0338] 13 C NMR (100 MHz, CDC13) δ 143.6, 140.9, 129.4, 125.6, 54.2, 31.1, 21.3 ppm.

[0339] HRMS (ESI, m / z): calculated for C 11 H 17 NOSNa + [M+Na] +234.0923, found: 234.0924.

[0340] [α] 25 D = -16.4 (c = 0.75 in CHCI3).

[0341] HPLC analysis: 97:3 e.r. (Chiralcel OD-H, 20:80 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 3.7 min, Rt(minor) = 4.1 min.

[0342]

[0343] Substituent R 1 is 4-methylphenyl, R 2 is trityl, prepared according to the procedure of Example 2 for 2 hours;

[0344] White solid, 36.2 mg, 91% yield, m.p. 155.5-156.4 °C.

[0345] 1 H NMR (400 MHz, CDCI3) δ 7.57 (d, J = 6.6 Hz, 2H), 7.44-7.24 (m, 17H), 5.19 (s, 3H).

[0346] 13 C NMR (100 MHz, CDCI3) δ 144.8, 144.3, 141.3, 129.8, 129.7, 128.1, 127.6, 125.7, 73.6, 21.4 ppm.

[0347] HRMS (ESI, m / z): calculated for C 26 H 23 NOSNa + [M + Na] + : 420.1393, found: 420.1386.

[0348] [α] 25 D = -24.9 (c = 0.5 in CHCI3).

[0349] HPLC analysis: 99:1 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 4.2 min, Rt(major) = 4.7 min.

[0350]

[0351] Substituent R 1 was 4-methylphenyl, R 2 was 1S,3S,5S,7S-adamantan-2-yl, prepared according to the procedure of Example 2, the acyl chloride was 3d, and the reaction was allowed to proceed for 3 hours;

[0352] White solid, 21.7 mg, 75% yield, m.p. 123.4-123.9 °C.

[0353] 1 H NMR (400 MHz, CDC13) δ 7.57 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 3.82 (s, 1H), 2.39 (s, 3H), 2.13 (q, J = 3.2 Hz, 3H), 2.03-1.95 (m, 3H), 1.93-1.85 (m, 3H), 1.73-1.64 (m, 6H).

[0354] 13 C NMR (100 MHz, CDC13) δ 143.8, 141.0, 129.5, 125.8, 54.5, 44.8, 36.2, 29.8, 21.4 ppm.

[0355] HRMS (ESI, m / z): calculated for C 17 H 23 NOSNa + [M+Na] + : 312.1393, found: 312.1394.

[0356] [α] 25 D = -14.3 (c = 0.4 in CHCI3).

[0357] HPLC analysis: 90:10 e.r. (Chiralcel OD-H, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(major) = 5.1 min, Rt(minor) = 5.6 min.

[0358]

[0359] Substituent R 1 was 4-methylphenyl, R 2 was N-benzhydryl, prepared according to the procedure of Example 2, the reaction was allowed to proceed for 3 hours;

[0360] White solid, 19.5 mg, 61% yield, m.p.: 127.3-127.9 °C.

[0361] 1 H NMR (400 MHz, CDC13) 7.70 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.55-7.34 (m, 6H), 7.28 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H).

[0362] 13 C NMR (100 MHz, CDC13) 176.2, 143.9, 142.4, 129.9, 128.4, 125.5, 21.6 ppm.

[0363] HRMS (ESI, m / z): calculated for C 20 H 17 NOSNa + [M+Na] + : 342.0923, found: 2342.0923.

[0364] [α] 25 D = -14.2 (c = 0.65 in CHCI3).

[0365] HPLC analysis: 97:3 e.r. (Chiralcel IA, 10:90 i-PrOH / n-Hexane, 1.0 mL / min), Rt(minor) = 25.1 min, Rt(major) = 29.7 min.

[0366] Although the above examples make a detailed description of the present application, it is only a part of the embodiments of the present application, not all the embodiments, and people can also obtain other embodiments according to the present embodiments without creativity, which all belong to the protection scope of the present application.

Claims

1. A method for preparing a chiral sulfinamide compound, characterized in that, Includes the following steps: 1) Sulfonyl chloride is mixed with sodium sulfite, sodium bicarbonate and water and then heated to obtain a heat-treated product; water is removed from the heat-treated product to obtain a solid, and the solid is extracted with ethanol and filtered to obtain a filtrate; The filtrate was concentrated under vacuum to obtain a solid. The solid was washed with ether and filtered. The obtained solid was dried under vacuum to obtain sodium benzenesulfonate. R is tolyl, phenyl, ethylphenyl, biphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, tert-butyl, 4-methylphenyl or 4-methylphenyl; 2) Dissolve the sodium benzenesulfinate obtained in step 1) with 2-chloro-6-nitrobenzoyl chloride or 2-bromo-6-nitrobenzoyl chloride or 2-methyl-6-nitrobenzoyl chloride 2(ethoxycarbonyl)-6-nitrobenzoyl chloride in chloroform and stir to obtain a mixed acid anhydride; 3) The mixed anhydride obtained in step 2) is mixed with quinine or quinidine, N,N-diisopropylethylamine, and an amine and stirred to obtain a chiral sulfinamide compound; the amine is hexamethyldisilazine or an aromatic amine; When the amine is hexamethyldisilazine, the chiral sulfinamide compound is 8a-8n; When the amine is an aromatic amine, the chiral sulfinamide compound is 80-9g; 2. The preparation method according to claim 1, characterized in that, In step 1), the volume ratio of the equivalent of sulfonyl chloride to the equivalent of sodium sulfite, the equivalent of sodium bicarbonate, and water is 1:2:2:10 ml. The conditions for the heat treatment include: a temperature of 80°C and a time of 4–6 hours; The vacuum drying time is 4 hours.

3. The preparation method according to claim 1, characterized in that, In step 2), the molar ratio of sodium benzenesulfinate to the molar ratio of 2-chloro-6-nitrobenzoyl chloride and the volume ratio of chloroform is 0.11 mmol:0.1 mmol:1 ml. The stirring conditions include: a temperature of 0°C and a time of 1 to 2 hours.

4. The preparation method according to claim 1, characterized in that, In step 3), the molar ratio of the mixed anhydride to quinine and N,N-diisopropylethylamine, and the molar ratio of the amine, is 0.1 mmol:0.02 mmol:0.13 mmol:0.14 mmol. The stirring conditions include a temperature of -10 to 0°C and a time of 36 to 48 hours.

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