CN114989058B - Preparation method of chiral chlorosulfonyl imine compound and derivative thereof - Google Patents

Preparation method of chiral chlorosulfonyl imine compound and derivative thereof Download PDF

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CN114989058B
CN114989058B CN202210624958.2A CN202210624958A CN114989058B CN 114989058 B CN114989058 B CN 114989058B CN 202210624958 A CN202210624958 A CN 202210624958A CN 114989058 B CN114989058 B CN 114989058B
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CN114989058A (en
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李光勋
唐卓
杨高峰
张施琪
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Chengdu Institute of Biology of CAS
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    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a preparation method of chiral chlorosulfonyl imine compounds and derivatives thereof, which is characterized in that under the catalysis of chiral phosphoric acid, the compounds in the formula (I) react with different types of chloro reagents (II) to obtain chiral chlorosulfonyl imine compounds in the formula (III). The chiral chlorosulfonyl imine (III) is used as a substrate for reaction, and reacts with different amine reagents, different sodium alkoxide reagents and different Grignard reagents respectively to prepare chiral sulfone imine amide (IV or V), chiral sulfone imine ester (VI) and chiral sulfone imine (VII) compounds. The chiral sulfone imine amide (IV or V), the chiral sulfone imine ester (VI) and the chiral sulfone imine (VII) which are derivatives of the chiral chloro sulfone imine have higher stability, good physicochemical properties, structural diversity and higher biological activity. Therefore, the invention lays a foundation for the development of related sulfur-containing medicaments, and has economical practicability and industrial application prospect.

Description

Preparation method of chiral chlorosulfonyl imine compound and derivative thereof
Technical Field
The invention belongs to the technical field of preparation methods of chiral hexavalent sulfur derivatives in the organic synthesis direction, and particularly relates to a preparation method of chiral chlorosulfonyl imine, chiral sulfonimide amide, chiral sulfonimide ester and chiral sulfonimide compounds.
Background
Since the first report of sulfonimide based materials in 1949 (Nature 1949,163,675), the hexavalent sulfur organic molecules of sulfonimide, sulfonimide amide and the like have been attracting attention from chemists. Sulfonimide compounds and sulfones are a pair of isosteres, and when the two carbon substituents on sulfur are not exactly the same, the introduction of a nitrogen atom imparts tetrahedral asymmetry to the sulfur atom (org.chem. Front.2019,6,1319). In comparison with sulfones, sulfonimide has special properties: first of all it has a moderate basicity, "free sulfonimide" (R 3 =h) can be phosphorylated in vivo; at the same time, the nitrogen atom is sufficiently basic to coordinate with the metal ion and form a salt with the mineral acid (J.Am. Chem. Soc.1989,111, 4467). Second, sulfonimide compounds can be used as hydrogen bond acceptors (R 3 Not equal to H) and hydrogen bond donors (R 3 =h) has a dual function. Nuclear magnetic resonance spectrum research shows that the sulfone imine group has stronger electron withdrawing capability than the sulfone group. In addition, there is a clear distinction between sulfonimide and the corresponding sulfones that sulfonimides are more soluble in protic solvents such as water and alcohols. Because of the unique nature of sulfonimide, numerous pharmaceutical chemists are attracted to constantly explore their use.
The sulfonimide structure has wide application, including application as a chiral auxiliary (Angew.Chem., int.Ed.2014,53,775); as asymmetrically catalyzed ligands (Angew.Chem., int.Ed.2004,43,5984), as C-H activated directing groups (Angew.Chem., int.Ed.2016,55,7821); and have a wide range of biological activities (Bioorg.Med.Chem.Lett.2012, 22,3800;ChemMedChem 2013,8,1067;J.Med.Chem.2004,47,6854).
The application prospect of the sulfonimide compound is wide, so that the sulfonimide compound has important research significance for the preparation and application of the sulfonimide compound. The current preparation methods for various chiral hexavalent sulfur substances comprise the following steps: (1) starting from chiral substrates. (2) strategy by kinetic resolution. (3) by means of a desymmetrization strategy. Chloro (fluoro) sulfonimide is a relatively versatile synthetic sulfonimide amide, sulfonimide ester, and an important intermediate for sulfonimide as the aza analogue of the corresponding sulfonyl chloride. At present, the preparation method of chlorosulfonyl imine is more: comprises the steps of taking sulfinamide as a substrate, taking sulfonamide as a substrate, taking sulfoxide tetrafluoride as a substrate and taking N-aryl sulfinimide as a substrate. However, chiral chlorosulfonyl imines are only obtained by using corresponding chiral sulfinamides as substrates in the methods, and little is known about chlorosulfonyl imines at present. Therefore, the development of a preparation method for synthesizing chiral chlorosulfonyl imine has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of chiral chlorosulfonyl imine compounds, which comprises the following steps: the corresponding chiral chlorosulfonyl imine compound is obtained through multi-step serial reaction under the catalysis of chiral phosphoric acid by taking simple and easily obtained sulfenamide as a raw material, so that the defects in the prior art are overcome. The chiral chlorosulfonyl imine can be used as a synthesis intermediate of chiral sulfone imine amide, chiral sulfone imine ester and chiral sulfone imine.
The preparation method of the chiral chlorosulfonyl imine compound is characterized by comprising the following specific operation steps of:
in the air environment, sulfenamide compound (I) is used as a substrate for reaction, chlorinated reagent (II) is used as a catalyst according to the molar ratio of 1:1-1:5, chiral phosphoric acid TRIP with the equivalent of 0.01-0.20 of the compound shown in the formula (I) is added into an organic solvent, and the reaction is carried out for 0.5-48 hours at the temperature of minus 25-40 ℃, so that the end point of the reaction is determined by thin layer chromatography. Then the chiral chlorosulfonyl imine compound of the formula (III) is obtained through column chromatography.
Chiral chlorosulfonyl imine (III) is used as a substrate for reaction, and is respectively added with different amine reagents, different alcohol reagents and different Grignard reagents according to a molar ratio of 1:2-1:3 into an organic solvent to react for 0.5-24 hours at-20-50 ℃, and the end point of the reaction is determined by thin layer chromatography. Then obtaining chiral sulfonimide amide (IV or V), chiral sulfonimide ester (VI) and chiral sulfonimide (VII) compounds through column chromatography.
R is substituent groups in sulfenamide (I), chiral chlorosulfonyl imine (III), chiral sulfone imine amide (IV or V), chiral sulfone imine ester (VI) and chiral sulfone imine (VII) compounds 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from alkyl, heterocycle, phenyl, alkene, substituted phenyl, benzyl.
The preparation method of the chiral chlorosulfonyl imine compound and the derivative thereof is characterized in that the organic solvent is benzene, toluene, xylene, methylene dichloride, chloroform, carbon tetrachloride, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloroethane, diethyl ether, n-butyl ether and ethyl acetate.
The preparation method of the chiral chlorosulfonyl imine compound and the derivative thereof is characterized in that the chlorine source is a selective chloro reagent (II). The amine reagent is various aliphatic amine and aromatic amine, the alcohol reagent is various aliphatic alcohol and aromatic alcohol, and the Grignard reagent is various alkyl Grignard reagent and aromatic Grignard reagent.
The invention simplifies the traditional complex synthesis steps, is simple and easy to operate, has wide substrate applicability and can tolerate various functional groups. The invention adopts a metal-free catalytic system, which is economical and environment-friendly, and avoids metal residues in the synthesis process of some drug molecules. The invention can obtain various chiral chlorosulfonyl imine compounds with high yield and high optical purity (ee value > 99%) by using simple and easily obtained starting materials. The chiral sulfone imine amide, the chiral sulfone imine ester and the chiral sulfone imine can be prepared by means of a nucleophilic substitution strategy by means of the synthesized chiral chloro sulfone imine intermediate, the enantioselectivity is not reduced, and the method has economic practicability and industrial application prospect.
Drawings
FIG. 1 is a characteristic point diagram of a sulfonimide substance
FIG. 2 is a diagram showing a process for producing chloro (fluoro) sulfonimide
FIG. 3 is a diagram of a preparation method of the present invention
Detailed Description
EXAMPLE 1 preparation of Chlorosulfonylimine 3a
1a (0.1 mmol) was added at room temperature, TRIP (5 mol%) and methylene chloride (2 mL) were stirred for 5min, and 2a (0.2 mmol) was added under stirring. After the disappearance of the raw material 1a is observed by thin layer chromatography, stirring is stopped, and the target product 3a is directly obtained by column chromatography separation.
3a as a pale yellow solid; melting point 76-79 ℃; yield 96%;98% ee (HPLC, diacel Chiralcel AD-H column,98:2 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝33.7min(major)and 38.4min(minor))；[α] D 20 ＝-220°(c＝0.2,CH 2 Cl 2 )；IR(KBr):2975,1718,1662,1597,1449,1386,1311,1248,1166,1140,872,810,752,710cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.26(d,J＝7.9Hz,2H),8.17(d,J＝7.5Hz,2H),7.82(t,J＝7.4Hz,1H),7.71(t,J＝7.8Hz,2H),7.60(t,J＝7.4Hz,1H),7.48(t,J＝7.6Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ170.83,143.05,135.29,134.09,133.38,129.83,129.78,128.42,127.10.HRMS(ESI):C 13 H 10 ClNO 2 S Neutral mass:279.0121,Observed([M+Na]) + :302.0006.
Example 2: preparation of chlorosulfonylimine 3b
The objective product 3b was prepared by using 1b and 2a as starting substrates for the reaction, and the preparation method was the same as in example 1.
3b colorless oil, yield 95%;94% ee (HPLC, diacel Chiralcel AD-H column,96:4 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝23.5min(major)and 27.9min(minor))；[α] D 20 ＝-94°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2923,1660,1598,1451,1402,1376,1312,1267,1173,1147,1084,808,707cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.24-8.08(m,4H),7.60(t,J＝7.3Hz,1H),7.48(t,J＝8.1Hz,4H),2.55(s,3H). 13 C NMR(101MHz,Chloroform-d)δ170.86,146.86,140.22,134.21,133.27,130.36,129.76,128.37,127.18,21.84.HRMS(ESI):C 14 H 12 ClNO 2 S Neutral mass:293.0277,Observed([M+Na]) + :316.0159.
Example 3: preparation of chlorosulfonylimine 3c
The objective product 3c was prepared by using 1c and 2a as starting substrates for the reaction, and the preparation method was the same as in example 1.
3c a colorless oil; the yield thereof was found to be 96%;96% ee (HPLC, diacel Chiralcel IC-H column,85:15 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝32.0min(minor)and 34.2min(major))；[α] D 20 ＝-89°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1661,1586,1488,1452,1407,1313,1262,1240,1177,1143,1095,705cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.30(dd,J＝8.9,4.8Hz,2H),8.15(d,J＝7.6Hz,2H),7.61(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),7.39(t,J＝8.4Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ170.67,166.53(C-F, 1 J C-F ＝261.59Hz),138.86(C-F, 4 J C-F ＝3.03Hz),133.95,133.45,130.27(C-F, 3 J C-F ＝9.09Hz),129.76,128.44,117.25(C-F, 2 J C-F ＝23.23Hz). 19 F NMR(376MHz,Chloroform-d)δ-99.70.HRMS(ESI):C 13 H 9 ClFNO 2 S Neutral mass:297.0027,Observed([M+H]) + :298.0108.
Example 4: preparation of chlorosulfonylimine 3d
The target product 3d was prepared using 1d and 2a as starting substrates for the reaction, in the same manner as in example 1.
3d colorless oil; the yield thereof was found to be 96%;95% ee (HPLC, diacel Chiralcel AD-H column,98:2 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝31.9min(major)and 36.1min(minor))；[α] D 20 ＝-110°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1660,1572,1452,1277,1258,1151,1091,964,823,753,708,575cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.20(d,J＝8.8Hz,2H),8.15(d,J＝7.2Hz,2H),7.68(d,J＝8.8Hz,2H),7.61(t,J＝7.4Hz,1H),7.48(t,J＝7.6Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ170.66,142.26,141.32,133.88,133.49,130.14,129.78,128.57,128.45.HRMS(ESI):C 13 H 9 Cl 2 NO 2 S Neutral mass:312.9731,Observed([M+Na]) + :335.9622.
Example 5: preparation of chlorosulfonylimine 3e
The target product 3e was prepared using 1e and 2a as starting substrates for the reaction, in the same manner as in example 1.
3e as a colorless oil; the yield thereof was found to be 97%;94% ee (HPLC, diacel Chiralcel AD-H column,80:20 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝10.9min(major)and 12.5min(minor))；[α] D 20 ＝-61°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1660,1565,1452,1390,1312,1262,1173,1149,1068,818,707cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.1Hz,4H),7.85(d,J＝8.4Hz,2H),7.61(t,J＝7.2Hz,1H),7.49(t,J＝7.5Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ170.64,141.94,133.88,133.49,133.13,130.92,129.78,128.53,128.45.HRMS(ESI):C 13 H 9 BrClNO 2 S Neutral mass:356.9226,Observed([M+H]) + :357.9286.
Example 6: preparation of chlorosulfonylimine 3f
The objective product 3f was prepared by using 1f and 2a as starting substrates for the reaction, and the preparation method was the same as in example 1.
3f colorless oil; the yield thereof was found to be 96%;94% ee (HPLC, diacel Chiralcel AD-H column,80:20 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝12.6min(major)and 14.1min(minor))；[α] D 20 ＝-83°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1732,1662,1609,1449,1385,1327,1262,1211,1174,1147,1084,751cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.27(d,J＝7.8Hz,2H),8.06(d,J＝8.1Hz,2H),7.81(t,J＝7.4Hz,1H),7.71(t,J＝7.8Hz,2H),7.27(d,J＝7.8Hz,2H),2.44(s,3H). 13 C NMR(101MHz,Chloroform-d)δ170.75,144.20,143.17,135.16,131.48,129.88,129.77,129.13,127.12,21.76.HRMS(ESI):C 14 H 12 ClNO 2 S Neutral mass:293.0277,Observed([M+Na]) + :316.0171.
Example 7: preparation of Chlorosulfonylimine 3g
3g of the target product was prepared using 1g of the starting substrate of the reaction with 2a, in the same manner as in example 1.
3g of a colorless oil; the yield thereof was found to be 96%;97% ee (HPLC, diacel Chiralcel AD-H column,98:2 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝26.2min(major)and 31.3min(minor))；[α] D 20 ＝-39°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1665,1600,1451,1258,1146,1091,851,761,539cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.26(d,J＝7.7Hz,2H),8.18(dd,J＝8.7,5.6Hz,2H),7.83(t,J＝7.4Hz,1H),7.72(t,J＝7.8Hz,2H),7.14(t,J＝8.6Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ169.69,166.04(C-F, 1 J C-F ＝255.53Hz),142.98,135.32,132.47(C-F, 3 J C-F ＝10.1Hz),130.43(C-F, 4 J C-F ＝3.03Hz),129.84,127.06,115.52(C-F, 2 J C-F ＝22.22Hz). 19 F NMR(376MHz,Chloroform-d)δ-105.02.HRMS(ESI):C 13 H 9 ClFNO 2 S Neutral mass:297.0277,Observed([M+Na]) + :319.9897.
Example 8: preparation of Chlorosulfonylimine 3h
The target product 3h was prepared using 1h and 2a as starting substrates for the reaction, in the same manner as in example 1.
3h of colorless oil; the yield thereof was found to be 94%;98% ee (HPLC, diacel Chiralcel AD-H column,95:5 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝19.3min(minor)and 22.2min(major))；[α] D 20 ＝-66°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2926,1734,1663,1591,1450,1338,1260,1214,1169,1145,1106,1087,755cm -1 . 1 H NMR(400MHz,DMSO-d 6 )δ8.02(d,J＝7.5Hz,2H),7.89(d,J＝8.6Hz,2H),7.72(t,J＝7.4Hz,1H),7.65(t,J＝7.6Hz,2H),7.56(d,J＝8.6Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ164.98,139.75,138.72,134.23,130.86,130.61,129.62,129.19,128.14.HRMS(ESI):C 13 H 9 Cl 2 NO 2 S Neutral mass:312.9731,Observed([M+Na]) + :335.9606.
Example 9: preparation of chlorosulfonylimine 3i
The target product 3i was prepared using 1i and 2a as starting substrates for the reaction, in the same manner as in example 1.
3i a colorless oil; the yield thereof was found to be 94%;96% ee (HPLC, diacel Chiralcel AD-H column,98:2 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝38.7min(major)and 45.3min(minor))；[α] D 20 ＝-80°(c＝0.1,CH 2 Cl 2 ).IR(KBr):2925,1661,1584,1448,1262,1170,1146,1107,817,750,677,543cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.25(d,J＝7.8Hz,2H),8.02(d,J＝8.5Hz,2H),7.83(t,J＝7.4Hz,1H),7.72(t,J＝7.8Hz,2H),7.61(d,J＝8.4Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ170.04,142.92,135.35,133.04,131.72,131.27,129.85,128.52,127.07.HRMS(ESI):C 13 H 9 BrClNO 2 S Neutral mass:356.9226,Observed([M+Na]) + :379.9141.
Example 10: preparation of chlorosulfonylimine 3j
The target product 3j was prepared using 1j and 2a as starting substrates for the reaction, in the same manner as in example 1.
3i a colorless oil; the yield thereof was found to be 93%;92% ee (HPLC, diacel Chiralcel AD-H column,85:15 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝27.2min(major)and 37.1min(minor))；[α] D 20 ＝-59°(c＝01,CH 2 Cl 2 ).IR(KBr):2923,1665,1606,1522,1446,1350,1258,1166,1144,1105,816,716cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.32(s,4H),8.27(d,J＝7.6Hz,2H),7.87(t,J＝7.5Hz,1H),7.75(t,J＝7.9Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ169.03,150.65,142.62,139.34,135.62,130.74,129.97,127.05,123.57.HRMS(ESI):C 13 H 9 ClN 2 O 4 S Neutral mass:323.9972,Observed([M+H]) + :325.0031.
Preparing chiral sulfonimide amide (IV or V), chiral sulfonimide ester (VI) and chiral sulfonimide (VII) compounds:
example 11: preparation of chiral sulfonimide amide 5a
3a (0.1 mmol) was added thereto at room temperature, and 1, 2-dichloroethane (2 mL) was stirred for 5min, while 4a (0.2 mmol) was added thereto under stirring. After the disappearance of the raw material 3a is observed by thin layer chromatography, stirring is stopped, and the target product 5a is directly obtained by column chromatography separation.
5a colorless oil; the yield thereof was found to be 89%;95% ee (HPLC, diacel Chiralcel OD-H column,80:20 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝8.8min(minor)and 11.8min(major))；[α] D 20 ＝-10°(c＝0.03,CH 2 Cl 2 ).IR(KBr):2923,1638,1597,1581,1492,1448,1311,1262,1142,1093,1068,952,714cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.21-8.07(m,2H),7.94-7.83(m,2H),7.64(t,J＝7.4Hz,1H),7.58-7.48(m,3H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),7.25-7.16(m,2H),3.33(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.62,141.04,137.12,136.02,133.18,132.08,129.47,129.04,128.12,128.03,128.00,127.90,38.78.HRMS(ESI):C 20 H 18 N 2 O 2 S Neutral mass:350.1089,Observed([M+H]) + :351.1168.
Example 12: preparation of chiral sulfonimide amide 5b
3a and piperidine 4b were used as starting substrates for the reaction to prepare the target product 5b in the same manner as in example 11.
5b a colorless oil; the yield thereof was found to be 94%;95% ee (HPLC, diacel Chiralcel IC-H column,70:30 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝26.9min(major)and 35.7min(minor))；[α] D 20 ＝+28°(c＝0.05,CH 2 Cl 2 ).IR(KBr):3060,2952,2911,2854,1634,1578,1466,1377,1315,1291,1245,1212,1149,1095,950,713cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.29-8.09(m,2H),8.05-7.88(m,2H),7.63(t,J＝7.3Hz,1H),7.56(dd,J＝13.5,6.5Hz,2H),7.51(d,J＝7.2Hz,1H),7.43(t,J＝7.4Hz,2H),3.23(hept,J＝5.9,5.3Hz,4H),1.69(p,J＝5.6Hz,4H),1.52(p,J＝6.2,5.6Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ172.66,136.73,136.08,133.04,132.00,129.44,129.19,128.00,127.72,46.50,25.29,23.65.HRMS(ESI):C 18 H 20 N 2 O 2 S Neutral mass:328.1245,Observed([M+H]) + :329.1314.
Example 13: preparation of chiral sulfonimide amide 5c
3a and morpholine 4c as starting substrates for the reaction to give the desired product 5c, in the same manner as in example 11.
5c a colorless oil; the yield was 95%;95% ee (HPLC, diacel Chiralcel IC-H column,70:30 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝31.7min(major)and 37.4min(minor))；[α] D 20 ＝+14°(c＝0.03,CH 2 Cl 2 ).IR(KBr):3065,2980,2889,2853.1635,1580,1449,1317,1285,1248,1139,1112,1091,1076,956,836,724,565cm -1 1 H NMR(400MHz,Chloroform-d)δ8.26-8.13(m,2H),8.02-7.91(m,2H),7.67(dd,J＝8.4,6.3Hz,1H),7.61(t,J＝7.5Hz,2H),7.54(t,J＝7.3Hz,1H),7.44(t,J＝7.5Hz,2H),3.88-3.76(m,4H),3.30-3.18(m,4H). 13 C NMR(101MHz,Chloroform-d)δ172.61,135.72,135.40,133.46,132.25,129.48,129.40,128.08,127.86,66.18,45.69.HRMS(ESI):C 17 H 18 N 2 O 3 S Neutral mass:330.1038,Observed([M+H]) + :331.1115.
Example 14: preparation of chiral sulfonimide amide 5d
3a and aniline 4c were used as starting substrates for the reaction to prepare the target product 5d, in the same manner as in example 11.
5d colorless oil; yield 78%;97% ee (HPLC, diacel Chiralcel IC-H column,70:30hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝8.8min(major)and 10.2min(minor))；[α] D 20 ＝+133°(c＝0.1,CH 2 Cl 2 ).IR(KBr):3094,2925,1597,1568,1498,1299,1280,1217,1144,952,851,724cm -1 . 1 H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.23(d,J＝7.3Hz,2H),7.95(d,J＝7.5Hz,2H),7.56(t,J＝7.3Hz,2H),7.46(q,J＝7.8Hz,4H),7.33-7.23(m,2H),7.21-7.06(m,3H). 13 C NMR(101MHz,Chloroform-d)δ172.96,139.21,135.62,135.24,133.49,132.67,129.66,129.48,129.25,128.15,127.15,125.69,122.33.HRMS(ESI):C 19 H 16 N 2 O 2 S Neutral mass:336.0932,Observed([M+Na]) + :359.0822.
Example 15: preparation of chiral sulfonimide amide 5e
3a and cyclohexylamine 4e were used as starting substrates for the reaction to give the desired product 5e, in the same manner as in example 11.
5e as a colorless oil; the yield thereof was found to be 96%;95% ee (HPLC, diacel Chiralcel IC-H column,70:30 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝8.4min(major)and 13.2min(minor))；[α] D 20 ＝+154°(c 0.05,CH 2 Cl 2 ).IR(KBr):3432,2954,2911,1623,1449,1378,1317,1296,1143,1067,751,715,687cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J＝7.4Hz,2H),8.04(d,J＝7.4Hz,2H),7.77(d,J＝7.3Hz,1H),7.60(t,J＝7.3Hz,1H),7.51(dt,J＝15.0,7.5Hz,3H),7.39(t,J＝7.6Hz,2H),3.40-3.16(m,1H),2.18-1.99(m,1H),1.74(d,J＝12.7Hz,1H),1.62(d,J＝11.4Hz,2H),1.48(dd,J＝23.3,10.2Hz,2H),1.41-1.17(m,4H). 13 C NMR(101MHz,Chloroform-d)δ172.81,140.76,135.68,133.14,132.21,129.44,129.17,128.00,127.10,52.01,34.74,33.15,25.13,24.58,24.48.HRMS(ESI):C 19 H 22 N 2 O 2 S Neutral mass:342.1402,Observed([M+Na]) + :365.1290.
Example 16: preparation of chiral sulfonimide ester 5f
3a and sodium phenolate 4f were used as starting substrates for the reaction to prepare the desired product 5f in the same manner as in example 11.
5f colorless oil; the yield thereof was found to be 65%;96% ee (HPLC, diacel Chiralcel AD-H column,90:10 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝23.8min(minor)and 30.2min(major))；[α] D 20 ＝+16°(c＝0.05,CH 2 Cl 2 ).IR(KBr):3444,2954,2923,1651,1457,1378,1312,1272,1138,1070,967,848,713,616,543cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J＝7.4Hz,2H),8.11(d,J＝7.7Hz,2H),7.73(t,J＝7.5Hz,1H),7.61(t,J＝7.8Hz,2H),7.54(t,J＝7.3Hz,1H),7.44(t,J＝7.6Hz,2H),7.37-7.27(m,3H),7.15(d,J＝7.5Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ171.74,149.24,136.39,135.18,134.40,132.53,129.71,129.69,129.28,128.23,128.12,127.47,122.84.HRMS(ESI):C 19 H 15 NO 3 S Neutral mass:337.0773,Observed([M+Na]) + :360.0658.
Example 17: preparation of chiral sulfonimide ester 5g
3a and 4g as starting substrates for the reaction 5g of the target product was prepared in the same manner as in example 11.
5g of a colorless oil; the yield thereof was found to be 82%;95% ee (HPLC, diacel Chiralcel IC-H column,92:8 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝39.2min(major)and 46.8min(minor))；[α] D 20 ＝-12°(c＝0.05,CH 2 Cl 2 ).IR(KBr):2931,1653,1465,1450,1311,1272,1151,1091,1047,955,900,823,790,721cm -1 . 1 H NMR(600MHz,Chloroform-d)δ8.14(d,J＝7.9Hz,2H),8.08(d,J＝8.1Hz,2H),7.70(t,J＝7.5Hz,1H),7.58(t,J＝7.8Hz,2H),7.52(t,J＝7.4Hz,1H),7.41(t,J＝7.7Hz,2H),7.06(d,J＝7.4Hz,1H),7.00(t,J＝7.8Hz,1H),6.95(d,J＝8.1Hz,1H),2.25(s,3H),2.12(s,3H). 13 C NMR(151MHz,Chloroform-d)δ171.72,147.99,139.28,136.97,135.33,134.30,132.43,130.67,129.68,129.26,128.65,128.16,128.08,126.01,120.25,20.10,13.00.HRMS(ESI):C 21 H 19 NO 3 S Neutral mass:365.1086,Observed([M+H]) + :366.1170.
Example 18: preparation of chiral sulfonimide ester for 5h
3a and 4h as starting substrates for the reaction to give the desired product 5h, in the same manner as in example 11.
5h of colorless oil; yield 36%;95% ee (HPLC, diacel Chiralcel AD-H column,90:10 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝32.9min(minor)and 44.8min(major))；[α] D 20 ＝+14°(c＝0.05,CH 2 Cl 2 ).IR(KBr):2955,2911,1647,1483,1457,1378,1312,1272,1142,1097,967,854,767,712cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.24-8.18(m,2H),8.15(dd,J＝8.5,1.2Hz,2H),7.75(tt,J＝6.9,1.2Hz,1H),7.63(t,J＝7.8Hz,2H),7.54(dt,J＝6.6,2.5Hz,5H),7.45(td,J＝7.7,1.8Hz,4H),7.40-7.35(m,1H),7.25-7.18(m,2H). 13 C NMR(101MHz,Chloroform-d)δ171.82,148.56,140.57,139.72,136.36,135.15,134.48,132.61,129.73,129.34,128.87,128.35,128.28,128.16,127.72,127.10,123.13.HRMS(ESI):C 25 H 19 NO 3 S Neutral mass:413.1086,Observed([M+Na]) + :436.0991.
Example 19: preparation of chiral sulfonimide ester 5i
3a and 4i as starting substrates for the reaction to give the desired product 5i, the preparation was the same as in example 11.
5i colorless oil; the yield thereof was found to be 73%;95% ee (HPLC, diacel Chiralcel AD-H column,90:10 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝24.2min(minor)and 35.4min(major))；[α] D 20 ＝+36°(c＝0.05,CH 2 Cl 2 ).IR(KBr):3447,2955,2911,1651,1463,1378,1312,1272,1146,1068,970,844,741cm -1 .Colorless oil(30.3mg 73％),m.p.106-107℃. 1 H NMR(400MHz,Chloroform-d)δ8.21-8.14(m,2H),8.10(dd,J＝8.5,1.2Hz,2H),7.75(tt,J＝7.0,1.2Hz,1H),7.67-7.59(m,2H),7.59-7.52(m,1H),7.48-7.38(m,4H),7.09-6.97(m,2H). 13 C NMR(101MHz,Chloroform-d)δ171.72,148.25,135.99,134.92,134.67,132.84,132.75,129.72,129.43,128.21,128.19,124.61,121.04.HRMS(ESI):C 19 H 14 BrNO 3 S Neutral mass:414.9878,Observed([M+Na]) + :437.9786.
Example 20: preparation of chiral sulfonimide ester 5j
3a and 4j as starting substrates for the reaction to give the desired product 5j, the preparation was the same as in example 11.
5j is a colorless oil; the yield thereof was found to be 93%;97% ee (HPLC, diacel Chiralcel AD-H column,80:20 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝22.1min(minor)and 33.4min(major))；[α] D 20 ＝+10°(c＝0.05,CH 2 Cl 2 ).IR(KBr):2951,2924,1653,1617,1580,1527,1478,1349,1312,1272,1144,865,733,714,548cm -1 . 1 H NMR(600MHz,Chloroform-d)δ8.19(d,J＝8.7Hz,2H),8.12(t,J＝8.5Hz,4H),7.80-7.73(m,1H),7.64(t,J＝7.7Hz,2H),7.57-7.51(m,1H),7.42(t,J＝7.6Hz,2H),7.33(d,J＝8.8Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ171.47,153.80,146.40,135.93,135.01,134.60,132.98,129.74,129.63,128.28,128.05,125.41,123.76.HRMS(ESI):C 19 H 14 N 2 O 5 S Neutral mass:382.0623,Observed([M+Na]) + :405.0521.
Example 21: preparation of chiral sulfonimide 5k
3a and 4k as starting substrates for the reaction to give the desired product 5k, the preparation was the same as in example 11.
5k colorless oil; the yield was 90%;93% ee (HPLC, diacel Chiralcel IC-H column,70:30 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝43.1min(minor)and 47.0min(major))；[α] D 20 ＝+30°(c＝0.03CH 2 Cl 2 ).IR(KBr):2955,2920,1634,1457,1312,1378,1275,1226,1170,1133,937,843,715cm -1 . 1 H NMR(600MHz,Chloroform-d)δ8.26(dd,J＝8.2,1.2Hz,2H),8.09-8.02(m,2H),7.95(d,J＝8.4Hz,2H),7.60-7.54(m,1H),7.54-7.49(m,3H),7.43(t,J＝7.7Hz,2H),7.32(d,J＝8.1Hz,2H),2.39(s,3H). 13 C NMR(151MHz,Chloroform-d)δ173.91,144.35,140.27,136.78,135.93,133.12,132.15,130.23,129.52,129.48,128.04,127.66,127.51,21.55.HRMS(ESI):C 20 H 17 NO 2 S Neutral mass:335.0980,Observed([M+Na]) + :358.0869.
Example 22: preparation of chiral sulfonimide 5l
3a and 4l as starting substrates for the reaction to give 5l of the desired product, in the same manner as in example 11.
5l of a colorless oil; the yield thereof was found to be 84%;91% ee (HPLC, diacel Chiralcel IC-H column,70:30hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝54.6min(minor)and 64.8min(major))；[α] D 20 ＝+38°(c＝0.03,CH 2 Cl 2 ).IR(KBr):2955,2920,1632,1457,1378,1312,1277,1224,1134,838,719,548cm -1 . 1 H NMR(600MHz,Chloroform-d)δ8.24(dd,J＝8.2,1.2Hz,2H),8.06-8.02(m,2H),8.02-7.97(m,2H),7.59-7.54(m,1H),7.54-7.49(m,3H),7.43(t,J＝7.7Hz,2H),7.03-6.98(m,2H),3.84(s,3H). 13 C NMR(151MHz,Chloroform-d)δ173.83,163.52,140.67,135.98,132.94,132.09,130.81,129.84,129.49,129.42,128.02,127.38,114.86,55.68.HRMS(ESI):C 20 H 17 NO 3 S Neutral mass:351.0929,Observed([M+Na]) + :374.0792.
Example 23: preparation of chiral sulfonimide 5m
3a and 4m were used as starting substrates for the reaction to prepare the target product 5m in the same manner as in example 11.
5m colorless oil; the yield thereof was found to be 88%;81% ee (HPLC, diacel Chiralcel IC-H column,70:30hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝31.7min(minor)and 34.7min(major))；[α] D 20 ＝+70°(c＝0.05,CH 2 Cl 2 ).IR(KBr):3088,2955,2825,1635,1579,1448,1400,1311,1272,1224,1136,1026,933,715cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.31-8.19(m,2H),8.15-8.05(m,2H),7.74(ddd,J＝9.0,4.4,1.1Hz,2H),7.67-7.51(m,4H),7.46(t,J＝7.5Hz,2H),7.20-7.10(m,1H). 13 C NMR(101MHz,Chloroform-d)δ173.68,140.84,140.61,135.52,134.61,133.81,133.33,132.33,129.57,128.48,128.09,127.37.HRMS(ESI):C 17 H 13 NO 2 S 2 Neutral mass:327.0388,Observed([M+Na]) + :350.0284.
Example 24: preparation of chiral sulfonimide 5n
3a and 4n as starting substrates for the reaction to give the desired product 5n, the preparation was the same as in example 11.
5n colorless oil; yield 36%;94% ee (HPLC, diacel Chiralcel IC-H column,70:30 hexane/2-pro-panol, 1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝24.2min(minor)and 35.4min(major))；[α] D 20 ＝+24°(c＝0.05,CH 2 Cl 2 ).IR(KBr):3053,2955,2920,1610,1576,1457,1378,1313,1287,1219,1130,1067,928cm -1 . 1 H NMR(400MHz,Chloroform-d)δ8.23-8.10(m,2H),8.06-7.93(m,2H),7.72-7.63(m,1H),7.63-7.56(m,2H),7.56-7.49(m,1H),7.42(t,J＝7.5Hz,2H),2.80(tt,J＝7.9,4.8Hz,1H),1.74(ddt,J＝10.3,7.3,5.2Hz,1H),1.45(ddt,J＝10.4,7.2,5.2Hz,1H),1.37-1.29(m,1H),1.10(dtd,J＝9.0,7.7,5.4Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ173.66,139.29,135.76,133.34,132.03,129.54,129.41,127.99,127.24,33.43,7.02,5.46.HRMS(ESI):C 16 H 15 NO 2 S Neutral mass:285.0823,Observed([M+Na]) + :308.0720.
Example 25: preparation of chiral sulfonimide 5o
3a and 4o were used as starting substrates for the reaction to prepare the target product 5o in the same manner as in example 11.
5o colorless oil; the yield thereof was found to be 72%;96% ee (HPLC, diacel Chiralcel AD-H column,90:10 hexane/2-pro anol,1mL/min: temperature:25 ℃,254nm;retention time:t) R ＝23.9min(major)and 30.6min(minor))；[α] D 20 ＝+20°(c＝0.03,CH 2 Cl 2 ).IR(KBr):3444,2955,2920,1624,1578,1457,1378,1311,1283,1202,1173,1134,1051,841cm -1 . 1 H NMR(600MHz,Chloroform-d)δ8.24-8.12(m,2H),8.03-7.96(m,2H),7.67(t,J＝7.4Hz,1H),7.60(t,J＝7.8Hz,2H),7.50(t,J＝7.4Hz,1H),7.41(t,J＝7.7Hz,2H),3.61(q,J＝7.4Hz,2H),1.30(t,J＝7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ174.12,136.59,135.73,133.73,132.07,129.57,129.43,127.99,50.66,7.25.HRMS(ESI):C 15 H 15 NO 2 S Neutral mass:273.0823,Observed([M+Na]) + :296.0716.

Claims (3)

1. A preparation method of a chiral chlorosulfonyl imine compound of formula III is characterized by comprising the following steps: in an air environment, sulfenamide compound I is used as a substrate for reaction, a chloro reagent II is used as a catalyst according to the molar ratio of 1:1-1:5, 0.01-0.20 equivalent of chiral phosphoric acid TRIP of the compound of the formula I is added into an organic solvent, the reaction is carried out for 0.5-48 hours at the temperature of minus 25-40 ℃, the end point of the reaction is determined by thin layer chromatography, and then the chiral chloro sulfone imine compound of the formula III is obtained by column chromatography;
substituent R 1 、R 2 Each independently selected from alkyl, heterocycle, phenyl, alkene, substituted phenyl, benzyl.
2. A preparation method of chiral chlorosulfonyl imine derivatives of formula IV, formula V, formula VI and formula VII is characterized in that: in an air environment, sulfenamide compound I is used as a substrate for reaction, a chloro reagent II is used as a catalyst according to the molar ratio of 1:1-1:5, 0.01-0.20 equivalent of chiral phosphoric acid TRIP of the compound of the formula I is added into an organic solvent, the reaction is carried out for 0.5-48 hours at the temperature of minus 25-40 ℃, the end point of the reaction is determined by thin layer chromatography, and then the chiral chloro sulfone imine compound of the formula III is obtained by column chromatography; the chiral chlorosulfonyl imine (III) is used as a substrate for reaction, and is respectively added into an organic solvent with different amine reagents, different sodium alkoxide reagents and different Grignard reagents according to the molar ratio of 1:2-1:3, and reacts for 0.5-24 hours at the temperature of minus 20-50 ℃, the end point of the reaction is determined by thin layer chromatography, and then the derivative of the chiral chlorosulfonyl imine compound is obtained by column chromatography;
substituent R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from alkyl, heterocycle, phenyl, alkene, substituted phenyl, benzyl.
3. The process according to claim 1 or 2, wherein the organic solvent is benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloroethane, diethyl ether, n-butyl ether, ethyl acetate.
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