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Three-dimensional and large-steric-hindrance disulfide compound as well as synthesis method and application thereof

A synthesis method and a large sterically hindered technology, which can be applied in the fields of organic chemistry methods, chemical instruments and methods, hydrogenated polysulfide/polysulfide preparation, etc. Problems such as the abundance of hindered disulfides and the inability to achieve structural changes

Active Publication Date: 2020-06-19
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing method of synthesizing large steric hindered disulfides usually requires the use of tertiary thiols to react with activated mercapto compounds. However, due to the limited structure of known tertiary thiols, the abundance and structure of three-dimensional large steric hindered disulfides On the other hand, highly activated thiol compounds are sensitive to water, heat, light, etc., and are not easy to store, which also limits the application of large sterically hindered disulfides in the fields of biology and pharmacy

Method used

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  • Three-dimensional and large-steric-hindrance disulfide compound as well as synthesis method and application thereof
  • Three-dimensional and large-steric-hindrance disulfide compound as well as synthesis method and application thereof
  • Three-dimensional and large-steric-hindrance disulfide compound as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Synthesis of compound 3a

[0075] 1 HNMR (400MHz; CDCl 3 ):δ7.65-7.61(m,2H),7.43(d,J=8.0Hz,1H),7.36(t,J=7.6Hz,1H),7.21(d,J=8.4Hz,2H),7.02 (d, J=8.0Hz, 2H), 3.98(d, J=18.0Hz, 1H), 3.61(s, 3H), 3.54(d, J=18.0Hz, 1H), 2.31(s, 3H); 13 CNMR (100MHz; CDCl 3 ): δ196.1, 168.3, 151.4, 138.0, 135.6, 134.5, 132.3, 129.6, 129.5, 128.0, 126.0, 125.2, 64.7, 53.3, 38.4, 21.1; 1294,1213,962,804,735cm -1 ;HRMS(ESI)C 18 h 17 o 3 S 2 [M+H] + :calcd345.0614,found345.0626.

Embodiment 2

[0077] Synthesis of compound 3b

[0078] mg, 97%), 1 HNMR (400MHz; CDCl 3 ): δ7.61-7.57(m,2H),7.41(d,J=7.6Hz,1H),7.34(t,J=7.2Hz,1H),7.13(d,J=8.0Hz,2H),6.98 (d, J=8.0Hz, 2H), 5.04-4.97(m, 1H), 3.90(d, J=16.0Hz, 1H), 3.51(d, J=16.0Hz, 1H), 2.29(s, 3H) ,1.21-1.18(m,6H); 13 CNMR (100MHz; CDCl 3 ):δ196.7,167.4,151.6,137.8,135.5,134.7,132.6,129.5,129.4,127.8,125.9,125.0,70.7,65.1,38.3,21.5,21.3,21.0; IR(KBr)2361,1713,16405, 1269,1101,920,806,746cm -1 ;HRMS(ESI)C 20 h 20 NaO 3 S 2 [M+Na] + :calcd395.0746,found395.0765.

Embodiment 3

[0080] Synthesis of compound 3c

[0081] mg, 87%), 1 HNMR (400MHz; CDCl 3 ): δ7.60(t, J=8.0Hz, 1H), 7.56(d, J=7.6Hz, 1H), 7.40(d, J=7.6Hz, 1H), 7.33(t, J=7.6Hz, 1H ), 7.11(d, J=8.0Hz, 2H), 6.97(d, J=8.0Hz, 2H), 3.84(d, J=16.0Hz, 1H), 3.50(d, J=16.0Hz, 1H), 2.29(s,3H),1.42(s,9H); 13 CNMR (100MHz; CDCl 3 ):δ197.3,166.9,151.8,137.7,135.3,134.9,132.8,129.4,129.3,127.7,125.8,124.9,83.9,65.9,38.5,27.8,21.0; IR(KBr)2924,1701,14211,13794, 1251,1143,991,810,727,694cm -1 ;HRMS(ESI)C 21 h 23 o 3 S 2 [M+H] + :calcd387.1083,found387.1061.

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Abstract

The invention belongs to the technical field of organic compound process application. The invention discloses a synthesis method for constructing a three-dimensional and large-steric-hindrance disulfide compound (III). In a reaction solvent, N-dithiophthalimide (I) and ester (II) with alpha hydrogen are used as reaction raw materials, lewis base or cinchona base is used as a catalyst, and variousthree-dimensional and large-steric-hindrance disulfide compounds (III) with quaternary carbon centers are obtained at a high yield under a specific temperature condition. The synthesis method providedby the invention has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and good functional group tolerance. According to theinvention, disulfide connection and modification of some drug molecules, biological small molecules and fluorescent molecules are realized, some chiral disulfide compounds are obtained, a rapid and stable connection mode is provided for connection of pharmaceutical chemistry, especially ADC drugs, and the compounds are expected to be widely applied in the field of pharmaceutical chemistry.

Description

technical field [0001] The invention belongs to the technical field of organic compound technology application, and in particular relates to a class of three-dimensional and large-steric hindered disulfide compounds and a synthesis method and application thereof. Background technique [0002] Disulfide compounds are a very important class of compounds, which widely exist in various natural products, medicines, pesticides, and materials, and are an important class of cleavable linkers in antibody-drug conjugates (ADCs) , for linking antibodies and small molecule drugs. Due to the particularity of the structure of the bulky disulfide, it is more stable as a linker, so it is more widely used in ADC drugs. Among them, Mylotarg and Besponsa is a clinical ADC anti-cancer developed using a bulky disulfide as a linker. drug. [0003] The existing method of synthesizing large steric hindered disulfides usually requires the use of tertiary thiols to react with activated mercapto com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/22C07C323/61C07C323/52C07C323/56C07C323/60C07D333/34C07D493/04C07D493/10C07D493/18C07D311/58C07D405/12C07H13/04C07H1/00C07H9/04C07H19/06C09K11/06C07K5/062C07K1/02C07K1/107
CPCC07B2200/07C07C319/22C07D311/58C07D333/34C07D405/12C07D493/04C07D493/10C07D493/18C07H1/00C07H9/04C07H13/04C07H19/06C07K5/06034C09K11/06C09K2211/1007C09K2211/1011C09K2211/1014C09K2211/1029C09K2211/1044C09K2211/1088C09K2211/1092C07C2601/04C07C2601/08C07C2601/14C07C2602/08C07C2602/10C07C323/61C07C323/52C07C323/56C07C323/60
Inventor 姜雪峰高文超
Owner EAST CHINA NORMAL UNIV
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