WO2024017221A1 - PROCÉDÉ DE SYNTHÈSE D'UNE α-AZIDO CÉTONE CONTENANT UN STÉRÉOCENTRE TERTIAIRE - Google Patents

PROCÉDÉ DE SYNTHÈSE D'UNE α-AZIDO CÉTONE CONTENANT UN STÉRÉOCENTRE TERTIAIRE Download PDF

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WO2024017221A1
WO2024017221A1 PCT/CN2023/107817 CN2023107817W WO2024017221A1 WO 2024017221 A1 WO2024017221 A1 WO 2024017221A1 CN 2023107817 W CN2023107817 W CN 2023107817W WO 2024017221 A1 WO2024017221 A1 WO 2024017221A1
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Prior art keywords
tert
butoxycarbonyl
azido
nmr
product
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PCT/CN2023/107817
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English (en)
Chinese (zh)
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郭文岗
周英
乐鑫
江枫
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常州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the chiral product obtained by the present invention can be used as a useful organic synthesis building block for the preparation of biologically active molecules, heterocycles and chiral ligands, and specifically relates to the synthesis of an ⁇ -azido ketone containing a tertiary chiral center. method.
  • Organic azides are high value-added synthetic building blocks with a wide range of applications in chemical biology, materials science, and medicinal chemistry. Therefore, the synthesis and application of organic azide compounds have aroused great research interest among chemists in the past few decades.
  • the ⁇ -carbonyl azides synthesized by chiral catalytic methods reported in the literature all have quaternary carbon chiral centers, and the asymmetric catalytic synthesis methods of ⁇ -azido ketones containing tertiary chiral centers are still limited. There are no relevant literature reports.
  • the purpose of this application is to provide a synthetic method for ⁇ -azido ketones containing tertiary stereocenters.
  • Y Ph, Me, F, Br, Cl, any substituent.
  • the synthesis method includes: under the action of a catalyst (such as SQ3), the sulfonium oxide ylide derivative reacts with the azide reagent HN3 produced in situ to generate the ⁇ -azido ketone, and the sulfonium oxide ylide derivative ( ⁇ -).
  • a catalyst such as SQ3
  • the sulfonium oxide ylide derivative reacts with the azide reagent HN3 produced in situ to generate the ⁇ -azido ketone
  • the sulfonium oxide ylide derivative ⁇ -
  • the structural formula of sulfonium carbonyl oxide (sulfonium carbonyl oxide) is
  • the present invention adopts the in-situ reaction between TMSN 3 and benzoic acid to produce the azide reagent HN 3 , and other methods that can produce HN 3 in situ are applied to the reaction with sulfonium ylide to synthesize chiral ⁇ -carbonyl azide compounds, which all belong to the content of the present invention. logical expansion.
  • the proton source for the in situ generated azide reagent HN 3 can be benzoic acid, N ⁇ Boc ⁇ L ⁇ Proline, N ⁇ Boc ⁇ D ⁇ Proline, N ⁇ Boc ⁇ L ⁇ Leucine, N ⁇ Boc ⁇ D ⁇ Leucine, N-Boc-L-tert-Leucine, N-Boc-D-tert-Leucine, N-Boc-L-Valine, N-Boc-D-Valine, H 2 O, MeOH, HFIP, AcOH, (p Any one of -OH)C 6 H 4 CO 2 H and (p-Cl)C 6 H 4 CO 2 H.
  • the sulfonium oxide ylide derivative of the present invention is protonated by HN 3 produced in situ to form an unstable sulfonium ion intermediate 1', and other stable sulfonium ions and azide reagents are used to synthesize chiral ⁇ -carbonyl azide
  • the compounds all belong to the logical expansion of the content of the present invention.
  • the structural formula of the sulfonium ion intermediate 1' is:
  • the catalyst SQ3 used is the preferred catalyst of the present invention, and its structure is:
  • it also includes the following steps: cooling the system added with sulfonium oxide ylide derivatives, proton source, squarylamide catalyst and CHCl 3 to -15 ⁇ 0°C (-15 ⁇ 0°C can obtain a yield range of 50-95 %, ee range 80-95%); continue stirring at the same temperature, add TMSN 3 , and then continue stirring at the same temperature until the reaction is completed.
  • the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1 to 2:1, and the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 1 to 4: 1.
  • the reaction temperature is -15°C
  • the molar ratio of the proton source to the sulfonium oxide ylide derivative is 1.1:1; the molar ratio of TMSN 3 to the sulfonium oxide ylide derivative is 2:1.
  • a specific preferred preparation method using the proton source as benzoic acid includes the following steps: sulfonium oxide ylide derivative 1 represented by the following formula, TMSN 3 and benzoic acid are used as raw materials, and squarylamide is used as a catalyst to synthesize a third-order stereoscopic structure
  • sulfonium oxide ylide derivative 1 represented by the following formula
  • TMSN 3 and benzoic acid are used as raw materials
  • squarylamide is used as a catalyst to synthesize a third-order stereoscopic structure
  • the reaction formula is as follows:
  • the dosage of sulfonium oxide ylide derivative is 0.2mmol; the dosage of benzoic acid is 0.22mmol; the dosage of squarylamide catalyst derivative is 20mol% of sulfonium oxide ylide; the dosage of TMSN 3 is 0.4mmol; the dosage of CHCl 3 is about 1mL .
  • the chiral product obtained by the present invention also has certain application value in the synthesis of ligands and bioactive compounds.
  • the product was a light yellow oil (120h, 39.4mg, 83% yield, 90%ee).
  • the product was a white solid (120 h, 60.2 mg, 96% yield, 85% ee).
  • the product was a white solid (120 h, 59.4 mg, 88% yield, 90% ee).
  • the product was colorless oil (120h, 48.8mg, 92% yield, 85%ee).
  • the product was a colorless oil (168h, 40.2mg, 74% yield, 92%ee).
  • the product was colorless oil (168h, 35.4mg, 56% yield, 91%ee).
  • the product was colorless oil (168h, 31.6mg, 50% yield, 84%ee).
  • the product was colorless oil (168 h, 36.1 mg, 67% yield, 96% ee).
  • the product was colorless oil (168h, 53.1mg, 87% yield, 96%ee).
  • the product was a colorless oil (168 h, 52.7 mg, 79% yield, 91% ee).
  • the product was colorless oil (120h, 43.7mg, 76% yield, 77%ee).
  • the product was colorless oil (168h, 23.5mg, 46% yield, 67%ee).
  • Chiral aminoalcohols are an important class of pharmaceutical intermediates and an important chiral ligand widely used in chiral synthetic chemistry (Chem. Rev. 1996, 96, 835-875; J. Med. Chem. 2005, 48,4220-4223).
  • the present invention uses the following application examples to illustrate:
  • the chiral azide compound obtained by the present invention can be converted into the corresponding chiral triazole heterocyclic compound through a copper-catalyzed click reaction. It is worth noting that studies have proven that ⁇ -carbonyltriazole compounds containing tertiary chiral centers have certain anti-tumor activity (Eur.J.Med.Chem.2010,45,5044-5050; ARKIVOC 2012,279-296 ), but due to the constraints of related asymmetric catalytic synthesis methods, there have been no chiral synthesis reports of ⁇ -carbonyltriazole compounds containing tertiary chiral centers so far, so people cannot further explore the structure of the chiral centers. The relationship between type and drug activity. Based on this, the present invention demonstrates that the obtained chiral azide compounds can be converted into related chiral triazole heterocyclic compounds:
  • Example 1 Effect of other types of catalysts on the reaction results of the present invention—chiral phosphoric acid a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard.All the reactions described above provided clean conversion. b Determined by Chiral HPLC analysis.
  • Example 2 The influence of other types of catalysts on the reaction results of the present invention - other hydrogen bonding catalysts a Determined by crude 1 H NMR anaylsis using CH 2 Br 2 as an internal standard. b Determined by Chiral HPLC analysis. c The reaction gave a messy mixture, likely due to the incompatibility of the reaction with the basic cinchona alkaloid functionality.
  • the SQ3 catalyst used in the present invention is effective in the target reaction. It has significant advantages in stereoselectivity control; at the same time, because the reaction conditions of the present invention are relatively mild, the optical purity of the product will not be affected by racemization (the product is sensitive to acids and bases due to the electron-withdrawing properties of the carbonyl group and the azide group) And easy to racemize).
  • Example 3 Effect of chiral proton source on the reaction results of the present invention - amino acids as chiral protons a Determined by crude 1 H NMR analysis using CH 2 Br 2 as an internal standard. b Determined by chiral HPLC analysis. c ent ⁇ SQ3was used as the catalyst.
  • Example 4 The influence of other achiral proton sources on the reaction results of the present invention - alcohols and carboxylic acids as proton sources Reaction scale: 1a (0.1mmol), TMSN 3 (0.2mmol), proton source (0.11mmol), SQ3 (0.01mmol), solvent (0.5 mL),24h.Yield was determined by 1 H NMR spectra of the crude mixture using CH 2 Br 2 as an internal standard.Ee was determined by HPLC on a chiral stationary phase.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de synthèse d'une α-azido cétone contenant un centre chiral tertiaire, le procédé de synthèse comprenant : sous l'action d'un catalyseur de squaramide, la réaction d'un dérivé ylure de sulfoxonium avec un réactif d'azidation HN3 généré in situ à partir de TMSN3 et d'une source de protons, de façon à générer l'α-azido cétone. Les conditions de réaction sont douces, et aucun métal n'est nécessaire ; et le procédé présente un bon rendement et une bonne sélectivité énantiomérique.
PCT/CN2023/107817 2022-07-18 2023-07-18 PROCÉDÉ DE SYNTHÈSE D'UNE α-AZIDO CÉTONE CONTENANT UN STÉRÉOCENTRE TERTIAIRE WO2024017221A1 (fr)

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CN202210854830.5 2022-07-18
CN202210854830.5A CN115108937B (zh) 2022-07-18 2022-07-18 含三级立体中心的α-叠氮酮的合成方法

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CN115108937B (zh) * 2022-07-18 2023-08-22 常州大学 含三级立体中心的α-叠氮酮的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821277A (en) * 1964-10-30 1974-06-28 Basf Ag Ypsilon-methoxy-ypsilon-carbanilino-alpha,omega-dicyanopentane
CN115108937A (zh) * 2022-07-18 2022-09-27 常州大学 含三级立体中心的α-叠氮酮的合成方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821277A (en) * 1964-10-30 1974-06-28 Basf Ag Ypsilon-methoxy-ypsilon-carbanilino-alpha,omega-dicyanopentane
CN115108937A (zh) * 2022-07-18 2022-09-27 常州大学 含三级立体中心的α-叠氮酮的合成方法

Non-Patent Citations (3)

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Title
DAY DAVID PHILIP, MORA VARGAS JORGE ANDRÉS, BURTOLOSO ANTONIO CARLOS BENDER: "Direct Synthesis of α-Fluoro-α-Triazol-1-yl Ketones from Sulfoxonium Ylides: A One-Pot Approach", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 86, no. 17, 3 September 2021 (2021-09-03), pages 12427 - 12435, XP093130645, ISSN: 0022-3263, DOI: 10.1021/acs.joc.1c01441 *
GUO WENGANG, JIANG FENG, LI SHIJIA, SUN JIANWEI: "Organocatalytic asymmetric azidation of sulfoxonium ylides: mild synthesis of enantioenriched α-azido ketones bearing a labile tertiary stereocenter", CHEMICAL SCIENCE, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 13, no. 39, 12 October 2022 (2022-10-12), United Kingdom , pages 11648 - 11655, XP093130640, ISSN: 2041-6520, DOI: 10.1039/D2SC03552A *
PATONAY TAMOS, HOFFMAN ROBERT V.: "A General and Efficient Synthesis of .alpha.-Azido Ketones", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 59, no. 10, 1 May 1994 (1994-05-01), pages 2902 - 2905, XP093130642, ISSN: 0022-3263, DOI: 10.1021/jo00089a043 *

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