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WO2014012495A1 - Composé chiral d'α-méthylène-β-lactame, et procédé de préparation et application de ce dernier - Google Patents

Composé chiral d'α-méthylène-β-lactame, et procédé de préparation et application de ce dernier Download PDF

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WO2014012495A1
WO2014012495A1 PCT/CN2013/079543 CN2013079543W WO2014012495A1 WO 2014012495 A1 WO2014012495 A1 WO 2014012495A1 CN 2013079543 W CN2013079543 W CN 2013079543W WO 2014012495 A1 WO2014012495 A1 WO 2014012495A1
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丁奎岭
王晓明
孟繁烨
王正
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/10—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • the present invention relates to the field of medical chemistry, and in particular to a chiral ⁇ -methylene- ⁇ -lactam compound and a preparation method and application thereof. Background technique
  • Chiral ⁇ -lactams are a class of structural units that are widely found in natural products and drugs.
  • ⁇ -lactam antibiotics are a kind of drugs with ⁇ -lactam quaternary ring as the parent structure, which has extremely important significance in anti-infective clinical application because of its strong antibacterial action.
  • the synthesis of new antibiotics and their structural transformation are imminent. Therefore, the development of a highly efficient synthesis method for a novel ⁇ -lactam compound having pharmacological activity has important academic significance and potential application value.
  • the asymmetric allyl substitution reaction of the transition metal or small molecule catalyzed MBH adduct is prepared by chiral (X-methylene- ⁇ -aminocarboxylic acid derivative).
  • X-methylene- ⁇ -aminocarboxylic acid derivative An important method of the substance, but unfortunately, there has not been a weakly nucleophilic aromatic amine as a nucleophilic reagent, high region and enantioselective synthesis (X-methylene- ⁇ -arylaminocarboxylic acid derivative) Report. Summary
  • the present invention also provides the above chiral (X-methylene- ⁇ -lactam compound synthesis method, including its key intermediate chirality (Synthesis method of X-methylene- ⁇ -aminocarboxylic acid derivative.
  • a ⁇ -lactam structure is provided as shown in Formula I: Wherein R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted: d- 6 fluorenyl, C ⁇ . Cyclodecyl, C 6 _ 2 .
  • the aryl group means substitution with a substituent selected from the group consisting of halogen, Cr6 alkyl, d- 6 methoxy, d- 6 halogenated fluorenyl, -OR 11 , or -NR 12 ,
  • R u and R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl Base, tert-butyldiphenylsilyl or diphenylmethylsilyl;
  • the compound of formula I is in a configuration or an S configuration; or * indicates that the compound of formula I is a racemate.
  • the compound is:
  • the compound is a racemate composed of a compound of the formula 1-1 and a compound of the formula 1-2.
  • R, R 2 , * are as defined above.
  • the compound is of formula II Wherein Ar is selected from substituted or unsubstituted C 5 _ 2 .
  • the aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, C ⁇ alkyl, CM alkoxy, C haloalkyl, -OR 11 or -NR 12 wherein R U and R 12 are each Independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxy, benzyl, oxy-oxyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;
  • R and R 2 are not simultaneously a phenyl group.
  • R, R 2 , * are as defined above;
  • R 3 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl;
  • LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 2 Me), or bis(ethoxy)phosphinooxy (POEt 2 ).
  • the catalyst is reacted with the chiral phosphine ligand and the transition metal catalyst precursor in an inert gas atmosphere at -78 ° C to 100 ° C in an organic solvent. 1.0 hours.
  • the reaction is 0.5 to 0 at 25 ° C.
  • the molar ratio of the chiral phosphine ligand to the transition metal catalyst precursor is (1 to 10): 1. Preferably, it is (1 to 2): 1.
  • the transition metal catalyst precursor is a palladium catalyst precursor, which is Pd(OAc) 2 , PdCl 2 , Pd 2 (dba) 3 Pd 2 (dba) 3 'CHCl 3 , Pd (dba) 2 , one or more of [Pd(C 3 H 5 )Cl] 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(CH 3 CN)Cl 2 .
  • the chiral phosphine ligand has the following structure:
  • R 4 , R 5 , R 6 , and RRR 9 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted, alkyl, decyloxy, C 3 ⁇ C 3 o fluorenyl or aryl base;
  • R 1Q and R 11 are each independently selected from the group substituted or unsubstituted: 3 ⁇ 4 ⁇ .
  • X is selected from CH 2 , NH, NCH 3 , 0 or S
  • n 0 to 4;
  • the molar ratio of the base, R 2 —NH 2 to the compound of the formula 1 is from 1 to 10:1 to 10:1; and/or the catalyst The molar ratio to the compound of formula 1 is 0.00001 to 0.1:1.
  • the base is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, hydrazine, hydrazine-bis(trimethylsilyl)acetamide (BSA).
  • BSA hydrazine-bis(trimethylsilyl)acetamide
  • TBAT tetra-n-butylammonium difluorotriphenylsilicate
  • the molar ratio of the base to the compound of the formula 2 is from 1 to 10:1.
  • the molar ratio of the base to the compound of the formula 2 is from 1 to 2:1.
  • the reaction temperature of the step (b) is -80 ° C to 150 ° C, preferably -20 ° C to 110 ° C.
  • the reaction time is from 0.5 to 48 hours, preferably from 6 to 12 hours.
  • the base is bis(hexamethyldisilazide)tin (Sn[N(TMS) 2 ] 2 ), hexamethyldisilazide
  • Sn[N(TMS) 2 ] 2 hexamethyldisilazide
  • LHMDS lithium diisopropylamide
  • t-butylmagnesium chloride t-butylmagnesium bromide
  • isopropyl magnesium chloride isopropyl magnesium bromide.
  • the organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N, At least one of N-dimethylformamide or dimethyl sulfoxide.
  • the prevention or treatment is achieved by inhibiting the growth of tumor cells.
  • * represents a stereogenic center, in a configuration or an S configuration
  • RR 2 is independently selected from the group consisting of substituted or unsubstituted groups: d- 6 fluorenyl, C. Cyclodecyl, C 6 _ 2 .
  • Aryl refers to a substituent selected from the group of substituents: halogen, d- 6 alkyl, d- 6 alkoxy or - 6 haloalkyl, -OR U,
  • R U and R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyl Dimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl;
  • R 3 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.
  • a complex of a chiral phosphine ligand and a transition metal catalyst precursor is used as a catalyst to catalyze the asymmetric allyl amination reaction of R 2 —NH 2 with the compound of formula 1 under the action of a base.
  • R, R 2 , R 3 , and * are as defined above.
  • step (a) the selection of the organic solvent, base, chiral phosphine ligand, transition metal catalyst precursor and reaction conditions is the same as step (a) in the second aspect of the invention.
  • the aryl group means substitution with a substituent selected from the group consisting of halogen, C ⁇ alkyl, CM alkoxy, C haloalkyl, -OR 11 or -NR 12 wherein R U and R 12 are each Independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxy, benzyl, oxy-oxyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;
  • * indicates a stereogenic center, and the hydrazine compound is in a configuration or an S configuration; or * indicates that the compound of the formula II is a racemate.
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from the group consisting of substituted or unsubstituted: CM fluorenyl, Cw. Cyclodecyl, C 5 _ 2 .
  • the aryl group means substitution with a substituent selected from the group consisting of halogen, d- 6 alkyl, CM alkoxy, C haloalkyl, -OR 11 , or -NR 12 , wherein R U , R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl; X is derived from a nitrogen, oxygen or sulfur atom;
  • a formula VI is provided, the structure is as shown in the formula:
  • Ar is selected from substituted or unsubstituted C 5 _ 2 .
  • Aryl refers to a substituent selected from the group of substituents: halogen, d- 6 alkyl, CM alkoxy, CM haloalkyl, -OR 11, or -NR 12, wherein R U, R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;
  • Ar is selected from substituted or unsubstituted C 5 _ 2 .
  • Cyclodecyl C 5 _ 2 .
  • Aryl hydroxy or amino; said substitution means selected Substituted from the following group of substituents: halogen, d- 6 alkyl, CM alkoxy, CM haloalkyl, -OR 11 or -NR 12 , wherein R U ,
  • R 12 is each independently selected from the group consisting of hydrogen, acetyl, propionyl, t-butoxymethyl, benzyl, benzyloxy, trityl, trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl or diphenylmethylsilyl;
  • * indicates a stereogenic center, either a configuration or an S configuration; or a racemate.
  • Ar is selected from substituted or unsubstituted C 5 _ 2 .
  • the aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- 6 alkyl, CM alkoxy, CM haloalkyl, -OR U , or -NR 12 , wherein R U , R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;
  • R 3 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.
  • the preparation method of the compound of the formula VIII is similar to the preparation method of the compound of the formula 2.
  • the use of the compound of the sixth, seventh, eighth, or ninth aspect for the preparation of a medicament for preventing and/or treating a tumor is provided.
  • the prevention or treatment is achieved by inhibiting the growth of tumor cells.
  • the present invention uses a complex of a bisphosphine ligand of a chiral aromatic snail ketal skeleton and a metal palladium as a catalyst to realize a high region for the first time.
  • Fig. 1 is a view showing the single crystal structure of the compound -3d obtained in Example 16.
  • Example 2 is a single crystal structure diagram of the compound obtained in Example 36 (W ⁇ -Sa).
  • the inventors of the present application have extensively and intensively studied to prepare a novel chiral phosphine ligand, and use the phosphine ligand as a catalyst to realize a high region and a high enantioselectivity of the MBH adduct of the olefin.
  • a propylation reaction, a chiral ⁇ -amino group (X-methylene carboxylic acid derivative) is synthesized in one step, and a chiral biologically active ⁇ -lactam compound can be synthesized by one-step conversion. , has the effect of inhibiting tumor growth. On this basis, the present invention has been completed.
  • alkyl means a saturated linear or branched hydrocarbon moiety, such as -CH 3 or -CH (CH 3) 2.
  • alkoxy refers to a group formed by linking an alkyl group to an oxygen atom, such as -OCH 3 , -OCH 2 CH 3 .
  • cycloalkyl denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl.
  • aryl refers to a hydrocarbyl moiety containing one or more aromatic rings including, but not limited to, phenyl, benzyl, phenylene, naphthyl, naphthylene, anthracenyl, fluorenyl, phenanthryl.
  • alkyl, alkoxy, cycloalkyl, and aryl groups described herein include both substituted and unsubstituted moieties.
  • Possible substituents on the alkyl, alkoxy, cycloalkyl, and aryl groups include, but are not limited to: dC 6 alkyl, dC 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 block , C 3 -C 1 () cyclodecyl, C 3 -C 1 () cycloalkenyl, C r C 6 decyloxy, aryl, hydroxy, halogen, amino.
  • the phosphine ligand used in the present invention has the following
  • R 4 , R 5 , R 6 , RR ⁇ R 9 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted: a C 10 alkyl group, a Ci ⁇ C 4 alkoxy group, C a cycloalkyl or aryl group of 3 to C 3 o;
  • R 1Q and R 11 are each independently selected from the group consisting of a substituted or unsubstituted group: a C 3 -C 1Q cyclodecyl group, a ⁇ ⁇ fluorenyl group, a 2-furyl group, or an aryl group;
  • the substituted group is substituted with the following substituents: halogen, C r6 Huan group, halogenated d- 6 Huan group, or d- 6 Huan group.
  • the substituent group is substituted by mono-, di- or tri-substituted by: halo, C r6 Huan group, C r6 haloalkyl, or. ⁇ alkoxy.
  • R 4, R 5, R 6, R 7, R 8, R 9 are each independently selected from hydrogen, Huan group of ⁇ ⁇ ⁇ [4 alkoxy, C 3 ⁇ C 3Q of Cycloalkyl, halogen or phenyl;
  • R 1Q and R 11 are independently selected from a C 3 -C 1 ( cycloalkyl ) group, a C do alkyl group, a 2-furyl group, or a phenyl group, and the cycloalkyl group, the hospital group, and the phenyl group are optionally Substituted by the following substituents: halogen, d- 6 alkyl, d- 6 haloalkyl, or. ⁇ alkoxy.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, hydrazino group, ⁇ alkoxy group, and C 3 ⁇ C 1 () . Cyclodecyl, phenyl or halogen;
  • R u and R 1Q are each independently selected from a phenyl group, a substituted phenyl group, a C 3 ⁇ C 6 cycloalkyl group or a C 2 ⁇ C 6 alkyl group, and the substitution is monosubstituted, disubstituted or Trisubstituted: halogen, d- 6 fluorenyl, d- 6 halodecyl, or - 6 alkoxy;
  • X is selected from CH 2 , 0, NCH 3 , or 8.
  • R 4 and R 9 are the same group; R 5 and R 8 are the same group; and R 6 and R 7 are the same group.
  • R 1Q and R 11 are the same group.
  • the phosphine ligand is
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 1Q , R 11 are as defined above for the compound of formula 2
  • the compound of the formula 2 of the present invention has the following structure:
  • * indicates a stereogenic center, in a configuration, or an S configuration
  • RR 2 is independently selected from the group consisting of substituted or unsubstituted groups: d- 6 fluorenyl, C ⁇ . Cyclodecyl, C 6 _ 2 .
  • Aryl refers to a substituent selected from the group of substituents: halogen, d- 6 alkyl, d- 6 alkoxy or - 6 haloalkyl, -OR u, -N 12, wherein R u And R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl or diphenylmethylsilyl;
  • R 3 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.
  • R 3 is benzyl or adamantyl.
  • * represents a stereoisomer center, and the compound of formula 2 is in a configuration.
  • R and R 2 are each independently selected from the group consisting of substituted or unsubstituted: d- 6 fluorenyl, C 3 -1Q cyclodecyl; said substitution means selected from the group consisting of Substituent substitution: halogen, d- 6 alkyl, d- 6 alkoxy or d- 6 haloalkyl, -OR U ,
  • R u and R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyl Dimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl.
  • a complex of a chiral phosphine ligand and a transition metal catalyst precursor is used as a catalyst to catalyze the asymmetric allyl amination reaction of R 2 —NH 2 with the compound of formula 1 under the action of a base.
  • R, R 2 , R 3 , * are as defined above;
  • LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 2 Me), or bis(ethoxy)phosphinooxy (POEt 2 ).
  • the compound of formula 1 is a Morita-Baylis-Hillman adduct.
  • the organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide Or at least one of dimethyl sulfoxide.
  • the base is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, N,0-bis(trimethylsilyl)
  • BSA acetamide
  • TBAT tetra-n-butylammonium difluorotriphenylsilicate
  • An aqueous alkali solution such as an aqueous potassium carbonate solution may be used in a concentration of 0.1 to 8.0 moles per liter, preferably 0.5 to 5 moles per liter.
  • the base is an aqueous solution of potassium carbonate (1 to 2 moles per liter) or triethylamine.
  • the catalyst is obtained by reacting the chiral phosphine ligand and the transition metal catalyst precursor in an inert gas atmosphere in an organic solvent at -78 ° C to 100 ° C for 0.1 to 1.0 hours. Preferably, the reaction is carried out at 0 to 25 ° C for 0.5 to 1.0 hour.
  • R', RR 9 , R 1Q , and R 11 are as described above.
  • the transition metal catalyst precursor is a palladium catalyst precursor, which is Pd(OAc) 2 , PdCl 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 -CHC13, Pd(dba) 2 , [Pd(C 3 One or more of H 5 )Cl] 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , and Pd(CH 3 CN)Cl 2 .
  • the palladium catalyst precursor is [Pd(C 3 H 5 )Cl] 2 .
  • the molar ratio of the base, R 2 -NH 2 to the compound of formula 1 is 1 to 10: 1 to 10: 1;
  • the molar ratio of the catalyst to the compound of formula 1 is 0.00001 to 0.1:1.
  • the molar ratio of the base, R 2 -NH 2 to the compound of formula 1 is 1 to 3: 1 to 3: 1; and/or
  • the molar ratio of the catalyst to the compound is 0.01 to 0.05:1.
  • Forming a complex with a transition metal catalyst precursor as a catalyst catalyzes the reaction of R 2 -NH 2 with the compound of formula 1 to prepare a key intermediate compound of formula 2-1.
  • the complex with the transition metal catalyst precursor is used as a catalyst to catalyze the reaction of R 2 -NH 2 with the compound of formula 1 to prepare the enantiomer of the key intermediate compound of formula 2-1.
  • the compound of the formula I of the present invention is a type of ⁇ -methylene ⁇ -lactam compound having the following structure:
  • R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted: d- 6 fluorenyl, C ⁇ . Cyclodecyl, C 6 _ 2 .
  • the aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, Cr6 alkyl, d- 6 methoxy, d- 6 halogenated fluorenyl, -OR 11 , or -NR 12 ,
  • R u and R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl a tert-isobutyldiphenylsilyl or diphenylmethylsilyl; * represents a stereogenic center, and the compound of formula I is in a configuration or in an S configuration;
  • * represents a stereogenic center, and the compound of formula I is in a configuration.
  • the RR 2 each independently unsubstituted or substituted with a group selected from the following group: d- 6 Huan group, C 3 - 10 cycloalkyl; refers to the substituent selected from the group Substituent substitution: halogen, d- 6 alkyl, d- 6 alkoxy, d- 6 haloalkyl,
  • R u and R 12 are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl Base, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl; * represents a stereogenic center, and the compound of formula I is in the S configuration.
  • the RR 2 is independently selected from the group consisting of substituted C 6 _ 2 .
  • the aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- 6 alkyl, d- 6 haloalkyl, -OR 11 , or -NR 12 , wherein R u and R 12 are each independently Selected from hydrogen, acetyl, propionyl, tert-butoxy, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl a silyl group or a diphenylmethylsilyl group; * represents a stereogenic center, and the compound of formula I is in a configuration.
  • R 1 is selected from phenyl, optionally substituted by the following substituents: halogen, d- 6 alkyl, d- 6 haloalkyl, d- 6 alkoxy, -OR u , or -N 12 ;
  • R 2 is selected from d- 6 alkyl, C 3 -1( ) cycloalkyl, benzyl or substituted phenyl, optionally substituted by the following substituents: halogen, d- 6 alkyl, d- 6 haloalkyl , d- 6 alkoxy, -OR u , or -N 12 ;
  • R u and R 12 are as described above.
  • * represents a stereoisomer center
  • the compound of formula I is in the S configuration
  • R, R 2 are not phenyl or d- 6 alkoxy substituted phenyl.
  • * indicates that the compound of formula I is a racemate, and R, R 2 are not phenyl or d- 6 alkoxy substituted phenyl.
  • the substitution is a monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, preferably a monosubstituted, disubstituted, or trisubstituted.
  • the substituents may be the same or different, such as a -OR 11 substituted phenyl group, which may be substituted by 1, 2, 3 or 4 -OR 11 ,
  • Each R 11 is independently hydrogen, acetyl, propionyl, tert-butoxy, base, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl
  • the compound is:
  • a method of preparing a compound of formula I of the invention comprising the steps of:
  • R, R 2 , * are as defined above;
  • R 3 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl;
  • LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 2 Me), or bis(ethoxy)phosphinooxy (POEt 2 ).
  • the organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide Or at least one of dimethyl sulfoxide.
  • the base is bis(hexamethyldisilazide)tin (S n [N(TMS) 2 ] 2 ), hexamethyldisilazide lithium (LHMDS)
  • LHMDS hexamethyldisilazide lithium
  • LDA lithium diisopropylamide
  • tert-butylmagnesium chloride tert-butylmagnesium chloride
  • t-butylmagnesium bromide isopropylmagnesium chloride
  • isopropyl magnesium bromide isopropyl magnesium bromide.
  • the base is bis(hexamethyldisilazide)tin (Sn[N(TMS) 2 ] 2 ) or hexamethyldisilazide Lithium base (LHMDS).
  • the molar ratio of the base to the compound of the formula 2 is from 1 to 10:1.
  • the molar ratio of the base to the compound of the formula 2 is from 1 to 2:1.
  • the reaction temperature of the step (b) is -80 ° C to 150 ° C, preferably -20 ° C to 110 ° C.
  • the reaction time is from 0.5 to 48 hours, preferably from 6 to 12 hours.
  • the compound of the formula 2-1 is ring-closed under the action of a base to give a compound of the formula 1-1.
  • the enantiomer of the compound of formula 2-1 is cleaved under the action of a base to give a compound of formula 1-2.
  • the compound of the formula I, II, III, IV, V, VI, VII of the invention the leukemia cell HL60, the lung cancer cell A549, the hepatoma cell HepG-2, the breast cancer cell MDA-MB-231, the gastric cancer MKN-45 and the like
  • the cells have a significant inhibitory effect. Therefore, it is possible to prepare a medicament for preventing and treating cancer. Preferably, it is used for the preparation of a medicament for preventing/treating leukemia, lung cancer or liver cancer.
  • the medicament may be a pharmaceutical composition prepared from a compound of formula I, ⁇ , III, IV, V, VI, VII as an active ingredient together with a pharmaceutically acceptable excipient or carrier.
  • a “pharmaceutically acceptable excipient or carrier” may be one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • the compounds of formula I, ⁇ , III, IV, V, VI, VII of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as other antitumor drugs.
  • Representative anti-tumor drugs include (but are not limited to): cisplatin, carboplatin, camptothecin, doxorubicin, bleomycin, fluorouracil.
  • a novel class of ⁇ -lactam compounds are provided for the preparation of antitumor drugs.
  • aniline is used as a nucleophilic reagent
  • N,O-bis(trimethylsilyl)acetamide (BSA) is used as a base
  • BSA N,O-bis(trimethylsilyl)acetamide
  • a bisphosphine ligand (foot-size?)-La and a metal salt Pd 2 (dba) 3 are used.
  • the catalyst was prepared in situ to catalyze the asymmetric allyl amination of substrate la under different solvents. Reaction formula
  • aniline is used as a nucleophilic reagent
  • dichloromethane is used as a solvent
  • a bisphosphine ligand (scale)?-La and a metal salt Pd 2 (dba) 3 are used to prepare a catalyst in the presence of a different base.
  • Asymmetric allyl amination of la The reaction formula is as follows:
  • aniline is used as a nucleophilic reagent
  • dichloromethane is used as a solvent
  • a bisphosphine ligand (foot-size?)-La is used to prepare a catalyst in situ.
  • One mole per liter of potassium carbonate aqueous solution is used as a base, and the catalytic substrate is used.
  • Asymmetric allyl amination of la. The reaction formula is as follows:
  • the reaction was as follows: Under an argon atmosphere, a metal palladium salt precursor (0.01 mmol for palladium atoms) and (foot gauge? La (8.2 mg, 0.0125 mmol) were added to a schlenk tube, respectively, and anhydrous dichloromethane was added. (5 mL), after stirring at room temperature for 10 minutes, add the substrate la (117.1 mg, 0.5 mmol), aqueous potassium carbonate (1M, 1.5 mL, 1.5 mmol) and aniline (140 mg, 1.5 mmol). After three hours, it was extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give the product.
  • aniline is used as a nucleophilic reagent
  • dichloromethane is used as a solvent
  • a bisphosphine ligand strip-La and [Pd(C 3 H 5 )Cl] 2 is prepared in situ, and 1 mol per liter of potassium carbonate solution is used.
  • the reaction formula is as follows:
  • aniline is used as a nucleophile, and different bisphosphine ligands (scales L and metal salts [Pd(T!-C 3 H 5 )Cl] 2 are prepared in situ to catalyze the asymmetric olefin of the substrate lb.
  • the propyl amination reaction has the following reaction formula:
  • a different amine is used as a nucleophile
  • a bisphosphine ligand (foot-size?)-Lc and a metal salt [Pd(T!-C 3 H 5 )Cl] 2 are prepared in situ to catalyze the substrate lb.
  • Symmetrical allyl amination reaction (reaction formula is as follows):
  • an aniline is used as a nucleophilic reagent, a bisphosphine ligand (scale)?-Lc and a metal salt [Pd(T!-C 3 H 5 )Cl] 2 are prepared in situ to catalyze the asymmetric olefin of the substrate 1.
  • Propyl amination reaction (reaction formula is as follows):
  • p-methoxyaniline is used as a nucleophilic reagent
  • a bisphosphine ligand (scale)?-Lc and a metal [Pd(C 3 H 5 )Cl] 2 are used as catalysts in the field to catalyze a substrate.
  • Asymmetric allyl amination of lc (reaction formula is as follows):
  • 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is combined with a metal [Pd(C 3 H 5 )C in situ to prepare a complex as a catalyst.
  • Catalytic substrate lc reaction formula is as follows):
  • 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is combined with a metal [Pd(C 3 H 5 )C in situ to prepare a complex as a catalyst.
  • Asymmetric allyl amination reaction of the substrate Id (reaction formula is as follows):
  • 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is prepared in situ with a metal [Pd(C 3 H 5 )Cl] 2 complex.
  • Example 12 In this embodiment, p-fluoroaniline is used as a nucleophile, a bisphosphine ligand (scale)?-Lc and a metal [Pd(C 3 H 5 )Cl] 2 3 ⁇ 4 field are used as a catalyst to catalyze a substrate.
  • compound 2b was used as a substrate to cyclize to produce ⁇ -lactam 3b under the action of bis(hexamethyldisilazide)tin (Sn[N(TMS) 2 ]2).
  • the reaction formula is as follows
  • the compound 2c is used as a substrate, and the ⁇ -lactam 3c is cyclized by the action of bis(hexamethyldisilazide)tin (Sn[N(TMS) 2 ]2). Reaction formula
  • ⁇ -lactam is prepared by cyclization of compound 2c as a substrate under the action of lithium hexamethyldisilazide (LHMDS).
  • LHMDS lithium hexamethyldisilazide
  • the ⁇ -lactam 3d was prepared by the method of Example 14.
  • reaction was as follows: substrate 2d (360.2 mg, 1.0 mmol of BSn [N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) was added to a Schlenk tube, anhydrous toluene (5 mL) was added and the mixture was heated to reflux for 3-12 hours. After cooling to room temperature, it was concentrated and purified by column chromatography.
  • Fig. 1 is an X-ray crystal diffraction pattern of the compound 3d obtained in the present Example. From Fig. 1, it was confirmed that the obtained compound 3d had an absolute configuration of (5). The absolute configuration of the compounds 3a-3c, 3e-3u prepared in Examples 13-15, 17-33 was determined by comparison with the Cotton effect of (5)-3d, and the absolute configuration was (5).
  • reaction was as follows: substrate 2e (360.2 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3f was prepared by the method of Example 14.
  • reaction was as follows: substrate 2 h (371.4 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3 ⁇ was prepared by the method of Example 14.
  • reaction was as follows: substrate 2i (295.1 mg, 1.0 mmol) and Sn[N(TMS) 2 ]2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After hours, after concentration, purification by column chromatography.
  • the ⁇ -lactam 3j was prepared by the method of Example 14.
  • reaction was as follows: substrate 2j (295.1 mg, 1.0 mmol) and Sn[N(TMS) 2 ]2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3k was prepared by the method of Example 14.
  • reaction was as follows: substrate 2k (295.1 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added, and heated to reflux for 3-12 hours. After cooling to room temperature, concentration and purification by column chromatography.
  • the ⁇ -lactam 31 was prepared by the method of Example 14.
  • the ⁇ -lactam 3n was prepared by the method of Example 14.
  • reaction was as follows: substrate 2n (359.0 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3 After -12, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3o was prepared by the method of Example 14.
  • the ⁇ -lactam 3p was prepared by the method of Example 14.
  • reaction was as follows: substrate 2p (315.7 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 , concentrated, purified by column chromatography.
  • reaction was as follows: substrate 2q (341.1 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3r was prepared by the method of Example 14.
  • reaction was as follows: substrate 2r (401.4 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • the ⁇ -lactam 3s was prepared by the method of Example 14.
  • the ⁇ -lactam 3t was prepared by the method of Example 14.
  • the ⁇ -lactam 3u was prepared by the method of Example 14.
  • reaction was as follows: substrate 2u (389.1 mg, 1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.
  • Collect log phase leukemia cell HL60 cells adjust the cell suspension concentration to a cell concentration of 2.5 X 10 4 /ml, per well (96 The wells were added to the cell suspension 90 ⁇ l, and the compounds of the formula 3a to 3u ⁇ /well of different concentration gradients were added, and 4 wells were inoculated at each concentration as repeated experiments to improve the accuracy of the experimental data. In addition, there is a separate zero hole on each plate (only culture medium, no cells and drugs).
  • the culture was continued in the incubator until the third day, and the inhibitory effect of the compound of the formula 3a ⁇ 3u on the leukemia cell line HL60 was detected by the Methyl-Thiazol-Tetrozolium (MTT) reduction method, and the compound 3a-3u was detected on the leukemia cell.
  • HL60 half-inhibitory concentration IC 5 o).
  • the half-inhibitory concentration (IC 5 o) of compound 3a-3u on leukemia cell HL60 was lower than 8 ( ⁇ g mL, in which compound 3b, 3c, 3t, 31, 3s, 3u, etc., half-inhibitory concentration of leukemia cell HL60 (IC) 50 ) is about 20-3 ( ⁇ g/mL ; compound 3g, 3h, 3j, 3k, 3m, 3r, etc.
  • the half-inhibitory concentration (IC 5 Q) of leukemia cells HL60 is about 0.1-10 ⁇ 3 ⁇ 4 ⁇ ; 3g, 3h, 3k , 3m, 3r and other HL60 half-inhibitory concentration (IC 5 o) of leukemia cells 1 g / mL.
  • the logarithmic lung cancer cells A549 were collected, and the cell suspension concentration was adjusted so that the cell concentration was 2 X 10 4 /ml, and 100 ⁇ l of the cell suspension was added to each well (96-well plate) to make the number of cells in each well 4000. After the cells were cultured for 24 hours in the incubator, the culture solution was aspirated and 100 ⁇ l of each of the compounds of the formula 3a to 3u with different concentration gradients were added, and 4 wells were inoculated as repeated experiments to improve the accuracy of the experimental data. And set the corresponding vehicle control and cell-free zeroing. The culture was continued for 72 hours.
  • the inhibitory effect of the compound of formula 3a ⁇ 3u on lung cancer cell A549 was determined by sulforhodamine B (SRB) protein staining method.
  • SRB sulforhodamine B
  • the culture solution was decanted and added with ice precooled 10% of three.
  • the cells were fixed in chloroacetic acid solution, left at 4 ° C for 1 h, washed 5 times with distilled water, and naturally dried in the air. Then a 4 mg/ml SRB (Sigma, St Louis, MO, USA) solution was added, stained for 15 min at room temperature, de-stained, washed 5 times with 1% glacial acetic acid, and air dried.
  • the Tris solution pH 10.5 was added, and the OD value was measured at a wavelength of 515 nm using a tunable wavelength microplate reader (VERSAmaxTM, Molecular Device Corporation, Sunnyvale, CA, USA), and the IC 50 value was calculated by the Logit method.
  • a tunable wavelength microplate reader VERSAmaxTM, Molecular Device Corporation, Sunnyvale, CA, USA
  • the half-inhibitory concentration (IC 5 ) of 3e, 3f, 3q, etc. on lung cancer cells A549 is about 20-5 ( ⁇ g/mL; compound 3i, 3j, 31, 3m, 3t, 3u, 3g, etc.
  • Concentration CIC 5Q ) is about 0.1-2 ( ⁇ g mL ; among them, 3i, 3j, 31, 3m, etc., half-inhibitory concentration of lung cancer cells A549 (IC 5 Q) l ( ⁇ g mL.
  • the compound 30a prepared in Example 35 was a hydrogenated substrate, and the compound 7a was used as a catalyst (catalyst 7a) to prepare a chiral aromatic
  • the reaction was carried out as follows: 30a (46.4 mg, 0.1 mmol), Catalyst 7a (1.6 mg, EtOAc, EtOAc)
  • hydrogen gas was charged to 50 atm, and reacted at room temperature for 24 hours.
  • the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography.
  • the yield of ( ⁇ J?)-5a was 93% and the ee value was >99%.
  • Fig. 2 is an X-ray crystal diffraction pattern of the compound obtained in the present example, and the obtained compound was confirmed from Fig. 2
  • the absolute configuration of -5a is (foot-size?), and the absolute configuration of the chiral aromatic spiroketal compound 5b-5j prepared in the following examples is determined by comparison with the Cotton effect of (scale)? .
  • Catalyst 7a was prepared by the method of Angew. Chem. Int. Ed. 2009, 48, 5345.
  • the compound 30b prepared in Example 35 was a hydrogenated substrate, and the compound 7a was used as a catalyst to prepare a chiral aromatic snail ketal compound (i?J?J?)-5b.
  • the reaction was as follows: 30b (49.2 mg, 0.1 mmol), Catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of anhydrous dichloromethane was added to a hydrogenated flask and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After venting the hydrogen, the reactor was opened, the solvent was removed under reduced pressure, and the product was determined by nuclear magnetic resonance. In contrast, the residue was separated by column chromatography. The yield of ( ⁇ -5b was 85% and the ee value was >99%.
  • the compound 30c prepared in Example 35 was a hydrogenated substrate, and Compound 7a was used as a catalyst to prepare a chiral aromatic snail ketal compound (i?J?J?)-5c.
  • the reaction was carried out as follows: 30c (53.3 mg, 0.1 mmol), Catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of water-free methylene chloride was placed in a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield obtained was 86% and the 66 value was >99%.
  • the compound 30d prepared in Example 35 was a hydrogenated substrate, and a chiral aromatic snail ketal compound (i?J?J?)-5d was prepared using the compound 7a as a catalyst.
  • the reaction was carried out as follows: 30d (49.2 mg, 0.1 mmol), Catalyst 7a (3.2 mg, 0.002 mmol), 2 mL of water-free chloroform was added to a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield of ( ⁇ -5d was 88%, and the value of 66 was >99%.
  • Example 35 The compound prepared in Example 35 was a hydrogenated substrate, and the optically active chiral aromatic spiroke compound ⁇ )-51 was prepared using Compound 7a as a catalyst.
  • the reaction was carried out as follows: 30 h (45.0 mg, 0.1 mmol), catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of anhydrous dichloromethane was added to a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the residue was separated by column chromatography. Yield ( ⁇ )-5h, yield 60%. The ee value is 95%. After one step of recrystallization, it can reach >99% ee.
  • the compound 30a prepared in Example 35 was a hydrogenated substrate, and the compound 7b was used as a catalyst to prepare a chiral aromatic spiroke compound (&&5)-5a.
  • the reaction was carried out as follows: 30a (46.4 mg, O.lmmol), catalyst 7b (1.6 mg, 0.001 mmol), 2 mL of water-free chloroform was added to a hydrogenated bottle, and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield of 0 ⁇ ,5)-5a was found to be 91%, and the ee value was >99%.
  • Example 38 Referring to the method of Example 6, using p-fluoroaniline as a nucleophilic reagent, a bisphosphine ligand (&&5)-La and a metal salt [Pd(C 3 H 5 )Cl] : a site-forming complex as a catalyst, a catalytic bottom Asymmetric allyl amination of substance lb gives the formula (-2).
  • Reference Example 14 is a compound of the -3c compound.
  • Example 6 using cyclohexylamine, n-butylamine and benzylamine as nucleophiles, bisphosphine ligands 0S, 5)-La and metal salts [Pd(C 3 H 5 )Cl] 2 in situ preparation
  • the complex acts as a catalyst to catalyze the asymmetric allyl amination of substrate lb to give compounds of formula (i?)-2v, (R)-2w, (R)-2x, respectively.
  • Example 6 using p-benzyloxyaniline as a nucleophilic reagent, a bisphosphine ligand &5)-La and a metal [Pd(C 3 H 5 )Cl] 2 in situ preparation of a complex as a catalyst, a catalytic bottom Asymmetric allyl amination of the lg to give a compound of formula (i?)-2y.
  • the bisphosphine ligand (&&5)-La and the metal salt [Pd(C 3 H 5 )Cl] 2 were prepared in situ. It was used as catalyst, the catalytic substrate lh asymmetric allylic amination reaction formula (-22 compound.
  • Example 14 a compound of the formula (R)-2y, (R)-2z was used as a substrate to prepare a ⁇ -lactam compound of the formula (R)-3y, (R)-3z.
  • the value is lower than 6 ( ⁇ g/mL, and the two compounds (R)-3y and (R)-3z exhibit IC 5 G values even lower than 10 ⁇ / ⁇ , ⁇ , prepared in Examples 40 and 43
  • the inhibitory effect of the compound on lung cancer cell ⁇ 549 showed IC 5 .
  • the value was lower than 55 g mL, while the (R)-3v, (R)-3w compound showed IC 5 value.
  • the ligand (&?)-lc can be used to prepare the compound (i?)-2aa, 2ab, 2ac, 2ad.
  • the racemic compound 2aa, 2ab, 2ac, 2ad can be prepared correspondingly using racemic ligands.
  • a compound of the formula (5)-2aa, 2ab, 2ac, 2ad was used as a substrate to prepare a ⁇ -lactam (S)-3aa, 3ab, 3ac, 3ad compound.
  • the reaction was as follows: Substrate (1.0 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were placed in a Schlenk tube, anhydrous toluene (5 mL) was added, and cooled to room temperature. Reduction, column chromatography purification.
  • racemic product (i?)-3aa, 3ab, 3ac, 3ad can be prepared accordingly.
  • the racemic compound 2a e ⁇ 2ap can be prepared correspondingly using racemic ligands.
  • a compound of the formula (5)-2ae ⁇ 2ap was used as a substrate to prepare a ⁇ -lactam compound of the formula (5)-3ae ⁇ 3ap.
  • the reaction was as follows: Substrate (10 mmol) and Sn[N(TMS) 2 ] 2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added, heated to reflux for 3-12 hours, cooled to After room temperature, it was concentrated and purified by column chromatography.
  • racemic product 3ae ⁇ 3ap can be prepared accordingly.
  • the compound (S)-4s was prepared from the compound (S)-3s.
  • the procedure was as follows: 3s (415 mg, 1 mmol) was added to the reaction vessel, and 5 ml of ethyl acetate, 10% Pd/C (40 mg) was added, and the reaction vessel was charged and charged with 5 atmospheres of hydrogen. After reacting at room temperature for 6 hours, the reaction kettle was opened, and after concentration, column chromatography was performed.
  • Compound (S)-4s was prepared starting from compound (S)-3s. The procedure is as follows: Add 3s (325 mg, 1 mmol), acetone 5 ml, N-methyl-N-oxidized morpholine C175 mg, 1.5 mol) and osmium tetroxide in a 25 ml reaction flask (0.1 ml, 2%) Stir at room temperature for 12 hours. Quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, partitioned and evaporated.
  • Compound 0S)-4ab was prepared starting from compound 0S)-3ab. The procedure is as follows: Add 3ab (369 mg, 1 mmol), tetrahydrofuran 5 ml to 50 ml of Schlenk, cool to zero degrees Celsius, slowly add borane in tetrahydrofuran solution (1.2 ml, 1 M), return to room temperature, continue stirring for 5 hours. . Aqueous sodium hydroxide solution (2 ml, 1 M), hydrogen peroxide (30%, 3 ml) was added, and the mixture was stirred at room temperature for 2 hr.
  • Compound 0S)-4u was prepared starting from compound 0S)-3u. The procedure was as follows: 3 ml (343 mg, 1 mmol), anhydrous toluene 5 ml, ⁇ - ⁇ -diphenylnitrone (240 mg, 1.2 mmol) were added to 50 ml of Schlenk, and heated under reflux for 6 hours. After cooling to room temperature, concentrate and purify by column chromatography.
  • Compound 0S)-4aa was prepared starting from compound 0S)-3aa. The procedure is as follows: Add 3aa (353 mg, 1 mmol), tetrahydrofuran 5 ml, hydrobromic acid (2 ml) to a 25 ml round bottom flask, react at room temperature for 5 hours, neutralize with saturated aqueous sodium hydrogencarbonate, and extract with dichloromethane. Liquid, organic.
  • Compound 5ab was prepared starting from compound 4ab. The procedure was as follows: 3 ml (369 mg, 1 mmol), tetrahydrofuran 5 ml was added to 50 ml of Schlenk, and the mixture was cooled to zero degrees Celsius. A solution of boron hydride in tetrahydrofuran (1.2 ml, 1 M) was added dropwise. After returning to room temperature, stirring was continued for 5 hours. . Add sodium hydroxide aqueous solution (2ml, 1M), hydrogen peroxide (30%, 3 ml), stir at room temperature for 2 hours, quench with saturated aqueous sodium thiosulfate, extract with dichloromethane, partition, organic phase and column chromatography purification.
  • Compound 5aa was prepared starting from compound 4aa. The procedure is as follows: 4aa (434 mg, 1 mmol), anhydrous tetrahydrofuran 5 ml, n-butylamine (109 mg, 1.5 mmol), and heated under reflux for 5 hours. The organic phase is concentrated and purified by column chromatography.
  • Compound 5u was prepared starting from compound 3u. The procedure is as follows: Add 3u (343 mg, 1 mmol), anhydrous toluene 5 ml, palladium acetate (22 mg, 0.1 mmol), triphenylphosphine (57 mg, 0.22 mmol), potassium carbonate (207 mg, 50 ml) to a 50 ml Schlenk tube. 1.5 mmol), phenylboronic acid C 146 mg, 1.2 mmol), heated under reflux for 5 hours, and the organic phase was concentrated and purified by column chromatography.
  • the tumor cell inhibiting effects of the compounds prepared in Examples 46, 48 and 49 to 60 were tested by the method of Example 34.
  • the results showed that the inhibitory effects of the compounds prepared in Examples 46, 48 and 49-60 on leukemia cell HL60 showed an IC 50 value of less than 20 gmL, while (5)-3ah ⁇ (5)-3ap, racemic 5aa, 5ab , 5u and (i?)-3aa-3ad exhibit IC 5 o values even below 10 gmL; the compounds prepared in Examples 46, 48 and 49-60 inhibited lung cancer cell A549 and showed IC 5Q values lower than 15 g/mL, and (5)-4u, (S)-4r, (5)-5 and (i?)-3al!
  • the ⁇ (i?)-3ap compound exhibits an IC 5 Q value range of even less than 10 ⁇ mL, which has a good inhibitory effect on tumor cells.

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Abstract

L'invention porte sur un composé chiral d'α-méthylène-β-lactame et sur un procédé de préparation et une application de ce dernier. Le procédé selon l'invention comprend une étape clé au cours de laquelle on procède à une réaction asymétrique d'amination d'allyles en catalysant une classe d'adduits de Morita-Baylis-Hillman au moyen d'un complexe formé d'un ligand phosphine chiral et d'un palladium métallique comme catalyseur, ladite étape permettant d'obtenir un dérivé chiral central clé d'acide amino-carboxylique α-méthylène-β-substitué avec une activité et une sélectivité élevées, et une étape de cyclisation permettant d'obtenir un composé d'α-méthylène-β-lactame chiral. Cette classe de composés possède une activité antitumorale.
PCT/CN2013/079543 2012-07-20 2013-07-17 Composé chiral d'α-méthylène-β-lactame, et procédé de préparation et application de ce dernier Ceased WO2014012495A1 (fr)

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WO2017167183A1 (fr) * 2016-03-29 2017-10-05 复旦大学 Composé de diaryl-b-lactame et son procédé de préparation et utilisation pharmaceutique associée
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CN105985378A (zh) * 2015-01-28 2016-10-05 中国石油天然气股份有限公司 一种含氮、磷配位原子的多齿有机配体的合成方法
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