CN106831522A

CN106831522A - Lactam analog compound and preparation method thereof

Info

Publication number: CN106831522A
Application number: CN201510882223.XA
Authority: CN
Inventors: 余金权; 戴辉雄; 孔维俊; 刘悦进; 徐辉
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2015-12-03
Filing date: 2015-12-03
Publication date: 2017-06-13
Anticipated expiration: 2035-12-03
Also published as: CN106831522B

Abstract

The invention discloses lactam analog compound and preparation method thereof.Preparation method of the invention includes：In the presence of atent solvent, under the catalysis of palladium catalyst, in the presence of oxidant, compound of formula I is reacted with Formula II compound, obtained formula III or formula IV compound.Preparation method of the invention can be used air as oxidant, and without any additive, reaction speed is fast, and reaction system is clean, and the accessory substance of reaction is only a molecule H₂O, very atom economy, meet economic and environment-friendly sustainable development technical requirements, and easy to operate, can implement in a mild condition, with low cost.

Description

Lactam analog compound and preparation method thereof

Technical field

The present invention relates to organic synthesis field, and in particular to lactam analog compound and preparation method thereof.

Background technology

Nitrogen heterocyclic ring is the common compound of a class in organic chemistry, is widely present in natural products and life In thing bioactive molecule.Wherein, beta-lactam antibiotic due to its good effect small toxicity, it has also become mesh The important drugs of preceding treatment infectious diseases.The a large amount of of antibiotic use so that the drug resistance enhancing of bacterium, The structure of such medicine is chemically modified and synthesized, is always doctor to research and develop the more preferable antibiotic of drug effect The important goal of medicine circle.Synthesize the main method of such compound at present for cycloaddition reaction, for example：1、 [2+2] cycloaddition reaction (Studinger reactions) of ketenes and imines；2nd, the condensation of enol ester and imines Reaction (Gilman and Speeter reacts)；3rd, addition of the metal carbene to imines；4th, alkene is to different The addition reaction of cyanate；5th, addition reaction of the cyclopropylamine to carbonyl.There is reaction in these methods Thing prepares complicated, substrate narrow application range, the low various deficiencies of yield.

In recent years, transition metal-catalyzed C-H bond activation reactions have become grinding for organic chemistry filed Study carefully focus.C-H keys can be converted into by useful functional group with a step using the method, it is not necessary to anti- Answer thing carries out function dough in advance, embodies Atom economy and step economy.But utilize C-H The example that the step of method one of bond activation builds the four-membered ring beta-lactam report with tension force is still less.Example Such as, Shi et al. using divalent palladium realize benzyl position C-H bond activation intramolecular aminating reactions, synthesis β- Lactams [Angew.Chem.Int.Ed.2013,52,13588. such as Shi, B.-F.].Cramer et al. is utilized Zeroth order palladium is reacted by the C-H bond activations C―C bond formation of benzyl position as catalyst and constructs beta-lactam Four-membered ring [Angew.Chem.Int.Ed.2014,53,9064. such as Cramer, N.].But in above-mentioned example Substrate is limited in scope, activation be benzyl position C-H.Urged using cheap metal Cu, Ni, Fe etc. C-H the bond activations of change there has also been certain development.Such as Ge Haibo et al. successively report CuCl and Ni(dme)₂I₂The sp of catalysis³The amination of C-H bond activation intramoleculars builds reaction [Ge, H. etc. of beta-lactam Angew.Chem.Int.Ed.2014,53,3706；The Chem.Eur.J.2014,20,9530. such as Ge, H.]. These reactions still have many weak points, such as generally need to add substantial amounts of metal onidiges in reacting, Such as silver salt or mantoquita, the temperature of simultaneous reactions is higher, compatible very poor for heterocycle.Therefore utilize The strategy of C-H bond activations, develops more environmental protection, and economical and energy saving, method easy to operate builds Nitrogen heterocyclic ring, particularly beta-lactam and gamma-lactam, are always the target of organic chemist's pursuit.

The content of the invention

The technical problems to be solved by the invention are, there is provided a kind of lactam analog compound and its preparation Method.Carbon-hydrogen bond activation site of the invention is special, is not only limited to benzyl position of the prior art, is interior The preparation of amides compound provides a kind of new direction.

The invention provides a kind of lactam analog compound, it is compound or the formula IV institute shown in formula III The compound for showing：

Wherein, R¹、R²、R³It is each independently selected from hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or Undersaturated aliphatic alkyl, substituted or unsubstituted C₁~C₂₀It is alkoxy, substituted or unsubstituted C₁~C₂₀Alkylthio group, substituted or unsubstituted methylene-dioxy, halogen, nitro, cyano group ,-CO₂R⁶、 -OC(O)R⁷、-P(O)(R⁸)(R⁹)、-P(O)(OR¹⁰)(OR¹¹)、-SO₂NR¹²R¹³、-NR¹⁴R¹⁵、 -C(O)NR¹⁶R¹⁷, substituted or unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₆~C₁₄Aryloxy group, Substituted or unsubstituted C₂~C₉Heteroaryl, substituted or unsubstituted C₂~C₉Heterocyclic radical；Or R¹、R²、 R³The carbon atom being directly connected collectively forms substituted or unsubstituted C₃~C₆Cycloalkyl, or take Generation or unsubstituted C₂~C₉Heterocyclic radical；But R in formula IV compound²It is not hydrogen；

R⁶It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R⁷It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R⁸It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R⁹It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹⁰It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹¹It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹²It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹³It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₆~C₁₄Aryl sulfonyl, substitution or unsubstituted C₁~C₁₀Alkyl sulphonyl, substituted or unsubstituted C₁~C₁₀Acyl group, substituted or unsubstituted C₂~C₉ Heteroaryl, or substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹⁴It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₆~C₁₄Aryl sulfonyl, substitution or unsubstituted C₁~C₁₀Alkyl sulphonyl, substituted or unsubstituted C₁~C₁₀Acyl group, substituted or unsubstituted C₂~C₉ Heteroaryl, or substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹⁵It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹⁶It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R¹⁷It is hydrogen, substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution or Unsubstituted C₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or it is substituted or unsubstituted C₂~C₉Heterocyclic radical；

R⁴It is substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution do not take The C in generation₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or substituted or unsubstituted C₂~C₉ Heterocyclic radical；

R⁵It is substituted or unsubstituted C₁~C₂₀Saturation or undersaturated aliphatic alkyl, substitution do not take The C in generation₆~C₁₄Aryl, substituted or unsubstituted C₂~C₉Heteroaryl, or substituted or unsubstituted C₂~C₉ Heterocyclic radical；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀When saturation or substituted undersaturated aliphatic alkyl, replace base It is one or more, and selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, do not take The C in generation₁~C₂₀Alkoxy, halo C₁~C₂₀Alkyl, hydroxyl, unsubstituted C₆~C₁₄Aryl；

R¹、R²And R³In, described C₁~C₂₀When alkoxy is substituted, substitution base is one or more, And selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkane Epoxide, halo C₁~C₂₀Alkyl, hydroxyl, unsubstituted C₆~C₁₄Aryl；

R¹、R²And R³In, described C₁~C₂₀When alkylthio group is substituted, substitution base is one or more, And selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkane Epoxide, halo C₁~C₂₀Alkyl, hydroxyl, unsubstituted C₆~C₁₄Aryl；

R¹、R²And R³In, when described methylene-dioxy is substituted, substitution base is one or more, And selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkane Epoxide, halo C₁~C₂₀Alkyl, hydroxyl, unsubstituted C₆~C₁₄Aryl；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄When aryl is substituted, substitution base is one or more, and is selected from One or more of：Unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀It is alkoxy, unsubstituted C₆~C₁₄Aryl, unsubstituted C₂~C₉Heteroaryl, halogen, halo C₁~C₂₀It is alkyl, unsubstituted C₁~C₁₀Acyl group ,-NR¹³R¹⁴、-CO₂R⁷, cyano group and phosphono；

R¹、R²And R³In, described C₆~C₁₄When aryloxy group is substituted, substitution base is one or more, And selected from one or more of：Unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkoxy, Halo C₁~C₂₀Alkyl, halogen and unsubstituted C₁~C₁₀Acyl group；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉When heteroaryl is substituted, substitution base is one or more, and is selected from One or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkoxy, Halo C₁~C₂₀Alkyl, unsubstituted C₁~C₁₀Acyl group and tertbutyloxycarbonyl (Boc)；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉When heterocyclic radical is substituted, substitution base is one or more, and is selected from One or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkoxy, Halo C₁~C₂₀Alkyl and unsubstituted C₁~C₁₀Acyl group；

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉Heteroaryl and C₂~C₉In heterocyclic radical, hetero atom be nitrogen, oxygen and One or more in sulphur；

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆Cycloalkanes Base, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical is by one Or multiple substitution bases selected from one or more of are replaced：Halogen, unsubstituted C₁~C₂₀Alkyl, Halo C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkoxy and unsubstituted C₁~C₁₀Acyl group；

R¹³And R¹⁴In, described C₆~C₁₄When aryl sulfonyl is substituted, substitution base is one or many It is individual, and selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀ Alkoxy and halo C₁~C₂₀Alkyl；

R¹³And R¹⁴In, described C₁~C₁₀When alkyl sulphonyl is substituted, substitution base is one or many It is individual, and selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀ Alkoxy and halo C₁~C₂₀Alkyl；

R¹³And R¹⁴In, described C₁~C₁₀When acyl group is substituted, substitution base is one or more, and Selected from one or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alcoxyl Base and halo C₁~C₂₀Alkyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀Saturation or the preferred C of undersaturated aliphatic alkyl₁~C₁₀Saturation or Undersaturated aliphatic alkyl, more preferably C₁~C₅Saturated aliphatic hydrocarbons, most preferable, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group or the tert-butyl group.

R¹、R²And R³In, described C₁~C₂₀The preferred C of alkoxy₁~C₁₀Alkoxy, more preferably methoxy Base, ethyoxyl or isopropoxy.

R¹、R²And R³In, described C₁~C₂₀The preferred first sulfydryl of alkylthio group, second sulfydryl or the third sulfydryl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄The preferred C of aryl₆~C₁₀Aryl, more preferably phenyl or naphthyl.

R¹、R²And R³In, described C₆~C₁₄The preferred C of aryloxy group₆~C₁₀Aryloxy group, more preferably benzene oxygen Base or naphthoxy.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉The preferred C of heteroaryl₄~C₈Heteroaryl, more preferably furyl, benzo Furyl, thienyl, benzothienyl, indyl, isoindolyl, pyrrole radicals, thiazolyl, oxazoles Base, pyrazolyl, imidazole radicals, pyranose, pyridazinyl, pyrazinyl, pyrimidine radicals, pyridine radicals, quinolyl, Isoquinolyl or carbazyl, most preferably thienyl, furyl, pyridine radicals or indyl.Described C₂~C₉ Preferred carbon atom is connected with precursor structure in heteroaryl.As described C₂~C₉When heteroaryl is substituted, take Dai Ji is preferably replaced on hetero atom.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉The preferred C of heterocyclic radical₄~C₈Heterocyclic radical, more preferably tetrahydric quinoline group, Tetrahydro indole base, oxazolinyls, pyrrolin base, tetrahydro pyridyl, tetrahydrofuran base, morpholinyl, Piperazinyl, piperidyl, pyrrolinyl or imidazolinyl.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted or unsubstituted C₃~C₆During cycloalkyl, described C₃~C₆The preferred cyclopenta of cycloalkyl or cyclohexyl.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted or unsubstituted C₂~C₉During heterocyclic radical, described C₂~C₉Unfixed four to seven yuan of the preferred hetero atom position of heterocyclic radical is miscellaneous Cyclic group, more preferably dihydrofuran base, THP trtrahydropyranyl, pyrrolin base or tetrahydro pyridyl.

R¹³And R¹⁴In, described C₆~C₁₄The preferred benzenesulfonyl of aryl sulfonyl, p-toluenesulfonyl Or benzyl sulfonyl.

R¹³And R¹⁴In, described C₁~C₁₀The preferred mesyl of alkyl sulphonyl or ethylsulfonyl.

R¹³And R¹⁴In, described C₁~C₁₀The preferred acetyl group of acyl group, propiono or phenylacyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀It is described in the substitution base of saturation or undersaturated aliphatic alkyl C₁~C₂₀The preferred C of alkyl₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀It is described in the substitution base of saturation or undersaturated aliphatic alkyl C₁~C₂₀The preferred C of alkoxy₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or Isopropoxy.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀It is described in the substitution base of saturation or undersaturated aliphatic alkyl Halo C₁~C₂₀The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₁~C₂₀It is described in the substitution base of saturation or undersaturated aliphatic alkyl C₆~C₁₄The preferred phenyl or naphthyl of aryl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀Alkyl It is preferred that C₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀Alcoxyl The preferred C of base₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described halo C₁~C₂₀ The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₆~C₁₄Aryl It is preferred that phenyl or naphthyl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀Alkyl It is preferred that C₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀Alcoxyl The preferred C of base₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described halo C₁~C₂₀ The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₆~C₁₄Aryl It is preferred that phenyl or naphthyl.

R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀Alkyl is excellent Select C₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀Alkoxy It is preferred that C₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²And R³In, in the substitution base of described methylene-dioxy, described halo C₁~C₂₀Alkane The preferred halo C of base₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₆~C₁₄Aryl is excellent Select phenyl or naphthyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀The preferred C of alkyl₁~C₁₀ Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀Alkoxy is preferred C₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₆~C₁₄The preferred phenyl of aryl Or naphthyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₂~C₉The preferred pyrrole of heteroaryl Pyridine, furans, thiophene or indoles.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described halo C₁~C₂₀Alkyl is preferred Halo C₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₁₀The preferred acetyl of acyl group Base, propiono or phenylacyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described-NR¹³R¹⁴It is preferred that N, N- bis- Methyl or N, N- diethyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described-CO₂R⁷It is preferred thatOr

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described phosphono preferably-P (O) (R⁹)(R¹⁰) Or-P (O) (OR⁹)(OR¹⁰)。

R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀Alkyl It is preferred that C₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀Alcoxyl The preferred C of base₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described halo C₁~C₂₀ The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₁₀Acyl group It is preferred that acetyl group, propiono or phenylacyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀The preferred C of alkyl₁~C₁₀ Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀Alkoxy is preferred C₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described halo C₁~C₂₀Alkyl is excellent Select halo C₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₁₀The preferred second of acyl group Acyl group, propiono or phenylacyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀The preferred C of alkyl₁~C₁₀ Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀Alkoxy is preferred C₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described halo C₁~C₂₀Alkyl is excellent Select halo C₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₁₀The preferred second of acyl group Acyl group, propiono or phenylacyl.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆Cycloalkanes Base, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉The substitution of heterocyclic radical In base, described C₁~C₂₀The preferred C of alkyl₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or Isopropyl.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆Cycloalkanes Base, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉The substitution of heterocyclic radical In base, described halo C₁~C₂₀The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆Cycloalkanes Base, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉The substitution of heterocyclic radical In base, described C₁~C₂₀The preferred C of alkoxy₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, Positive propoxy or isopropoxy.

Work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆Cycloalkanes Base, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉The substitution of heterocyclic radical In base, described C₁~C₁₀The preferred acetyl group of acyl group, propiono or phenylacyl.

R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀Alkane The preferred C of base₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀Alkane The preferred C of epoxide₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described halo C₁~C₂₀ The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀Alkane The preferred C of base₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀Alkane The preferred C of epoxide₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described halo C₁~C₂₀ The preferred halo C of alkyl₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkyl is preferred C₁~C₁₀Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkoxy is excellent Select C₁~C₁₀Alkoxy, more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described halo C₁~C₂₀Alkyl It is preferred that halo C₁~C₁₀Alkyl, more preferably trifluoromethyl.

R¹、R²And R³Preferably it is each independently selected from following any group：Hydrogen, methyl, phenyl,

In described lactam analog compound, the compound shown in described formula III is preferably as follows anyization Compound：

In described lactam analog compound, the compound shown in described formula IV is preferably as follows anyization Compound：

The term being related in the present invention is explained as follows, and does not do the term of specific explanations according to the routine of this area Understanding and cognition is explained：

Term " saturation or undersaturated aliphatic alkyl " refer to have specify carbon number purpose straight chain or The saturated aliphatic hydrocarbons or unsaturated fatty hydrocarbons base of side chain, including alkyl, alkyl, alkynyl etc..Its In, " C₁~C₂₀Saturation or unsaturated fatty hydrocarbons base " represents the saturation containing 1~20 carbon atom or not The aliphatic alkyl of saturation.

Term " alkoxy " refer to precursor structure by oxygen bridge connect with the carbon number purpose ring Shape or acyclic alkyl groups.Thus, the definition of " alkoxy " comprising alkyl and cycloalkyl.

Term " alkyl " refers to have the saturated aliphatic hydrocarbon for specifying carbon number purpose side chain or straight chain Base.Such as in " C₁~C₁₀Defined in alkyl " for be included in straight chain or branched structure have 1,2,3, 4th, 5,6,7,8,9 or 10 groups of carbon atom, be specifically including but not limited to methyl, ethyl, Propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl, neopentyl, hexyl, uncle Hexyl, heptyl, different heptyl, octyl group and iso-octyl etc..

Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine, more preferably fluorine in the present invention Or chlorine.

Term " alkylthio group " refer to precursor structure by sulphur bridge connect with the carbon number purpose ring Shape or acyclic alkyl groups.Thus, the definition of " alkylthio group " comprising alkyl and cycloalkyl.

The structure of term " methylene-dioxy " is

Term " nitro " refers to

Term " cyano group " refers to

Term " aryl " refers to the substitution base for having and specifying carbon number purpose to have aromatic ring structure property, The example of aryl unit include phenyl, substitution phenyl, naphthyl, tetralyl, indanyl, Xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).It is appreciated that in " aryl ", Connection with precursor structure is carried out by aromatic ring.

Term " aryloxy group " refer to precursor structure by oxygen bridge connect with carbon number purpose virtue Base.Thus, the definition of " aryloxy group " comprising aryl.

Term " heteroaryl " refers to that, with the 5-14 monocyclic or polycyclic moiety of annular atom, each ring contains 4-6 atom, wherein there is one or more to be selected from the hetero atom of N, O or S, remaining is carbon." heteroaryl Base " has armaticity.For example, " C₂~C₉Heteroaryl " represents the heteroaryl with 2-9 carbon atom, Including but not limited to, furans, the furans of substitution, benzofuran, the benzofuran of substitution, thiophene, take The thiophene in generation, benzothiophene, the benzothiophene of substitution, indoles, indoles, iso-indoles, the substitution of substitution Iso-indoles, pyrroles, the pyrroles of substitution, thiazole, the thiazole, oxazoles of substitution, substitution oxazoles, pyrrole Azoles, substitution pyrazoles, imidazoles, substitution imidazoles, pyrans, substitution pyrans, pyridazine, substitution rattle away Piperazine, pyrazine, the pyrazine of substitution, pyrimidine, the pyrimidine of substitution, pyridine, the pyridine of substitution, quinoline, take Quinoline, isoquinolin, the isoquinolin of substitution, carbazole, the carbazole of substitution in generation etc..

Term " heterocyclic radical " refers to the ring group of saturation or fractional saturation, and it does not have armaticity, by one or more Individual ring (preferably 1-2) is constituted, and each ring has 5-7 atom, including one or more (preferably 1-2) selected from the hetero atom of N, O or S.For example, " C₂~C₉Heterocyclic radical ", including but not limited to, Tetrahydroquinoline, tetrahydro indole, oxazolinyls, pyrrolin base, tetrahydro pyridyl, tetrahydrofuran base, Morpholinyl, pyrrolinyl, piperazinyl, piperidyl, imidazolinyl.

Term " cycloalkyl " refers to saturation or part is unsaturated monocyclic, polycyclic or bridge joint carbon ring substituents, It does not have armaticity.C can be expressed as with the 3-20 ring of carbon atom₃~C₂₀Cycloalkyl.The art Language includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, 1H- Indenyl, indanyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6,7,8- tetrahydro-naphthalenyls, 8,9- dihydros -7H- Benzo ring heptene -6- bases, 6,7,8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 5,6,7,8,9,10- hexahydros-benzo ring Octenyl, fluorenyl, two rings [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, Buddha's warrior attendant Alkyl, octahydro -4,7- methylene -1H- indenyls and octahydro -2,5- methylene-pentalene base etc..Cycloalkyl Can be connected on precursor structure through any carbon atom.

Term " acyl group " refers to that organic or inorganic oxyacid removes remaining atom after one or more hydroxyls Group, " C₁~C₁₀Acyl group " refers to 1~10 acyl group of carbon atom.Term " acyl group " bag in the present invention Include but be not limited to, formoxyl, acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, uncle Bytyry, valeryl, isovaleryl, valeryl, caproyl, tertiary caproyl, heptanoyl group, different heptan Acyl group, caprylyl and different caprylyl etc..

Term " halo " refers to what is be optionally substituted by halogen, and substituted halogen can be one or more, substituted Position can be optional position.If multiple halogens replace, the halogen for being replaced can be with identical or different. Such as " halo C₁~C₁₀Alkyl " refers to C₁~C₁₀The hydrogen of any number and optional position is by halogen in alkyl The group formed after element substitution.

Present invention also offers a kind of preparation method of lactam analog compound, it is comprised the following steps：

(1), in solvent, in the presence of oxidant, described formula III compound is reacted, Obtain V-1 compounds；

(2), in solvent, in the presence of a reducing agent, the described compound of Formula V -1 is carried out to reduce instead Should, obtain V-2 compounds；

Wherein, each substitution base is the same as those described above.

Step (1) preferably includes following steps：Formula III compound is dissolved in solvent, the water with oxidant Solution mix, react 10~50 minutes (preferably 30 minutes), then again with oxidant with solid hybrid reaction.

In step (1), described solvent can be solvent commonly used in the art, preferably acetonitrile.Described General the carrying out not influence reaction of the consumption of solvent is defined, and preferably 0.3mol/L~0.01mol/L is more excellent 0.2mol/L is selected, the concentration refers to molar concentration of the formula III compound phase for solvent for use.

In step (1), the preferred one-electron oxidation agent of described oxidant, more preferably ammonium ceric nitrate, sulphur One or more in sour cerium ammonium, cerium chloride, cerous sulfate and cerous nitrate.Described oxidant can be with water-soluble The form of liquid, it is also possible to mixed with reactant in solid form.The mole dosage of described oxidant Preferably 1~5 times of formula III compound, more preferably 3 times.Described oxidant is when with the shape of the aqueous solution When formula is mixed with reactant, the preferred 0.4mol/L of its volumetric concentration.

In step (1), the preferred room temperature of temperature of described reaction.

In step (1), the process of described reaction can by this area conventional method (such as TLC or HPLC) it is monitored, as reaction end when typically being disappeared using formula III compound, preferably 0.5~2 is small When, more preferably 1 hour.

Prepare V-1 compounds method terminate after, product can be further purified by post processing.Institute The post processing stated preferably includes following steps：Decompression boils off solvent, is isolated and purified by thin layer chromatography board. The step of described thin layer chromatography board is isolated and purified and condition can routinely be selected by this area, and it is used The preferred petroleum ether of solvent system：Ethyl acetate=7:1(v/v).

In step (2), the condition and step of described reduction reaction can be according to the conventional reduction in this area The condition and step of reaction are selected.

In step (2), the preferred palladium/carbon-hydrogen of described reducing agent, palladium/carbon-ammonium formate, sodium borohydride, One or more in sodium cyanoborohydride and acetic acid sodium borohydride.

In step (2), the consumption of described reducing agent is preferably 1~10 equivalent of the compound of Formula V -1.

In step (2), when described reducing agent is palladium/carbon-hydrogen, the side of V-2 compounds is being prepared In method, following steps are preferably included：Under reducing atmosphere, by the described compound of Formula V -1, palladium/carbon and Solvent mixes, and reacts 1~5 hour.

In step (2), the preferred room temperature of temperature of described reduction reaction.

In step (2), described reduction reaction is preferably reacted at 1 atmosphere pressure.

In step (2), the solvent ethyl acetate of described reduction reaction.The use of described solvent General the carrying out not influence reaction of amount is defined, preferably 1.0~0.001mol/L, more preferably 0.1~0.03mol/L, The concentration is molar concentration of the compound phase of Formula V -1 for solvent for use.

In step (2), the process of described reaction can by this area conventional method (such as TLC or HPLC) it is monitored, as reaction end when typically being disappeared using the compound of Formula V -1, preferably 3 hours.

Prepare V-2 compounds method terminate after, product can be further purified by post processing.Institute The post processing stated preferably includes following steps：System is filtered with diatomite, ethyl acetate washing filter cake, is subtracted Pressure boils off the solvent in filtrate.

In step (1), the preparation method of described formula III compound preferably includes following steps：Lazy In the presence of property solvent, under the catalysis of palladium catalyst, in the presence of oxidant, by compound of formula I (N- alkoxy amide classes compound) is reacted with Formula II compound (different nitrile compounds), obtains described Formula III compound；

Wherein, R²It is H, remaining respectively replaces base as defined above described.

The preparation method of described formula III compound preferably includes following steps：By oxidant, Formulas I The mixing of compound, Formula II compound and palladium catalyst, reacts 0~15 minute at room temperature, then heats to 20~140 DEG C are reacted 0.1~40 hour.

In the preparation method of described formula III compound, described atent solvent refer to be not involved in it is above-mentioned anti- The organic solvent answered, preferably toluene, ethylbenzene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl first Acid amides, N, N '-dimethyl acetamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide, 1,2- dichloroethanes, second One or more in ether, glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane and acetone, more It is preferred that one or more in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran and toluene；Most preferably Isosorbide-5-Nitrae-dioxy six Ring.

In the preparation method of described formula III compound, the consumption of described atent solvent is generally not shadow The carrying out of reaction is rung, preferably 0.05~2.0mol/L, the concentration refers to compound of formula I relative to institute With the molar concentration of solvent.

In the preparation method of described formula III compound, the preferred zero valent palladium catalyst of described palladium catalyst And/or divalence palladium catalyst.Described zero valent palladium catalyst and divalence palladium catalyst can routinely make for this area Palladium catalyst.The palladium of described zero valent palladium catalyst preferably three (dibenzalacetone) two and/or four (triphens Base phosphine palladium).The described preferred palladium of divalence palladium catalyst, palladium bichloride, trifluoracetic acid palladium, fluoroform Sulfonic acid palladium, double acetonitrile palladium chlorides, palladium dydroxide, allyl palladium chloride and the [cyclopentadienyls of 1,1'- double (diphenylphosphines) two Iron] one or more in palladium chloride.

In the preparation method of described formula III compound, the mole dosage of described palladium catalyst is preferably 0.1~20mol% of Formula II compound, more preferably 0.2~5mol%, most preferably 0.5~2.5mol%.

In the preparation method of described formula III compound, the preferred air of described oxidant, oxygen, mistake Hydrogen oxide, potassium peroxydisulfate, sodium peroxydisulfate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, One or more in copper chloride and copper bromide, more preferably pressure is the air or oxygen of 0.5-100 atmospheric pressure Gas, further preferred pressure is the air or oxygen of 0.8-10 atmospheric pressure, and most preferably pressure is 1-5 air The air or oxygen of pressure.

In the preparation method of described formula III compound, in addition to air and/or oxygen, described oxidant Consumption be preferably generally 1~4 equivalent of compound of formula I.If air and/or oxygen are used as oxidant, It is general reaction system is carried out under being in the oxidizing gas atmosphere.

In the preparation method of described formula III compound, described compound of formula I and Formula II compound Mol ratio preferably 5:1~1:5, more preferably 1:1~1:3, most preferably 1:2.

In the preparation method of described formula III compound, preferably 60~100 DEG C of the temperature of described reaction, More preferably 100 DEG C.

In the preparation method of described formula III compound, the process of described reaction can be normal by this area Rule method (such as TLC or HPLC) is monitored, when typically being disappeared using compound of formula I as reaction eventually Point, more preferably preferably 0.2~20 hour, 0.5~10 hour.

After the preparation method of described formula III compound terminates, also product can be further purified by post processing Thing.Described post processing is preferably included：Cooling reaction system, decompression boils off solvent, by thin-layer chromatography Plate is isolated and purified.The step of described thin layer chromatography board is isolated and purified and condition can routinely be carried out by this area Selection, the preferred petroleum ether of solvent system that it is used：Ethyl acetate=10:1~20:1(v/v).

Present invention also offers a kind of preparation method of described lactam analog compound, it includes following step Suddenly：In the presence of atent solvent, under the catalysis of palladium catalyst, in the presence of oxidant, by formula I (N- alkoxy amide classes compound) is reacted with Formula II compound (different nitrile compounds), is obtained To described formula III compound；

Wherein, R²It is H, remaining respectively replaces base as defined above described；Wherein each reactions steps and condition Described in the preparation method of the same formula III compound.

Present invention also offers a kind of preparation method of described lactam analog compound, it includes following step Suddenly：In solvent, in the presence of oxidant, described formula III compound is reacted, obtained institute The compound of Formula V -1 stated；

Wherein, each substitution base is the same as those described above；Wherein each reactions steps and the same compound of Formula V -1 of condition Described in preparation method.

Present invention also offers a kind of preparation method of malonic acid class compound, it is comprised the following steps：

(1), in solvent, in the presence of oxidant, described formula III compound is reacted, Obtain described V-1 compounds；

(2), in solvent, in the presence of a reducing agent, the compound of Formula V -1 is carried out into reduction reaction, is obtained To V-2 compounds；

(3), in the presence of acid, the compound of Formula V -2 and methyl alcohol are reacted, the compound of Formula V -3 is obtained；

Wherein, each group is the same as those described above；The reaction condition of step (1) and step (2) is as previously described.

In step (3), described preparation method can be the conventional esterification process in this area, preferably include Following steps：The compound of Formula V -2 and methyl alcohol are mixed, is then mixed with acid again, it is anti-at 60~90 DEG C Answer 1~5 hour.

In step (3), described acid preferably trifluoracetic acid, TFMS, methanesulfonic acid, hydrochloric acid, One or more in sulfuric acid and nitric acid.Described acid is preferably the highest volume existed under its nature Concentration, typically participates in reacting, for example, 98% sulfuric acid solution with its aqueous solution.Described sour mole Consumption can be added by the conventional selection of this area according to actual needs, not particular/special requirement, typically Can realize that above-mentioned esterification is defined.

In step (3), the mole dosage of described methyl alcohol is more than or equal to the described compound of Formula V -2 Mole, preferably enable to the reactant for participating in reacting to form homogeneous scattered solution and be defined.

In step (3), preferably 80 DEG C of the temperature of described reaction.

In step (3), the process of described reaction can by this area conventional method (such as TLC or HPLC) it is monitored, as reaction end when typically being disappeared using the compound of Formula V -2, preferably 2 hours.

After the preparation method of the described compound of Formula V -3 terminates, also product can be further purified by post processing Thing.Described post processing is preferably included：Cooling reaction system, with alkaline aqueous solution neutralization reaction system, Then it is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, decompression boils off solvent after filtering, after Isolated and purified through thin layer chromatography board.The step of described thin layer chromatography board is isolated and purified and condition can be by abilities Domain is routinely selected, the preferred petroleum ether of the solvent system that it is used：Ethyl acetate=10:1(v/v). The preferred NaHCO of described alkaline aqueous solution₃The aqueous solution.

The method of formula V-3 compounds preferably includes following steps：In the presence of atent solvent, Under the catalysis of palladium catalyst, in the presence of oxidant, by compound of formula I (N- alkoxy amide class chemical combination Thing) reacted with Formula II compound (different nitrile compounds), obtain described formula III compound；

Present invention also offers a kind of preparation method of lactam analog compound, it is comprised the following steps：It is molten In agent, in the presence of acid, described formula IV compound is reacted, obtained the compound of Formula V -5；

Wherein, remaining group is the same as those described above and R²It is not hydrogen.

The method of formula V-5 compounds, preferably includes following steps：By formula IV compound, acid and Solvent mixes, and is reacted 10~50 minutes at 60 DEG C~90 DEG C.

In the method for formula V-5 compounds, the preferred hexafluoroisopropanol of described solvent.Described is molten General the carrying out not influence reaction of the consumption of agent is defined, preferably with described sour equivalent.

In the method for formula V-5 compounds, described acid can be the conventional acid of the such reaction in this area, It is preferred that one or more in trifluoracetic acid, TFMS, methanesulfonic acid, hydrochloric acid, sulfuric acid and nitric acid. Mole dosage of the described sour mole dosage preferably at least with formula IV compound is identical.

In the method for formula V-5 compounds, preferably 80 DEG C of the temperature of described reaction.

In the method for formula V-5 compounds, the process of described reaction can be by this area routine side Method (such as TLC or HPLC) is monitored, as reaction end when typically being disappeared using formula IV compound, It is preferred that 20 minutes.

After the method for formula V-5 compounds terminates, also product can be further purified by post processing. Described post processing is preferably included：Cooling reaction system, decompression boils off solvent, by thin layer chromatography board point From purifying.The step of described thin layer chromatography board is isolated and purified and condition can routinely be selected by this area, The preferred petroleum ether of solvent system that it is used：Ethyl acetate=10:1(v/v).

In the method for formula V-5 compounds, the preparation method of described formula IV compound is preferably wrapped Include following steps：In the presence of atent solvent, under the catalysis of palladium catalyst, in the effect of oxidant Under, compound of formula I (N- alkoxy amide classes compound) is entered with Formula II compound (different nitrile compounds) Row reaction, obtains described formula IV compound；

Wherein, R³It is hydrogen, remaining respectively replaces base described and R as defined above²It is not H.

The preparation method of described formula IV compound preferably includes following steps：By oxidant, Formulas I The mixing of compound, Formula II compound and palladium catalyst, reacts 0~15 minute at room temperature, then heats to 20~140 DEG C are reacted 0.1~40 hour.

In the preparation method of formula IV compound, described atent solvent refers to be not involved in above-mentioned reaction Organic solvent, preferably toluene, ethylbenzene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide, N, N '-dimethyl acetamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide, 1,2- dichloroethanes, ether, second One or more in glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane and acetone, more preferably 1, One or more in 4- dioxane, tetrahydrofuran and toluene；Most preferably Isosorbide-5-Nitrae-dioxane.

In the preparation method of formula IV compound, the consumption of described atent solvent does not influence generally instead The carrying out answered, preferably 0.05~0.20mol/L, the concentration refer to compound of formula I molten relative to used The molar concentration of agent.

In the preparation method of formula IV compound, the preferred zero valent palladium catalyst of described palladium catalyst and/or Divalence palladium catalyst.Described zero valent palladium catalyst and divalence palladium catalyst can be commonly used in the art Palladium catalyst.The palladium of described zero valent palladium catalyst preferably three (dibenzalacetone) two and/or four (triphenylphosphines Palladium).The described preferred palladium of divalence palladium catalyst, palladium bichloride, trifluoracetic acid palladium, TFMS Palladium, double acetonitrile palladium chlorides, palladium dydroxide, allyl palladium chloride and [1,1'- double (diphenylphosphine) ferrocene] One or more in palladium chloride.

In the preparation method of formula IV compound, the mole dosage of described palladium catalyst is preferably Formula II 0.1~20mol% of compound, more preferably 0.2~5mol%, most preferably 0.5~2.5mol%.

In the preparation method of formula IV compound, the preferred air of described oxidant, oxygen, peroxidating Hydrogen, potassium peroxydisulfate, sodium peroxydisulfate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, chlorine Change one or more in copper and copper bromide, more preferably pressure is the air or oxygen of 0.5-100 atmospheric pressure, Further preferred pressure is the air or oxygen of 0.8-10 atmospheric pressure, and most preferably pressure is 1-5 atmospheric pressure Air or oxygen.

In the preparation method of formula IV compound, in addition to air and/or oxygen, the use of described oxidant Amount is preferably generally 1~4 equivalent of compound of formula I.If air and/or oxygen are used as oxidant, typically Reaction system is set to be carried out under being in the oxidizing gas atmosphere.

In the preparation method of formula IV compound, described compound of formula I and Formula II compound mole Than preferably 5:1~1:5, more preferably 1:1~1:3, most preferably 1:2.

In the preparation method of formula IV compound, preferably 60~100 DEG C of the temperature of described reaction is more excellent Select 100 DEG C.

In the preparation method of formula IV compound, the process of described reaction can be by this area routine side Method (such as TLC or HPLC) is monitored, as reaction end when typically being disappeared using compound of formula I, It is preferred that 0.2~20 hour, more preferably 0.5~10 hour.

After the preparation method of described formula IV compound terminates, also product can be further purified by post processing Thing.Described post processing is preferably included：Cooling reaction system, decompression boils off solvent, by thin-layer chromatography Plate is isolated and purified.The step of described thin layer chromatography board is isolated and purified and condition can routinely be carried out by this area Selection, the preferred petroleum ether of solvent system that it is used：Ethyl acetate=10:1~20:1(v/v).

Present invention also offers a kind of preparation method of lactam analog compound, it is comprised the following steps：It is molten In agent, in the presence of oxidant, described formula IV compound is reacted, obtained the change of Formula V -6 Compound；

Wherein, each substitution base described and R as defined above²It is not hydrogen.

In the method for preparing V-6 compounds, following steps are preferably included：Formula IV compound is dissolved in Solvent, mixes with the aqueous solution of oxidant, react 10~50 minutes (preferably 30 minutes), then again with Oxidant with solid hybrid reaction.

In the method for preparing V-6 compounds, described solvent can be solvent commonly used in the art, preferably Acetonitrile.General the carrying out not influence reaction of the consumption of described solvent is defined, preferably 0.3mol/L ~0.01mol/L, more preferably 0.2mol/L, the concentration refer to formula IV compound phase for solvent for use Molar concentration.

In the method for preparing V-6 compounds, the preferred one-electron oxidation agent of described oxidant, more preferably One or more in ammonium ceric nitrate, Cericammoniumsulfate, cerium chloride, cerous sulfate and cerous nitrate.Described oxygen Agent can be in form of an aqueous solutions, it is also possible to is mixed with reactant in solid form.Described oxidation The mole dosage of agent is preferably 1~5 times of formula IV compound, more preferably 3 times.Described oxidant is worked as When participating in reaction in form of an aqueous solutions, the preferred 0.4mol/L of its volumetric concentration.

In the method for preparing V-6 compounds, the preferred room temperature of temperature of described reaction.

In the method for preparing V-6 compounds, the process of described reaction can be by this area conventional method (such as TLC or HPLC) is monitored, as reaction end when typically being disappeared using formula IV compound, It is preferred that 0.5~2 hour, more preferably 1 hour.

Prepare V-6 compounds method terminate after, product can be further purified by post processing.Institute The post processing stated preferably includes following steps：Decompression boils off solvent, is isolated and purified by thin layer chromatography board. The step of described thin layer chromatography board is isolated and purified and condition can routinely be selected by this area, and it is used The preferred petroleum ether of solvent system：Ethyl acetate=15:1(v/v).

In the method for preparing V-6 compounds, the preparation method of described formula IV compound is preferably included Following steps：In the presence of atent solvent, under the catalysis of palladium catalyst, in the presence of oxidant, Compound of formula I (N- alkoxy amide classes compound) and Formula II compound (different nitrile compounds) are carried out instead Should, obtain described formula IV compound；

In the preparation method of formula IV compound, preferably 60~100 DEG C of the temperature of described reaction, more It is preferred that 100 DEG C.

Present invention also offers a kind of preparation method of described lactam analog compound, it includes following step Suddenly：In the presence of atent solvent, under the catalysis of palladium catalyst, in the presence of oxidant, by formula I (N- alkoxy amide classes compound) is reacted with Formula II compound (different nitrile compounds), is obtained To described formula IV compound；

Wherein, R³It is hydrogen, remaining respectively replaces base described and R as defined above²It is not H；It is wherein each anti- Answer described in the preparation method of step and the same formula IV compound of condition.

Present invention also offers a kind of preparation method of quinolines, it is comprised the following steps：Solvent In, in the presence of bronsted acid and/or lewis acid, described formula III compound is reacted, Obtain Formula IV compound；

Wherein, R¹It is substituted or unsubstituted phenyl；Work as R¹For substitution phenyl when, R6 ', R7 ', R8 ' and R9 ' is C₆~C₁₄Aryl or C₂~C₉Substitution base on heteroaryl, the position of its substitution is corresponding In described substitution base in C₆~C₁₄Aryl or C₂~C₉The position of substitution on heteroaryl, described C₆~C₁₄ Aryl or C₂~C₉Substitution base on heteroaryl is defined as described above.

In the method for formula VI compounds, following steps are preferably included：By formula III compound and molten Agent mixes, then mixes with bronsted acid and/or lewis acid, in room temperature to 30 points of reaction at 100 DEG C Clock was to 16 hours.

In the method for formula VI compounds, the preferred dichloromethane of described solvent, 1,2- dichloroethanes With one or more in chloroform.General the carrying out not influence reaction of the consumption of described solvent is defined, It is preferred that 0.05mol/L~2.0mol/L.

In the method for formula VI compounds, described bronsted acid preferably trifluoracetic acid, trifluoro One or more in methanesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and nitric acid.

In the method for formula VI compounds, the preferred BFEE of described lewis acid, three Aluminium chloride, silicon tetrachloride, titanium tetrachloride, butter of tin, TFMS scandium, TFMS ketone, One or more in silver trifluoromethanesulfonate and Trimethylsilyl trifluoromethanesulfonate, more preferably BF₃·Et₂O、 AlCl₃With one or more in TFMS trimethyl silicone grease (TMSOTf).

In the method for formula VI compounds, described bronsted sour and/or lewis acidic mole 2~4 equivalents of consumption preferred formula III compounds.

In the method for formula VI compounds, preferably 50 DEG C~80 DEG C of the temperature of described reaction.

In the method for formula VI compounds, the process of described reaction can be by this area routine side Method (such as TLC or HPLC) is monitored, as reaction end when typically being disappeared using formula III compound, It is preferred that 40 minutes~15.5 hours, preferably 1~11 hour, most preferably more preferably 2~7 hours, 5 hours.

After the preparation method of described Formula IV compound terminates, also product can be further purified by post processing Thing.Described post processing is preferably included：Cooling reaction system, then with ethyl acetate and alkaline aqueous solution Mixing, organic phase is extracted with ethyl acetate, then anhydrous sodium sulfate drying, and decompression boils off solvent, by Thin layer chromatography board is isolated and purified.The step of described thin layer chromatography board is isolated and purified and condition can be by this areas Routine is selected, the solvent system ethyl acetate that it is used：N-hexane=15:1(v/v).It is described Alkaline aqueous solution can be saturation NaHCO₃The aqueous solution and/or triethylamine.Described triethylamine can be commercially available Triethylamine, without water removal operation, it contains a small amount of water, therefore is considered as alkaline aqueous solution herein.

In the method for formula VI compounds, the preparation method of described formula III compound is preferably included Following steps：In the presence of atent solvent, under the catalysis of palladium catalyst, in the presence of oxidant, Compound of formula I (N- alkoxy amide classes compound) and Formula II compound (different nitrile compounds) are carried out instead Should, obtain described formula III compound；

Wherein, R²It is H, remaining respectively replaces base as defined above described；Wherein, formula III compound Each reaction condition and step of preparation method are the same as those described above.

In the present invention, room temperature refers to 10~30 DEG C.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product this Invent each preferred embodiments.

Agents useful for same of the present invention and raw material are commercially available.

Positive effect of the invention is：Quickly made using carbon-hydrogen bond activation the present invention relates to one kind The method of 4- imino groups-beta-lactam or 5- imino groups-gamma-lactam shown in standby formula III or formula IV, and Using the lactam analog compound for preparing, further derivative is obtained in the middle of many useful organic syntheses Body.Simplification based on formula III compound and formula IV compounds process for production thereof, these prior arts are more difficult The organic synthesis intermediate that cumbersome approaches can just be prepared is prepared or needs at present, can be simple Ground synthesis is obtained.The method of the present invention not only efficiency high, selectivity it is high, economic and environment-friendly, while step it is few, It is easy to operate and wide in the extreme to the scope of application of substrate, with very good Atom economy.

The 5- imino groups γ-interior acyl shown in 4- imino groups beta-lactam and formula IV in the present invention shown in formula III The preparation method of amine can be used air as oxidant, and without any additive, reaction speed can soon extremely 1 hour, reaction system was clean, and accessory substance is only a molecule H₂O, very atom economy, meet Economic and environment-friendly sustainable development technical requirements, and the method is easy to operate, can implement in a mild condition, It is with low cost.

Further, 4- imino groups-beta-lactam and formula 5- imino groups-gamma-lactam compounds in the present invention Various highly useful intermediates can be further converted to.

Specific embodiment

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for Illustrate the present invention rather than limitation the scope of the present invention.The reality of unreceipted actual conditions in the following example Proved recipe method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, Otherwise percentage and number is calculated by weight.

Solvent for use is commercially available, and can be purified according to the solvent processing method of standard.Agents useful for same is equal For commercially available, without purifying.

Pd₂(dba)₃It is three (dibenzalacetone) two palladium, Pd (PPh₃)₄For tetrakis triphenylphosphine palladium, Pd(OAc)₂It is palladium.The synthetic method of raw material 1a-1t, 4a-4g refers to document [L.E.Fisher Deng J.Org.Chem.1993,58,3643-3647].

1. preparation example

Embodiment 1 (3 is suitable, and 4 the is anti-) -3- benzylidenes -1- tert-butyl groups -4- methoxy iminos azetidine -2- ketone (3a)

Under air (1atm), to addition amide compound 1a 35.4mg (0.20 in 35mL reaction tubes Mmol), tert-butyl isonitrile 48 μ L (0.40mmol), Pd₂(dba)₃3.7mg (0.004mmol), 1,4- dioxane (dioxane) 2mL.Bottle stopper is screwed, is put into oil bath, 15 points are stirred at room temperature Clock, then heats to 100 DEG C of reactions, reacts 6 hours.Room temperature, vacuum rotary steam are cooled to after having reacted Remove solvent.With plate separation is prepared, (petroleum ether is 20 with the volume ratio of ethyl acetate to crude product：1), obtain To product 3a 35.2mg (68%)；¹H NMR(400MHz,CDCl₃) δ 7.94 (d, J=6.4Hz, 2H),7.42–7.37(m,3H),7.28(s,1H),3.89(s,3H),1.54(s,9H)；¹³C NMR(100 MHz,CDCl₃)δ163.0,151.1,135.1,133.5,132.6,130.8,130.3,128.7,62.7,57.0, 27.7；HRMS(ESI-TOF)m/z Calcd for C15H19N2O2(M+H)⁺:259.1441,found: 259.1446.

Embodiment 2 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (4- methyl benzylidenes)-a word used for translation Fourth pyridine -2- ketone (3b)

Using step similar to Example 1, difference is using corresponding starting compound 1b generations Alternative compound 1a.6 hours reaction time, yield 67%.¹H NMR(400MHz,CDCl₃)δ7.84 (d, J=8.0Hz, 2H), 7.25 (s, 1H), 7.19 (d, J=7.9Hz, 2H), 3.88 (s, 3H), 2.36 (s, 3H),1.53(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.3,151.4,140.9,135.1, 131.4,130.9,130.8,129.4,62.6,56.9,27.7,21.6；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₂(M+H)⁺:273.1598,found:273.1602.

Embodiment 3 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (3- methyl benzylidenes)-a word used for translation Fourth pyridine -2- ketone (3c)

Using step similar to Example 1, difference is using corresponding starting compound 1c generations Alternative compound 1a.6 hours reaction time, yield 69%.¹H NMR(400MHz,CDCl₃)δ7.79 (s, 1H), 7.74 (d, J=7.6Hz, 1H), 7.30-7.18 (m, 2H), 7.18 (d, J=7.6Hz, 1H), 3.88(s,3H),2.37(s,3H),1.54(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.2, 151.2,138.3,135.4,133.4,132.3,131.4,131.2,128.6,128.1,62.7,57.0,27.7, 21.3；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₂(M+H)⁺:273.1598,found: 273.1605.

Embodiment 4 (3 is suitable, and 4 is anti-) -1- the tert-butyl groups -3- (4- methoxybenzylidenes) -4- methoxy iminos Azetidine -2- ketone (3d)

Using step similar to Example 1, difference is using corresponding starting compound 1d generations Alternative compound 1a.6 hours reaction time, yield 68%.¹H NMR(400MHz,CDCl₃)δ7.92 (d, J=8.7Hz, 2H), 7.22 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H),1.51(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.6,161.3,151.6,134.8, 132.8,129.9,126.5,114.1,62.6,56.9,55.3,27.7；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₃(M+H)⁺:289.1547,found:289.1552.

Embodiment 5 (3 is suitable, and 4 is anti-) -1- the tert-butyl groups -3- (4- chlorobenzenes methylene) -4- methoxy imino azetes Pyridine -2- ketone (3e)

Using step similar to Example 1, difference is using corresponding starting compound 1e generations Alternative compound 1a.8 hours reaction time, yield 62%.¹H NMR(400MHz,CDCl₃)δ7.89 (d, J=8.5Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 7.22 (s, 1H), 3.88 (s, 3H), 1.54 (s, 9H)；¹³C NMR(100MHz,CDCl₃)δ162.9,150.7,136.3,133.6,133.1,132.1, 132.0,129.0,62.7,57.1,27.6；HRMS(ESI-TOF)m/z Calcd for C₁₅H₁₈ClN₂O₂ (M+H)⁺:293.1051,found:293.1060.

Embodiment 6 (3 is suitable, and 4 is anti-) -3- (4- bromobenzenes the methylene) -1- tert-butyl group -4- methoxy imino azetes Pyridine -2- ketone (3f)

Under air (1atm), to addition amide compound 1f 25.6mg (0.10 in 25mL reaction tubes Mmol), tert-butyl isonitrile 24 μ L (0.20mmol), Pd₂(dba)₃2.3mg (0.005mmol), Isosorbide-5-Nitrae- Dioxane (dioxane) 1mL.Teflon plugs are screwed, is put into oil bath, 15 points are stirred at room temperature Clock, then heats to 100 DEG C of reactions, reacts 6 hours.Room temperature, vacuum rotary steam are cooled to after having reacted Remove solvent.With plate separation is prepared, (petroleum ether is 20 with the volume ratio of ethyl acetate to crude product：1), obtain To product 3f 22.9mg (68%).6 hours reaction time, yield 60%.¹H NMR(400MHz, CDCl₃) δ 7.82 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 3.88 (s, 3H),1.54(s,9H)；¹³C NMR(100MHz,CDCl₃)δ162.9,150.7,133.6,133.3, 132.4,132.3,132.0,124.9,62.8,57.2,27.6；HRMS(ESI-TOF)m/z Calcd for C₁₅H₁₈BrN₂O₂(M+H)⁺:337.0546,found:337.0551.

Embodiment 7 (3 is suitable, and 4 the is anti-) -1- tert-butyl group -4- methoxy iminos -3- (4- trifluoromethyls benzylidene) - azetidine -2- ketone (3g)

Using step similar to Example 6, difference is using corresponding starting compound 1g generations Alternative compound 1f.8 hours reaction time, yield 60%.¹H NMR(400MHz,CDCl₃)δ8.07 (d, J=8.0Hz, 2H), 7.64 (d, J=7.6Hz, 2H), 7.29 (s, 1H), 3.90 (s, 3H), 1.55 (s, 9H)；¹³C NMR(150MHz,CDCl₃)δ162.5,150.4,136.7,135.2,133.0,131.6(q, ), J=32.6Hz 130.9,125.6 (q, J=3.8Hz), 123.8 (q, J=272.6Hz), 62.8,57.3, 27.6；HRMS(ESI-TOF)m/z Calcd for C₁₆H₁₈F₃N₂O₂(M+H)⁺:327.1315,found: 327.1324.

Embodiment 8 (3 is suitable, and 4 the is anti-) -1- tert-butyl group -4- methoxy iminos -3- (naphthyl -2- methylene) azete Pyridine -2- ketone (3b)

Using step similar to Example 6, difference is using corresponding starting compound 1h Instead of compound 1f.6 hours reaction time, yield 60%.¹H NMR(400MHz,CDCl₃)δ8.28 (dd, J=8.5,1.7Hz, 1H), 8.24 (s, 1H), 7.88-7.81 (m, 3H), 7.54-7.46 (m, 2H), 7.46(s,1H),3.91(s,3H),1.56(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.2, 151.2,135.2,134.0,133.1,132.7,132.0,131.3,128.8,128.5,127.7,127.5,127.0, 126.4,62.8,57.1,27.7；HRMS(ESI-TOF)m/z Calcd for C₁₉H₂₁N₂O₂(M+H)⁺: 309.1598,found:309.1602.

Embodiment 9 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (1- phenylethylenes) azetidine - 2- ketone (3i)

Using step similar to Example 1, difference is to be replaced using corresponding starting compound 1i Compound 1a.6 hours reaction time, yield 86%.¹H NMR(400MHz,CDCl₃)δ7.32– 7.30(m,3H),7.26–7.23(m,2H),3.31(s,3H),2.47(s,3H),1.52(s,9H)；¹³C NMR(100MHz,CDCl₃)δ165.4,150.0,144.6,140.3,129.5,128.4,128.1,126.9, 61.4,56.8,27.7,20.7；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₂(M+H)⁺: 273.1598,found:273.1604.

The trans- 1- tert-butyl groups -3- cyclohexylidenes -4- methoxy iminos azetidine -2- ketone (3j) of embodiment 10

Using step similar to Example 1, difference is using corresponding starting compound 1j generations Alternative compound 1a.6 hours reaction time, yield 55%.¹H NMR(400MHz,CDCl₃)δ3.82 (s,3H),2.69–2.63(m,4H),1.72–1.56(m,6H),1.50(s,9H)；¹³C NMR(100 MHz,CDCl₃)δ165.8,151.6,150.9,126.0,62.2,56.6,33.5,30.7,28.2,28.0,27.8, 26.0；HRMS(ESI-TOF)m/z Calcd for C₁₄H₂₃N₂O₂(M+H)⁺:251.1754,found: 251.1761.

The trans- 1- tert-butyl groups -4- methoxy iminos -3- of embodiment 11 (subunits of 2- third) azetidine -2- ketone (3k)

Using step similar to Example 6, difference is using corresponding starting compound 1k Instead of compound 1f.6 hours reaction time, yield 36%.¹H NMR(400MHz,CDCl₃)δ3.82 (s,3H),2.15(s,3H),2,13(s,3H),1.50(s,9H)；¹³C NMR(100MHz,CDCl₃)δ 165.5,150.7,143.7,129.0,62.1,56.5,27.8,23.8,20.9；HRMS(ESI-TOF)m/z Calcd for C₁₁H₁₉N₂O₂(M+H)⁺:211.1441,found:211.1446.

The cis- 1- tert-butyl groups -3- (the diphenyl methylene) -4- methoxy iminos azetidine -2- ketone (3l) of embodiment 12

Using step similar to Example 1, difference is to be replaced using corresponding starting compound 1l Compound 1a.6 hours reaction time, yield 79%.¹H NMR(400MHz,CDCl₃)δ7.42– 7.30(m,8H),7.22–7.20(m,2H),3.32(s,3H),1.54(s,9H)；¹³C NMR(100 MHz,CDCl₃)δ163.8,150.0,146.6,139.6,137.0,131.0,130.7,130.0,129.8, 128.8,127.6,126.9,61.7,57.0,27.7；HRMS(ESI-TOF)m/z Calcd for C₂₁H₂₃N₂O₂(M+H)⁺:335.1754,found:335.1759.

Embodiment 13 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (3- pyridine methylenes) azete Pyridine -2- ketone (3m)

Using step similar to Example 6, difference is using corresponding starting compound 1m Instead of compound 1f.1 hour reaction time, yield 55%.¹H NMR(400MHz,CDCl₃)δ8.80 (d, J=1.8Hz, 1H), 8.65 (dt, J=8.1,1.9Hz, 1H), 8.58 (dd, J=4.7,1.3Hz, 1H), 7.35 (dd, J=8.1,4.8Hz, 1H), 7.26 (s, 1H), 3.90 (s, 3H), 1.54 (s, 9H)；¹³C NMR (100MHz,CDCl₃)δ162.5,151.7,150.8,150.3,137.1,135.0,130.9,129.6, 123.7,62.8,57.3,27.6；HRMS(ESI-TOF)m/z Calcd for C₁₄H₁₈N₃O₂(M+H)⁺: 260.1394,found:260.1399.

Embodiment 14 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (4- pyridine methylenes) azete Pyridine -2- ketone

Using step similar to Example 6, difference is using corresponding starting compound 1n Instead of compound 1f.4 hours reaction time, yield 58%.¹H NMR(400MHz,CDCl₃)δ8.67 (dd, J=4.6,1.5Hz, 2H), 7.79 (dd, J=4.6,1.5Hz, 2H), 7.20 (s, 1H), 3.90 (s, 3H), 1.55(s,9H)；¹³C NMR(100MHz,CDCl₃)δ161.9,150.5,149.9,140.2,137.7, 131.9,123.9,62.9,57.5,27.6；HRMS(ESI-TOF)m/z Calcd for C₁₄H₁₈N₃O₂ (M+H)⁺:260.1394,found:260.1394.

Embodiment 15 (3 is suitable, and 4 the is anti-) -1- tert-butyl group -4- methoxy iminos -3- (1- (3- pyridines) ethylidene) Azetidine -2- ketone (3o)

Using step similar to Example 6, difference is using corresponding starting compound 1o generations Alternative compound 1f.2 hours reaction time, yield 67%.¹H NMR(400MHz,CDCl₃)δ8.55 (dd, J=4.9,1.5Hz, 1H), 8.48 (d, J=1.8Hz, 1H), 7.58 (dt, J=7.9,2.0Hz, 1H), 7.29–7.24(m,1H),3.35(s,3H),2.48(s,3H),1.52(s,9H)；¹³C NMR(100MHz, CDCl₃)δ164.6,149.3,149.2,149.1,140.2,136.0,135.1,131.2,121.9,61.7,57.1, 27.7,20.3；HRMS(ESI-TOF)m/z Calcd for C₁₅H₂₀N₃O₂(M+H)⁺:274.1550, found:274.1561.

Embodiment 16 (3 is suitable, and 4 is anti-) -1- the tert-butyl groups -3- (3- furals) -4- methoxy imino azetes Pyridine -2- ketone (3p)

Using step similar to Example 6, difference is using corresponding starting compound 1p Instead of compound 1f.Reaction temperature is 80 DEG C, 10 hours reaction time, yield 48%.¹H NMR (400MHz,CDCl₃)δ7.81(s,1H),7.40(s,1H),6.93(s,1H),6.82(s,1H),3.88(d, J=0.5Hz, 3H), 1.53 (s, 9H)；¹³C NMR(100MHz,CDCl₃)δ165.4,149.6,147.3, 143.6,129.2,119.8,117.6110.9,62.0,57.1,27.7；HRMS(ESI-TOF)m/z Calcd for C₁₃H₁₇N₂O₃(M+H)⁺:249.1234,found:249.1239.

Embodiment 17 (3 is suitable, and 4 the is anti-) -1- tert-butyl groups -3- (1- (2- furans) ethylidene) 4- methoxy iminos Base azetidine -2- ketone (3q)

Using step similar to Example 6, difference is using corresponding starting compound 1q generations Alternative compound 1f.1 hour reaction time, yield 71%.¹H NMR(400MHz,CDCl₃)δ7.58 (d, J=3.6Hz, 1H), 7.53-7.48 (m, 1H), 6.50 (ddd, J=3.6,1.7,0.5Hz, 1H), 3.86 (s,3H),2.55(s,3H),1.54(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.6,151.3, 149.6,143.9,130.8,128.0,115.6,112.4,62.3,56.9,27.8,18.9；HRMS(ESI-TOF) m/z Calcd for C₁₄H₁₉N₂O₃(M+H)⁺:263.1390,found:263.1395.

Embodiment 18 (3 is suitable, and 4 is anti-) -1- the tert-butyl group -4- methoxy iminos -3- (3- furals) azete Pyridine -2- ketone (3r)

Using step similar to Example 6, difference is using corresponding starting compound 1r generations Alternative compound 1f.6 hours reaction time, yield 60%.¹H NMR(400MHz,CDCl₃)δ7.72 (d, J=3.6Hz, 1H), 7.49 (d, J=5.0Hz, 1H), 7.33 (s, 1H), 7.08 (dd, J=4.8,4.0 Hz,1H),3.87(s,3H),1.53(s,9H)；¹³C NMR(100MHz,CDCl₃)δ162.9,151.2, 136.8,133.4,131.1,129.5128.2,125.3,62.6,57.0,27.7；HRMS(ESI-TOF)m/z Calcd for C₁₃H₁₇N₂O₂S(M+H)⁺:265.1005,found:265.1010.

Embodiment 19 (3 is suitable, and 4 the is anti-) -1- tert-butyl group -4- methoxy iminos -3- (1- (2- thiophene) ethylidene) Azetidine -2- ketone (3s)

Using step similar to Example 6, difference is using corresponding starting compound 1s Instead of compound 1f.1 hour reaction time, yield 62%.¹H NMR(400MHz,CDCl₃)δ 7.93 (d, J=3.8Hz, 1H), 7.43 (d, J=5.0Hz, 1H), 7.08 (t, J=4.4Hz, 1H), 3.87 (s, 3H),2.64(s,3H),1.55(s,9H)；¹³C NMR(100MHz,CDCl₃)δ163.8,149.6, 140.6,135.3,131.0,129.2,128.5,127.7,62.4,56.9,27.8,23.7；HRMS (ESI-TOF)m/z Calcd for C₁₄H₁₉N₂O₂S(M+H)⁺:279.1162,found:279.1167.

The cis- 3- of embodiment 20 (the trans- 1- tert-butyl groups -2- methoxy iminos -4- oxa- -3- methylene) indoles -1- Carboxylic acid tert-butyl ester (3t) and trans- 3- (the cis- 1- tert-butyl groups -2- methoxy iminos -4- oxa- -3- methylene) Yin Diindyl -1- carboxylic acid tert-butyl esters (3t ')

Using step similar to Example 6, difference is using corresponding starting compound 1t generations Alternative compound 1f.4 hours reaction time, 3t yields 44%, 3t ' yields 23%.¹H NMR(400 MHz,CDCl₃) δ 8.83 (s, 1H), 8.19 (d, J=8.0Hz, 1H), 7.70 (d, J=7.9Hz, 1H), 7.40 (d, J=0.6Hz, 1H), 7.34 (m, 2H), 3.92 (s, 3H), 1.69 (s, 9H), 1.55 (s, 9H)；¹³C NMR(100MHz,CDCl₃)δ163.8,151.6,149.2,135.3,130.7,130.0,129.2, 124.9,123.3,123.0,118.3,115.4,114.3,84.5,62.7,56.9,28.1,27.8；HRMS (ESI-TOF)m/z Calcd for C₂₂H₂₈N₃O₄(M+H)⁺:398.2074,found:398.2074(3t).¹H NMR(400MHz,CDCl₃) δ 8.34 (s, 1H), 8.16 (d, J=7.9Hz, 1H), 7.65 (d, J= 7.9Hz, 1H), 7.38-7.29 (m, 2H), 7.17 (d, J=0.9Hz, 1H), 3.90 (s, 3H), 1.70 (s, 9H),1.56(s,9H)；¹³C NMR(100MHz,CDCl₃)δ165.5,150.2,149.3,135.0, 130.0,129.8,129.4,124.9,123.4,118.3,117.3,115.4,113.2,84.5,62.2,57.1, 28.2,27.8；HRMS(ESI-TOF)m/z Calcd for C₂₂H₂₈N₃O₄(M+H)⁺:398.2074, found:398.2074(3t’).

The cis- 1- tert-butyl groups -5- methoxy iminos -3- methyl 4-phenyls -2- pyrrolones (5a) of embodiment 20

Using step similar to Example 1, difference is using corresponding starting compound 4a Instead of compound 1a.57.3mg 4a (0.30mmol), 9.2mg Pd₂(dba)₃(5mol%), the tert-butyl group The μ L (0.60mmol) of isonitrile 72, Isosorbide-5-Nitrae-dioxane 3mL, 100 DEG C of reaction temperature, reaction time 6 Hour, yield 87%.¹H NMR(400MHz,CDCl₃)δ7.38–7.26(m,3H),7.21(d,J =8.0Hz, 2H), 3.61 (s, 3H), 1.77 (s, 3H), 1.70 (s, 9H)；¹³C NMR(100MHz, CDCl₃)δ169.9,150.6,137.2,135.2,134.3,128.4,127.52,127.47,62.5,58.1, 29.7,9.1；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₂(M+H)⁺:273.1598,found: 273.1604.

The cis- 1- tert-butyl groups -5- methoxy iminos -3- methyl -4- p-methylphenyls -2- pyrrolones (5b) of embodiment 21

Using step similar to Example 6, difference is using corresponding starting compound 4b generations Alternative compound 1f, 3 hours reaction time, yield 51%.¹H NMR(400MHz,CDCl₃)δ7.15 (d, J=8.0Hz, 2H), 7.10 (d, J=8.2Hz, 2H), 3.63 (s, 3H), 2.37 (s, 3H), 1.77 (s, 3H),1.69(s,9H)；¹³C NMR(100MHz,CDCl₃)δ170.1,150.7,137.3,137.0, 135.3,131.3,128.4,128.2,62.6,58.1,29.7,21.3,9.2；HRMS(ESI-TOF)m/z Calcd for C₁₇H₂₃N₂O₂(M+H)⁺:287.1754found:287.1758.

Embodiment 22 cis- 4- (4- the bromophenyls) -1- tert-butyl group -5- methoxy imino -3- methyl -- 2- pyrrolones (5c)

Using step similar to Example 1, difference is using corresponding starting compound 4c generations Alternative compound 1a reaction temperatures are 80 DEG C, 10 hours reaction time, yield 63% (Z+E).¹H NMR (400MHz,CDCl₃) δ 7.54 (d, J=8.1Hz, 2H), 7.29 (d, J=8.1Hz, 2H), 3.91 (s, 3H),1.93(s,3H),1.64(s,9H)；¹³C NMR(100MHz,CDCl₃)δ171.8,146.0, 141.1,131.7,131.1,131.0,130.1,122.8,62.6,58.3,30.8,9.6；HRMS(ESI-TOF) m/z Calcd for C₁₆H₂₀BrN₂O₂(M+H)⁺:351.0703,found:351.0713.

Embodiment 23 the cis- 1- tert-butyl groups -4- (4- fluorophenyls) -5- methoxy imino -3- methyl -2- pyrrolones (5d)

Using step similar to Example 6, difference is using corresponding starting compound 4d generations Alternative compound 1f, 3 hours reaction time, yield 71%.¹H NMR(400MHz,CDCl₃)δ7.19 (dd, J=8.1,5.7Hz, 2H), 7.04 (t, J=8.6Hz, 2H), 3.63 (s, 3H), 1.77 (s, 3H), 1.69 (s,9H)；¹³C NMR(100MHz,CDCl₃) δ 169.8,162.1 (d, J=246.9Hz), 150.4, (d, J=1.1Hz), 137.6,134.2,130.2 114.6 (d, J=21.6Hz), 62.6,58.2,29.7,9.1； HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₀FN₂O₂(M+H)⁺:291.1503,found: 291.1509.

The trans- 2- tert-butyl groups -3- methoxy iminos -2,3,5,6- tetrahydro cyclopentyls alkane of embodiment 24 and pyrroles's -1- ketone (5e)

Using step similar to Example 6, difference is using corresponding starting compound 4e Instead of compound 1f, 0.5 hour reaction time, yield 77%.¹H NMR(400MHz,CDCl₃)δ 3.90(s,3H),2.85–2.80(m,2H),2.51–2.46(m,2H),2.33–2.26(m,2H),1.62 (s,9H)；¹³C NMR(100MHz,CDCl₃)δ166.9,150.8,147.2,146.8,62.7,58.0, 31.2,29.6,27.3,25.6；HRMS(ESI-TOF)m/z Calcd for C₁₂H₁₉FN₂O₂(M+H)⁺: 223.1441,found:223.1450.

The trans- 2- tert-butyl groups -3- methoxy iminos -2,3,4,5,6,7- hexahydros iso-indoles -1- ketone (5f) of embodiment 25

Using step similar to Example 6, difference is using corresponding starting compound 4f generations Alternative compound 1f.0.5 hour reaction time, yield 74%.¹H NMR(400MHz,CDCl₃)δ3.89 (s,3H),2.74–2.53(m,2H),2.29–2.12(m,2H),1.68–1.66(m,4H),1.63(s, 9H)；¹³C NMR(100MHz,CDCl₃)δ170.0,152.5,137.2,136.7,62.9,57.6,29.6, 26.2,22.5,21.1,20.3；HRMS(ESI-TOF)m/z Calcd for C₁₃H₂₁N₂O₂(M+H)⁺: 237.1598,found:237.1601.

The embodiment 261- tert-butyl groups -5- methoxy iminos -3,4- dimethyl pyrrole -2- ketone (5g)

Using step similar to Example 6, difference is using corresponding starting compound 4g generations Alternative compound 1f.3 hours reaction time, yield 51%.¹H NMR(400MHz,CDCl₃)δ3.91 (s,3H),2.18(s,3H),1.80(s,3H),1.62(s,9H)；¹³C NMR(100MHz,CDCl₃)δ 170.5,152.5,134.4,132.9,63.0,57.8,29.7,15.1,8.1；HRMS(ESI-TOF)m/z Calcd for C₁₁H₁₉N₂O₂(M+H)⁺:211.1441,found:211.1444.

2nd, product conversion

Embodiment 27

Addition 3a (20.0mg, 0.078mmol) in hydrogenation pipe, 4.0mg Pd/C, 3mL absolute methanols, Stirrer.Hydrogen three times (30bar) is substituted, is reacted 16 hours at room temperature, lead to system after reaction completely Cross the chromatographic column equipped with a small amount of silica gel to filter, methyl alcohol drip washing, vacuum rotary steam removes solvent and obtains s1, yield 99%.¹H NMR(400MHz,CDCl₃) δ 7.30-7.19 (m, 5H), 3.94 (dd, J=5.1,3.9 Hz, 1H), 3.84 (s, 3H), 3.17 (dd, J=13.9,5.1Hz, 1H), 3.05 (dd, J=13.9,3.9Hz, 1H),1.13(s,9H)；¹³C NMR(100MHz,CDCl₃)δ166.8,151.1,135.6,129.7, 128.1,126.8,62.0,56.8,56.2,31.1,27.1；HRMS(DART-Positive)m/z Calcd for C₁₅H₂₁N₂O₂(M+H)⁺:261.1596,found:261.1595.

Embodiment 28

To 3a (258mg, 1.0mmol) is added in the tube sealing of the 25mL equipped with stirrer, 5.0 are added mL CH₃CN dissolves it, and the ceric ammonium nitrate solution that will be dissolved in 5.0mL water is added thereto (2.0mmol), React 30 minutes at room temperature.Then 1.0mmol ammonium ceric nitrate solids are added thereto to again, continue to react 30 minutes complete to 3a reactions.Vacuum rotary steam removes solvent, column chromatography for separation (PE：EtOAc=7:1 It is eluant, eluent), obtain 186mg s2, yield 81%.¹H NMR(400MHz,CDCl₃)δ7.93(dd, J=6.4,2.9Hz, 2H), 7.50-7.38 (m, 3H), 6.92 (s, 1H), 1.57 (s, 9H)；¹³C NMR (100MHz,CDCl₃)δ168.4,167.4,137.2,132.4,131.3,131.1,131.0,128.9,57.2, 27.8；HRMS(DART-Positive)m/z Calcd for C₁₄H₁₆O₂N(M+H)⁺:230.1176, found:230.11174.

Embodiment 29

To in the eggplant-shape bottle of 50mL add 34.0mg s2 (0.148mmol), 3.7mg Pd/C (11%), The ethyl acetate of 5.0mL is used as solvent.Hydrogen three times (1atm) is substituted, is reacted 3 hours at room temperature.Instead After the completion of answering, filtered with diatomite, ethyl acetate rinse three times, the product s3 that filtrate is spin-dried for pure, produced Rate 99%.¹H NMR(400MHz,CDCl₃) δ 7.32-7.21 (m, 5H), 3.79 (t, J=5.0Hz, 1H), 3.06 (d, J=5.0Hz, 2H), 1.20 (s, 9H)；¹³C NMR(100MHz,CDCl₃)δ170.0, 135.3,129.5,128.4,127.1,61.2,56.3,30.8,27.3；HRMS(ESI-TOF)m/z Calcd for C₁₄H₁₈NO₂(M+H)⁺:232.1332,found:232.1334.

Embodiment 30

To addition 13.0mg s3 (0.05mmol) and 1mL methyl alcohol in the 25mL tube sealings equipped with stirrer, Then the concentrated sulfuric acids are dripped to addition two in reaction system.Stopper is screwed, reaction tube is put into and is preheated to 80 DEG C Oil bath pan in, react 2 hours.After system is cooled to room temperature, 2mL saturations NaHCO is counted₃ The aqueous solution.It is extracted with ethyl acetate (5mL × 3), merges organic phase, anhydrous sodium sulfate drying, decompression rotation Solvent is evaporated off, silica gel prepares plate and separates (PE/EtOAc), obtains 13.2mg s4, yield 89%.¹H NMR(400MHz,CDCl₃)δ7.29–7.29(m,5H),6.04(br,1H),3.66(s,3H),3.35 (dd, J=7.9,7.1Hz, 1H), 3.25-3.13 (m, 2H), 1.28 (s, 9H)；¹³C NMR(100MHz, CDCl₃)δ171.8,166.5,137.9,128.9,128.4,126.7,55.6,52.3,51.4,36.4,28.5； HRMS(ESI-TOF)m/z Calcd for C₁₅H₂₂NO₃(M+H)⁺:264.1594,found: 264.1594.

Embodiment 31

To the dichloromethane that 12.6mg 3a and 1mL are added in the tube sealing of the 25mL equipped with stirrer. To adding BF in the solution₃.Et₂O(25μL,4.0equiv).After stopper is screwed, reaction tube is put into pre- In heat to 80 DEG C of oil bath pan, react 15.5 hours.After being cooled to room temperature, added in reaction system The ethyl acetate of 10mL and the saturation NaHCO of 1mL₃The aqueous solution.Organic phase is extracted with ethyl acetate Take (10mL × 3), merge organic phase, anhydrous sodium sulfate drying.After vacuum rotary steam, crude product purified by silica gel Prepare plate and separate (EtOAc/hexane=15:1) 7.8mg 6a, yield 60%, are obtained.¹H NMR(400 MHz,CDCl₃)δ8.62(s,1H),7.96(s,1H),7.66–7.53(m,3H),7.19–7.12(m, 1H),3.93(s,3H),1.58(s,9H)；¹³C NMR(100MHz,CDCl₃)δ167.8,154.9, 150.3,142.1,132.1,128.9,126.5,121.8,121.0,110.0,52.2,51.5,29.0；HRMS (ESI-TOF)m/z Calcd for C₁₅H₁₉N₂O₂(M+H)⁺:259.1441,found:259.1446.

Embodiment 32

To adding 13.7mg 3b (0.05mmol) and 2mL in the tube sealing of the 25mL equipped with stirrer Dichloromethane.To adding BF in the solution₃.Et₂O(12μL,2.0equiv).After stopper is screwed, will be anti- Should pipe be put into and be preheated in 50 DEG C of oil bath pan, react 2 hours.After being cooled to room temperature, to reactant The ethyl acetate of 10mL and the triethylamine of 0.5mL are added in system.After vacuum rotary steam, crude product silicon Glue prepares plate and separates (EtOAc/hexane=15:1) 12.5mg 6b, yield 91%, are obtained.¹H NMR (400MHz,CDCl₃) δ 8.57 (s, 1H), 7.95 (s, 1H), 7.47 (d, J=8.2Hz, 1H), 7.43 (s, 1H), 6.98 (d, J=8.0Hz, 1H), 3.91 (s, 3H), 2.47 (s, 3H), 1.58 (s, 9H)；¹³C NMR (100MHz,CDCl₃)δ168.0,155.1,150.5,142.8,141.7,128.6,125.7,124.0, 119.0,109.1,52.1,51.4,29.0,22.1；HRMS(ESI-TOF)m/z Calcd for C₁₆H₂₁N₂O₂(M+H)⁺:273.1598,found:273.1599.

Embodiment 33

Reactions steps are similar to 6b is prepared, the difference is that with 3e as reaction substrate, AlCl₃Instead of BF₃.Et₂O, reaction temperature is 80 DEG C, and the reaction time is 11 hours, yield 57%.¹H NMR(400 MHz,CDCl₃) δ 8.57 (s, 1H), 8.06 (s, 1H), 7.63 (d, J=1.9Hz, 1H), 7.49 (d, J= 8.6Hz, 1H), 7.09 (dd, J=8.6,2.0Hz, 1H), 3.92 (s, 3H), 1.57 (s, 9H)；¹³C NMR (100MHz,CDCl₃)δ167.6,155.3,150.7,141.7,138.0,130.0,125.5,122.7, 119.3,110.1,52.3,51.6,28.9；HRMS(ESI-TOF)m/z Calcd for C₁₅H₁₈ClN₂O₂ (M+H)⁺:293.1051,found:293.1052.

Embodiment 34

Reactions steps are similar to 6b is prepared, the difference is that reacted at room temperature as reaction substrate with 3i, Reaction time is 40 minutes, yield 63%.¹H NMR(400MHz,CDCl₃) δ 7.82 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.21 (dd, J=8.2,7.0 Hz,1H),6.02(s,1H),3.97(s,3H),2.61(s,3H),1.57(s,9H)；¹³C NMR(100 MHz,CDCl₃)δ169.7,152.8,147.9,145.2,130.4,127.3,124.3,122.0,121.9, 114.9,52.2,51.6,29.1,16.9；HRMS(ESI-TOF)m/z Calcd for C₁₉H₂₁N₂O₂ (M+H)⁺:273.1598,found:273.1599.

Embodiment 35

Reactions steps are similar to 6b is prepared, the difference is that reacted at room temperature as reaction substrate with 3l, Reaction time is 1 hour, yield 68%.¹H NMR(400MHz,CDCl₃) δ 7.70 (d, J=8.3 Hz, 1H), 7.53 (t, J=7.6Hz, 1H), 7.48-7.38 (m, 3H), 7.31-7.26 (m, 3H), 7.06 (t, J=7.6Hz, 1H), 6.33 (br, 1H), 3.35 (s, 3H), 1.59 (s, 9H)；¹³C NMR(100MHz, CDCl₃)δ169.4,153.0,150.2,148.6,138.0,130.7,128.8,127.9,127.7,127.2, 126.8,121.9,121.4,113.8,51.7,51.7,29.1；HRMS(ESI-TOF)m/z Calcd for C₁₉H₂₁N₂O₂(M+H)⁺:335.1754,found:335.1754.

Embodiment 36

To the dichloroethanes that 25.8mg 3a and 2.0mL are added in the tube sealing of the 25mL equipped with stirrer. To addition Trimethylsilyl trifluoromethanesulfonate (28 μ L, 2.0equiv) in the solution.After stopper is screwed, will Reaction tube is put into and is preheated in 100 DEG C of oil bath pan, reacts 2 hours.After being cooled to room temperature, to reaction The ethyl acetate of 10mL and the saturation NaHCO of 1mL are added in system₃The aqueous solution.Organic phase is used Ethyl acetate extracts (10mL × 3), merges organic phase, anhydrous sodium sulfate drying.After vacuum rotary steam, slightly Product silica gel prepares plate and separates (EtOAc/hexane=15:1) 10.9mg 6f, yield 54%, are obtained.¹H NMR(400MHz,CDCl₃)δ8.70(s,1H),7.68–7.60(m,3H),7.28–7.20 (m,1H),6.56(br,2H),3.96(s,3H)；¹³C NMR(100MHz,CDCl₃)δ167.0,156.4, 150.2,142.7,132.6,129.0,125.7,122.8,122.4,110.0,52.3；HRMS(ESI-TOF) m/z Calcd for C₁₁H₁₁N₂O₂(M+H)⁺:203.0815,found:203.0820.

Embodiment 37

Reactions steps are similar to 6b is prepared, the difference is that with 3h as reaction substrate, reacted at 50 DEG C, Reaction time is 5 hours, yield 82%.¹H NMR(400MHz,CDCl₃)δ9.10–9.05(m, 1H), 8.64 (s, 1H), 7.80 (dd, J=6.8,2.1Hz, 1H), 7.67-7.59 (m, 2H), 7.53-7.47 (m,2H),6.59(br,2H),3.95(s,3H)；¹³C NMR(100MHz,CDCl₃)δ167.2,156.8, 141.5,135.3,129.6,129.0,127.7,126.3,125.6,125.1,123.6,119.2,108.0,52.2； HRMS(ESI-TOF)m/z Calcd for C₁₉H₂₁N₂O₂(M+H)⁺:309.1598,found: 309.1598.

Embodiment 38

Reactions steps are similar to 6b is prepared, the difference is that with 3f as reaction substrate, reacted at 80 DEG C, Reaction time is 7 hours, yield 52%.¹H NMR(400MHz,CDCl₃)δ8.64(s,1H),7.78 (s, 1H), 7.49 (d, J=8.6Hz, 1H), 7.32 (dd, J=8.6,1.8Hz, 1H), 7.03-6.26 (br, 2H),3.96(s,3H).¹³C NMR(100MHz,CDCl₃)δ166.7,156.9,150.8,142.4, 130.1,128.2,127.3,126.3,120.9,110.1,52.4.HRMS(ESI-TOF)m/z Calcd for C₁₁H₁₀BrN₂O₂(M+H)⁺:280.9920,found:280.9921.

Embodiment 39

To adding 5a in the 25mL tube sealings equipped with stirrer, the trifluoroacetic acid of 0.5mL and 0.5mL's Hexafluoroisopropanol.After screwing stopper, reaction tube is put into be preheated in 80 DEG C of oil bath pan and reacts 20 Minute.After the completion of reaction, room temperature is cooled to, vacuum rotary steam removes solvent, be prepared by crude product purified by silica gel Version is separated, and obtains the s5 of 20.0mg, yield 93%.¹H NMR(400MHz,CDCl₃)δ8.22(br, 1H), 7.53 (d, J=6.6Hz, 2H), 7.49-7.38 (m, 3H), 4.00 (s, 3H), 2.08 (s, 3H)；¹³C NMR(100MHz,CDCl₃)δ170.4,147.6,140.5,132.2,129.71,129.68,129.2, 128.3,63.1,9.7；HRMS(ESI-TOF)m/z Calcd for C₁₂H₁₃N₂O₂(M+H)⁺: 217.0972,found:217.0974.

Embodiment 40

Reactions steps are similar to s2 is prepared, and the amount of 5a materials is 0.5mmol, yield 62%.¹H NMR (400MHz,CDCl₃)δ7.52-7.39(m,5H),2.12(s,3H),1.63(s,9H)；¹³C NMR (100MHz,CDCl₃)δ173.1,172.1,136.6,136.4,129.5,129.2,129.1,128.4,57.3, 29.0,9.6；HRMS(DART-Positive)m/z Calcd for C₁₅H₁₈O₂N(M+H)⁺:244.1332, found:244.1329.

The all documents referred in the present invention are all incorporated as reference in this application, just as each text Offer and be individually recited as with reference to such.In addition, it is to be understood that reading above-mentioned instruction content of the invention Afterwards, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values are same Fall within the application appended claims limited range.

Claims

1. a kind of lactam analog compound, it is the chemical combination shown in compound or formula IV shown in formula III Thing：

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、 R¹⁶And R¹⁷In, described C₂~C₉When heteroaryl is substituted, substitution base is one or more, and is selected from One or more of：Halogen, unsubstituted C₁~C₂₀Alkyl, unsubstituted C₁~C₂₀Alkoxy, Halo C₁~C₂₀Alkyl, unsubstituted C₁~C₁₀Acyl group and tertbutyloxycarbonyl；

2. lactam analog compound as claimed in claim 1, it is characterised in that：R¹、R²、R³、 R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷In, institute The C for stating₁~C₂₀Saturation or undersaturated aliphatic alkyl are C₁~C₁₀Saturation or undersaturated aliphatic hydrocarbon Base；

And/or, R¹、R²And R³In, described C₁~C₂₀Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²And R³In, described C₁~C₂₀Alkylthio group is first sulfydryl, second sulfydryl or the third mercapto Base；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄Aryl is C₆~C₁₀Aryl；

And/or, R¹、R²And R³In, described C₆~C₁₄Aryloxy group is C₆~C₁₀Aryloxy group；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉Heteroaryl is C₄~C₈Heteroaryl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉Heterocyclic radical is C₄~C₈Heterocyclic radical；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substitution or does not take The C in generation₃~C₆During cycloalkyl, described C₃~C₆Cycloalkyl is cyclopenta or cyclohexyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substitution or does not take The C in generation₂~C₉During heterocyclic radical, described C₂~C₉Heterocyclic radical is unfixed four to seven yuan of hetero atom position Heterocyclic group, preferably dihydrofuran base, THP trtrahydropyranyl, pyrrolin base or tetrahydro pyridyl；

And/or, R¹³And R¹⁴In, described C₆~C₁₄Aryl sulfonyl be benzenesulfonyl, to toluene sulphur Acyl group or benzyl sulfonyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀Alkyl sulphonyl is mesyl or ethylsulfonyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀Acyl group is acetyl group, propiono or phenylacyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described C₁~C₂₀Alkyl is C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described C₁~C₂₀Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described halo C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described C₆~C₁₄Aryl is phenyl or naphthyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described halo C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₆~C₁₄ Aryl is phenyl or naphthyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described halo C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₆~C₁₄ Aryl is phenyl or naphthyl；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described halo C₁~C₂₀ Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₆~C₁₄ Aryl is phenyl or naphthyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀Alkane Base is C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀Alkane Epoxide is C₁~C₁₀Alkoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₆~C₁₄Virtue Base is phenyl or naphthyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₂~C₉Heteroaryl Base is pyridine, furans, thiophene or indoles；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described halo C₁~C₂₀ Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₁₀Acyl Base is acetyl group, propiono or phenylacyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described-NR¹³R¹⁴For N, N- dimethyl or N, N- diethyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described-CO₂R⁷For

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described phosphono is -P(O)(R⁹)(R¹⁰) or-P (O) (OR⁹)(OR¹⁰)；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described halo C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₁₀ Acyl group is acetyl group, propiono or phenylacyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀Alkane Base is C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀Alkane Epoxide is C₁~C₁₀Alkoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described halo C₁~C₂₀ Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₁₀Acyl Base is acetyl group, propiono or phenylacyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀Alkane Base is C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀Alkane Epoxide is C₁~C₁₀Alkoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described halo C₁~C₂₀ Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₁₀Acyl Base is acetyl group, propiono or phenylacyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described C₁~C₂₀Alkyl is C₁~C₁₀Alkyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described halo C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described C₁~C₂₀Alkoxy is C₁~C₁₀Alkoxy；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described C₁~C₁₀Acyl group is acetyl group, propiono or phenylacyl；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described halogen For C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀ Alkyl is C₁~C₁₀Alkyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀ Alkoxy is C₁~C₁₀Alkoxy；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described halogen For C₁~C₂₀Alkyl is halo C₁~C₁₀Alkyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkane Base is C₁~C₁₀Alkyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkane Epoxide is C₁~C₁₀Alkoxy；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described halo C₁~C₂₀ Alkyl is halo C₁~C₁₀Alkyl.

3. lactam analog compound as claimed in claim 2, it is characterised in that：R¹、R²、R³、 R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷In, institute The C for stating₁~C₂₀Saturation or undersaturated aliphatic alkyl are C₁~C₅Saturated aliphatic hydrocarbons；

And/or, R¹、R²And R³In, described C₁~C₂₀Alkoxy is methoxyl group, ethyoxyl or isopropyl Epoxide；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄Aryl is phenyl or naphthyl；

And/or, R¹、R²And R³In, described C₆~C₁₄Aryloxy group is phenoxy group or naphthoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉Heteroaryl is furyl, benzofuranyl, thiophene Base, benzothienyl, indyl, isoindolyl, pyrrole radicals, thiazolyl, oxazolyls, pyrazolyl, Imidazole radicals, pyranose, pyridazinyl, pyrazinyl, pyrimidine radicals, pyridine radicals, quinolyl, isoquinolyl or Carbazyl, most preferably thienyl, furyl, pyridine radicals or indyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉Heterocyclic radical be tetrahydric quinoline group, tetrahydro indole base, Oxazolinyl, pyrrolin base, tetrahydro pyridyl, tetrahydrofuran base, morpholinyl, piperazinyl, piperidines Base, pyrrolinyl or imidazolinyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described C₁~C₂₀Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described C₁~C₂₀Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₁~C₂₀The substitution base of saturation or undersaturated aliphatic alkyl In, described halo C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkoxy, described halo C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²And R³In, described C₁~C₂₀In the substitution base of alkylthio group, described halo C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²And R³In, in the substitution base of described methylene-dioxy, described halo C₁~C₂₀ Alkyl is trifluoromethyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀Alkane Base is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described C₁~C₂₀Alkane Epoxide is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₆~C₁₄In the substitution base of aryl, described halo C₁~C₂₀ Alkyl is trifluoromethyl；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²And R³In, described C₆~C₁₄In the substitution base of aryloxy group, described halo C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀Alkane Base is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described C₁~C₂₀Alkane Epoxide is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heteroaryl, described halo C₁~C₂₀ Alkyl is trifluoromethyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀Alkane Base is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described C₁~C₂₀Alkane Epoxide is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、 R¹⁴、R¹⁵、R¹⁶And R¹⁷In, described C₂~C₉In the substitution base of heterocyclic radical, described halo C₁~C₂₀ Alkyl is trifluoromethyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described C₁~C₂₀Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described halo C₁~C₂₀Alkyl is trifluoromethyl；

And/or, work as R¹、R²、R³The carbon atom being directly connected collectively forms substituted C₃~C₆ Cycloalkyl, or the C for replacing₂~C₉During heterocyclic radical, described C₃~C₆Cycloalkyl or C₂~C₉Heterocyclic radical In substitution base, described C₁~C₂₀Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹³And R¹⁴In, described C₆~C₁₄In the substitution base of aryl sulfonyl, described halogen For C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀ Alkyl is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described C₁~C₂₀ Alkoxy is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of alkyl sulphonyl, described halogen For C₁~C₂₀Alkyl is trifluoromethyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkane Base is methyl, ethyl, n-propyl or isopropyl；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described C₁~C₂₀Alkane Epoxide is methoxyl group, ethyoxyl, positive propoxy or isopropoxy；

And/or, R¹³And R¹⁴In, described C₁~C₁₀In the substitution base of acyl group, described halo C₁~C₂₀ Alkyl is trifluoromethyl.

4. lactam analog compound as claimed in claim 3, it is characterised in that：R¹、R²、R³、 R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷In, institute The C for stating₁~C₂₀Saturation or undersaturated aliphatic alkyl are methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group or the tert-butyl group.

5. lactam analog compound as claimed in claim 1, it is characterised in that：R¹、R²、R³、 R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶And R¹⁷In, institute The C for stating₂~C₉Carbon atom is connected with precursor structure in heteroaryl；

And/or, as described C₂~C₉When heteroaryl is substituted, substitution base is replaced on hetero atom；

And/or, R¹、R²And R³It is each independently selected from following any group：Hydrogen, methyl, phenyl,

6. lactam analog compound as claimed in claim 1, it is characterised in that：

In described lactam analog compound, the compound shown in described formula III is following any chemical combination Thing：

In described lactam analog compound, the compound shown in described formula IV is following any chemical combination Thing：

7. a kind of preparation method of lactam analog compound, it is comprised the following steps：(1), in solvent, In the presence of oxidant, described formula III compound is reacted, obtained V-1 compounds；

Wherein, R¹、R³、R⁴And R⁵Definition such as any one of claim 1~6 in R¹、R³、R⁴With R⁵Definition described in.

8. the preparation method of lactam analog compound as claimed in claim 7, it is characterised in that：Step Suddenly (1) comprises the following steps：Formula III compound is dissolved in solvent, is mixed with the aqueous solution of oxidant, Reaction 10~50 minutes, then again with oxidant with solid hybrid reaction；

And/or, in step (1), described solvent is acetonitrile；

And/or, in step (1), the consumption of described solvent is 0.3mol/L~0.01mol/L, and this is dense Degree refers to molar concentration of the formula III compound phase for solvent for use；

And/or, in step (1), described oxidant is one-electron oxidation agent；

And/or, in step (1), described oxidant in form of an aqueous solutions, or in solid form with Reactant is mixed；

And/or, in step (1), the mole dosage of described oxidant is the 1~5 of formula III compound Times；

And/or, in step (1), described oxidant ought be mixed with reactant in form of an aqueous solutions During conjunction, its volumetric concentration is 0.4mol/L；

And/or, in step (1), the temperature of described reaction is room temperature；

And/or, in step (2), described reducing agent is palladium/carbon-hydrogen, palladium/carbon-ammonium formate, boron hydrogen Change one or more in sodium, sodium cyanoborohydride and acetic acid sodium borohydride；

And/or, in step (2), the consumption of described reducing agent is 1~10 equivalent of the compound of Formula V -1；

And/or, in step (2), when described reducing agent is palladium/carbon-hydrogen, preparing V-2ization In the method for compound, comprise the following steps：Under reducing atmosphere, by the described compound of Formula V -1, palladium / carbon and solvent mix, and react 1~5 hour；

And/or, in step (2), the temperature of described reduction reaction is room temperature；

And/or, in step (2), described reduction reaction is reacted at 1 atmosphere pressure；

And/or, in step (2), the solvent of described reduction reaction is ethyl acetate；Described solvent Consumption be 1.0~0.001mol/L, preferably 0.1~0.03mol/L, the concentration be the compound phase pair of Formula V -1 In the molar concentration of solvent for use；

And/or, step (1) is comprised the following steps：In the presence of atent solvent, in palladium catalyst Under catalysis, in the presence of oxidant, compound of formula I is reacted with Formula II compound, obtained institute The formula III compound stated；Wherein, R²It is H, R¹、R³、R⁴And R⁵Definition such as claim 1~6 Described in any one；

9. the preparation method of lactam analog compound as claimed in claim 8, it is characterised in that：

Step (1) is comprised the following steps：Formula III compound is dissolved in solvent, the aqueous solution with oxidant Mixing, react 30 minutes, then again with oxidant with solid hybrid reaction；

And/or, in step (1), the consumption of described solvent is 0.2mol/L；

And/or, in step (1), described oxidant is ammonium ceric nitrate, Cericammoniumsulfate, cerium chloride, One or more in cerous sulfate and cerous nitrate；

And/or, in step (1), the mole dosage of described oxidant is 3 times of formula III compound；

And/or, the preparation method of formula III compound comprises the following steps：By oxidant, compound of formula I, Formula II compound and palladium catalyst mix, and react 0~15 minute at room temperature, then heat to 20~140 DEG C Reaction 0.1~40 hour；

And/or, in the preparation method of formula III compound, described atent solvent is toluene, ethylbenzene, Tetrahydrofuran, 1,4- dioxane, N, N '-dimethyl formamide, N, N '-dimethyl acetamide, N- first Base pyrrolidones, dimethyl sulfoxide, 1,2- dichloroethanes, ether, glycol dimethyl ether, acetonitrile, acetic acid One or more in ethyl ester, dichloromethane and acetone；

And/or, in the preparation method of formula III compound, the consumption of described atent solvent is 0.05~2.0 Mol/L, the concentration refers to molar concentration of the compound of formula I relative to solvent for use；

And/or, in the preparation method of formula III compound, described palladium catalyst is zero valent palladium catalyst And/or divalence palladium catalyst；

And/or, in the preparation method of formula III compound, the mole dosage of described palladium catalyst is formula 0.1~20mol% of II compounds；

And/or, in the preparation method of formula III compound, described oxidant is air, oxygen, mistake Hydrogen oxide, potassium peroxydisulfate, sodium peroxydisulfate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, One or more in copper chloride and copper bromide；

And/or, in the preparation method of formula III compound, in addition to air and/or oxygen, described oxidation The consumption of agent is 1~4 equivalent of compound of formula I；If air and/or oxygen are used as oxidant, then make anti- Answer system is carried out under being in the oxidizing gas atmosphere；

And/or, in the preparation method of formula III compound, described compound of formula I and Formula II compound Mol ratio be 5:1~1:5；

And/or, in the preparation method of formula III compound, the temperature of described reaction is 60~100 DEG C.

10. the preparation method of lactam analog compound as claimed in claim 9, it is characterised in that：

In the preparation method of formula III compound, described zero valent palladium catalyst is three (dibenzalacetones) Two palladiums and/or four (triphenylphosphine palladiums)；

And/or, in the preparation method of formula III compound, described divalence palladium catalyst is palladium, Palladium bichloride, trifluoracetic acid palladium, TFMS palladium, double acetonitrile palladium chlorides, palladium dydroxide, allyl chloride Change one or more in palladium and [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride；

And/or, in the preparation method of formula III compound, the mole dosage of described palladium catalyst is formula 0.2~5mol% of II compounds, preferably 0.5~2.5mol%；

And/or, in the preparation method of formula III compound, described oxidant is that pressure is 0.5-100 The air or oxygen of atmospheric pressure, further preferred pressure is the air or oxygen of 0.8-10 atmospheric pressure, more excellent Select the air or oxygen that pressure is 1-5 atmospheric pressure；

And/or, in the preparation method of formula III compound, described compound of formula I and Formula II compound Mol ratio be 1:1~1:3, preferably 1:2.

A kind of preparation method of 11. lactam analog compounds as described in any one of claim 1~6, its Comprise the following steps：In the presence of atent solvent, under the catalysis of palladium catalyst, in the work of oxidant Under, compound of formula I is reacted with Formula II compound, obtained formula III compound；

Wherein, R²It is H, R¹、R³、R⁴And R⁵As described in any one of claim 1~6；It is wherein each The reaction step of the formula III compounds process for production thereof in reactions steps and condition such as any one of claim 8~10 Described in rapid and condition.

A kind of 12. preparation methods of lactam analog compound, it is comprised the following steps：In solvent, in oxygen In the presence of agent, the formula III compound as described in any one of claim 1~6 is reacted, obtained To the compound of Formula V -1；

Wherein, R¹、R³、R⁴And R⁵Definition as described in any one of claim 1~6；It is wherein each The step of reactions steps and condition such as any one of claim 7~10 Chinese style V-1 compounds process for production thereof and Described in condition.

A kind of 13. preparation methods of malonic acid class compound, it is comprised the following steps：

(1), in solvent, in the presence of oxidant, by the formula as described in any one of claim 1~6 III compounds are reacted, and obtain V-1 compounds；

(3), in the presence of acid, the described compound of Formula V -2 and methyl alcohol are reacted, the change of Formula V -3 is obtained Compound；

Wherein, R¹、R³And R⁵Definition such as any one of claim 1~6 in R¹、R³And R⁵Determine It is adopted described；The reaction condition of step (1) and step (2) in any one of claim 7~10 as walked Suddenly described in the reaction condition of (1) and step (2).

A kind of 14. preparation methods of lactam analog compound, it is comprised the following steps：In solvent, in acid In the presence of, the formula IV compound as described in any one of claim 1~6 is reacted, obtain formula V-5 compounds；

Wherein, R¹、R²、R⁴And R⁵Definition such as any one of claim 1~6 in R¹、R²、R⁴With R⁵Definition described in, and R simultaneously²It is not hydrogen.

The preparation method of 15. lactam analog compounds as claimed in claim 14, it is characterised in that：

The method of formula V-5 compounds is comprised the following steps：Formula IV compound, acid and solvent are mixed Close, reacted 10~50 minutes at 60 DEG C~90 DEG C；

And/or, in the method for formula V-5 compounds, described solvent is hexafluoroisopropanol；

And/or, in the method for formula V-5 compounds, the consumption of described solvent and described acid etc. Equivalent；

And/or, in the method for formula V-5 compounds, described acid is trifluoracetic acid, fluoroform sulphur One or more in acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and nitric acid；

And/or, in the method for formula V-5 compounds, described sour mole dosage at least with formula The mole dosage of IV compounds is identical；

And/or, in the method for formula V-5 compounds, the temperature of described reaction is 80 DEG C；

And/or, the method for formula V-5 compounds is comprised the following steps：In the presence of atent solvent, Under the catalysis of palladium catalyst, in the presence of oxidant, compound of formula I is carried out with Formula II compound Reaction, obtains formula IV compound；Wherein, R³It is hydrogen, R¹、R²、R⁴And R⁵Definition such as right will Ask described in 1~6 any one and R simultaneously²It is not H；

The preparation method of 16. lactam analog compounds as claimed in claim 15, it is characterised in that：

The preparation method of formula IV compound comprises the following steps：By oxidant, compound of formula I, Formula II Compound and palladium catalyst mix, and react 0~15 minute at room temperature, then heat to 20~140 DEG C instead Answer 0.1~40 hour；

And/or, in the preparation method of formula IV compound, described atent solvent is toluene, ethylbenzene, Tetrahydrofuran, 1,4- dioxane, N, N '-dimethyl formamide, N, N '-dimethyl acetamide, N- first Base pyrrolidones, dimethyl sulfoxide, 1,2- dichloroethanes, ether, glycol dimethyl ether, acetonitrile, acetic acid One or more in ethyl ester, dichloromethane and acetone；

And/or, in the preparation method of formula IV compound, the consumption of described atent solvent for 0.05~ 0.20mol/L, the concentration refers to molar concentration of the compound of formula I relative to solvent for use；

And/or, in the preparation method of formula IV compound, described palladium catalyst is zero valent palladium catalyst And/or divalence palladium catalyst；The palladium of described zero valent palladium catalyst preferably three (dibenzalacetone) two and/or four (triphenylphosphine palladium)；The described preferred palladium of divalence palladium catalyst, palladium bichloride, trifluoracetic acid palladium, three Fluorine methanesulfonic acid palladium, double acetonitrile palladium chlorides, palladium dydroxide, allyl palladium chloride and [1,1'- double (diphenylphosphine) Ferrocene] one or more in palladium chloride；

And/or, in the preparation method of formula IV compound, the mole dosage of described palladium catalyst is formula 0.1~20mol% of II compounds, preferably 0.2~5mol%, more preferably 0.5~2.5mol%；

And/or, in the preparation method of formula IV compound, described oxidant is air, oxygen, mistake Hydrogen oxide, potassium peroxydisulfate, sodium peroxydisulfate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulphate, One or more in copper chloride and copper bromide, preferably pressure is the air or oxygen of 0.5-100 atmospheric pressure, Further preferred pressure is the air or oxygen of 0.8-10 atmospheric pressure, and more preferably pressure is 1-5 atmospheric pressure Air or oxygen.

And/or, in the preparation method of formula IV compound, in addition to air and/or oxygen, described oxidation The consumption of agent is 1~4 equivalent of compound of formula I；If air and/or oxygen typically make as oxidant Reaction system is carried out under being in the oxidizing gas atmosphere；

And/or, in the preparation method of formula IV compound, described compound of formula I and Formula II compound Mol ratio be 5:1~1:5, preferably 1:1~1:3, more preferably 1:2；

And/or, in the preparation method of formula IV compound, the temperature of described reaction is 60~100 DEG C.

A kind of 17. preparation methods of lactam analog compound, it is comprised the following steps：In solvent, in oxygen In the presence of agent, the formula IV compound as described in any one of claim 1~6 is reacted, obtained To the compound of Formula V -6；

Wherein, R¹、R²、R⁴And R⁵Definition as described in any one of claim 1~6, and R simultaneously² It is not hydrogen.

The preparation method of 18. lactam analog compounds as claimed in claim 17, it is characterised in that：

The method for preparing V-6 compounds is comprised the following steps：Formula IV compound is dissolved in solvent, with oxygen Agent the aqueous solution mixing, react 10~50 minutes, then again with oxidant with solid hybrid reaction；

And/or, in the method for preparing V-6 compounds, described solvent is acetonitrile；

And/or, in the method for preparing V-6 compounds, the consumption of described solvent is 0.3mol/L ~0.01mol/L, the concentration refers to molar concentration of the formula IV compound phase for solvent for use；

And/or, in the method for preparing V-6 compounds, described oxidant is one-electron oxidation agent；

And/or, in the method for preparing V-6 compounds, described oxidant in form of an aqueous solutions, or Mixed with reactant in solid form；

And/or, in the method for preparing V-6 compounds, the mole dosage of described oxidant is formula IV 1~5 times of compound；

And/or, in the method for preparing V-6 compounds, described oxidant ought join in form of an aqueous solutions During with reaction, its volumetric concentration is 0.4mol/L；

And/or, in the method for preparing V-6 compounds, the temperature of described reaction is room temperature；

And/or, the method for preparing V-6 compounds is comprised the following steps：In the presence of atent solvent, Under the catalysis of palladium catalyst, in the presence of oxidant, compound of formula I and Formula II compound are carried out instead Should, obtain formula IV compound；Wherein, R³It is hydrogen, R¹、R²、R⁴And R⁵Definition such as claim Described in 1~6 any one and R²It is not H；

The step of preparation method of formula IV compound and condition are such as formula IV in claim 15 or 16 Described in the step of preparation method of compound and condition.

The preparation method of 19. lactam analog compounds as claimed in claim 18, it is characterised in that：

The method for preparing V-6 compounds is comprised the following steps：Formula IV compound is dissolved in solvent, with oxygen Agent the aqueous solution mixing, react 30 minutes, then again with oxidant with solid hybrid reaction；

And/or, in the method for preparing V-6 compounds, the consumption of described solvent is 0.2mol/L, The concentration refers to molar concentration of the formula IV compound phase for solvent for use；

And/or, in the method for preparing V-6 compounds, described oxidant is ammonium ceric nitrate, cerous sulfate One or more in ammonium, cerium chloride, cerous sulfate and cerous nitrate；

And/or, in the method for preparing V-6 compounds, the mole dosage of described oxidant is formula IV 3 times of compound.

A kind of preparation method of 20. lactam analog compounds as described in any one of claim 1~6, its Comprise the following steps：In the presence of atent solvent, under the catalysis of palladium catalyst, in the work of oxidant Under, compound of formula I is reacted with Formula II compound, obtained formula IV compound；

Wherein, R³It is hydrogen, R¹、R²、R⁴And R⁵Definition as described in any one of claim 1~6 and R²It is not H；It is prepared by wherein each reactions steps and the condition such as compound of formula IV of claim 15 or 16 Described in the reactions steps and condition of method.

A kind of 21. preparation methods of quinolines, it is comprised the following steps：In solvent, in Blang In the presence of this special acid and/or lewis acid, by the formula III chemical combination as described in any one of claim 1~6 Thing is reacted, and obtains Formula IV compound；

Wherein, R¹It is substituted or unsubstituted phenyl；Work as R¹For substitution phenyl when, R6 ', R7 ', R8 ' and R9 ' are the C as described in claims 1 to 3 or 5~6 any one₆~C₁₄Aryl or C₂~C₉It is miscellaneous Described in substitution base on aryl.

The preparation method of 22. quinolines as claimed in claim 21, it is characterised in that：

The method of formula VI compounds is comprised the following steps：Formula III compound and solvent are mixed, then Mix with bronsted acid and/or lewis acid, it is small to reacting 30 minutes to 16 at 100 DEG C in room temperature When；

And/or, in the method for formula VI compounds, described solvent is dichloromethane, 1,2- bis- One or more in chloroethanes and chloroform；The consumption of described solvent is 0.05mol/L~2.0mol/L；

And/or, in the method for formula VI compounds, described bronsted acid is trifluoracetic acid, One or more in TFMS, methanesulfonic acid, hydrochloric acid, sulfuric acid and nitric acid；

And/or, in the method for formula VI compounds, described lewis acid is BFEE, Alchlor, silicon tetrachloride, titanium tetrachloride, butter of tin, TFMS scandium, TFMS ketone, One or more in silver trifluoromethanesulfonate and Trimethylsilyl trifluoromethanesulfonate；

And/or, in the method for formula VI compounds, described bronsted sour and/or lewis acid Mole dosage for formula III compound 2~4 equivalents；

And/or, in the method for formula VI compounds, the temperature of described reaction is 50 DEG C~80 DEG C；

And/or, the method for formula VI compounds is comprised the following steps：In the presence of atent solvent, Under the catalysis of palladium catalyst, in the presence of oxidant, compound of formula I is carried out with Formula II compound Reaction, obtains described formula III compound；R²It is H；

Wherein, each step and condition are as claimed in claim 11 in the preparation method of formula III compound.