CN106986810B - Chiral 3- replaces isoindoline ketone compound and the preparation method and application thereof - Google Patents

Chiral 3- replaces isoindoline ketone compound and the preparation method and application thereof Download PDF

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CN106986810B
CN106986810B CN201610037827.9A CN201610037827A CN106986810B CN 106986810 B CN106986810 B CN 106986810B CN 201610037827 A CN201610037827 A CN 201610037827A CN 106986810 B CN106986810 B CN 106986810B
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CN106986810A (en
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王德先
敖宇飞
张韵
王梅祥
祝介平
王其强
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Institute of Chemistry CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
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Abstract

The invention discloses a kind of chirality 3- to replace isoindoline ketone compound and the preparation method and application thereof.The compound is shown in formula I.Under the conditions of preparation method includes: existing for the chiral phosphoric acid catalyst, Formula II and two component four-centre reaction of Ugi occurs for formula III or tri- component four-centre reaction of Ugi occurs for formula IV, Formula V and formula III, end of reaction obtains the Formulas I.The present invention selects the raw material and chiral catalyst cheap and easy to get easily largely prepared, make raw material that two component four-centre reaction of Ugi or tri- component four-centre reaction of Ugi occur, one step is efficiently prepared chiral 3- and replaces isoindoline ketone compound, reaction condition is mild, products therefrom is stable in the air, and yield is very high, and the enantioselectivity of product is very high, the easily separated purifying of product, has a good application prospect.

Description

Chiral 3- replaces isoindoline ketone compound and the preparation method and application thereof
Technical field
The invention belongs to organic chemistry filed, it is related to a kind of chirality 3- and replaces isoindoline ketone compound and its preparation side Method.
Background technique
Chiral 3- replaces isoindoline ketone compound, and skeleton is present in many natural products and has bioactivity Compound in.Such as isoindolobenzazepine Alkaloid (S)-(+)-lennoxamine (E.Valencia, Tetrahedron Lett.1984,25,599.), anxiolytic (R)-Pazinaclone (Z.Hussein, Br.J.Clin.Pharmacol.1993,36,357；I.Takahashi, Synlett1996,353), NHE1 inhibitor compound 3(G.Schubert,US 20050124681,2005；J.C.Carry, FR 2840302A1,2003), dopamine D4Receptor is short of money Anti-agent (S)-PD172938 (T.R.Belliotti, Bioorg.Med.Chem.Lett.1998,8,1499.) etc..
But existing chirality 3- replaces the synthetic method of isoindoline ketone compound also considerably less, conventional method is Using chiral auxiliary group agent by the nucleophilic addition of cis-selectivity (for example, S.M.Allin, Tetrahedron Lett.1997,38,3627；E.Deniau, Tetrahedron:Asymmetry 2005,16,875.), hydro-reduction reaction (for example, S.M.Allin, Tetrahedron Lett.1999,40,143；E.Deniau,Tetrahedron: Asymmetry2003,14,2253；A.A.Bahajaj,Tetrahedron2004,60,1247；M.D.Chen, Tetrahedron2004,60,1651；E.Deniau, Tetrahedron:Asymmetry2008,19,2735.), Diels- Alder reaction (H.McAlonan, J.Chem.Soc.Perkin Trans.12002,69.), Heck reaction (R.Grigg, Tetrahedron Lett.1990,31,3075.) and the cyclization of free yl induction (L.Shen, Org.Lett.2005,7,775.) etc..And replace isoindoline for directly preparing chiral 3- by catalytic asymmetric reaction The method of ketone compounds mainly passes through the asymmetric reduction reaction to 3- alkoxy carbonyl methylene isoindolinone (M.Nishimura, JP2010241770,2010), chiral ligand effect under metal rhodium or copper catalysis reaction (B.Ye, Angew.Chem.Int.Ed.2014,53,7896；V.Bisai, Angew.Chem.Int.Ed.2014,53,10737.) and It is obtained under chiral phase-transfer catalyst effect with the reaction (S.Lebrun, Eur.J.Org.Chem.2015,1995.) of intramolecular It arrives.For the method using chiral auxiliary group, it there is chiral auxiliary group selection difficulty, need to introduce and cut off auxiliary The disadvantages of group step, other functional groups and auxiliary group are incompatible in substrate；For being directly catalyzed asymmetric method, deposit It is difficult to synthesize in substrate, need using metal, it is understood that there may be metal residual, it is complicated for operation, need anhydrous and oxygen-free condition etc. to lack Point.Therefore there is an urgent need to develop new efficient method to carry out synthesis of chiral 3- substitution isoindoline ketone compound.
Summary of the invention
The object of the present invention is to provide a kind of chirality 3- to replace isoindoline ketone compound and the preparation method and application thereof.
Chirality 3- provided by the invention replaces isoindoline ketone compound or its pharmaceutically acceptable salt, and structure is logical Formula is shown in formula I,
In the Formulas I general structure, * represents chirality, is R or S；
R1Any one in following radicals: hydrogen atom, fluorine, chlorine, bromine, C1-C4Linear or branched alkyl group and C1-C4Alkane Oxygroup；Specifically, R1It can be methyl, methoxyl group or hydrogen atom；
R2Any one in following radicals: naphthalene, phenyl, the naphthalene containing substituent group and the benzene containing substituent group Base；Wherein, in the naphthalene containing substituent group and the phenyl containing substituent group, substituent group be selected from fluorine, chlorine, bromine, straight chain or Branch C1-C4Alkyl, C1-C4At least one of alkoxy, trifluoromethyl and ester group；The ester group concretely methyl formate Base；Specifically, R2Can for rubigan, p-bromophenyl, phenyl, to methyl formate phenyl, p-fluorophenyl, m-bromophenyl, adjacent first Phenyl or p-trifluoromethyl phenyl；
R3Any one in following radicals: C1-C6Alkyl, C3-C7Naphthenic base, phenyl and the benzene containing substituent group Base；Wherein, in the phenyl containing substituent group, substituent group is selected from fluorine, chlorine, bromine, C1-C4Alkyl and C1-C4In alkoxy extremely Few one kind, specifically, R3Can for tert-butyl, phenyl, normal-butyl, p-methoxyphenyl, p-bromophenyl or
Specifically, compound shown in the Formulas I can be any one in the compound as shown in following formula I a to Formulas I x:
The method provided by the invention for preparing chirality 3- shown in above-mentioned Formulas I and replacing isoindoline ketone compound, is method One or method two；
Wherein, the method one includes the following steps:
Under the conditions of existing for the chiral phosphoric acid catalyst and molecular sieve, compound shown in compound shown in Formula II and formula III Two component four-centre reaction of Ugi occurs, end of reaction obtains compound shown in the Formulas I；
The method two includes the following steps:
Under the conditions of existing for the chiral phosphoric acid catalyst and molecular sieve, compound shown in compound, Formula V shown in formula IV and Tri- component four-centre reaction of Ugi occurs for compound shown in formula III, and end of reaction obtains compound shown in the Formulas I；
The Formula II is into Formula V, R1To R3Define it is identical as the definition in the Formulas I.
The reaction equation of the above method one and method two is successively as follows:
In this method, compound shown in Formula II general structure can be led to according to following methods reported in the literature by formula IV structure Compound shown in formula is largely prepared with compound shown in Formula V general structure: K.B.Sloan, J.Heterocyclic Chem.1985,22,429。
In this method, compound shown in formula IV general structure can directly be bought by public commercial source or according to following Method reported in the literature is largely prepared: Z.D.Chen, WO 2012058254A1,2012.
The chiral phosphoric acid catalyst is compound shown in Formula IV or Formula VII；
The molecular sieve is selected fromMolecular sieve,Molecular sieve,Any one in molecular sieve and 13X molecular sieve.
In the method one, the dosage of the chiral phosphoric acid catalyst is the mole dosage of compound shown in the Formula II 0.1%-200%, preferably 5-70%, specially 10%, 15%, 20%, 30%, 40%；
The dosage of compound shown in the formula III is the 10-1000% of the mole dosage of compound shown in the Formula II, excellent Select 20-300%, more specifically 120%；
In the method two, the dosage of the chiral phosphoric acid catalyst is the mole dosage of compound shown in the formula IV 0.1%-200%, preferably 5-70%, specially 30%, 40%, 60%；
The dosage of compound shown in the formula III is the 20-1000% of the mole dosage of compound shown in the formula IV, excellent Select 20-300%, more specifically 120%；
The dosage of compound shown in the Formula V is the 10-1000% of the mole dosage of compound shown in the formula IV, preferably 20-300%, more specifically 100%.
In the method one, the amount ratio of compound shown in the molecular sieve and the Formula II is 0.1 mM: 1mg- 100mg, preferably 0.1 mM: 5-50mg；
In the method two, the amount ratio of compound shown in the molecular sieve and the formula IV is 0.1 mM: 1mg- 100mg, preferably 0.1 mM: 5-50mg.
In the four-centre reaction step of the method one and method two, temperature is -40 to 110 DEG C, preferably -35 DEG C to 25 DEG C, specially 0 DEG C；
Time is -120 hours 5 minutes, preferably -120 hours 10 minutes, specially 72 hours.
The four-centre reaction of the method one and method two carries out in a solvent；
The solvent be chosen in particular from methylene chloride, chloroform, carbon tetrachloride, 1,2- dichloroethanes, ethyl acetate, benzene, In toluene, ether, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and water at least It is a kind of.
The substitution isoindoline ketone compound of chirality 3- shown in the Formulas I that aforementioned present invention provides or its is pharmaceutically acceptable Salt inhibits the application in tumour cell product in preparation, also belongs to protection scope of the present invention.The tumour cell is colon cancer Cell, specially colon cancer cell HCT-116.
The present invention selects the raw material and chiral catalyst cheap and easy to get easily largely prepared, makes raw material that two component of Ugi occur Tri- component four-centre reaction of four-centre reaction or Ugi, a step are efficiently prepared chiral 3- and replace isoindoline ketone compound, Reaction condition is mild, and products therefrom is stable in the air, and yield is very high, and the enantioselectivity of product is very high, and product easily divides From purifying, have a good application prospect.
Detailed description of the invention
Fig. 1 is compound Ia-Ix to cell growth inhibition test (MTT Assay).
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but the present invention is not limited to following embodiments.Institute State method is conventional method unless otherwise instructed.The raw material can obtain unless otherwise instructed from public commercial source. Used in following embodimentsMolecular sieve is purchased from Alfa Aesar company, product number B21165.
Chiral phosphoric acid catalyst shown in Formula IV or Formula VII used can be prepared as follows and obtain in the present invention:
Wherein, compound shown in Formula IV can be prepared as follows and obtain:
The preparation of 1.1 compounds 2:
By compound 1 (5.000g) and PtO2(1.000g) is added in acetic acid (120mL), after hydrogen exchange, connects hydrogen Balloon, after reacting for 24 hours at room temperature, direct silica gel column chromatography after vacuum distillation obtains compound 2,5.157g, yield 99.4%.
The preparation of 1.2 compounds 3:
Compound 2 (2.944g) is added in methylene chloride (55mL), is cooled to -30 DEG C, then instill bromine thereto, Drop continues to react 6h at this temperature after finishing, and saturation sodium hydrogensulfite is added thereto and separates organic after stirring 1h at room temperature Phase, successively with saturation NaHCO3, it is saturated NaCl and washes organic phase, anhydrous Na2SO4It is dry, direct silica gel column chromatography after vacuum distillation, Obtain compound 3,4.025g, yield 88.6%.
The preparation of 1.3 compounds 4:
By compound 3 (0.678g), p-nitrophenyl boric acid (0.751g), Pd (OAc)2(0.014g), P (Ad)2(Bu) (0.027g), is added in reaction flask, nitrogen protection, in injection 15mL DME and 7.5mL K2CO3(1mol/L), is warming up to back For 24 hours, reaction solution is transferred in separatory funnel for stream, reaction, and 10mL methylene chloride is added, and uses saturated ammonium chloride respectively, is saturated chlorine Change sodium to wash, anhydrous Na2SO4Dry, direct silica gel column chromatography after vacuum distillation obtains compound 4,0.782g, yield 97.1%.
The preparation of 1.4 Formula IV:
By compound 4 (0.308g), it is added in pyridine (3.5mL), is slowly dropped into POCl under ice-water bath3, drip Bi Housheng Then reaction solution is cooled to 0 DEG C, is being slowly dropped into H thereto by temperature to 12h is reacted at 90 DEG C2O, drop are warming up to 90 DEG C after finishing Then 10mL DCM is added thereto, is transferred to separatory funnel by lower reaction 12h, successively use the hydrochloric acid of 1mol/L, saturated sodium-chloride Washing, anhydrous Na2SO4Dry, direct silica gel column chromatography after vacuum distillation obtains compound shown in Formula IV, 0.299g, yield 87.0%.
1H NMR (500MHz, DMSO) δ 8.26 (d, J=8.8Hz, 4H), 7.96 (d, J=8.7Hz, 4H), 7.30 (s, 2H),2.96–2.77(m,4H),2.74–2.62(m,2H),2.28–2.17(m,2H),1.85–1.71(m,6H),1.64–1.50 (m,2H).
In addition, compound shown in formula IV a can be prepared in accordance with the following steps:
The reaction equation is as follows:
By 4- methoxyl group -2- bromobenzoic acid (2.50mmol), it is added in dry tetrahydrofuran, and be cooled to -78 DEG C, Then it is slowly dropped into n-BuLi (5.25mmol) thereto.After drop finishes, 0.5h is reacted in continuation at -78 DEG C, then thereto Dry n,N-Dimethylformamide (2.1mL) is added, after finishing, 2h is reacted in continuation at -78 DEG C, and saturation is then added NH4Cl quenching reaction, then with 2M hydrochloric acid tune pH to acidity, ethyl acetate extraction merges organic phase, and saturation NaCl washing is anhydrous MgSO4Dry, solvent is removed in vacuum rotation, and gains silica gel column chromatography separates to obtain formula IV a structure compound represented 170mg, yield 38%.
The compound is solid:
Mp:138-139 DEG C of fusing point；
IR(KBr)ν3277,3080,2955,2922,1739,1607,1492,1289,1258,1164,1073,1019, 773,690cm-1；
1H NMR(400MHz,DMSO-d6, 120 DEG C) and δ 7.73 (d, J=7.0Hz, 1H), 7.32 (s, 1H), 7.29-7.17 (m,1H),3.90(s,3H)；
13C NMR(100MHz,DMSO-d6)δ168.0,163.0,128.5,119.6,112.8,56.5；
MS(ESI)m/z179.0[M-H]-；
Anal.Calcd.for C9H8O4:C,60.00；H,4.48.Found:C,59.95；H,4.36.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in formula IV a.
Compound shown in formula IV b can be prepared in accordance with the following steps:
The reaction equation is as follows:
According to the similar approach of compound shown in formula IV a, compound 113mg shown in formula IV b, yield 27% can be obtained.
The compound is solid:
Mp:122-123 DEG C of fusing point；
IR(KBr)ν3277,3080,2955,2922,1739,1607,1492,1289,1258,1164,1073,1019, 773,690cm-1；
1H NMR(400MHz,DMSO-d6, 120 DEG C) and δ 7.73 (d, J=7.0Hz, 1H), 7.32 (s, 1H), 7.29-7.17 (m,1H),3.90(s,3H)；
13C NMR(100MHz,DMSO-d6)δ168.0,163.0,128.5,119.6,112.8,56.5；
MS(ESI)m/z179.0[M-H]-；
Anal.Calcd.for C9H8O4:C,60.00；H,4.48.Found:C,59.95；H,4.36.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in formula IV b.
Compound shown in formula IV c can be prepared in accordance with the following steps:
The reaction equation is as follows:
According to the similar approach of compound shown in formula IV a, compound 170mg shown in formula IV c, yield 38% can be obtained.
The compound is solid:
Mp:138-139 DEG C of fusing point；
IR(KBr)ν3323,3075,2953,2918,1732,1708,1656,1595,1499,1285,1223,1066, 899cm-1；
1H NMR(500MHz,CD3CN)δ7.53(s,1H),7.29(s,2H),6.52(s,1H),5.57(s,1H),3.88 (s,3H)；
13C NMR(125MHz,CD3CN)δ169.5,162.8,140.3,129.7,125.6,123.2,108.4,98.6, 56.7；
MS(ESI)m/z179.0[M-H]-；
Anal.Calcd.for C9H8O4:C,60.00；H,4.48.Found:C,59.88；H,4.56.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in formula IV c.
Compound shown in Formula II a can be prepared as follows and obtain:
The reaction equation is as follows:
By formula IV a structure compound represented (10.0mmol), Formula V a structure compound represented (10.5mmol) is added Into 40mL methylene chloride, after reacting for 24 hours at room temperature, solvent is rotated into obtain solid, then with ethyl acetate and petroleum ether to this Solid is recrystallized, and Formula II a structure compound represented 2.288g, yield 79% are obtained.
The compound is solid:
Mp:169-170 DEG C of fusing point；
IR(KBr)ν3338,3070,2954,2923,1743,1611,1601,1493,1320,1254,1088,1068, 881,821cm-1；
1H NMR(500MHz,CD3CN)δ7.78–7.72(m,1H),7.28–7.22(m,2H),7.19–7.12(m,2H), 6.97-6.87 (m, 2H), 6.77 (d, J=10.5Hz, 1H), 5.76 (d, J=10.4Hz, 1H), 3.90 (s, 3H)；
13C NMR(125MHz,CD3CN)δ169.7,165.9,149.2,144.8,130.1,127.3,125.1,120.7, 118.6,116.9,108.9,87.3,56.9；
MS(ESI)m/z290.1[M+H]+；
Anal.Calcd.for C15H12ClNO3:C,62.19；H,4.17；N,4.83.Found:C,62.06；H,4.20； N,4.82.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II a.
Compound shown in Formula II b can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II b compound represented, obtain 2.054g yield 74%.
The compound is solid:
Mp:177-178 DEG C of fusing point；
IR(KBr)ν3344,3078,2955,2922,1737,1605,1494,1245,1088,866,818cm-1；
1H NMR(500MHz,CD3CN) δ 7.89 (dd, J=8.2,4.9Hz, 1H), 7.48-7.37 (m, 2H), 7.29- 7.20 (m, 2H), 6.96-6.89 (m, 2H), 6.85 (d, J=10.7Hz, 1H), 5.81 (d, J=10.5Hz, 1H)；
13C NMR(125MHz,CD3CN) δ 168.9,167.4 (d, J=201.3Hz), 149.2 (d, J=8.4Hz), 144.5,130.1,128.4 (d, J=8.1Hz), 125.4,125.1 (d, J=1.3Hz), 119.5 (d, J=19.3Hz), 117.0,112.1 (d, J=20.0Hz), 87.5 (d, J=2.1Hz)；
MS(ESI)m/z278.0[M+H]+；
Anal.Calcd.for C14H9ClFNO2:C,60.56；H,3.27；N,5.04.Found:C,60.53；H,3.09； N,4.99.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II b.
Compound shown in Formula II c can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II c compound represented, obtain 1.882g yield 65%.
The compound is solid:
Mp:172-173 DEG C of fusing point；
IR(KBr)ν3335,2954,2923,1747,1599,1497,1319,12801255,1063,820cm-1；
1H NMR(500MHz,CD3CN)δ7.60–7.51(m,1H),7.38–7.29(m,2H),7.28–7.21(m,2H), 6.96-6.87 (m, 2H), 6.85-6.77 (m, 1H), 5.76 (d, J=10.4Hz, 1H), 3.89 (s, 3H)；
13C NMR(125MHz,CD3CN)δ169.9,162.8,144.8,138.4,130.3,130.0,125.7,125.2, 123.0,116.9,108.5,88.2,56.6；
MS(ESI)m/z290.1[M+H]+；
Anal.Calcd.for C15H12ClNO3:C,62.19；H,4.17；N,4.83.Found:C,62.25；H,4.12； N,4.93.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II c.
Compound shown in Formula II d can be prepared as follows and obtain: the reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II d compound represented, obtain 2.072g yield 92%.
The compound is solid:
Mp:117-172 DEG C of fusing point；
IR(KBr)ν3344,3055,2958,2921,1748,1604,1512,1499,1286,1259,1213,1069, 869cm-1；
1H NMR(400MHz,CD3CN) δ 7.87 (d, J=7.6Hz, 1H), 7.80 (t, J=7.5Hz, 1H), 7.70-7.65 (m, 2H), 7.27 (t, J=7.9Hz, 2H), 6.99-6.92 (m, 3H), 6.90 (t, J=7.4Hz, 1H), 5.69 (d, J= 10.5Hz,1H)；
13C NMR(100MHz,CD3CN)δ170.2,146.6,145.9,135.3,131.6,130.4,128.9,125.8, 124.8,121.1,115.6,88.7；
MS(ESI)m/z226.1[M+H]+；
Anal.Calcd.for C14H11NO2:C,74.65；H,4.92；N,6.22.Found:C,74.62；H,4.87；N, 6.18.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II d.
Compound shown in Formula II e can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II e compound represented, obtain 1.703g yield 56%.
The compound is solid:
Mp:173-175 DEG C of fusing point；
IR(KBr)ν3347,2958,2928,1749,1594,1522,1492,1283,1255,1214,1095,1079, 873,818,745cm-1；
1H NMR(400MHz,CD3CN) δ 7.86 (d, J=7.5Hz, 1H), 7.83-7.76 (m, 1H), 7.69-7.65 (m, 2H), 7.43-7.34 (m, 2H), 6.90-6.87 (m, 3H), 5.81 (d, J=10.4Hz, 1H)；
13C NMR(100MHz,CD3CN)δ170.1,146.3,145.3,135.3,133.0,131.6,128.7,125.8, 124.8,117.4,112.5,88.2；
MS(ESI)m/z 304.0[M+H]+；
Anal.Calcd.for C14H10BrNO2:C,55.29；H,3.31；N,4.61.Found:C,55.22；H,3.34； N,4.70.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II e.
Compound shown in Formula II f can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II f compound represented, obtain 2.562g yield 90%.
The compound is solid:
Mp:202-203 DEG C of fusing point；
IR(KBr)ν3339,3057,2953,2924,1759,1710,1608,1527,1286,1266,1214,1179, 1093,1068,885,771cm-1；
1H NMR(400MHz,CD3CN)δ7.93–7.88(m,3H),7.83-7.80(m,1H),7.74–7.65(m,2H), 7.01-6.96 (m, 3H), 6.18 (d, J=9.9Hz, 1H), 3.83 (s, 3H)；
13C NMR(125MHz,CD3CN)δ170.0,167.5,150.2,146.2,135.4,132.2,131.7,128.6, 125.9,124.9,122.5,114.7,87.2,52.3；
MS(ESI)m/z284.1[M+H]+；
Anal.Calcd.for C16H13NO4:C,67.84；H,4.63；N,4.94.Found:C,67.82；H,4.58；N, 4.95.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II f.
Compound shown in Formula II g can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II g compound represented, obtain 1.677g yield 69%.
The compound is solid:
Mp:177-179 DEG C of fusing point；
IR(KBr)ν3342,3054,2959,2923,1745,1510,1466,1215,1092,1075,872,825, 783,745cm-1；
1H NMR(400MHz,CD3CN) δ 7.86 (d, J=7.6Hz, 1H), 7.83-7.75 (m, 1H), 7.72-7.60 (m, 2H), 7.08-6.98 (m, 2H), 6.97-6.91 (m, 2H), 6.87 (d, J=10.9Hz, 1H), 5.65 (d, J=10.6Hz, 1H)；
13C NMR(100MHz,CD3CN) δ 170.2,158.2 (d, J=234.2Hz), 146.5,142.3 (d, J= 1.8Hz), 135.3,131.6,128.8,125.8,124.8,117.1 (d, J=7.6Hz), 116.7 (d, J=22.6Hz), 89.2；
MS(ESI)m/z 244.1[M+H]+；
Anal.Calcd.for C14H10FNO2:C,69.13；H,4.14；N,5.76.Found:C,69.13；H,4.22；N, 5.78.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II g.
Compound shown in Formula II h can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II h compound represented, obtain 2.181g yield 72%.
The compound is solid:
Mp:176-178 DEG C of fusing point；
IR(KBr)ν3347,3065,2963,2927,1751,1598,1519,1481,1466,1286,1213,1072, 863,769,745,683cm-1；
1H NMR(400MHz,DMSO-d6) δ 7.90 (d, J=7.6Hz, 1H), 7.86 (t, J=7.3Hz, 1H), 7.77- 7.68 (m, 2H), 7.55 (d, J=10.5Hz, 1H), 7.24-7.10 (m, 3H), 7.03-6.92 (m, 2H)；
13C NMR(100MHz,DMSO-d6)δ169.0,147.1,145.5,134.5,131.1,130.7,127.3, 124.8,124.1,122.4,121.9,116.7,113.5,87.2；
MS(ESI)m/z 304.0[M+H]+；
Anal.Calcd.for C14H10BrNO2:C,55.29；H,3.31；N,4.61.Found:C,55.22；H,3.01； N,4.55.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II h.
Compound shown in Formula II i can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II i compound represented, obtain 1.481g yield 57%.
The compound is solid:
Mp:178-179 DEG C of fusing point；
IR(KBr)3350,2956,2922,1748,1600,1520,1494,1466,1285,1214,1090,870, 820,745,708cm-1；
1H NMR(400MHz,CD3CN) δ 7.86 (d, J=7.5Hz, 1H), 7.80 (t, J=7.4Hz, 1H), 7.72-7.62 (m, 2H), 7.26 (d, J=8.8Hz, 2H), 6.93 (d, J=8.7Hz, 2H), 6.88 (d, J=10.7Hz, 1H), 5.80 (d, J =10.3Hz, 1H)；
13C NMR(100MHz,CD3CN)δ170.1,146.3,144.8,135.3,131.6,130.1,128.7,125.8, 125.3,124.8,117.0,88.3；
MS(ESI)m/z 260.0[M+H]+；
Anal.Calcd.for C14H10ClNO2:C,64.75；H,3.88；N,5.39.Found:C,64.72；H,3.85； N,5.40.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II i.
Compound shown in Formula II j can be prepared as follows and obtain: the reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II j compound represented, obtain 2.063g yield 81%.
The compound is solid:
Mp:157-158 DEG C of fusing point；
IR(KBr)ν3373,3073,2955,2928,1759,1603,1515,1459,1254,1230,1069,1027, 874,746cm-1；
1H NMR(400MHz,CDCl3) δ 7.95 (d, J=7.6Hz, 1H), 7.75 (t, J=7.3Hz, 1H), 7.71-7.61 (m,2H),7.19–7.11(m,1H),7.01–6.81(m,4H),5.25(s,1H),3.82(s,3H)；
13C NMR(100MHz,CDCl3)δ169.3,147.4,145.6,134.4,133.5,130.7,128.1,125.6, 123.4,121.3,120.5,112.7,110.3,87.0,55.5；
MS(ESI)m/z256.1[M+H]+,278.1[M+Na]+；
Anal.Calcd.for C15H13NO3:C,70.58；H,5.13；N,5.49.Found:C,70.51；H,5.04；N, 5.58.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II j.
Compound shown in Formula II k can be prepared as follows and obtain: the reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II k compound represented, obtain 2.068g yield 81%.
The compound is solid:
Mp:201-202 DEG C of fusing point；
IR(KBr)ν3346,3061,2957,2928,1759,1710,1608,1527,1285,1265,1214,1179, 1093,1067,885,770cm-1；
1H NMR(400MHz,CD3CN) δ 7.85 (d, J=7.5Hz, 1H), 7.79 (t, J=7.5Hz, 1H), 7.71-7.59 (m, 2H), 6.97-6.78 (m, 5H), 5.41 (d, J=10.7Hz, 1H), 3.74 (s, 3H)；
13C NMR(100MHz,CD3CN)δ170.3,155.1,146.8,139.3,135.2,131.5,129.0,125.7, 124.8,117.4,115.7,90.1,56.1；
MS(ESI)m/z256.1[M+H]+,278.1[M+Na]+；
Anal.Calcd.for C15H13NO3:C,70.58；H,5.13；N,5.49.Found:C,70.64；H,5.21；N, 5.59.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II k.
Compound shown in Formula II l can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II l compound represented, obtain 2.053g yield 75%.
The compound is solid:
Mp:194-196 DEG C of fusing point；
IR(KBr)ν3340,3053,2960,2923,1747,1633,1603,1526,1466,1284,1263,1211, 1069,870,841,744cm-1；
1H NMR(500MHz,CDCl3) δ 7.97 (d, J=7.6Hz, 1H), 7.85-7.59 (m, 6H), 7.45 (t, J= 7.5Hz, 1H), 7.40 (s, 1H), 7.33 (t, J=7.4Hz, 1H), 7.09 (dd, J=8.7,1.9Hz, 1H), 6.98 (s, 1H), 4.85(bs,1H)；
13C NMR(125MHz,CDCl3)δ169.4,145.4,141.4,134.7,134.6,131.0,129.6,129.3, 128.2,127.8,126.9,126.9,125.9,123.9,123.5,118.0,109.6,87.5；
MS(ESI)m/z276.1[M+H]+；
Anal.Calcd.for C18H13NO2:C,78.53；H,4.76；N,5.09.Found:C,78.73；H,4.70；N, 5.01.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II l.
Compound shown in Formula II m can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II m compound represented, obtain 2.053g yield 75%.
The compound is solid:
Mp:160-162 DEG C of fusing point；
IR(KBr)ν3343,3051,2956,2923,1750,1584,1537,1466,1407,1278,1216,1096, 1073MS cm-1；
1H NMR(400MHz,CD3CN) δ 7.96 (d, J=8.1Hz, 1H), 7.93-7.76 (m, 4H), 7.73-7.65 (m, 1H), 7.56-7.39 (m, 4H), 7.26 (d, J=7.2Hz, 1H), 7.06 (d, J=10.8Hz, 1H), 6.09 (d, J= 10.7Hz,1H)；
13C NMR(100MHz,CD3CN)δ170.3,147.0,141.3,135.3,135.3,131.6,129.3,128.9, 127.3,127.1,126.3,125.7,125.5,125.2,122.1,121.8,110.1,89.2；
MS(ESI)m/z276.1[M+H]+；
Anal.Calcd.for C18H13NO2:C,78.53；H,4.76；N,5.09.Found:C,78.67；H,4.87；N, 5.19.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II m.
Compound shown in Formula II n can be prepared as follows and obtain:
The reaction equation is as follows:
According to the similar approach with compound shown in preparation formula IIa, it can be prepared by Formula II n compound represented, obtain 2.111g yield 72%.
The compound is solid:
Mp:214-215 DEG C of fusing point；
IR(KBr)ν3344,3066,2954,2921,1737,1624,1540,1339,1320,1157,1100,1070, 867,828,738,700cm-1；
1H NMR(400MHz,CD3CN) δ 7.88 (d, J=7.6Hz, 1H), 7.85-7.77 (m, 1H), 7.74-7.64 (m, 2H), 7.57 (d, J=8.5Hz, 2H), 7.06 (d, J=8.5Hz, 2H), 6.95 (d, J=10.2Hz, 1H), 6.15 (d, J= 10.0Hz,1H)；
13C NMR(100MHz,CD3CN) δ 170.0,149.3,146.2,135.4,131.7,128.6,127.6 (q, J= 4.0Hz), 126.0 (q, J=268.0Hz), 125.9,124.8,121.9 (q, J=32.0Hz), 115.1,87.3；
MS(ESI)m/z 294.1[M+H]+；
Anal.Calcd.for C15H10F3NO2:C,61.44；H,3.44；N,4.78.Found:C,61.33；H,3.46； N,4.83.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II n
Compound shown in Formula II o can be prepared as follows and obtain:
The reaction equation is as follows:
It according to the similar approach preparation formula IVe of compound shown in preparation formula Iva, but does not isolate and purify, direct plunges into next In step.Then according to according to the similar approach with compound shown in preparation formula IIa, by do not purify formula IV e come preparation formula IIo institute The compound shown.Obtain 0.749g, two step yields 61%.
The compound is solid:
Mp:183-184 DEG C of fusing point；
IR(KBr)ν3341,3068,2954,2923,1747,1600,1522,1494,1486,1310,1249,1093, 855,819cm-1；
1H NMR(400MHz,CD3CN) δ 7.69 (dd, J=8.2,4.5Hz, 1H), 7.61-7.49 (m, 2H), 7.31- 7.21 (m, 2H), 6.97-6.90 (m, 2H), 6.88 (d, J=10.7Hz, 1H), 5.82 (d, J=10.5Hz, 1H)；
13C NMR(100MHz,CD3CN) δ 169.0 (d, J=3.5Hz), 165.0 (d, J=246.7Hz), 144.6, 142.1 (d, J=2.0Hz), 131.1 (d, J=9.1Hz), 130.1,127.0 (d, J=8.9Hz), 125.4,122.9 (d, J= 24.0Hz), 117.1,112.2 (d, J=24.0Hz), 88.5；
MS(ESI)m/z278.0[M+H]+；
Anal.Calcd.for C14H9ClFNO2:C,60.56；H,3.27；N,5.04.Found:C,60.57；H,3.27； N,5.02.
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formula II o.
Embodiment 1, chirality 3- shown in preparation formula Ia structural formula replace isoindoline ketone compound
The reaction equation is as follows:
By Formula II a structure compound represented (0.20mmol), isonitrile (0.24mmol) shown in formula III a structure, Formula IV Shown chiral phosphoric acid catalyst (0.02mmol, 10mol%),Molecular sieve powder (10mg) is added to bis- chloroethene of 2mL 1,2- In alkane, keeping temperature of reaction system is 0 DEG C, and thin-layer chromatographic analysis shows that raw material II a runs out of full cut-off by reaction time 72h and stops Reaction directly uses 200-300 mesh silica gel column chromatography, isolated Formulas I a structure compound represented 73.2mg, yield 98%. Compound shown in Ia structure is tested using high performance liquid chromatography, chromatographic column is ADH column, and it is 2 that mobile phase, which is by volume ratio: The mixed liquor of 1 n-hexane and isopropanol composition, flow velocity 0.5mL/min, Detection wavelength 254nm, as the result is shown Ia structure institute The enantioselectivity of the compound shown is 96%.
The product is solid；
Mp:245-246 DEG C of fusing point；
IR(KBr)ν3310,3069,2966,2930,1701,1666,1609,1545,1495,1366,1282,1240, 1095,837cm-1；
1H NMR(400MHz,CDCl3) δ 7.74 (m, 3H), 7.38 (d, J=8.9Hz, 2H), 7.21 (d, J=1.5Hz, 1H), 7.04 (dd, J=8.5,2.0Hz, 1H), 5.52 (s, 1H), 5.37 (s, 1H), 3.90 (s, 3H), 1.14 (s, 9H)；
13C NMR(100MHz,CDCl3)δ168.0,166.5,164.3,142.9,137.0,130.2,129.5,125.9, 123.0,120.8,117.3,106.5,65.8,56.1,51.9,28.4；
MS(ESI)m/z373.1[M+H]+；
Anal.Calcd.for C20H21ClN2O3:C,64.43；H,5.68；N,7.51.Found:C,64.49；H,5.77； N,7.60.
[α]D 25=-148 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I a.
Embodiment 2, chirality 3- shown in preparation formula Ia structural formula replace isoindoline ketone compound
The reaction equation is as follows:
By compound shown in formula IV a (0.10mmol), compound shown in Formula V a (0.10mmol) is added to 1, the 2- bis- of 1mL In chloroethanes, reaction is stayed overnight at room temperature, then above-mentioned solution is cooled to 0 DEG C, is addedMolecular sieve powder (5mg), formula III a Shown in chiral phosphoric acid catalyst (0.03mmol, 30mol%) shown in isonitrile (0.12mmol) and VI, continue at 0 DEG C Reaction, thin-layer chromatographic analysis show that raw material Iva stops reaction after reaction time 72h consumption completely, directly use 200-300 Mesh silica gel column chromatography, isolated Formulas I a structure compound represented 34.2mg, yield 92%.Using high performance liquid chromatography to Ia Compound shown in structure is tested, chromatographic column be ADH column, mobile phase be by volume ratio be 2:1 n-hexane and isopropanol group At mixed liquor, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, chemical combination shown in Ia structure as the result is shown The enantioselectivity of object is 86%.
Compound structure analyzes and identifies data consistent with Example 1.
Embodiment 3, chirality 3- shown in preparation formula Ib structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 20mol%), and preparation formula Ib compound represented obtains 69.3mg, yield 96%.Compound shown in Ib structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ib structure compound represented is 92% as the result is shown.
The compound is solid:
Mp:251-252 DEG C of fusing point；
IR(KBr)ν3284,3075,2960,2924,1717,1705,1607,1556,1497,1486,1366,1238, 1091,844,828cm-1；
1H NMR(500MHz,DMSO-d6) δ 8.53 (s, 1H), 7.95-7.82 (m, 1H), 7.77 (d, J=8.1Hz, 2H), 7.59-7.46 (m, 3H), 7.43 (t, J=8.6Hz, 1H), 5.87 (s, 1H), 1.23 (s, 9H)；
13C NMR(125MHz,DMSO-d6) δ 166.2,164.9 (d, J=248.6Hz), 164.8,143.7 (d, J= 10.5Hz), 137.4,128.8,128.2,128.0,126.1 (d, J=10.0Hz), 121.1,116.9 (d, J=23.4Hz), 109.3 (d, J=24.8Hz), 63.8,51.0,28.1；
MS(ESI)m/z361.1[M+H]+；
Anal.Calcd.for C19H18ClFN2O2:C,63.25；H,5.03；N,7.76.Found:C,63.17；H, 5.01；N,7.64；
[α]D 25=-156 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I b.
Embodiment 4, chirality 3- shown in preparation formula Ib structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.06mmol, 60mol%), and preparation formula Ib compound represented obtains 37.1mg, yield 89%.Compound shown in Ib structure is tested with performance liquid chromatographic column, chromatographic column is ADH column, and mobile phase is by volume Than the mixed liquor of n-hexane and isopropanol composition for 2:1, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, the enantioselectivity of Ib structure compound represented is 88% as the result is shown
Compound structure analyzes and identifies data consistent with Example 3.
Embodiment 5, chirality 3- shown in preparation formula Ic structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ic compound represented obtains 74.0mg, yield 99%.Compound shown in Ic structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ic structure compound represented is 89% as the result is shown.
The compound is solid:
Mp:209-210 DEG C of fusing point；
IR(KBr)ν3320,3070,2966,2929,1705,1667,1494,1367,1282,1065,1026,827cm-1；
1H NMR(400MHz,CDCl3) δ 7.78-7.73 (m, 2H), 7.63 (d, J=8.4Hz, 1H), 7.44-7.37 (m, 2H), 7.31 (d, J=2.3Hz, 1H), 7.19 (dd, J=8.4,2.4Hz, 1H), 5.41 (s, 1H), 5.39 (s, 1H), 3.87 (s,3H),1.13(s,9H)；
13C NMR(125MHz,CDCl3)δ168.2,166.7,161.1,136.8,132.7,132.1,130.6,129.6, 123.7,121.8,121.1,107.0,65.7,55.9,51.8,28.4；
MS(ESI)m/z373.1[M+H]+；
Anal.Calcd.for C20H21ClN2O3:C,64.43；H,5.68；N,7.51.Found:C,64.46；H,5.65； N,7.30；
[α]D 25=-177 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I c.
Embodiment 6, chirality 3- shown in preparation formula Ic structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 40mol%), and preparation formula Ic compound represented obtains 33.8mg, yield 91%.Compound shown in Ic structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ic structure compound represented is 80% as the result is shown
Compound structure analyzes and identifies data consistent with Example 5.
Embodiment 7, chirality 3- shown in preparation formula Id structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Id compound represented obtains 61.0mg, yield 99%.Compound shown in Id structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 9:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Id structure compound represented is 87% as the result is shown.
The compound is solid:
Mp:194-195 DEG C of fusing point；
IR(KBr)ν3306,3068,2961,2925,1705,1667,1601,1549,1501,1467,754,728cm-1；
1H NMR(300MHz,CDCl3) δ 7.93 (d, J=7.4Hz, 1H), 7.79 (d, J=8.1Hz, 3H), 7.65 (t, J =7.4Hz, 1H), 7.56 (t, J=7.4Hz, 1H), 7.46 (t, J=7.9Hz, 2H), 7.23-7.21 (m, 1H), 5.53 (s, 1H),5.38(s,1H),1.10(s,9H)；
13C NMR(100MHz,CDCl3)δ168.1,166.7,140.6,138.1,133.2,131.0,129.6,129.4, 125.5,124.4,122.8,120.4,66.0,51.8,28.4；
MS(ESI)m/z 309.2[M+H]+；
Anal.Calcd.for C19H20N2O2:C,74.00；H,6.54；N,9.08.Found:C,73.91；H,6.48；N, 8.93；
[α]D 25=-180 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I d.
Embodiment 8, chirality 3- shown in preparation formula Ie structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ie compound represented obtains 76.2mg, yield 98%.Compound shown in Ie structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ie structure compound represented is 93% as the result is shown.
The compound is solid:
Mp:235-236 DEG C of fusing point；
IR(KBr)ν3306,3078,2960,2925,1708,1666,1546,1494,1467,1366,1339,1221, 729cm-1；
1H NMR(400MHz,CDCl3) δ 7.81 (d, J=7.6Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.73-7.67 (m,2H),7.66–7.61(m,1H),7.57–7.46(m,3H),5.57(s,1H),5.44(s,1H),1.14(s,9H)；
13C NMR(100MHz,CDCl3)δ168.2,166.4,140.4,137.3,133.5,132.5,130.7,129.6, 124.4,122.7,121.3,118.3,66.0,51.9,28.4；
MS(ESI)m/z 387.1[M+H]+；
Anal.Calcd.for C19H19BrN2O2:C,58.93；H,4.95；N,7.23.Found:C,58.84；H,4.96； N,7.08；
[α]D 25=-164 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I e.
Embodiment 9, chirality 3- shown in preparation formula If structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula If compound represented obtains 68.8mg, yield 94%.Compound shown in If structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of If structure compound represented is 91% as the result is shown.
The compound is solid:
Mp:203-204 DEG C of fusing point；
IR(KBr)ν3326,2957,2925,1721,1713,1670,1605,1366,1282,769,729cm-1；
1H NMR(400MHz,CDCl3) δ 8.10 (d, J=8.9Hz, 2H), 7.92 (d, J=8.9Hz, 2H), 7.87 (d, J =7.6Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.55 (t, J=7.5Hz, 1H), 5.52 (s,1H),5.48(s,1H),3.93(s,3H),1.12(s,9H)；
13C NMR(100MHz,CDCl3)δ168.3,166.5,166.3,142.2,140.5,133.7,131.1,130.6, 129.6,126.4,124.6,122.7,118.9,66.0,52.3,51.9,28.4；
MS(ESI)m/z 367.2[M+H]+；
Anal.Calcd.for C21H22N2O4:C,68.84；H,6.05；N,7.65.Found:C,68.70；H,6.11；N, 7.69；
[α]D 25=-151 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I f.
Embodiment 10, chirality 3- shown in preparation formula If structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 40mol%), and preparation formula If compound represented obtains 33.2mg, yield 91%.Compound shown in If structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of If structure compound represented is 88% as the result is shown
Compound structure analyzes and identifies data consistent with Example 9.
Embodiment 11, chirality 3- shown in preparation formula Ig structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ig compound represented obtains 64.0mg, yield 98%.Compound shown in Ig structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ig structure compound represented is 89% as the result is shown.
The compound is solid:
Mp:204-205 DEG C of fusing point；
IR(KBr)ν3292,3078,2961,2924,1713,1661,1552,1509,1367,1229,833,733, 723cm-1；
1H NMR(400MHz,CDCl3) δ 7.82 (d, J=7.6Hz, 1H), 7.79-7.70 (m, 3H), 7.63 (t, J= 7.2Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 7.18-7.07 (m, 2H), 5.55 (s, 1H), 5.46 (s, 1H), 1.13 (s, 9H)；
13C NMR(100MHz,CDCl3) δ 168.1,166.5,160.0 (d, J=244.2Hz), 140.5,134.2 (d, J =2.9Hz), 133.3,130.8,129.5,124.4,122.7,122.1 (d, J=8.0Hz), 116.3 (d, J=22.3Hz), 66.3,51.9,28.4；
MS(ESI)m/z 327.2[M+H]+；
Anal.Calcd.for C19H19FN2O2:C,69.92；H,5.87；N,8.58.Found:C,69.95；H,5.81； N,8.54；
[α]D 25=-168 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I g.
Embodiment 12, chirality 3- shown in preparation formula Ih structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ih compound represented obtains 64.0mg, yield 98%.Compound shown in Ih structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ih structure compound represented is 91% as the result is shown.
The compound is solid:
Mp:251-253 DEG C of fusing point；
IR(KBr)ν3299,3070,2958,2923,1715,1662,1590,1552,1482,1364,1326,777, 731cm-1；
1H NMR(400MHz,CDCl3) δ 8.11 (s, 1H), 7.91 (d, J=7.5Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.73-7.63 (m, 2H), 7.57 (t, J=7.5Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.31 (t, J=8.0Hz, 1H),5.45(s,1H),5.38(s,1H),1.14(s,9H)；
13C NMR(100MHz,CDCl3)δ168.2,166.3,140.5,139.5,133.6,130.8,130.6,129.6, 128.3,124.6,123.4,123.0,122.8,118.2,66.0,52.0,28.4；
MS(ESI)m/z 387.1[M+H]+；
Anal.Calcd.for C19H19BrN2O2:C,58.93；H,4.95；N,7.23.Found:C,58.82；H,4.77； N,7.12；
[α]D 25=-170 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I h.
Embodiment 13, chirality 3- shown in preparation formula Ih structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 40mol%), and preparation formula Ih compound represented obtains 34.9mg, yield 90%.Compound shown in Ih structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ih structure compound represented is 87% as the result is shown
Compound structure analyzes and identifies data consistent with Example 12.
Embodiment 14, chirality 3- shown in preparation formula Ii structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ii compound represented obtains 64.1mg, yield 94%.Compound shown in Ii structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ii structure compound represented is 91% as the result is shown.
The compound is solid:
Mp:235-236 DEG C of fusing point；
IR(KBr)ν3302,3075,2960,2925,1709,1663,1549,1496,1467,1456,1366,1340, 1094,832,730cm-1；
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=7.6Hz, 1H), 7.81-7.72 (m, 3H), 7.65 (t, J= 7.5Hz, 1H), 7.56 (t, J=7.4Hz, 1H), 7.45-7.37 (m, 2H), 5.46 (s, 1H), 5.37 (s, 1H), 1.13 (s, 9H)；
13C NMR(100MHz,CDCl3)δ168.1,166.4,140.4,136.8,133.4,130.7,130.6,129.5, 124.4,122.7,121.1,66.1,51.9,28.4；
MS(ESI)m/z 343.1[M+H]+；
Anal.Calcd.for C19H19ClN2O2:C,66.57；H,5.59；N,8.17.Found:C,66.73；H,5.72； N,8.18；
[α]D 25=-186 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I i.
Embodiment 15, chirality 3- shown in preparation formula Ii structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.03mmol, 30mol%), and preparation formula Ii compound represented obtains 33.3mg, yield 97%.Compound shown in Ii structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ii structure compound represented is 90% as the result is shown
Compound structure analyzes and identifies data consistent with Example 14.
Embodiment 16, chirality 3- shown in preparation formula Ij structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ij compound represented obtains 63.2mg, yield 93%.Compound shown in Ij structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ij structure compound represented is 56% as the result is shown.
The compound is solid:
Mp:200-201 DEG C of fusing point；
IR(KBr)ν3323,3070,2965,2926,1682,1534,1504,1466,1366,1260,1234,753, 731cm-1；
1H NMR(400MHz,CD3CN) δ 7.80 (d, J=7.5Hz, 1H), 7.70-7.63 (m, 2H), 7.62-7.53 (m, 1H),7.44–7.35(m,2H),7.20–7.11(m,1H),7.09–7.01(m,1H),6.69(s,1H),5.51(s,1H), 3.84(s,3H),1.14(s,9H)；
13C NMR(100MHz,CD3CN)δ169.0,167.5,156.1,143.5,133.4,132.1,130.3,130.2, 129.9,126.8,124.5,123.5,121.9,113.3,67.5,56.5,52.1,28.6；
MS(ESI)m/z 339.2[M+H]+,361.2[M+Na]+；
Anal.Calcd.for C20H22N2O3:C,70.99；H,6.55；N,8.28.Found:C,70.77；H,6.64；N, 8.26；
[α]D 25=-120 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I j.
Embodiment 17, chirality 3- shown in preparation formula Ik structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ik compound represented obtains 64.9mg, yield 96%.Compound shown in Ik structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ik structure compound represented is 62% as the result is shown.
The compound is solid:
Mp:190-191 DEG C of fusing point；
IR(KBr)ν3316,3063,2960,2925,1698,1667,1545,1513,1467,1378,1366,1299, 1249,1182,729cm-1；
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=7.5Hz, 1H), 7.77 (d, J=7.6Hz, 1H), 7.70-7.59 (m, 3H), 7.54 (t, J=7.4Hz, 1H), 6.98 (d, J=9.1Hz, 2H), 5.46 (s, 1H), 5.43 (s, 1H), 3.84 (s, 3H),1.11(s,9H)；
13C NMR(100MHz,CDCl3)δ168.0,166.7,157.3,140.6,132.9,131.1,131.0,129.3, 124.2,122.7,122.3,114.7,66.3,55.6,51.7,28.4；
MS(ESI)m/z 339.2[M+H]+,361.2[M+Na]+；
Anal.Calcd.for C20H22N2O3:C,70.99；H,6.55；N,8.28.Found:C,70.92；H,6.66；N, 8.31；
[α]D 25=-117 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I k.
Embodiment 18, chirality 3- shown in preparation formula I l structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula I l compound represented obtains 69.7mg, yield 97%.Compound shown in I l structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of I l structure compound represented is 86% as the result is shown.
The compound is solid:
Mp:235-237 DEG C of fusing point；
IR(KBr)ν3320,3062,2960,2925,1705,1667,1601,1541,1510,1468,1379,1364, 1330,1221,729cm-1；
1H NMR(500MHz,CDCl3) δ 8.20 (d, J=2.1Hz, 1H), 8.03 (dd, J=9.0,2.3Hz, 1H), 7.91 (d, J=5.6Hz, 1H), 7.90 (d, J=4.1Hz, 1H), 7.87-7.79 (m, 3H), 7.70-7.61 (m, 1H), 7.55 (t, J =7.5Hz, 1H), 7.52-7.43 (m, 2H), 5.64 (s, 1H), 5.61 (s, 1H)；
13C NMR(125MHz,CDCl3)δ168.4,166.8,140.7,135.7,133.8,133.3,131.0,131.0, 129.5,129.5,128.0,127.7,126.9,125.9,124.4,122.8,119.4,117.6,66.3,51.8,28.4；
MS(ESI)m/z 359.2[M+H]+；
Anal.Calcd.for C23H22N2O2:C,77.07；H,6.19；N,7.82.Found:C,76.75；H,6.25；N, 7.66；
[α]D 25=-185 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I l.
Embodiment 19, chirality 3- shown in preparation formula I l structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.03mmol, 30mol%), and preparation formula I l compound represented obtains 31.0mg, yield 86%.Compound shown in I l structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of I l structure compound represented is 80% as the result is shown
Compound structure analyzes and identifies data consistent with Example 18.
Embodiment 20, chirality 3- shown in preparation formula Im structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Im compound represented obtains 52.8mg, yield 74%.Compound shown in Im structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Im structure compound represented is 82% as the result is shown.
The compound is solid:
Mp:241-242 DEG C of fusing point；
IR(KBr)ν3321,3057,2965,2922,1682,1545,1468,1405,1366,1252,1222,1292, 797,773,729cm-1；
1H NMR(500MHz,CDCl3) δ 8.03-7.93 (m, 2H), 7.90 (d, J=8.2Hz, 1H), 7.87-7.73 (m, 2H), 7.68 (t, J=7.4Hz, 1H), 7.60 (t, J=7.5Hz, 1H), 7.57-7.42 (m, 4H), 5.84 (s, 1H), 5.60 (s,1H),0.97(s,9H)；
13C NMR(125MHz,CDCl3)δ169.1,166.4,142.0,134.8,133.7,133.0,130.5,130.1, 129.5,129.1,129.1,127.5,126.7,125.7,124.6,123.2,122.9,68.4,51.8,28.3；
MS(ESI)m/z 381.2[M+Na]+；
Anal.Calcd.for C23H22N2O2:C,77.07；H,6.19；N,7.82.Found:C,76.72；H,6.27；N, 7.64；
[α]D 25=-200 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I m.
Embodiment 21, chirality 3- shown in preparation formula In structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.03mmol, 15mol%), and preparation formula In compound represented obtains 66.8mg, yield 89%.Compound shown in In structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of In structure compound represented is 94% as the result is shown.
The compound is solid:
Mp:242-243 DEG C of fusing point；
IR(KBr)ν3283,3078,2958,2924,1716,1663,1612,1553,1367,1327,1165,1116, 1063,840,726cm-1；
1H NMR(400MHz,CDCl3) δ 7.97 (d, J=8.6Hz, 2H), 7.88 (d, J=7.6Hz, 1H), 7.78 (d, J =7.6Hz, 1H), 7.74-7.62 (m, 3H), 7.56 (t, J=7.4Hz, 1H), 5.50 (s, 1H), 5.47 (s, 1H), 1.14 (s, 9H)；
13C NMR(100MHz,CDCl3)δ168.4,166.2,141.3,140.5,133.8,130.5,129.7,127.0 (q, J=33.0Hz), 126.7 (q, J=3.0Hz), 124.1 (q, J=269.0Hz), 124.7,122.8,119.3,66.0, 52.0,28.4；
MS(ESI)m/z 377.1[M+H]+；
Anal.Calcd.for C20H19F3N2O2:C,63.82；H,5.09；N,7.44.Found:C,63.74；H,5.15； N,7.47；
[α]D 25=-170 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I n.
Embodiment 22, chirality 3- shown in preparation formula Io structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Io compound represented obtains 68.5mg, yield 95%.Compound shown in Io structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Io structure compound represented is 88% as the result is shown.
The compound is solid:
Mp:230-231 DEG C of fusing point；
IR(KBr)ν3330,3082,2969,2927,1710,1667,1606,1549,1496,1367,1252,1091, 829,744cm-1；
1H NMR(500MHz,CDCl3) δ 7.69 (d, J=7.5Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 7.55-7.49 (m, 1H), 7.35 (d, J=8.8Hz, 2H), 7.32-7.24 (m, 1H), 5.82 (s, 1H), 5.52 (s, 1H), 1.23 (s, 9H)；
13C NMR(125MHz,CDCl3) δ 166.5 (d, J=1.8Hz), 164.2,157.2 (d, J=201.1Hz), 136.2,134.7 (d, J=2.6Hz), 131.5 (d, J=5.2Hz), 131.0,129.3,126.0 (d, J=13.0Hz), 122.3,120.6 (d, J=2.9Hz), 119.8 (d, J=15.7Hz), 63.8 (d, J=1.5Hz), 52.2,28.4；
MS(ESI)m/z361.1[M+H]+；
Anal.Calcd.for C19H18ClFN2O2:C,63.25；H,5.03；N,7.76.Found:C,63.19；H, 5.09；N,7.85；
[α]D 25=-146 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I o.
Embodiment 23, chirality 3- shown in preparation formula Ip structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Ip compound represented obtains 64.9mg, yield 97%.Compound shown in Ip structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ip structure compound represented is 88% as the result is shown.
The compound is solid:
Mp:240-242 DEG C of fusing point；
IR(KBr)ν3271,3080,2928,2852,1705,1655,1553,1501,1366,752,726cm-1；
1H NMR(400MHz,CDCl3) δ 7.83-7.71 (m, 4H), 7.65-7.57 (m, 1H), 7.48 (t, J=7.5Hz, 1H), 7.41 (t, J=8.0Hz, 2H), 7.21 (t, J=7.4Hz, 1H), 5.92 (d, J=8.1Hz, 1H), 5.62 (s, 1H), 3.73–3.58(m,1H),1.68–1.36(m,5H),1.32–1.09(m,2H),1.08–0.71(m,3H)；
13C NMR(100MHz,CDCl3)δ168.2,166.7,140.5,138.1,133.2,131.0,129.6,129.4, 125.4,124.3,122.9,120.2,65.5,48.6,32.4,32.4,25.3,24.6,24.5；
MS(ESI)m/z 335.2[M+H]+；
Anal.Calcd.for C21H22N2O2:C,75.42；H,6.63；N,8.38.Found:C,75.29；H,6.73；N, 8.48；
[α]D 25=-152 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I p.
Embodiment 24, chirality 3- shown in preparation formula Iq structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 20mol%), and preparation formula Iq compound represented obtains 45.9mg, yield 74%.Compound shown in Iq structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 4:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Iq structure compound represented is 89% as the result is shown.
The compound is solid:
Mp:187-188 DEG C of fusing point；
IR(KBr)ν3256,3085,2956,2923,1705,1656,1503,1493,1466,1371,752cm-1；
1H NMR(400MHz,CDCl3) δ 7.95-7.74 (m, 4H), 7.64 (t, J=7.5Hz, 1H), 7.52 (t, J= 7.4Hz, 1H), 7.43 (t, J=7.9Hz, 2H), 7.22 (t, J=7.4Hz, 1H), 5.84 (s, 1H), 5.66 (s, 1H), 3.33- 2.88 (m, 2H), 1.32-1.12 (m, 2H), 1.02-0.87 (m, 2H), 0.70 (t, J=7.3Hz, 3H)；
13C NMR(100MHz,CDCl3)δ168.3,167.6,140.4,138.1,133.1,131.0,129.5,129.4, 125.3,124.2,122.9,120.1,65.6,39.3,31.2,19.6,13.6；
MS(ESI)m/z 309.2[M+H]+；
Anal.Calcd.for C19H20N2O2:C,74.00；H,6.54；N,9.08.Found:C,74.12；H,6.68；N, 9.18；
[α]D 25=-157 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I q.
Embodiment 25, chirality 3- shown in preparation formula Ir structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 20mol%), and preparation formula Ir compound represented obtains 48.5mg, yield 74%.Compound shown in Ir structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Ir structure compound represented is 56% as the result is shown.
The compound is solid:
Mp:243-244 DEG C of fusing point；
IR(KBr)ν3292,3061,2955,2924,1697,1678,1598,1544,1500,1443,1367,752cm-1；
1H NMR(500MHz,CDCl3) δ 8.63 (s, 1H), 7.87 (d, J=8.2Hz, 2H), 7.83 (d, J=7.7Hz, 1H), 7.61 (t, J=7.5Hz, 1H), 7.55 (d, J=8.0Hz, 2H), 7.46 (d, J=7.6Hz, 1H), 7.39 (t, J= 7.9Hz, 2H), 7.34 (t, J=7.5Hz, 1H), 7.28-7.18 (m, 3H), 7.07 (t, J=7.4Hz, 1H), 5.75 (s, 1H)；
13C NMR(125MHz,CDCl3)δ168.8,166.3,140.0,138.1,137.4,133.3,131.1,129.7, 129.7,129.1,125.7,125.0,124.3,122.9,120.4,120.2,66.6；
MS(ESI)m/z 329.1[M+H]+；
Anal.Calcd.for C21H16N2O2:C,76.81；H,4.91；N,8.53.Found:C,76.96；H,5.00；N, 8.51；
[α]D 25=-184 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I r.
Embodiment 26, chirality 3- shown in preparation formula Is structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.04mmol, 20mol%), and preparation formula Is compound represented obtains 53.7mg, yield 75%.Compound shown in Is structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Is structure compound represented is 61% as the result is shown.
The compound is solid:
Mp:238-239 DEG C of fusing point；
IR(KBr)ν3274,3062,2956,2927,1705,1668,1511,1371,1245,755cm-1；
1H NMR(500MHz,CDCl3)δ8.10(s,1H),7.93–7.77(m,3H),7.68–7.57(m,2H),7.41 (t, J=7.7Hz, 3H), 7.33 (d, J=8.8Hz, 2H), 7.23 (t, J=7.3Hz, 1H), 6.77 (d, J=8.8Hz, 2H), 5.73(s,1H),3.73(s,3H)；
13C NMR(125MHz,CDCl3)δ168.6,165.9,157.0,140.1,138.1,133.4,131.0,130.1, 129.8,129.7,125.7,124.4,123.0,122.2,120.2,114.2,66.3,55.6；
MS(ESI)m/z 359.1[M+H]+；
Anal.Calcd.for C22H18N2O3:C,73.73；H,5.06；N,7.82.Found:C,73.46；H,5.06；N, 7.68；
[α]D 25=-175 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I s.
Embodiment 27, chirality 3- shown in preparation formula It structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.06mmol, 30mol%), and preparation formula It compound represented obtains 73.3mg, yield 90%.Compound shown in It structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of It structure compound represented is 78% as the result is shown.
The compound is solid:
Mp:268-270 DEG C of fusing point；
IR(KBr)ν3270,2956,2923,1732,1682,1596,1532,1488,1465,1363,757,723cm-1；
1H NMR(500MHz,DMSO-d6) δ 10.94 (s, 1H), 7.86 (d, J=7.3Hz, 1H), 7.83-7.67 (m, 4H), 7.62 (t, J=7.1Hz, 1H), 7.58-7.38 (m, 4H), 7.44 (t, J=7.5Hz, 2H), 7.19 (t, J=7.0Hz, 1H),6.13(s,1H)；
13C NMR(125MHz,DMSO-d6)δ167.1,165.6,140.4,138.3,137.6,132.9,131.7, 131.7,129.4,129.0,124.7,123.7,122.3,121.5,120.5,115.8,64.6；
MS(ESI)m/z407.0[M+H]+；
Anal.Calcd.for C21H15BrN2O2:C,61.93；H,3.71；N,6.88.Found:C,62.00；H,3.70； N,6.89；
[α]D 25=-198 (c=0.25, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I t.
Embodiment 28, chirality 3- shown in preparation formula Iu structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to the similar approach of embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is not Together, this reaction uses the catalyst (0.02mmol, 10mol%), and preparation formula Iu compound represented obtains 61.6mg, yield 83%.Compound shown in Iu structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and mobile phase is by volume ratio For the mixed liquor that the n-hexane and isopropanol of 2:1 form, flow velocity: 0.5mL/min detects 25 DEG C of temperature, Detection wavelength 254nm, The enantioselectivity of Iu structure compound represented is 90% as the result is shown.
The compound is solid:
Mp:245-246 DEG C of fusing point；
IR(KBr)ν3266,3080,2927,2853,1706,1655,1553,1496,1467,1365,1093,830, 730cm-1；
1H NMR(400MHz,CDCl3) δ 7.81-7.69 (m, 4H), 7.63 (t, J=7.4Hz, 1H), 7.49 (t, J= 7.5Hz, 1H), 7.36 (d, J=8.9Hz, 2H), 5.91 (d, J=8.1Hz, 1H), 5.55 (s, 1H), 3.88-3.44 (m, 1H), 1.66–1.44(m,5H),1.31–1.12(m,2H),1.09–0.75(m,3H)；
13C NMR(125MHz,CDCl3)δ168.3,166.4,140.3,136.8,133.4,130.7,130.6,129.6, 129.5,124.4,122.8,121.0,65.6,48.8,32.6,32.5,25.3,24.7,24.7；
MS(ESI)m/z369.1[M+H]+；
Anal.Calcd.for C21H21ClN2O2:C,68.38；H,5.74；N,7.59.Found:C,68.27；H,5.67； N,7.53；
[α]D 25=-158 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I u.
Embodiment 29, chirality 3- shown in preparation formula Iv structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to similar approach described in embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is different, This reaction uses the catalyst (0.06mmol, 30mol%), and preparation formula Iv compound represented obtains 60.6mg, yield 88%. Compound shown in Iv structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and it is 2:1 that mobile phase, which is by volume ratio, N-hexane and isopropanol composition mixed liquor, flow velocity: 0.5mL/min, detect 25 DEG C of temperature, as a result Detection wavelength 254nm is shown The enantioselectivity for showing Iv structure compound represented is 82%.
The compound is solid:
Mp:207-208 DEG C of fusing point；
IR(KBr)ν3265,3086,2956,2926,1708,1655,1567,1496,1467,1366,1093,828cm-1；
1H NMR(400MHz,CDCl3) δ 7.79-7.71 (m, 3H), 7.63 (t, J=7.4Hz, 2H), 7.46 (t, J= 7.5Hz,1H),7.38–7.29(m,2H),6.29(s,1H),5.58(s,1H),3.34–2.93(m,2H),1.36–1.17(m, 2H), 1.09-0.90 (m, 2H), 0.74 (t, J=7.3Hz, 3H)；
13C NMR(100MHz,CDCl3)δ168.3,167.3,140.3,136.8,133.4,130.7,130.6,129.6, 129.5,124.3,122.9,121.0,65.6,39.5,31.2,19.7,13.6；
MS(ESI)m/z343.1[M+H]+；
Anal.Calcd.for C19H19ClN2O2:C,66.57；H,5.59；N,8.17.Found:C,66.66；H,5.58； N,8.02；
[α]D 25=-154 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I v.
Embodiment 30, chirality 3- shown in preparation formula Iw structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to similar approach described in embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is different, This reaction uses the catalyst (0.04mmol, 20mol%), and preparation formula Iw compound represented obtains 66.8mg, yield 85%. Compound shown in Iw structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and it is 2:1 that mobile phase, which is by volume ratio, N-hexane and isopropanol composition mixed liquor, flow velocity: 0.5mL/min, detect 25 DEG C of temperature, as a result Detection wavelength 254nm is shown The enantioselectivity for showing Iw structure compound represented is 66%.
The compound is solid:
Mp:245-247 DEG C of fusing point；
IR(KBr)ν3258,3051,2958,2927,1709,1666,1541,1511,1495,1467,1369,1297, 1245,1094,831cm-1；
1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.91–7.79(m,3H),7.79–7.67(m,2H), 7.62 (t, J=7.2Hz, 1H), 7.52 (d, J=8.9Hz, 2H), 7.45 (d, J=8.9Hz, 2H), 6.88 (d, J=8.9Hz, 2H),6.09(s,1H),3.70(s,3H)；
13C NMR(100MHz,DMSO-d6)δ167.2,164.6,155.9,140.6,137.3,133.0,131.4, 131.3,129.3,129.0,128.5,123.7,122.3,121.9,121.2,114.0,64.5,55.2；
MS(ESI)m/z393.1[M+H]+；
Anal.Calcd.for C22H17ClN2O3:C,67.26；H,4.36；N,7.13.Found:C,67.22；H,4.28； N,6.90；
[α]D 25=-210 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I w.
Embodiment 31, chirality 3- shown in preparation formula Ix structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to similar approach described in embodiment 1,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is different, This reaction uses the catalyst (0.08mmol, 40mol%), and preparation formula Ix compound represented obtains 73.0mg, yield 94%. Compound shown in Ix structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and it is 2:1 that mobile phase, which is by volume ratio, N-hexane and isopropanol composition mixed liquor, flow velocity: 0.5mL/min, detect 25 DEG C of temperature, as a result Detection wavelength 254nm is shown The enantioselectivity for showing Ix structure compound represented is 82%.
The compound is solid:
Mp:189-190 DEG C of fusing point；
IR(KBr)ν3310,3062,2949,2926,1743,1706,1670,1536,1496,1468,1368,1282, 1153,1094,827,731cm-1；
1H NMR(400MHz,CDCl3) δ 7.81-7.76 (m, 2H), 7.76-7.69 (m, 2H), 7.63 (t, J=7.2Hz, 1H), 7.48 (t, J=7.4Hz, 1H), 7.42-7.35 (m, 2H), 6.74 (s, 1H), 5.50 (s, 1H), 3.65 (s, 3H), 1.39 (s,3H),1.36(s,3H)；
13C NMR(125MHz,CDCl3)δ174.3,168.3,166.7,139.9,136.7,133.2,130.8,130.7, 129.7,129.5,124.4,122.8,121.5,65.8,56.9,52.7,24.5,24.3；
MS(ESI)m/z387.1[M+H]+；
Anal.Calcd.for C20H19ClN2O4:C,62.10；H,4.95；N,7.24.Found:C,61.95；H,4.84； N,7.15；
[α]D 25=-135 (c=0.50, CHCl3)；
From the foregoing, it will be observed that above compound structure is correct, it is compound shown in Formulas I x.
Embodiment 32, chirality 3- shown in preparation formula Ix structural formula replace isoindoline ketone compound
The reaction equation is as follows:
According to similar approach as described in example 2,72h is reacted, only chiral phosphoric acid catalyst dosage shown in VI is different, This reaction uses the catalyst (0.06mmol, 60mol%), and preparation formula Ix compound represented obtains 34.8mg, yield 90%. Compound shown in Ix structure is tested with high performance liquid chromatography, chromatographic column is ADH column, and it is 2:1 that mobile phase, which is by volume ratio, N-hexane and isopropanol composition mixed liquor, flow velocity: 0.5mL/min, detect 25 DEG C of temperature, as a result Detection wavelength 254nm is shown The enantioselectivity for showing Ix structure compound represented is 78%
Compound structure analyzes and identifies data consistent with Example 49.
Embodiment 33, anti-tumor activity experiment
Chirality 3- prepared by the present invention replaces isoindoline ketone compound to be directed to colon cancer cell HCT-116, the cell From ATCC, anti-tumor experiment is as follows:
Utilize the active influence of compound on intracellular shown in mtt assay measurement Formulas I general structure.Mtt assay is also known as MTT colorimetric Method is a kind of method for detecting cell survival and growth.Its testing principle is the succinate dehydrogenase energy in living cells mitochondria The bluish violet crystallization for making exogenous MTT be reduced to water-insoluble and is deposited in cell first a ceremonial jade-ladle, used in libation (Formazan), and dead cell without This function.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, measure it at 490nm wavelength with enzyme-linked immunosorbent assay instrument Absorbance value can reflect living cells quantity indirectly.Operating process is as follows: being made into individually with the culture solution containing 10% tire calf serum Cell suspension, with 1000-10000, every hole cell inoculation to 96 orifice plates, after being cultivated 24 hours in 37 degree of cell incubators, Drug to be measured is added, using dimethyl sulfoxide (DMSO) as control, continuation is cultivated 48 hours in 37 degree of cell incubators；Every hole Add MTT solution (5mg/ml is prepared with PBS, pH=7.4) 20ul (200ul culture medium), continues to be incubated for 4h, terminate culture, carefully Culture supernatant in hole is drawn, every hole adds 150ul DMSO, and decolorization swinging table vibrates 10min, dissolves crystal sufficiently；Selection 490nm (570nm) wavelength measures each hole absorbance value on enzyme linked immunological monitor, records result；Further by experimental result It is handled: calculating each experimental group and the ratio of con, using this ratio as ordinate, with different pharmaceutical or drug concentration for horizontal seat Mark does bar chart or line chart.
Mtt assay investigates chirality 3- shown in the Formulas I that present invention preparation provides and isoindoline ketone compound is replaced to be directed to colon Cancer cell HCT-116 anti-tumor activity experiment as a result, as shown in Figure 1, the experimental results showed that, concentration be 100 μm of ol when, If, Il, It in compound shown in Formulas I general structure have the growth for significantly inhibiting cell.

Claims (3)

1. compound shown in Formulas I e, Formulas I f, Formulas I k and Formulas I n or its pharmaceutically acceptable salt,
2. compound described in claim 1 or its pharmaceutically acceptable salt inhibit the application in tumour cell product in preparation； The tumour cell is colon cancer cell.
3. application according to claim 2, it is characterised in that: the colon cancer cell is colon cancer cell HCT-116.
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