CN101723893B - 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof - Google Patents

2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof Download PDF

Info

Publication number
CN101723893B
CN101723893B CN200910199930.3A CN200910199930A CN101723893B CN 101723893 B CN101723893 B CN 101723893B CN 200910199930 A CN200910199930 A CN 200910199930A CN 101723893 B CN101723893 B CN 101723893B
Authority
CN
China
Prior art keywords
replaces
compound
preparation
quinoline ketone
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN200910199930.3A
Other languages
Chinese (zh)
Other versions
CN101723893A (en
Inventor
侯雪龙
雷柏林
丁昌华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN200910199930.3A priority Critical patent/CN101723893B/en
Publication of CN101723893A publication Critical patent/CN101723893A/en
Application granted granted Critical
Publication of CN101723893B publication Critical patent/CN101723893B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as a preparation method and application thereof. The 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound can be used for synthesizing a compound with physiological activity and has the following structures.

Description

2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound, preparation method and application
Technical field
The present invention includes a class 2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound, preparation method and application thereof, 2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compounds and can synthesize and have the synthetic of physiologically active compound Martinella compounds and body compound thereof.2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound and has following structure:
Figure G2009101999303D00011
Background technology
Have 2,3-bis-replaces-2,3-dihydro-quinolinone compounds is the very useful compound of a class in organic synthesis, many types natural product intermediate all has 2,3-bis-replaces-2,3-dihydro quinoline ketone compound fragment, and 2-aryl-2,3-dihydro-quinolinone compounds itself just has certain physiologically active.Synthetic 2-replaces the certain report of method of-2,3-dihydro-quinolinone compounds.(Some?examples：J.Heterocyclic.Chem.，1994，31，145；J.Med.Chem.1998，41，1155；Synlett?1998，649；J.Med.Chem.2000，43，167；Synlett?2000，45；)。And the method report of synthesis of chiral 2-replacement-2,3-dihydro-quinolinone compounds is also fewer.(Org.Lett.2005，7，5317；Arch.Pharm.Res.2006，29，369)。And the resolved product of 2,3-, bis-these compounds of replacement-2,3-dihydro-quinolinone compounds can be applied in natural product.(Org.Lett.2001，3，2189；Tetrahedron?Lett.2002，43，9405.J.Org.Chem.2003，68，442：Heterocycles?2004，63，1685)。
Summary of the invention
The object of this invention is to provide a class 2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound;
Object of the present invention also provides an above-mentioned class 2, and 3-bis-replaces the preparation method of-2,3-dihydro quinoline ketone chiral compound;
Another object of the present invention is to provide an above-mentioned class 2,3-bis-replaces the purposes of-2,3-dihydro quinoline ketone chiral compound, can be by 2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound and is applied to the synthetic of physiologically active compound Martinella compounds.
A class 2 of the present invention, 3-bis-replaces-2,3-dihydro quinoline ketone chiral compound and has following structural formula:
Figure G2009101999303D00021
Wherein:
R 1for hydrogen, C 1～6alkyl, phenyl, ethanoyl, methylsulfonyl, p-toluenesulfonyl or tert-butoxycarbonyl;
R 2for C 1～10alkyl, phenyl or naphthyl; Monosubstituted, two replacement or polysubstituted phenyl; Monosubstituted or dibasic naphthyl; Especially the C recommending 1～10alkyl be: CH 3, CH 2cH 3, CH 2cH 2cH 3, aryl;
R 3for C 1～10alkyl, phenyl, monosubstituted, two replace or polysubstituted phenyl;
R 4for C 1～10alkyl, phenyl, monosubstituted, two replace or polysubstituted phenyl;
for
Figure G2009101999303D00023
monosubstituted, two replacement or polysubstituted phenyl;
Above-mentioned monosubstituted, two replace or the substituting group of polysubstituted phenyl is C 1～4alkoxyl group, C 1～4perfluoroalkyl, C 1～4alkyl or halogen atom.
A class 2 of the present invention, the preparation method that 3-bis-replaces-2,3-dihydro-quinolinone compounds is as follows:
By chiral ferrocene ligands, allylation reagent, 2-replaces-2,3-dihydro-quinolinone and alkali and in organic solvent, reacts 8-18h 20 ℃ to-78 ℃ time;
Wherein, recommendation response thing mol ratio is that described Er Mao Tie oxazoline phosphine nitrogen ligand, the mol ratio that 2-replaces-2,3-dihydro-quinolinone, allylation reagent and alkali are 0.06～0.006: 1～2: 0.5～1: 1～2.
The structural formula of described chiral ferrocene ligands is:
Figure G2009101999303D00024
The structure that described 2-replaces-2,3-hydrogen quinolinones compound is:
Figure G2009101999303D00031
Product structure is:
Figure G2009101999303D00032
Wherein,
R 1for hydrogen, C 1～6alkyl, phenyl, ethanoyl (Ac), methylsulfonyl (Ms), p-toluenesulfonyl (Ts) or tert-butoxycarbonyl (Boc);
R 2for C 1～10alkyl, phenyl, naphthyl; Monosubstituted, two replace or polysubstituted phenyl, monosubstituted or dibasic naphthyl; Especially recommend: CH 3, CH 2cH 3, CH 2cH 2cH 3or phenyl;
R 3for C 1～10alkyl, phenyl, monosubstituted, two replace or polysubstituted phenyl;
R 4for C 1～10alkyl, phenyl, monosubstituted, two replace or polysubstituted phenyl;
Figure G2009101999303D00033
for
Figure G2009101999303D00034
, monosubstituted, two replace or polysubstituted phenyl;
Above-mentioned monosubstituted, two replace or the substituting group of polysubstituted phenyl is C 1～4alkoxyl group, C 1～4perfluoroalkyl, C 1～4alkyl or halogen atom;
R 5for C 1～6alkyl, phenyl or benzyl;
R 6for C 1～6alkyl, phenyl or benzyl;
R 7for not replacing, monosubstituted or dibasic 1,1 '-binaphthol, described substituting group is C 1～4alkoxyl group, C 1～4perfluoroalkyl, C 1～4alkyl or halogen atom;
R 8for carbonic ether, phosphoric acid ester or acetic ester.
Alkali described in preparation method of the present invention is sodium methylate, potassium ethylate, potassium tert.-butoxide, butyllithium, phenyl lithium, lithium diisopropyl amido, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium, triethylamine, pyridine, cesium hydroxide, sodium hydrogen or potassium hydrogen.Described organic solvent is benzene, toluene, hexanaphthene, sherwood oil, tetrahydrofuran (THF), acetonitrile, diethyl ether hexane or dioxane, DMF or N,N-dimethylacetamide.
Product can adopt chirality column chromatographic isolation and purification, the leacheate wash-out of V sherwood oil/V ethyl acetate=10/1-1/1.
Compound of the present invention not only preparation method is simple, easy suitability for industrialized production, and, can synthesizing for physiologically active compound Martinella compounds midbody compound.The structure of described midbody compound is:
Wherein: R 1, R 2as previously mentioned; R 9for hydrogen, C 1～6alkyl, phenyl, ethanoyl, methylsulfonyl, p-toluenesulfonyl, tert-butoxycarbonyl or benzyl.
Embodiment
By following embodiment, will contribute to understand the present invention, but not limit content of the present invention.
Embodiment 1: at-50 ℃, 2,3-replaces the synthetic of-2,3-dihydro-quinolinone compounds
R 5＝Ph
R 6＝Et
R 1=ethanoyl (Ac); R 7under=(R)-2-(2 '-hydroxyl-1-1 '-naphthyl) { (R)-2-(2 '-hydroxyl-1-1 '-binapthyl) } argon shield, [Pd (C 3h 5) Cl] 2(0.003mmol) and ligand L *(0.006mmol) be dissolved in tetrahydrofuran (THF) (1mL), at room temperature stir 0.5 hour, in another reaction tubes, fill substrate (0.10mmol) in 1.0mL tetrahydrofuran (THF),-78 ℃ add hexamethyldisilazane lithium (LiHMDS) (0.10mL, 0.10mmol, 1.0M in THF), keep this temperature to stir after 0.5 hour, the catalyzer and the allylation reagent (0.05mmol) that add in situ preparation, stirring reaction 10min, then rises to room temperature reaction.GC tracks to reaction to be finished, and adds saturated aqueous common salt cancellation reaction, separatory, and extracted with diethyl ether for water (10mL x 3), merges organic phase, uses anhydrous magnesium sulfate drying.Removal of solvent under reduced pressure, plate layer chromatography purifying oil ether: ether=3: 1, obtain product 3 and reclaim raw material 1.
When take 1a during as substrate, productive rate: 45%; Ee:99%; 1h NMR (400MHz, CDCl 3) δ 2.43 (s, 3H), 3.22-3.28 (m, 1H), 3.35-3.40 (m, 1H), 6.47 (br, 1H), 7.15-7.22 (m, 7H), 7.44-7.48 (m, 1H), 7.93 (d, J=7.6Hz 1H); 13c NMR (100MHz, CDCl 3): δ 193.1,170.0, and 141.7,137.9,134.3,128.5,127.5,127.2,126.7,126.0,125.4,125.0,54.6,42.5,23.3; IR (film, cm -1) 3059 (w), 2941 (w), 1693 (s), 1682 (s), 1663 (s), 1601 (s), 1461 (m), 694 (m); Mass spectrum (EI) m/z (relative intensity): 265 (M +, 64), 266 (13), 223 (100), 146 (97), 119 (20), 90 (17), 77 (20), 43 (32); Mass spectrum high resolution (EI): theoretical value: C 17h 15nO 2[M+] 265.1103; Measured value: 265.1101; Liquid phase analysis: chiral column (Chiralpak IC, 95/5), normal hexane/Virahol (hexane/i-Propanol=50/50), 0.7mL/min, 214nm, t r(major) 15.33min, t r(minor) 35.56min; [α] d 20=-219.1 ° of (0.66, CHCl 3).
Product 3a, productive rate: 48%; Ee:93%; 1h NMR (400MHz, CDCl 3): δ 2.41-2.58 (m, 5H), 3.30 (ddd, J=1.6Hz, J=3.6Hz, J=6.0Hz, 1H), 5.18-5.22 (m, 2H), 5.87-5.98 (m, 1H), 6.08 (br, 1H), 7.14-7.22 (m, 7H), 7.48-7.52 (m, 1H), 7.95 (d, J=8.0Hz 1H); 13c NMR (100MHz, CDCl 3): δ 194.7,170.7, and 141.2,137.9,134.4,134.1,128.4,128.2,127.5,127.3,126.5,124.8,124.1,118.6,58.4,51.4,34.5,23.2; IR (film, cm -1) 3059 (w), 2941 (w), 1693 (s), 1682 (s), 1663 (s), 1601 (s), 1461 (m), 694 (m); Mass spectrum (EI) m/z (relative intensity): MS (EI) m/z (rel) 305 (M +, 7), 264 (13), 222 (15), 180 (4), 146 (2), 77 (3), 58 (25), 43 (100); Mass spectrum high resolution (EI): theoretical value: C 20h 19nO 2[M+] 305.1416; Measured value: 305.1420; Liquid phase analysis: Chiralcel OJ-H, hexane/i-Propanol=95/5,0.7mL/min, 254nm, t r(minor) 35.72min, t r(major) 41.28min; [α] d 20=90.5 ° of (0.72, CHCl 3).
When take 1b during as substrate, productive rate: 43%; Ee:99%; 1h NMR (400MHz, CDCl 3) δ 2.34 (s, 3H), 3.22-3.32 (m, 2H), 6.43 (br, 1H), 6.89-6.91 (m, 1H), 7.01-7.03 (m, 2H), 7.20-7.24 (m, 1H), 7.52-7.54 (m, 3H), 7.96 (d, J=8Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 192.7,169.7, and 142.4,137.1,134.6,133.7,129.2,127.9,127.2,126.9,126.0,125.4,124.7,123.0,55.5,42.5,23.2; IR (film, cm -1) 3067 (w), 2977 (w), 1683 (s), 1660 (s), 1602 (s), 1574 (m), 1021 (m), 771 (m); Mass spectrum (EI) m/z (relative intensity): 343 (M +, 1), 303 (20), 301 (21), 264 (100), 146 (54), 77 (9), 58 (19), 43 (96); Mass spectrum high resolution (EI): theoretical value: C 17h 14brNO 2[M+] 343.0208; Measured value: 343.0211; Liquid phase analysis: ChiralpakIC, hexane/i-Propanol=50/50,1.0mL/min, 214nm, t r(major) 16.52min, t r(minor) 23.32min; [α] d 20=-77.7 ° of (0.56, CHCl 3).
Product 3b, productive rate: 38%; Ee:82%; 1h NMR (400MHz, CDCl 3) δ 2.32 (s, 3H), 2.52-2.58 (m, 2H), 3.19-3.23 (m, 1H), 5.19-5.26 (m, 2H), 5.90 (br, 1H), 6.00-6.07 (m, 1H), 6.84 (d, J=6.8Hz, 1H), 7.00-7.08 (m, 2H), 7.22-7.27 (m, 1H), 7.55 (dd, J=1.2Hz, J=6.8Hz, 1H), 7.62-7.66 (m, 1H), 7.99 (dd, J=1.2Hz, J=6.4Hz, 1H), 8.15 (br, 1H); 13c NMR (100MHz, CDCl 3): δ 194.2,171.5, and 142.8,137.3,135.3,134.3,133.8,129.5,127.9,127.8,127.5,124.5,123.2,123.0,122.5,119.0,60.6,51.1,36.2,24.1; IR (film, cm -1) 3074 (w), 2946 (w), 1683 (s), 1600 (s), 1576 (s), 1479 (s), 1230 (m), 761 (m); Mass spectrum (EI) m/z (relative intensity): 3074 (w), 2946 (w), 1683 (s), 1600 (s), 1576 (s), 1479 (s), 1230 (m); Mass spectrum high resolution (EI): theoretical value: C 20h 18brNO 2: 383.0521[M+] 305.1416; Measured value: 383.0527; Liquid phase analysis: Chiralpak IC, hexane/i-Propanol=90/10,0.7mL/min, 214nm, t r(major) 15.69min, t r(minor) 17.29min; [α] d 20=5.3 ° of (0.74, CHCl 3).
When take 1c during as substrate, productive rate: 44%; Ee:96%; 1h N MR (400MHz, CDCl 3) δ 2.43 (s, 3H), 3.26-3.35 (m, 1H), 3.35-3.40 (m, 1H), 6.47 (br, 1H), 7.03-7.48 (m, 7H), 7.91-7.93 (m, 1H); 13c NMR (100MHz, CDCl 3): δ 192.3,169.9, and 141.3,140.2,134.3,130.5,129.9,129.8,127.2,125.6,125.5,125.1,124.8,122.7,53.8,42.1,23.1; 2962 (w), 2976 (w), 1686 (s), 1661 (s), 1601 (m), 1479 (s), 1276 (s), 1231 (s), 775 (s); Mass spectrum (EI) m/z (relative intensity): 343 (M +, 22), 345 (21), 303 (54), 301 (56), 146 (100), 90 (21), 77 (18), 43 (71); Ultimate analysis theoretical value: C 17h 14brNO 2: C 59.32, and H 4.10, and N 4.07, measured value: C 59.33, and H 4.27, and N 3.99; Liquid phase analysis: ChiralpakIC, hexane/i-Propanol=50/50,0.7mL/min, 214nm, t r(major) 12.59min, t r(minor) 30.95min; [α] d 20=-158.5 ° of (0.77, CHCl 3).
Product 3c, productive rate: 47%; Ee:91%; 1h NMR (400MHz, CDCl 3) δ 2.32 (s, 3H), 2.52-2.58 (m, 2H), 3.19-3.23 (m, 1H), 5.19-5.26 (m, 2H), 5.90 (br, 1H), 6.00-6.07 (m, 1H), 6.84 (d, J=6.8Hz, 1H), 7.00-7.08 (m, 2H), 7.22-7.27 (m, 1H), 7.55 (dd, J=1.2Hz, J=6.8Hz, 1H), 7.62-7.66 (m, 1H), 7.99 (dd, J=1.2Hz, J=6.4Hz, 1H), 8.15 (br, 1H); 13c NMR (100MHz, CDCl 3): δ 194.2,171.5, and 142.8,137.3,135.3,134.3,133.8,129.5,127.9,127.8,127.5,124.5,123.2,123.0,122.5,119.0,60.6,51.1,36.2,24.1; IR (film, cm -1) 3076 (w), 1671 (s), 1660 (s), 1575 (m), 1479 (s), 1228 (m), 923 (w), 764 (m); Mass spectrum (EI) m/z (relative intensity): MS (EI) m/z (rel) 383 (M +, 4), 385 (4), 344 (5), 342 (8), 300 (7), 77 (2), 58 (29), 43 (100); Mass spectrum high resolution (EI): theoretical value: C 20h 18brNO 2: 383.0521; [M+] 383.0514; Measured value: 383.0527; Liquid phase analysis: Chiralpak IC, hexane/i-Propanol=90/10,0.7mL/min, 214nm, t r(minor) 18.12min, t r(major) 20.39min; [α] d 20=87.3 ° of (0.94, CHCl 3).
When take 1d during as substrate, productive rate: 44%; Ee:99%; 1h NMR (400MHz, CDCl 3) δ 2.41 (s, 3H), 3.20-3.25 (m, 1H), 3.00-3.35 (m, 1H), 3.60 (s, 3H), 6.39 (br, 1H), 6.61-6.64 (m, 1H), 6.73-6.75 (m, 2H), 7.07 (q, J=7.6Hz, 2H), 7.40-7.44 (m, 2H), (7.87 d, J=7.6Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 192.5,169.7, and 159.4,141.5,139.3,134.0,129.2,126.7,125.5,124.9,124.7,118.6,112.6,112.1,54.6,54.4,42.2,22.9; IR (film, cm -1) 2980 (w), 1698 (s), 1597 (s), 1478 (s), 1226 (s), 1037 (m), 769 (s), 695 (m); Mass spectrum (EI) m/z (relative intensity): 295 (M +, 40), 253 (60), 252 (100), 146 (60), 119 (13), 90 (14), 77 (13), 43 (47); Mass spectrum high resolution (EI): theoretical value: C 18h 17nO 3: [M+] 295.1208; Measured value: 295.1211; Liquid phase analysis: ChiralpakIC, hexane/i-Propanol=90/10,0.7mL/min, 214nm, t r(major) 12.82min, t r(minor) 28.02min; [α] d 20=-77.7 ° of (0.56, CHCl 3).
Product 3d, productive rate: 42%; Ee:93%; 1h NMR (400MHz, CDCl 3) δ 2.38-2.54 (m, 5H), 3.27 (ddd, J=2Hz, J=3.6Hz, J=2Hz, 1H), 3.68 (s, 3H), 5.18-5.22 (m, 2H), 5.91-5.93 (m, 1H), 6.04 (br, 1H), 6.67-6.74 (m, 3H), 7.09-7.19 (m, 2H), 7.49-7.53 (m, 2H), 7.94 (dd, J=1.2Hz, J=6.8Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 194.9,170.9, and 159.8,141.5,139.7,134.6,134.3,129.7,127.8,125.0,124.3,119.0,118.8,113.0,112.7,58.7,55.1,51.8,34.7,23.4; IR (film, cm -1) 3086 (w), 2914 (w), 1683 (s), 1667 (s), 1601 (s), 1480 (s), 1056 (m), 761 (m); Mass spectrum high resolution (ESI): theoretical value: C 21h 21nO 3na:358.1414 (M+Na) +, measured value: 358.1428; Liquid phase analysis: PhenomenexCellulose-2, hexane/i-Propanol=90/10,0.7mL/min, 214nm, t r(major) 28.68min, t r(minor) 31.18min; [α] d 20=117.5 ° of (0.65, CHCl 3).
When take 1e during as substrate, productive rate: 46%; Ee:99%; 1h NMR (400MHz, CDCl 3) δ 2.43 (s, 3H), 3.25-3.27 (m, 1H), 3.29-3.30 (m, 1H), 6.49 (br, 1H), (7.04-7.07 m, 2H), 7.20-7.22 (m, 2H), 7.31-7.34 (m, 2H), (7.46-7.51 m, 1H), 7.94 (dd, J=1.6Hz, J=6.4Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 192.7,170.0, and 141.5,137.1,134.5,131.7,128.5,127.3,125.8,125.6,124.9,121.6,54.0,42.3,23.2; IR (film, cm -1) 2956 (w), 1694 (m), 1667 (s), 1599 (m), 1478 (s), 1367 (m), 1008 (m), 777 (m); Mass spectrum (EI) m/z (relative intensity): 343 (M +, 25), 345 (24), 301 (51), 303 (47), 146 (86), 90 (28), 77 (27), 43 (100); Mass spectrum high resolution (EI): theoretical value: C 17h 14brNO 2: [M+] 343.0208; Measured value: 343.0211; Liquid phase analysis: Chiralpak IC, hexane/i-Propanol=50/50,1.0mL/min, 214nm, t r(major) 12.12min, t r(minor) 35.15min; [α] d 20=-199.2 ° of (0.77, CHCl 3).
Product 3e, productive rate: 38%; Anti:syn:13:1; Ee of (anti-4a): 90%; 1h NMR (400MHz, CDCl 3) (taken as a mixture of diastereomers): δ (major diastereomer) 2.41-2.53 (m, 5H), 3.23 (ddd, J=1.6Hz, J=4Hz, J=2.8Hz, 1H), 5.17-5.22 (m, 2H), (5.85-5.95 m, 1H), 6.09 (br, 1H), 7.03-7.05 (m, 2H), (7.18 t, J=8.0Hz, 1H), 7.28-7.32 (m, 3H), 7.49-7.53 (m, 1H), 7.94 (dd, J=1.2Hz, J=6.8Hz, 1H); (minor diastereomer) 3.06-3.12 (m, 1H), 4.91-4.95 (m, 1H), 5.07-5.09 (m, 1H), 8.09 (dd, J=1.2Hz, J=6.4Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 194.8,170.8,141.1,137.3,134.8,134.0,131.8,128.6,127.9,125.3,124.4,124 .2,121.6,119.0,57.9,51.5,34.6,23.3; IR (film, cm -1) 2980 (w), 1708 (s), 1687 (s), 1602 (m), 1479 (s), 1370 (m), 1160 (s), 760 (m); Mass spectrum (EI) m/z (relative intensity): MS (EI) m/z (rel) 383 (M +, 44), 385 (45), 344 (79), 342 (100), 299 (35), 180 (17), 77 (13), 43 (92); Mass spectrum high resolution (EI): theoretical value: C 20h 18brNO 2: C 20h 18brNO 2; [M+] 383.0521; Measured value: 383.0522; Liquid phase analysis: PhenomenexCellulose-2, hexane/i-Propanol=90/10,0.7mL/min, 214nm, t r(major) 19.92min, t r(minor) 23.34min; [α] d 20=103.0 ° of (1.28, CHCl 3).
Embodiment 2: substrate 2-replaces the synthetic of-2,3-dihydro-quinolinone compounds, take and synthesizes substrate 1a as example.
Figure G2009101999303D00091
In dry 50mL round-bottomed flask, with methyl alcohol (20mL), dissolve DL-proline (DL-proline) (3.45g, 30mmol), stir and add o-aminoacetophenone (6.7g after 15 minutes, 60mmol), system at room temperature stirs after 10 minutes and adds phenyl aldehyde (8.1g, 60mmol) again.After reaction 48h, add the aqueous solution (20mL) of saturated ammonium chloride, with dichloromethane extraction (40mL * 3), organic phase Na 2sO 4dry, removal of solvent under reduced pressure column chromatography purification (petrol ether/ethyl acetate=8/1) obtains light yellow solid 4 (9.50g, 71%). 1hNMR (400MHz, CDCl 3): δ 2.78 (dq, J=2Hz, J=1.6Hz, 1H), 2.86-2.93 (m, 1H), 4.51 (br, 1H), (4.76 q, J=9.6Hz, J=8.4Hz, 1H), (6.71 d, J=8.4Hz, 1H), (6.78-6.82 m, 1H), 7.33-7.48 (m, 6H), 7.87-7.89 (m, 1H); 13c NMR (100MHz, CDCl 3): δ 193.3,151.6, and 140.9,135.4,128.9,128.4,127.5,126.5,118.8,118.2,58.3,46.3; Mass spectrum (EI) m/z (relative intensity): 223 (M +, 100), 224 (17), 208 (10), 146 (88), 119 (26), 105 (14), 92 (22), 77 (20).
In the dry round-bottomed flask with reflux of 50mL, product (the 1.32g that adds step to obtain, 6 mmol), Glacial acetic acid (20mL) and diacetyl oxide (20mL), (reflux) frozen water (100mL) that refluxes, then uses saturated NaHCO 3in solution, arrive PH=7 left and right with system; With extracted with diethyl ether (80mL * 3), Na 2sO 4dry, column chromatography purification after removal of solvent under reduced pressure (petrol ether/ethyl acetate=5/1) obtains white solid 1a (1.3g, 82%). 1h NMR (400MHz, CDCl 3): δ 2.43 (s, 3H), 3.22-3.28 (m, 1H), 3.35-3.40 (m, 1H), 6.47 (br, 1H), 7.15-7.22 (m, 7H), 7.44-7.48 (m, 1H), 7.93 (d, J=7.6Hz 1H); 13cNMR (100MHz, CDCl 3): δ 193.1,170.0, and 141.7,137.9,134.3,128.5,127.5,127.2,126.7,126.0,125.4,125.0,54.6,42.5,23.3; Mass spectrum (EI) m/z (relative intensity): 265 (M +, 64), 266 (13), 223 (100), 146 (97), 119 (20), 90 (17), 77 (20), 43 (32); IR (film, cm -1) 3059 (w), 2941 (w), 1693 (s), 1682 (s), 1663 (s), 1601 (s), 1461 (m), 694 (m); Mass spectrum high resolution (EI): theoretical value: C 17h 15nO 2: 265.1103; Measured value: 265.1101.
Synthetic substrate 1b. 1h NMR (400MHz, CDCl 3): δ 2.34 (s, 3H), 3.22-3.32 (m, 2H), 6.43 (br, 1H), 6.89-6.91 (m, 1H), 7.01-7.03 (m, 2H), 7.20-7.24 (m, 1H), 7.52-7.54 (m, 3H), 7.96 (d, J=8Hz, 1H); 13c NMR (100MHz, CDCl 3): δ 192.7,169.7, and 142.4,137.1,134.6,133.7,129.2,127.9,127.2,126.9,126.0,125.4,124.7,123.0,55.5,42.5,23.2; Mass spectrum (EI) m/z (relative intensity): 343 (M +, 1), 303 (20), 301 (21), 264 (100), 146 (54), 77 (9), 58 (19), 43 (96); IR (film, cm -1) 3067 (w), 2977 (w), 1683 (s), 1660 (s), 1602 (s), 1574 (m), 1021 (m), 771 (m); Mass spectrum high resolution (EI): theoretical value: C 17h 14brNO 2: 343.0208; Measured value: 343.0211.
Synthetic substrate 1c. 1h N MR (400MHz, CDCl 3) δ 2.43 (s, 3H), 3.26-3.35 (m, 1H), 3.35-3.40 (m, 1H), 6.47 (br, 1H), 7.03-7.48 (m, 7H), 7.91-7.93 (m, 1H); 13c NMR (100MHz, CDCl 3): δ 192.3,169.9, and 141.3,140.2,134.3,130.5,129.9,129.8,127.2,125.6,125.5,125.1,124.8,122.7,53.8,42.1,23.1; Mass spectrum (EI) m/z (relative intensity): 343 (M +, 22), 345 (21), 303 (54), 301 (56), 146 (100), 90 (21), 77 (18), 43 (71); IR (film, cm -1) 2962 (w), 2976 (w), 1686 (s), 1661 (s), 1601 (m), 1479 (s), 1276 (s), 1231 (s), 775 (s); Ultimate analysis: theoretical value: C 17h 14brNO 2: C 59.32, and H 4.10, and N 4.07; Measured value: C59.33, H 4.27, N 3.99.
Synthetic substrate 1d. 1h NMR (400MHz, CDCl 3): δ 2.41 (s, 3H), 3.20-3.25 (m, 1H), 3.00-3.35 (m, 1H), 3.60 (s, 3H), 6.39 (br, 1H), 6.61-6.64 (m, 1H), (6.73-6.75 m, 2H), 7.07 (q, J=7.6Hz, 2H), 7.40-7.44 (m, 2H), (7.87 d, J=7.6Hz, 1H); 13c NMR (100 MHz, CDCl 3): δ 192.5,169.7, and 159.4,141.5,139.3,134.0,129.2,126.7,125.5,124.9,124.7,118.6,112.6,112.1,54.6,54.4,42.2,22.9; Mass spectrum (EI) m/z (relative intensity): 295 (M +, 40), 253 (60), 252 (100), 146 (60), 119 (13), 90 (14), 77 (13), 43 (47); IR (film, cm -1) 2980 (w), 1698 (s), 1597 (s), 1478 (s), 1226 (s), 1037 (m), 769 (s), 695 (m); Mass spectrum high resolution (EI): theoretical value: C 18h 17nO 3: 295.1208; Measured value: 295.1211.
Embodiment 3: resolved product has the synthetic of physiologically active compound intermediate synthetic.
Synthesizing of compound 4: in 25mL round-bottomed flask, add product 3a (0.33mmol) and methylene dichloride (5mL), pass into ozone and become light blue to system at-78 ℃.Stopped reaction, adds methylene dichloride (3mL) to reaction system, passes into argon gas and removes unnecessary ozone.At-5 ℃, add dimethyl sulphide (0.4mL), at this temperature, react 10min, be then warmed up to room temperature reaction 1h.Stopped reaction, adds water (10mL) diluted system, separatory, and with dichloromethane extraction water (10mL * 3), MgSO 4dry, removal of solvent under reduced pressure, plate layer chromatography sherwood oil: ether=3: 1, obtain product 4.Productive rate: 70%; 1h NMR (400MHz, CDCl 3): δ 2.41 (s, 3H), 2.87-2.95 (m, 2H), 3.80-3.84 (m, 1H), 6.17-6.18 (m, 1H), 7.16-7.26 (m, 6H), 7.50-7.54 (m, 2H), 7.91 (d, J=7.6Hz, 1H), 9.89 (s, 1H); 13cNMR (100MHz, CDCl 3): δ 198.4,194.8, and 170.8,141.6,137.7,134.8,128.7,127.7,127.6,126.8,125.5,125.2,124.8,58.5,45.5,43.6,23.2; IR (film, cm -1) 2858 (w), 1720 (s), 1684 (s), 1665 (s), 1598 (s), 1480 (s), 1283 (s), 1214 (m), 770 (m); Mass spectrum high resolution (ESI): theoretical value: C 19h 17nO 3na:330.1101 (M+Na) +, measured value: 330.1110.
Synthesizing of compound 5: under argon shield, with anhydrous methanol (3mL) dissolved compound 4 (0.133mmol), then add aniline hydrochloride (0.665mmol) and sodium cyanoborohydride (0.106mmol) in dry reaction tubes.System at room temperature stirs after 30min, add again sodium cyanoborohydride (0.106mmol), after stirring 1h under room temperature, add sodium cyanoborohydride (0.333mmol), reaction is spent the night, TLC monitoring reaction finishes, add saturated sodium bicarbonate solution to urge to go out reaction, have dichloromethane extraction (10mL * 3), MgSO 4dry organic phase, removal of solvent under reduced pressure, plate layer chromatography sherwood oil: ether=5: 1, obtain product 5.Productive rate: 85%; Ee:93%; 1h NMR (400MHz, CDCl 3): δ 2.04-2.30 (m, 2H), 2.56-2.30 (m, 4H), 2.98-3.02 (m, 1H), 3.22 (d, J=13.2Hz, 1H), 3.28-3.30 (m, 1H), 3.56 (d, J=8.8Hz, 1H), (4.06 d, J=13.2Hz, 1H), 6.21 (br, 1H), 6.88 (d, J=6.4Hz, 1H), 7.01-7.03 (m, 2H), 7.07-7.27 (m, 11H); 13c NMR (100MHz, CDCl 3): δ 170.1,140.8, and 139.5,139.1,134.0,129.9,128.4,128.1,128.0,127.9,127.6,126.8,126.7,126.6,125.6,64.7,60.2,57.2,52.3,44.5,31.2,22.7; Mass spectrum (EI) m/z (relative intensity): MS (EI) m/z (rel) 382 (M +, 60), 383 (19), 339 (58), 234 (27), 206 (53), 120 (21), 91 (100), 43 (26); IR (film, cm -1) 2967 (w), 2789 (m), 1656 (s), 1604 (w), 1584 (w), 1493 (m), 1384 (m), 759 (m), 698 (m); Mass spectrum high resolution (EI): theoretical value: C 26h 26n 2o:382.2045; Theoretical value: 382.2041; Liquid phase analysis: Phenomenex Cellulose-2, hexane/i-Propanol=80/20,0.7mL/min, 214nm, t r(major), 12.45min, t r(minor) 15.29min; [α] d 20=-52.7 ° of (0.435, CHCl 3).
Embodiment 4: midbody compound has the synthetic of physiologically active compound synthetic.
Figure G2009101999303D00121
Compound 7 synthetic: with anhydrous methanol (3mL) dissolved compound 6 (0.2mmol), add palladium carbon (0.02mmol) under a normal atmosphere in reaction tubes, system at room temperature after stirring reaction 6h, finishes reaction; With removing palladium carbon after diatomite filtration, removal of solvent under reduced pressure, plate layer chromatography sherwood oil: ether=5: 1, obtain product crude product.By upper step crude product with adding salt of wormwood (0.2mmol) after dissolve with methanol, backflow 4h, TLC monitoring reaction finishes, and adds 10% aqueous hydrochloric acid (10mL) to urge the reaction of going out; With dichloromethane extraction (10mL * 3), MgSO 4dry organic phase, removal of solvent under reduced pressure, plate layer chromatography sherwood oil: ether=2: 1, obtain product 7; Productive rate 80%.
Known have the synthetic of physiologically active compound 8: methylene dichloride in reaction tubes (5mL) dissolved compound 7 (0.1mmol), add at twice tert-Butyl dicarbonate (DIBOC) (0.02mmol) and 4-N, N-lutidine (DMAP) is (0.01mmol) catalyzer, system is at room temperature after stirring reaction 6h, TLC monitoring reaction finishes, and adds 10% aqueous hydrochloric acid (10mL) to urge the reaction of going out; With dichloromethane extraction (10mL * 3), MgSO 4dry organic phase, removal of solvent under reduced pressure, plate layer chromatography sherwood oil: ether=5: 1, obtain product 8; Productive rate 94%.

Claims (3)

1. one kind 2,3-bis-replaces-2,3-dihydro quinoline ketone chiral compound, has following structural formula:
Figure FSB0000117744940000011
Wherein:
R 1for ethanoyl;
R 2for Me, i-Pr, Ph, o-Br-C 6h 4, p-Br-C 6h 4, p-F-C 6h 4p-CF 3-C 6h 4p-MeO-C 6h 4m-MeO-C 6h 4or 3,4-O CH 3o-C 6h 3.
2. as described in claim 12,3-bis-replaces the preparation method of-2,3-dihydro quinoline ketone chiral compounds, it is characterized in that: under argon shield, and [Pd (C 3h 5) Cl] 20.003 mmol and Er Mao Tie oxazoline phosphine nitrogen ligand 0.006 mmol are dissolved in 1mL tetrahydrofuran (THF), at room temperature stir 0.5 hour, in another reaction tubes, fill substrate 0.10 mmol in 1.0 mL tetrahydrofuran (THF)s,-78 ℃ add hexamethyldisilazane lithium 0.10mL, 0.10mmol, described hexamethyldisilazane lithium is the tetrahydrofuran solution of 1.0M, keep this temperature to stir after 0.5 hour, the catalyzer and the allylation reagent 0.05mmol that add in situ preparation, stirring reaction 10min, then rise to room temperature reaction, GC tracks to reaction to be finished;
Described substrate is that the structure of 2-replacement-2,3-dihydro-quinolinone is:
Figure FSB0000117744940000012
The structure of described Er Mao Tie oxazoline phosphine nitrogen ligand is:
Described allylation reagent is:
Figure FSB0000117744940000014
Wherein, R 1, R 2as claimed in claim 1; R 5for phenyl; R 6for ethyl; R 7for (R)-2-(2 '-hydroxyl-1-1 '-naphthyl);
for allylic carbonic ether, phosphoric acid ester or acetic ester.
One kind as claimed in claim 12,3-bis-replaces-2,3-dihydro quinoline ketone chiral compounds for the preparation of midbody compound synthetic with physiologically active compound Martinella compounds, the structure of described midbody compound is:
Figure FSB0000117744940000022
Wherein: R 1, R 2as claimed in claim 1; R 9for hydrogen, C 1～6alkyl, phenyl, ethanoyl, methylsulfonyl, p-toluenesulfonyl, tert-butoxycarbonyl or benzyl.
CN200910199930.3A 2009-12-04 2009-12-04 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof Expired - Fee Related CN101723893B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN200910199930.3A CN101723893B (en) 2009-12-04 2009-12-04 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910199930.3A CN101723893B (en) 2009-12-04 2009-12-04 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN101723893A CN101723893A (en) 2010-06-09
CN101723893B true CN101723893B (en) 2014-04-23

Family

ID=42445519

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910199930.3A Expired - Fee Related CN101723893B (en) 2009-12-04 2009-12-04 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN101723893B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584800A (en) * 2011-12-16 2012-07-18 四川大学 Compound containing framework of chiral indolone and angelica lactone and asymmetric synthesis method
CN103601676B (en) * 2013-11-29 2016-06-08 南京大学 High enantioselectivity N-ethanoyl-2-replaces the synthetic method of-2,3-two hydrogen-4-quinolinones compound

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009001A1 (en) * 1992-10-15 1994-04-28 Merck & Co., Inc. Pyrroloquinoline bradykinin antagonist
WO2009015179A1 (en) * 2007-07-23 2009-01-29 Syndax Pharmaceuticals, Inc. Novel compounds and methods of using them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009001A1 (en) * 1992-10-15 1994-04-28 Merck & Co., Inc. Pyrroloquinoline bradykinin antagonist
WO2009015179A1 (en) * 2007-07-23 2009-01-29 Syndax Pharmaceuticals, Inc. Novel compounds and methods of using them

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Antoinette E. Nibbs等.Catalytic Asymmetric Alkylation of Substituted Isoflavanones.《Organic Letters》.2009,第11卷(第17期),4010-4013. *
Dawei Ma等.Aromatic Nucleophilic Substitution or CuI-Catalyzed Coupling Route to Martinellic Acid.《J. Org. Chem.》.2003,第68卷(第2期),442-451. *
Laura Kersten等.Synthesis of spiro-pyridones and spiro-quinolones by sequential palladium on carbon-catalyzed allylation and ring closing metathesis reactions.《Tetrahedron Letters》.2009,第50卷(第5期),506-508. *
Ryo Shintani等.Asymmetric Synthesis of 2-Aryl-2,3-dihydro-4-quinolones by Rhodium-Catalyzed 1,4-Addition of Arylzinc Reagents in the Presence of Chlorotrimethylsilane.《Organic Letters》.2005,第7卷(第23期),5317-5319. *

Also Published As

Publication number Publication date
CN101723893A (en) 2010-06-09

Similar Documents

Publication Publication Date Title
CN104892547B (en) A kind of method that catalysis of carbonyl is combined to alpha-keto amide compound
Kim et al. Synthesis of 1, 2, 5-and 1, 2, 3, 5-substituted pyrroles from substituted aziridines via Ag (I)-catalyzed intramolecular cyclization
CN101723893B (en) 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof
CN102030648B (en) Asymmetric synthesis method of 3-(3,4-dihydroxy phenyl)-2-hydracrylate
Carlos et al. Catalytic asymmetric synthesis of 3-aryl phthalides enabled by arylation–lactonization of 2-formylbenzoates
TW201726593A (en) Method for producing optically active 2-(2-fluorobiphenyl-4-yl) propanoic acid
CN112812097B (en) Method for synthesizing 3- (2-pyridine) substituted pyrrole compound by visible light catalysis
CN107501165B (en) Asymmetric synthesis method of chiral tetrahydrocarbazole derivative
Yang et al. A stereoselective approach to 6-alkylated piperidinone & 2-piperidine via three-component vinylogous Mannich reactions (VMR) and a concise synthesis of (S)-anabasine
WO2007134421A1 (en) 2-VINYL INDOLES, PYRIDO AND AZEPINO INDOLE DERIVATIVES, 2-ALKYNYL INDOLES, 2-ALKYNYL BENZO[b]FURANS, THEIR PRECURSORS AND NOVEL PROCESSES FOR THE PREPARATION THEREOF
CN102295611B (en) Synthetic method for medicines of neurokinin 1 receptor antagonists
Han et al. Diastereoselective three-component reactions of aryldiazoacetates with alcohols/water and alkynals: application to substituted enelactones
Zhang et al. Novel asymmetric total synthesis of the natural (+)-6-epicastanospermine
CN104387383B (en) A kind of synthetic method of Eliquis precursor compound
CN103450065B (en) Prepare the method for ezetimibe
CN103864773A (en) Preparation method for rivaroxaban and intermediate thereof
Xie et al. Asymmetric Synthesis of (+)‐(11R, 12S)‐Mefloquine Hydrochloride
CN110590644A (en) Chiral 1, 2-dihydropyridine compounds and preparation method and application thereof
Faigl et al. Novel stereoselective synthesis of 1, 2, 3-trisubstituted azetidines
Abrunhosa-Thomas et al. Efficient synthesis of β’-amino-α, β-unsaturated ketones
CN107382858B (en) Series of 1,2,3, 4-tetrahydroisoquinoline-4-ketone compounds, and synthetic method and application thereof
Masusai et al. A synthesis of γ-trifluoromethyl α, β-unsaturated γ-butyrolactones using CF 3 SiMe 3 as a trifluoromethylating agent
Banik et al. Enantioselective fluorination of 3-indolinone-2-carboxylates with NFSI catalyzed by chiral bisoxazolines
WO2010108384A1 (en) Phosphor-nitrogen ligand derived from tetrahydroquinoline and indoline, preparation method and use thereof
Monfray et al. A facile enantioselective synthesis of 2-(2-aminoethyl) allylsilanes, new synthons for piperidine synthesis

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20140423

Termination date: 20181204

CF01 Termination of patent right due to non-payment of annual fee