CN103951670A - Polyfunctional pyrroline and spiro-oxindole splicing derivative and preparation method thereof - Google Patents

Polyfunctional pyrroline and spiro-oxindole splicing derivative and preparation method thereof Download PDF

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CN103951670A
CN103951670A CN201410215397.6A CN201410215397A CN103951670A CN 103951670 A CN103951670 A CN 103951670A CN 201410215397 A CN201410215397 A CN 201410215397A CN 103951670 A CN103951670 A CN 103951670A
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major
minor
derivative
splicing
oxoindole
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刘雄利
袁伟成
景德红
杨俊�
周英
俸婷婷
余章彪
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Guizhou University
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

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Abstract

The invention discloses a polyfunctional pyrroline and spiro-oxindole splicing derivative. The polyfunctional pyrroline and spiro-oxindole splicing derivative is synthesized by directly catalyzing different substituted 3-nitrogen substituted oxindole and alpha, beta-unsaturated dinitrile by an alkaline catalyst to undergo a Michael addition-cyclization process. The derivative comprises potential bioactive pyrrole and spiro-oxindole skeletons, is a potential drug molecule intermediate or a drug analogue, can provide a compound source for bioactivity screening, and has important application values for drug screening and pharmaceutical industries. A method is simple and practicable to operate, is cheap and easy in raw material synthesis, can be carried out in various organic solvents, has better air stability and wide applicability, and has good compatibility with various substituent groups.

Description

Polyfunctional group pyrrolin and volution Oxoindole splicing derivative and preparation method thereof
Technical field
The present invention relates to technical field of chemistry, especially a kind of polyfunctional group pyrrolin and volution Oxoindole splicing derivative and preparation method thereof.
Background technology
Having bioactive molecular skeleton heterozygosis two, to become a molecular skeleton be extremely important research field in organic chemistry and medical chemistry.(1) polyfunctional group Oxoindole extensively exists in natural product and synthetic drugs molecule, wherein, especially 3-pyrroles's volution Oxoindole is because have biological activity widely, attract the extensive concern of many chemists and medical chemistry team, for example, Spirotryprostatins A, B extract in the aspergillin fungi from meat soup fermented liquid, are found to be the medicine of potential treatment cancer; Strychnofoline has antimitotic activity for melanoma and Ehrlich tumour cell; Vinealeucoblastine(VLB) is the alkaloid separating from natural phant, can be used for treating chorioepithelioma, lymphosarcoma, reticulum cell sarcoma, acute leukemia, mammary cancer, Goddess's glucagonoma, ovarian cancer, carcinoma of testis, neuroblastoma and malignant melanoma.(2) polysubstituted pyrrolin belongs to important nitrogen heterocyclic ring, this ring is also extensively present in bioactive natural product alkaloid, as drug molecule fluconazole, Piracetam and natural product molecule cuskhygrine, Securinine etc. all comprise pyrrole ring.In view of pyrrole skeleton and 3, the two Oxoindole framework compounds that replace of 3'-have potential biological activity, therefore, the pyrrolin that potential biological activity polyfunctional group is replaced and potential biological activity 3, the pyrrolin volution Oxoindole that the two replacement of 3'-Oxoindole skeleton is spliced into the replacement of 3-polyfunctional group may produce significant new compound molecule on a series of structure and activities, and the synthetic of them can provide compound source for bioactivity screening.
Summary of the invention
The object of the invention is: a kind of polyfunctional group pyrrolin and volution Oxoindole splicing derivative and preparation method thereof are provided, it is the important medicine intermediate of a class and drug analogue, drug screening and pharmaceutical industry are had to important using value, and its synthetic method is very economical easy.
The present invention is achieved in that polyfunctional group pyrrolin and volution Oxoindole splicing derivative, and this compound has the structure as shown in logical formula I:
In formula, R 1for the ester group of difference replacement; R 2for alkyl or the different aryl replacing; R 3for hydrogen, halogen or alkyl; R 4for the aryl of difference replacement.
Described hetero-aromatic ring be containing in N, O or S one or more five to ten-ring hetero-aromatic ring base.
The preparation method of polyfunctional group pyrrolin and volution Oxoindole splicing derivative, by α, β-unsaturated dintrile and 3-nitrogen replace Oxoindole under basic catalyst condition, be in molar ratio the ratio of 4:3 in organic solvent through Michael addition cyclization course, obtain polyfunctional group pyrrolin and splice derivative with volution Oxoindole.
Described basic catalyst is organic bases or mineral alkali, and the add-on of basic catalyst is the 1-100% of Oxoindole molar weight.
Described organic bases is DBU, DMAP, DABCO, Et 3the derivative of N, quinine or quinine; Described mineral alkali is Na 2cO 3.
Described organic solvent is acetonitrile, methyl alcohol, ethanol, propyl alcohol, Virahol, ether, tetrahydrofuran (THF), benzene,toluene,xylene, trimethylbenzene, dioxane, glycol dimethyl ether, isopropyl ether, chloroform, methylene dichloride or oil of mirbane.
α, the temperature of reaction that β-unsaturated dintrile and 3-nitrogen replace Oxoindole is 25-100 oC, the reaction times is 3-48 hour.
Reaction principle of the present invention is as follows:
Wherein, R 1, R 2, R 3, R 4as mentioned above.Cat. be basic catalyst.
By adopting technique scheme, the 3-nitrogen replacing with difference replaces Oxoindole and α, β-unsaturated dintrile, in the direct catalysis of basic catalyst through Michael addition (Michael reaction) cyclization course, polyfunctional group pyrrolin and volution Oxoindole splicing derivative are synthesized, this analog derivative comprises potential biological activity pyrrole skeleton and volution Oxoindole skeleton, can be for bioactivity screening provides compound source, the screening to medicine and pharmaceutical industry have important using value.Operation is simple in the present invention, and raw material is synthetic to be cheaply easy to get, and can in various organic solvents, carry out, and also has good air stability, and suitability is wide, has good compatibility for various substituting groups.
Accompanying drawing 1 is the derivative crystalline structure data of the X of embodiments of the invention 1 compound 18;
Accompanying drawing 2-8 is embodiments of the invention 1the nuclear magnetic spectrogram data of compound 1～3.
Embodiment
Embodiments of the invention 1: the preparation of polyfunctional group pyrrolin and volution Oxoindole splicing derivative.Compound 1: in round-bottomed flask, add successively 3-NHBoc n-formyl sarcolysine base Oxoindole 0.3 mmol (78.6 mg), α, β-unsaturated phenyl dintrile 0.4 mmol (61.6 mg), DBU 0.9 mg(2 mol%), add again 6.0 mL methylene chloride, stirring at room temperature reaction response 8 hours.After TLC detects completely, solvent is removed in underpressure distillation, residual oily matter silica gel column chromatography (300-400 order) separates (sherwood oil: ethyl acetate=3:1), obtains faint yellow solid, and the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 190.1-191.2 oc; 5.2:1 dr, yield 97%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.03 (s, 9H, major), 1.05 (s, 2H, minor), 2.69 (s, 3H, major), 3.17 (s, 0.6H, minor), 4.46 (s, 1H, major), 4.70 (s, 0.2H, minor), 6.41 (br s, 2.4H, major+minor), 6.46 (d j=7.8 Hz, 0.3H, minor), 6.68 (d, j=7.8 Hz, 1H, major), 6.74-6.89 (m; 0.3H, minor), 6.94-6.96 (m, 2.8H; major+minor), 7.01-7.04 (m, 0.9H; minor), 7.17-7.21 (m, 4.3H; major+minor), 7.33-7.35 (m, 1H; major), 7.40-7.43 (m, 1H major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.5,26.4,27.4,53.4,55.6; 58.6,73.5,84.2,107.6,107.9; 118.5,122.0,122.3,123.2,123.9; 127.7,128.0,128.2,128.3,128.4; 129.3,129.5,131.1,134.8; 143.1,151.2,158.3,172.0; IR (KBr) ν3432,2177,1736,1646,1360,1160,759,702 cm -1. HRMS (ESI) Calcd. for C 24h 25n 4o 3[M+H] +: 417.1921; Found:417.1929.
The compound of preparing by embodiment 2～18the same compound of preparation method 1, feed ratio and compound 1identical, can obtain compound 2～18, reaction yield and dr value are shown in figure mono-, but what need emphasize is that compound of the present invention is not limited to the represented content of figure mono-.
The present embodiment is prepared compound 2: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 174.1-175.5 oc; 4.6:1 dr, yield 90%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.03 (s, 9H, major), 1.05 (s, 2H, minor), 2.74 (s, 3H, major), 3.19 (s, 0.7H, minor), (4.52 s, 1H, major), 4.79 (s, 0.2H, minor), 6.57 (br s, 2.5H, major+minor), 6.74 (d j=7.8 Hz, 1H, major), 6.82 (d, j=7.5 Hz, 0.3H, minor), 6.95 (d, j=7.5 Hz, 0.3H, minor), 7.07-7.23 (m, 3.8H, major+minor), 7.39 (d, j=7.5 Hz, 1H, major), 7.45 (d, j=7.5 Hz, 1H, major), 7.93 (d, j=8.4 Hz, 0.5H, minor), 8.08 (d, j=8.2 Hz, 2H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.8,26.5,27.4,53.0,55.0; 57.3,73.0,84.7,108.0,108.3; 108.6,118.0,122.1,122.7,123.2; 123.7,124.0,128.5,129.2,129.5; 130.0,130.1,130.4,130.5,142.8; 142.9,147.9,150.9,158.6,171.5; IR (KBr) ν3354,2357,2173,1715,1654,1609,1515,1352,1098,751 cm -1. HRMS (ESI) Calcd. for C 24h 24n 5o 5[M+H] +: 462.1772; Found:462.1786.
Adopt the present embodiment to prepare compound 3: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 194.1-196.2 oc; 3.6:1 dr, yield 91%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.01 (s, 2H, minor), 1.04 (s, 9H, major), 2.88 (s, 3H, major), 3.16 (s, 0.8H, minor), (4.87 s, 1H, major), 5.08 (s, 0.3H, minor), 6.58-6.63 (m, 3.1H, major+minor), 6.73 (d j=7.8 Hz, 1H, major), 6.97-6.99 (m, 0.6H, minor), 7.09-7.18 (m, 3.6H, major+minor), 7.28-7.36 (m, 2.2H, major+minor), 7.41 (d j=7.2 Hz, 1H, major), 7.50 (d, j=7.5 Hz, 1H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.9,26.4,27.4,49.1,50.8,58.0; 72.1,84.4,107.8,107.9,118.5,118.6; 121.6,121.8,123.2,124.3,126.6; 126.8,128.8,129.1,129.2,129.3; 129.7,130.4,131.3,134.0,134.2; 134.6,143.2,151.1,158.3,171.4; IR (KBr) ν3411,2197,1728,1699,1368,735 cm -1. HRMS (ESI) Calcd. for C 24h 24clN 4o 3[M+H] +: 451.1531; Found:451.1532.
Adopt the present embodiment to prepare compound 4: white solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 184.1-186.4 oc; 4.5:1 dr, yield 93%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.03 (s, 9H, major), 1.04 (s, 2H, minor), 2.75 (s, 3H, major), 3.18 (s, 0.7H, minor), (4.39 s, 1H, major), 4.64 (s, 0.2H, minor), 6.51-6.56 (m, 2.6H, major+minor), 6.73 (d j=7.8 Hz, 1H, major), 6.86-6.99 (m; 3.5H, major+minor), 7.14-7.21 (m, 3.5H; major+minor), 7.34-7.41 (m, 2.3H, major+minor); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.6,26.4,27.4,52.9,55.1,57.7; 72.8,73.1,84.4,107.7,108.1,118.3; 121.9,122.4,123.4,123.8,126.4,126.6; 127.8,128.3,128.4,128.5,129.2,129.3; 129.6,129.8,130.9,133.9,137.4,137.5; 142.9,151.0,158.4,171.7,174.9; IR (KBr) ν3403,2185,1719,1709,1650,1364,1147,743,686,530 cm -1. HRMS (ESI) Calcd. for C 24h 24clN 4o 3[M+H] +: 451.1531; Found:451.1535.
Adopt the present embodiment to prepare compound 5: yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 180.1-182.2 oc; 6.5:1 dr, yield 91%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.02 (s, 9H, major), 1.04 (s, 1H, minor), 2.74 (s, 3H, major), 3.17 (s, 0.5H, minor), (4.42 s, 1H, major), 4.67 (s, 0.1H, minor), 6.47 (br s, 2.1H, major+minor), 6.57 (d j=7.8 Hz, 0.3H, minor), 6.71 (d, j=7.8 Hz, 1H, major), 6.88-6.93 (m, 2.7H, major+minor), 7.03 (d, j=8.4 Hz, 0.4H, minor), 7.14-7.19 (m, 3.2H, major+minor), 7.33-7.42 (m, 2H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.6,26.4,27.4,52.8,54.9,58.0; 73.2,84.3,107.8,108.1,118.3; 122.0,122.5,123.3,123.7,128.1; 128.2,128.8,129.3,129.6,129.7; 129.8,130.8,133.5,133.7,134.0; 143.0,151.1,158.4,171.8,175.0; IR (KBr) ν3440,2189,1707,1650,1495,1368,1143,747 cm -1. HRMS (ESI) Calcd. for C 24h 24clN 4o 3[M+H] +: 451.1531; Found:451.1536.
Adopt the present embodiment to prepare compound 6: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 187.1-189.3 oc; 2.3:1 dr, yield 90%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.02 (s, 4H, minor), (1.05 s, 9H, major), (2.90 s, 3H, major), (3.17 s, 1.5H, minor), (4.85 s, 1H, major), (5.05 s, 0.4H, minor), 6.51 (br s, 3H, major+minor), 6.60-6.65 (m, 1.6H, major+minor), 6.74 (d j=7.8 Hz, 1H), 6.89-6.98 (m, 0.6H, minor), 7.06-7.15 (m, 2.8H, major+minor), 7.15-7.25 (m, 0.9H), (7.32-7.43 m, 4.9H, major+minor), 7.48 (d j=7.8 Hz, 1H); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.9,26.4,27.4,27.5,51.4,53.1; 58.7,72.0,84.4,107.8,107.9,118.4; 121.6,121.8,123.2,124.3,124.4,127.2; 127.3,129.1,129.3,129.5,129.7,130.7; 131.2,131.6,132.5,132.7,135.8,136.3; 143.3,143.6,151.1,158.2,171.3,174.8; IR (KBr) ν3407,2373,2320,2197,1732,1662,1368,1160,751,526 cm -1. HRMS (ESI) Calcd. for C 24h 24brN 4o 3[M+H] +: 495.1026; Found:495.1043.
Adopt the present embodiment to prepare compound 7: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 190.1-193.2 oc; 4.9:1 dr, yield 93%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.03 (s, 9H, major), 1.04 (s, 1.9H, minor), 2.74 (s, 3H, major), 3.17 (s, 0.7H, minor), (4.40 s, 1H, major), 4.65 (s, 0.2H, minor), 6.47 (br s, 2.23 H, major+minor), 6.75 (d j=7.8 Hz .3H, minor), 6.71 (d, j=7.8 Hz, 1H, major), 6.81-6.87 (m, 2.7H, major+minor), 6.92 (d, j=7.5 Hz, 0.3H, minor), 7.13-7.19 (m, 1.8H, major+minor), 7.32-7.42 (m, 4H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.7,26.4,27.4,52.9,55.0,58.0; 72.8,73.2,84.4,107.8,108.1,118.3; 121.7,122.0,122.3,122.5,123.2; 123.8,129.7,129.8,130.0,130.1; 130.8,131.1,131.2,134.0,134.2; 143.0,151.1,158.4,171.8,175.0; IR (KBr) ν3432,2189,1740,1707,1654,1613,1495,1368,1139,751,538 cm -1. HRMS (ESI) Calcd. for C 24h 24brN 4o 3[M+H] +: 495.1026; Found:495.1026.
Adopt the present embodiment to prepare compound 8: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 10.1-182.2 oc; 5.5:1 dr, yield 92%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.01 (s, 10H, major+minor), 2.12 (s, 0.7H, minor), 2.25 (s, 3H, major), 2.70 (s, 3H, major), (3.15 s, 0.5H), 4.41 (s, 1H), (4.65 s, 0.1H, minor), 6.49 (br s, 2.5H, major+minor), 6.68 (d j=7.8 Hz, 1H, major); (6.80-6.83 m, 2.8H, major+minor); (6.92-7.00 m, 2.4H, major+minor); 7.11-7.16 (m; 1.2H, major+minor), 7.30-7.40 (m; 2H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 20.9,21.0,25.5,26.3,27.3,53.0; 55.2,58.5,73.3,84.0,107.5,107.9; 118.6,121.8,122.2,123.1,123.8; 128.1,128.2,128.5,128.6,129.2; 129.4,131.2,131.8,131.9,137.1; 137.6,143.0,151.1,158.1,172.0; IR (KBr) ν3350,2189,1723,1658,1613,1470,1376,1151,759 cm -1. HRMS (ESI) Calcd. for C 25h 27n 4o 3[M+H] +: 431.2078; Found:431.2082.
Adopt the present embodiment to prepare compound 9: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 197.121-198.3 oc; 5.6:1 dr, yield 92%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.02 (s, 9H, major), (1.04 s, 2H, minor), (2.13 s, 0.7H, minor), (2.24 s, 3H, major), (2.70 s, 3H, major), (3.16 s, 0.7H, minor), (4.41 s, 1H, major), (4.65 s, 0.2H, minor), (6.43 br s, 2.5H, major+minor), 6.52 (d j=7.2 Hz, 0.3H, minor); (6.67-6.77 m, 4.1H, major+minor); (6.99-7.01 m, 0.4H, minor); (6.99-7.09 m, 2.5H, major+minor); (7.12-7.18 m, 1H, major); (7.32-7.41 m, 2.2H, major+minor); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 21.1,21.3,25.5,26.3,27.4,53.3,55.5; 58.5,58.7,73.0,73.4,84.1,107.5,107.8; 118.5,121.9,122.1,123.1,123.9,125.3; 125.4,127.7,128.3,128.8,129.0,129.2; 129.5,131.3,134.8,135.0,137.4,137.5; 142.5,143.1,151.2,158.2,171.9,175.2; IR (KBr) ν3399,2189,1723,1650,1392,1249,1155,755 cm -1. HRMS (ESI) Calcd. for C 25h 27n 4o 3[M+H] +: 431.2078; Found:431.2082.
Adopt the present embodiment to prepare compound 10: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 186.1-188.2 oc; 3.5:1 dr, yield 91%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.03 (s, 11H, major+minor), 2.85 (s, 3H, major), 3.19 (s, 1H, minor), 4.65 (s, 1H, major), 4.88 (s, 0.3H, minor), 6.50 (br s, 2.4H, major+minor), 6.56 (d j=7.2Hz, 0.3H, minor), 6.69-6.76 (m; 1.6H, major+minor), 6.81-6.84 (m, 1.4H; major+minor), 6.88-6.90 (m, 1H, major); (6.94-6.96 m, 0.6H, minor); (7.12-7.17 m, 2.4H, major+minor); (7.33-7.37 m, 2H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.8,26.4,27.4,48.4,50.5,59.0; 72.7,73.0,84.3,107.6,108.1,118.3; 118.4,121.8,122.4,122.8,123.2,123.9; 125.1,125.3,126.5,126.6,126.7,126.8; 129.1,129.5,129.7,130.6,138.5,139.2; 143.2,151.0,158.1,171.6,174.8; IR (KBr) ν3415,2189,1715,1372,1151,763,502 cm -1. HRMS (ESI) Calcd. for C 22h 23n 4o 3s [M+H] +: 423.1485; Found:423.1491.
Adopt the present embodiment to prepare compound 11: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 184.1-187.0 oc, 5.0:1 dr, yield 91%, 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.01 (s, 9H, major), 1.03 (s, 1.3H, minor), 2.70 (s, 3H, major), 3.14 (s, 0.6H, minor), 3.69-3.70 (m, 4.2H, major+minor), 3.79 (s, 3H, major), 4.41 (s, 1H, major), 4.63 (s, 0.2H, minor), 6.44-6.55 (m, 5H, major+minor), 6.65-6.68 (m, 2H, major), 6.77-6.79 (m, 0.3H, minor), 6.93-6.95 (m, 0.2H, minor), 7.11-7.12 (m, 0.2H, minor), 7.12-7.17 (m, 1H, major), 7.30-7.35 (m, 1H), 7.40 (d, j=7.2 Hz, 1H, major), 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.6,26.3,27.3,53.2,55.4,55.7,55.8, 58.6,73.1,73.6,84.1,107.6,107.8, 110.6,111.5,111.6,118.5,118.6,120.7, 120.8,122.0,122.2,123.1,123.7,126.9, 127.4,129.4,131.0,142.5,143.2,148.4, 148.8,151.2,158.1,158.2,172.1,175.2, IR (KBr) ν3436,3334,2353,2185,1715,1515,1364,1245,1151,1021,747 cm -1. HRMS (ESI) Calcd. for C 26h 29n 4o 5[M+H] +: 477.2132, Found:477.2129.
Adopt the present embodiment to prepare compound 1 2: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 208.1-209.2 oc; 6.4:1 dr, yield 93%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 0.66-0.76 (m, 3.2H, major+minor), 2.71 (s, 3H, major), 3.20 (s, 0.5H, minor), 3.83-3.89 (m, 2.2H, major+minor), (4.50 s, 1H, major), 4.75 (s, 0.2H, minor), 6.47 (br s, 2.2H, major+minor), 6.52 (d j=7.2Hz, 0.2H, minor), 6.71 (d, j=7.8Hz, 1H, major), 6.74 (d, j=7.5 Hz, 0.2H, minor), 6.94-7.03 (m, 3.2H, major+minor), 7.13-7.21 (m, 4H), 7.32-7.43 (m, 2H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 13.1,25.6,26.5,53.3,55.6; 59.0,62.7,73.2,107.6,107.9; 118.3,122.2,122.3,123.2,124.1; 127.7,128.0,128.2,128.3,129.4; 129.7,130.6,134.6,134.9; 143.1,152.2,157.7,171.8; IR (KBr) ν3436,2181,1723,1650,1380,1331,1249,751,502 cm -1. HRMS (ESI) Calcd. for C 22h 21n 4o 3[M+H] +: 389.1608; Found:389.1619.
Adopt the present embodiment to prepare compound 13: faint yellow solid, nucleus magnetic resonance and high resolution mass spectrum test result etc. are as follows: m.p. 190.1-191.2 oc; 6.4:1 dr, yield 85%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 0.41-0.55 (m, 6.9H, major+minor), (1.25-1.39 m, 1.3H, major+minor), (2.67 s, 3H, major), (3.19 s, 0.6H, minor), (3.60-3.70 m, 2.3H, major+minor), (4.46 s, 1H, major), 4.74 (s, 0.1H, minor), 6.49 (br s, 2.5H, major+minor), 6.70 (d j=7.8 Hz, 1H, major), 6.75 (d, j=7.2 Hz, 0.2H, minor), (6.92-6.97 m, 2.6H, major+minor), (7.02-7.04 m, 0.8H, minor), (7.13-7.20 m, 4H, major), (7.32-7.37 m, 1H, major), 7.43 (d j=7.2 Hz, 1H, major); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 18.3,18.4,25.6,26.5,27.2,27.3; 53.8,56.2,58.9,73.3,73.5; 107.8,108.2,118.2,118.3,122.2; 122.4,123.4,124.0,127.7,128.0; 128.2,128.3,129.5,129.7,130.5; 134.5,142.9,152.6,157.9,171.7; IR (KBr) ν3423,2357,2189,1732,1719,1352,1245,1115,747 cm -1. HRMS (ESI) Calcd. for C 24h 25n 4o 3[M+H] +: 417.1921; Found:417.1924.
Adopt the present embodiment to prepare compound 14: faint yellow solid, nucleus magnetic resonance and high resolution mass spectrum test result etc. are as follows: m.p. 198.1-199.7 oc; 5.6:1 dr, yield 87%; 1h NMR (DMSO-d 6, 300 MHz) δ(major+minor): 1.01 (s, 10H, major+minor), 4.45 (s, 1.2H, major+minor), 6.56 (d, j=0.2 Hz, minor), 6.67 (d, j=1H, major), 6.79-6.81 (m, 0.2H, minor), 6.84-6.87 (m, 2H, major), 7.98-7.01 (m, 0.7H, minor), 7.06-7.11 (m, 1.6H, major+minor), 7.21-7.29 (m, 4H, major), 7.50 (d j=7.2 Hz, 1H, major), 7.56-7.60 (m, 2.2H, major+minor), 10.06 (s, 1H, major), 10.59 (s, 0.2H, minor); 13c NMR (DMSO-d 6, 75 MHz) δ(major+minor): 26.9,52.5,54.7,56.5,56.7,72.4; 73.2,83.7,83.9,109.5,109.6,118.8; 121.1,122.3,122.5,124.0,127.2,127.5; 127.8,128.4,128.6,129.0,129.3; 131.1,135.3,136.1,141.5,141.8; 151.0,157.6,157.8,173.5,176.8; IR (KBr) ν3432,2353,2193,1736,1711,1376,1155,755 cm -1. HRMS (ESI) Calcd. for C 23h 23n 4o 3[M+H] +: 403.1765; Found:403.1777.
Adopt the present embodiment to prepare compound 15: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 202.1-204.2 oc; ; 5.5:1 dr, yield 90%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 0.56-0.61 (m, 3H, major), 1.01 (s, 9H, major), 1.04 (s, 1H, minor), 2.90-2.97 (m, 1H, major), 3.46-3.51 (m, 0.2H, minor), 3.52-3.64 (m, 1H, major), 4.02-4.13 (m, 0.2H, minor), 4.47 (s, 1H, major), 4.71 (s, 0.2H, minor), 6.44 (br s, 2.1H, major+minor), 6.51-6.53 (d j=7.2 Hz, 0.3H, minor), 6.67 (d, j=7.8 Hz, 1H, major), (6.71-6.76 m, 0.2H, minor), (6.93-7.01 m, 3.1H, major+minor), (7.12-7.18 m, 3.8H, major+minor), (7.30-7.32 m, 1H, major), 7.42 (d j=7.2 Hz, 1H); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 12.0,12.7,27.4,34.3,35.0,53.4,53.6; 55.8,58.6,72.9,73.5,84.1,107.6,107.9; 118.5,118.6,122.0,122.2,122.9,124.0; 127.7,127.8,128.0,128.1,128.4,128.5; 128.7,129.2,129.4,130.9,134.3,134.9; 141.7,142.4,151.3,158.4,171.5,174.7; IR (KBr) ν3427,3244,2185,1711,1572,1376,1164,767,473 cm -1. HRMS (ESI) Calcd. for C 25h 27n 4o 3[M+H] +: 431.2078; Found:431.2064.
Adopt the present embodiment to prepare compound 16: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 190.1-191.4 oc; 4.5:1 dr, yield 90%; 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.04 (s, 11H, major+minor), (2.12 s, 0.7H, minor), (2.40 s, 3H, major), (2.67 s, 3H, major), (3.14 s, 0.7H, minor), (4.44 d, 1H, major), 4.68 (s, 0.2H, minor), 6.44 (br s, 2.6H, major+minor), 6.58 (d j=7.8Hz, 1H, major), 6.70 (s, 0.3H, minor), 6.83 (s, j=7.5 Hz, 0.4H, minor), 6.94-7.04 (m, 3.2H, major+minor), 7.13-7.23 (m, 5H); 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 20.7,21.1,25.5,26.4,27.4,53.2; 55.6,58.4,73.0,73.5,84.1,107.3; 107.7,118.6,118.7,122.6,124.7,127.6; 127.8,127.9,128.0,128.3,128.4,129.3; 129.7,131.2,131.8,132.8,135.0,135.2; 140.2,140.7,151.2,158.3,171.8,175.1; IR (KBr) ν3333,2169,1723,1662,1376,1241,702 cm -1. HRMS (ESI) Calcd. for C 25h 27n 4o 3[M+H] +: 431.2078; Found:431.2090.
Adopt the present embodiment to prepare compound 17: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 180.1-183.2 oc, 6.3:1 dr, yield 91%, 1h NMR (CDCl 3, 300 MHz) δ(major+minor): 1.06 (s, 9H, major), 1.08 (s, 1.6H, minor), 2.67 (s, 3H, major), 3.17 (s, 0.5H, minor), 4.43 (s, 1H, major), 4.70 (s, 0.2H, minor), 6.43 (br s, 2.4H, major+minor), 6.60-6.64 (m, 1H, major), 6.64-6.66 (m, 0.2H, minor), 6.67-6.70 (m, 0.2H, minor), 6.93-6.95 (m, 2.5H, major+minor), 7.03-7.09 (m, 1.6H, major+minor), 7.20-7.22 (m, 4H, major), 13c NMR (CDCl 3, 75 MHz) δ(major+minor): 25.7,26.6,27.5,53.4,55.7,58.5,73.6,84.5,108.1 (d, j cF =7.8 Hz, minor), 108.6 (d, j cF =7.8 Hz, major), 110.3 (d, j cF =25.2 Hz, major), 112.1 (d, j cF =25.2 Hz, minor), 115.4 (d, j cF =25.2 Hz, minor), 115.7 (d, j cF =25.2 Hz, major), 118.2,127.9,128.0,128.1,128.2,128.3,128.4,132.6 (d, j cF =7.5 Hz, major), 134.4,139.0,159.5 (d, j cF =241.2 Hz, major), 158.1,171.7, IR (KBr) ν3354,2357,2336,1715,1650,1491,1360,1274,1123,820,698 cm -1. HRMS (ESI) Calcd. for C 24h 24fN 4o 3[M+H] +: 435.1827, Found:435.1838.
Adopt the present embodiment to prepare compound 18: faint yellow solid, the results such as nucleus magnetic resonance and high resolution mass spectrum test are as follows: m.p. 171.1-171.5 oc; >20:1 dr, yield 86%; 1h NMR (CDCl 3, 300 MHz) δ1.11 (s, 9H), 4.59 (s; 1H), 6.51 (br s, 2H); 6.59 (d, J=7.2 Hz, 2H); 6.71 (d, J=7.6 Hz, 1H); 7.00-7.02 (m, 2H), 7.20-7.33 (m; 8H), 7.49-7.51 (m, 1H); 13c NMR (CDCl 3, 75 MHz) δ: 27.6,56.5,58.3,73.9,84.4,109.3,118.6,122.3,123.7,125.5,127.8,128.3,128.4,128.8,129.3,130.3,133.4,134.2,142.7,151.2,158.5,171.1; ν3342,2169,1723,1682,1450,1261,847,699 cm -1. HRMS (ESI) Calcd. for C 29h 26n 4naO 3[M+Na] +: 501.1903; Found:501.1914.
Embodiments of the invention 2: compound 1: in round-bottomed flask, add successively 3-NHBoc n-formyl sarcolysine base Oxoindole 0.3 mmol (78.6 mg), α, β-unsaturated phenyl dintrile 0.4 mmol (61.6 mg), quinine 9.7 mg(10 mol%), add again 6.0 mL solvent toluenes, stirring at room temperature reaction response 48 hours.After TLC detects completely, solvent is removed in underpressure distillation, and residual oily matter silica gel column chromatography (300-400 order) separates (sherwood oil: ethyl acetate=3:1), obtains faint yellow solid.Productive rate: 98%, dr:4.2/1.
The preparation of employing the present embodiment, feed ratio and compound 1identical, can obtain respectively compound 2(productive rate 91%, dr:3.8/1), compound 3(productive rate 92%, dr:5.0/1), compound 4(productive rate 93%, dr:4.6/1), compound 5(productive rate 94%, dr:3.7/1), compound 6(productive rate 97%, dr:3.0/1), compound 7(productive rate 95%, dr:3.8/1), compound 8(productive rate 97%, dr:4.5/1), compound 9(productive rate 96%, dr:4.1/1), compound 10(productive rate 97%, dr:4.6/1), compound 11(productive rate 96%, dr:5.1/1), compound 12(productive rate 96%, dr:5.2/1), compound 13(productive rate 98%, dr:4.3/1), compound 14(productive rate 96%, dr:4.2/1), compound 15(productive rate 94%, dr:3.2/1), compound 16(productive rate 97%, dr:3.1/1), compound 17(productive rate 95%, dr:3.8/1), compound 18(productive rate 82%, dr:, 14/1).
Embodiments of the invention 3: compound 1: in round-bottomed flask, add successively 3-NHBoc n-formyl sarcolysine base Oxoindole 0.3 mmol (78.6 mg), α, β-unsaturated phenyl dintrile 0.4 mmol (61.6 mg), sodium carbonate 3.2 mg(10 mol%), add again 6.0 mL etoh solvents, stirring at room temperature reaction response 16 hours.After TLC detects completely, solvent is removed in underpressure distillation, and residual oily matter silica gel column chromatography (300-400 order) separates (sherwood oil: ethyl acetate=3:1), obtains faint yellow solid.Productive rate: 98%, dr:3.1/1.
The preparation of employing the present embodiment, feed ratio and compound 1identical, can obtain respectively compound 2(productive rate 92%, dr:3.4/1), compound 3(productive rate 93%, dr:4.1/1), compound 4(productive rate 92%, dr:4.5/1), compound 5(productive rate 95%, dr:5.0/1), compound 6(productive rate 97%, dr:4.8/1), compound 7(productive rate 95%, dr:4.1/1), compound 8(productive rate 97%, dr:3.5/1), compound 9(productive rate 94%, dr:4.7/1), compound 10(productive rate 95%, dr:3.4/1), compound 11(productive rate 94%, dr:3.2/1), compound 12(productive rate 94%, dr:3.8/1), compound 13(productive rate 92%, dr:2.8/1), compound 14(productive rate 94%, dr:2.1/1), compound 15(productive rate 95%, dr:3.4/1), compound 16(productive rate 94%, dr:3.7/1), compound 17(productive rate 95%, dr:4.2/1), compound 18(productive rate 88%, dr:15/1).

Claims (7)

1. polyfunctional group pyrrolin and a volution Oxoindole splicing derivative, is characterized in that: this compound has the structure as shown in logical formula I:
In formula, R 1for the ester group of difference replacement; R 2for alkyl or the different aryl replacing; R 3for hydrogen, halogen or alkyl; R 4for the aryl of difference replacement.
2. polyfunctional group pyrrolin according to claim 1 and volution Oxoindole splicing derivative, is characterized in that: described hetero-aromatic ring be containing in N, O or S one or more five to ten-ring hetero-aromatic ring base.
3. the preparation method of a polyfunctional group pyrrolin as claimed in claim 1 and volution Oxoindole splicing derivative, it is characterized in that: by α, β-unsaturated dintrile and 3-nitrogen replace Oxoindole under basic catalyst condition, in organic solvent, carry out Michael reaction ring-closure reaction for the ratio of 4:3 in molar ratio, obtain polyfunctional group pyrrolin and volution Oxoindole splicing derivative.
4. the preparation method of polyfunctional group pyrrolin according to claim 3 and volution Oxoindole splicing derivative, it is characterized in that: described basic catalyst is organic bases or mineral alkali, the add-on of basic catalyst is the 1-100% of Oxoindole molar weight.
5. the preparation method of polyfunctional group pyrrolin according to claim 4 and volution Oxoindole splicing derivative, is characterized in that: described organic bases is DBU, DMAP, DABCO, Et 3the derivative of N, quinine or quinine; Described mineral alkali is Na 2cO 3.
6. the preparation method of polyfunctional group pyrrolin according to claim 3 and volution Oxoindole splicing derivative, is characterized in that: described organic solvent is acetonitrile, methyl alcohol, ethanol, propyl alcohol, Virahol, ether, tetrahydrofuran (THF), benzene,toluene,xylene, trimethylbenzene, dioxane, glycol dimethyl ether, isopropyl ether, chloroform, methylene dichloride or oil of mirbane.
7. the preparation method of polyfunctional group pyrrolin according to claim 3 and volution Oxoindole splicing derivative, is characterized in that: α, the temperature of reaction that β-unsaturated dintrile and 3-nitrogen replace Oxoindole is 25-100 oC, the reaction times is 3-48 hour.
CN201410215397.6A 2014-05-21 2014-05-21 Polyfunctional pyrroline and spiro-oxindole splicing derivative and preparation method thereof Pending CN103951670A (en)

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CN104230942A (en) * 2014-08-19 2014-12-24 华东师范大学 Spiro[pyrrolinyl-3,2'-oxoindole] derivatives, and synthesis method and application thereof
CN107089986A (en) * 2017-05-24 2017-08-25 遵义医学院 3,3 ' loop coil Oxoindoles containing difluoromethyl group and its preparation method and application
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