CN102731484B - Preparation method for prodigiosins analogue - Google Patents

Preparation method for prodigiosins analogue Download PDF

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CN102731484B
CN102731484B CN201210201792.XA CN201210201792A CN102731484B CN 102731484 B CN102731484 B CN 102731484B CN 201210201792 A CN201210201792 A CN 201210201792A CN 102731484 B CN102731484 B CN 102731484B
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analogue
pyrrole
prodigiosin
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CN102731484A (en
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郝二宏
于长江
焦莉娟
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Anhui Normal University
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Anhui Normal University
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Abstract

The present invention relates to a preparation method for a prodigiosins analogue, wherein the method comprises: adopting 3-halogenated pyrrole or isoindolealdehyde or an imine compound and an pyrrole derivative as raw materials, wherein a molar ratio is 1:10-100; carrying out a reaction in an organic solvent for 1-24 hours at a temperature of 20-80 DEG C under magnetic stirring and a condition of Lewis acid; carrying out extraction, water washing, drying, and reduced pressure concentration; and carrying out silica gel column chromatography separation to obtain the prodigiosins analogue. Compared with the method in the prior art, the method of the present invention has the following advantages that: the process is simple, the synthesis efficiency is high, and the foundation is established for large scale industrial productions of prodigiosins and analogues thereof.

Description

A kind of preparation method of prodigiosin analogue
Technical field:
The present invention relates to a kind of preparation method of prodigiosin analogue, belong to organic chemical industry and technical field of fine.
Background technology:
Prodigiosin (Prodigiosins, be called for short PG) and analogue be a class containing the natural pigment of methoxypyrrole skeleton structure, it is the secondary metabolite of some actinomycetes, husky thunder bacterium and other bacteriums, having very strong antitumor, antibacterium, antimycotic, the multiple biological activity such as anti-malarial and immunosuppression, is the potential cancer-resisting substance of a class.Recent study finds that prodigiosin has autoimmunity depression activity and has resistance effect to the various human such as adenocarcinoma of lung, prostate cancer cancer cells, under identical Dosages, to normal cell without any toxic action.
Prodigiosin and analogue thereof have become the extremely potential PTS of one.Prodigiosin can the apoptosis of inducing cancer cell in addition, under extremely low concentration, can kill the most of planktonic organism causing red tide fast, in the improvement of water pollution, demonstrate huge power.Research shows; natural pigment prodigiosin has good dye uptake and anti-microbial property on the fabrics such as silk, wool, modified acryl fibre; up-to-date research shows that prodigiosin and analogue thereof also can be used as ultraviolet protective material, and therefore prodigiosin can be used as the dyestuff of multifunction environment-protection type or dye additive is applied to dyeing.It can keep the long period in sour environment, can transport Cl in human body -(Chem. Commun. 2005,30,5781-5783.; Chem.Commun. 2005,30,3773-3775.) and cause Cu 2+inducing DNA double bond cracking etc. (Chem Res Toxicl, 2002,15,2480-2486).
The PG cytotoxic properties of different structure is different.The difference replacement of PGC-6 methoxyl group also can have an impact to its effect, and when it is replaced by the alkoxyl group more grown, activity can decline.Define new PG derivative according to the molecular modification that these achievements in research are carried out, its activity index exceeds several times (Chembiochem. 2001,2,60-68) than parent molecule.Wherein the prodigiosin derivative Obatoclax of synthetic has entered the clinical class I/II phase as kinds cancer medicine and has studied (Chem. Eur. J. 2011,17,14074).Its another analogue PNU-156804 presents than prodigiosin and the higher immunosuppressive activity of analogue thereof and lower toxicity (J. Med. Chem. 2000,43,2557).Therefore the research of prodigiosin derivative and analogue has broad application prospects in fields such as cancer therapy.
The sixties in 20th century is early stage, and first passage is complete synthesis obtains prodigiosin in Rapoport seminar (J. Am. Chem. Soc. 1962,84,635-642), has started the beginning that prodigiosin is complete synthesis.The whole process of experiment is divided into four steps, but more complicated and difficulty.Seminar (Synlett, 1996,6,513-514 such as D ' Alessio and Dairi; Patent WO 97/30029; Tetrahedron Lett, 2006,47,2605-2606) propose the scheme of new preparation PG analogue according to tripyrrole precursor structure three kinds of different fracture modes: (1) first C ring is connected with B ring be then coupled by Suzuki close with A loops again (simulate biosynthesizing route is first be connected with A ring by B ring in the past) PG precursor substance, combined coefficient improves, but can not be used for the undecyl PG of synthesis of natural; (2) commercial 4-methoxy-3-Pyrrolin-2-one is utilized to obtain prodigiosin derivative and analogue precursor 4-methoxy-2 thereof through two-step reaction, 2'-bipyrrole-5-carboxaldehyde, is then coupled different pyrroles and derivative thereof from it and obtains different PG derivatives and analogue.
Although achieve certain achievement about the chemosynthesis research of prodigiosin and analogue thereof, chemical synthesis fails to prepare prodigiosin derivative and analogue in a large number always.The method of current existing synthesis prodigiosin derivative, step is complicated, and needs the Suzuki coupling of using precious metal palladium catalysis, substrate restricted application.
Summary of the invention:
The invention provides a kind of synthetic method of novel simplification, namely synthesized the method for prodigiosin derivative and analogue thereof by Lewis acid, improve combined coefficient, for prodigiosin and analogue industrial mass production lay the foundation.
The 3-halogenated pyrrole of different substituents or isoindole aldehyde or imine compound and pyrrole derivatives make raw material, their mol ratio is 1:10-100, in organic solvent, under magnetic agitation, under temperature 20 DEG C ~ 80 DEG C conditions, under Lewis acid condition, react 1 ~ 24 hour, through extraction, washing, drying, concentrating under reduced pressure, then be separated obtained prodigiosin analogue through silica gel column chromatography.
Described organic solvent is selected from methylene dichloride, trichloromethane, 1,2-methylene dichloride.
Described Lewis acid is selected from POCl 3, CH 3cOOH, CH 3sO 3h, CF 3sO 3h.
In described raw material, 3-halogenated pyrrole or isoindole aldehyde or imine compound molecular structure are as general formula V, VI:
X=Cl, Br, I, CF in general formula A 3sO 3; Y, Z with define in general formula I identical; R 8=R 9=H, C 1-12straight chain or branched-chain alkyl, C 1-12cycloalkyl, (CH 2) mo(CH 2) nh.
The general structure of the prodigiosin derivative that the present invention is made and analogue is I:
In general formula I: Y, Z are H, C 1-12alkyl, cycloalkyl ,-CHCH-,-CR 8cR 9-, phenyl, Cl, Br, I, OR 8, NR 8r 9, CN, (CH=CH 2) (C 6h 4) R 8, (CH 2) mo(CH 2) nh, (CH 2) ncOOM, (CH 2) mcOM or (CH 2) msO 3m; R 4=H, CH 3, aryl; R 1, R 2, R 3, R 5, R 6, R 7for H, C 1-12alkyl, cycloalkyl, phenyl, naphthyl, F, Cl, Br, I, OR 8, NR 8r 9, CN, (CH=CH 2) (C 6h 4) R 8, (CH 2) mo(CH 2) nh, (CH 2) ncOOM, (CH 2) mcOM or (CH 2) msO 3m; R 8=R 9=H, C 1-12straight chain or branched-chain alkyl, C 1-12cycloalkyl, (CH 2) mo(CH 2) nh; N, m=0 – 15; M=H, Li, Na, K, NH 4.
In said structure general formula, the preferred structure of prodigiosin derivative and analogue is formula II, III and IV:
In general formula I I,
R 4during for H,
R 1, R 2, R 3, R 4, R 5, R 6, R 7be H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for CH 2cH 3;
R 4for CH 3time,
R 1, R 2, R 3, R 4, R 5, R 6, R 7be H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for CH 2cH 3;
R 1, R 3for CH 3, R 2, R 4, R 5, R 6, R 7be H;
In general formula III, IV,
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 4, R 6for CH 2cH 3;
The present invention compared with prior art, has that technique is simple, combined coefficient is high, for prodigiosin and analogue industrial mass production lay the foundation.
Accompanying drawing explanation
Fig. 1 is the X-ray single crystal diffraction structure iron of product IIj.
Fig. 2 is the X-ray single crystal diffraction structure iron of product IIIa.
Embodiment
Below in conjunction with case study on implementation, the invention will be further described.
Embodiment 1:
The syntheses and properties of Compound II per a:
Method one:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.69 ml, 10 mmol) and 5-chloro-2-aldehyde isoindole (90 mg, 0.5 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(470 l, 5 mmol), after reacting 16 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain yellow powder, productive rate is 61% (79 mg).
Method two:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.69 ml, 10 mmol) and 5-chloro-2-imines isoindole (125 mg, 0.5 mmol) respectively, and add POCl 3(470 l, 5 mmol), after back flow reaction 5 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain yellow powder, productive rate is 56% (72 mg).
1H NMR (300 MHz, CDCl 3): δ 11.52(s, 1H), 10.07(s, 1H), 8.03(d, J = 7.2 Hz, 1H), 7.83(d, J = 7.2 Hz, 1H), 7.45-7.40(m, 2H), 7.23-6.97(m, 3H), 6.60(s, 1H), 6.41(s, 1H), 6.25(s, 1H). 13C NMR (75 MHz, CDCl 3): δ 157.1, 143.7, 142.0, 134.6, 130.7, 128.4, 127.1, 126.8, 124.6, 122.8, 122.3, 119.5, 117.1, 114.0, 113.8, 111.3, 110.6. HRMS (EI) Calcd. for C 17H 13N 3 [M] +: 259.1109, found 259.1112.
Embodiment 2:
The syntheses and properties of Compound II per b:
Method one:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.5 ml, 5 mmol) and 5-chloro-2-aldehyde isoindole (90 mg, 0.5 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(470 l, 5 mmol), after reacting 2 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain red powder, productive rate is 75% (118 mg).
Method two:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.5 ml, 5 mmol) and 5-chloro-2-imines isoindole (125 mg, 0.5 mmol) respectively, and add POCl 3(470 l, 5 mmol), after back flow reaction 2 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain red powder, productive rate is 78% (123 mg).
1H NMR (300 MHz, CDCl 3): δ 8.73(s, 1H), 7.87-7.82(m, 2H), 7.42(d, J = 7.2 Hz, 1H), 7.34(d, J = 7.2 Hz, 1H), 7.06(s, 1H), 6.01 (s, 1H), 5.86 (s, 1H), 2.58 (s, 3H), 2.34(s, 3H), 2.31(s, 6H). 13C NMR (75 MHz, CDCl 3): δ 155.3, 142.3, 141.9, 135.4, 134.9, 131.3, 128.1, 127.9, 127.2, 125.2, 124.3, 124.1, 121.7, 119.2, 112.1, 111.2, 110.9, 14.3, 13.6, 13.3, 11.4. HRMS (EI) Calcd. for C 21H 21N 3 [M] +: 315.1735, found 315.1731.
Case study on implementation 3:
The syntheses and properties of Compound II per c:
2,4-dimethyl pyrrole is made into 2, the 4-dimethyl-3-N-ethyl pyrrole N-s that mole number is identical, other are with embodiment 2 method one, and productive rate is 73% (135 mg).
Method two:
2,4-dimethyl pyrrole is made into 2, the 4-dimethyl-3-N-ethyl pyrrole N-s that mole number is identical, other are with embodiment 2 method two, and productive rate is 76% (141 mg).
1H NMR (300 MHz, CDCl 3): δ 8.40(s, 1H), 7.85-7.80(m, 2H), 7.38-7.30(m, 2H), 7.04(s, 1H), 2.53-2.24(m, 16H), 1.19-1.08(m, 6H). 13C NMR (75 MHz, CDCl 3): δ 154.7, 142.4, 141.8, 134.9, 132.3, 127.6, 127.3, 127.1, 125.3, 124.0, 123.4, 122.4, 121.6, 119.2, 111.0, 17.6, 17.6, 15.6, 15.5, 11.9, 11.7, 9.6. HRMS (EI) Calcd. for C 25H 29N 3 [M] +: 371.2361, found 371.2359.
Embodiment 4:
The syntheses and properties of Compound II per d:
Method one:
2,4-dimethyl pyrrole is made into 2,4-dimethyl-3-acetyl pyrrole, elutriant to be sherwood oil and ethyl acetate volume ratio be 2/1 mixed system cross post, other are with embodiment 2 method one, and productive rate is 57% (114 mg).
Method two:
2,4-dimethyl pyrrole is made into 2, the 4-dimethyl-3-acetyl pyrroles that mole number is identical, elutriant to be sherwood oil and ethyl acetate volume ratio be 2/1 mixed system cross post, other are with embodiment 2 method two, and productive rate is 60% (120 mg).
1H NMR (300 MHz, CDCl 3): δ11.99(s, 1H), 11.77(s, 1H), 8.04(s, 1H), 7.85(s, 1H), 7.44-7.42(m, 3H), 2.62-2.41(m, 18H). 13C NMR (75 MHz, CDCl 3): δ194.4, 194.1, 157.5, 144.7, 141.8, 141.1, 139.1, 135.6, 128.4, 128.1, 127.9, 126.7, 124.3, 123.9, 123.5, 123.3, 120.5, 112.3, 96.4, 31.8, 31.7, 16.2, 15.4, 14.8, 12.8. HRMS (EI) Calcd. for C 25H 25N 3O 2 [M] +: 399.1947, found 399.1949.
Embodiment 5:
The syntheses and properties of Compound II per e:
Method one:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.69 ml, 10 mmol) and 5-chloro-2-ethanoyl isoindole (97 mg, 0.5 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(470 l, 5 mmol), react 16 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain red powder, productive rate is 78% (106 mg).
Method two:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.69 ml, 10 mmol) and 5-chloro-2-imines isoindole (125 mg, 0.5 mmol) respectively, and add POCl 3(470 l, 5 mmol), back flow reaction 5h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain red powder, productive rate is 73% (100 mg).
1H NMR (300 MHz, CDCl 3): δ 12.53(s, 1H), 9.32(s, 1H), 8.03-7.98(m, 2H), 7.44-7.35(m, 2H), 7.14-7.10(m, 2H), 6.77(s, 1H), 6.45(s, 1H), 6.33(s, 1H), 2.75(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 154.0, 142.9, 140.9, 135.4, 134.7, 129.2, 128.0, 127.3, 125.9, 123.8, 123.6, 122.2, 121.4, 114.4, 112.2, 111.1, 110.1, 17.5. HRMS (EI) Calcd. for C 18H 15N 3[M] +: 273.1266, found 273.1269.
Embodiment 6:
The syntheses and properties of Compound II per f:
Method one:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add 2,4-dimethyl pyrrole (0.5 ml, 5 mmol) and 5-chloro-2-ethanoyl isoindole (97 mg, 0.5 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(470 l, 5 mmol), back flow reaction 2 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) and obtain red powder, productive rate is 79% (130 mg).
Method two:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add 2,4-dimethyl pyrrole (0.5 ml, 5 mmol) and 5-chloro-2-imines isoindole (125 mg, 0.5 mmol) respectively, and add POCl 3(470 l, 5 mmol), back flow reaction 2 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) again and obtain red powder, productive rate 79% (130 mg).
1H NMR (300 MHz, CDCl 3): δ 13.25(s, 1H), 8.40(s, 1H), 8.02(d, J = 7.5 Hz, 1H), 7.83(d, J = 7.5 Hz, 1H), 7.39(t, J = 7.2, 1H), 7.31(t, J = 7.2Hz, 1H), 6.00(s, 1H), 5.83(s, 1H), 2.84(s, 3H), 2.53(s, 3H), 2.38(s, 3H), 2.31(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 151.8, 141.8, 140.7, 135.5, 133.7, 131.8, 130.5, 129.5, 127.6, 127.2, 124.9, 123.9, 123.6, 123.0, 121.7, 113.3, 111.5, 18.1, 16.5, 14.0, 13.5. HRMS (EI) Calcd. for C 22H 23N 3 [M] +: 329.1892, found 329.1887.
Embodiment 7:
The syntheses and properties of Compound II per g:
Method one:
2,4-dimethyl pyrrole is made into 2, the 4-dimethyl-3-N-ethyl pyrrole N-s that mole number is identical, other are with embodiment 6 method one, and productive rate is 72% (138 mg).
Method two:
2,4-dimethyl pyrrole is made into 2, the 4-dimethyl-3-N-ethyl pyrrole N-s that mole number is identical, other are with embodiment 6 method two, and productive rate is 65% (125 mg).
1H NMR (300 MHz, CDCl 3): δ 13.23(s, 1H), 8.27(s, 1H), 8.04(d, J = 7.8 Hz, 1H), 7.86(d, J = 7.5 Hz, 1H), 7.40(t, J = 7.2 Hz, 1H), 7.31(t, J = 7.2 Hz, 1H), 2.89(s, 3H), 2.58-2.32(m, 16H), 1.19(t, J = 7.5 Hz, 3H), 1.11(t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl 3): δ 151.8, 142.0, 140.8, 135.6, 131.6, 131.1, 129.1, 127.1, 126.9, 125.2, 124.9, 124.7, 124.1, 123.6, 123.1, 121.9, 121.3, 18.5, 17.7, 17.5, 15.9, 15.7, 13.5, 11.8, 11.8, 11.7. HRMS (EI) Calcd. for C 26H 31N 3 [M] +: 385.2518, found 385.2520.
Embodiment 8:
The syntheses and properties of Compound II per h:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add pyrroles (0.69 ml, 10mmol) and chloro-7,9-dimethylbiphenyl two pyrroles of 1-(128 mg, 0.5 mmol) respectively, and add POCl fast 3(470 l, 5 mmol), room temperature reaction 12 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) again and obtain green powder, productive rate 87% (125 mg). 1H NMR (300 MHz, CDCl 3): δ 10.38(s, 1H), 8.04(d, J = 7.2 Hz, 1H), 7.87(d, J = 7.2 Hz, 1H), 7.45-7.38(m, 2H), 7.17-7.13(m, 2H), 6.90(s, 1H), 6.37(s, 1H), 5.78(s, 1H), 2.27(s, 3H), 2.08(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 155.6, 142.5, 140.3, 137.2, 134.1, 129.7, 127.8, 127.5, 127.1, 126.0, 122.5, 122.3, 119.1, 113.1, 112.0, 111.7, 110.9, 12.8, 11.6. HRMS (EI) Calcd. for C 19H 17N 3 [M] +: 287.1422, found 287.1419.
Embodiment 9:
The syntheses and properties of Compound II per i:
Chloro-for 1-7,9-dimethylbiphenyl two pyrroles are made into chloro-7, the 9-dimethyl-8-ethyl benzodipyrroles of 1-, and other are with embodiment 9, and productive rate is 85% (134 mg). 1H NMR (300 MHz, CDCl 3): δ10.13(s, 1H), 8.02(d, J = 7.5 Hz, 1H), 7.86(d, J = 7.5 Hz, 1H), 7.43(t, J = 7.2 Hz, 1H), 7.36(d, J = 7.2 Hz, 1H), 7.15(s, 1H), 7.10(s, 1H), 6.94(s, 1H), 6.38(s, 1H), 2.36(q, J = 7.5 Hz, 2H), 2.22(s, 3H), 2.10(s, 3H), 1.05(t, J = 7.5, 3H). 13C NMR (75 MHz, CDCl 3): δ154.7, 142.2, 133.9, 127.7, 127.5, 126.5, 125.9, 125.7, 124.3, 122.0, 121.9, 119.0, 112.6, 112.3, 112.0, 111.4, 110.9, 17.5, 15.4, 11.4, 9.7. HRMS (EI) Calcd. for C 21H 21N 3 [M] +: 315.1735, found 315.1732.
Embodiment 10:
The syntheses and properties of Compound II per j:
Chloro-for 1-7,9-dimethylbiphenyl two pyrroles are made into chloro-7, the 9-dimethyl-8-ethanoyl benzodipyrroles of 1-, and other are with embodiment 9, and productive rate is 78% (60 mg). 1H NMR (300 MHz, CDCl 3): δ12.19(s, 1H), 11.69(s, 1H), 8.17-8.11(m, 2H), 7.48-7.29(m, 6H), 6.39(s, 1H), 2.49-2.44(m, 9H). 13C NMR (75 MHz, CDCl 3): δ195.3, 156.7, 144.7, 142.4, 142.3, 135.2, 128.9, 128.2, 127.9, 127.7, 124.3, 123.5, 122.9, 121.0, 114.3, 111.8, 111.7, 32.2, 16.4, 13.1. HRMS (EI) Calcd. for C 21H 19N 3O [M] +: 329.1528, found 329.1534.
Fig. 1 is the single crystal diffraction figure of Compound II per j, and made by the structure of single crystal diffraction to compound and accurately having pointed out, crystalline structure shows this compound and possesses higher level conjugacy.
Embodiment 11:
The syntheses and properties of Compound II per k:
Pyrroles is made into 2,4-identical dimethyl-3-N-ethyl pyrrole N-s of mole number, and other are with embodiment 9, and productive rate is 89% (76 mg). 1H NMR (300 MHz, CDCl 3): δ 8.39(s, 1H), 7.85-7.80(m, 2H), 7.39(d, J = 6 Hz, 1H), 7.31(d, J = 6 Hz, 1H), 7.03(s, 1H), 5.84(s, 1H), 2.53-2.28(m, 14H), 1.16(t, J = 6 Hz, 3H). 13C NMR (75 MHz, CDCl 3): δ 155.3, 142.6, 141.8, 135.1, 128.3, 127.9, 127.6, 127.2, 125.5, 124.6, 123.2, 122.7, 121.7, 119.3, 110.9, 110.8, 17.6, 15.6, 13.7, 12.0, 11.7, 11.5. HRMS (EI) Calcd. for C 23H 25N 3 [M] +: 343.2048, found 343.2054.
Embodiment 12:
The syntheses and properties of Compound II per l:
Pyrroles is made into the identical 3-skatole of mole number, and other are with embodiment 9; Back flow reaction 15 h, after reaction terminates, extraction, drying, concentrating under reduced pressure obtains thick product, then (stationary phase is silica gel through column chromatography, elutriant is sherwood oil is the mixed system of 4/1 with ethyl acetate volume ratio) be separated and obtain red powder, productive rate is 76% (90 mg). 1H NMR (300 MHz, CDCl 3): δ 8.49(s, 1H), 7.87(d, J = 7.8 Hz, 1H), 7.83(d, J = 7.8 Hz, 1H), 7.69(d, J = 7.8 Hz, 1H), 7.43-7.16(m, 5H), 7.11(s, 1H), 5.88(s, 1H), 2.73(s, 3H), 2.34(s, 3H), 2.29(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 155.3, 142.2, 141.5, 137.1, 136.9, 135.0, 130.0, 129.9, 128.4, 127.4, 125.7, 123.9, 121.8, 120.0, 119.7, 119.2, 114.8, 113.8, 111.6, 111.3, 13.9, 11.5, 11.1. HRMS (EI) Calcd. for C 24H 21N 3 [M] +: 351.1735, found 351.1742.
Embodiment 13:
The syntheses and properties of Compound II per m:
Pyrroles is made into the identical indoles of mole number, and reflux 15 h, and other are with embodiment 9, and productive rate is 51% (86 mg). 1H NMR (300 MHz, CDCl 3): δ 11.8(s, 1H), 8.60(s, 1H), 8.48(s, 1H), 7.94-7.83(m, 3H), 7.41-7.31(m, 5H), 7.12(s, 1H), 5.88(s, 1H), 2.40(s, 3H), 2.31(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 158.7, 143.0, 141.6, 136.7, 135.8, 135.5, 128.4, 128.1, 127.5, 126.6, 126.5, 125.9, 123.7, 122.3, 121.7, 121.7, 119.3, 113.4, 112.0, 111.8, 111.0, 13.9, 11.6. HRMS (EI) Calcd. for C 23H 19N 3 [M] +: 337.1579, found 337.1578.
Embodiment 14:
The syntheses and properties of compound III a:
Method one:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add 2,4-dimethyl pyrrole (0.5 ml, 5 mmol) and 3-methoxyl group-5-chloro-2-aldehyde pyrroles (102 mg, 0.5 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(470 l, 5 mmol), back flow reaction 8 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 5/2 with ethyl acetate volume ratio) and obtain red-purple pressed powder dyestuff, productive rate is 43% (64 mg).
Method two:
In 50ml round-bottomed flask, under argon shield, add 20 ml ClCH 2cH 2cl, adds 2,4-dimethyl pyrrole (0.5 ml, 5 mmol) and 3-methoxyl group-5-chloro-2-imines pyrroles (102 mg, 0.5 mmol) respectively, and adds POCl 3(470 l, 5 mmol), back flow reaction 6 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 5/2 with ethyl acetate volume ratio) and obtain red-purple pressed powder dyestuff, productive rate is 38% (56 mg).
1H NMR (300 MHz, CDCl 3): δ 12.51(s, 1H), 12.03(s, 1H), 6.92(s, 1H), 6.04-5.90(m, 3H), 4.01(s, 3H), 2.54(s, 3H), 2.41(s, 3H), 2.33(s, 3H), 2.27(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 169.4, 158.9, 138.7, 136.2, 133.1, 130.5, 126.5, 124.5, 124.2, 116.2, 114.2, 111.6, 95.7, 58.5, 13.8, 12.3, 12.1, 11.6. HRMS (EI) Calcd. for C 18H 21N 3O [M] +: 295.1685, found 295.1682.
Fig. 2 is the single crystal diffraction figure of compound III a, has been made accurately pointing out by the structure of single crystal diffraction to compound, due to the impact of methyl steric hindrance, causes 2,4-dimethyl pyrrole five-ring place plane and two faces, pyrroles's methine place to be departed from a little.
Embodiment 15:
The syntheses and properties of compound III b:
Method one:
2,4-methylpyrrole is made into 2,4-dimethyl-3-N-ethyl pyrrole N-, and other are with embodiment 14 method one, and productive rate is 41% (72 mg).
Method two:
2,4-methylpyrrole is made into 2,4-dimethyl-3-N-ethyl pyrrole N-, and other are with embodiment 14 method two, and productive rate is 35% (61 mg).
1H NMR (300 MHz, CDCl 3): δ 12.45(s, 1H), 12.39(s, 1H), 11.87(s, 1H), 6.91(s, 1H), 6.08(s, 1H), 4.01(s, 3H), 2.53(s, 3H), 2.42-2.38(m, 7H), 2.28(s, 3H), 2.21(s, 3H), 1.06(t, J = 6.9 Hz, 6H). 13C NMR (75 MHz, CDCl 3): δ 165.5, 146.4, 144.5, 136.2, 135.3, 128.1, 127.4, 126.4, 123.9, 119.8, 117.8, 110.5, 92.4, 58.6, 17.5, 17.3, 15.6, 15.0, 11.8, 9.9. HRMS (EI) Calcd. for C 22H 29N 3O [M] +: 351.2311, found 351.2308.
Embodiment 16:
The syntheses and properties of compound III c:
In 50ml round-bottomed flask, under argon shield, add 20 ml ClCH 2cH 2cl, adds pyrroles (0.69 ml, 10 mmol) and 1-chloro-3-methoxyl group-7,9-dimethyl-8-ethyl two pyrroles (102 mg, 0.5 mmol) respectively, and adds POCl fast 3(470 l, 5 mmol), after back flow reaction 8 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 3/1 with ethyl acetate volume ratio) and obtain red-purple powder, productive rate is 41% (60 mg). 1H NMR (300 MHz, CDCl 3): δ 14.01(s, 1H), 12.54(s, 1H), 7.22(s, 1H), 7.02(s, 1H), 6.87(s, 1H), 6.33(s, 1H), 6.06(s, 1H), 3.99(s, 3H), 2.45-2.40(m, 5H), 2.22(s, 3H), 2.18(s, 3H), 1.07(d, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl 3): δ 178.9, 165.5, 137.0, 128.0, 127.1, 124.7, 122.8, 116.6, 113.1, 111.4, 93.0, 58.6, 25.0, 17.4, 14.9, 12.5, 10.0. HRMS (EI) Calcd. for C 18H 21N 3O [M] +: 295.1685, found 295.1686.
Embodiment 17:
The syntheses and properties of compound IV a:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add 2,4-dimethyl pyrrole (2 ml, 20 mmol) and 5-chloro-2-aldehyde pyrroles (129 mg, 1 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(940 l, 10 mmol), room temperature reaction 24 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 2/1 with ethyl acetate volume ratio) again and obtain blue solid dyestuff powder, productive rate 48% (63 mg). 1H NMR (300 MHz, CDCl 3): δ 12.95(s, 1H), 12.52(s, 1H), 12.40(s, 1H), 7.11(s, 1H), 6.80(s, 1H), 6.07(s, 1H), 5.92(s, 1H), 2.60(s, 3H), 2.42(s, 3H), 2.35(s, 3H), 2.28(s, 3H). 13C NMR (75 MHz, CDCl 3): δ 149.9, 147.5, 141.5, 138.6, 136.6, 130.9, 129.5, 126.5, 118.5, 118.2, 115.8, 115.5, 114.0, 14.5, 14.2, 13.4, 12.1. HRMS (EI) Calcd. for C 17H 19N 3 [M] +: 265.1579, found 265.1584.
Embodiment 18:
The syntheses and properties of compound IV b:
In 50ml round-bottomed flask, under argon shield, add 20 ml CH 2cl 2, add 2,4-dimethyl pyrrole (2 ml, 20 mmol) and 5-chloro-2-aldehyde pyrroles (129 mg, 1 mmol) respectively, and add the POCl be dissolved in 1 ml methylene dichloride fast 3(940 l, 10 mmol), back flow reaction 6 h, after reaction terminates, extraction, dry, concentrating under reduced pressure obtains thick product, be separated through column chromatography (stationary phase is silica gel, and elutriant is sherwood oil is the mixed system of 2/1 with ethyl acetate volume ratio) and obtain blue solid dyestuff powder, productive rate is 46% (74 mg). 1H NMR (300 MHz, CDCl 3): δ 12.91(s, 1H), 12.39(s, 1H), 12.29(s, 1H), 7.07(s, 1H), 6.80-6.76(m, 2H), 2.58-2.21(m, 16H), 1.07(s, 6H). 13C NMR (75 MHz, CDCl 3): δ 148.6, 146.8, 137.9, 136.0, 135.8, 129.3, 129.1, 127.6, 126.2, 126.0, 117.9, 117.3, 115.0, 17.4, 17.2, 14.8, 11.8, 9.9. HRMS (EI) Calcd. for C 21H 27N 3 [M] + : 321.2205, found 321.2201.
Shown case study on implementation is only for describing summary of the present invention, and do not limit the present invention, technician can implement from main separation in affiliated field.

Claims (2)

1. a preparation method for prodigiosin analogue, is characterized in that:
Raw material is made with 3-halogenated pyrrole or isoindole aldehyde or imine compound and pyrrole derivatives, their mol ratio is 1:10-100, in organic solvent, under magnetic agitation, under temperature 20 DEG C ~ 80 DEG C conditions, under Lewis acid condition, react 1 ~ 24 hour, through extraction, washing, drying, concentrating under reduced pressure, then be separated obtained prodigiosin analogue through silica gel column chromatography;
The structure of described prodigiosin analogue is formula III and IV:
In general formula III, IV,
R 1, R 3, R 5, R 7for CH 3, R 2, R 6for H;
R 1, R 3, R 5, R 7for CH 3, R 2, R 6for CH 2cH 3;
Described pyrrole derivatives is 2,4-dimethyl pyrrole, 2,4-dimethyl-3-N-ethyl pyrrole N-s;
In described raw material, 3-halogenated pyrrole or isoindole aldehyde or imine compound molecular structure are as general formula V, VI:
In general formula V and VI, Y is H, Z is H or methoxyl group, X=Cl, Br, R 8=R 9=C 1-12straight chain or branched-chain alkyl;
Described Lewis acid is selected from POCl 3, CH 3cOOH, CH 3sO 3h, CF 3sO 3h.
2. the preparation method of a kind of prodigiosin analogue according to claim 1, is characterized in that:
Described organic solvent is selected from methylene dichloride, trichloromethane.
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