CN102731484A - Preparation method for prodigiosins analogue - Google Patents
Preparation method for prodigiosins analogue Download PDFInfo
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- CN102731484A CN102731484A CN201210201792XA CN201210201792A CN102731484A CN 102731484 A CN102731484 A CN 102731484A CN 201210201792X A CN201210201792X A CN 201210201792XA CN 201210201792 A CN201210201792 A CN 201210201792A CN 102731484 A CN102731484 A CN 102731484A
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- 0 CC([C@](C)[C@](C)(C=CC=C)C(NC)=C*CN)N Chemical compound CC([C@](C)[C@](C)(C=CC=C)C(NC)=C*CN)N 0.000 description 2
- SRQYZVKVPAGUKI-UHFFFAOYSA-N CCC1=C(C)NCC1 Chemical compound CCC1=C(C)NCC1 SRQYZVKVPAGUKI-UHFFFAOYSA-N 0.000 description 1
- UIXNDAUVBXNUFF-JLHYYAGUSA-N CCC1C(/C(/C)=N/CC)=CC=CC1 Chemical compound CCC1C(/C(/C)=N/CC)=CC=CC1 UIXNDAUVBXNUFF-JLHYYAGUSA-N 0.000 description 1
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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
Technical field:
The present invention relates to a kind of preparation method of prodigiosin analogue, belong to organic chemical industry and fine chemical technology field.
Background technology:
Prodigiosin (Prodigiosins; Be called for short PG) and analogue be one type of natural pigment that contains methoxyl group pyrrole skeleton structure; It is the secondary metabolite of some actinomycetes, husky thunder bacterium and other bacteriums; Having multiple biological activitys such as very strong antitumor, antibacterium, antimycotic, malaria and immunosuppression, is one type of potential cancer-resisting substance.Recent study finds that prodigiosin has the autoimmunity depression activity and various human cancer cells such as adenocarcinoma of lung, prostate cancer are had the resistance effect, under identical effect dosage, does not have any toxic action to normal cell.
Prodigiosin and analogue thereof have become a kind of PTS that has development potentiality.But the apoptosis of prodigiosin inducing cancer cell under extremely low concentration, can kill the most of planktonic organism that causes red tide fast in addition, is demonstrating huge power aspect the improvement of water pollution.Research shows; The natural pigment prodigiosin has good dye uptake and anti-microbial property on 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, so dyestuff or dye additive that prodigiosin can be used as multifunction environment-protection type are applied to dyeing.It can keep the long period in sour environment, can in human body, transport Cl
-(Chem. Commun. 2005,30,5781-5783.; Chem.Commun. 2005,30,3773-3775.) and cause Cu
2+The two bond cleavages of inducing DNA separate etc. (Chem Res Toxicl, 2002,15,2480-2486).
The PG cell toxicant characteristic of different structure is different.The difference replacement of PGC-6 methoxyl group also can exert an influence to its effectiveness, when its is replaced by longer alkoxyl group, and active meeting decline.The molecular modification of carrying out according to these achievements in research has formed new PG verivate, and its activity index exceeds several times than parent molecule, and (Chembiochem. 2001,2,60-68).Wherein the prodigiosin verivate Obatoclax of synthetic has got into clinical class as multiple cancer treatment drugs and the I/II phase has studied (Chem. Eur. J. 2011,17,14074).Its another analogue PNU-156804 demonstrates than higher immunosuppressive activity of prodigiosin and analogue thereof and lower toxicity (J. Med. Chem. 2000,43,2557).Therefore the research of prodigiosin verivate and analogue has broad application prospects in fields such as cancer therapy.
The sixties in 20th century is early stage, and (J. Am. Chem. Soc. 1962,84 635-642) first through the complete synthesis prodigiosin that obtained, has started the complete synthesis beginning of prodigiosin in Rapoport seminar.The whole process of experiment was divided into for 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) proposed the scheme of new preparation PG analogue according to three kinds of different fracture modes of tripyrrole precursor structure: (1) links to each other the C ring to join through the Suzuki coupling then earlier and closes (simulating the biosynthesizing route is the B ring to be encircled with A to link to each other earlier) again with the A loops in the past and get the PG precursor substance with the B ring, the combined coefficient raising, but can not be used for the undecyl PG of synthesis of natural; (2) utilize commercial 4-methoxy-3-Pyrrolin-2-one to obtain prodigiosin verivate and analogue precursor 4-methoxy-2 thereof through two-step reaction; 2'-bipyrrole-5-carboxaldehyde has obtained different PG verivate and analogue with different pyrroles and verivate thereof with its coupling couplet then.
Though the chemosynthesis research about prodigiosin and analogue thereof has obtained certain achievement, chemical synthesis fails to prepare in a large number prodigiosin verivate and analogue always.The method of present existing synthetic prodigiosin verivate, complicated steps, and need use the catalytic Suzuki coupling of precious metal palladium, substrate restricted application.
Summary of the invention:
The invention provides a kind of compound method of novel simplification, promptly, improved combined coefficient, for prodigiosin and analogue industrial mass production lay the foundation through the method for synthetic prodigiosin verivate of Lewis acid and analogue thereof.
The 3-halogenated pyrrole of different substituents or isoindole aldehyde or imine compound and pyrrole derivatives are made raw material, and their mol ratio is 1:10-100, in organic solvent; Under the magnetic agitation, under 20 ℃ ~ 80 ℃ conditions of temperature, under the Lewis acid condition; Reacted 1 ~ 24 hour, through extraction, washing; Drying, concentrating under reduced pressure separates making the prodigiosin analogue again through silica gel column chromatography.
Said organic solvent is selected from methylene dichloride, trichloromethane, 1,2-methylene dichloride.
Said Lewis acid is selected from POCl
3, CH
3COOH, CH
3SO
3H, CF
3SO
3H.
3-halogenated pyrrole or isoindole aldehyde or imine compound molecular structure such as general formula V, VI in the said raw material:
X=Cl, Br, I, CF among the general formula A
3SO
3Definition is identical in Y, Z and the general formula I; R
8=R
9=H, C
1-12Straight chain or branched-chain alkyl, C
1-12Naphthenic base, (CH
2)
mO (CH
2)
nH.
The prodigiosin verivate that the present invention is made and the general structure of analogue are I:
In the general formula I: Y, Z are H, C
1-12Alkyl, naphthenic base ,-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
7Be H, C
1-12Alkyl, naphthenic base, 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
1-12Naphthenic base, (CH
2)
mO (CH
2)
nH; N, m=0 – 15; M=H, Li, Na, K, NH
4
The preferred structure of prodigiosin verivate and analogue is formula II, III and IV in the said structure general formula:
Among the 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
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
R
4Be CH
3The time,
R
1, R
2, R
3, R
4, R
5, R
6, R
7Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
R
1, R
3Be CH
3, R
2, R
4, R
5, R
6, R
7Be H;
Among general formula III, the IV,
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
The present invention compared with prior art has that technology is simple, combined coefficient is high, for prodigiosin and analogue industrial mass production lay the foundation.
Description of drawings
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 present invention is described further.
Embodiment 1:
Synthetic and the sign of compound I Ia:
Method one:
In the 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 adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(470 l, 5 mmol), react 16 h after, after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining yellow powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), productive rate is 61% (79 mg).
?
Method two:
In the 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) are behind back flow reaction 5 h, after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining yellow powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), 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:
Synthetic and the sign of compound I Ib:
Method one:
In the 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 adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(470 l, 5 mmol), react 2 h after, after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining red powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), productive rate is 75% (118 mg).
Method two:
In the 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) are behind back flow reaction 2 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate obtaining red powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), 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:
Synthetic and the sign of compound I Ic:
With 2, the 4-dimethyl pyrrole make into mole number identical 2,4-dimethyl--3-N-ethyl pyrrole N-, other are with embodiment 2 methods one, productive rate is 73% (135 mg).
Method two:
With 2, the 4-dimethyl pyrrole make into mole number identical 2,4-dimethyl--3-N-ethyl pyrrole N-, other are with embodiment 2 method twos, 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:
Synthetic and the sign of compound I Id:
Method one:
With 2, the 4-dimethyl pyrrole makes 2 into, and 4-dimethyl--3-acetyl pyrrole, elutriant are that sherwood oil and ETHYLE ACETATE volume ratio are that 2/1 mixed system is crossed post, and other are with embodiment 2 methods one, and productive rate is 57% (114 mg).
Method two:
With 2, the 4-dimethyl pyrrole make into mole number identical 2,4-dimethyl--3-acetyl pyrrole, elutriant are that sherwood oil and ETHYLE ACETATE volume ratio are that 2/1 mixed system is crossed post, other are with embodiment 2 method twos, 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:
Synthetic and the sign of compound I Ie:
Method one:
In the 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 adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(470 l, 5 mmol) react 16 h, after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining red powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), productive rate is 78% (106 mg).
Method two:
In the 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 is after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining red powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), 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:
Synthetic and the sign of compound I If:
Method one:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add 2 respectively, 4-dimethyl pyrrole (0.5 ml, 5 mmol) and 5-chloro-2-ethanoyl isoindole (97 mg, 0.5 mmol), and adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(470 l, 5 mmol), back flow reaction 2 h are after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate obtaining red powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system), productive rate is 79% (130 mg).
Method two:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add 2 respectively, 4-dimethyl pyrrole (0.5 ml, 5 mmol) and 5-chloro-2-imines isoindole (125 mg, 0.5 mmol), and add POCl
3(470 l, 5 mmol), back flow reaction 2 h are after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system) 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:
Synthetic and the sign of compound I Ig:
Method one:
With 2, the 4-dimethyl pyrrole make into mole number identical 2,4-dimethyl--3-N-ethyl pyrrole N-, other are with embodiment 6 methods one, productive rate is 72% (138 mg).
Method two:
With 2, the 4-dimethyl pyrrole make into mole number identical 2,4-dimethyl--3-N-ethyl pyrrole N-, other are with embodiment 6 method twos, 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:
Synthetic and the sign of compound I Ih:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add respectively the pyrroles (0.69 ml, 10mmol) with 1-chloro-7,9-dimethylbiphenyl two pyrroles (128 mg, 0.5 mmol), and add POCl fast
3(470 l, 5 mmol), room temperature reaction 12 h are after reaction finishes; Extraction, drying, concentrating under reduced pressure obtains thick product; Separate through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system) 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:
Synthetic and the sign of compound I Ii:
1-chloro-7,9-dimethylbiphenyl two pyrroles are made 1-chloro-7 into, 9-dimethyl--8-ethyl benzodipyrrole, 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:
Synthetic and the sign of compound I Ij:
1-chloro-7,9-dimethylbiphenyl two pyrroles are made 1-chloro-7 into, 9-dimethyl--8-ethanoyl benzo two pyrroles, 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 I Ij, through single crystal diffraction the structure of compound has been made accurately and having pointed out, and crystalline structure shows that this compound possesses the higher level conjugacy.
Embodiment 11:
Synthetic and the sign of compound I Ik:
The pyrroles make into mole number identical 2,4-dimethyl--3-N-ethyl pyrrole N-, other are with embodiment 9, 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:
Synthetic and the sign of compound I Il:
Make the pyrroles into mole number identical 3-skatole, other are with embodiment 9; Back flow reaction 15 h, after reaction finishes, extraction; Drying, concentrating under reduced pressure obtain thick product, and (stationary phase is a silica gel through column chromatography again; Elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 4/1 mixed system) separate 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:
Synthetic and the sign of compound I Im:
Make the pyrroles into mole number identical indoles, 15 h that reflux, 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:
Synthetic and the sign of compound III a:
Method one:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add 2 respectively, 4-dimethyl pyrrole (0.5 ml, 5 mmol) and 3-methoxyl group-5-chloro-2-aldehyde pyrroles (102 mg, 0.5 mmol), and adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(470 l, 5 mmol), back flow reaction 8 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate obtaining red-purple pressed powder dyestuff again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 5/2 mixed system), productive rate is 43% (64 mg).
Method two:
In the 50ml round-bottomed flask, under argon shield, add 20 ml ClCH
2CH
2Cl adds 2 respectively, 4-dimethyl pyrrole (0.5 ml, 5 mmol) and 3-methoxyl group-5-chloro-2-imines pyrroles (102 mg, 0.5 mmol), and add POCl
3(470 l, 5 mmol), back flow reaction 6 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate obtaining red-purple pressed powder dyestuff again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 5/2 mixed system), 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, through single crystal diffraction the structure of compound has been made accurately and having pointed out, because the influence of methyl sterically hindered causes 2,4-dimethyl pyrrole five-ring plane, place and two pyrroles's methines place face depart from a little.
Embodiment 15:
Synthetic and the sign of compound III b:
Method one:
2, the 4-methylpyrrole makes 2 into, 4-dimethyl--3-N-ethyl pyrrole N-, and other are with embodiment 14 methods one, and productive rate is 41% (72 mg).
Method two:
2, the 4-methylpyrrole makes 2 into, 4-dimethyl--3-N-ethyl pyrrole N-, and other are with embodiment 14 method twos, 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:
Synthetic and the sign of compound III c:
In the 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 respectively, 9-dimethyl--8-ethyl two pyrroles (102 mg, 0.5 mmol), and add POCl fast
3(470 l, 5 mmol) are behind back flow reaction 8 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate obtaining the red-purple powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 3/1 mixed system), 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:
Synthetic and the sign of compound IV a:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add 2 respectively, 4-dimethyl pyrrole (2 ml, 20 mmol) and 5-chloro-2-aldehyde pyrroles (129 mg, 1 mmol), and adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(940 l, 10 mmol), room temperature reaction 24 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 2/1 mixed system) again and obtain the 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:
Synthetic and the sign of compound IV b:
In the 50ml round-bottomed flask, under argon shield, add 20 ml CH
2Cl
2, add 2 respectively, 4-dimethyl pyrrole (2 ml, 20 mmol) and 5-chloro-2-aldehyde pyrroles (129 mg, 1 mmol), and adding has been dissolved in the POCl in the 1 ml methylene dichloride fast
3(940 l, 10 mmol), back flow reaction 6 h; After reaction finishes, extraction, drying; Concentrating under reduced pressure obtains thick product; Separate obtaining the blue solid dyestuff powder again through column chromatography (stationary phase is a silica gel, and elutriant is a sherwood oil with the ETHYLE ACETATE volume ratio is 2/1 mixed system), 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 in case study on implementation only be used to describe summary of the present invention, do not limit the present invention, the technician can independently select in affiliated field to implement.
Claims (6)
1. the preparation method of a prodigiosin analogue is characterized in that:
Make raw material with 3-halogenated pyrrole or isoindole aldehyde or imine compound and pyrrole derivatives, their mol ratio is 1:10-100, in organic solvent; Under the magnetic agitation, under 20 ℃ ~ 80 ℃ conditions of temperature, under the Lewis acid condition; Reacted 1 ~ 24 hour, through extraction, washing; Drying, concentrating under reduced pressure separates making the prodigiosin analogue again through silica gel column chromatography.
2. the preparation method of a kind of prodigiosin analogue according to claim 1 is characterized in that:
Said organic solvent is selected from methylene dichloride, trichloromethane, 1,2-methylene dichloride.
3. the preparation method of a kind of prodigiosin analogue according to claim 1 is characterized in that:
Said Lewis acid is selected from POCl
3, CH
3COOH, CH
3SO
3H, CF
3SO
3H.
4. the preparation method of a kind of prodigiosin analogue according to claim 1 is characterized in that:
3-halogenated pyrrole or isoindole aldehyde or imine compound molecular structure such as general formula V, VI in the said raw material:
X=Cl, Br, I, CF among the general formula A
3SO
3Definition is identical in Y, Z and the general formula I; R
8=R
9=H, C
1-12Straight chain or branched-chain alkyl, C
1-12Naphthenic base, (CH
2)
mO (CH
2)
nH.
5. the general structure of the made prodigiosin analogue of claim 1 is I:
In the general formula I: Y, Z are H, C
1-12Alkyl, naphthenic base ,-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
7Be H, C
1-12Alkyl, naphthenic base, 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
1-12Naphthenic base, (CH
2)
mO (CH
2)
nH; N, m=0 – 15; M=H, Li, Na, K, NH
4
6. according to right 5 described analogues, it is characterized in that: the structure of described analogue is formula II, III and IV:
Among the 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
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
R
4Be CH
3The time,
R
1, R
2, R
3, R
4, R
5, R
6, R
7Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
R
1, R
3Be CH
3, R
2, R
4, R
5, R
6, R
7Be H;
Among general formula III, the IV,
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be H;
R
1, R
3, R
5, R
7Be CH
3, R
2, R
4, R
6Be CH
2CH
3
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181752A (en) * | 1996-02-15 | 1998-05-13 | 法玛西雅厄普约翰公司 | Process for the prepn. of 2, 2' -bipyrrolyl-pyrromethene (prodigiosins) derivatives |
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|---|---|---|---|---|
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| CN103145719A (en) * | 2013-02-27 | 2013-06-12 | 中国科学院化学研究所 | Preparation method of prodigiosin derivative |
| CN103145719B (en) * | 2013-02-27 | 2015-04-29 | 中国科学院化学研究所 | Preparation method of prodigiosin derivative |
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