FIELD OF THE INVENTION:
[0001] The present invention relates to field of novel compounds of the pyrroloquinoline alkaloids group and process for the preparation thereof. Particularly, the present invention relates to novel anti-malarial compounds and process of synthesis thereof. Further, the present invention also discloses the process for the synthesis of known antimalarial natural products and their potential antimalarial analogues.
Background and prior art:
[0002] Alkaloids are highly important pharmacophores and currently available methods for the synthesis of substituted pyridine based alkaloids are tedious, lengthy and low yielding.
[0003] The natural products Marinoquinoline A-F, Aplidiopsamine A and related natural products have very good antimalarial activity but till date their synthesis is not known.
[0007] But there is a need in the art to provide synthetic routes of synthesis of anti-malarial compounds isolated from natural resources such that therapies are available for drug resistant strains of plasmodium. It would be advantageous if such processes are simple, with reactants freely available and result in good yields and selectivity.
[0008] Further there is a continuous need for novel compounds that possess anti-malarial properties, such that clinicians have alternatives available to combat drug resistance in subjects infected with malaria.
Object of invention:
[0009] The main object of the present invention is to provide novel compounds of the pyrroloquinoline alkaloids group and process for the preparation thereof.
[0010] Another object of the invention is to provide novel compounds of the pyrroloquinoline alkaloids group that possess therapeutic activity.
[0011] Another object of the invention is to provide novel and efficient palladium catalyzed C-H activation methodology for the synthesis of substituted Pyrroloquinoline based alkaloids.
SUMMARY OF THE INVENTION
[0012] Accordingly, the present invention provides a compound of formula I,
wherein R, R1, R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
X is selected from halide or hydrogen
R3 is of formula III, and
R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
and pharmaceutically acceptable salt thereof.
[0013] In one embodiment of the present invention, a process for the preparation of compound of formula I is provided,
said process comprising the following steps:
- a. refluxing ketone of formula
wherein R, is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl with aniline of formula
wherein R is selected from H, halide, alkyl, aryl and hetero alkyl/aryl,
X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3 in mole ratio 1:1 in a solvent preferably dry toluene for a period ranging between 12-24 hours followed by work up to obtain corresponding imine of formula
wherein R is selected from H, halide, alkyl, aryl and hetero alkyl/aryl,
X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3,
- b. Catalyzing the conversion of corresponding imine of step (a) in the presence of Pd catalyst, ligand, base and solvent at temperature ranging between 100-120°C for a period between 8-24 hrs to obtain corresponding quinoline of formula;
wherein R is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl, - c. Catalyzing the conversion of quinoline compound of step (b) to obtain corresponding substituted quinoline of formula
- d. reacting substituted quinoline obtained in step (d) with substituted or unsubstituted quinazolin-4(3H)-one compound to obtain a product of formula I.
R' is of formula III, and
R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,
- e. optionally deprotecting the -SO2Ph group by methanol and K2CO3.
[0014] One embodiment of the present invention relates to the process according to claim 2, wherein the yield is in the range of 40 % to 98 %.
[0015] In another embodiment of the present invention the catalyst is preferably Pd(OAc)
2 in the range of 1 mol% to 20 mol%, and the catalyst is used in the presence of a ligand.
[0016] In still another embodiment of the present invention the ligand is selected from triphenyl phosphate, PPh
3, Neocuproine, Tricyclohexylphosphine PCy
3, preferably PPh
3 in the range of 1 mol% to 40 mol%.
[0017] In yet another embodiment of the present invention the base is selected from K
2CO
3, Cs
2CO
3, Ag
2CO
3, KOtBu, preferably Ag
2CO
3 in the range of 1 mol% to 200 mol%.
[0018] In yet another embodiment of the present invention the solvent is chosen from 1,4-dioxane, dry toluene, dimethylformamide DMF, Benzene, tetrahydrofuran THF, preferably 1,4-dioxane.
[0019] In yet another embodiment of the present invention the catalyst is N-bromo succinimide NBS and radical initiators are Aza iso butyro nitrile (AIBN), Aza Bis cyanide (ABCN), Benzyl peroxide (BPO).
[0020] Also described is a compound of formula I,
wherein R, R1, -R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
X is selected from halide or hydrogen,
R3 is of formula III, and
wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
and pharmaceutically acceptable salt thereof useful as antimalarial agents.
[0021] Further described is a compound of formula I,
wherein R, R1, -R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
X is selected from halide or hydrogen,
R3 is of formula III,
wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,.
and pharmaceutically acceptable salt thereof useful as antimycobacterial agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022]
Figure 1: 1H NMR spectra of compound 8
Figure 2: 13C NMR spectra of compound 8
Figure 3: DEPT NMR spectra of compound 8
Figure 4: 1H NMR spectra of compound of table 2, entry 1
Figure 5: 13C NMR spectra of compound of table 2, entry 1
Figure 6: DEPT NMR spectra of compound of table 2, entry 1
Figure 7: 1H NMR spectra of compound of table 2, entry 2
Figure 8: 13C NMR spectra of compound of table 2, entry 2
Figure 9: DEPT NMR spectra of compound of table 2, entry 2
Figure 10: 1H NMR spectra of compound of table 2, entry 3
Figure 11: 13C NMR spectra of compound of table 2, entry 3
Figure 12: DEPT NMR spectra of compound of table 2, entry 3
Figure 13: 1H NMR spectra of compound of table 2, entry 4
Figure 14: 13C NMR spectra of compound of table 2, entry 4
Figure 15: DEPT NMR spectra of compound of table 2, entry 4
Figure 16: 1H NMR spectra of compound of table 2, entry 5
Figure 17: 13C NMR spectra of compound of table 2, entry 5
Figure 18: DEPT NMR spectra of compound of table 2, entry 5
Figure 19: 1H NMR spectra of compound of table 2, entry 6
Figure 20: 13C NMR spectra of compound of table 2, entry 6
Figure 21: DEPT NMR spectra of compound of table 2, entry 6
DETAILED DESCRIPTION OF THE INVENTION
[0023] With the view to provide novel alternatives in antimalarial therapy,, the present invention provides herein novel compounds of general formula I, referred hereinafter as NCLite-M1.
[0024] The present invention provides the novel compounds and pharmaceutically acceptable salt thereof. of general formula I
wherein R, R1, R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,
X is selected from halide or hydrogen,
R3 is of formula III, wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,.
[0025] In the present invention compound of formula I consists of NCLite-M1 as depicted herein.
[0026] The present invention provides a process for preparation of novel compounds of formula I beginning from compound 2,
2-Iodo-N-(1-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)ethylidene)aniline,
said process comprising:
- a. Refluxing a compound containing a carbonyl group selected from ketone and an aniline in dry solvent, particularly, toluene followed by work-up to obtain compound 2;
- b. Catalyzing the conversion of compound 2 of step (a) in the presence of Pd catalyst, ligand, base and solvent to obtain corresponding quinolone compound 3;
[0027] The process for the preparation of compound I & II is depicted in Scheme 1.
[0028] The process of preparation of compound of formula II is depicted below in Scheme 2 which leads to the formation of Aplidiopsamine A and Marinoquinoline A.
[0029] The process of Scheme 1 may lead to formation of NCLite-M1 is depicted below in the Scheme 3.
[0030] In an aspect of invention, the yield of compound of formula I may be in the range of 25% to 98%.
[0031] In an aspect of invention, the yield of compound of formula II may be in the range of 40% to 98%.
[0032] In a preferred embodiment, the Pd catalyst used in the process above is Pd(OAc)
2 in the range of 1 mol% to 20 mol%.
[0033] In a preferred embodiment, the ligand used in the process above is selected from PPh
3, Neocuproine, and PCy3 in the range of 1 mol% to 40 mol%, and is preferably PPh
3 in the range of 1 mol% to 40 mol%.
[0034] In a preferred embodiment, the base used in the process above is selected from K
2CO
3, Cs
2CO
3, Ag
2CO
3, KOtBu in the range of 1 mol% to 200 mol%, and is preferably Ag
2CO
3 in the range of 1 mol% to 200 mol%.
[0035] In a preferred embodiment, the solvent used in the process above is chosen from 1, 4-dioxane, dimethyl formamide, DMF, Benzene, tetrahydrofuran THF and is preferably 1,4-dioxane.
[0036] The catalyst used for the process of step (c) may be NBS and radical initiator like AIBN, ABCN and is preferably BPO catalyzed NBS.
[0037] In an aspect of the invention, the compound of formula I & II may possess activity against other known or unknown pathogens and are useful in treating a subject in need of a treatment against such pathogens.
[0038] The compound NCLite-M1 was tested for anti-malarial activity against a known parasite Plasmodium falciprum 3D7, which is chloroquine sensitive strain and the results are tabulated herein.
[0040] Described is also a pharmaceutical composition comprising a compound of formula (I & II), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
[0041] The pharmaceutical compositions described can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,
[0042] Accordingly, compound of formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
[0043] Pharmaceutical compositions described are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
[0044] The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention in any manner.
Examples:
Example 1
1-(1-(methylsulfonyl)-1H-pyrrol-2-yl)ethanone (1):
[0045]
Procedure:
[0046] To a solution of acetic anhydride (1.3 mL, 0.13 mmol) in 5 mL of 1,2-dichloroethane at 25 °C was added BF
3-OEt
2 (3.4 mL, 0.27 mmol). The mixture was stirred for 10 min, a solution of methylsulfonyl protected pyrrole (500 mg, 0.61 mmol) in 2 mL of 1,2-dichloroethane was added, and the mixture was stirred at 25 °C for 90 min. The reaction was quenched with cold water, and the reaction products were extracted into dichloromethane. The residue remaining after concentration at reduced pressure was chromatographed in a column of silica gel (70-230 mesh), eluting with ethyl acetate-petroleum ether (1:9) to afford 1-(1-(methylsulfonyl)-1H-pyrrol-2-yl)ethanone (440 mg, 68%).
R
f = 0.50 (4:1 PE:EtOAc); MP 62-64 °C; IR(Nujol) :
vmax 2925, 2854, 1711, 1679, 1539, 1459, 1375, 938, 847, 768 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 2.49 (s, 3H), 3.72 (s, 3H), 6.28 (t,
J = 3.7 Hz, 1H), 7.11 (dd,
J = 1.7, 3.7 Hz, 1H), 7.56 (dd,
J = 1.8, 3.2 Hz, 1H);
13C NMR (125 MHz, CDCl
3): δ 27.2, 43.1, 110.1, 124.8, 129.9, 133.2, 187.3; HRMS-ESI(m/z): calcd for [C
7H
9O
3NS+H]
+, 188.0376; found 188.0379.
Example 2
2-Iodo-N-(1-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)ethylidene)aniline (2):
Procedure:
[0047] To a dry two
neck round bottom flask, equipped with Dean-Stark apparatus, containing freshly activated 4Å molecular sieves, ketone
1 (100 mg, 0.40 mmol), Iodoaniline (439 mg, 2.00 mmol) and
p-toluenesulphonic acid (8 mg, 0.04 mmol), was added dry toluene under argon atmosphere and the reaction mixture was refluxed for 18 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Evaporation of ethyl acetate followed by silica gel chromatography (49:1 PE:EtOAc) furnished 2 as yellow solid (145 mg, 80%).
R
f = 0.50 (19:1 PE:EtOAc); MP 145-147 °C; IR(Nujol):
vmax 2928, 2851, 1456, 1374, 721 cm
-1;
1H NMR (400 MHz, Acetone-D
6): δ 2.03 (s, 3H), 6.49 (t,
J = 3.1 Hz, 1H), 6.70 (dd,
J = 1.5, 7.8 Hz, 1H), 6.85 (ddd,
J = 1.5, 7.8 Hz, 1H), 7.03 (dd,
J = 1.8, 3.7 Hz, 1H), 7.36-7.48 (m, 3H), 7.63 (t,
J = 7.5 Hz, 1H), 7.75-7.81 (m, 4H);
13C NMR (100 MHz, Acetone-D
6): δ 19.5, 89.1, 111.9, 119.6, 120.5, 125.6, 127.8, 129.0, 129.6, 129.8, 134.1, 135.7, 139.5, 141.4, 152.3, 158.5; HRMS-ESI(m/z): calcd for [C
18H
15O
2N
2IS+H]
+, 450.9972; found 450.9960.
Example 3
4-Methyl-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (3):
[0048]
Procedure A (in round bottom flask with reflux condenser):
[0049] To a two neck round bottom flask, equipped a with a water condenser, was added Pd(OAc)
2 (2 mg, 0.01 mmol), PPh
3 (6 mg,0.02 mmol) and Ag
2CO
3 (61 mg, 0.22 mmol). To this was added solution of
2 (50 mg, 0.11 mmol) in 1,4-dioxane (1 ml) by means of a syringe and the reaction mixture was refluxed for 2 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (4:1 PE:EtOAc) to yield
3 as a brown solid (32 mg, 91%).
Procedure B (in sealed tube):
[0050] To a sealed tube containing magnetic stirring bar was added Pd(OAc)
2 (1 mg, 2 mol%), PPh
3 (2 mg, 4 mol%) and Ag
2CO
3 (24 mg, 0.09 mmol). To this was added solution of 2 (100 mg, 0.22 mmol) in 1,4-dioxane (1 ml) by means of a syringe and the tube was sealed and heated at 120 °C for 10 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (4:1 PE:EtOAc) to yield 3 as a brown solid (67 mg, 93%).
R
f = 0.50 (7:3 PE:EtOAc); MP 143-145 °C; IR(CHCl
3) :
vmax 3148, 3060, 2928, 2851, 1618, 1577, 1366, 1176, 990, 751, 685, 592 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 2.90 (s, 3H), 7.22 (d,
J = 3.7 Hz, 1H), 7.43 (t,
J = 7.9 Hz, 2H), 7.54 (q,
J = 7.0 Hz, 2H), 7.62 (m, 1H), 7.68 (d,
J = 7.3 Hz, 2H), 8.02 (d,
J = 8.2 Hz, 1H), 8.05-8.09 (m, 2H);
13C NMR (125 MHz, CDCl
3): δ 26.1, 105.6, 121.5, 122.8, 126.1, 126.4, 128.0, 128.53, 128.55, 129.5, 131.8, 134.1, 134.7, 139.3, 143.3, 146.7; HRMS-ESI(m/z): calcd for [C
18H
14O
2N
2S+H]
+, 323.0849; found 323.0839.
Example 4
Marinoquinoline A:
[0051]
Procedure:
[0052] To the solution of
3 (50 mg, 0.15 mmol) in MeOH (2 ml) was added K
2CO
3 (42 mg, 0.31 mmol). The reaction mixture was refluxed for 1 h. Then it was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using silica gel column chromatography (1:1 PE:EtOAc) to obtain Marinoquinoline A as a white solid (27 mg, 96%).
R
f = 0.30 (1:1 PE:EtOAc); MP 237-239 °C; IR(Nujol):
vmax 3379, 2917, 2857, 1465, 1451, 1377, 751 cm
-1;
1H NMR (500 MHz, Acetone-D
6): δ 2.87 (s, 3H), 7.15 (d,
J = 2.8 Hz, 1H), 7.50-7.57 (m, 2H), 7.62 (d,
J = 2.7 Hz, 1H), 8.05 (dd,
J = 2.1, 7.3 Hz 1H), 8.25 (dd,
J = 2.1, 7.3 Hz, 1H), 11.29 (br s, 1H);
13C NMR (125 MHz, Acetone-D
6): δ 21.0, 101.9, 123.7, 124.1, 125.7, 126.1, 127.4, 128.5, 129.5, 129.7, 143.3, 146.8; HRMS-ESI(m/z): calcd for [C
12H
10N
2+H]
+, 183.0917; found 183.0914.
Example 5
4-(Bromomethyl)-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (4):
[0053]
Procedure:
[0054] To the solution of
3 (60 mg, 0.18 mmol) in dry carbon tetrachloride (3 ml) was added NBS (132 mg, 0.74 mmol) and radical initiator benzoyl peroxide (9 mg, 0.03 mmol). The reaction mixture was refluxed for an 8 h and then cooled to room temperature. The precipitated solid was filtered of and the filtrate was concentrated. Crude product was rapidly passed through silica gel column (7:1.5 PE:EtOAc) to obtain 4 (56 mg, 75%). The purity of the obtained product was more than 90% and it was used for further reaction as soon as possible to avoid decomposition.
R
f = 0.60 (7:3 PE:EtOAc); IR (Nujol):
vmax 2923, 2862, 1459, 1374, 1185, 1083, 727, 587 cm
-1;
1H NMR (400 MHz, CDCl
3): δ 5.30 (s, 2H), 7.28 (d,
J = 3.4 Hz, 1H), 7.44 (t,
J = 7.6 Hz, 2H), 7.54 (d,
J = 7.5, 1H), 7.61 (d,
J = 8.3 Hz, 1H), 7.65-7.71 (m, 1H), 7.75 (d, J = 8.3 Hz, 2H), 8.06 (d,
J = 3.8 Hz, 1H), 8.10 (t,
J = 8.5 Hz, 2H);
13C NMR (100 MHz, CDCl
3): δ 33.9, 106.9, 122.1, 122.9, 126.6, 127.4, 128.6, 129.3, 129.6, 129.8, 132.9, 134.3, 136.6, 138.1, 143.5, 144.9; HRMS-ESI(m/z): calcd for [C
18H
13O
2N
2SBr(79)+H]
+, 400.9959; found 400.9942 and [C
18H
13O
2N
2SBr(81)+H]
+, 402.9939; found 402.9917.
Example 6
4-((6-Chloro-9H-purin-9-yl)methyl)-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (5):
[0055]
Procedure:
[0056] A two neck dry round bottom flask containing 6-chloropurine (38 mg, 0.24 mmol), K
2CO
3 (43 mg, 0.31 mmol) and dry DMF (0.5 ml) was stirred at 50 °C under argon atmosphere for 1 h. It was then cooled to room temperature and to the reaction mixture was added a solution of
4 (50 mg, 0.12 mmol) in dry DMF (0.5 ml). The reaction mixture was heated to 50 °C and stirred at the same temperature for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent the crude compound was purified using silica gel column chromatography (4:1 PE:EtOAc) to yield 5 as off white solid (42 mg, 70%).
R
f = 0.40 (3:2 PE:EtOAc); MP 223-225 °C; IR(Nujol):
vmax 2923, 1462, 1376, 1176, 727 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 6.17 (s, 2H), 7.31 (d,
J = 3.7 Hz, 1H), 7.52 (t,
J = 7.9 Hz, 2H), 7.54-7.58 (m, 2H), 7.64 (t,
J = 7.3, 1H), 7.70-7.74 (m, 1H), 7.82(d,
J = 7.6, 2H), 8.05 (d,
J = 3.7 Hz, 1H), 8.06-8.09 (m, 1H), 8.31(s, 1H), 8.58 (s, 1H);
13C NMR (125 MHz, CDCl
3): δ 47.9, 107.2, 121.9, 122.8, 126.4, 126.5, 127.4, 128.5, 129.5, 129.9, 131.2, 132.3, 134.6, 136.2, 138.4, 141.1, 142.8, 147.6, 150.5, 151.7, 152.5; HRMS-ESI(m/z): calcd for [C
23H
15O
2N
6ClS+H]
+, 475.0738; found 475.0727.
Example 7
Aplidiopsamine A (6):
[0057]
Procedure:
[0058] To a dry sealed tube containing
5 (20 mg, 0.04 mmol) was added saturated methanolic ammonia solution (5 ml). The tube was sealed with Teflon cap and the reaction mixture was refluxed at 150 °C for 24 h. After cooling to room temperature ammonia was allowed to escape and methanol was evaporated. The crude product was purified using column chromatography on silica gel (49:1 DCM:MeOH) to yield Aplidiopsamine A as an off white solid (9 mg, 69%).
R
f = 0.40 (19:1 DCM:MeOH); MP 229-231 °C; IR(Nujol):
vmax 3351, 2923, 1684, 1462, 1374, 1116, 1152, 735, 716 cm
-1;
1H NMR (400 MHz, DMSO-D
6): δ 5.94 (s, 2H), 7.20 (s, 1H), 7.25 (br s, 2H), 7.43-7.55 (m, 2H), 7.75 (d,
J = 7.8 Hz, 2H), 8.07(s, 1H), 8.26 (d,
J = 7.8, 1H), 8.33 (s, 1H), 12.39 (br s, 1H);
13C NMR (100 MHz, DMSO-D
6): δ 44.8, 101.6, 118.7, 123.4, 125.9, 126.9 (2 C), 128.2, 128.4, 129.2(2 C), 141.7, 142.5, 143.6, 150.1, 152.7, 156.2; HRMS-ESI(m/z): calcd for [C
17H
13N
7+H]
+, 316.1305; found 316.1304.
Example 8
3-((3-(Phenylsulfonyl)-3H-pyrrolo[2,3-c]quinolin-4yl)methyl)quinazolin-4(3H)-one(7):
[0059]
Procedure:
[0060] To a two neck dry round bottom flask was added
6 (50 mg, 0.34 mmol), K
2CO
3 (60 mg, 0.43 mmol) and dry DMF (0.5 ml) under argon atmosphere. The reaction mixture was stirred at 50 °C for 1 h, then cooled to room temperature followed by addition of a solution of 4 (70 mg, 0.17 mmol) in dry DMF (0.5 ml). It was heated to 50 °C and stirred at same temp for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude compound was purified using silica gel column chromatography (7:3 PE:EtOAc) to yield
7 as a white solid (60 mg, 73%).
R
f = 0.50 (1:1 PE:EtOAc); MP 201-203 °C; IR(Nujol):
vmax 2925, 2854, 1675, 1612, 1461, 1376, 1176, 726, cm
-1;
1H NMR (500 MHz, CDCl
3): δ 5.85 (s, 2H), 7.26 (d,
J = 3.8 Hz, 1H), 7.43-7.55 (m, 5H), 7.60 (t,
J = 7.3 Hz, 1H), 7.72-7.79 (m, 3H), 7.85 (d,
J = 7.3 Hz, 2H), 8.00 (d,
J = 3.8 Hz, 1H), 8.01-8.05 (m, 1H), 8.11 (s, 1H), 8.23 (d,
J = 7.6 Hz, 1H);
13C NMR (125 MHz, CDCl
3): δ 49.9, 107.1, 121.9, 122.3, 122.6, 126.5, 126.8, 126.9, 127.4, 128.1, 129.7, 129.8,131.9, 134.0, 134.5, 135.8, 138.4, 142.2, 142.9, 148.4, 161.3; HRMS-ESI(m/z): calcd for [C
26H
18O
3N
4S+Na]
+, 489.0992; found 489.0980.
Example 9
NCLite-M1 (8):
[0061]
3-((3
H-pyrrolo[2,3-
c]quinolin-4-yl)methyl)quinazolin-4(3
H)-one
Procedure:
[0062] To a two neck round bottom flask was added
7 (20 mg, 0.04 mmol), K
2CO
3 (17 mg, 0.12 mmol) and methanol (1 ml). The reaction mixture was refluxed for 1 h, brought to room temperature and quenched with water. Extraction with dichloromethane, drying over sodium sulphate and evaporation gave the crude compound, which was purified using column chromatography on silica gel (1:1 PE: EtOAc) to yield NCLite-M1 as white solid (12 mg, 90%).
R
f = 0.30 (1:1 PE:EtOAc); MP 211-213 °C; IR(Nujol):
vmax 3286, 2925, 2855, 1668, 1614, 1464, 1375, 766, 739 cm
-1;
1H NMR (400 MHz, DMSO-D
6): δ 5.78 (s, 2H), 7.20 (t,
J = 2.5 Hz, 1H), 7.43(t,
J = 8.3, 1H), 7.48-7.58 (m, 2H), 7.70 (d,
J = 8.3, 1H), 7.74-7.80 (m, 2H), 7.88 (t,
J = 8.5, 1H), 8.12 (d,
J = 7.8 Hz, 1H), 8.27 (d,
J = 7.8 Hz, 1H), 8.6 (s, 1H), 12.39 (br s, 1H);
13C NMR (100 MHz, DMSO-D
6): 47.1, 101.5, 121.87, 121.94, 123.3, 125.7, 125.8, 126.4, 126.9, 127.2, 127.5, 127.9, 128.2, 129.1, 134.7, 141.6, 143.7, 148.5, 149.6, 160.5; HRMS-ESI(m/z): calcd for [C
20H
14ON
4+H]
+, 327.1240; found 327.1231.
Example 10:
General Procedure for imine formation and cyclization (Table 2, entry 1-6):
[0063] To a dry two neck round bottom flask, equipped with Dean-Stark apparatus, containing freshly activated 4Å molecular sieves, ketone (1.2 equiv.), Iodoaniline (1 equiv.) and
p-toluenesulphonic acid (0.1 equiv.), was added dry toluene under argon atmosphere and the reaction mixture was refluxed for 12-24 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Evaporation of ethyl acetate provided crude imine, which was used further without any purification.
[0064] To a sealed tube containing magnetic stirring bar was added Pd(OAc)
2 (0.02 equiv.), PPh
3 (0.04 equiv.) and Ag
2CO
3 (0.4 equiv.). To this was added solution of crude imine (1 equiv.) in 1,4-dioxane by means of a syringe and the tube was sealed and heated at 120 °C for 8-24 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (PE:EtOAc) to yield cyclized product in 51-90% yield over two steps.
Table 1. Optimization studies on cyclization of iodo-imine 2 to pyrroloquinoline 3.
entr y | catalyst (equiv) | ligand (equiv) | base (equiv) | solvent | temp | time | yield |
01 |
- |
Neocuproine (0.50) |
KOtBu (2.5) |
Benzene |
100 °C |
18h |
trace |
02 |
Pd(OAc)2 (0.10) |
PPh3 (0.20) |
Ag2C03 (2.0) |
DMF |
100 °C |
02 h |
51% |
03 |
Pd(OAc)z (0.20) |
PPh3 (0.40) |
Ag2C03 (4.0) |
DMF |
100 °C |
02 h |
64% |
04 |
Pd(OAch (0.20) |
PPh3 (0.40) |
Ag2C03 (2.0) |
THF |
reflux |
04 h |
63% |
05 |
Pd(OAch (0.10) |
PPh3 (0.20) |
Ag2C03 (2.0) |
1,4-dioxane |
reflux |
03 h |
91% |
06 |
Pd(OAc)2 (0.04) |
PCy3 (0.08} |
Cs2C03 (2.0) |
THF |
110°C |
24 h |
23% |
07 |
Pd(OAc)2 (0.04) |
PCy3 (0.08) |
K1C03(2.0) |
DMF |
110 °C |
24 h |
35% |
08 |
Pd(0Ac)2 (0.10) |
PCy3 (0.20) |
Ag2C03 (2.0) |
DMF |
110°C |
24 h |
31% |
09 |
Pd(0Ac)2 (0.05) |
PPh3 (0.10) |
Ag2C03 (1.0) |
1,4-dioxane |
120°c |
07 h |
90% |
10 |
Pd(0Ac)2 (0.03) |
PPh3 (0.06) |
Ag2C03 (0.6) |
1,4-dioxane |
120°c |
08 h |
89% |
11 |
Pd(0Ac)2 (0.02) |
PPh3 (0.04) |
Ag2C03 (0.4) |
1,4-dioxane |
120°C |
10h |
93% |
|
12 |
Pd(O Ac)z |
PPh3 (0.02) AgzC03 (0.2) 1,4-dioxane 120°C 24 h 72% |
Note: Reactions shown in entries 1 and 6-12 were carried out in a sealed tube |
Example 11
[0065]
Reaction condition: imine substrate (1 equiv), Pd(OAc)
2 (0.02 equiv), PPh
3 (0.04 equiv), Ag
2CO
3(0.4 equiv), 1,4-dioxane, sealed tube, 120 °C
4-methyl-3-(methylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (Table 2, entry 1):
[0066]
[0067] Reaction Time: 8 h, R
f = 0.50 (7:3 PE:EtOAc); MP 152-154 °C, 82%; IR(Nujol) :
vmax 2928, 1459, 1377, 995, 743 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 3.19 (s, 3H), 3.36 (s, 3H), 7.21 (d,
J = 3.6 Hz, 1H), 7.58 (t,
J = 8.1 Hz, 1H), 7.68 (t,
J = 8.3 Hz, 1H), 7.84 (d,
J = 3.7 Hz, 1H), 8.12 (t,
J = 8.5 Hz, 2H);
13C NMR (125 MHz, CDCl
3): δ 26.2, 43.4, 105.6, 121.7, 122.9, 126.4, 128.2, 128.3, 128.7, 131.0, 139.3, 143.4, 145.9; HRMS-ESI(m/z): calcd for [C
13H
12O
2N
2S+H]
+, 261.0692; found 261.0696.
Imine: HRMS-ESI(m/z): calcd for [C
13H
13O
2N
2SI+H]
+, 388.9815; found 388.9812.
7-chloro-4-methyl-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (Table 2, entry 2):
[0068]
[0069] Reaction Time: 10 h, R
f = 0.30 (9:1 PE:EtOAc); MP 178-180 °C, 70%; IR(Nujol) :
vmax 2924, 2854, 2725, 1614, 1462, 1376, 822, 726, 685 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 2.88 (s, 3H), 7.21 (d,
J = 3.7 Hz, 1H), 7.46-7.52 (m, 3H), 7.60 (t,
J = 7.6 Hz, 1H), 7.71 (d,
J = 8.5, 2H), 8.02 (s, 1H), 8.03 (d,
J = 6.7 Hz, 1H), 8.10 (d,
J = 3.7, 1H);
13C NMR (125 MHz, CDCl
3): δ 26.1, 105.5, 120.0, 124.2, 126.5, 126.9, 127.8, 128.6, 129.7, 132.3, 133.7, 134.3, 134.6, 139.2, 143.9, 147.9; HRMS-ESI(m/z): calcd for [C
18H
13ClN
2SO
2+H]
+, 357.0459; found 357.0462.
Imine: HRMS-ESI (m/z): calcd for [C
18H
14N
2O
2ClSI+H]
+, 484.9582; found 484.9580.
4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]quinoline (Table 2, entry 3):
[0070]
[0071] Reaction Time: 5 h, R
f = 0.40 (4:1 PE:EtOAc); semi-solid, 62%; IR(Nujol) :
vmax 2925, 1642, 1542, 1458, 1376, 1175, 761, 726, 686 cm
-1;
1H NMR (400 MHz, CDCl
3): δ 2.85 (s, 3H), 6.93 (d,
J = 3.8 Hz, 1H), 7.38 (t,
J = 7.5 Hz, 2H), 7.42-7.51 (m, 2H), 7.52-7.61 (m, 1H), 7.72 (d,
J = 8.8 Hz, 2H), 7.98 (d,
J = 3.8 Hz, 1H), 8.07 (d,
J = 8.3 Hz, 1H), 8.93 (d,
J = 8.5 Hz, 1H);
13C NMR (100 MHz, CDCl
3): δ 22.5, 107.1, 117.1, 123.2, 124.5, 125.9, 126.8, 127.7, 129.0, 129.45, 129.50, 134.3, 134.6, 138.0, 145.7, 153.9; HRMS-ESI(m/z): calcd for [C
18H
14O
2N
2S+H]
+, 323.0849; found 323.0853.
Imine: HRMS-ESI (m/z): calcd for [C
18H
15N
2IO
2S+H]
+, 450.9972; found 450.9972.
6-phenylphenanthridine (Table 2, entry 4):
[0072]
[0073] Reaction Time: 10 h, R
f = 0.40 (19:1 PE:EtOAc); MP 104-106 °C, 90%; IR(Nujol) :
vmax 2923, 2945, 2851, 1607, 1459, 1374, 760, 718, 697, 672 cm
-1;
1H NMR (500 MHz, CDCl
3): δ 7.50-7.58 (m, 3H), 7.61 (t,
J = 7.6 Hz, 1H), 7.65-7.80 (m, 4H), 7.86 (t,
J = 7.9 Hz, 1H), 8.10 (d,
J = 8.2, 1H), 8.26 (d,
J = 7.9 Hz, 1H), 8.62 (d,
J = 7.9 Hz, 1H), 8.71 (d,
J = 8.2 Hz, 1H);
13C NMR (125 MHz, CDCl
3): δ 121.9, 122.2, 123.8, 125.2, 126.9, 127.1, 128.4, 128.7, 128.8, 128.9, 129.7, 130.3, 130.6, 133.5, 139.6, 143.7, 161.3; HRMS-ESI(m/z): calcd for [C
19H
13N+H]
+, 256.1121; found 256.1121.
Imine: HRMS-ESI (m/z): calcd for [C
19H
14NI+H]
+, 384.0244; found 384.0244.
6-phenylphenanthridine-2-carbonitrile (Table 2, entry 5):
[0074]
[0075] Reaction Time: 10 h, R
f = 0.50 (19:1 PE:EtOAc); MP 233-235 °C, 85%; IR(Nujol) :
vmax 2924, 2224, 1609, 1462, 1377, 961, 829, 776, 688, 670 cm
-1;
1H NMR (400 MHz, CDCl
3): δ 7.52-7.62 (m, 3H), 7.60-7.76 (m, 3H), 7.90-7.98 (m, 2H), 8.16 (d,
J = 8.0 Hz, 1H), 8.29 (d,
J = 8.3 Hz, 1H), 8.66 (d,
J = 8.3 Hz, 1H), 8.95 (d,
J = 1.5 Hz, 1H);
13C NMR (100 MHz, CDCl
3): δ 110.2, 119.1, 122.2, 123.9, 125.5, 127.8, 128.5, 128.6, 129.4, 129.7, 130.4, 131.5, 131.6, 132.4, 138.9, 145.5, 164.3; HRMS-ESI(m/z): calcd for [C
20H
12N
2+H]
+, 281.1073; found 218.1075.
Imine: HRMS-ESI (m/z): calcd for [C
20H
13N
2I+H]
+, 409.0196; found 409.0193.
2-phenyl-1H-indole-5-carbonitrile (Table 2, entry 6):
[0076]
[0077] Reaction Time: 24 h, R
f = 0.40 (4:1 PE:EtOAc); MP 194-196 °C, 51%;
1H NMR (500 MHz, CDCl
3): δ 6.87 (d,
J = 1.5 Hz, 1H), 7.37-7.50 (m, 5H), 7.66 (d,
J = 8.5 Hz, 2H), 7.96 (s, 1H), 8.73 (brs, 1H);
13C NMR (125 MHz, CDCl
3): δ 100.2, 103.4, 111.7, 120.7, 125.2, 125.4, 126.0, 128.6, 129.0, 129.2, 131.2, 138.4, 140.2; HRMS-ESI(m/z): calcd for [C
15H
10N
2+H]
+, 219.0917; found 219.0917. Imine: HRMS-ESI (m/z): calcd for [C
15H
11N
2I+H]
+, 347.0040; found 347.0042.
Example 3:
Antimalarial activity:
[0079] A known parasite 3D7 was used, which is Chloroquine sensitive strain. 2 mg of the compound NCLite-M1 which has a molecular weight of 326.35, was dissolved in 10 mL of EtOH and used as a stock. The results are tabulated in Table 3. As seen from table 3, the compound is active at concentration as low as 2 µMoles in crude form. Further studies using highly pure compound and its soluble salts are planned.
Table 3: Antimalarial activity of NCLite-M1
Sr No | Concentration | |
| | % inhibition by NCLite-M1 |
1 |
2-5 µM |
17.6% |
2 |
25 µM |
19.5 % |
3 |
50 µM |
77.2 % |
4 |
75 µM |
89.4 % |
Advantages of invention:
[0080]
- a. Novel anti-malarial agents
- b. Novel and simple synthetic process of synthesis of novel and known anti-malarial agents provided.
- c. Process applicable for synthesis of other natural products