SU1318165A3 - Method for producing n-methylsulfonyl-1,2,8,8a-cycloprop (c)-benzo-(1,2,-b:4,3-b)-dipyrrol-4(5)-on - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R<1>, R<2> and R<3> are independently selected from hydrogen, C1-5 alkyl and Ph; and R<4> is HSO2, (C1-5 alkyl)sulfonyl, PhSO2, PhCOCH2SO2 or ZCH2COO in which Z is CH2I, CCl3, HSO2CH2, (C1-5 alkyl)sulfonylmethyl, PhSO2CH2, Ph or fluorenylmethyl. The compounds illustrated can be prepared by an 11-step process, starting from 4-chloro-3-nitrophenol and ether derivatives thereof. Many of the intermediates in this process are novel and have, as do the illustrated compounds, antibacterial activity. Novel intermediates have the formulae (I), (II), (III) or (IV> <IMAGE> wherein R<5> is H, CH3, benzyl, allyl, CH3SCH2, CH3OCH2, CH3O- CH2CH2OCH2, CCl3CH2, (C1-5 alkyl)3 SiCH2CH2 or Ph3SiCH2CH2; R<7> is CH3O, C2H5O, C1-5 alkyl or Ph; X is HSO3, (C1-5 alkyl) SO3, PhSO3, Cl, Br, I or OH; X' is as X (except OH, or CH3COO; X'' is as X, or CH3COO; and Y is H, NO2 or NH2.

Description

This invention relates to the preparation of a novel compound N-methylsulphonyl-1,258,8a-cycrolol (c) -benzo-(I, 2-c; 4,3-b) -dipyrrol-4 (5H) -one

802СНз

with antibacterial action.

The chain of the invention is to develop a method for producing a new compound having a valuable pharmacological property of enhanced action with

The invention is illustrated by the following examples.

Example. Step 1. Preparation of 2-aryl-1,3-propanediol (3) from aryl diethyl malonate (2).

100 g of diisobutyl aluminum hydride (0.70 mol) in 400 ml of toluene are added to 400 ml of THF in a nitrogen atmosphere with cooling on an ice-free ba. 33.0 g (0.105 mol) of arylmalonate (2) in 100 ml of THF are added to the stirred solution at such a rate that the reaction temperature does not exceed 5. Upon completion of addition, the ice bath is removed. After a reaction period of just 3 hours, the reaction mass is cooled, adding it in portions with stirring to a solution of cold 3 n. HC1 (about 1 ,, 5 l). The mixture is then extracted with 1 L of Et OAc and then 1000 ml of CHjCl. The collected organic phases are dried with sodium sulfate and concentrated to red-brown, the residue (21.2 g). Chromatography of the residue using 500 g of silica gel and 60% Et OAc (hexane-100% Et OAc as solvent) gave 11.7 g (49% yield) of diol (3) (U 62,598) as a light red oil ( which hardens if you put it in the fridge).

NMR (CDCl1): 7.5-7.0 (m, 3N); 3.80 (s, 3N); 4.0-3.3 (m, 7H includes 2 OH) MS calculated for C, 227.0794; found 227.0780.

Calculated,%: C, 51.86; H 5.76; N 6.16.

fO

15

20 25

30 40 45 50

: 55

652

Found,%: C 53.40; H 5.77; N 5.99.

Step 2. Preparation of 2-aryl-1,3-propanediol-bismesylate (4) from 2-aryl-1J3-propanediol (3).

To 4.7 g (0.2 mol) of diol (3) in 100 ml of dry pyridine in a nitrogen atmosphere at 0–5 ° C, 6.8 g (0.06 mol) of meta-sulfonyl chloride are added with stirring. After stirring for 30 minutes at 5 ° C and for. The solution is concentrated in vacuo for 90 minutes at room temperature, then it is dissolved in CHjCl (IHHH1). The organic phase is separated and dried over sodium sulfate and concentrated. Trituration of the concentrate together with Et OAc to an off-white solid is obtained in a powder. Chromatography of the mother liquors through silica gel (with solvent Et OAc) gave a total yield of 6.65 g (86%), mp. 122-123 ° C (after recrystallization from acetone) of compound (4), bis-mesylate (U 62,597).

 NMR (acetone-d): 7.7-7.2 (m, 3N); 4.62 (d, 4H, Hz) 4.11 (t.SH, I 7 Hz); 3.92 (s, 3N); 3.06 (s, .6H).

Determination of D: C 37,59; H 4.47; N 3.65.

С, Н „НО, 8

Found,%: C 37.35; H 4.44; N 3.59.

This compound was tested in a standard test by the method of diffusion in vitro against the culture of mouse leukemia cells of the strain. L 1210, and received the following results:

LDgg (µg / ml) 6.0, (µg / ml) 18 ..

Step 3. Preparation of 6-methoxyin-dolmn-bis-esilate (5) from 2-aryl-1,3-. propane diol-bismesylate (4).

To 1.91 g (0.005 mol) of compound 4 in 30 ml of THF, 20 ivin Et OAc and 150 ml of ethanol, 1.5 ml of triethylamine and 400 mg of platinum dioxide are added. The resulting solution is subjected to a pressure of 0.4924-0.703 kg / cm by shaking it for 30 minutes. Then the solution is filtered through Celite and concentrated in vacuo. After repeated formation of azeotropic mixtures with methylene chloride in vacuum, the residue is finally dissolved in 100 ml of methylene chloride and cooled in a nitrogen atmosphere in an ice bath. Then 155 ml of triethylamine are added to the stirred solution and an additional 900 µL of methanesulfonyl is added dropwise.

chloride. After stirring for 30 minutes, the solution is cooled to room temperature over 60 MHif. Then the solution is washed with 1 N, a solution of hydrogen chloride, dried with sodium sulfate and concentrated. The residue obtained is quickly chromatographed with 150 g of silica gel, eluting first with 500 ml of 60% Et OAc hexane and then 1000 ml of 80% Et OAc hexane. 1.3 g (yield 78%) of the whitish compound 5,6-methoxyindolin-bismesylate (and 62,586) are obtained with a mp. 122-123 ° C (after recrystallization from ethanol),

NMR (DMF - d): 7.36 (d, 1H, I 8.5 Hz); 7.00 (d, 1H, Hz); 6.69 (dz, 1H, 8.5 Hz); 4.47 (2H, d, Hz; 4.3-3.6 (m, ZN); 3.80 (s, ZN); 3.20 (s, ZN); 3.07 (s, ZN),

Calculated,%: C, 42.97; H 5.11; N 4.18.

C, H, NSj, Og

Found,%: C 42.87; H 5.27; N4.29,

This compound was tested in a standard test by the method of diffusion in a test tube against a culture of leukemia cells of mouse strain L 1210, and the following results were obtained;

LDjp (µg / ml) 4.8; S05d (µg / ml) 10.

Step 4, Preparation of 6-methoxyin-dolinacetate (6) from 6-methoxyindolin-bismesylate (5),

To .13.0 g (39 mmol) of 6-methoxy-inolin-bismesylate (5) in 30 ml of DMF was added 800 ml of abs, ethanol, and then 32 g of sodium acetate. - The resulting heterogeneous solution is heated under reflux in a nitrogen atmosphere for 24 hours, after which it is cooled and concentrated in vacuo. The residue is treated for 2 hours with 100 ml of acetic anhydride (with stirring at room temperature) and concentrated in vacuo. The residue is taken up, the organic phase is separated, dried with sodium sulfate, filtered through charcoal and concentrated to an oil, which solidifies the yield of 11.6 g of compound 6, 6-methoxy-indoline-acetate as necessary. Further purification using chromatography is possible. silica gel and 60% Et OAc (hexane as solvent).

NMR (CDCl1) 7.17 (d, 1H, 5 Hz); 7.02 (d, 1H, Hz); 6.60 (dd, 1H,

-five

0

five

Q

Q g -

five

654

8.5 Hz); 4.18 (d, 2H, Hz); 4.1-3.4- (m, 3N); 3.78 (s, ZN); 2.91 (s, 3N); 2.05 (s, ZN).

Calculated,%: C 52.16; H 5.76; N4.68,

C ,, H, NO S

Found,%: C 52.13; H 5.79; N 5.27,

MS calculated 299.0827; found 299.0823.

Step 5. Preparation of 5-nitro-metoxy-indoin acetate (7) from 6-methoxy-indoline-acetate (6).

To 500 mg (1.67 mmol) of 6-methoxyindolin-acetate (6) in 20 ml of nitromethane are added 90 µl of 90% nitric acid. Then the solution cooled to 0-5 ° C is stirred for 30 minutes and then heated to room temperature for another 30 minutes. The solution is diluted with methylene chloride and aqueous sodium bicarbonate. The organic phase is taken up, dried over sodium sulfate and concentrated. The residue is chromatographed with 50 g of silica gel (60% Et OAc solvent) hexane-100% Et OAc. Thus, 440 mg of a yellow solid are obtained (yield 76%), mp. 175-177 (after recrystallization from ethanol) representing the compound (7), 5-nitro-6-methoxy-indoline acetate (U 62,696),

NMR (DMF - d): 7.91 (s, 1H); 7.20 (s. H); 4.27 (d, 2H, Hz); 4.3-3.7 (m, 3N); 3.98 (s, 3N); 3.17 (s, 3N) ;, 2.07 (s, 3N).

Calculated,%: C 45.34; H 4.68; N 8.14.

C ,, H ,,

Found,%: C 44.81; H 4.77; N 8.16 ..

This compound was tested in a standard test by the method of diffusion in a test tube against the culture of leukemia cells of strain L 1210, and the following results were obtained:

 (mkg / ml) 50, L, „(mkg / ml) 50.

Step 6. Preparation of 5-amino-6-methoxy-indoline acetate (8) from 5-nitro-6-methoxy-indoline acetate (7)

To 4.5 g (13 mmol) of 5-nitro-6-methoxy-indoline-acetate (7) in 50 ml of THF and 150 ml of ethanol is added 500 mg of platinum dioxide and 0.707 kg / shake under hydrogen pressure. cm to complete the absorption of hydrogen

51

(approximately 60 minutes). Then filtered and concentrated in vacuo. After concentration, 3.0 g of product precipitates. The latter is filtered and the mother liquors are quickly chromatographed on 100 g of silica gel with Et OAc as eluent, thus obtaining another 0.6 g of product. The total yield is 3.6 g (88%); the melting point of the compound 8,5-amino-6-methoxyindoline acetate (and 62,697) is 134-135 after recrystallization from acetone, cyclohexane}.

NMR (CDCl1): 7.02 (s, 1H); 6.65 (s, H); 4.16 (d, Hz); 4.1-3.5 (m, 3N); 3.83 (s, 3N); 3.6 (sh, s, 2H); 2.83 (s, 3N),.

Calculated,%: C 49.67; And 5.77; N8.91,

C ,, H, 8N., 05S

Found,%: C 49.74; H 5.72, N 8.94,

The compound is tested in a standard test by the method of diffusion in a test tube against a culture of mouse leukemia cells of Strain L 1210, and the following results were obtained:

 (µg / ml) 50, and} to (µg / ml) 50

Step 7, Preparation of 4,5-pyrrolo-6 methoxy-indoline (9) from 5-amino-6-me toxi-indoline acetate (8)

To a 14 ml dry atmosphere in a nitrogen atmosphere at-75 was added 6.0 ml of a solution, 20. To the resulting stirred solution were added 370 μl (2.5 mmol) CH, (CH, S), (polluted from CHj) Br /CHCO.jC2H5- and methylcaptide, according to the anTgorov method Wick E, H, Jamanishi T, Wartheimer H, C, Hoff I, E, Proctor B, F, and Goldblith S, A, I. Arg.Food chem ,, 9,289 / 1961 /. After 5 minutes, a solution of 470 mg (2.2 mol) I, 8-bis-dimethylaminononaphthalene and 628 mg (2.0 mmol) of anilinoindoline (8) in 3.0 ml of dry, red is added dropwise over 15 minutes. the solution is stirred for 2 hours, at -75 °, then 350 µl of triethylamine in 650 µl is added dropwise over a few minutes. Remove the cooling bath. When the temperature of the reaction mass reaches room temperature, the mass is briefly concentrated in vacuo. 5 ml of Et OAc, 25 ml of ether and 6 ml of 2N HC1 are added to the residue and vigorously stirred for

656

2 hours. Separate the organic phase and extract the aqueous phase with a mixture of Et OAc and (1: 1), collect the organic layers, dry with sulfate

sodium and concentrate. The residue is then loaded with 10 ml of THF and treated with 3.0 ml of 2 Mj BHjSMe overnight at room temperature in a nitrogen atmosphere. Alternatively, diastereomeric oxyindoles (B) obtained by treatment with acid can be selected at this stage by chromatography using silica gel (50 g; eluent 60-90% Et OAc, hexane),

GC-MS: IU (15%); 227 (100%); -2 1% SE-30 ,,

NMR (CDCl1): 8.4 (w, s, 1H); 7, I (s, III); 4.5-3.7 (m, 5H); 3.90 (s, 3N); 2.95 (s, 3N); 2.0 (s, 3N); 1.92 (s, 3N);

.1, 82 (s, 3N) - a larger diastoreomer; a smaller diastoreomer shows the following differences: 1.99 (s, 3N); 1.76 (s, 3N), for SCHj CH, NH group detected at 7.7 the CH group region

is 4.3-3.6 ppm The aqueous phase obtained as a result of the acid treatment is neutralized and extracted with methylene chloride, the methylene chloride-solution is isolated, concentrated and chromatographed on silica gel with 50% acetone (cyclohexane), which gives back 40% of the starting material (anilinindoline) and 20% diacylated source material

Reductive cleavage (oxy-Cindole B) with borane dimethyl sulfide is carried out by cooling with 1N. hydrochloric acid to complete gas evolution, and dissolving in methylene chloride, water. The separated organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel (50%) of acetone (cyclohexane), thus yielding 155 mg

product (9), 4,5-pyrrolo-6-methoxy-indoline (and 62,233); the yield is 25% (85% based on the recovered starting material), t, mp, 182-183 (after recrystallization from

chloroform ,, temp: phase transition 160 c),

NMR (CDCij) 8.3 (w, s ,, 1H); 6.96 (s, 2H); 4.2-3.5 (m, 5H + OH); 3.92 (s, 3N); 2.87 (s, 3N); 2.41 (s, 3N), Calculated,%: C 54.17; H 5.84; N 9.03,

C ,, H ,,. S

71

Found,%: C 53.49; H 5.96; N, 9.42.

GC-MS: 0-acetate - m (EM 352 (13% 213 (100%) - 2-l% SE-30; temperature 150-260 °) 10 ° (min), one peak, This is

Disinfection was tested in a standard test by the method of diffusion in a test tube against the culture of mouse leukemia cells of strain L-1210, and the following results were obtained:

LDjQ (µg / ml) 4; LB (µg / ml) 4.

Step 8. Preparation of 4,5-pyrrolo-6-hydroxyindoline (IQ) from 4,5-pyrrolo-6-methoxy-indoline (9).

To 10 ml of dry, degassing. 350 ml of butyl mercaptan are added at room temperature in a nitrogen atmosphere at room temperature with hexamethylphosphoric acid. The solution is cooled in an ice-water bath and 2.0 ml of 1.5 M n-butyl lithium in hexane is added dropwise. After cooling the reaction mass to room temperature with stirring, 100 mg (0.3 mmol) of indole (9) are added. The solution is heated to 100 ° C. for 2.5 hours. The reaction is checked by thin layer chromatography (using 50% acetone) (cyclohexane) and when the conversion is completed at about 75% (by spraying vanillin) of phosphoric acid, the heating is stopped. . The cooled solution is poured into 1 and. HCl (100 ml) and extracted with 20 ml of Et OAc. The separated organic phase is washed with an additional 50 ml of water. The aqueous phases are collected and extracted back with 20 ml of Et OAc. The organic phases are then collected, dried over sodium sulfate, concentrated in vacuo, and eluted onto a column with 100 g of silica gel with a solution of 50% acetone (cyclohexane). 25 mg of the starting material and 45 mg of the product 10,4,5-pyrrolo-6-hydroxy indoline (and 62,370) are obtained (yield 44% of the isolated product and 69%, calculated on the starting material returned).

NMR (acetyl - dg): 7.8 (w, s, 1H); 7.03 (s, 1H); 6.83 (s, 1H); 4.25-3.25 (m, 5H); 2.86 (s, 3N); 2.36 (s, 3N). This product is treated with acetic anhydride (1.0 W) and 20 mg of NaOAc overnight, after which it is added to a mixture of methylene chloride and water. The organic phase is separated, dried with sodium sulfate and concentrated.

658

NMR (CDCl1): 7.8 (w, s.1H); 7, 16 (s, 1H); 6.97 (s, 1H); 4.42, 4.20 (dd, 2H); 4.2-3.7 (m, 3N); 2.86 (s, RN) 2.40 - (s, RN); 2.35 (s, 3N); 2.06 (s, ZN

GC-MS: m / e M 380 (25%); 199 (200%) - 2-1%; SE-30. This compound was tested in a standard test by the method of diffusion in a test tube against cell culture to leukemia of strain L 1210 and the following results were obtained:

 (µg / ml) 5 ,, (µg / ml) 5.

Step 9. Preparation of 4,5-pyrrolo-6-hydroxyindolin bromide (11) from 4,5-pyrrolo-6-hydroxyindolinic alcohol (10).

To 25 mg (65 µmol) of alcohol 10 in 1.0 ml of dry acetonitrile in a nitrogen atmosphere, at room temperature, 33 mg (100 µmol) GHGD and 26 mg (100 µmol) of triphenylphosphine are added. After stirring for 30 minutes, another 11 mg of CBg and 8 mg are added. Then the reaction mass is dissolved in methylene chloride (water) in just 60 minutes. The organic phase is then collected, dried over sodium sulfate and concentrated. The resulting residue is placed on three plates each of 250 microns silica gel 20x2Q fM in size and eluted with 50% acetone (cyclohexane). As a result, about 8 mg of product with a higher Rf value (0.64; alcohol Rf value of 0.45 alcohol), which is the compound 11,4,5-pyrrolo-6-oxyindoline bromide (and 62,694), is obtained. one

NMR (CDCl1): 8.5 (w, s, 1H); 7.1

(c.lH); 6.9 (s, H); 4.23 (d, 2H, I 6 Hz); 4.0-3.5 (m, 3N); 2.89 (s, ZN); 2.38 (s, 3N).

Beilstein's test is positive.

MS is calculated for C, Hj, N; 05 BrSSi 430.0382, found 430.0375 (mono-TMS); m / e M 430/432 (14%), 271 (90% 147 (100%).

This compound was tested in a standard test by the method of diffusion in a test tube against a cell culture of leukemia of strain L 1210, and the following results were obtained: LD50 (μg / ml) 0.12, LD, o (μg / ml) 0.37 or 4 5-pyrrolo-6-hydroxyindo linmesylate (11) from 4,5-pyrrolo-6-hydroxyindoline alcohol (10).

To 20 mg (65 µmol) of alcohol (10) in 1.0 ml of pyridine in an ice bath with stirring under nitrogen atmosphere, add 8 µl of methanesulfonyl91

chloride (70 μmol). After 30 minutes, add another 2 µl. The reaction was dissolved in 2N hydrochloric acid (methylene chloride) in 60 minutes. Then the organic phase is separated, dried over sodium sulfate and concentrated. According to TLC, a product with a lower Rf value (0.28 in 50% acetone) cyclohexane, an Rf alcohol value, 0.46), and a smaller amount of a product with a higher Rf value (0.66), are obtained in a larger amount. Preparative TLC (3 plates each of 250 µm silica gel 20x20 cm in size) gave 2 mg of material with a higher Rf value (the NMR spectrum indicates the presence of only one group, which may be chloride) and 9 mg of material with a lower IMM Rf, i.e. compounds (11) (and 62,695).

NMR (acet. Dg): 8.6 (w, s, 1H); 6.97 (s, 1H); 6.74 (s, 1H); 4.3 (m, 2H) 4.1-3.6 (m, 3N); 2.96 (s, 3N); 2.79 (s, 3N); 2.26 (s, ZN).

This compound was tested in a standard test using the diffusion method in a test tube against a culture of leukemia cells in strain 1H strain L 1210, and the following results were obtained:

 (µg / ml) 1, 0; 1. Sun, o (µg / ml; 353

Step 10. Preparation of 1,2,8,8a-cyclopropane (c) benzo- (1.2b: 4.3 - b) - dipyrrole-4- (5H) -one (12, N-methylsulfonyl).

If you use the technique to obtain 4,5-pyrrolo-6-hydroxyindolinbromide (stage 10) and concentrate in vacuum and apply the reaction mass before its final processing directly on the plates with a thick layer of silica gel instead of isolating the bromide product with a higher Rf value (0 , 64), find a product with a lower Rf value (0.32), which is obtained as compound 12.

NMR (CDCl3): 9.5 (ha, s, 1H): 6.83

(ds, na); 6.34 (s, Hb); 4.10 (d, Hc); 3.93 (dd, H6); 3.04 (s, 3N); 2.93 (m, He); 2.00 (d, 3N); 1.97 (dd, Hf), 1.37 (dd, Kg).

using BSTFA 1% TMC-Cl) gives m / e

318:

ten

 jg (µg / ml) 0, 13, LDqp (µg / ml)

t5

2025

thirty

35

40

45

50

55

6510

 386 (388) - 22.12% corresponds to the product 1+ Me.SiCl.

UV: (methanol) D 224,272,338.

This compound was tested in a standard test by the method of diffusion in a test tube against a culture of leukemia cells of strain of strain L 1210, and the following results were obtained:

LD of 0.42.

The resulting compound was found to be active against certain bacteria, for example. Bacillus subtilis, Klebsiella pneumonia, Sarcina lutea, Staphylococcus aureus, Myco bacterium avium. Consequently, it can be used to disinfect washed and stacked dishes for food contaminated with Saureus. The proposed compound can be used for bacteriostatic rinsing of the washed clothes, for impregnating papers and fabrics; In addition, it is suitable for inhibiting the growth of susceptible microorganisms in diffusion tests in the dish and other microbiological media, it can be used for the same purposes as the antibiotic CC-1065. The purpose of such compounds is well known in the field of antibiotics. Conventional, known bacteriological techniques can be used for the use of these compounds.

The resulting compound (12) shows less toxicity than the antitumor substance CC-1065. For example, when administered intravenously in mice, the LD value after 60 days is approximately 0.009 mg / kg, and when administered intraperitoneally after 120 days it is approximately 0.001 mg / kg In contrast, a single intraperitoneal dose of 100 mg / kg of compound (12) causes only 2/6 mortality on the second day, and after 66 days mortality is not observed at all. When giving single doses of less than 100 mg / kg, no lethality is observed at all, after 66 days.

Claims (1)

Invention Formula The method of obtaining N-methylsulfonip-1,2,8,8a-cycloprop (c) -benzo- (1,2-in: 4,3-b) -dipyrrol-4 (5H) -one of formula N S02CH3 characterized in that the 2-phenyl-1, 3-propanediol of the formula ShZO methanesulfonyl chloride in the presence of pyridine under an inert gas atmosphere, the resulting nitro compound of the formula .. reduced by hydrogen in the presence of platinum dioxide and triethylamine with the additional addition of methanesulfonyl chloride and subsequent treatment with base to form a compound of the formula OS02CHO, SNZO which is reacted with sodium acetate in dimethylformamide and standard and then with acetic anhydride, a compound of the formula CH About OolSl OOSN-s S02CH-J reduced by hydrogen in the presence of platinum dioxide, on the resulting compound of the formula HpN G-OSOS snzow R CH (CH, S) CHCOOC, jH act. in an inert atmosphere in dry methylene chloride at -75 ° C and 1,8-bis-dimethylamino-naphthalene, the azasulfonium salt thus formed in situ is subjected to Sommle Gauser rearrangement in the presence of a base to give the corresponding oxindole, which is then reduced by boron dimethyl sulfide in the atmosphere inert gas to the compound of formula 35 on the latter is acted by alkyl mercaptan in hexamethylphospho triamide, to give a compound of formula 45 which is treated with methanesulfonyl chloride in the presence of an acid acceptor, such as pyridine, followed by applying the resulting 50  CH-j OS02CH treatment with 90% nitric acid in the presence of nitromethane, a compound of the formula zodaz on a thick silica gel plate.