SU1641820A1 - Method for preparing 5- or 6-substituted 9-iodine-benzimidazo- (2,1-b)-quinazolinones-12 (5 or 6) - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of compounds of the common f-ly I or II

Description

where R is H, CH, lower alkyl-C2 C is benzyl, hydroxyalkyl, cyanalkyl, car, boxy- and carboxyalkyl, feacil, aroyl, which exhibit immunosuppressive activity, which can be used in medicine. Purpose -. the creation of a new method of obtaining new substances of the specified class. The synthesis is carried out by the reaction of the corresponding substituted benzimidazo (2,1-b) quinazolin-12 (5 or 6H) with bromine and iodide.

potassium or sodium in a molar ratio of 1: 2: 1 in an aqueous medium, followed by boiling the reaction mixture until decolorization and neutralization with a base — sodium carbonate or ammonia. New substances are obtained in high yield (97-98%) with activity to suppress the mycelium of fungi and bacteria, as well as to suppress the development of diseases. 3 tab.

i

The invention relates to organic chemistry, namely to a new method of producing new 5 or 6-substituted 9-iodobenziO

N N

R

(and)

midazolo (2,1-in) quinazolinone-12 (5 or 6H) of the general formula

where R is H, CHj lower alkyl Cr-C4, benzyl, hydroxyalkyl, cyanalkyl, carboxy-, carbalkoxyalkyl, phenacyl, arsyl.

Derivatives of 6 (5H) -ben.zimidazo- (2,1-в) quinazolinone- 12 are a new class of immunosuppressive agents and can be used in pharmacology, as well as intermediates in the synthesis of new drugs or fungicides.

. . about

. BUT;

NN R

where R is AND, CHj, lower alkyl, benzyl, hydroxyalkyl, cyanalkyl carboxy and carbalkoxyalkyl, phenacyl, aroyl, in an aqueous medium act with bromine and an equivalent amount of sodium or potassium iodide, followed by boiling the reaction mixture until decolouration and neutralization with a base such as sodium carbonate or ammonia.

Example 1. Preparation of benzimidazo (2,1-b) quinazolinone-12 -9-iodine by the action of potassium iodide or sodium after the addition of bromine, 2.35 g (0.01 mol) of benzimidazo (2,1-в) quinazolinone-12 1.66 g (0.01 mol) of potassium iodide (or 1.5 g (0.01 mol) of sodium iodide) are suspended in 50 ml of water and 3E2 g (0.02 mol) is added dropwise with careful stirring; ) bromine. The formation of brown periodide is observed. The periodide aqueous suspension is brought to a boil and boil until the periodide crystals decolour (5-15 min). Cool, neutralize with 10% soda solution or concentrated ammonia, and colorless crystals are filtered.

Yield 3.54 g (98.2%), m.p. 347-348 ° C. (from DMF).

Analysis and data of the IR spectrum are given in table. 1. Compounds 1b – 0 given in Table 1 were obtained analogously.

Example 2. Effect of potassium iodide or sodium on benzimidazo (2,1-b) quinazolinone-12 without the action of bromine.

but). 1.66, g (0.01 mol) of potassium iodide (or 1.5 g (0.01 mol)) The invention is the development of a new method for the preparation of new 5- or 6-substituted 9-iodo-benzimidazo (2.1 -c) quinazolinone-12 (5shsh6N), possessing valuable properties.

The goal is achieved by the proposed method, consisting in that 5 or b-substituted benzimidazo (2,1-в) quinazolinones-12 (5 or 6H) of the general formula

(Iii)

N N 1

R

i

sodium chloride) is dissolved in 5 ml of water and 2.35 g (0, Of m) of benzimidazo (2.1-v) / schnazolinone-12 (6H) are added to boiling and boiled for 15 minutes. The formation of brown ion is not observed. Cool, filter the source benzimidazo (2,1-in) quinazolinone-12 6H) (2.33 g).

b). The effect of iodine on benzimidazo (2,1-b) quinazolinone-12 without the effect of br oma,

1.66 g (0.01 mol) of potassium iodide (or 1.5 g (0.01 mol) of sodium iodide) is dissolved in 5 ml of water and 0.8 g (0.005 mol) of bromine is added. The resulting dark precipitate of iodine is allowed to settle (5-10 minutes) and 2.35 g (0.01 mol) of benzimidazo (2,1-in) quinazolinone-12 (611) are introduced with stirring. The formation of brown ion iodoni perbromide was not observed. Suspended in water iodine and benzimidazo (2, 1-c) quinazolinone-12 (bN). Heat to boiling and boil for 15 minutes. Years t purple iodine vapor; the reaction mixture does not discolor. Cool, filter the mixture of iodine and benzimidazo (2, 1-c) quinazolinone-12. The initial product (II) is separated by crystallization from DMLA. Belinstein's test and elemental analysis show that iodine did not enter the molecule.

The yield of benzimidazo (2,) quinazolinone-12 (6H) 2.3 g

Example 3. Preparation of 9-iodo-6-methyl benzimidazo (2,. 1-b) quinosolin-12-one by counter synthesis.

but). Preparation of 9-iodobenzimidazo- (2,1-b) quinazolin-12-one.

five

3.25 g (0.01 mol) of 5/6-iodobenzimidazole-2-sulfonic acid and 1.37 g (0.01 mol) of anthranilic acid are fused at 140-160 ° C for

2 hours until complete elimination of SЈЈ. Cool, filter and neutralize with ammonia. Colorless skalls.

Yield 2.18 g (60.4%), m.p. 347-348 ° C (from DMF).

Found,%: C 46.4 N; 2.3 3 35.2 N 11.7

C14H83N3 °

Calculated,%: C 46.5; II 2.2;

335.2; H 11.6.

b) Methylation of 9-iodobenzimide zo (2,1-c) quinazolinone-12 under interfacial catalysis conditions.

3.61 g (0.01 mol) of 9-iodobenzimidazo (2,1-b) quinazolinone-12 are added to a solution of 3 g of NaOH in 3 ml of water and with thorough stirring, 10 ml of acetone and 2.13 g are added. (0.015 mol) of methyl iodide. Stir at room temperature until the green color of the eomeric ion disappears (1 h). Dilute with double volume of cold water and filter. Colorless crystals of 9-iodo-6-methylbenzimidazo (2,1-b) quinazolinone-12 are obtained.

Output 3.3 g (87.6%), so pl. 251- 252 ° С (from LIFA).

Found,%: C 48; 1 2.6; I 33.9; N 11.1

C, yHwIN, 0

Calculated,%: C 48.0; H 2.7; I 33.9; N 11.2.

Example 4. 6- (1,2-diiodo-3-propyl) benzimidazo (2.1 c) quinazolin-12-one. 2.75 g (0.01 mol) of 5-allylbenzimidazo (2,1-b) quinazolinone-12 are suspended in a solution of 3.32 g (0.02 mol) of potassium iodide in 50 ml of water and, with vigorous stirring, add drop by drop, 1.6 g (0.01 mol of bromine. The brown solution is heated in a water bath to 40-60 ° C and kept at this temperature until complete bleaching (5-10 minutes). Cool. The color crystals are filtered.

Yield 4.55 g (86.1%), m.p. 199-200 ° C (from PMFA).

Found,%: C 38.49; H 2.48; I 48.12; N 7.86.

Calculated,%: C 38.56, H 2.46; I 48.01; N 7.94.

8206

Example 5. Preparation of 5-methyl-9-iodobenzimidazo (2,1-b) quinaiolin-12.

but). The action of potassium iodide or sodium on perbromide.

2.49 g (0.01 mol) of 5-methylbenzimidazo (2,1-b) quinae-12 is suspended in 40 ml of water and with careful

while stirring, 3.2 g (0.02 mol) of bromine are added dropwise. A solution of 1.66 g (0.01 mol) of potassium iodide or 1.5 g (0.01 mol) of iodide is added to the forming orange perbromide.

5 ml in 10 ml of water. A transition of orange perbromide to brown periodide is observed. The aqueous suspension of the formed periodide is heated to the boiling point and boiling point, t t until the crystals glow (5-15 minutes). Cool, neutralize with soda or ammonia and colorless crystals are removed from the filter. The output of 3.67 g (97,9%), so pl. 253-254 ° C (from DMF).

5 B). The effect of bromine on a suspension of 5-methylbenzimidazo (2,1-в) quinazolin-12 in an aqueous solution of potassium iodide or sodium, 2.49 g (0.01 mol) of 5-methylbenzimidazo (2,1-в) quinazolino0 by-12 is suspended in a solution of 1.66 g (0.01 mol) of potassium iodide (or 1.5 g (0.01 mol) of sodium iodide) in 50 ml of water and with thorough stirring, 3.2 g (0.02 g) are added dropwise mole) bromine The formation of a brown periodide is observed. Bring the aqueous cvcnenzium of the periodide to a boil and boil until the periodidium crystals become discolored (5-15 min). Cool, neutralize with 10% soda solution or concentrated ammonia, and colorless crystals are filtered off.

The output of 3.67 g (97,9%), so pl. 253-254 ° M (and DMF).

Analysis and data of the IR spectrum are given in table. 2

Given in Table. 2 compounds 1b – o were obtained similarly.

Example 6. Effect of potassium iodide or sodium on benzimidazole in the absence of bromine.

1.66 g (0.01 mol) of potassium iodide (or 1.5 g (0.01 mol) of sodium iodide) is dissolved in 5 ml of water and 2.49 g (0.01 mol) of 5-methylbenzimidazo ( 2,1-c) quinazolinone-12 (5H) is heated to boiling and boiled for 15 minutes. The formation of brown ion is not observed. Cool, from filtering 5

0

five

0

71

initial 5-methylbenzimidazo (2,1-to quinazolinone-12 (5H) (2.33

b). The effect of iodine on benzymidazole in the absence of bromine.

1.66 g (0.01 mol) of iodide, potassium (or 1.5 g (0.01 mol) of sodium iodide) is dissolved in 5 ml of water and 0.8 g (0.005 mol) of bromine is added. The formed dark osaka iodine is allowed to settle (5-10 min) and 2.49 g (0.01 mol) of 5-methylbenzimidazo (2,1-в) quinazolinone-12 (5H) are introduced with stirring. The formation of brown ion of perbromide was not observed. Iodine is suspended in water and 5-methylbenzimidazo (2,1-v) quinazolinone-12 (5H) is heated to boiling and boiled for 15 years. Purple iodine vapor: the reaction mixture does not fade. The iodine and 5 are filtered off -methylbenzimidazo (2,1-b) quinazolinone-12 (5H). The starting product (I) is isolated by crystallization from DMF. Belinstein's test and elemental analysis show that iodine did not enter the molecule about

The output of 5-methylbenzimidazo (2,1-in) - quinazolinone-12 (5) 2.7 g,

Example 7. Obtaining 9-iodine-5-methylbenzimidazo (2,1-in) quinazolin-12 counter synthesis,

but). Preparation of 9-iodobenzimidazo- (2,1-b) quinazolinone-12.

3.25 g (0.01 mol) of 5/6-iodobenzimium dazole-2-sulfonic acid and 1.37 g (0.01 mol) of anthranilic acid are fused at 140-160 ° C for 2 hours until complete separation of the

nor 50. Cool, process

20 ml of 10% HC1, the hydrochloride is filtered and neutralized with ammonia o Colorless crystals

Yield 2.18 g (60.4%), m.p. 347-348 ° C (from DMF).

Found,%: C 46.4; H 2.3; I 35.2 N 11.7s

C 4H61N30

Calculated,%: C 46.5; ll 2,2; I 35.2; N 11.6.

b). Methylation of 9-iodobenzimidazo (2,1-в) quinazolin-12-one in the neutral medium

3.61 g (0.01 mol) of 9-iodobenzimidazo (2,1-b) quinazolinone-12 and 1.42 g (0.01 mol) of methyl iodide in 10 ml of DMF are heated under reflux for 1 h o Cool, the precipitated hydroiodide is filtered and it

0

five

1820

0

eight

ammonium distilled. Colorless crystals of 9-iodine-5-methylbenzimidazo (2.1-c) quinazolinone-12.

Yield 3.04 g (81.3%), m.p. 253-254 ° C (from DMF).

Found,%: C 47.8; H 2.7; I 33.8; H 11.3.

C S-H40IN30

I Calculated,%; C 48.0; H 2.7; I 33.9; N 11.2.

Example

8. 5- (1,2-diiod-3-propyl) benzimidazo 2,1-c) quinazolin-12-one.

2.75 g (0.01 mol) of 5-allylbenzimidazo (2,1-b) quinazolinone-12 are suspended in a solution of 3.32 g (0.02 mol) of potassium iodide in 50 ml of water and, with vigorous stirring, add dropwise 1.6 g (0.01 mol) of bromine. The brown solution is heated in a water bath to 40-60 ° C and maintained at this temperature until completely discolored (5-10 minutes). Cool. Colorless 5 crystals are filtered off.

Yield 4.59 g (86.7%), m.p. 203-204 ° С (from DMF).

Found,%: C 38.60; H 2.51;

I 47.92; N 7.16. C1 HWIZN30

Calculated,%: C 38.56; H 2.46; I 48.01, N 7.94.

The physicochemical properties of the new compounds are given in Tables 1 and 2 of the fungicidal activity in Table 3.

Thus, the proposed method allows to obtain 5 or 6-substituted 9-iodobenzimidazo- (2,1-b) quinazolinones-12, which are not previously described (9–98%) in high yield.

Claims (1)

Invention Formula Method for preparing 5- or 6-substituted 9-iodo-benzimidazo (2,1-b) -quinazolinone-12 (5 or 6) total fomrula (I) or (II) 50 OR where R has the indicated meanings, is treated with bromine and potassium iodide or sodium at a ratio of 15 (III) or (IV) to bromine - iodine potassium or sodium, equal to 6 Mixed -9- | 10dS | CH1HCHMNLSCHO- (. L-D} xlina4cuiiuioiiij-12 ((SII) ABOUT  xx-yo Based on the total content of the cue ranoi enov found 38.10, calculated 38.33. On the total content of halogens found 34.955, calculated 35.02 5-Zame "Einy-9-yolbenznmilaeo- (2,1-in} quinaznolnoly-12 (5H) ABOUT Data on total halogen content 1: 2: 1 molar% in an aqueous medium, followed by boiling the reaction mass until decolorization and neutralization with a base, such as sodium carbonate or ammonia, T a and l and I 1 T l l n n c l 2 II benzimidazo derivatives (2,1-in) R YS: V-N tG5 kAAJU N N R 1641820 12 Table 3