DE2003825A1 - Process for the preparation of 1-acyl-2-aminobenzimidazole and 1,3-bisacyl-2-imino-benzimidazole derivatives - Google Patents

Description

Haruo Ogura Tokyo, Japan

Process for the preparation of 1-acyl-2-aminobenzimidazole- and 1 ^ -Bisacyl-S-imino-benzimidazole-

Derivatives

The invention relates to benzimidazole derivatives and to a process for producing the same. She judges refer in particular to 1-acyl-benzimidazole-ji, 3-bieacylbenzimidazole-j Imidazo- (1,2-a) -benzimidazole- and 9-acylimidazo-Γ 1,2-a} -benzimidazole derivatives and their physiologically compatible salts with the formula:

N-CH ₂ COR

nHX or

(III)

. nHX

CH ₂ COR ₂ (IV)

009850/2154

n ^ vO / i ⁷ "· '^ *''* ■

-Z-

or

(V)

.nffiC

CH ₂ COR (VI)

H ₁ and R _{2 are} hydrogen, alkyl or aryl groups. η represents an integer from 0 to 1 and HX stands for the anionic part of a physiologically compatible salt. As used herein, the term "physiologically acceptable salt" refers to salts of 1-acyl-benzimidazole-; 1,3-bieacyl-benzimidazole-; 9-acyl-imidazo- (1,2-a) -benzimidazole-; and imidazo (1,2-a) benzimidaseole compounds which are essentially non-toxic to humans at the usual dosages. Such physiologically acceptable salts include, for example, non-toxic acid * addition salts, such as the hydrochloride and the hydrobromide.

The new benzimidazole compounds are crystalline solids which have varying solubility in organic solvents and which are slightly soluble in water. However, their salts are more soluble in water than the compounds themselves. In Chemical Reports £ 2, 1928 (1959), R. Gompper and P. Bffenberge describe a process for the synthesis of imidazo- (1 _f 2-a) -benzimidazole compounds, in which 2,3-diphenylimidazo- (1,2-a) -benzimidazole is formed from orthophenylenediamine and 2-chlorophenyl-oxazole by thermal ring closure.

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In contrast, the present invention relates to a novel process in which 2-amino-benzimidazole (I) is condensed with a <* -halocarbonyl compound (II), whereby a 1-acyl-benzimidazole compound (III) is obtained. The 1-acyl-benzimidazol-obtained compound is condensed with a d -halo-carbonyl compound, thereby obtaining a 1 ^ -Bisacyl-benzimidazol-compound (IV). The compounds (III) and (IV | IV) obtained are then converted into the corresponding imidazo- (i, 2-a) -benzimidazole compounds (V) and (VI, VI '), which in each case by thermal ring closure in accordance with the following Reaction scheme happens:

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NH,

+ XCH ₂ -OE ₁

ti

(D

(ID

• nHX

CH ₂ COR,

• nHX

(III)

CH ₂ CO-R ₁ (IV)

If-CH ₂ COR ₁

• nHX

(VI)

(VI)

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In carrying out the method of the invention, will the (X -halo-carbonyl compound (II) to the solution of the 2-Amino-benzimidazole compound (I) given in a solvent, whereby the intermediate compounds (III) and (IV) can be obtained.

The reaction proceeds rapidly at temperatures from about ⁰ ° C. to room temperature. If the reaction temperature is above this range, the formation of the intermediate compound tends to decrease. At temperatures from 50 to 150 ^° C., the formation of the intermediate compound (IV) is preferred over the formation of the compound (III).

Suitable inert organic solvents which can be used as reaction media include, for example, various alcohols as well as CCI4 ^{and CHC1} 3 · Both the 1-acyl-benzimidazole compound (III) and the 1,3-bisacyl-benzimidazole compound ( IV) in good yield.

Usable (X-halocarbonyl compounds include CX -halo ketones such as bromoacetone, chloroacetone, phenacyl bromide, phenacyl chloride, p-chlorophenacvl-bromiclfP-chlorophenacyl chloride, p-bromophenacyl bromide, p-bromophenacyl chloride <-Halogen; C -aldehydes, such as & bromoacetaldehyde-dimethylacetal, 0 (-bromoacetaldehyde-ethyl acetal, iX-chlorotcetaldehyde-dimethyl acetal, (X -chloro-acetaldehyde-diethylacetal and their mixtures and finally (X-halofenic acid ester, like (X -chloroacetic acid-methyl ester, Qt -Bromessigsäure-methylester, ft -Chloressigsäureäthylester, C <-Bromessigsäure ethyl ester, and mixtures thereof.

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The ratio of the substance used as starting J ^, - halo-carbonyl compound is about 1 to 2 moles to one mole of the 2-aminobenzimidazole compound. However, this ratio can be changed without having any effect on the yield of the desired reaction products.

According to the invention, the acylbenzimidazole compounds (III, IV, IV) and the imidazo- (i, 2-a) benzimidazole compounds (V, VI, VI ¹ ) are obtained in the form of their salts with hydrohalic acids. These products Kgs _k NEN therefore continue to be transferred into their free bases, if ™ man dissolving the compounds in a minimal amount of solvent and to this a solution of basic salts such as sodium bicarbonates, sodium carbonate, sodium hydroxide added. Conversely, the free bases can of course be converted into their physiologically compatible salts.

The resulting hydrohalic acid salts of the acylbenzimidazole compounds (III, IV, IV) can be converted into the free bases of the corresponding imidazo- (i, 2-a) benzimidazole compounds (V, VI, VI ¹ ) if the former in a minimal amount of solvent up f dissolve and for this purpose either an alkaline solution of alkalis such as alkali hydroxides or a solution of weak alkali such as sodium carbonate and Natriumbicprbonat inflicts, whereby the free bases of the acyl-benzimidazole compounds (III, IV, IV ) and by refluxing these compounds.

It is one of the advantages of this invention that the # -halo-carbonyl compound connects directly to the hydrogen atom the imino group is directly condensed, which in

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1-position of the benzimidazole compound (I) is arranged instead of the hydrogen atom of the amino group in the 2-position being alkylated. Another advantage of this invention is that either of the two types of closed ring compounds can be produced by selecting the radicals R ₁ or R _{2 of} the general formula X-CH ₂ -CC-R ₁ or R ₂ , in view of the fact that the Structure of the imidazo- (i, 2-a ) -benzimidazole compound (V, VI, VI ¹ ) represents a closed ring structure in which three nitrogen atoms are arranged around the carbon atom.

Eg it was found that the abovementioned benzimidazole compounds and their physiologically acceptable salts with the indicated general formula, in which the substituents R ₁ and R _{2 represent} the indicated radicals, are new preconditions and that these new compounds have antibiotic echo and antiviral properties .

It has been shown that these effects of 1-acyl-benzicidaswx ·· Compounds and their physiologically acceptable salts are those of the luiidaso- Ci »2-a) -benzimidazole compounds and their physiologically compatible salts are superior.

Among the i-phenacyl ^ -aminobenzimidazole compounds and Their physiologically compatible salts have special effectiveness the compounds listed in the following Formula are given, as well as their physiologically acceptable salts.

f \ H -CH ₂ OO - \ 7

- X

• nHX 2
(where X represents a halogen atom)

009850/2154 BADORIQINAL

The invention is illustrated in the examples.

example 1

i-Phenacyl ^ -amino-bünzimidazole (1a) and 1,3-bisphenacyl-2-iminobenzimidazole (2a).

0.1 mol of 2-amino-benzimidazole, dissolved in 100 ml of methyl alcohol, was admixed with 0.1 mol of phenacyl bromide. The mixture was left to stand for 10 days at room temperature. Light brown, prism-like crystals separated out and were filtered off with suction. The product was recrystallized from methyl alcohol, whereby white, prism-like crystals of 1,3-bisphenacyl-2-iminobenzimidazole- (2a) -hydrobromide were obtained. Melting point: 283 to 284 ° C (decomposition). IR cm ": V c = 0.1690. The yield was 40 #.

The obtained compound was converted into its free base by dissolving the compound in methyl alcohol and adding a 10 # aqueous sodium bicarbonate solution until the precipitation of the corresponding compound was completed.
)

The product was recrystallized from methyl alcohol. It was white, needle-shaped crystals are having a melting point of 218 ⁰ C (decomposition) IR cnf ^1:. Ve = 0 1690th

After the hydrogen bromide salt of this compound (2a) had been filtered off, the piltrate was cooled to ⁰ ° C., whereby white, needle-shaped crystals were obtained.

The product was recrystallized from methyl alcohol to give 1-phenacyl-2-aminobenzimidazole (1a) hydrobromide

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with a melting point of 308 to 311 ^° C. (decomposition) was obtained. IR cm ": Yc = O 1690. The yield was 35 #.

obtained compound was converted into a free base (1a) by dissolving the compound in methyl alcohol and adding a 10 # aqueous sodium bicarbonate solution until the precipitation of the corresponding compound ceased. The product was recrystallized from methyl alcohol. It was white, needle-shaped crystals (1a) having a melting point 282-285 ⁰ C. (decomposition) represents IR cm ^"1:. Vo = 0 1687th

Example 2

2-phenylimidazo-Q2-aJl -benzimidazole (3a)

1-Phenacyl-2-aminobenzimidazole (1a) hydrobromide obtained by following the procedure of Example 1 was dissolved in methyl alcohol. A pale yellow precipitate was obtained by adding an aqueous 10% sodium hydroxide solution. The product was recrystallized from methyl alcohol to obtain white crystals of 2-Phenylimidazo- (i, 2-a) -benzimidazole (3a) obtained with a melting point of 269 to 27O ⁰ C (decomposition). IR cm "" ¹ : Vc = N 1619. Yield: 85 #.

After refluxing the methanolic solution of des for 24 hours 1-Phenaoyl-2-aminobenzlmidazole (1a) became the methyl alcohol distilled off at reduced pressure. By recrystallization the residue obtained from the methanolic solution were white, needle-shaped crystals of 2-phonyl-imidazo - (, 2-a) -benzimidazole (3a) obtained.

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By IR and UV spectroscopic analyzes and mixing investigations, the product obtained was with that of the Example 1 identified.

Example 3

1, S-bispbenacyl ^ -iminobenzimidazole (2a) and 2-phenyl-9-phenacylimidazo- (i _t 2-a) -benzimidazole (4a).

a) 0.01 mol of phenacyl bromide were added to 0.01 mol according to Procedure of Example 1 obtained i-phenacyl-2-aminobenzimidazole (1a) given. The product was dissolved in methyl alcohol and cooled to give a crystalline solid after refluxing for 5 hours on cooling. This product was recrystallized from methyl alcohol, producing white, prism-like crystals of 1,3-bisphenacyl-2-iminobenzimidazole (2a) hydrobromide in a yield of 75 #.

The product was determined by IR and UV spectroscopic investigations and by mixed investigations with that of the Example 1 identified.

The hydrobromide of the corresponding compound (2a) was obtained from a umkrietallisiert Alkobollösung with a yield of 95 f> after it was heated under reflux to obtain white, needle-shaped crystals of 2-phenyl-9-phenacylimidazo- (1,2-aJ - benzimidazole (4a) hydrobromide with a melting point of 268 to 269 ⁰ C (decomposition). The yield was 95 $> ·

This product was converted into a free base with a white crystalline form and a melting point of 218 ^° C. (decomposition) following the procedure of Example 1.

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b) 0.01 mol of phenacyl bromide was added to 0.01 mol of 2-Phony1-imidazo- (1,2-a) -benzimidazole (5a). The product was dissolved in methyl alcohol by refluxing for 5-8 hours on a water bath. Thereafter, the methyl alcohol was distilled off, whereby pale yellow crystals were obtained. The crystals were collected by suction and recrystallized AU3 methyl alcohol to obtain white, satin-like crystals of 2-phenyl-9-phenacyl-imidazo (I, 2-B _-) benzimidazole (4a) hydrobromide obtained in a yield of 80 i " became. This product was identified with that according to the procedure of Example 1 by means of IR and UV spectroscopic measurements and by mixed testing.

Example 4

i-p-chloro-phenacyl ^ -aminobonzimidazole (Ib) and 1,3-bis (p-chloro-phenacyp ^ -iminobenzimidazole (2b).

0.1 mole of 2-aniinobenziniidazole was dissolved in 200 moles of methyl alcohol. 0.1 mol of p-chlorophenacyl bromide was added to this solution. The product was left to stand at room temperature for 24 hours. A white, prism-like, crystalline precipitate precipitated out and was filtered off with suction. The product obtained was recrystallized from methyl alcohol to give 1,3-bis (p-chlorophenacyl) -2-iminobenzimidazol (2b) hydrobromide was obtained with a melting point of 260 ⁰ C (decomposition). IR cm "" ¹ : Vc = 0.1697. The yield was 33 #. The product was dissolved in methyl alcohol. A 10% aqueous sodium bicarbonate solution was added to this solution until the precipitation of the compound (2b) had ended. The product was recrystallized from dimethylformamide, giving white, needle-shaped crystals

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this compound with a melting point of 205 to 207 ⁰ C (decomposition) were obtained. IR cm: ^ c = 0 1691.

After the hydrobromide of the compound (2b) was filtered off, the filtrate was concentrated to 50 ml. White, needle-shaped crystals precipitated out and were filtered off. The obtained product was recrystallized from methyl alcohol, whereby 1-p-chlorophenacyl-2-aininobenzimidazole (1b) hydrobromide having a melting point of 310 to 312 C (decomposition) was obtained. IR cm: "^ c = 0 1689. The yield was 20 # The product was dissolved in methyl alcohol.", And by adding a 10 followed by aqueous sodium bicarbonate Löeung in the free base of compound (1b) transferred.

The product was recrystallized from dimethylformamide, whereby white, needle-shaped crystals of the compound (1b) with a melting point of 273 ^° C. (decomposition) were obtained . IR cm " ¹ : Yc = 0.1681.

Example 5

1,3-Bi8phenacyl-2-iminobenzimidazole (2a) and 1,3-bis (p-chlorophenacyl) -2-iminobenzimidazole (2b).

The procedure of Examples 1 to 4 was repeated, but using CCl ^ instead of methyl alcohol . In this case were obtained with a yield of 40 tf> i-phenacyl-2-aminobcnzimidazol (1a) and ip-chlorophenacyl ^ -aminobenziraidazol (1b).

The procedure described in Examples 1 to 4 was repeated, but working in butanol instead of methyl alcohol. It was 1 hour on

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Heated to reflux. There were thereby with 50 ^ igor yield 1,3-Bisphynacyl-2-iminobenzimidazole (2a) and 1,3-BiS (pchlorphenacyl) -2-iminobenzimidazole (2b) obtained.

Example 6

2-p-0hlorphGny limidazo - (i _y 2-a / -benziaidazo l (3b).

I-p-Chlorophenoyl-2-aminobenzimidazole prepared according to Example 4 (Ib) -hydrobroaid was dissolved in methanol. A 10% aqueous sodium hydroxide solution was used for this purpose given. The precipitated white, needle-shaped crystals were recrystallized from dinothyli'ormaldehyde.

The white, needle-shaped crystals de3 2-p-chlorophenylimidazo- (i, 2-a) -benzimidazole (3b) were obtained in a yield of 92 <fo . Melting point: 275 to 276 ^° C. (decomposition). IR cm " ¹ : Yo = IJ 1611.

Example 7

1,3-Bia (p-chlorophenyl) -2-iminobenzinidazole (2b) and 2 ~ (p ~ chlorophenyl) -9- (p-chlorophenacyl) i-midazo - , 2-a) -bonzimidazole (4b).

The procedure of Example 3 was repeated, except that p-Chlorine derivative was used. It got the same result obtained: namely, p-chlorophenacyl bromide was added to 2-aminobensimidazole in an equivalent amount, whereby 1 »3-bis (p-chlorophenacyl) -2-iminobenzimidazole (2a) hydrobromide (Example 4) was obtained. The product was refluxed in methyl alcohol, leaving white, needle-shaped

QO9850 / 21 5A BATH ORIGINAL

Crystals of 2- (p-Chloropbonyl) -9- (-chlorophenacylimidazo-Ij, 2-αJ-benzimidazole (4b) hydrobromide with a melting point of 321 to 323 ⁰ O (decomposition) were obtained
The product turned into white, needle-shaped crystals
converted to free base of the corresponding compound with a melting point of 218 to 219 ° 0 (decomposition).

Example 8

P 1 ~ p-Broinphenacyl-2-aminobenzimidazole (Ic) and

1,3-bis (p-bromophenacyl -) -2-iminobüqgimidazole (2c).

Following the procedure of Example 1, 0.1 mol of 2-aminobenzimidazole was dissolved in 300 ml of methyl alcohol, and 0.1 mol of bromophenacyl bromide was added. The solution was left to stand for 10 days at room temperature and then concentrated to 50 ml. This gave pale brown, needle-like crystals of 1,3-bis (p-bromophenacyl) -2-iminobenzimidazole (2c) hydrobromide, which were recrystallized from dimethylformamide. The product obtained had a melting point of 265 ^° C. (decomposition). IR cm "" ^1: 7o = O 1687. ^T he yield bek bore 38 b?.

The product was dissolved in methyl alcohol and a 10% sodium bicarbonate solution was added until the precipitation had ended. The product obtained was recrystallized from dimethyl formaldehyde to obtain white, needle-shaped crystals of this compound were obtained with a melting point of 222-224 ⁰ C (decomposition). IR cm " ¹ : Vc = 0.1688.

! laughing at filtering off the hydrobromide from compound (2c) the filtrate was concentrated under reduced pressure and

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-j? ' '■■■■ ■ "· ■' *

BAD ORIQINAt

the residue obtained is recrystallized from the corresponding methyl alcohol solution. The product obtained, T-bromo-phenacyl-2-aminobenzimidazole (Tc) -hydrobromide, had a melting point of 279 to 280 ° C. (decomposition). IR cm " ¹ j Vc = 0.1673. The yield was $ 28.

The product was dissolved in methyl alcohol and a 10 # solution of sodium bicarbonate was added to produce the free base. The free base was recrystallized from methanol to obtain white, needle-shaped crystals having a melting point 285-286 ⁰ C. (decomposition) were obtained. IR cm ": Vc = 0.1622.

Example 9

2-p-chlorophenylimidago- \ 1 »2-aj-benzimidazole 3h) and 2-pE romphcnylimidazo- (i _f 2. ~ a.) -Benzimidazole (3c).

Following the procedure of Example 2, ip-chlorophenacyl-2-amino-benzimidazql (1b) (Example 4) was dissolved in methyl alcohol and a 10% aqueous sodium bicarbonate solution was added. The white precipitate of the product obtained was urakristallisiert from dimethylformamide, thereby / woiße, needle-shaped crystals of 2-p-chloro-phenylimidazo- (i, 2-aj-benzim.idazols (3b) (with a melting point 275-276 C decomposition ^O ), with a yield of 92 <fo , '

In the same way, following the procedure of the example 8 obtained i-p-bromophenacyl-2-aminobenzimidazole (Ic) in Dissolved methyl alcohol and with a 10 ^ igen aqueous Sodium bicarbonate solution added »

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BAD ORIOINAL

'' JMm ^ ■:> -um

The wcii3c precipitate of the corresponding yorbond was uracrystallized from dimethylformamide, whereby white, needle-shaped crystals of 2-p-bronphenylimidazo- (i, 2-a) -bonzimidazole (3c) with a melting point of 279 to 280 C (decomposition) were obtained. IR cm: V c = N 1622. The yield was 96 fo.

Example! 10

T> 3-bis (p-bromophonacyl) -2-iminobenzimidazole (2 c) and 2- (p-bromophenyl) - 9 - (p-bromophenacyl) -imidazo-Ci, 2-a) -bcnziinidazole (4c) .

Following the procedure of Example 8, equivalent amounts of p-bromophenacyl bromide were added to the methanolic solution des 1-p-bromophenacyl - ^ - aminobenzimidazole (1c) given, whereby the 1,3-bio (p-bromophenacyl) -2-iminobenzimidazole (2c) -hydrobromide (Example 8) was obtained.

The product was converted into white, needle-shaped crystals of 2- (p-bromophonyl) -9- (pbromophenacyl) imidazo- (1,2-aJ-benzimidazole (4c) -hydrobromida with a melting point of 239 bis by heating under reflux for 10 hours 24O ⁰ O (decomposition). It was then converted into the free base of the corresponding compound according to the procedure of the example. This was white, needle-shaped crystals with a melting point of 240 to 242 ⁰ C (decomposition).

009850/21 Si * BAD OR) GINAl.

Example 11

2-methylimidazo- 'J, 2-aJ-benzimidazole.

0.1 mole of 2-aminobenzimidazole and 0.1 mole of bromoacetone were dissolved in 100 ml of butyl alcohol and placed in an oil bath
a! temperature of 130 to 135 ⁰ C heated under reflux for 30 minutes. During this time the reaction was complete. The solvent was distilled off from the reaction mixture under reduced pressure. The residue was dissolved in CHCl 2. A 10 # aqueous sodium bicarbonate solution was added to its methanolic solution.
The resulting solution was subjected to silica gel chromatography. The white, needle-shaped crystals of 2-methylimidazo- \\ , 2-a ) -benzimidazole were with 30

Yield obtained from the CHCl-z fraction. The melting point was. 251 to 253 ⁰ C (decomposition). IR cm " ¹ : Yg = N 1660.

Example 12

2-methyl-9-acetonylimidazo-Ci ^ -al-benzimidazole.

0.1 mol of 2-aminobenzimidazole and 0.1 mol of bromoacetone were dissolved in 100 ml of butyl alcohol. ^{The whole was kept at 0} ° C. for 24 hours, during which time white, needle-shaped crystals formed. The crystals were recrystallized from methyl alcohol, whereby 2-methyl-9-acetonylimidazo-0,2-a) -benzimidazole hydrobromide was obtained in a yield of 16 <f ₀ . The melting point was 208 to 210 ^° C. IR cm " ¹ : ^ c = 0 1728.

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Claims (7)

Claims 1. Process for the preparation of i-acyl-2-aminobenzimidazole and 1, 3-bisacyl-2-imino-benzimidazole derivatives and their physiologically compatible salts of the general formulas: N-CH ₂ COR ₁ CH ₂ COR ₁ in which R ₁ denotes hydrogen, alkyl or aryl groups, characterized in that 2-aminobenzimidazole derivatives are condensed with Cf \ -halocarbonyl compounds in the presence of a solvent. 2. The method according to claim 1, characterized gekennzelch net that the solvent from the group alcohols, CCl. and selects CHCl *.
4 ■> 3. The method according to claim 1 or 2, characterized in that at least one of the 0 ( -halocarbonyl compounds from the group O ^ -halo-ketones, Ά- halogen aldehydes and O (-halogen fatty acid esters is selected. 009350/2154 4. Ancestors "naoh · ι.incai .dux * claims 1 to 3, thereby g ü k e η η ζ Ό i c h not that · .man 1 to 2 mol of the • 'V-halo-carbonyl compound with 1 mol of the 2-amino-iuiiäazol-Vorb "in.iun, j implements. 5. Process for the preparation of 1,3-bisacyl-2-iiainobotizimidazole-Di.?. 'Ivaton and their physiologically compatible salts, characterized by the fact that one in the presence of the solvent 1-aoyl-2.-anino-b-gnzimidazole with an o (-halo-carboriyl compound. G * Process for the preparation of 9-acyl-imidazo- 1,2-a bonsimidaEol, thereby gcke η η ζ calibrated η et that iinidaz, o- (1,2-a) -benzimidazole in the presence of an IIO using a o (-HalOßun-carbonyl pre-bond converts. 7. Compounds of general formulas; 2H ₂ COR ₂ and 0 09 850/2154 ORIGINAt v / orin R ₁ and Rp, which can be different or different, denote hydrogen, alkyl or aryl groups. 6. VerMrulun ^ eti dor general Pcrmel: ■ <=> ■ ^x in v / clchor X Gin means Halogonatom, as well as their physiologically-compatible Snlze. 009850/21 BAD LOCAL