DE1695680A1 - Process for the preparation of cycloheptapyrrole derivatives - Google Patents

Description

The invention relates to a new and improved process for the preparation of cycloheptapyrrole derivatives.

In particular, it relates to a new and improved process for the preparation of cycloheptapyrrole derivatives the general formula

(D

wherein X is a lower alkyl group, phenyl group, halogen atom or lower alkoxy group, wherein η is an integer from 0 to 35 inclusive, wherein the Xs can be the same or different when η is an integer 2 or 3, wherein R is hydrogen atom or a ^{lower alkyl group and R 1 is} a lower alkyl group.

BATH ORIGINAL

109817/2168

In the above formula (I), the lower alkyl group can be represented, for example, by one of the following groups: methyl, ethyl, n-propyl, i-propyl, n-butyl, tert. -Butyl and n-pentyl. The lower alkoxy group can be represented, for example, by one of the following groups; Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, tert. -Butoxy and n-pentoxy. The halogen atom can be represented, for example, by bromine, chlorine or iodine. So far, two different methods have been available for producing cyeloheptapyrrole compounds which have the same structure as the above-mentioned derivatives (I). Japanese Patent No. 305,627 that a troponyl hydrazone can be converted into the corresponding cycloheptapyrrole with ring formation by heating in the presence of an acid catalyst. This older method can be considered satisfactory for the preparation of specific cycloheptapyrrole derivatives containing a lower alkyl group at the 3-position, although there is potential for further improvement in terms of yield and other factors by using this older method for the purpose of economical preparation there is such cycloheptapyrrole derivatives which have no substituents in the 3-position. The Journal of the Pharmaceutical Society of Japan, 82 (1962), 898 describes that 2-methylcyclohepta- £ b] -pyrrol-8 (1H) -one can be prepared by reacting a 3-halogeno-2-aminotropon with ethyl acetoacetate to form 2-methyl-3-ethoxycarbonylcyclohepta- (b) -pyrrol-8 (1H) -one with subsequent hydrolysis and decarboxylation.

109817/2168 - 3 -

The latter method, however, cannot be considered economically advantageous as it is proportionate it is difficult to find the starting material, namely the 3-halogeno-2-aminotropon, convenient to obtain which has been prepared by methylating a 3-halogenotropolon with subsequent amination with ammonia, as this process includes components such as the use of the very toxic and explosive gaseous agent diazomethane as a reagent in the first stage; the requirement of a complicated one Separating agent because of the simultaneous generation of a large amount of by-products, namely 2-halo-7-methoxytropone; and the simultaneous rearrangement into the undesired 6-membered compound, namely halobenzamide in the second amination stage, resulting in a reduced Yield of the desired tropone leads.

It is therefore a purpose of the present invention to provide a new and advantageous method of manufacture of cycloheptapyrrole derivatives (I) to be demonstrated with simple process management and high yield.

Further features emerge from the following, more specific description.

According to the invention, the cycloheptapyrrole derivative (I) are produced by a new process, which is characterized by the reaction of the tropolone derivative of general formula

GH GOR '

² (H)

109817/2168

wherein X, η and R 'have the meaning described above, with the amine derivative of the formula

RNH ₂ (III)

wherein R has the meaning described above, or with the Amine derivative of the formula

RNHCHO (IV)

wherein R has the meaning described above, in the presence of a basic substance.

In one embodiment of the invention, the

"The reaction is preferably carried out by reacting the Tropolone derivative (II) with the amine derivative (III) in a suitable inert organic solvent, such as alcohols, for example methanol, ethanol and n-propanol, ethers, for example dioxane and anisole and the like. Alternatively the reaction can also be carried out satisfactorily by using an excess amount of the amine derivative (III) both as a reagent and as a solvent in the absence of such an inert organic solvent. the

k reaction temperature is not a critical feature of the invention and can be applied mainly on the solvent-dependent, but it is generally in the range of room temperature to about 15> 0 ⁰ G, preferably room temperature for liquid ammonia, and about 100 to 130 ⁰ C for other solvents . The reaction time is not critical and depends mainly on the reaction temperature and the solvent used, but it is customary and preferred to carry out the reaction for several hours to several days. After the

109817/2168,

Reaction, the reaction product can be recovered and purified by any of the usual means, for example by Removal of the unreacted amine reagent and the solvent by distillation with subsequent recrystallization the residue from a suitable organic solvent such as ethanol or cyclohexane.

In another embodiment of the invention, the reaction is preferably carried out by using the tropolone derivative (II) is reacted with the amine derivative (IV) in Presence of a basic substance and a suitable organic solvent. Suitable examples of the applicable basic substance include carbonates, bicarbonates and hydroxides of alkali metals and alkaline earth metals, such as carbonates, bicarbonates and hydroxides of potassium, sodium, calcium and barium; Alkali metal salts of organic acids such as Sodium acetate, potassium acetate and sodium oxalate; Alkali metal alcoholates, such as sodium methylate and sodium ethylate; and organic bases such as triethylamine, pyridine and picolines. Suitable examples of the organic solvent to be used include hydrocarbons such as benzene, toluene and xylenes; Ethers such as dioxane and anisole; Alcohols like Methanol and ethylene glycol; and mixtures thereof, these being anhydrous or aqueous, but preferably anhydrous can. Alternatively, the reaction can also be carried out satisfactorily by using an excessive amount of the amine derivative (IV) both as a reagent and as a solvent in the absence of such an organic one Solvent. The reaction temperature is not a critical feature of the invention, it is generally in the range

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from about 50 to 170 ^° C. The reaction time is not critical, but the reaction is generally complete in one hour to several hours, which depends mainly on the reaction temperature used. After the reaction has ended, the reaction product can be recovered and purified in the usual way, for example by collecting the precipitating reaction product by means of filtration with subsequent recrystallization from a suitable organic solvent such as ethanol or cyclohexane.

The cycloheptapyrrole compounds (I) are useful as "intermediates for various medicines, for example as a hypotensor.

The invention is explained in more detail by the following examples

example 1

A mixture of 1.0 g of 3-acetonyltropolone with JO ml liquid ammonia was allowed to stand in a sealed tube for 3 days. The ammonia was then distilled off . and the residue is recrystallized from ethanol, whereby one 0.77 S 2-methylcyclohepta- {b) -pyrrol-8 (1H) -one as crystals obtained that melt at 191 ° C.

Example 2

A mixture of 5> 0 g of 3-acetonyltropolone with 60 ml of a. Ethanolic solution saturated with ammonia was left to stand for 5 days at room temperature. The ammonia and ethanol were distilled off and the residue was recrystallized from ethanol to give 1.7 g of 2-Methylcyclohepta-rb1-pyrrol-8 (1H) -one obtained as crystals, at 191 ⁰ C 0 schmelzen.1 9 817/2168

~ ⁷ ~ Ί695680

Example 3

A mixture of 1.0 g of I-acetonyl tropolone with 40 ml a 10 # strength ethanol solution of monomethylamine was placed in a sealed tube at 100 ° C. for 6 hours heated. The ethanol was then distilled off and the residue was chromatographed on an alumina column with benzene. After removal of the benzene, the crystalline substance obtained was recrystallized from cyclohexane, whereby 0.7 g of 1,2-dimethylcyclohepta-ibJ-pyrrol-8 (1H) -one was obtained as crystals which melt at 76 to 77.degree.

Example 4

A mixture of 1.0 g of 5j7-dibromo-3-acetonyltropolone with 30 ml of liquid ammonia was left to stand for 2 days in a sealed tube at room temperature. The ammonia was then distilled off, the residue was dissolved in dioxane, and the insoluble substances were removed by filtration. After treatment of the filtrate with activated charcoal, the dioxane was distilled off to obtain 0.6 g of 5,7-dibromo-2-methylcyclohepta-j ^ bJ -pyrrole-8 (1H) -one as crystals which do not melt at 300 ⁰ C .

Example 5

A mixture of 2.0 g of 3-acetonyl-6-isopropyltropolon with 40 ml of a 10 #igen ethanolic solution of monomethylamine was heated for 6 hours in a sealed tube to 13O ⁰ C. The monomethylamine and the ethanol were then distilled off, the oily residue was subjected to distillation under reduced pressure, 1.2 g of 1,2-dimethyl

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ö-isopropylcyclohepta- ^ j-pyrrole-SCiH ^ on as pale yellow oily Substance obtained that boils at 180 to 200 ° C / 0.2 mm Hg. The picrate of it forms yellow crystals that appear at 204- to Melting 205 ° C.

Example 6

110 ml of formamide and then 10 g of potassium carbonate were added to 11.2 g of 3-acetonyltropolone. The mixture obtained was stirred on an oil bath at a bath temperature of 130 to 135 ^° C. for 3.5 hours. After cooling, the

w precipitated crystalline substance is filtered off. The filtrate was concentrated under reduced pressure to leave an additional amount of crystalline matter. The combined crystalline substances were dissolved in a 10 # aqueous hydrochloric acid. The resulting solution was filtered to remove a small amount of insoluble substances. After adding aqueous sodium hydroxide to the filtrate, a crystalline substance was precipitated, which was recovered by filtration, washed with water and then converted from ethanol.

was crystallized, 8.0 g of 2-methylcyclohepta- (b] - pyrrol-8 (1H) -one, which ^{melts at 19I 0} C, were obtained.

Example 7

The same procedure as in Example 6 was repeated except that 3 »g of 5,7-dibromo-3-acetony / tropolone, 34 ml of formamide and 1.6 g of potassium carbonate were used. • to afford 1.1 g of 5, V-dibromo ^ -methylcyclohepta- [b \ -pyrrole-8 (1H) -one, which does not melt at 3OO ⁰ C.

109817/2168 " ⁹

ORIGINAL INSPECTED

1P95680

Example 8

A mixture of 30 g of 5-acetonyltropolone and 2.4 g of potassium carbonate in 25 ml of methylformamide was stirred for 2 hours at 150 to 155 ° C. on an oil bath. Then the reaction mixture was treated in the same manner as in Example 6, but recrystallized from cyclohexane to give 2.0 g of 1,2-Dimethylcyclohepta-ibj-pyrrol-8 (1H) -one received, the at 76-77 ⁰ C melts.

Example 9

A mixture of 2.4 g of 3-acetonyl-6-isopropyltropolon and 1.8 g of potassium carbonate in 24 ml of methylene Forma Raid was stirred for 2.5 hours at I50 to 155 ⁰ C on an oil bath.

After concentration under reduced pressure, the remaining oily substance was dissolved in a 10 # aqueous hydrochloric acid solved. The resulting solution was filtered to remove a small amount of insoluble substances and that Filtrate was made alkaline to deposit an oily substance, which was then extracted into chloroform and dried over anhydrous sodium sulfate, and then became the Solvent distilled off. The remaining oily substance was subjected to distillation under reduced pressure subjected to 1.0 g of i ^ -dimethyl-G-isopropylcyclohepta- £ bj -pyrrol-8 (1H) -one was obtained as a yellow oily substance which boils at 180 to 200 ° C / 0.2 mm Hg. The corresponding Picrate melts at 204 to 205 ° C.

Example 10

A mixture of 4.0 g of 3-benzoylmethyltropolone and 2.8 g of potassium carbonate in 40 ml of formamide was used for 5 hours

10 9 817/2168 _{0RIGINAL mpBym>} . 10 -

120 to 130 ⁰ G stirred on an oil bath. After concentration under reduced pressure, the residue was taken up in ethanol, heated and filtered while still hot in order to remove the insoluble substances which were not dissolved in ethanol. After the filtrate was concentrated, the crystalline substances were precipitated. The substances were collected by filtration and recrystallized from ethanol to obtain 2.5 g of 2-Phenylcyclohepta- £ b] pyrrole-8 (1H) -one, which melts bsi 212 ⁰ C.

Example 11

A mixture of 2.4 g of 5 ^ ^ -Diniethoxy -acetonyl tropolone and 1.5 g of potassium carbonate in 24 ml of formamide was stirred for 5 hours at 130 to 135 ⁰ C on an oil bath. The reaction mixture was then treated in the same manner as in Example 6 to give a crude crystalline substance which was recrystallized from ethyl acetate and 1.0 g of 2-methyl-5,7-dimethoxycyclohepta- ^ bJ -pyrrole-8 ( 1H) -one showed melting at 204 ⁰ C.

Patent claims:

- 11 109817/2168

Claims (3)

Patent claims: ¹ ZSS ϊξ :; 5 "- ™ ζγξζ ^ ϊ sz ss ϊΞ- 1, method of connecting the all common formula wherein X is a lower alkyl group, phenyl group, halogen atom or a lower alkoxy group, wherein η represents an integer from 0 to 3 inclusive, wherein the Xs may be the same or different when η is an integer 2 or 3, and wherein R is Hydrogen atom or a lower alkyl group and R ^{1 stands} for a lower alkyl group, characterized in that a compound of the general formula CH nOR 2 OH 0 wherein X, η and R ^{1 have} the meaning described above, reacts with a compound of the formula RKH ₂ wherein R has the meaning described above, or with one Compound of formula RMHCHO 109817/2168 -12- - Ί2 - '169F680 where R. has the meaning described above, in the presence a basic substance. 2. Process for the preparation of a compound of the formula wherein X is a lower alkyl group, phenyl group, halogen atom or a lower alkoxy group, wherein η represents an integer from 0 to 3 inclusive, wherein the Xs may be the same or different when η is an integer 2 or 3, and wherein R is Hydrogen atom or a lower alkyl group and R ^{1 stands} for a lower alkyl group, characterized in that a compound of the general formula CH COR '2 wherein X, η and R ^{1 have} the meaning described above, reacts with a compound of the formula RNH ₂ wherein R has the meaning described above. 3. Process for the preparation of a compound of the general formula 109817/2168 - 13 - R ¹ wherein X is a lower alkyl group, phenyl group, halogen atom or a lower alkoxy group, wherein η represents an integer from O to 3 inclusive, wherein the Xs may be the same or different when η is an integer 2 or 3, and wherein R is Hydrogen atom or a lower alkyl group and R ^{1 stands} for a lower alkyl group, " characterized in that a compound of the general formula GH ₂ COR ¹ wherein X, η and R ^{1 have} the meaning described above, reacts with a compound of the formula RNHCHO wherein R has the meaning described above, in the presence of a basic substance. 4-. Process for the preparation of 2-methylcyclohepta ip] -pyrrol-8 (1H) -one, characterized in that 3-acetonyltropolone is reacted with liquid ammonia or with formamide in the presence of potassium carbonate » 109817/2168