KR790000978B1 - Process for the preparation of amino pyrrole derivatives - Google Patents

Abstract

Aminopyrroles (I; R = H, C1-4 alkyl, benzyl and halo substituted benzyl ; R' = H, C1-4 alkyl, phenyl and C1-4 alky1, C1-4 alkoxybenzyloxy, halogen group, hydroxy; R2,, R3 = H; R4 = C2-4 aliphatic acyl, benzoyle, halogen group and substituted phenyl, carbo-C1-4 alkoxy, carboxy, carbamoyl ; R5 = H, C1-4 alkyl, carbo-C1-4 alkoxy, carboxy, trifluoromethyl, carbamoyl), useful as antiphlogistic agents, were prepd. by reaction of α-aminonitryl(II) or its salts and III (X =-C=C=- or -CH2-C=O).

Description

Method for preparing amino pyrrole derivatives

The present invention relates to a process for the preparation of an aminopyrrole derivative of formula (I), which is pharmaceutically effective.

In the above structural formula

R is hydrogen, C ₁ -C ₄ alkyl, benzyl or halo-substituted benzyl

R ₁ is hydrogen, C ₁ -C ₄ alkyl, phenyl or substituted phenyl

R ₂ is hydrogen, C ₁ -C ₄ alkyl, formyl, C ₁ -C ₄ aliphatic acyl, benzoyl, [carbo (C ₁ -C ₄ ) alkoxy]-(C ₂ -C ₄ ) aliphaticacyl, carbamyl, phenyl Carbamyl, thiocarbamyl, phenylthiocarbamyl, benzoylthiocarbamyl, carboxyphenyl, benzenesulfonyl, C ₁ -C ₄ alkylsulfonyl, toluenesulfonyl or phenacylsulfonyl.

R ₃ is hydrogen or C ₁ -C ₄ alkyl.

R ₄ is C ₂ -C ₄ aliphatic acyl, benzoyl, substituted benzoyl, carbo (C ₁ -C ₄ ) alkoxy, carboxy, carbamyl, methylcarbamyl or phenylcarbamyl.

R ₅ represents hydrogen, C ₁ -C ₄ alkyl, carbo (C ₁ -C ₄ ) alkoxy, [carbo (C ₁ -C ₄ ) alkoxy] methyl, trifluoro methyl, carboxy, carbamyl or carbamoyl ,

R ₂ and R ₃ together form C ₂ -C ₄ alkylidene, benzylidene or halo-substituted benzylidene

R ₄ and R ₅ together may represent —CO— (CH ₂ ) _n −, _where n is an integer of 2-4. (Provided that when R ₁ and R ₅ simultaneously represent methyl and R represents hydrogen, one of R ₂ and R ₃ is not hydrogen and R ₄ is not carethoxy.)

"C ₁ -C ₄ alkyl" as used herein denotes alkyl radicals having 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl. "Halo-substituted benzyl" refers to benzyl radicals in which aromatic rings are substituted with fluorine, chlorine or cancellation, such as P-chlorobenzyl, O-chlorobenzyl, P-fluorobenzyl, O-bromobenzyl, m-bromo Benzyl. "Substituted phenyl" means a phenyl radical substituted with 1-3 groups selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy benzyloxy, cancelled, chlorine, fluorine, hydroxy, nitro,

"C ₂ -C ₄ aliphatic acyl" is an aliphatic acyl radical having 2-4 carbon atoms such as acetyl, propionyl, butyryl and isopropyl,

"C ₁ -C ₄ alkoxy" is an alkoxy group having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,

“Substituted benzoyl” refers to a benzoyl radical having 1-3 substituents selected from fluorine, chlorine, cancelled, C ₁ -C ₄ alkoxy,

“C ₁ -C ₄ alkylidene” radicals are ethylene, propylidene, isopropylidene, butylidene, isobutylidene,

"Halo-substituted benzylidene" means chlorine such as O-chlorobenzylidene, m-chlorobenzylidene, P-chlorobenzylidene, P-fluorobenzylidene, O-fluorobenzylidene, m-bromobenzylidene, Refers to a benzylidene radical substituted in an aromatic ring with fluorine or withdrawal.

When the R ₄ and R ₅ radicals together represent a —CO— (CH ₂ ) _n —group, the carbonyl group is bonded to the carbon atom of the pyrroring having the substituent R ₄ .

Preferred compounds of formula (I) are those in which R is hydrogen, methyl, benzyl or benzyl substituted chlorine, R ₁ represents hydrogen, phenyl or methyl, methoxy, fluorine, phenyl substituted R ₂ is hydrogen, Acetyl, methyl or methylsulfonyl, R ₃ is hydrogen or methyl, R ₄ is acetyl, propionyl, butyryl, isobutyryl, carbomethoxy, carethoxy, carboxy, carbamyl or benzoyl, R ₅ is Hydrogen, methyl, carbomethoxy, carbamyl or carboxy, R ₂ and R ₃ together represent benzylidene or chlorine substituted benzylidene, and R ₄ and R ₅ together represent -CO- (CH ₂ ) _3- ; Carbonyl groups which form a group, are compounds which are bonded to the carbon atom of the pyrroring having a R ₄ radical.

The method for preparing the compound of formula (I) according to the present invention is as follows.

It is obtained by reacting the α-aminonitrile of the general formula (II) or an acid addition salt thereof with the compound of the following formula (III).

In the above structural formula

-그룹(-CH₂-부분은 치환체 R₄와 연결된다.)을 나타낸다. 이 분야의 전문가라면 누구나 β-디카보닐 화합물 또는 아세틸렌카보닐 화합물이 나타내는 성질과 유사한 화학적 성질을 가지는 물질이, 예를들면 X가 -CH=C-hal(hal은 할로겐 원소로 염소가 적당하며 할로겐 원소를 갖는 탄소원자는 라디칼 R₅에 연결된다)인 구조식(Ⅲ)의 화합물처럼 사용될 수 있다는 것은 자명한 일이다.R is hydrogen, R ₁ , R ₄ , R ₅ are the same as in formula (I) and X is -C≡C-group or -CH _2-

-Group (-CH ₂ -moiety is linked to substituent R ₄ ). Anyone skilled in the art would have a material with chemical properties similar to those represented by β-dicarbonyl compounds or acetylenecarbonyl compounds. For example, X is -CH = C-hal (hal is a halogen element, and chlorine is a suitable halogen. It is obvious that a carbon atom having an element can be used as a compound of the formula (III), which is connected to the radical R ₅ ).

Starting materials aminonitrile can be obtained according to the methods described in star or bitter "organic synthesis" (22, 13, 1942 and 22, 23, 1942).

The compound of formula III can be obtained as a product or obtained by modifying them.

In general, this reaction produces a ring-opening compound represented by the following formula (IV) or its tautomeric imine form as an intermediate product, which, if necessary, can be separated and purified according to conventional analytical methods before cycling to the final product of formula (I). There is a number. However, it can also be used as raw material for the next cycling reaction.

Reactants (II) and (III) react in equimolar amounts in the presence of anhydrous organic solvents selected from benzene, dioxane, tatrahydrofuran, lower alkanols and the like. A small amount of P-toluene sulfonic acid is also added as a catalyst and the mixture is refluxed for 2-28 hours. The intermediate compound of formula IV can be separated and purified or used for the next cycle reaction, in which basic catalysts such as carbonates, hydroxides, alkoxides, hydrides of Group I, II metals of the periodic table Proceed in the presence of an amide.

In this case, the reaction may be carried out in the presence of a solvent (preferably anhydrous lower alkanol having up to 4 carbon atoms) at room temperature, but the reaction mixture may be removed to terminate the cycle in 1-30 hours. It is sometimes necessary to heat or backflow.

In some cases, when X represents a -C≡C-component, the production of the aminopy derivatives of formula (I) can occur in only one reaction step. In this case, the aminonitrile of formula (II) or an acid addition salt thereof and the compound of formula (III) wherein X is -C≡C- group are mixed together in equimolar ratio. At this time, an organic solvent such as anhydrous C ₁ -C ₄ alkanol, chloroform, tetrahydrofuran, benzene and the like is reacted in the presence of alkali or alkaline earth metal carbonate or hydroxide and the reaction mixture is refluxed for about 3-5 hours.

The compound of final product structure (I) is recovered from the reaction mixture according to conventional methods in the form of a free base or in the form of a pharmaceutically possible salt.

The reaction mixture is evaporated to remove the solvent, the residue is treated with a solvent, the solvent is evaporated again and the resulting solid, liquid or oily substance is purified by recrystallization, fractional distillation or distillation under reduced pressure. If a crystalline solid is obtained immediately, it is recovered by filtration and, if necessary, purified by recrystallization. Preferred recrystallization solvents are C ₁ -C ₄ lower alkanols, ethyl ethers or mixtures thereof.

Pharmaceutically possible salts of the compound of formula (I) include hydrosololide, hydrobromide, hydroiodide, sulphate, fourstate, benzoate, oxalate, acetate, methanesulfonate, sizohexylsulfonate, and the like. These salts can be readily obtained as free bases by treating pharmaceutically possible acids and returning these organic bases by reaction with base agents in an amount of at least one molar ratio.

According to the above method, the compounds of formula (I) wherein R, R ₂ , R ₃ and hydrogen are hydrogen and salts thereof can be obtained. When substituents R ₂ and R ₃ are not hydrogen, the compound of formula (I) can be obtained by reacting with a suitable reactant. For example, a second carboxy group is reacted with a mono-halide of C ₃ -C ₅ dicarboxylic acid esterified with C ₁ -C ₄ alkanol so that R ₂ is [carbo (C ₁ -C ₄ ) alkoxy]-(C ₂ -C ₄ ) to obtain a compound which is an aliphatic acyl, while reacting with an alkylating agent such as a mixture of formic acid and formaldehyde, C ₁ -C ₄ alkyl halide or C ₁ -C ₄ alkyl sulphate R ₂ or R ₃ , R ₂ and R ₃ both yield C ₁ -C ₄ alkyl. Compounds in which R ₂ is C ₂ -C ₄ aliphatic acyl radical or benzoyl are obtained by reacting a compound of formula (I) with a halide or anhydride of C ₂ -C ₄ aliphatic or benzoin acid, while benzenesulfonyl, toluenesulfonyl, C ₁ -C ₄ alkylsulfonyl and phenacylsulfonyl derivatives are obtained by reaction with benzenesulfonyl, toluenesulfonyl, C ₁ -C ₄ alkylsulfonyl, phenacylsulfonyl halite, respectively.

Derivatives of carbamyl and thiocarbamyl groups and their methyl-, phenyl-, benzoyl-like derivatives are obtained by reacting aminopyrroles of the formula (I), wherein R ₂ and R ₃ are hydrogen, with a suitable isocyanate or isothiocyanate compound. 3 which is included mill substituting one of the hydrogen atoms of the amino group in the position to obtain the same molar ratio to react a 3-amino-pyrrole and acid catcher in R ₂ is a carboxy-phenyl compound of the formula (Ⅰ) R ₂ is hydrogen Obtained by reacting a compound with an benzoin acid substituted with a halogen element in an aromatic ring. Compounds in which R ₂ and R ₃ together represent C ₂ -C ₄ alkylidene, benzylidene or halo-substituted benzylidene are readily obtained according to the method for obtaining the Schiffs base from amine and carbonyl compound.

In general, the reaction of substituting with a nitrogen atom does not occur under reaction conditions of substituting R ₂ and R ₃ radicals with the nitrogen atom at the 3-position. A convenient way to substitute substituents according to formula (I) to the nitrogen atom ham of pyrroling is to use a C ₁ -C ₄ alkyl, benzyl or halo-substituted benzyl halide and a strong base agent, wherein R ₂ is hydrogen. (Alkali metal or alkali metal hydride is suitable) in the presence of nitrogen gas in an inert organic solvent such as dimethylformamide. This reaction proceeds at room temperature. The aminopyrrole substituted in position 1 is separated from the reaction mixture in good yield. Under these reaction conditions, even when R ₂ or R ₃ or R ₂ and R ₃ represent hydrogen, these atoms may be substituted with the substituents described above. Thus, the amino group at the 3-position in the obtained compound may be substituted with one or two C ₁ -C ₄ alkyl groups at the same time. However, if R ₂ and or R ₃ are compounds of the formula (I) where hydrogen is substituted in the nitrogen atom nucleus, it is necessary to protect the amino group at the 3-position. Such protection is, for example, by reaction with a carbonyl compound or alkyl sulfonyl or benzene sulfonyl halide, respectively, to obtain the corresponding Schiff base or alkylsulfonyl or benzenesulfonyl amino derivatives. Subsequently, substitution is carried out at the 1 position and the protecting group is released by acidic hydrolysis to obtain a compound in which R ₂ and or R ₃ are hydrogen.

Sulfonylation of the amino group at position ₃ gives a compound of formula (1) wherein R is hydrogen, R ₂ is hydrogen and R ₃ is a C ₁ -C ₄ alkyl group. The amine nitrogen of the compound of formula (1) wherein R is hydrogen, R ₂ is benzenesulfonyl, C ₁ -C ₄ alkylsulfonyl, toluenesulfonyl or phenacylsulfonyl, and R ₃ is hydrogen is a C ₁ -C ₄ alkyl group Alkylation with an alkylated amine. The R ₂ group is hydrolyzed with acid to leave.

The radicals R ₄ and R ₅ can also be substituted with the substituents described above by known chemical reactions. For example, to obtain a compound of formula (1) wherein R ₄ or R ₅ or R ₄ and R ₅ are carboxy groups, the corresponding mono- or di-carbo (C ₁ -C ₄ ) alkoxy under alkaline or acidic conditions Hydrolysis of the derivative yields the desired compound. Structural formula (1), wherein R ₄ or R ₅ or R ₄ and R ₅ represent carbamyl groups is obtained by saturating an alcoholic solution of the corresponding mono- or di-carbo (C ₁ -C ₄ ) alkoxy compound with ammonia. R ₅ is a carbamoyl of compounds R ₅ is obtained by reacting hydrazine compound and the carbonyl (C ₁ -C ₄₎ alkoxy in formula (ⅰ) at room temperature.

The pyrroleamino derivatives of formula (I) prepared according to the present invention have very interesting pharmaceutical properties, i.e. have pronounced anti-inflammatory and central nervous system inhibitory properties.

Anti-inflammatory ability was confirmed by edema testing induced by carrageenin in rats. (CA Winter et al., Proc. Soc. Exptl. Biol. Med., 111, 544, 1962) Examples 1, 2, 3, 7, 14, 15, 16, 18, 20, 21, 23, 27, 34, 82, 47, 50, 52, 59, 70, 71, 74 a), 74 b), 78, 79, 87 compounds of LD ₅₀ administered 1 / 50-1 / 5 Dosing in a dose resulted in about 40-80% reduction in edema. Under the same experimental conditions, an anti-inflammatory agent such as phenylbutazone (4-butyl-1,2-diphenyl-pyrazolidine-3,5-dione) reduced about 45%, but was administered in a quarter or more of LD ₅₀ . It is when. It is also noted that the toxicity of the aminopyrrole derivatives, which is the object of the present invention, is very low. Indeed, with some exceptions, the LD ₅₀ of the compounds according to the invention is always at least 1,000 mg / kg PO, but the LD ₅₀ of the corresponding phenyl butazone is about 390 mg / kg PO. Toxicity is described in Lichtfield & Wilcoxou, J. Pharm. Exp. Ther.) Was measured according to the method described in 96, 99, 1949.

The following table shows the anti-inflammatory effect described above in detail.

[table]

The compounds prepared according to the invention also have other biological properties required for potent anti-inflammatory agents. Indeed, the compound exhibits pronounced antipyretic and analgesic effects, which are two, ten and four times greater than acetylsalicylic acid, respectively. Moreover, it exhibits very low ulceration, about 5-10 times lower than other commonly known anti-inflammatory agents, such as acetylsalicylic acid and phenylbutazone. Painless action is L.O. Randall and J.J. Selitto Arch. Int. It was measured according to Pharmaco dyn., No. 4, CXI, 409p, 1957. Antipyretic effect is R.H. According to Buller and his colleagues, J. Pharm Pharmacol., 9, 128, 1957, ulceration was measured by Thuilliet and his colleagues, Chim. Therap., 3,53, 1968.

As mentioned above, aminolpyrrole derivatives are also effective in the central nervous system. This property was measured by the general method according to S. Irwin, Psychopharmacologia (Berl.) 13,222, 1968. Some compounds that exhibit particularly effective anti-inflammatory effects, such as the compounds of Examples 1 and 15, also exhibit a good degree of sedation and muscle relaxation. This property is useful for patients with severe inflammation. Further compounds according to the invention also have very beneficial ansiolytic properties.

These properties are described in G. Maffil, J. Pharm. Examination was performed according to the "Pole Climbing avoidance test" for mice according to Pharmacol., 11,129, 1959. In a representative experimental example, the compounds of Examples 4,30,46 are particularly effective at inhibiting secondary conditional reflection (CR ₂ ) in rats at doses that are not effective for primary conditional reflection (CR) and unconditional reflection (UR). Do. Secondary condition reflection is related to the anxiety of the animal and its inhibition is directly affected by the administration of anxiety agent.

The results are summarized in the following table and the toxicity is also shown. It has also been shown that meprobamate (2-methyl-2-propyl-1,3-propanediol dicarbamate) has a lower anxiety effect than the test compound.

[table]

For oral administration, the active compounds are formulated into pharmaceutical dosage forms such as tablets, capsules, solutions and the like. Dosage units may contain conventional excipients such as starch, gums, fatty acids, alcohols, sugars and the like. Rectal administration is administered by suppository in combination with conventional carriers such as cacao butter, oak, gyeongnam or polyoxyethylene glycol and derivatives thereof. Dosage is about 0.05-2.00g per day, it is recommended to divide several times.

The following example is an example for explaining in detail the manufacturing method according to the present invention.

Example 1

4-acetyl-3-amino-5-methyl-2-phenyl-pyrrolehydrochloride

a) A solution of 2 g (0.015 mol) of 2-amino-2-phenylacetonitrile and 1.4 g (0.014 mol) of acetylacetone in 30 ml of anhydrous benzene on an oil roof in the presence of 100 mg of P-toluenesulfoninic acid for 2 hours. Reflux. After cooling the reaction mixture is filtered and the solvent is evaporated to give an oily residue which is distilled under reduced pressure. The boiling point of the ring-opening compound (middle product) thus obtained is 150 ° C./0.1 mmHg.

b) 0.4 g of sodium is dissolved in 15 ml of anhydrous ethanol, and then a solution of 2.5 g of the compound of a) is added dropwise to anhydrous ethanol and the mixture is left at room temperature for 4 hours. Dry hydrogen chloride is bubbled into the ethanol solution, the precipitate is obtained, filtered and recrystallized from ethanol / diethyl ether. Yield 2.0 g Melting point 242 ° C. (decomposition). This free base is obtained by extraction with ethyl acetate of a hydrochloride solution that is alkaline with 5% sodium hydride. Melting point 220 ° C. (methano).

Example 2

3-Amino-4-carethoxy-5-methyl-2-phenyl-pyrrole hydrochloride

a) A solution of 6 g (0.042 moles) of 2-amino-2-phenylacetonitrile and 5 g (0.042 moles) of ethylacetoacetate in 30 ml of anhydrous benzene was dissolved in 4 days in a 100-day bath in the presence of 100 mg of P-toluenesulfoninic acid. Time backflow. After cooling, the reaction mixture is filtered and the solvent is evaporated to give an oily residue which is distilled under reduced pressure to give a ring-opening intermediate product. Boiling point 0.05: 140 ° C

b) 0.80 g of sodium is dissolved in 15 ml of anhydrous ethanol, and a solution of 5 g of the compound according to a) is added dropwise to 35 ml of anhydrous ethanol and the reaction mixture is allowed to stand at room temperature for 4 hours. Dry hydrogen chloride is bubbled into the ethanol solution to obtain a precipitate which is filtered and recrystallized from a mixture of ethanol and dimethyl ether. Yield 4 g Melting point 249-252 ° C. (from ethanol / ethylether).

Example 3-42

The following compounds were prepared using alkali metal alkoxides or carbonates as cyclization basic catalysts with starting compounds of the appropriate compounds of formulas II and III according to the two-step method described in Example 1. If the ring-opening intermediates are separated, their chemical and physical properties are known while the intermediates are immediately cyclized to the final product.

3. 3-Amino-4-benzoyl-5-methyl-2-phenyl-pyrrolehydrochloride

The ring-opening intermediate is obtained from 2-amino-2-phenyl-acetonitrile and benzoylacetone. Melting point 134-135 ° C. (diethyl ether / hexane) The title compound is obtained with a total yield of 60%. Melting Point 285-290 ° C. (Methanol / Diethylether) Free Base dissolves at 203-205 ° C. (Methanol).

4. 3-Amino-6,7-dihydro-2-phenyl-indol-4- (5H) -one hydrochloride

The ring-opening intermediate is obtained from 2-amino-2-phenyl-acetonitrile and sizolohexane-1,3-dione. Melting point: 138-140 ° C. (benzene) Total yield of the title compound: 58% Melting point 290-291 ° C. (ethanol / diethyl ether)

5. 3-Amino-4-benzoyl-2-phenyl-pyrrole hydrochloride

A ring-opening intermediate is obtained from 2-amino-2-phenyl-acetonitrile and benzoylacetaldehyde. Melting point 88-90 ° C. (hexanes). 47% yield of the title compound, melting point: 272-274 ° C (ethanol)

6. 4-Acetyl-3-amino-2-ethyl-5-methyl-pyrrolehydrochloride

The ring-opening intermediate is obtained from 2-amino-butytonitrile and acetyl acetone. Boiling point 0.02: 100 ° C., title compound yield: 49%, melting point: 254-248 ° C. (ethanol / diethyl ether). Melting point of free base: 219-221 ° C. (Methanol).

7. 3-Amino-4-carbethoxy-2-phenyl pyrrole hydrochloride

45% from 2-amino-2-phenylacetonitrile and ethylpropinoate. Melting Point: 244 ° -245 ° C (Ethanol / Diethyl Ether)

8. 3-Amino-4-benzoyl-5-carethoxy-2-phenyl-pyrrolehydrochloride

48% of the title compound is obtained from 2-amino-2-phenyl-acetonitrile and benzoylpivinic acid ethyl ester at a melting point of 218-219 ° C. (ethanol / diethyl ether).

9. 4-acetyl-3-amino-2-phenyl-pyrrolehydrochloride

A ring-opening intermediate product having a boiling point of 0.05: 140 ° C. is obtained from 2-amino-2-phenyl-acetonitrile and acetylacetaldehyde. Total yield 56% of the title compound, insoluble to 335 ° C.

10. 4-acetyl-3-amino-2- (P-methoxyphenyl) -pyrrole

Ring opening intermediates are obtained from 2-amino-2- (P-methoxyphenyl) -acetonitrile and acetylacetaldehyde. Boiling point 0.03: 180 ° C. Title compound yield 44%, Melting point: 198-200 ° C. (diethyl ether)

11.3-Amino-4-benzoyl-5-methyl-pyrrole hydrochloride

The intermediate product is obtained from aminoacetonitrile and benzoylacetone. Melting point: 111-112 ° C (diethyl ether) Title compound yield: 52%, Melting point: 225-270 ° C (ethanol / diethyl ether)

12. 4-Acetyl-3-amino-5-methyl-pyrrole hydrochloride

Ring opening intermediate products are obtained from aminoacetonitrile and acetylacetone. Melting Point: 1056108 ° C (Diethyl Ether) Yield of the title compound: 64%, Melting Point: 211-212 ° C (ethanol)

13. 3-Amino-4-carethoxy-5-carethoxymethyl-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and 1,3-dicarbethoxyacetone

Yield: 42%

Melting Point: 232-236 ° C (Diethyl Ether / Ethanol)

14. 4-acetyl-3-amino-5-methyl-2- (P-tolyl) -pyrrole

Starting material: 2-amino-2- (P-tolyl) -acetonitrile and acetyl acetone

Yield: 94%

Melting Point: 232-234 ° C (ethanol / dierol ether)

15. 4-Acetyl-3-amino-2- (P-methoxyphenyl) -5-methyl-pyrrole

Starting material: 2-amino-2- (P-methoxyphenyl) -amitonitrile and acetyl acetone

Yield: 92%

Melting Point: 222-223 ° C (Ethanol)

16. 3-Amino-4-carethoxy-5-methyl-2- (P-tolyl) -pyrrolehydrochloride

Starting material: 2-amino-2- (P-tolyl) -acetonitrile and ethylacetoacetate

Boiling point of intermediate product 0.05: 160 ℃

Yield: 88%

Melting Point: 266-268 ° C (Methanol)

17. 3-Amino-4-carethoxy-2-phenyl-5-trifluoromethyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenylacetonitrile and trifluoro acetyl ethyl acetate

Yield: 52%

Melting Point: 203-205 ° C (Ethanol)

18. 4-Acetyl-3-amino-2- (P-fluorophenyl) -5-methyl-pyrrole

Starting material: 2-amino-2- (P-fluorophenyl) -acetonitrile and acetyl acetone

Boiling point of intermediate product 0.3: 150 ℃

Title compound yield: 47%

Melting Point: 211-212 ° C (Ethanol)

19. 3-Amino-4-carbethoxy-2- (P-fluorophenyl) -5-methyl-pyrrolehydrochloride

Starting material: 2-amino-2- (P-fluorophenyl) -acetonitrile and ethyl aceto acetate

Boiling point of intermediate product 0.2: 220 ℃

Yield of the title compound: 53%

Melting Point: 258-260 ° C (Ethanol / Diethyl Ether)

20. 3-Amino-4-carethoxy-5-methyl-pyrrolehydrochloride

Starting material: amino acetonitrile and ethyl aceto acetate

Melting Point of Intermediate: 90-98 ° C (Methanol)

Yield of the title compound: 44%

Melting Point: 211-214 ° C (Methanol)

21. 3-Amino-4-isobutylyl-5-methyl-2-phenyl-pyrrole

Starting material: 2-amino-2-phenyl-acetonitrile and -5-methyl-hexane-2,4-dione

Boiling point of intermediate product 0.3: 150 ℃

Yield of the title compound: 64%

Melting Point: 180-183 ° C (Methanol / Diethyl Ether)

22. 3-Amino-5-methyl-2-phenyl-4-propionyl-pyrrole

Starting material: 2-amino-2-phenyl-4-acetonitrile and hexane-2,4-dione

Boiling point of intermediate product 0.3: 160 ℃

Yield of the title compound: 53%

Melting Point: 166-168 ° C (Methanol)

23. 4-Acetyl-3-amino-5-methyl-2- (m-tolyl) -pyrrole

Starting material: 2-amino-2- (m-tolyl) -acetonitrile and acetyl acetone

Boiling point of intermediate product 0.02: 170 ℃

Yield of the title compound: 59%

Melting Point: 195-197 ° C (Ethanol)

24. 4-Acetyl-3-amino-2-ethyl-5-methyl-pyrrole hydrochloride

Starting material: 2-amino-butyronitrile and acetyl acetone

Yield: 73%

Melting Point: 245-248 ° C (Methanol)

25. 3-Amino-4- (P-methoxybenzoyl) -5-methyl-2-phenyl-rirol

Starting material: 2-amino-2-phenyl-acetonitrile and (P-methoxy benzoyl) -acetone

Yield: 43%

Melting Point: 219-221 ° C (Ethanol)

26. 4-Acetyl-3-amino-2- (P-benzyloxyphenyl) -5-methyl-pyrrole

Starting material: 2-amino-2- (P-benzyloxyphenyl) -acetonitrile and acetylacetone

Yield: 51%

Melting Point: 245-250 ° C (Ethanol)

27. 4-acet-3-amino-2- (P-chlorophenyl) -5-methyl-pyrrole

Starting material: 2-amino-2- (P-chlorophenyl) -acetonitrile and acetyl acetone

Yield: 67%

Melting Point: 205-208 ° C (Ethanol)

28. 3-Amino-4-carbethoxy-2- (P-methoxyphenyl) -5-methyl-pyrrolehydrochloride

Starting material: 2-amino-2- (P-methoxyphenyl) -acetonitrile and ethyl acetoacetate

Yield: 44%

Melting Point: 234-236 ° C (Methanol)

29. 3-Amino-4-benzoyl-2- (P-fluorophenyl) -5-methylpyrrole

Starting material: 2-amino-2- (P-fluoroferyl) -acetonitrile and benzoyl acetone

Boiling point of intermediate product 0.2: 120 ℃

Yield of the title compound: 66%

Melting Point: 209-210 ° C. (Ethanol / Diethyl Ether)

30. 4-Acetyl-3-amino-2- (0-tolyl) -5-methyl-pyrrole

Starting material: 2-amino-2- (0-tolyl) -acetonitrile and acetylacetone

Intermediate Product Boiling Point 0.2: 120 ℃

Yield of the title compound: 77%

Melting Point: 258 ° C (Methanol)

31. 3-Amino-4-carbomethoxy-5-carbomethoxymethyl-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and 1,3-dicarbomethoxy-acetone

Yield: 48%

Melting Point: 210-213 ° C (Methanol)

32. 3-Amino-5-methyl-4-methylcarbamyl-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and α-acetyl-N-methyl-acetamide

Yield: 55%

Melting Point: 247-250 ℃ (ethanol)

33. 3-Amino-4- (0-chlorobenzoyl) -5-methyl-2-phenyl-pyrrole

Starting material: 2-amino-2-phenyl-acetonitrile and 0-chlorobenzoyl-acetone

Yield: 51%

Melting Point: 214-216 ° C (Ethanol)

34. 3-Amino-4-carbamyl-5-methyl-2-phenyl-pyrrole hydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and α-acetylacetamide

Melting Point of Intermediate: 128-130 ° C (Diethyl Ether)

Yield of the title compound: 49%

Melting Point: 307-309 ° C (Methanol)

35. 3-Amino-4-butyryl-2-phenyl-5-propyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and nonane-4,6-dione

Yield: 60%

Melting Point: 228-230 ° C. (Decomposition, Methanol / Diethyl Ether)

36. 3-Amino-4-butyryl-5-methyl-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and heptane-2,4-dione

Yield: 48%

Melting Point: 240-245 ° C (Decomposition, Methanol / Diethyl Ether)

37. 3-Amino-4, 5-dicarbomethoxy-2- (P-chlorophenyl) -pyrrolehydrochloride

Starting material: 2-amino-2- (P-chlorophenyl) -acetonitrile and dicarbomethoxyacetylene

Melting Point of Intermediate: 74-76 ° C (Diethyl Ether)

Yield of the title compound: 48%

Melting Point: 216-218 ° C (Methanol / Diethyl Ether)

38. 3-Amino-4,5-dicarbomethoxy-2- (P-tolyl) -pyrrole hydrochloride

Starting material: 2-amino-2- (P-tolyl) -acetonitrile and dicarbomethoxy-acetylene

Melting Point of Intermediate: 76-77 ° C (Diethyl Ether / hexane)

Yield of the title compound: 70%

Melting Point: 193-196 ° C (Methanol / Diethyl Ether)

39. 3-Amino-4, 5-dicarethoxy-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and dicarbethoxy acetylene

Boiling point of intermediate product: 0.03: 140 ℃

Yield of the title compound: 78%

Melting Point: 193-196 ° C (Ethanol / Diethyl Ether)

40. 3-Amino-4, 5-dicarbomethoxy-2- (P-methoxyphenyl) -pyrrolehydrochloride

Starting material: 2-amino-2- (P-methoxyphenyl) -acetonitrile and dicarbomethoxyacetylene

Melting point of intermediate product: 86-88 ℃ (hexane)

Yield of the title compound: 63%

Melting Point: 195-197 ° C (Methanol / Diethyl Ether)

41. 3-Amino-4, 5-dicarbomethoxy-2-ethyl-pyrrolehydrochloride

Starting material: 2-amino-butyronitrile and dicarbomethoxy acetylene

Yield: 66%

Melting Point: 209-210 ° C (Diethyl Ether / Methanol)

42. 3-Amino-4, 5-dicarbomethoxy-2-phenyl-pyrrolehydrochloride

Starting material: 2-amino-2-phenyl-acetonitrile and dicarbomethoxy acetylene

Yield: 39%

Melting Point: 205-207 ° C (Methanol / Diethyl Ether)

Melting Point of Organic Base: 142-143 ° C (Diethyl Ether)

Example 43

4-acetyl-3- (2-carethoxyacetylamino) -5-methyl-2-phenyl-pyrrole

16 g (0.0748 mol) of the compound of Example 1 was dissolved in 300 ml of chloroform. A saturated sodium bicarbonate solution is added and 14 g (0.0933 mol) of malonic acid ethyl ester are added dropwise and the mixture is stirred at room temperature for 2 hours. The solution is concentrated to dryness and the residue is treated with diesel ether and filtered. Recrystallization from acetone / hexanes carried 13.5 g of the title compound.

Melting Point: 178-180 ℃

Example 44-45

According to Example 43, the following compounds are prepared.

44. 4-Carbethoxy-3- (2-carethoxyacetylamino) -5-methyl-2-phenylpyrrole

Obtained from the compound of Example 2, and malonic acid ethyl ester chloride.

Yield: 86%

Melting Point: 156-158 ℃ (Acetone)

45. 4-Acetyl-3-benzoylamino-5-methyl-2-phenyl-pyrrole

Obtained from the compound of Example 1 and benzoyl chloride.

Yield: 79%

Melting Point: 301-303 ° C (ethanol / water)

Example 46-50

Acetic anhydride and aminopyrrole derivatives are reacted in the presence of pyridine and acylated to afford the following compounds.

46. 3-Acetylamino-4-carethoxy-5-methyl-2-phenyl-pyrrole

Obtained using the compound of Example 2 as an aminopyrrole reaction partner.

Yield: 89%

Melting Point: 213-215 ° C (Ethanol)

47. 3-Acetylamino-4-benzoyl-5-methyl-pyrrole

Obtained using the compound of Example 11 as an aminopyrrole reaction partner.

Yield: 86%

Melting Point: 182-183 ℃ (Ethyl Acetate / Water)

48. 4-Acetyl-3-acetylamino-5-methyl-pyrrole

Obtained using the compound of Example 12 as an aminopyrrole reaction partner.

Yield: 72%

Melting Point: 206-208 ° C (Methanol)

49. 4-acetyl-3-acetylamino-5-methyl-2-phenyl-pyrrole

Obtained using the compound of Example 1 as an aminopyrrole reaction partner.

Yield: 80%

Melting Point: 215-217 ° C (acetone / hexane)

50. 3-Acetylamino-4-carethoxy-5-methyl-pyrrole

Obtained using the compound of Example 20 as an aminopyrrole reaction partner.

Yield: 90%

Melting Point: 165-160 ° C (Ethyl Acetate)

Example 51

4-acetyl-3-benzenesulfonamide-5-methyl-2-phenyl-pyrrole

6 g (0.332 mole) of Example 1 compound is suspended in 100 ml of 10% sodium hydroxide solution and 20 ml (0.0154 mole) of benzenesulfonyl chloride is added at 5 ° C. with stirring. The resulting oily precipitate is separated from the aqueous layer, dissolved in ethyl acetate, washed three times with 10% sodium thoroxide hydroxide solution, and the combined alkali solution layers are adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates are collected and recrystallized from ethanol solution.

Yield: 6.7g Melting point: 170-173 ℃

Example 52

4-acetyl-3-methanesulfonamido-5-methyl-2-phenyl-pyrrole

To a solution of 5 g (0.0278 moles) of Example 1 compound dissolved in 40 ml of pyridine, 2.6 g (0.0228 moles) of methanesulfonyl chloride was added by stirring at 0 ° C. Stirring is continued for 4 hours and the solution is left at 0 ° C. overnight. The reaction mixture is poured into 10% hydrochloric acid solution, the precipitates are collected and recrystallized from ethanol solution.

Yield 4.1g Melting Point: 172-175 ℃

Example 53-56

According to Example 52, the following compounds are prepared.

53. 4-Carboethoxy-3-methanesulfon amado-5-methyl-2-phenyl-pyrrole

Obtained from the compound of Example 2 and methanesulfonyl chloride.

Yield: 83%

Melting Point: 173-174 ° C (Ethanol Solution)

54. 4,5-Dicarbomethoxy-3-methanesulfon amado-2-phenyl-pyrrole

Obtained from the compound of Example 42 and methanesulfonyl chloride.

Yield: 77%

Melting Point: 158-160 ° C (Ethanol Solution)

55. 4-Acetyl-5-methyl-3-phenacylsulfonamido-2-phenyl-pyrrole

Example 1 Obtained from a compound and phenacylsulfonyl chloride.

Yield: 89%

Melting Point: 201-203 ° C (acetone / hexane)

56. 4-benzoyl-5-methyl-2-phenyl-3- (P-toluenesulfone amido) -pyrrole

Obtained from the compound of Example 3 and P-toluenesulfonyl chloride.

Yield: 83%

Melting Point: 230-233 ℃ (ethanol / water)

Example 57

4-acetyl-3-methyl-3- (N-methylphenacylsulfonamido) -2-phenyl-pyrrole

5.0 g (0.0126 mole) of compound of Example 55, 5.0 g of potassium carbonate and 15 ml (0.159 mole) of dimethylsulfate were added to 400 ml of acetone, and the mixture was refluxed for 35 hours. The reaction mixture is concentrated to small volume, 400 ml of water is added, and the product precipitate obtained is filtered and recrystallized from hexane.

Yield 4.5g Melting Point 195-197 ℃

Example 58-60

The following compounds are prepared according to Example 57.

58. 4-Acetyl-5-methyl-3- (N-methylbenzenesulfonamido) -2-phenyl-pyrrole

Obtained from the compound of Example 51 and dimethylsulfate.

Yield: 72%

Melting Point: 247-249 ℃ (Acetone / Water)

59. 4-Acetyl-3-dimethylamino-5-methyl-2-phenyl-pyrrole

Obtained from the compound of Example 1 and dimethyl sulfate.

Yield: 68%

Melting Point: 153-155 ° C (Chloroform)

60. 4-benzoyl-3- (N-ethyl-P-toluene sulfonamido) -5-methyl-2-phenyl-pyrrole

Obtained from the compound of Example 56 and dimethylsulfate.

Yield: 67%

Melting Point: 224-225 ° C (Ethanol)

Example 61

4-benzoyl-3-isopropylamino-5-methyl-2-phenyl-pyrrole

It is obtained by reacting an equimolar amount of the compound of Example 3 with isopropyl bromide at room temperature.

Yield: 31%

Melting Point: 132-136 ℃ (hexane)

Example 62

4,5-Dicarbomethoxy-2-phenyl-3-ureido-pyrrole

To a solution of 5 g of Example 42 compound dissolved in 50 ml of acetic acid, a solution of 13 g of sodium thorium cyanate dissolved in 20 ml of water was added by stirring at room temperature. The solution is left at 0 ° C. for about 1 hour and the crystallized product is filtered off and recrystallized from methanol.

Yield: 5.1 g Melting point: 246-248 ° C

Example 63-67

According to Example 62, the following compounds can be prepared.

63. 4-Acetyl-5-methyl-2-phenyl-3-ureido-pyrrole

Example 1 Obtained from a compound and natorium cyanate.

Yield: 84%

Melting Point: 234-238 ° C (acetone / hexane)

64. 4-Carethoxy-5-methyl-2-phenyl-3-ureido-pyrrole

Example 2 Obtained from a compound and natrium cyanate.

Yield: 66%

Melting Point: 217-219 ° C (ethanol)

65. 4-Carethoxy-5-methyl-2-phenyl-3- (3-phenylureido) -pyrrole

Example 2 Obtained from compound and phenyl isocyanate.

Yield: 70%

Melting Point: 224-226 ° C (Methanol / Mole)

66. 4-Acetyl-5-methyl-2-phenyl-3- (3-phenylureido) -pyrrole

Example 1 Obtained from compounds and phenisocyanates.

Yield: 62%

Melting Point: 256-257 ° C (acetone)

67. 4-Acetyl-3- (3-benzoylthioureido) -5-methyl-2-phenyl-pyrrole

Example 1 Obtained from a compound and benzoylisothiocyanate.

Yield: 69%

Melting Point: 228-230 ℃ (ethanol / water)

Example 68

4-acetyl-3-formamido-2- (P-methoxyphenyl) -5-methyl-pyrrole

The solution obtained by dissolving 5 g (0.0206 mol) of Example 15 compound in 50 ml of 85% formic acid was refluxed for 15-20 minutes, then the reaction mixture was cooled and poured into ice water. The precipitate is filtered off and recrystallized from methanol.

Yield: 2.5g Melting point: 210-211 ° C

Example 69

4-carethoxy-3-formamido-5-methyl-2-phenyl-pyrrole

Example 2 Prepared according to Example 68 from a compound.

Yield: 83%

Melting Point: 180-182 ℃ (ethanol / water)

Example 70

4-acetyl-3- (P-chlorobenzylideneamino) -5-methyl-2-phenyl-pyrrole

Example 1 A solution of 5.0 g (0.0234 moles) of a compound in 200 ml of ethanol was added to a solution of 5.0 g (0.0358 moles) of P-chlorobenzaldehyde in 100 ml of ethanol at 45-50 ° C., and the reaction mixture was added to about 4 Time backflow. After cooling it is poured into water saturated with 1,200 ml of sodium thorium chloride and the precipitate obtained is filtered off and recrystallized from ethanol / water.

Yield: 9.5 g Melting point: 214-215 ° C

Example 71-73

According to Example 70, the following compounds are prepared.

71. 4-Acetyl-3-benzylideneamino-5-methyl-2-phenyl-pyrrole

Example 1 Obtained from compounds and benzaldehydes.

Yield: 87%

Melting Point: 173-176 ° C (Methanol)

72. 4-Carbamyl-3-isopropylideneamino-5-methyl-2-phenyl-pyrrole

Example 34 Obtained from compounds and acetone.

Yield: 82%

Melting Point: 221-223 ° C (ethanol / hexane)

73. 3-benzylidene amino-4,5-dicarbomethoxy-2-phenyl-pyrrole

Example 42 Obtained from compounds and benzaldehydes.

Yield: 78%

Melting Point: 218-220 ° C (Methanol)

Example 74

4-acetyl-3-amino-1,5-dimethyl-2-phenyl-pyrrole

a) Example 71 A solution of 1.4 g (0.00467 moles) of a compound dissolved in 25 ml of dimethylformamide is added dropwise to a sodium hydride cooling suspension in 10 ml of dimethylformamide. The reaction mixture is stirred at about 0-5 ° C. for 15 minutes and then 1 ml of methyl iodide (0.0161 mol) is added. Stirring was continued at about 0 ° C. for 30 minutes, stirred at room temperature for 30 minutes, and then 150 ml of water was added to the reaction mixture and extracted with dimethyl ether. The organic phase is separated and the solvent is evaporated. The residue (1.2 g) is recrystallized from isoprotanol / water to give 4-acetyl-3-benzylideneamino-1,5-dimethyl-2-phenyl-pyrrole with a melting point of 136-138 ° C.

b) The solution obtained by dissolving 1.0 g (0.00316 mol) of the compound in 30 ml of 10% hydrochloric acid solution is heated to 80-90 ° C. for about 2 hours. After cooling, the precipitate obtained by neutralization with natrium hydroxide is recrystallized from ethanol / water.

Yield: 0.8 g Melting point: 124-126 ° C

Melting Point of Corresponding Hydrochloride: 208-209 ° C. (Ethanol / Diethyl Ether)

Example 75

4-acetyl-3-amino-1-ethyl-5-methyl-2-phenyl-pyrrole

Example 71 4-Acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenyl-pyrrole is obtained from compound and ethyl iodide according to example 74 a). Melting Point: 139-141 ℃ (Isopropanol / Water)

This compound is hydrolyzed according to Example 74 b) to afford the title compound.

Yield: 54%

Melting Point: 107-108 ° C (Ethanol)

Example 76

4-acetyl-3-amino-5-methyl-2-phenyl-1-propyl-pyrrole

Example 71 4-Acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propyl-pyrrole is obtained in the oil phase according to example 74 a) from the compound and propyl iodide. This is hydrolyzed according to example 74 b).

Yield: 50% Melting point: 113-115 ° C. (ethanol)

Example 77

4-acetyl-3-amino-1- (P-chlorobenzyl) -5-methyl-2-phenyl-pyrrole

Example 71 4-acetyl-3-benzylideneamino-1- (P-chlorobenzyl) -5-methyl-2-phenyl-pyrrole is obtained according to example 74 a) from the compound and P-chlorobenzyl chloride. Melting Point: 136-137 ℃ (ethanol / water)

This compound is hydrolyzed according to example 74 b) to afford the title compound.

Yield: 58%

Melting Point: 164-166 ° C (ethanol / water)

Example 78

4-acetyl-1- (0-chlorobenzyl) -5-methyl-3-dimethylamino-2-phenyl-pyrrole

Example 59 The title compound is obtained according to example 74 a) from the compound and 0-chlorobenzyl chloride.

Yield: 67%

Melting Point: 103-105 ° C (Isopropanol)

Example 79

4-acetyl-1- (P-chlorobenzyl) -5-methyl-3-dimethyl-amino-2-phenyl-pyrrole

Example 59 The title compound is obtained according to example 74 a) from the compound and P-chlorobenzyl chloride.

Yield: 52%

Melting Point: 118-119 ℃ (hexane)

Example 80

4-Carbethoxy-3- (N-methyl-methanesulfonamide) -1,5-dimethyl-2-phenyl-pyrrole

Example 53 The title compound is obtained according to example 74 a) from a compound and methyliodide.

Yield: 71%

Melting Point: 138-140 ℃ (ethanol / acetone)

Example 81

4-acetyl-3- (0-carboxyphenyl) -amino-5-methyl-2-phenyl-pyrrole

2 g (0.00934 mol) of compound of Example 1 and 1.87 g (0.00934 mol) of 0-bromobenzoic acid, 2 g of sodium thorium acetate, and 0.5 g of copper powder suspended in 150 ml of water were refluxed for 4 hours. Cool and leave overnight. The precipitate is filtered off and recrystallized from methanol solution.

Yield: 1.5 g Melting point: 260-262 ° C

Example 82

3-Amino-5-carbamyl-4-carbomethoxy-2-phenyl-pyrrole

5 g (0.0161 mol) of Example 42 compound solution is saturated with ammonia gas and left for 2 days. Filtration to crystallize the product.

Yield: 2.8 g Melting point: 177-179 ° C (methanol / mol)

Example 83

3-amino-4,5-dicarboxy-2-phenyl-pyrrole

A solution of 15 g (0.0545 moles) of Example 42 compound dissolved in 200 ml of methanol was added to 90 ml of 10% lysine hydroxide and refluxed with stirring for 20 minutes. The solution is poured into water and acidified with 10% hydrochloric acid solution. The precipitate is obtained by filtration and recrystallization with dimethylformamide / ethylether.

Yield: 12.5g Melting point: 191-194 ℃

(This compound contains 1 mole of water.)

Example 84

3-Amino-5-carboxy-4-carbomethoxy-2-phenyl-pyrrole

A solution of 10 g (0.0322 mol) of Example 42 compound in 150 ml of methanol and 30 ml of 10% sodium hydride solution was refluxed for 3 hours. Methanol is evaporated and the solution is adjusted to pH 7 with 10% hydrochloric acid solution.

The product separated by filtration is dissolved in a sodium bicarbonate solution and neutralized with 10% hydrochloric acid solution.

Yield: 5g Melting point: 206-207 ° C

Example 85

3-Amino-4-carboxy-5-carbomethoxy-2-phenyl-pyrrole

2 g (0.00644 moles) of Example 42 compound are dissolved in 20 ml of concentrated sulfuric acid and the solution is left at room temperature for about 35 minutes, then poured into ice water and neutralized with 10% sodium thorium hydroxide solution. Filter and recrystallize with methanol solution.

Yield: 0.5g Melting point: 218-219 ° C

Example 86-88

Hydrolysis according to Example 85 affords the following compounds.

86. 4-carboxy-3- (2-carethoxyacetylamino) -5-methyl-2-phenyl-pyrrole

Example 44 Obtained in 64% yield from the compound.

Melting Point: 92-98 ℃ (ethanol)

87. 3-Acetylamino-4-carboxy-5-methyl-2-phenyl-pyrrole

Example 46 Obtained in 49% yield from a compound.

Melting Point: 258-260 ℃ (ethanol / water)

88. 4-carboxy-3-methanesulfonamido-5-methyl-2-phenyl-pyrrole

Example 53 Obtained in 54% yield from a compound.

Melting Point: 269-271 ℃ (Acetone / Water)

Example 89

3-Amino-5-carbazoyl-4-carbomethoxy-2-phenyl-pyrrole

5 g (0.0161 mol) of Example 42 compound are dissolved in 60 ml of methanol and 1.3 g of pyridine is added. This solution is added to 25 ml of hydrazine in 20 ml of water and left at room temperature for 15 minutes. The crystals are filtered off and recrystallized from methanol.

Yield: 3g Melting point: 166-167 ° C

Example 90

4-acetyl-3-amino-5-methyl-2- (P-hydroxyphenyl) -pyrrole

Example 15 Obtained from compounds.

Yield: 71% Melting point: 273-274 ° C (ethanol / water)

Example 91

3-amino-5-methyl-2-phenyl-4-phenylcarbamyl-pyrrole

From 2-amino-2-phenyl-acetonitrile and acetyl-N-phenyl-acetamide in 73% yield following the method of Examples 1-42.

Melting Point: 271-273 ° C (ethanol)

Example 92

3-amino-4,5-dicarbomethoxy-2-phenyl-pyrrole hydrochloride

9.5 g (0.0565 mol) of 2-amino-2-phenyl-acetonitrile hydrochloride in 90 ml of anhydrous ethanol was added to 9.0 g of potassium carbonate, followed by stirring for 15 minutes, followed by 8.0 g (0.0630 mol) of 1,2-dicarbomethoxy acetylene is added and the mixture is refluxed for 3 and a half hours. After evaporating the solvent, the residue was washed with ethyl acetate and extracted three times with 10% hydrochloric acid solution. The hydrochloric acid solution is neutralized with a 10% sodium thorium hydroxide solution and extracted again with ethyl acetate. After evaporation of the solvent the solid obtained is recrystallized from a mixture of methanol and methanol ether saturated with hydrogen chloride.

Yield: 5g Melting point: 205-207 ° C

Melting point of free base: 142-143 ° C (diethyl ether)

Compounds of Examples 7,37,38,39,40,41 can also be prepared according to the above methods.

Example 93

4-acetyl-5-methyl-3-methylamino-2-phenyl-pyrrole

1.5 g (0.00366 mole) of Example 57 compound was suspended in 100 ml of acetic acid and 5 ml of concentrated hydrochloric acid at room temperature, and then 1.1 g of a small amount of zinc powder was added. The mixture is stirred for 2 hours at room temperature, zinc is filtered off and the filtrate is extracted twice with 200 ml of ethyl acetate. After evaporation of the ethyl acetate, the residue is washed with diesel ether and filtered.

Yield: 0.3g Melting point: 174-176 ℃

Example 94

4-benzoyl-3-ethylamino-5-methyl-2-phenyl-pyrrole

Obtained in 44% yield from the compound of Example 60 according to Example 93.

Melting Point: 178-180 ℃ (ethanol / water)

Example 95

3-acetylamino-4-benzoyl-5-methyl-2-phenyl-pyrrole

Obtained in 87% yield from the compound of Example 3 and acetylchloride according to example 43.

Melting Point: 140-142 ° C (ethanol / water)

Claims (1)

As described above in the text, the same molar amount of α-aminonitrile of the following structural formula (II) or an acid addition salt thereof is reacted with a compound of the following structural formula (III), the following structural formula (I) and pharmaceutically innocuous Method for preparing acid addition salts.

In the above structural formula R is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl and halosubstituted benzyl R ₁ is a substituent of 1 to 3 selected from hydrogen, alkyl of 1 to 4 carbon atoms, phenyl and alkyl of 1 to 4 carbon atoms, alkoxy benzyloxy, fluoro, chloro, bromo, hydroxy and nitro of 1 to 4 carbon atoms Is substituted phenyl R ₂ is hydrogen R ₃ is hydrogen R ₄ is phenyl substituted with 1 to 3 substituents selected from aliphatic acyl, benzoyl, fluoro, chloro, bromo and alkoxy having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, carboxy, Carbamyl, methylcarbamyl or phenylcarbamyl R ₅ is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, (alkoxy having 1 to 4 carbon atoms) methyl, trifluoromethyl, carboxy, carbamyl and carbazoyl R ₄ and R ₅ together represent —CO— (CH ₂ ) _n — where the carbonyl group is linked to a pyrrole cyclic carbon atom containing the substituent R _4, where n is 2,3 or 4 provided that Provided that ₁ and R ₅ are methyl and R is hydrogen, provided that one of R ₂ and R ₃ is not hydrogen and R ₄ is not carethoxy) X is -C≡C- or -CH _2-

-In which -CH ₂ is linked to the substituent R ₄ .