DE2145573A1 - INDOL COMPOUNDS, DERIVATIVES OF THE SAME AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

Ληία. : Ch-: ι.-pharra. Drive i.k Dr. iicii; u; iin Thiorniinn Grrsbii 4628 I, ü ne n / V / e stf.

9. 9. 1971

Indole · compounds, derivatives and processes for their

Manufacture

The Ex'findnr.ij concerns a new process ;; ur production novel Iiidol compounds do? * following formula {type 5)

OfI

R'-o.

R,

N ₃

where R

- alkyl, aryl, hay Iky.,

Alkyl, aryl, arcyl, alkoxy 1, aryloxy 1 or Aralkovvl

R ₁

= II, alkyl, aryl, alkenyl, hydroxyl, acyloxy, acyl, Corboxy, Ιίε-tloqcn, halogen-substituted alkyl and Ary 1'j rap, v.'ie:;. IJ. Trif luonrethyl odor -to IyI or gene-in 3 to cine -HC = CH-Ch "Cli-Gruppc and

K ¹

Sci remainder

u ^; .cn k '"i; r: on.

309811/1 101

BAD OFÖÖIMAL

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In particular, the following substituents are preferred in question:

R ₁ = methyl, ethyl, propyl, butyl

Phenyl, subst. Phenyl (Cl, CH ₃ , OCIl- etc.) benzyl, subst. Benzyl (")

R_ = methyl, phenyl, benzyl

R = OCII ₃ , OCII, O-benzyl, methyl, phenyl

R ¹ = acetyl, (trifluoroacetyl), (propionyl)

w ^R 4 / ^R 5 ~ ^C1 ' ^CfI 3' ^0CH 3 'CF ₃ , phenyl

Some of these compounds and derivatives thereof have interesting pharmaceutical properties. They show, for example, hypotensive appearance . They are also suitable as starting materials for the synthesis of other novel indole derivatives with a pharmacological effect.

According to the invention, the aforementioned compounds can be used by making enamines of the formula

Ii
/ V

HN ^R 2 '

I A

R ₁ - ■ ■ '

wherein R ,, R "and R- have the meaning given above with quinones of the formula

0 0

R.

«S

Ii 1 or ff

.0 0

ζ ■ 2 '" ³ 3 09811/1101

in which R ₄ and R- have the meaning given above and an acid, such as, for example, acetic acid, is reacted. The reaction between these components leads in part to yields of products according to the invention of 60-90% of theory.

I. The reaction thus proceeds, for example, as follows: 0

H 1-CII ₃ 0 *

II + (Ο + R * -COOH

CH ₃ 0 £

Instead of acetic acid, the following acids in particular come into consideration:

Formic acid, propionic acid, dichloiacetic acid, trifluoroacetic acid as well as phosphoric acid and sulfuric acid (with dioxane or benzene).

Depending on the choice of acid, the hydroxyl group becomes substituted in the 5-position by a corresponding aliphatic, aromatic or inorganic acid radical and at the same time becomes a hydroxyl group in the 4-position introduced.

The nature of the substituents P. ,, R ", R_ depends on the enamines chosen in each case, of which in particular the following can be considered:

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N ~ alkyl, N-aryl or N-aralkyl derivatives of: β - aminocrotonic acid esters β - amino cinnamic acid esters (and nitriles)

1 - Phenyl-3-amino-2-butcn-1-one 4 - Amino-3-penten-2-one β ~ Amino - ^ - phenyl-crotonic acid esters

and also from:

• 3 - amino-2-cyclohexen-l-one 3 - Amino-5,5-dimethyl-2-cyclohexen-1-one

2 - carbaethoxymethylene pyrrolidine

iininofumaric acid esters (R2 = COOR)

3 - Amino-2-pentene-l, 5-diacid (R ₃ = CH ₂ - COOR)

II. Leave the compounds according to the invention (type 5) modify themselves relatively easily. This can be done by acting on the 4- and / or 5-position /

a) by saponification, alkylation, acetylation and oxidation

b) by saponification and decarboxylation of the 3-position substituted CO-R-j group.

III. Finally, it is also possible through an oxidation

of the monohydroxy-indole derivatives (type 12) are the indole-quinone descendants of type 8, which can be converted into the 4,5-dihydroxyindoles of type 7 by reduction. This will be explained in more detail later.

-

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Regarding II a) Those shown after the procedural steps according to I. Compounds of types 4 and 5 can be converted into various derivatives in very good yields realize. For the sake of simplicity, the 3-substituted CO-R_ grouping is used in the following formulas replaced by the symbol R '. The listed connection types will be used later in the Relation to the description of their synthesis given by formula.

1.) When treating the compound types $. / 2.12.'IQr] ^ L a suitable derivative of an acid (e.g. an aliphatic or aromatic acid anhydride or acid halide, e.g. a carboxylic acid), possibly in the presence of an organic or inorganic base (e.g. pyridine or Alkali acetate), the acyl derivatives are formed.

R «and (or) R ^ri = acyl radical (e.g.

2.) When treating J> # 6 ^ 2-0 with water or alcohol in the presence of a basic catalyst, e.g. alkali hydroxide or alkali metal alcoholate and untex "N atmosphere the corresponding 4,5-dihydroxy-indole derivative 7 is formed,

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3.) Treatment of 2 * 12 and 11. (R ¹ = R "= H) with a suitable oxidizing agent (eg silver oxide) in an organic or aqueous solvent (eg acetone, benzene} produces 4,5-indolquinone JS .

4.) When treating the hydroxyindole derivatives 5,6,7,10,11 with a suitable basic catalyst (eg alkali hydroxide or carbonate) and an alkylating agent (eg Γ alkyl sulfate / alky! Halide) in a mixture of an organic solvent (for example, dioxane, alcohol) with V7asser or in an organic solvent (eg, alcohol, acetone) gives the corresponding 5-Äikoxyl-indole derivatives J) (selective Monoalkylierungi 4 or _f 5-dialkoxy-indole derivatives 9a.

£? R ^f = alkyl-; R ¹ '= H J 5

^ 9a; R ¹ = R ¹¹ = alkyl- "

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To II b)

1.) When treating the indole-3-carbalkoxyl derivatives (Rl = COOR) 5,6,7,9,9a with an acid of inorganic or organic nature (eg sulfuric acid, phosphoric acid or acetic acid) in the presence of water or a lower one Alkanecarboxylic acid (e.g. acetic acid) under H_ results in the derivatives (created by saponification and decarboxylation) 10.

* - O v. J ^ S ^ R 'and (or) R ¹ ' = hydrogen f [TJ alkyl-

^ W Λ, ^aryl "

j 2 aralkyl

R ₁ acyl

2.) When treating the indole-3-carbalkoxyl derivatives (RI = COOR) 5,6,7,9,9a with inorganic bases (e.g.

s - - - - -

Alkali hydroxides) in the presence of water or (or and) alcohol, and optionally an organic solvent (eg dioxane), the indole-3-carboxylic acids 11 or their salts are formed.

COOH ^{Rl un} ^ (or) R ¹¹ = hydrogen

Alkyl-aralkyl-aryl

3.) When the indolecarboxylic acids IJL are heated with or without a high-boiling solvent (if necessary with the addition of a suitable catalyst, eg p-toluenesulfonic acid) or in an organic acid or in a mineral acid solution, the decarboxylation products K are formed).

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To III.

1.) When treating 5-hydroxy-indole derivatives (e.g. 1-alkyl-, 1-aryl-, l-aralkyl-2-alkyl-2-aryl-2-aralkyl-S-carbonyl-S-hydroxyl- indole derivativec) with oxidizing agents such as nitric acid, chromium oxide, Freray ¹ s salt) in solvents or solvent mixtures result in the 4,5-indole quinones J3.

2.) When the 4,5-indolquinones Q are treated with suitable reducing agents (e.g. catalytically excited hydrogen = Pd / C + H ₂ , alkali hydrogen sulfite, alkali dithionite), the 4,5-dihydroxy-indole derivatives are formed

309811/1101

Examples

li ^> henyl-2-methyl-4-hydroxy-5-acetoxy-3-indolecarboxylic acid ethyl ester

5a; Mp: 233 °

1- (p-Chlorophenyl) - ^ - methyl - ^ - hydroxy-S-acetoxy-S-indolecarboxylic acid ester

5b; M.p .: 213 ° "" "

1- (p-Nitrophenyl) -2-methyl-4-hydroxy-5-acetoxy-3-indole carboxylic acid ester

5c ; M.p .: 234

1,2-Dimethyl-4-hydroxy-5-acetoxy-3-indolecarboxylic acid ethyl ester 5d; Mp: 207 °

L-Cyclohexyl - ^ - methyl - ^ - hydroxy-S-acetoxy-S-indolecarboxylic acid ethyl ester

5e; M.p .: 150 °

1-Benzyl-a-methyl - ^ - hydroxy-S-acetoxy-S-indolecarboxylic acid ethyl ester

5f; M.p. 165 °

1-phenyl-2-methyl-3-acetyl-4-hydroxy-5-acetoxy-indole £ 5; M.p. 269 °

55 g p-benzoquinone v / earth in absolute. Glacial acetic acid (500 ml) dissolved and heated to boiling, then a solution of the enamine (1/2 mol) in glacial acetic acid (500 ml) is slowly added dropwise with stirring. After the addition has ended, the mixture is stirred with warming for a further hour. Your cooling crystallizes the connection or the solvent is stripped off in vacuo and the residue is crystallized with alcohol or benzene. Of the Precipitate is filtered off with suction, washed with glacial acetic acid and removed

- 10 -

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- ίο -

Benzene recrystallized. Yield: IO - 50% of theory

Re IIa / 1:

1-Phenyl-2-methyl-4, S-diacetoxy-S-indolecarboxylic acid ethyl ester £ a; M.p .: 171 ° (ligroin)

1-Phenyl-2-methyl-4-3CCtOXy-S-We ^ oXy-3-indolcarboxylic acid ae thy l · ¹ ester
_k 6b; M.p .: 110 (ligroin)

W. ~~

1-Cyclohexyl-2-methyl-4, S-diacetoxy-S-indolecarboxylic acid, ethyl ester

6j c ; Volume: 108 (isopropanol)

1,2-Dinethyl-4,5-diacetoxy-3-indolecarboxylic acid ethyl ester 6d? M.p .: 155 ° (ligroin)

To prepare them, the corresponding hydroxyindole derivatives are heated to boiling in acetic anhydride with the addition of a few drops of pyridine. After stripping off the solvent, it is recrystallized.
Yield: 95% of theory

Re IIa / 2:

1-Phenyl-2-methy1-4, S-dihydroxy-S-inöolcarbonsäureaethylester

7 a ; M.p .: 194

1-Benzyl-2-methyl-4, S-dihydroxy-S-indolecarboxylic acid, ethyl ester 7b "; m.p .: 160 °"

- 11 -

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- li -

0.01 mol of 5a or 5f (or € a) v / earth dissolved in 100 ml of hot dioxane, mixed with a solution of 0.6 g (or 1.2 g) of KOH in 100 ml of water in an N atmosphere and heated to boiling for 3 hours. It is then diluted with water and the dioxane is distilled off. After cooling and suction filtration, it is recrystallized from toluene.
Yield: 92% of theory

Re IIa / 3 :

1-phenyl-2-methyl-3-carbaethoxy-4,5-indolequinone 8a; M.p .: 222 °

3.1 g of Tji are dissolved in 500 ml of acetone and, after addition of 9 g of silver oxide, stirred for 12 hours at room temperature. After filtration and concentration in vacuo, JBa is obtained in dark red needles.
Yield: 96% of theory

Re IIa / 4 :

1-phenyl-1-ethyl-1-hydroxy-S-methoxy-S-indolecarboxylic acid ethyl ester

9_ ; Mp: 181 °

^{900 mg Tjü ^ n} 300 ml acetone are dissolved in an N_ atmosphere, 3 g freshly calcined K_CO-> are added and the mixture is kept at the boil for one hour while stirring. Then 1 g of dimethyl sulfate was added and the mixture was refluxed for a further 2 hours. The reaction mixture was filtered hot and concentrated to dryness in vacuo. The residue was recrystallized from ligroin.
Yield: 8O % of theory

- 12 -

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In an N atmosphere, 900 mg of J7a were dissolved in 100 ml of dioxane, a 10% KOH solution is added, the mixture is heated to boiling while stirring and, after cooling, 1 g of dimethyl sulfate is added. It was stirred for 1/2 hour, heated for one hour and mixed with 500 ml of water. After cooling down, it was sucked off, washed with water, dried and recrystallized. Yield: 75% of theory

Re IIb / 1:

0.01 mol of 1-benzyl ^ -methyl ^ -hydroxy-S-methoxy-S-indolecarboxylic acid ethyl ester is _{heated to boiling under nitrogen in a mixture of 5 g of H-SO 4} and 20 ml of glacial acetic acid. After cooling, the reaction mixture is poured into ice and neutralized with sodium hydroxide solution. After cooling, it is suction filtered and recrystallized from alcohol.
Yield: 80% of theory

Re IIb / 2:

0.01 mol l-benzyl ^ -methyl-'l-hydroxy-S-methoxy-B-indole carbon-

ethyl acid esters are heated to the boil for 3 hours in a mixture of 60 ml of 2N potassium hydroxide solution and 500 ml of alcohol.

The solvent is removed in vacuo and the residue p. it Water added. After acidification and cooling, it is sucked off and recrystallized from alcohol

Yield: 75% of theory

3 0 9 8 11/1101

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Re IIb / 3:

0.01 mol of 1-eenzyl-2-ir.ethyl-4-hydroxy-5-methoxy-3-indolecarboxylic acid is heated in 50 ml of glacial acetic acid for 2 hours, then it is concentrated in vacuo and diluted with water. The precipitation is suctioned off and recrystallized from alcohol. Yield: 90% of theory

To III / l ;

Phenyl-2-methyl-3-carbaethoxy-4,5-indolquinone 8_ m.p .: 222 ° C

3 g of l-phenyl - ^ - methyl-S-hydoxy-S-indolecarboxylic acid ethyl ester are dissolved in 1.2 l of acetone with a mixture of 200 ml of KII ₂ PO. Solution (0.167 mol) , 20 g of Fremy's salt and 500 ml of water are added. The undissolved portion is brought into solution by adding water or acetone. After standing for 24 hours, water is added and the mixture is extracted with methylene chloride, the extracts are evaporated in vacuo and recrystallized from benzene.
Yield: 50 % of theory

Regarding IIT / 2:

1-Phenyl-2-ynethyl-4, S-dihydroxy-S-indolecarboxylic acid ethyl ester 7ci M.p .: 194 ° C

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3 0 9 0 1 1/110 1

1-Phenyl-2-methyl-3-carbaethoxy-4,5-indolquinone is dissolved in acetone and an aqueous dithionite solution is added up to
complete discoloration has occurred . The organic solvent is then stripped off in vacuo and water is added. The precipitate is removed and, after drying, recrystallized from benzene.
Yield: 97% of theory

- 15 309811/1101

Claims (1)

Claims Ever. Process for the preparation of indole compounds and their derivatives, characterized in that enamines with quinnene and an acid according to the following reaction scheme A * Λ il ° ^the A ^ l ^{+ saare} '1 ζ OW i- / are implemented in which
R. Alkyl, aryl, aralkyl Ro = alkyl, aryl, aralkyl, alkoxyl, aryloxy1 or aralkoxyl H, alkyl, aryl, alkoxyl, hydroxyl, acyloxy, acyl, carboxy, halogen, halogen-substituted alkyl and aryl groups such as tri fluorine thy 1 or -to IyI - 16 309811/1101 f isj.'j-wvj ^ ji »· ■. * '** il U. Sl !; 3 ^. ^ - «- or straight one -HC = CH-CH = CH- group and R ¹ = acid residue mean. 2. Further development of the method according to claim 1, characterized characterized in that the indole compounds (5) according to general known methods (saponification, alkylation, acylation, oxidation and decarboxylation) in derivatives of the claim formulas 6, 7, 8, 9, 9a, 10, 11 and 12 shown. 3. Indole derivatives according to the general structural formulas 5, 6, 7, 8, 9, 9a, 10, 11 and 12 Il ⁰ ' Il. ⁰ R 'and (or) 3 acyl base (e.g. R ₁ . > ι. '2 ^ά if H Ot i / ^R 3 η O "Ti ³ 30981 1/1 1 (11 2U5573 9; R ¹ = alkyl-; R ' ¹ = 11 9a; R ¹ "= R I _ Alkyl R ¹ and (or) R ¹ · hydrogen Alkyl-aryl- • aralkyl-acyl- , COOH ¹ S ^R 1 R ¹ and (or) R ¹¹ = Hydrogen alkyl aralkyl aryl AZ 309811/1101 2U5573 4.1 ~ l ^3- henyl-2-methyl ~ 4-hydroxy-5-acetoxy-3-incl , 1 "(p-chlorophenyl) ^ - niefchyl - ^ -
carboxylic acid ethyl ster . 1- (p-Nitrophenyl) -2-ynethyl "4-hydroxy-5-acetoj: y-3-inc3olcarbon- ^ acid ethyl ester -. W. " .-. ■■ - 7.1, ^ -Dimethyl - ^ .- hydroxy-S-acctoxy-S-indolecarboxylic acid gaethyl ester 8. l-Cyclo] iexyl-2-methyl-4-hydroxy-5-acetoxy-3 "indolcarboxylic acid" aethy! ester l _# l-Benzyl ^ -methyl ^ -hydroxy-S-acetoxy-S-indolecarboxylic acid aethy! ester - ".". 10 _e 1-phenyl-2-methyl-3-acetyl-4-hydroxy-5-acetoxy-indole , l-Phenyl-2 ~ methyl ~ 4 , B-diacetoxy-B-indolecarboxylic acid, ethyl esters: "LI ^> henyl-2-njethyl-4-acetoxy-5" ynethoxy-3 "indolecarboxylic acid cacthy] ester. 30981 1/1101 2U5573 . ¹ ~ ^c y ^c;} - ^ohex yl "2-ynethyl-4,5-diacetoxy-3-indole carbonate, ethyl ester 14 _# 1,2 - Dimethyl-4,5-diacetoxy-3-indolecarbonic acid ethyl ester 15. ' 1-Phyl-2-Kicthyl-4 , S-dihydroxy-S-indolecarboxylic acid acetate Iß _# 1-Bcnzy l-2-raethyl-4, B-dihydroxy-S-indolecarboxylic acid caethyl lest.cr iy _# 1-Phonyl-2-diethyl-3-carbaethoxy-4,5-indolquinone 13.1-Phc: nyl-2-methyl-4-hydroxy-5-nietho>; y'-3-indolecarboxylic acid>: e- 19. l-Benzyl ^ -methyl ^ -hydroxy-S-methoxy-indole 20. l-Benzyl-2-πιethyl-4-hydroxy-5-ethoxy-3-indolecarboxylic acid 309811/1101