DE1806406A1 - Process for the preparation of 3-indolinyl-2-aminopropionitriles - Google Patents

Description

CH 4000 Basel 21 (Switzerland / Switzerfand)

• 5a - 2712 *

Proceed for the preparation of 3-indoline \ 1-2-amino-propionitriles

The present invention relates to a new method <sur preparation of 3- (3'-hydroxy-indolin-2'-one-3'-yl) -2-aminoliropioni Irilon and the new compounds obtained by this process.

J) As a process according to the invention for the preparation of the new 3- (3 ^l -llydroxy-indolin-2 ^l -on-3 ^l -yl) -2-amino-propionitrile of the all-in-one η form 1 I:

R, i ^Ol1

I '

-CH ₁ - CH - CN!

ι ^{! θ} Λ ⁽ⁱ⁾

R ₃ R ₁ R ₂

in which. ...

R ^ is an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical,

Rj is an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical or a monocarbocyclic aryl radical, or

R ₁ and R-) together with the neighboring nitrogen atom form a 5-

up to 7-membered heterocyclic radicals, and the others May have heteroatoms as ring members,

Rj is hydrogen, an unsubstituted or substituted one aliphatic hydrocarbon structure or an acyl radical,

R ^ to Ry independently of one another each hydrogen or a lower Alx.yl-, Halalny] -, HydrooxyalKyl-, DialKylaminoalhyl-, Alh- ^ xy-, AlKoxyalkoxy-, AlKylainino-, Dialkylamino-,

909886/1654

BATHROOM 0RM3INAU

Acylamino, alkyl or alkylcarbamoyl, alkoxycarbo nyl or acyloxy radical, halogen, the hydroxyl, cyano, Carbaiioyl, carboxyl or Aii tr ο group mean,

is characterized by the fact that one is an isatin of the general

Formula II

(ID

in which R ₃ to R _{7 have} the meanings given under formula I, with lactonitrile (CH-j-CHOH-CN) and a secondary / imine of the general formula III

HN (III)

in which R _{1 and R 2 have} the meanings given under formula I, in practically equimolecular amounts at a temperature between 0 and 50 ° C., preferably at a temperature between 10 and 30 ° C. and optionally in the presence of an inert solvent or diluent.

i) The compounds of the formula J- are good to very good obtained good yields.

As unsubstituted or substituted aliphatic hydrocarbon radicals or acyl radicals include those under do not react with the other reactants under the given conditions.

The substituents R. and R ₂ are chosen so that the secondary amine of the formula III has a basicity which is favorable for the reaction with the other reactants.

As aliphatic hydrocarbon substituents R ,, R ^ and R-, the new compounds can be open-chain or cyclic, saturated or contain unsaturated radicals which preferably have 1 to 8 carbon atoms in a straight or branched chain or 3 have up to 8 carbon atoms as ring members, such as methyl, ethyl, cyclopentyl, cyclohexyl, cycloheptyl, Methallylrost, a propyl, propenyl, butyl, butenyl, pen ty] -, Cyclopentenyl, llexyl, cycl ohexenyl radical. Substituted aliphatic

909886 / IG 54

S \ "■ - '"■; ■■■■■■ -, ■

see substituents are preferably open-chain and can be or carry several identical or different substituents. Examples such substituents are halogen, hydroxyl, cyano, Di al KyI amino, alkoxy, alkoxyalkoxy groups, furthermore heterocyclic Residues, for example those of pyridine, piperidine, piperazine, Morpholine and their alkylated derivatives. Ali cyclic nouns tuents can be unsubstituted or straight-chain or branched lower alkyl radicals and be bound directly or via a lower alkyl radical to the skeleton. As an araliphatic Substi tuents R, and R-, come preferably the ßenzyl- and phenethyl radical into consideration. Phenyl, benzyl and phenethyl radicals can be substituted one or more times, for example by Alkyl, alkoxy, alkoxyalkoxy, ilalogenoalkyl, halogen, etc. under 5- to 7-membered heterocyclic radicals are used in the above Definition, in particular, of the radicals of fully hydrogenated heterocycles understood, preferably that of pyrrolidine, piperidine, Piperazines, morpholines and tetrahydroazepins. Acylreste R-, can be both aliphatic and aromatic in nature; from the aliphatic Particularly suitable acyl radicals are the lower ones and, among the aromatic, the benzoyl, phenylacetyl and phenylpropionyl radicals. Is in the definitions and in the preceding text of alkyl radicals or of radicals which are an alkyl group as a constituent have, the speech, so are preferably those with 1 to 6 carbon atoms in a straight or branched chain Understood. Halogen always means fluorine, chlorine, bromine and iodine, and the preferred haloalkyl group is trifluoromethyl.

When carrying out the process according to the invention, in order to avoid undesired side reactions, it is advantageous to use the individual reactants in practically equiniolar amounts in the reaction. Under "practically equimolar quantity"'! ¹ 'are smaller excesses of one or the other partner Reaktiont. mituinfasst, thereby making it possible to achieve optimum yields of compounds of formula I. In certain cases the reaction is exothermic, in others gentle warming to the temperatures mentioned accelerates the reaction. This largely depends on the type of secondary amine of the general formula III used. For example, the reaction with lower aliphatic amines is highly exothermic, while araliphatic or aromatic amines are slightly heated

909886 / 16S4 bad original

becomes necessary. To better distribute, the respondents to achieve in the reaction mixture, it is advantageous to use a solution or use diluents. All solvents which are inert towards the individual reactants are used for this purpose into consideration, such as, for example, hydrocarbons, halogenated aliphatic and aromatic hydrocarbons, aliphatic ketones with 4 to 8 carbon atoms,.-vniide, ether and ethereal Compounds, alcohols, esters etc. as well as water or mixtures of such solvents with one another and with water. Because of her better Polar solvents are preferred because of their solvency for the starting compounds, especially for the isatins of the formula II admit. ,

& s ejJE-i-nrl & s-gre erf-afa ^ en — w4 & ά - e4 ~ H «—- new — K4 a« -

, se - i o-FLGL-i-j-eh-the-intermediate as "s-chen prnrhiktp üwr-Ho-ke-ft-de ^ i-3 = iTtd-oly ± = a ~ ia-ni- ns vee-t * -. The new process works extremely economically as a one-pot process. The compounds of the formula I are obtained in good to very good yields, which are between 50 and 95 fo , and in high purity. In the preparation of compounds of the general formula I, in which one of the symbols R to Rj denotes the x \ "i tro group and H denotes hydrogen, the yields are somewhat lower. Such compounds are likewise obtained in the yields given by prior acylation of the corresponding nitroisatins by methods known per se and subsequent cleavage of the acyl radical. The compounds are crystalline or are obtained in crystalline form after recrystallization; they are readily soluble and stable in common organic solvents.

In the literature, isatins have the general formula II No reactions according to the type of process according to the invention described. In experiments, isatin with acetaldehyde, an amine, which means primary and secondary amines as well as ammonia to convert and aqueous HCN solution, we received a number of condensation products that are difficult to identify. It is therefore It is surprising that it is possible to start from lactonitrile. (CH.-CHOH-CN) and a secondary amine, to the inventive Indolinyl-amino-propionitrile to arrive.

The starting materials for the process according to the invention Isatins of the general formula II used are known

903886/1654

-r * M [* \\ O - <&& ■. BATH ORIGINAL

(2/2/1) ς. 20th June 1969

Subject: Patent application P 18 06 406.7 - Oase 5a-2712 * AGRIPAT S.A., Basel

Today page 5

Connections or can be made from known connections in a simple manner. [E. Giovanni ·· et al., Helv.chim.acta % 1 _{i ? i} 1381-1391 (1940)]. Acyloxy- and li ~ mono- or di-substituted garbamoyl-isatins are not described. One can be obtained by acylation of the corresponding hydroxy isatins] i), Giovanni'et al., · Loc. cit.] and the others from the corresponding esters [E. Giovanni "et al., HeIv. chim. acta ,. 51, 1392-1396 (1948)] by reaction with ammonia, primary or secondary amines or by partial saponification of a corresponding cyano-isatin; known processes.

The indolinonylamino-propionitrile of the general formula I, in where R ~ is not hydrogen, can also be obtained by an isatin of the formula II, in which R, denotes hydrogen, according to the invention with I & ctonitrile and a secondary amine of the formula III converts and then in the reaction product obtained hydrogen against one of the meaning of 31, 'corresponding other remainder exchanges.

For example, alkylating agents such as alkyl halides, dialkyl sulfates, Toluenesulfonic acid esters, etc., also acylating agents such as halides of aliphatic or aromatic carboxylic acids, etc. into consideration

Some of the compounds of the general formula I have fungistatic properties Effect, but the main thing is that they are easily prepared intermediates, which can be converted into known reactions Amino acid 3-indolyl-alanine (tryptophan) and its derivatives arrives. Tryptophan is a naturally occurring amino acid that is used to treat or prevent deficiency diseases (pellagra) is added to the diet or feed in the case of a low-protein diet and their derivatives are playing an increasingly important role as pharmaceuticals.

The following examples are intended to carry out the invention

d (fdd86 / 1 es4

BATH

explain the straight procedure in more detail. Then "is located a compilation of according to the invention produced Compounds of formula I. The temperatures are in degrees Celsius specified.

309886 / 16S4

example 1

161 g of 1-M-eihylisatin are suspended in 1 liter of methanol, 75 g of lactonitrile (96; ig) and 200 g of dibenzylamine are added and stirred for 43 hours at 20 to 25 °. After cooling to 10, the precipitate is separated off and recrystallized from ethyl acetate. The 3- (1'-methyl-3'-hydroxy-indolin-2'-one-3'-yl) -2-dibenzylamino-propionitrile thus obtained has a melting point of 164-165 °. The yield is 60 ^.

Example 2

32.2 g of 1-methylisatin are suspended in 200 ml of methanol, 15 g of lactonitrile (96 mg) and 22 g of dipropylamine are added and the mixture is stirred at room temperature for 18 hours. The precipitate is separated off, dried and recrystallized from ethyl acetate. The 3- (1'-methyl-3'-hydroxy-indolin-2 '-one-3'-yl J-2-di-n-propyl ami no-propi oni tri J has the (melting point 134-135 °. Bulge 34 #.

In the process described in the above examples, by way of corresponding IgA · ink, lactonitrile and entsj) computing the secondary amine are summarized in the following table under \ ^r ervendung equimolar amounts of 3- (3'-hydroxy-indolin-2'-one -3'-yl) -2-amino-propioni triIe obtained:

909 8-8 6/16 54 sad original

links

► Melting point yield

j3- (3'-Hydroxy-indolin-2'-on-3'-yl) - ^; ! 2-diethyl-amino-propionitri1 j

3- (3'-Hydroxy-indolin-2 ^l -on-3 ^l -yl) -!

2-piperidino-propionitrile!

! 3- (3'-Hydroxy-indolin-2 ¹ -on-3'-yl) - j j 2-pyrrolidino-propionitrile

3- (5'-chloro-3'-hydroxy-indolin-2'-one-3 -yl) -2-diethy1ami no-propioni tri1

3_ (5, 7'-dibromo-3'-hydroxy-indolin-2'-one-3 '-yl) -2-diethylarnino-propionitrile, ■ ί

3_ (5'-chloro-3'-hydroxy-indolin-2'-one-3'-y1) -2-dibenzylami no-propionitrile

3_ (3 • _Hydroxy-indolin-2'-one-3'-yl) -2-dibenzyl-amino-propionitrile .

3- (1'-piperidino-methyl-3'-hydroxy-indoline-2 '-on-3'-yl) -2-diethylaminopropionitrile

- (5 '> 7' -i) ibromo-3 '-hydroxy-indolin-2' on-3'-yl) -2-di benzylamino propionitrile

3- (1'-i) iäthylaminomethyl-3'-hydroxyindolin-2 .'-one-3 '-yl) -2-diethylaminopropionitrile

11 · 3- (l'-Methy] -3 '-hydroxy ^ -indolin-2 · -on-3'-yl) -2-diethylamino-propionitrile 3- (l'-methyl-3'-hydroxy-indoline- 2'-on- ¹ 3'-yl) -2-di-benzylamino-propionitrile

3- (3'-Hydroxy-indolin-2 ^l -on-3 ^f -yl) -2- ^:

dimethylamino-proijionitrile;

3- (5 ', 7'-I) ibromo-3' -hydroxy-indolin-2'-on-3'-yl) .- 2-piperidino-propionitrile

3- (3'-Hydroxy-indolin-2'-one-3 ^f -yl) -2-

rnorpholino-propionitri 1 I.

3- (5 ', 7'-Uichlor-3'-hydroxy-indoline-

2'-on-3'-yl) -2-piperidino-propio- _: nitrile

3- (l -Methyl-3'-hydroxy-indolin-2'-one-

3'-yl) -2-diallylamino-propionitrile

3- (3'-Hydroxy-indolin-2'-one-3 ^! -Yl) -2- ^!

di-n-pentylamino-propionitrile j

3- (l'-meth, yl-3'-hydroxy-indolin-2'-one - = - ^: on-3'-yl) -2-di.-n-pentylamino-propionitrile;

124-125

166-

139-142 ¹

) -167

135

145-146 ⁽

166 ⁽

150 ^c

94-96 ^C

157-158 ⁽

- 90 ^c

f-165

101-105

164-

120-122 *

175-176 ⁽

189-19O ¹

180 ^c
138-139 °

107-108

95 fo

95 fo

80 fo 82 fo

88 fo 50 fo 50 fo

81? £ 55? P

80 fo 63 / o 55 fo 90 ^ 60 ^ 75 fo

58 # 68 fo 85 #

70 #

909886/16 54 BATHROOM

links

. Melting point yield

I 3- (l'-MethyJ-5'-nitro-3'-hydroxy-in-

• dolin-2 '-on ~ 3' -yl) -2-dime thy lajnino- ! propioni tri1

. 3- (5'-Bromo-3'-hydroxy-indolin-2'-one-. 3'-yl) -2-piperidino-propionitrile 3- (1'-methyl-5'-nitro-3'-hydroxy-indoline-2 '-on-3'-yl) -2-piperidino- ; propioni tri1

i 3- (3'-llydroxy-indolin-2 '~ on-3 ^l -yl) -2-

(4 "-me thylpiperazino) -propioni tri1 ! 3- (l'-Methyi-3'-hydroxy-indolin-2'-one-

3'-yl) -2- (4 "-methylpiperazino) propionitrile

3- (3'-Hydroxy-indolin-2 ¹ -on-3 ¹ -yl) -2-

methyl-benzylamino-propioni tri1 3- (1'-methyl-5'-methoxy-3'-hydroxy-indoline-2 '-on-3'-yl) -2-dibenzylaminopropionitrile

3- (l'-methyl-3'-hydroxy-indolin-2'-one

3 '-yl) -2-piperidino-propionitrile

3- (l'-Diethylaminomethyl-3'-hydroxyindolin-2 ¹ -on-3 ^r -yl) -2-dibenzylamino-propioni oni tri1

3- (1'-Meth yl-3'-hydroxy-indolin-2'-one-

3 ^l -yl) -2-morpholino-propionitrile 3- (1'-benzyl-3'-hydroxy-indolin-2'-one-

3'-yl) -2-diethylaraino-propionitrile 3- (3'-hydroxy-indolin-2-one-3 ¹ -yl) -2-

di-n-propylamino-propionitri1 3- (l'-Benzyl-3'-hydroxy-indoline-2'-

on-3'-yl) -2-morpholino-propionitrile j 3- (5 ', 7 ^l -l>chloro-3'-hydroxy-indoline-

2'-on-3'-yl) -2-diethylamino-propionitrile

'3- (3'-Hydroxy-indolin-2'-one-3 ¹ -yl) -2-

dibutylamino-propionitrile ! 3- (1'-methyl-5'-nitro-3'-hydroxy-indoline-2 '-011-3' -yl) -2-morpholino-propionitrile

3- (l ^f -Methyl-2'-hydroxy-indolin-2'-one-

3 '-yl) -2-di-n-butylatenino-propionitrile

3- (1'-Methy1-3'-hydroxy-indolin-2'-one-

3'-yl) -2-dimethylamino-propioni tril

154 " 60 * 160-161 ° 55 160 ° 60 fo 180 ° 75 * 188 ° 50 117-119 ° 50 170-172 ° 53 % 156-158 ° 75 72-75 ° 60 173-174 ° 63 114-115 ° 50 * 125-126 ° 85 * 185-137 ° 55 * 206-208 ° 70 115 ° 61 185-136 ° 53 145-146 ° 86; 140 ° 91; BAD OBKaINAL

90988 6/16 54

AQ

links Melting point yield

3- (5'-Bromo-3'-hydroxy-indolin-2'-one-3 '-yl) -2-dime tliylami no-propionitrile

3- (5 ', 7'-dibromo-3'-hydroxy-indolin-2'-on-3'-yl) -2-dime thylamino-propioni tri1 I

■ 3 - (5'-Bromo-3 ^1- hydroxy-indolin-2'-one-3'-yl) -2-diethylamino-propionitrile

3- (1'-piperidinomethyl 1-3'-hydroxy-indoline-2 '-on-3' -yl) -2-pi peri dinopropionitrile

3- (5'-chloro-3'-hydroxy-indolin-2'-on-3'-yl) -2-piperidino-propioni tril

3- (5'-chloro-3'-hydroxy-indolin-2'-on-3'-yl) -2-dime thylami no-propi oni tril

3- (5'-chloro-3'-hydroxy-indolin-2'-one-3 '-yl j-2-morj) ho Ii no-propi oni tri 1

3- (5'-Chloro-3'-hydroxy-indolin-2'-on-3'-yl} -2- (4 "-methy1piperazinoj-propionitrile

3- (I ¹ -Methyl-5 ¹ , 7'-dichloro-3'-hydroxyindolin-2 '-one-3 ^l -yl) -2-diethylaminopropionitrile

3- (1'-methyl-5 ', 7'-dichloro-3'-hydroxyindoline-2 '-on-3'-yl) -2-piperidinopropionitrile

3- (1'-methyl-5 ', 7'-dichloro-3'-hydroxyindolin-2' -one-3 ^l -yl) -2-di-n-butylaminopropionitrile

3- (1'-methyl-5 ¹ , 7'-dichloro-3'-hydroxyindolin-2 '-on-3'-yl) -2-morpholinopropionitrile

3- (1 · -Methyl-5 ', 7 ⁽ -dich! Or-3'-hydroxy- indolin-2 ' -one-3 '-yl) -2- (4 "-methylpiperazino ) -propioni tri 1

3- (5 '-chloro-3'-hydroxy-indoline-2' -one 3 '-yl) -2-di-n-penty ^r l ami no-propi o nitrile 150 ^c

168

134-135

146-148

165

156

178

185

126-127

160

150

170-172

205

118-120 ^BC

3- (5 ', 7'-DiChIOr ^' - hydroxy-indolin-2'-one-3'-yl) -2-dimethylamino-propioni tril

3- (l '-.Lcetyl-3' -hydroxy-indolin-2 '-one-3' -yli ^ -di-n-propylainino-propio nitrile 110-112

75 fo

50 fo 58 A

85 fo 62 fo 65 fo 65 fo

55 fo 58 fo 75 fo 90 $> 68 fo 66 fo 55 fo 55 $> 80 $>

909886 / 16S4

Claims (3)

ΛΑ Claims 1. Process for the production of new 3-1 ndoli nyl-2-ami iiopropionitri1 on, characterized in that one is an isatin of general formula II ! l.l [ R ^ 6 y «7 R ₃ in the R., hydrogen, an unsubstituted or substituted one aliphatic hydrocarbon radical or an acyl radical, R., R _r , R, and R- independently of one another each hydrogen or a lower alkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl, alkoxy, alkoxyalkoxy, alkyl amino, JJi alkyl amino -, Acylamino, alkyl or di alkylcarbamoyl, alkoxycarbonjl or acyloxy radical, halogen, the hydroxyl, cyano, carbamoyl, carboxyl or nitro group, with lactonitrile (CIK-CHOH-CiN ') and a secondary ami η of the general formula III HN (III) ^ß 2 in the R, an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical, Rp is an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical or a monocarbocyclic aryl radical, or R-, and R, together with the neighboring nitrogen atom a 5- to 7-membered heterocyclic radical, which also contains further heteroatoms may have as ring members, mean to 3- (3'-hydroxy-indolin-2'-on-3'-yl) -2-aminopropionitriles der general formula I implements: 909886/1654 BATH ORIGINAL H, Ι " Ψ .. N r - CH ₂ - CH - CN ^B J in the Ii, to Ιί ~ di G under the formulas II and III given meanings to have. 2. A method according to claim 1, characterized in that the ItcaK 11 oius te i 1 takers in practically equimolar amounts with each other to l / L. 3. 3- (3 '-Hydroxy-i ndolin-2' -one-3 '-yl) -2-ami no-propioni trile of the general Foi'inel I. - CH ₂ - CH - CN ^6th I. 7 II ₃ 7 II ₃ in R. to R- have the meanings given in Ans |) ruch 1. Λ. 3 - (3'-hydroxy-indolin-2'-one-3'-yi) -2-ami no-propionitrile of the general formula I given in claim 1, in which R- to R- have the meanings given in claim 1 have and R, and Ii ₀ each mean the benzyl radical. 9 0 9 8 8 6/1 6 5