CS276469B6 - Method of production of cycloalkanosulfonamides - Google Patents

Abstract

Compounds of Formula XV wherein r 2 is' phenyl which is optionally once or twice substituted with halogen or trifluoromethyl x, x is 1 or 2 and y are 0 or 1, respectively by reacting cycloalkanols of formula XVI with halides sulfonic acid of the formula Hal-SO2-R2, v inert organic solvents, optionally in the presence of bases and subsequent oxidation reaction product in inert solvents. The compounds produced serve as intermediates for the manufacture of pharmacologically active compounds cycloalkane [1,2-b] indolsulfonamides.

Description

The invention relates to a process for the preparation of cycloalkanone sulfonamides of the following general formula

XV, which are used as intermediates in the preparation of new, pharmaceutically active, cycloalkano [1,2-b] indolesulfonamides of the general formula I

(AND),

in which

R 4 represents a hydrogen atom, a halogen atom or a methyl group,

R represents a phenyl group which is optionally substituted once or twice by a halogen atom or a trifluoromethyl group, x represents the number 1 or 2a and y represents the number 0 or 1, which may optionally occur in an isomeric farm or in the form of the corresponding salts.

The present invention relates to a process for the preparation of cycloalkanone sulfonamides of the general formula XV

(XV), in which ·

R represents a phenyl group which is optionally substituted once or twice by a halogen atom or a trifluoromethyl group, x represents the number 1 or 2a and y represents the number 0 or 1.

which consists in that the cycloalkanols of the general formula XVI

HIM

- (CH ₂ ) -nh jr _ X (XVI), in which x and y are as defined above, are treated with sulfonic acid halides of the general formula XVII, Hal - SO ₂ - R ² (XVII),

CS 276469 8 6 in which

R is as defined above and

Hal represents a halogen atom, preferably a chlorine atom or a bromine atom, in inert organic solvents, optionally in the presence of a base, after which the reaction product is oxidized in inert solvents.

A halogen atom generally means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom. Particularly preferably, the halogen atom is a fluorine atom or a chlorine atom.

Particularly preferably, the process according to the invention prepares compounds of formula XV, 2 in which R represents a phenyl group which is optionally substituted by a fluorine atom, a chlorine atom or a trifluoromethyl group, and x represents the number 1 or 2 and y represents the number 0 or 1.

Cycloalkanols of formula XVI, which are used as starting materials for the process of the invention, can be prepared by reacting cycloalkenones of formula XVIII

(XVIII), as defined above, with nitromethane in inert organic solvents, optionally in the presence of bases, and subsequent reduction of the compounds of formula XIX

0.

No. ₂ (xix), in which it has the meaning given above;

(cf. CA 92, 89 849 and CA 87, 22 191).

The sulfonic acid halides of the formula XVII, which are also used as starting materials for the process according to the invention, can be prepared by methods known per se (cf. Houben-Weyl, Methoden der organischen Chemie IX, 564).

The production of cycloalkanone sulfonamides according to the invention can be illustrated by the following reaction scheme:

CS 276469 B 6

degree o

+ H _{3 CN0 2} steps a)

nh ₂ o HalS0 ₂ -R ⁴

b) degree c)

HIM

O

NH-S0 ₂ -ir ích ₂ >, degree fl)

(ch ₂ ) _x o

nh-so ₂ -r

In the first step a) the metal alcohols, for example cycloalkenones, are reacted in methanol, ethanol, propanol in inert solvents or in ethers, for example diethyl ether, tetrahydrofuran or dioxane, or in chlorinated hydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride, in the presence of bases such as sodium hydride, sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, potassium tert-butoxide, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,5-diazabicyclo [5, 4,0] undec-5-ene, pyridine or triethylamine with nitro derivatives, such as nitromethane, at temperatures ranging from 0 ° C to 100 ° C to give the corresponding nitro derivatives.

In step b), the nitro derivatives are reduced in an inert solvent, such as ethers, for example tetrahydrofuran, dioxane or diethyl ether, in the presence of a reducing agent, such as hydrides, for example lithium aluminum hydride, Na [αΚΟΟΗ ^ ΟΙ ^ ΟΟΗ- ^ Η ^ or diisobutylaluminum hydride at temperatures in ranging from -20 ° C to +60 ° C to form cycloalkanols.

In step c) the cycloalkanols are converted by treatment with sulfonic acid halides in inert solvents such as ethers, for example dioxane, tetrahydrofuran or diethyl ether, or in chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or in ethyl acetate or pyridine, optionally in the presence of bases. as 1,5-diazabicyclo [4.3.0] non-5-ene, 1,5-diazabicyclo [5.4.0] undec-5-ene, pyridine or triethylamine at temperatures from -20 ° C to +60 ° C to sulfonamides.

. In step d) the sulfonamides are oxidized in inert solvents such as water, glacial acetic acid, acetone, pyridine or mixtures thereof by the action of oxidizing agents such as chromium compounds, for example chromium oxide, potassium dichromate, sodium dichromate, at temperatures from -20 ° C to +100 ° C to form cycloalkanonesulfonamides. .

CS 276469 B 6

The following examples further illustrate the process according to the invention, but do not limit its scope in any way.

Examples of design:

Example 1

3- (nitromethyl) cyclopentanone

100 g of 2-cyclopentenone are dissolved in 1.1 liters of isopropyl alcohol together with 666 ml of nitromethane and 5 g of 1,5-diazabicyclo [4.3.0] ηοπ-5-ene (DBN) and the solution is allowed to stand at room temperature. for 5 hours. The isopropyl alcohol is then distilled off as far as possible under reduced pressure, the residue is dissolved in ethyl acetate and the solution obtained is washed twice with 0.5 liter of dilute sulfuric acid each time. The organic phase is dried over sodium sulfate and evaporated. 154 g (88% of theory) of 3- (nitromethyl) cyclopentanone are thus obtained, which is sufficiently pure for the next reaction.

Rf = 0.52 (99: 1 mixture of methylene chloride and methanol).

Example 2

3- (aminomethyl) cyclopentano1

57.2 g (0.4 mol) of 3- (nitromethyl) cyclopentanone are dissolved in 573 ml of absolute tetrahydrofuran under a nitrogen atmosphere. A solution of 800 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran is added dropwise to this solution at 0 ° C. After completion of the dropwise addition, the reaction mixture was further stirred at 0 ° C for 1 hour. Then, the cooling bath was removed, and the temperature of the reaction solution was raised to 40 ° C. After the temperature dropped to 20 ° C, the reaction mixture was further stirred at this temperature for 1 hour. To the reaction mixture cooled to 0 ° C was then carefully added dropwise 100 ml of 45% sodium hydroxide solution. After completion of the dropwise addition, the reaction mixture was further stirred at room temperature for 1 hour, then the reaction mixture was filtered through celite and the celite was washed with 1.5 liters of tetrahydrofuran. The combined filtrates were evaporated thoroughly under reduced pressure. 22.5 g (49% of theory) of a viscous, oily product are thus obtained.

Rf = 0.01 (solvent system: 9: 1 mixture of methylene chloride and methanol).

Example 3 '

3- (benzenesulfonanidomethyl) cyclopentanol

HIM

EN 276469 B 6 g (0.078 mol) of 3- (aminomethyl) cyclopentanol are dissolved together with 13.8 g = 10 ml (0.078 mol) of triethylamine in 200 ml of tetrahydrofuran. 7.9 g = 10.8 ml (0.078 mol) of benzenesulfonic acid chloride are then added dropwise at 0-5 [deg.] C. After completion of the dropwise addition, the reaction mixture was further stirred at 0 ° C for 1 hour. The reaction mixture is then diluted with 200 ml of methylene chloride and washed twice with 150 ml of dilute sulfuric acid each time. The organic phase is then extracted twice with 150 ml of 2N sodium hydroxide solution each time, the combined extracts are acidified with concentrated hydrochloric acid and extracted twice with 150 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under reduced pressure. 9.1 g (39% of theory) of a viscous, oily mixture of isomers are thus obtained as product.

R _f = 9.51 and 0.45 (solvent system: methylene chloride-methanol 95: 5). . <

Example 4

3- (Benzenesulfonamidomethylcyclopentanone

7.5 g (0.0294 mol) of 3- (benzenesulfonamidomethyl) cyclopentanol are dissolved in 60 ml of glacial acetic acid. A solution of 2.79 g (0.0279 mol) of chromium oxide in 2 ml of water and 8.8 ml of glacial acetic acid is added dropwise at 0 DEG to 5 DEG C. and then the temperature of the reaction mixture is allowed to rise to room temperature. After stirring for 1 hour at room temperature, the reaction mixture is diluted with 200 ml of ether and washed twice with 150 ml of water each time. The organic phase is then extracted twice with 200 ml of 2N sodium hydroxide solution each time, the combined phases in sodium hydroxide solution are acidified with concentrated hydrochloric acid and extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under reduced pressure. 4.4 g (59% of theory) of a viscous, oily product are thus obtained.

Rf = 0.51 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 5

3- (4-fluorophenylsulfonamidomethyl) cyclopentanol

In a manner analogous to that described in Example 3, 19.8 g (0.172 mol) of 3- (aminomethyl) cyclopentanol are reacted with 28.3 g (0.172 mol) of 4-fluorophenylsulfonamide. 17.3 g (36% of theory) of a viscous, oily mixture of isomers are obtained as the reaction product.

Rf value = 0.53 and 0.46 (solvent system: mixture of methylene chloride and methanol in a ratio of 95: 5).

CS 276469 B 6

Example 6

3- (4-fluorophenylsulfonanidamethyl) cyclapentanone

In a manner analogous to that described in Example 4, 17.3 g (0.063 B mol) of 3- (4-fluorophenylsulfonamidomethylcyclopentanol) were oxidized to give 14.3 g (83% of theory) of a viscous, oily product.

Rf value = 0.76 (solvent system: 9: 1 mixture of methylene chloride and methyl alcohol).

Example 7

3- (4-chlorophenylsulfonanemidomethylcyclopentanol

16.8 g (0.146 mol) of 3- (aminomethyl) cyclopentanol are reacted in a manner analogous to that described in Example 3 with 4-chlorophenylsulfonic acid chloride. 16.6 g (39% of theory) of a viscous, oily product are thus obtained in the form of a mixture of isomers.

Rf = 0.46 and 0.44 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 8

3- (4-chlorophenylsulfonamidomethyl) cyclopentanone

In a manner analogous to that described in Example 4, 16.6 g (0.0573 mol) of 3- (4-chlorophenylsulfonamidomethyl) cyclopentanol were oxidized. 13.8 g (83.7% of theory) of a viscous, oily product are thus obtained.

Rj value = 0.7 (solvent system: mixture of methylene chloride and 95: 5).

methyl alcohol in the ratio

CS 276469 B 6

Example 9

4- (benzenesulfonamido) cyclohexanol

g (0.6 mol) of 4-aminocyclohexanol are reacted with 107 g (0.6 mol) of benzenesulfonic acid chloride in a manner analogous to that described in Example 3. 72.8 g (47% of theory) of crystalline product are thus obtained. Melting point 106-108 ° C.

Rf value = 0.38 (solvent system: 95: 5 mixture of methylene chloride and methanol).

Example 10

4- (benzenesulfonamido) cyclohexanone

72.8 g (0.285 mol) of 4- (benzenesulfonamido) cyclohexanol are oxidized in a manner analogous to that described in Example 4. After crystallization from petroleum ether, 57.5 g (80% of theory) of product with a melting point of 80-82 DEG C. are obtained.

Rf value = 0.66 (solvent system: 95: 5 mixture of methylene chloride and methanol).

In a manner analogous to that described in Example 9, the compounds listed in Table 1 were prepared:.

rCS 276469 8 6

Table 1

example number X yield value R ^ 11 Cl 80% 0.37 (solvent system: CH ₂ Cl ₂ : CH 2 OH = 95: 5) 13 F 75% 0.4 (solvent system: CH ₂ Cl ₂ : CH 2 OH = 95: 5) 15 CHj 48.7% 0.5 (solvent system: CH ₂ Cl ₂ : CH 2 OH = 95: 5)

In a manner analogous to that described in Example 10, the compounds listed in Table 2 below were prepared:

Table 2

example number X yield Rf value (solvent system) melting point (° C) 12 Cl 86% 0.77 CH ₂ Cl ₂ : CH 2 OH = 9: 1 103 to 104 (from petroleum ether) ¹⁴ . F 94> i 0.7 CH ₂ Cl ₂ : CH 2 OH = 9: 1 104 to 108 ' (from petroleum ether) • and ⁶ . CHj 90.7% 0.57 CH ₂ Cl ₂ : CH 2 OH = 95: 5 •

Example 17

3- (nitromethyl) cyclohexanone

CS 276469 B 6

21.9 g of cyclohexanone are left to stand together with 175 ml of nitromethane and 2.1 g of 5-diazabicyclo [4.3.0] non-5-ene (DBN) in 250 ml of isopropyl alcohol for 2 days at room temperature. The work-up is carried out analogously to the procedure given in Example 1 and gives 37.2 g (100% of theory) of 3- (nitromethyl) cyclohexanone which is sufficiently pure for the next reaction.

Value = 0.62 (solvent system: 99: 1 mixture of methylene chloride and methanol).

Example 18

3- (aminomethyl) cyclohexanol

37.2 g of 3- (nitromethyl) cyclohexanone are reduced in a manner analogous to that described in Example 2 using lithium aluminum hydride as reducing agent. 7.5 g (24.5% of theory) of viscous, oily 3- (aminomethyl) cyclohexanol are thus obtained.

Rf value = 0.04 (solvent system: 9: 1 mixture of methylene chloride and methanol).

Example 19

3- (4-fluorophenylsulfonamidamidomethylcyclohexanol

In a manner analogous to that described in Example 3, 7.5 g of 3- (aminomethylcyclohexanol and 11.3 g of 4-fluorophenylsulfonamide are reacted to give 11.05 g (66% of theory) of product as a viscous, oily mixture of isomers.

Rf = 0.41 = 0.30 (solvent system: 95: 5 methylene chloride / methanol).

Example 20

3 - (- 4-fluorophenylsulfonamidomethyl) cyclohexanone

CS 276469 B 6

In a manner analogous to that described in Example 4, 11 g of 3- (4-fluorophenylsulfonamidomethylcyclohexanol are oxidized with chromium oxide to give 9.3 g (86% of theory) of product in the form of a solid foam.

Value = 0.86 (solvent system: methylene chloride / methanol 9: 1).

Example 21 '

In a manner analogous to that described in the above examples, a compound of formula is prepared

R _f

CF 3 = 0.59 (solvent system: toluene / ethyl acetate 1: 1).

The value of Rj indicates the migration rate in the chromatgram.

Claims (2)

PATENT CLAIMS A process for the preparation of cycloalkanone sulfonamides of the general formula XV (XV), CS 276469 B 6 in which R represents a phenyl group which is optionally substituted once or twice X a halogen atom or a trifluoromethyl group, means the number 1 or 2 a y means the number 0 or 1, characterized by being on cycloalkanols of general formula XVI HIM (CH ₂ ) _y rNH ₂ (XVI), in which x and y are as defined above, act on sulfonic acid halides of formula XVII Hal - S0 ₂ - R ² (XVII), in which R is as defined above and Hal represents a halogen atom, preferably a chlorine or bromine atom, in inert organic solvents, optionally in the presence of a base, after which the reaction product is oxidized in inert solvents. 2. A process according to claim 1, wherein the corresponding compounds of formula XVI and XVII are used as starting materials to give compounds of formula XV in which R represents a phenyl group which is optionally substituted by a fluorine atom, a chlorine atom or a trifluoromethyl group, axay. have the meaning given in point 1,