HU213680B - Process for producing 2-carboxy-3-[2-(dimethylamino)-ethyl]-n-methyl-1h-indole-5-methanesulfonamide and their alkyl esther derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel compounds of formula (I) wherein R is hydrogen or (C1-C6) alkyl such as a compound of formula (III) wherein Alk is (C1-C6) alkyl and X is a leaving group; reacting with dimethylamine in the presence of a suitable solvent, and saponifying the resulting compound of general formula II in which Alk is a C1-C6 alkyl group, if desired, to give compounds of formula I wherein R is hydrogen. The compounds of the present invention are used in the preparation of 3- [2-dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamides as starting materials for treating migraine. Cttj Kl ll) H (Hl i HU 213 680 B Scope of the description: 6 pages (including 2 sheets))

Description

This invention relates to 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide and to C 1 -C 6 alkyl ester derivatives.

The compounds of the present invention are represented by formula (I) wherein R is hydrogen or (C 1 -C 6) alkyl.

The compounds of formula (I) above are used as starting materials for the preparation of 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamides which are useful in the treatment of migraine.

The compounds of formula (I) above and the starting materials used in their preparation are novel.

In U.S. Patent No. 1,189,064, 2-alkoxycarbonyl-3-haloethylindole compounds are prepared by Fisher indolysis of the corresponding phenyl hydrazones in an alcohol-saturated hydrochloric acid medium.

The α-keto-delta-valerolactones can be converted to the phenyl hydrazone by reaction with the appropriate phenyl hydrazine [J. Lehmann, Arch. Pharm., 320, 22-29 (1987)] and the aforementioned patent specification.

Spanish Patent No. 523039 discloses 4-hydrazino-N-methylbenzene methanesulfonamides which are starting materials for the process of the present invention.

In the process of the present invention, 2-carboxy-3- [2- (dimethylamino) ethyl-N-methyl-1H-indole-5-methanesulfonamide of the formula (I) wherein R is hydrogen and its 1- C 6 alkyl esters are prepared wherein R is C 1-6 alkyl, preferably methyl or ethyl.

In the process of the present invention, a compound of formula (III) wherein Alk is a C 1-6 alkyl group and X is a leaving group such as a halogen or a mesyl or tosyl group, preferably a tosyl group, is dimethylamine in an alcoholic medium at 0-100 ° C. temperature, preferably 75 ° C. The resulting ester derivative is then purified by extraction.

The dimethylamino acid of formula (I) is then obtained from the dimethylaminoester derivative of formula (II), wherein Alk is a C 1-6 alkyl group, preferably methyl or ethyl, by saponification in an alkaline medium, e.g. 5% ethanol in potassium hydroxide at 20-100 ° C, preferably 75 ° C. The product is then isolated in a known manner and purified by recrystallization.

The compound of formula (III) is prepared by the reaction scheme A.

The hydrazine hydrochloride of formula (VI) is reacted with the α-keto-delta-valerolactane of formula (VII) in an aqueous medium at a temperature of about 70 ° C and a pH of 2 as previously described in the prior art, The hydrazone of formula (V) is obtained which is no longer required to be purified.

The hydroxy esters of formula (IV), wherein Alk is preferably methyl or ethyl, are obtained by Fisher indolysis of the hydrazone of formula (V) and the resulting compound is transesterified in the same reaction medium. The process is carried out in anhydrous hydrochloric acid solution in an appropriate alcohol (e.g. methanol or ethanol) at a concentration of 3 to 10 n, preferably 5 n, in the case of ethanol. The reaction is carried out at 0-80 °, preferably at 20 °, and the compound of formula IV obtained is isolated in a known manner without further purification.

Compounds of formula (III) are swallowed from hydroxy esters of formula (IV), substituted by a halogen atom using known halogenating agents or reacted with mesyl or tosyl chloride.

The substitution reaction of the compound of formula (III) with dimethylamine is carried out under particularly mild reaction conditions for tosylate. These compounds are obtained by reacting the hydroxy ester of formula IV with tosyl chloride in the presence of a pyridine solvent in which the starting compounds of formula IV are present in an amount of 5-10 mol%, using 4-dimethylaminopyridine as the catalyst. The reaction temperature is usually 0 to 50 ° C, preferably 20 ° C.

The following non-limiting examples illustrate the process of the invention in greater detail.

EXAMPLE I Preparation of Hydrazone of Formula V g (0.371 mol) of α-ethoxyallyl-gamma-valerolactone is decarboxylated by refluxing in 150 ml of sulfuric acid to give a 0.371 molar solution of α-keto-delta-valerolactone, dropwise, pre-cooled To a solution of 95 g (0.378 mol) of 4-hydrazine-N-methylbenzene-methanesulfonic acid hydrochloride in 600 ml of water at 5 ° C in the presence of 19.4 g of potassium hydroxide. After the addition was complete, the pH was adjusted to 2 with 2N aqueous sodium hydroxide, and the mixture was heated at 60 ° for 15 minutes with vigorous stirring and then allowed to cool to room temperature. The resulting pale yellow precipitate was filtered off, washed with water and dried at 45 °. 111 g (96% based on hydrazone) of hydrazone V are obtained, m.p. 190-191 ° C

IR (KBr), cm -1: 3419, 3309, 3277, 2947, 1690, 1614,

1582, 1529, 1387, 1308, 1250, 1152, 1124, 1073,

1052, 840, 578 NMR _(DMSO-d6) ppm;

1.65 (m, 2H, gamma-lactone protons)

2.55 (d, J = 7, 3H, CH ₃ NH-)

3.45 (t, J = 7, 2H, β-lactone protons)

4.10 (broad signal, 2H, δ-lactone protons)

4.20 (s, 2H, -SO ₂ CH ₂ -)

6.85 (q, J = 7, IH, CH ₃ NH-)

7.30 (s, 4H, aromatic)

10.00 (s, 1H, -NH-N =)

Elemental analysis for C10H17N3O4S (mole: 311.36):

HU 213,680 Β Calculated: 50.15% 5.50% Found: 50.19% 5.48%

13.50% 10.30% 13.53% 10.31%

Example 2

2-Ethoxycarbonyl-3- (2-hydroxyethyl) -N-methyl-1H-indole-5-methanesulfonamide (IV, alk = Et)

Hydrazine (V) (70.0 g, 0.255 mol) was added to 700 ml of 10 víz HCl in ethanol with stirring and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 700 ml of anhydrous ethanol, stirred for an additional 15 hours at room temperature, then poured onto 700 g of ice and adjusted to pH 8-9 with solid anhydrous potassium carbonate. The ethanol was then evaporated in vacuo, the residue was extracted with ethyl acetate (4 x 250 mL), the organic layers were combined, washed with brine (250 mL) and dried over anhydrous magnesium sulfate. The solvent was then evaporated to give 47.4 g (62%) of product as a foam. This was purified on silica gel (ClCH ₂ / Ac = Et = 1/1) and the product recrystallized from ethanol / water, m.p. 153.5-155.5 ° C.

IR (KBr), cm ^-1 : 3336, 2928, 1694, 1553, 1445, 1378, 1317, 1253, 1155, 1119, 1090, 1040, 897, 846, 782, 531 NMR (DMSO-d 6), ppm:

1.35 (t, J = 7, 3H, -COOCH ₂ CH ₃ )

2.55 (s 3H, CH ₃ NH--)

3.25 (t, J = 7, 2H, -CH ₂ CH ₂ OH)

5:55 (t, J = 7, 2H, -CH ₂ CH ₂ OH)

4.29 (q, J = 7, 2H, -COOCH ₂ CH ₃ )

4.31 (s, 1H, -OH)

4.35 (s, 2H, -SO ₂ CH ₂ -)

6.75 (broad signal, 1H, CH ₃ NH-)

7.30 (AB system J = 8, 2H, C6 and C7 aromatic)

Elemental analysis for C ₅ H ₂ oN ₂ 0 ₅ S (M t .: 340.39) Calculated compound:

Calculated for CΗΗN S: 52.93% 5.92% Found: 52.97% 5.90%

8.23% 9.42%

8.26% 9.39%

Example 3

2-Ethoxycarbonyl-3- (2-tosyloxyethyl) -N-methyl-1H-indole-5-methanesulfonamide (III, alk = Et,

X = OTs) g (0.13 mol) of the compound of formula IV (Alk = Et) is dissolved in 256 ml of pyridine, 38 g of 1.5 equivalents of tosyl chloride and 1.7 g of 0.1 equivalents of 4-dimethyl are added. -aminopyridine and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into 1 L of pre-cooled 3N hydrochloric acid (0 ° C), and the mixture was extracted with dichloromethane (3 x 400 mL), the organic layers were combined, washed successively with saturated sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to give 55 g (86%) of the tosylate of formula III (alk = Et). The white solid was filtered off and purified on silica gel (C12CH2 / AcOEt). 130-131 ° C.

IR (KBr), cm -1: 3301,2968,2960,1545,1358,1316, 1254,1177,1122,1001,949,911,783,662,578,554, 533

NMR (DMSO-dg), ppm:

1.30 (t, J = 7, 3H, -COOCH ₇ CH ₃ )

2.30 (s, 3H, CH ₃ NH--)

2.65 (s, 3H, CH ₃ -Ph-SO ₂ -O-)

3.32 (t, J = 8, 2H, CH ₂ CH ₂ -OTs)

4.00-4.60 (complex system, 6H, SO ₂ CH ₂ -,

-COOCH ₂ CH ₃ Y -CH ₂ CH ₂ -OTs)

7.30 (Subsystem J = 10.4H, aromatic, atosyl)

7.35 (AB system J = 8, 2H, C6 and C7 aromatic)

9.05 (s, 1H, NH indole)

Elemental analysis for C ₂₂ H ₂ gN ₂ O ₇ S (m.p. 494.58):

C Η N S Calculated: 53.43% Found: 53.39%

5.30% 5.66% 12.96%

5.30% 5.61% 13.00%

Example 4

2-Ethoxycarbonyl-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (II, Alk = Et)

49.4 g (0.1 mol) of compound (III) (Alk = Et, X = OTs) are dissolved in 200 ml of 33% alcoholic dimethylamine solution. The resulting solution was stirred at room temperature for 15 hours and then heated under reflux for 30 minutes. The solvent was evaporated and the residue was dissolved in 200 ml of 3N hydrochloric acid and washed three times with 80 ml each of 80 ml of methylene chloride. The aqueous layers were cooled, adjusted to pH 12 with 10η sodium hydroxide, and extracted with methylene chloride (3 x 100 mL). The organic phases are combined, washed with 100 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated to give 30 g (83%) of the compound of formula II (Alk = Et), which is recrystallized from methanol. op. 153-155 ° C.

IR (KBr), cm ^-1 : 3343.2945, 2790, 1674, 1545, 1446, 1322, 1264, 1116, 1012, 781.736 NMR (CDCl3), ppm:

1.40 (t, J = 7, 3H, -COOCH ₂ CH ₃ )

2.30 (s, 6H, -N (CH ₃ ) ₂ )

2.50 (m, 2H, CH ₂ CH ₂ -N)

2.70 (s, 3H, CH ₃ NH-)

3.00 (m, 2H, CH ₂ CH ₂ -N)

4.25 (s, 2H, -SO ₂ CH ₂ -)

4.30 (q, J = 7, 2H, -COOCH ₂ CH ₃ )

7.25 (s, 2H, aromatic C 6 and C 7)

7.55 (s, 1H, aromatic C4)

9.30 am (s, ΙΗ, ΝΗ indol)

Elemental Analysis for: CpH4N5C / S (m.p. 367.46):

HU 213,680 Β

c H N S Calculated: 55.57% 6.86% 11.44% 8.72% Found: 56.00% 6.90% 11.41% 8.69% Example 5

2-Carboxyl-3- [2- (dimethylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide [(I), R = H]

14.3 g (0.04 mol) of the compound of formula II (Alk = Et) are dissolved in 140 ml of a 5% solution of potassium hydroxide in ethanol, and the resulting solution is refluxed for 5 hours. After cooling, the solvent was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3 x 70 mL). The aqueous layers were cooled to 5 ° and the pH adjusted to 6 with glacial acetic acid. Stirring is continued at 5 ° C for 1 hour and the precipitated solid is filtered off and dried at 45 ° C to give 12.6 g (96%) of the title compound. op. 245-250 ° C (dec.).

IR (KBr), cm ^-1 : 3405.3275.1600.1343, 1296.1120, 972 NMR (DMSO-d6), ppm:

2.65 (broad singlet, 9H, CH ₃ NH- and N (CH ₃ ) ₂ ) 3.05 (m, 2H, -CH ₂ CH ₂ -N)

3:35 (m, 2H, CH ₂ CH ₂ -N)

4.35 (s, 2H, -SO ₂ CH ₂ -)

5.10 (broad singlet, 1H, amino acid proton)

6.85 (broad signal, 1H, CH ₃ NH-)

7.25 (AB system J = 8, 2H, aromatic C 6 and C 7)

7.55 (s, 1H, C4 aromatic proton)

12.15 (s, ΙΗ, ΝΗ indole)

Elemental analysis for CjjH ^^O CSS (m.p. 339.41):

C H N S Calculated: 53.08% 6.24% 12.38% 9.45% Found: 53.10% 6.28% 12.36% 9.44%

PATENT CLAIMS

Claims (7)

A process for the preparation of a compound of formula I wherein R is hydrogen or C 1-6 alkyl, characterized in that a compound of formula III wherein Alk is C 1-6 alkyl and X is a leaving group - dimethyl with amine in the presence of a suitable solvent and saponifying the resulting compound of formula II, wherein Alk is C1-C6 alkyl, optionally to produce compounds of formula I wherein R is hydrogen. A process for the preparation of a compound of formula (I) according to claim 1 wherein R is methyl or ethyl, characterized in that the appropriate starting materials are used. Process according to any one of claims 1 or 2, characterized in that the starting compound of the formula (III) in which the leaving group is a halogen atom, a mesyl or tosyl group, preferably a tosyl group. 4. Process according to any one of claims 1 to 3, characterized in that the reaction of the compound of formula (III) with dimethylamine is carried out in an alcoholic solvent such as methanol, ethanol or isopropanol, preferably ethanol. 5. Process according to any one of claims 1 to 3, characterized in that the reaction of the starting compound (III) with dimethylamine is carried out at a temperature of 0 to 100 ° C, preferably 75 ° C. 6. Process according to any one of claims 1 to 3, characterized in that the saponification of the dimethylamino esters of formula (II) is carried out in an alcoholic alkali metal hydroxide or a hydroalcoholic medium, preferably in a 5% solution of potassium hydroxide in ethanol. 7. Process according to any one of claims 1 to 4, characterized in that the saponification of the dimethylamino esters of the formula (II) is carried out at a temperature of 20 to 100 ° C, preferably 75 ° C.