SK280586B6 - Process for preparing 2-carboxy-3-[2-(dimethylamino)-ethyl]-n- -methyl-1h-indole-5-methanesulfonamide and lower alkyl esters thereof - Google Patents

Abstract

Disclosed is a process for preparing 2-carboxy-3-[2- -(dimethylamino)-ethyl]-N-methyl-1H-indole-5-methanesulfonamide and its lower alkyl esters of the general formula (I) wherein R is H or a C1-6-alkyl group, which process can be characterised in that the compound of the general formula (III), wherein Alk denotes a C1-6-alkyl group and X is a leaving group, reacts with dimethylamine in an organic solvent. Thus produced dimethylaminoester of the general formula (I), wherein R is a C1-6-alkyl group, is optionally saponificated to obtain the compound of the general formula (I), wherein R is H.

Description

Preparation of 2-carboxy-3- [2- (dimethylamino) ethyl-l-methyl-indole-5-methanesulphonamide, and its lower alkyl esters of formula (I) wherein R represents a hydrogen atom or a _{first The 6-} alkyl group is carried out by reacting a compound of formula (III) wherein Alk is a C 1-6 alkyl group and X is a leaving group and is reacted with dimethylamine in an organic solvent. The resulting dimethylamino ester of formula (I) wherein R is C 1-6 -alkyl is optionally saponified to give a compound of formula (I) wherein R is hydrogen.

CH, -NH-SO.

'COOAlk

Technical field

The present invention relates to a process for the preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide and its lower alkyl esters of formula (I)

wherein R is hydrogen or C _1-6 -alkyl.

These compounds find use as intermediates in the synthesis of 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide, a product having useful therapeutic properties against migraine.

Neither the compounds of the invention nor the intermediates used for their preparation have been described hitherto.

BACKGROUND OF THE INVENTION

U.S. Pat. 1189064 (1986) describes a process for the preparation of 2-alkoxycarbonyl-3- (halomethyl) indoles by Fisher indolization of the corresponding phenylhydrazones in an alcoholic medium saturated with hydrogen chloride.

The preparation of phenylhydrazones of α-keto-δ-valerolactone by reaction of this lectone and the corresponding phenylhydrazines is described in J. Lehmann, Ar. Pharm., 320, p. 22-29 (1987) and also in the cited patent.

The preparation of 4-hydrazino-N-methylbenzenemethanesulfonamide, which is the starting product for the synthesis of the compounds of the invention, is described in ES 523039.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide and its lower alkyl esters of formula (I)

wherein R is hydrogen (the compound of formula (I) is a free acid) or a C _1-6 -alkyl group, preferably methyl or ethyl (the compound of formula (1) is a lower alkyl ester).

Compounds of formula (I) may be obtained from compounds of formula (III)

CH, -NH-SO>

wherein Alk is C 1-6 -alkyl, preferably methyl or ethyl, and X is a leaving group such as halogen, mesyl or tosyl, preferably tosyl, by reaction with an alcoholic solution of dimethylamine at a temperature ranging from 0 to 100 ° C, preferably at about 75 C. The dimethylamino esters of formula (I) (R = Alk) are then purified by extraction in an aqueous medium followed by alkalinization.

The free dimethylamino acid of formula (I) (R = H) is then obtained by saponification of the dimethylamino ester of formula (I) (R = methyl or ethyl) in an alkaline medium, e.g. 5% ethanolic potassium hydroxide solution at a temperature ranging from 20 to 100 ° C, preferably at about 75 ° C. The product obtained is then isolated by conventional methods and further purified by crystallization.

Compounds of formula (III) can be obtained according to the following reaction scheme.

(III) (Alk = Me or Et and X = Cl, Br, O-tosyl, O-mesyl)

Hydrazine hydrochloride of formula (VI) is reacted with α-keto-6-valerolactone of formula (VII) in an aqueous medium at 70 ° C and pH 2, as described in the literature (see prior art). The resulting hydrazone of formula (V) is isolated by filtration and optionally further purified.

Hydroxyesters of formula (IV) (wherein, for example, Alk is methyl or ethyl) are obtained by Fisher indolization of the hydrazone of formula (V), followed by transesterification, which is carried out in the same reaction medium. The process is carried out in a solution of dry hydrogen chloride in the corresponding alcohol (e.g. methanol or ethanol), at an acid concentration ranging from 3N to 10N, preferably 5N when ethanol is used. The reaction may be carried out at a temperature ranging from 0 to 80 ° C. The products of formula (IV) are isolated by conventional procedures; their further cleaning is not necessary.

Compounds of formula (III) are obtained from hydroxyesters of formula (IV) by substitution of a hydroxy group with a halogen atom, using conventional halogenating reagents or by reacting these compounds with mesyl chloride or tosyl chloride.

The substitution reaction of the leaving group in compounds of formula (III) with dimethylamine takes place using tosylates under particularly mild conditions. These compounds are conveniently obtained by reacting hydroxy esters of formula (IV) with tosyl chloride, in the presence of pyridine as solvent and 5 to 10 mole%, based on the compound of formula (IV), 4-dimethylaminopyridine as catalyst. The reaction may be carried out at a temperature ranging from 0 to 50 ° C, preferably at about 20 ° C.

The invention is illustrated by the following examples. These examples, which set forth the best embodiment of the invention, are merely illustrative and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Production of hydrazone of general formula (V)

A solution of .alpha.-keto-.beta.-valérolactone (0.371 mol), obtained by decarboxylation of 69 g (0.371 mol) of .alpha.-ethoxyalyl-.gamma.-butyrolactone in 150 ml of sulfuric acid, heated to reflux, is added dropwise 95 g (0.378 mol) of 4-hydrazine-N-methylbenzenemethanesulfonamide hydrochloride and 19.4 g of potassium hydroxide in 600 ml of water. After completion of the dropwise addition, the pH was adjusted to 2 with aqueous sodium hydroxide solution. The mixture was heated at 60 ° C for 15 minutes with vigorous stirring and then allowed to equilibrate to room temperature. The resulting pale yellow precipitate was filtered off and washed with water. The solid obtained is dried at 45 ° C to give 111 g (96% based on hydrazine) of the hydrazone of formula (V).

Melting point: 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-d ₆ ) , 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, 5-lactone protons), 4.20 (s, 2H: -SO ₂ CH _r ), 6.85 (q, J = 7, 1H; CH ₃ NH-) 7.30 (s, 4H; aromatic protons), 10.00 (s, 1H; -NH-N =)

For C ₁₀ H ₁₇ N ₃ O ₄ S (molecular weight: 311.36):

calculated: C 50.15; H, 5.50; N, 13.50; S 10.30 found: C 50.19; H, 5.48; N, 13.53; S 10.31%

Example 2

Preparation of 2-ethoxycarbonyl-3- (2-hydroxyethyl) -N-methyl-1H-indole-5-methanesulfonamide (compound of formula (IV), Alk = ethyl)

70.0 g (0.255 mol) of hydrazine (V) is added to 700 ml of a stirred 10N solution of dry hydrogen chloride in anhydrous ethanol. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is then poured onto 700 g of ice and adjusted to pH 8-9 with solid anhydrous potassium carbonate. The ethanol is distilled off in vacuo and the residue is extracted 4 times. 250 ml of saturated aqueous sodium chloride solution each and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to yield

47.4 g (62%) of the product as a foam. The crude product was purified by filtration through silica gel, eluting with dichloromethane: ethyl acetate (1: 1), followed by crystallization from a mixture of ethanol and water. Melting point: 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, CH ₃ ).

2:55 (s, 3H, CH ₃ NH), 3.25 (t, J = 7, 2H, -CH ₂ CH ₂ OH),

5:55 (ζ J = 7, 2H, -CH ₂ CH ₂ OH), 4.29 (q, J = 7, 2H, -COOCH ₂ CH _3), 4.31 (s, 1 H, OH), 4, 35 (s, 2 H -SO ₂ CH ₂ -) 6.75 (b, 1H, _NH-CH3), 7.30 (AB system, J ~ 8, 2H, aromatic protons of C 6 and C 7), 7 60 (s, 1H; aromatic proton at C4 position), 13.2 (s, 1H; NH indole) Elemental analysis for C ₁₅ H ₂₀ N ₂ O ₅ S (molecular weight: 340.39) calculated: C 52, 93; H, 5.92; N, 8.23; S, 9.42. Found: C, 52.97; H, 5.90; N, 8.26; S 9,39%

Example 3

Preparation of 2-ethoxycarbonyl-3- (2-tosyloxyethyl) -N-methyl-1H-indole-5-methanesulfonamide (compound of formula (III), Alk = ethyl, x = OTs)

To a stirred solution of 44.4 g (0.13 mol) of the compound of formula (IV) (Alk = ethyl) in 256 ml of pyridine was added 38 g (1.5 equivalents) of tosyl chloride and 1.7 g (0.1 equivalents). 4-dimethylaminopyridine and stirring was continued for 1 hour at room temperature. The reaction mixture was poured into 1 L of pre-cooled (0 ° C) 3N hydrogen chloride solution. The mixture was extracted three times, each time with 400 ml of dichloromethane. The combined organic layers were washed successively with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and the solvent was distilled off to dryness. This afforded 55 g (86%) of the tosyltate of formula (III) (Alk = ethyl) as a white solid which could be further purified by filtration through silica gel, using a mixture of dichloromethane and ethyl acetate as eluent. Melting point: 130-131 ° C

IR (KBr), cm ^-1 : 3301, 2968, 2960, 1545, 1358, 1316, 1256, 1177, 112, 1001, 949, 911, 783, 662, 578, 554, 533.

NMR (DMSO-d ₆ ), ppm: 1.30 (t, J = 7, 3H; -COOCH ₂ CH ₃ ), 2.30 (s, 3H; CH ₃ NH-), 2.65 (s, 3H; CHrPh) -SO ₂ -O-), 3.32 (t, J = 8, 2H; -CH ₂ CH ₂ OTs), 4.00 to 4.60 (complex system, 6H; -SO ₂ CH ₂ -, -COOOLCH , and -CH ₂ CH ₂ -OTs). 7.30 (AB system, J = 10, 4H; tosyl aromatic protons), 7.35 (AB system, J = 8, 2H; aromatic protons at C6 and C7 positions) 7.52 (s 1H; aromatic proton at position C4), 9.05 (s, 1H; NH indole).

For C ₂₂ H ₂₆ N ₂ O ₇ S (molecular weight: 494.58):

Calcd, C, 53.43; H, 5.30; N, 5.66; S, 12.96. Found: C, 53.39; H, 5.33; N, 5.61; S, 13.00

Example 4

Preparation of 2-ethoxycarbonyl-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indolmethanesulfonamide (compound of formula (I), R = ethyl)

49.4 g (0.1 mol) of the compound of formula (III) (Alk = ethyl, X = OTs) are dissolved in 200 ml of a 33% alcoholic dimethylamine solution. The solution was stirred at room temperature for 15 hours and then refluxed for 30 minutes. The solvent is evaporated to dryness and the residue is dissolved in 200 ml of 3N hydrochloric acid. The mixture was washed 3 times, each time with 80 ml of dichloromethane. The washed aqueous layer was cooled, adjusted to pH 12 with 10N sodium hydroxide and extracted 3 times with 100 ml of dichloromethane each time. The combined organic layers were washed with 100 mL of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give 30 g (83%) of the compound of formula (I) (R = ethyl). The crude product is crystallized from ethanol. Mp: 153-155 ° C

IR (KBr), cm ^-1 : 3343, 2945, 2790, 1674, 1545, 1446, 1322, 1246, 1116, 1012, 781,736

NMR (DMSO-d ₆ ), 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 protons at the C6 and C7 positions), 7.55 (s, 1H aromatic proton at position C4), 9.30 (s, 1H, NH indole).

For C ₁₇ H ₂₅ N ₃ O ₄ S (molecular weight: 367.46):

Calcd, C, 55.57; H, 6.86; N, 11.44; S, 8.72 Found: C, 56.00; H 6.90; N, 11.41; S 8.69%

Example 5

Preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (compound of formula (1), R = H)

14.3 g (0.04 mol) of the compound of formula (I) (R = ethyl) are dissolved in 140 ml of a 5% solution of potassium hydroxide in ethanol. The resulting solution was refluxed for 5 hours, then cooled and freed from the solvent by distillation. The residue is dissolved in 100 ml of water and the solution is washed 3 times with 70 ml of dichloromethane each time. The aqueous solution was then cooled to 5 ° C and adjusted to pH 6 with glacial acetic acid. Stirring was continued at 5 ° C for 1 hour and the precipitated solid was filtered off and dried at 45 ° C. There was thus obtained 12.6 g (96%) of the compound of formula (I), (R = H).

Melting point: 245-250 ° C (dec.) IR (KBr), cm -1: 3405.3275, 1600.1343, 1269.1120, 972. NMR (DMSO-d ₆ ), ppm: 2.65 (broad singlet) 9H; CH ₃ NH and -N (CH ₃ ) ₂ ), 3.05 (m, 2H; -CH ₂ N ₆ N), 3.35 (m, 2H; -CH ₂ CH ₂ -N), 4.35 (s, 2H; -SCi (CH2) 5.10 (broad singlet, 1H; amino acid proton), 6.85 (broad signal, 1H; CH5 NH-), 7.25 (AB system, J = 8, 2H; aromatic protons at C6 position) and C7), 7.55 (s, 1H; aromatic proton at position C4), 12.15 (s, 1H; NH indole).

H, C H _{2 I 15} N ₃ O ₄ S (molecular weight: 339.41):

Calcd. C 53.08; H, 6.24; N, 12.38; S, 9.45. Found: C, 53.10; H, 6.28; N, 12.36; S 9.44%

Example 6

Preparation of 2-methoxycarbonyl-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (compound of formula (I), Alk = methyl)

48.0 g (0.1 mol) of the compound of formula (III) (Alk = ethyl, X = OTs) are dissolved in 190 ml of a 33% ethanolic dimethylamine solution. The solution was stirred at room temperature for 17 hours and then refluxed for 20 minutes. The solvent is evaporated to dryness and the residue is dissolved in 200 ml of 3N hydrochloric acid. The mixture was washed 3 times, each time with 80 ml of dichloromethane. The combined organic layers were washed with 100 mL of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give 28 g (80%) of the compound of formula (I) (Alk = Me). The crude product was crystallized from a mixture of methanol and water.

Melting point: 165-167 ° C

IR (KBr), cm ^-1 : 3340, 2940, 2785, 1675, 1550, 1445, 1325, 1270, 1115, 1015, 785, 735

NMR (CDCl 3), ppm: 2.30 (s, 6H; -N (CH ₃ ) ₂ ), 2.55 (m 2H; -CH ₃ CH-N), 2.70 (s, 3H; CH ₃ NH-) , 3.05 (m, 2H, _{CH2 CH2} N), 3.95 (s, 3H, _COOCH3) 4.25 (s, 2 H, -SO ₂ CH ₂ -), 7.25 (s, 2H, aromatic protons of C 6 and C 7), 7.55 (s, 1H, aromatic proton at position C 4), 9.20 (s, 1H, indole NH) H, C | e, II, ₂ and ₃ O ₄ S (Molecular Weight: 353,44):

Calcd. C, 54.37; H, 6.56; N, 11.89; S 9.07% found: C 54.40; H, 6.59; N, 11.84; S 9,10%

Claims (9)

A process for the preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide and its lower alkyl esters of general formula (1) wherein R represents a hydrogen atom or C]. _6- alkyl, wherein Alk is C 1-6 -alkyl and X is a leaving group, reacted with dimethylamine in the presence of an organic solvent to form a dimethylamino ester of formula (I) wherein R is SK 280586-6 C _1-6 -alkyl, which is optionally saponified, to give a compound of formula (I) wherein R is hydrogen. The process according to claim 1, wherein the C 1-6 -alkyl group is a methyl group or an ethyl group. Method according to claim 1 or 2, characterized in that the leaving group is a halogen atom, a mesyl group or a tosyl group, preferably a tosyl group. A process according to claims 1 to 3, characterized in that the compound of formula (III) is reacted with a solution of dimethylamine in an alcoholic solvent such as methanol, ethanol or isopropyl alcohol, preferably ethanol. The process according to claims 1 to 4, wherein the reaction of the compound of formula (III) with dimethylamine is carried out at a temperature ranging from 100 ° C to 100 ° C. A process according to claim 5, wherein the reaction of the compound of formula (III) with dimethylamine is carried out at a temperature of 75 ° C. Process for the preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide according to claims 1 to 5, characterized in that the saponification of the dimethylamino ester of the general formula (I), wherein R is is a C 1-6 -alkyl group, is carried out in an alkali metal hydroxide solution in an alcohol or a mixture of alcohols and water, preferably in a 5% ethanolic potassium hydroxide solution. Process for the preparation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide according to claims 1 to 7, characterized in that the saponification of the dimethylamino ester of the general formula (I), wherein R C _1-6 -alkyl is carried out at a temperature ranging from 20 to 100 ° C. A process according to claim 8, characterized in that the saponification of the dimethylamino ester of formula (I), wherein R represents Cl. _6- alkyl, carried out at 75 ° C. End of document