NO300540B1 - Process for the preparation of 2-carboxy-3- [2- (dimethylamino) -ethyl] -N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof and intermediate in the preparation - Google Patents

Description

The present invention relates to a process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof, corresponding to the general formula I, and intermediate product corresponding to formula III

where R can be hydrogen or lower alkyl. These synthetic compounds find use as synthesis intermediates for the production of 3-[2-(dimethylamino)ethyl-N-methyl-1H-indole-5-methanesulfonamide, a product which has useful therapeutic properties in the treatment of migraine.

The intermediate products for their production as well as the method have not previously been described.

GB Patent No. 1 189 064 (1968) describes the preparation of 2-carboalkoxy-3-(haloethyl)indoles by Fisher's indolisation of the corresponding phenylhydrazones in alcoholic hydrogen chloride-saturated medium. The production of phenylhydrazones from α-keto-5-valerolactone by reaction of the latter with the corresponding phenylhydrazine is described by J. Lehmann (Arch. Pharm., 320, 22-29 (1987)), and also in the above-referenced patent.

ES 523 039 describes the production of 4-hydrazino-N-methyl-benzenemethanesulfonamide, which is the starting product for the present invention.

The objectives are to produce a method for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-S-methanesulfonamide and intermediate products in the reaction.

These purposes have been achieved with the present invention characterized by what appears in the claims.

The present invention describes a process for the preparation of 2-carboxy-3-[2-dimethylamino)ethyl-N-methyl-1H-indole-5-methanesulfonamide (formula I) and its lower alkyl esters with the general formula II, in which Alk is a lower alkyl group, preferably methyl or ethyl.

The relevant compounds can be prepared from the compounds of the general formula III

in

in

where Alk is as defined for compounds II, and X is a leaving group such as a halogen atom or a mesyl or tosyl group, preferably tosyl, by reacting them with a

alcoholic dimethylamine solution at a temperature in the range from 0°C to 100°C, preferably approx. 75°C. The produced dimethyl amino esters II are then purified by extraction in an aqueous medium and further alkalization.

The dimethylamino acid I is in turn produced by saponification of the dimethylamino esters II (Alk = Me or Et) in an alkaline medium, e.g. in a 5% ethanolic potassium hydroxide solution and at a temperature in the range from 20°C to 100°C, preferably at approx. 75°C. The product is then isolated in a conventional manner and further purified by recrystallization.

The compound III can be prepared according to the following synthesis principle.

The hydrazine hydrochloride VI is reacted with the α-keto-<S-valero-lactone VII in an aqueous medium at 70 °C and pH 2, according to the procedure described in the literature (see previous section), whereby the hydrazone V is prepared and isolated by filtration, while further Purification is not necessary.

The hydroxyester (IV), (e.g. Alk = Me or Et) is prepared by Fisher's indolization of the hydrazone V followed by transesterification in the same reaction medium. The method is carried out in dry hydrogen chloride solution in the corresponding alcohol (e.g. methanol or ethanol), at an acid concentration in the range from 3 N to 10 N, preferably 5 N, in the case of ethanol. The reaction can be carried out at a temperature in the range from 0°C to 80°C, preferably at approx. 20°C. The product IV is isolated in a conventional manner, as further purification is not necessary.

The compound III is produced from the hydroxy ester IV by substitution of the hydroxy group with a halogen atom using conventional halogenation reagents, or by reaction with mesyl chloride or tosyl chloride.

The substitution reaction of the leaving group from compound III with dimethylamine takes place under particularly mild conditions in the case of tosylates. Said compound is conveniently prepared by reacting the hydroxyester IV with tosyl chloride in the presence of pyridine as solvent and from 5 to 10 molar, with respect to IV, of 4-dimethylaminopyridine as catalyst. The reaction can be carried out at a temperature from 9°C to 50°C, preferably at approx. 20°C.

The present method shows inventive step because a person with knowledge in the field would not use the compound according to formula III (with -CH2-CH2-X in the 3-position and with -COOEt in the 2-position) to obtain compounds of formula II, since the transition from compound III to II is only possible by treatment with dimethylamine. The reaction with dimethylamine, with carboxyethyl substituent in the 2-position, would be expected to give a dimethylamide as a by-product of importance (II amide product in the scheme below), because the reaction of amine acylation using esters to obtain amides is well described (Jerry March; Advanced Organic Chemistry, 2nd Ed., 386-387, McGraw-Hill).

The reactivity of the amines of a carbonyl ester or lactonic in the 2-position of indole was indeed observed during the investigation of the present invention, when the conditions used were different from those required in the present application, in reactions such as:

Nevertheless, and despite the excess of dimethylamine used, in the conversion of compound III to compound II under the conditions described in the present patent, formation of the dimethylamidic compound of formula II amide was not observed.

DESCRIPTION OF PREFERRED EMBODIMENTS

Example 1: Preparation<g> of the hydrazone V

A solution of 0.371 mol of ar-keto-5-valerolactone, prepared by decarboxylation of 69 g (0.371 mol) of α-ethoxy-allyl-r-butyrolactone in 150 mL of H 2 SO 4 heated to reflux, was added dropwise to a solution of pre-cooled to 5°C of 95 g

0.378 mol 4-hydrazine-N-methylbenzenemethanesulfonamide hydrochloride and 19.4 g KOH in 600 ml water. After the addition is complete, the pH is adjusted to 2 with 2 N aqueous NaOH. The mixture is heated at 60°C for 15 min. under vigorous stirring, and is then allowed to achieve

room temperature. A pale yellow precipitate is formed which is filtered off and washed with water. The solid produced is dried at 45°C, whereby 111 g (96% with respect to hydrazine) of the hydrazone V is obtained.

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-d6), ppm: 1.65 (m, 2H; r-lactone protons)

2.55 (d J=7, 3H; CH3NH-)

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

4.10 (broad signal, 2H; 5-lactone protons)

4.20 (s, 2H; -SO2CH2-)

6.85 (q, J=7, 1H; CH3NH-)

7.30 (s, 4H; aromatic)

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

Analysis: C13<H>17<N>304S (M.W.: 311.36)

Percentage calculated: C 50.15; H 5.50; N 13.50; S 10.30

Percent found: C 50.19; H 5.48; N 13.53; S 10,31

Example 2: Preparation of 2-carbethoxy-3-[2-hydroxyethyl)-N-methyl-1H-indole-5-methanesulfonamide (IV, Alk = Et) 70.0 g (0.255 mol) of the hydrazine V is added to 700 ml of a stirred solution of 10 N hydrogen chloride in anhydrous ethanol. Stirring is continued at room temperature for 1 hour. The reaction mixture is diluted with 700 ml of anhydrous ethanol and stirred for a further 15 hours at room temperature and then poured over 700 g of ice and brought to pH 8-9 with solid anhydrous K2CO3. The ethanol is distilled off under vacuum, and the residue is extracted four times with 250 ml of ethyl acetate each time. The collected organic layers are washed with 250 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness, whereby 47.4 g (62%) of the product is obtained in the form of a foam. The crude product is purified by filtration through silica gel using CH2Cl2/Ac=Et (1:1) as eluent, followed by recrystallization from ethanol/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 2 CH 3 )

2.55 (s, 3H; CH3NH-)

3.25 (t J=7, 2H; -CH2CH2-OH)

5.55 (t J=7, 2H; -CH2CH2-OH)

4.29 (q J=7, 2H; -COOCH2CH3)

4.31 (S, 1H; -OH)

4.35 (s, 2H; -SO2CH2-)

6.75 (broad signal, 1H; CH3NH-)

7.3 0 (AB system J=8, 2H; aromatic in C6 and C7)

7.60 (s, 1H; aromatic proton in C4)

13.2 (s, 1H; NH indole)

Analysis: C15<H>20<N>2O5S (M.W.: 340.39)

Percentage calculated: C 52.93, H 5.92, N 8.23, S 9.42

Percent found: C 52.97, H 5.90, N 8.26, S 9.39

Example 3: Preparation of 2-carbethoxy-3-(2-tosyloxyethyl)-N-methyl-1H-indole-5-methanesulfonamide (III, Alk = Et,

X = OTS)

To a stirred solution of 44.4 g (0.13 mol) of compound IV (Alk - Et) in 256 ml of pyridine is added 38 g (1.5 equiv.) of tosyl chloride and 1.7 g (0.1 equiv.) 4-dimethylaminopyridine, and stirring is continued at room temperature for 1 hour. The reaction mixture is poured into 1 liter of 3 N HCl solution previously cooled to 0°C. The extraction is carried out with 3 x 400 ml of dichloromethane. The collected organic layers are washed sequentially with saturated aqueous sodium bicarbonate and aqueous sodium chloride solutions. After drying over anhydrous sodium sulfate, the solvent is distilled off to dryness, whereby 55 g (86%) of the tosylate of product III (Alk = Et) is obtained as a white solid which can optionally be further purified by filtration on silica gel with CH2Cl2/AcOEt as eluent.

Melting point: 130-131°C.

IR (KBr), cm_<1>:3301, 2968, 2960, 1545, 1358, 1316,

1256, 1177, 1122, 1001, 949, 911, 783,

662, 578, 554, 533.

NMR (CDCl 3 ), ppm: 1.30 (t J=7.3H; -COOCH 2 CH 3 )

2.30 (s, 3H; CH3NH-)

2.65 (s, 3H; CH3-Ph-SO2-0-)

3.32 (t J=8, 2H; -CH2CH2-OTs)

4.00-4.60 (complex system, 6H;

-SO2CH2-, -COOCH2CH3 V

-CH2CH2-OTs)

7.30 (AB system J=10, 4H, aromatic

from the tosyl group)

7.35 (AB system J=8, 2H, aromatic

in C6 and C7)

7.52 (s, 1H, aromatic in C4)

9.05 (s, 1H, NH indole)

Analysis: C22<H>26<N>2°7S2 (M.W.: 494.58)

Percentage calculated: C 53.43, H 5.30, N 5.66, S 12.96

Percent found: C 53.39, H 5.33, N 5.61, S 13.00

Example 4: Preparation of 2-carbethoxy-3-[2-(dimethylamino)-ethyl]-N-methyl-1H-indole-methanesulfonamide fII. Alk = Et)

49.4 g (0.1 mol) of III (Alk = Et, X = OTs) are dissolved in 200 ml of a 33% dimethylamine solution in alcohol. The solution is stirred at room temperature for 15 hours and then heated to reflux within 30 minutes. The solution is evaporated to dryness, the residue is dissolved in 200 ml of 3 N HC1 and washed with 3 x 80 ml of CH2Cl2. The washed aqueous layer is cooled, the pH is adjusted to 12 with 10 N NaOH and extracted with 3 x 100 ml CH 2 Cl 2 . The collected organic layers are washed with 100 ml of saturated NaCl solution and dried over anhydrous sodium sulfate. The solution is evaporated to dryness, whereby 30 g (83%) of II (Alk = Et) are obtained. The crude product is recrystallized from ethanol.

Melting point: 153-155°C

IR (KBr), cm~<1>:3343, 2945, 2790, 1674, 1545, 1446,

1322, 1264, 1116, 1012, 781, 736.

NMR (CDCl 3 ), ppm: 1.40 (t J=7.3H; -COOCH 2 CH 3 )

2.30 (S, 6H; -N(CH3)2)

2.50 (m, 2H; -CH2CH2-N)

2.70 (s, 3H; CH3NH-)

3.00 (m, 2H; -CH2CH2-N)

4.25 (s, 2H; -SO2CH2-)

4.30 (q, J=7, 2H; -COOCH2CH3)

7.25 (s, 2H; aromatic at C6 and C7)

7.55 (s, 1H; aromatic at C4)

9.30 (s, 1H; NH indole)

Analysis: C17<H>25<N>304S (M.W.: 367.46)

Percentage calculated: C 55.57, H 6.86, N 11.44, S 8.72

Percent 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-methanesulfonatom fl)

14.3 g (0.04 mol) of II (Alk = Et) are dissolved in 140 ml of a 5% KOH solution in ethanol. The resulting solution is heated to reflux for 5 hours, then cooled and the solvent distilled off to dryness. The residue is dissolved in 100 ml of water and washed with 3 x 70 ml of CH2C12. The aqueous solution is then cooled to 5°C, and the pH is 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, whereby 12.6 g (96%) of product I is obtained.

Melting point: 245-250°C (dec.)

IR (KBr), cm"<1>:3405, 3275, 1600, 1343, 1296, 1120, 972.

NMR (DMSO-d6), ppm: 2.65 (broad singlet, 9H; CH3NH-, and

-N(CH3)2)

3.05 (m, 2H; -CH2CH2-N)

3.35 (m, 2H; -CH2CH2-N)

4.35 (s, 2H; -SO2CH2-)

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

6.85 (broad signal, 1H; CH3NH-)

7.25 (AB system J=8, 2H,

aromatic in C6 and C7)

7.65 (s, 1H; aromatic proton in C4)

12.15 (s, 1H; nH indole)

Analysis: C15<H>21<N>3°4S (M.W.: 339.41)

Percentage calculated: C 53.08, H 6.24, N 12.38, S 9.45

Percent found: C 53.10, H 6.28, N 12.36, S 9.44

Claims (8)

1. Connection, characterized in that it corresponds to formula III: ,l wherein ALK is a lower alkyl group, preferably methyl or ethyl, and X is halogen, mesyl or tosyl leaving group, preferably a tosyl leaving group. 2. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof, characterized by reacting the compound with the general formula III where Alk is a lower alkyl group and X is a leaving group, with dimethylamine in the presence of a suitable solvent to give the dimethylaminoester compound of the general formula II which in turn, after saponification, gives 2-carboxy-3-[2-(dimethyl- amino) ethyl-N-methyl-1H-indole-5-methanesulfonamide of the formula I 3. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claim 2, characterized in that a lower alkyl group is used which is preferably a methyl or an ethyl group. 4. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claims 2 and 3, characterized in that a leaving group is used which is a halogen atom, a mesyl or tosyl group, preferably a tosyl group. 5. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claims 2-4, characterized in that the compound of the general formula III is reacted with a dimethylamine solution in an alcoholic solvent such as methanol, ethanol or iso-propanol, preferably ethanol. 6. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claims 2-5, characterized by carrying out the reaction of the compound III with dimethylamine at a temperature in the range from 0°C to 100°C, preferably at approx. 75°C. 7. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claims 2-6, characterized in that the saponification of the dimethylaminoester II is carried out in an alcoholic or hydro-alcoholic alkali hydroxide solution, preferably in a 5% ethanolic potassium hydroxide solution. 8. Process for the production of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and lower alkyl esters thereof according to claims 2-7, characterized in that saponification of the dimethylaminoester II is used which is carried out at a temperature in the range from 20°C to 100°C, preferably at approx. 75°C.