CZ366299A3 - Process for preparing indole derivatives - Google Patents

Abstract

The essence of the present invention is a process for the preparation of a compound of formula I, which is: comprises reacting a compound of formula II with a compound of formula ΠΙ in the presence of a strong base and a palladium (0) kalalyator, at elevated temperature in a solvent that does not adversely affect it reaction. The compounds of formula I can be further processed to compounds of formula V which are useful in the treatment of, inter alia, the compounds of formula V other migrants.

Description

Technical field

The invention relates to a novel process for the preparation of a known class of compounds, some of which are known to be pharmacologically active.

BACKGROUND OF THE INVENTION

For example, International Patent Application WO 92/06973 discloses a series of indole derivatives that are potent serotonin (5-HT) agonists. These compounds are indicated for the treatment of disorders resulting from insufficient serotonergic neurotransmission including hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania, and headache associated with vascular disorders.

Compounds covered by WO 92/06973 include (R-5- (methylaminosulfonylmethyl) -3- (N-methylpyrrolidin-2-ylraethyl) -1Hindole (Example 5A, known as CP-122 288) having the following structure:

• · · ♦ ·..........

..... · ······ · · · · · · * · · ··· · · ····

- 2 UK Patent No. 2,162,522 discloses an indole derivative (known as sumatriptan) which is marketed for the treatment of migraine under the trademark Imigran and has the following structure:

European Patent Application 0548813 discloses another indole derivative (see Example 29, known as BMS-180048), which is indicated in the treatment of migraine and has the following structure:

In the prior art, the synthesis of these compounds begins with a substituted benzyl halide, which then undergoes replacement with a suitable sulfur nucleophile (e.g., sodium sulfite). This product is then oxidized to the corresponding sulfonyl chloride and condensed with methylamine to give the desired secondary sulfonamide group. The resulting compound is then subjected to intramolecular cyclization to form the desired indole ring.

In the case of CP-122 288, this cyclization is a Heck reaction according to the following scheme:

• · ·

wherein P is a protecting group.

Reactions of this type may have a low yield (often around 25%) and result in a mixture of products that require column chromatography to purify them. This makes the production of the desired products expensive and inefficient.

SUMMARY OF THE INVENTION

The novel process of the present invention is summarized in Figure 3 where R and Hal are defined below and the compounds described above are compounds of formula V.

The present invention uses palladium catalyzed cross-interaction to introduce the sulfonamidomethylene unit in one portion into a preformed indole ring, thereby avoiding intramolecular cyclization and the problems associated with it as described above.

«· ·

Thus, the process of the present invention has the advantages of having a higher yield and not always requiring column chromatography as compared to the prior art.

Sakamoto et al. Disclose palladium catalyzed reactions of phenylsulfonylacetonitrile with various halogen-substituted aromatic compounds. The aromatic compounds involved do not contain active hydrogen and thus do not require protection during the reaction (see Synthesis, 1992, p. 552, and Chem. Pharm. Bull., 38 (6), p. 1513-1517 (1990)).

According to a first aspect of the present invention there is provided a process for the preparation of a compound of formula I

12, -, wherein R and R are independently N-protecting groups, and

R represents a C 1-4 alkyl group substituted with:

(i) a 5- or 6-membered nitrogen containing saturated heterocyclic group which may alternatively be substituted with a C 1-4 alkyl or pyrimidine ring which is itself substituted with a C 1-4 alkoxy, or (ii) di (C 1-4 alkyl) amino which comprising reacting a compound of formula II

(II) • 4 · 4

Wherein Hal represents Cl, Br or I, and 2 3

R and R are as defined above, with the compound of formula III

O.

IN

R‘CH, N v.

-CN (III) wherein R ^x is as defined above, in the presence of a strong base and a palladium (0) catalyst, at elevated temperature, in a solvent that does not adversely affect the reaction.

Preferred strong bases are sodium hydride and potassium t-butoxide.

A preferred palladium (0) catalyst is tetrakis (triphenylphosphine) palladium (0). This can be added to the reaction mixture as Pd (II) Cl ₂ IPCl 3 H ₂ O 2 ^and converted to palladium (0) species under the reaction conditions. Similarly, Pd (II) ((CH 2 CH 2) 2) can be added to the reaction mixture and converted to palladium (0) species under reaction conditions.

Suitable solvents include toluene, and preferably a mixture of toluene and ethylene glycol dimethyl ether (CH2OCH2 CHgOCH ₂₎ ·

This second solvent system has the advantage that the deprotonated compounds of formula III remain mobile in the reaction mixture and thus are available for reaction.

Preferably, the process is carried out at the reflux temperature of the solvent. In the solvent systems mentioned in the preceding paragraph, this will be approximately 80 ° C and 100 ° C respectively.

At these temperatures, the process should be completed within 1 to 3 hours.

Preferably Hal is Br.

According to a second aspect of the present invention there is provided a process for the preparation of a compound of formula V

wherein it is as defined above, which comprises (i) basic hydrolysis of the cyano group of a compound of formula I as defined above, followed by decarboxylation of the resulting carboxylic acid to form a compound of formula IV

1-3 wherein R is as defined above, followed by

2 (ii) replacement of R and R with hydrogen.

Preferably, step (i) is carried out using aqueous potassium hydroxide in ethanol at elevated temperature. The aqueous potassium hydroxide is preferably diluted (e.g., 1 to 2M). The reaction is preferably carried out at the reflux temperature of the reaction mixture (typically around 80 ° C) using the preferred conditions mentioned previously.

Under these conditions, the reaction is usually complete within 8 to 16 hours.

• «

- 7 12

Preferably, R and R are replaced by H under the same conditions in step (ii), but may be replaced sequentially. A preferred method for their simultaneous replacement is hydrogenolysis. Suitable hydrogenolysis conditions include palladium on carbon in the presence of hydrogen gas at 60 ° C and 4 psig, and sodium or calcium in liquid ammonia at -50 to -33 ° C.

In each aspect of the invention, it is preferred that R 6 represents benzyl, CH ₂ OCH ₂ (ΟθΗ), CH (C 8 H 6) ₂ or tert-butyl. CH 2 OCl 3 (CH 2 OH) is particularly important.

In each aspect of the invention, it is preferred that 2,

R represents an N-protecting group that is stable to the basic hydrolysis conditions, in particular the basic hydrolysis conditions used in step (i) of the second aspect of the invention. It has been found that basic hydrolysis and decarboxylation in this step is considerably increased when R remains at 2 point during the reaction. However, R may not be the same in every 2 aspect of the invention, but the selection of the appropriate R group in formula II in the first aspect of the invention eliminates the need to replace the unstable protecting group for step (i) of the second aspect of the invention. N-protecting groups that are stable to basic hydrolysis conditions include benzyl, Cl 2 OCl 2 (C ₆ H ₅ ), CH ₂ OCH ₂ CH ₂ Si (CH ₃ ) _3, and CH ₂ CHCH ₂ . However, since both are removable by hydrolysis, benzyl and CH ₂ OCH ₂ (ΟθΗ ^) take precedence.

Preferably R is CH ₂ CH ₂ N (CH ₃ ) ₂ or a group of formula Ia or Ib

[0057] Ib

- 8 3

Compounds of formula V in which R _f represents these groups are sumatriptan, CP-122,288 and BMS-180,048th

The invention further provides intermediate compounds of formulas I, III and IV as defined above.

Compounds of formulas II and III may be prepared by conventional methods as illustrated in the Examples.

2

When R is a group of Formula Ib and R is Cl 2 OCl 2 (C 8 H 4), the compound of Formula II can be prepared as shown in the accompanying Fig. 2.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples in which the abbreviations below may be used:

DMF dimethylformamide

Et ethyl

IMS industrial methylated substances hour hour

MeOH methanol min minute

LRMS low resolution mass spectroscopy

THF tetrahydrofuran.

Example 1 (R) -N-Methyl- [3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] methanesulfonamide (a) Methyl (N-benzyl-N-methylsulfamoyl) acetate

To a stirred solution of N-methylbenzylamine (7 mL, 54.2 mmol) in dichloromethane (10 mL) at 0-5 ° C under a nitrogen atmosphere was added dropwise a solution of methyl chlorosulfonylacetate (prepared by MJSzymonifky and JVHeck, Tetrahedron Lett., 1989, 30, 22, 2869) (4.25 g, 24.7 mmol) in dichloromethane (5 mL) maintaining the temperature below 5 ° C. The yellow solution was then warmed to ambient temperature over a 2 hour period before water (30 mL) was added. The organic phase was separated and evaporated in vacuo to give a yellow oil.

This was purified by flash column chromatography (diethyl ether: hexane 1: 1 as eluent) to give the title compound (a) (3.9 g, 61%) as a colorless oil.

^{Χ Η} NMR (300MHz, CDCip

2.83 (3H, s), 3.83 (3H, s), 4.02 (2H, s), 4.38 (2H, s), 7.277.42 (5H, m).

Found: C 51.31, H 5.92, N 5.42.

^C 11 ^H 15 ^NO 4 ^S requires: C 51.35, H 5.88, N 5.44%.

(b) (N-Benzyl-N-methylsulfanoyl) acetamide

THF

To a stirred solution of methyl (N-benzyl-N-methylsulfamoyl) acetate (from step (a), 3.9 g, 15.2 mmol) in tetrahydrofuran (10 mL) at ambient temperature was added aqueous ammonia (10 mL). , rel = 0.88) in one fraction. The orange solution was then stirred at ambient temperature for 18 hours before being poured into water (50 mL) and extracted with ethyl acetate (3x25 mL). The organic extract was evaporated in vacuo to give the compound under (b) (2.8 g, 76%) as a white solid.

Mp 124-127 ° C, ¹ H NMR (300MHz, CDCl 3? = 2.83 (3H, s), 3.92 (2H, s), 4.39 (2H, s), 5.61 (1H, bs) 6.50 (1H, bs), 7.20-7.45 (5H, m).

Found: C, 49.56; H, 5.78; N, 11.54. ^C 10 ^H 14 ^N 2 ^O 3 ^S requires: C 49.57, H 5.82, N 11.56%.

(c) N-Benzyl-1-cyano-N-methylmethanesulfonamide

.S ^ CONH,

(i) (COCI) ^ DMF (ii) Pyridine: Acetonitrile ·

O, ^N O

Compound (c) (2.36 g, 91%) was prepared as a white solid from (N-benzyl-N-methylsulfamoyl) acetamide (from step (b), 2.8 g, 1.6 mmol) according to the procedure of Bargar and Riley (Synthetic Communications, 1980, 10 (6), 479).

M.p. 68-70 [deg.] C.

@ ¹ H NMR (300 MHz, CDCl3) .delta. = 2.95 (3H, s), 3.96 (2H, s), 4.50 (2H, s), 7.10-7.53 (5H, m). Found: C 53.41, H 5.36, N 12.39. ^ε ΐΟ ^Η 12 ^Ν 2θ2® requires: C 53.55, H 5.39, N 12.49%.

11 (d) (R) -1-Benzyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole

To a stirred solution of (R) -5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (see Example 27 of WO 92/06973) (21.44 g, 73.2 mmol) in tetrahydrofuran (110 ml) sodium hydride (60% dispersion in mineral oil, 3.51 g, 87.7 mmol) was added in portions at 0 ° C under nitrogen atmosphere, maintaining the temperature below 5 ° C. Upon completion of the addition, the dark brown solution was stirred at 0-5 ° C for 1 hour before benzyl bromide (10.4 mL, 87.4 mmol) was added dropwise while maintaining the temperature below 5 ° C. The brown solution was then heated at ambient temperature for 1 hour before being poured into water (100 mL). The mixture was then extracted with ethyl acetate (3 x 25 mL) and the organic extracts were combined and evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane; diethylamine 1: 1: 0.1 as eluent) to give the title compound (d) (17.6 g, 63%) as a brown viscous oil.

¹ H NMR (300MHz, CDCl 3) 1.50-1.95 (4H, m), 2.19-2.35 (1H, m), 2.49 (4H, m), 2.56-2 70 (1H, m), 3.10-3.25 (2H, m), 5.20 (2H, s), 6.99 (1H, s), 7.03-7.16 (3H, m) 7.20-7.37 (4H, m), 7.69 (1H, s).

Found: C 65.83, H 6.08, N 7.24.

^C 21 ^H 23 ^{BrN 2} Y 3 ^{behind e: C} 65.80, H 6.05, N 7.31%.

[α] _D + 64.3 ° (c = 1.78, MeOH).

(e) N-Benzyl-1 - [(R) -1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-methylmethanesulfonamide · · ♦ • • * * * * * * * * * * * * * * * *

To a stirred solution of N-benzyl-1-cyano-N-methylmethanesulfonamide (from step (c), 643 mg, 2.9 mmol) in toluene (5 mL) at 0 ° C under nitrogen was added potassium tert-butoxide (615). mg, 5.5 mmol) in portions, keeping the heat below 5 ° C. The brown solution was then warmed to ambient temperature over a 10 minute period before tetrakis (triphenylphosphine) palladium (0) (181 mg, 0.16 mmol) was added in one portion. A solution of (R) -1-benzyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (from step (d), 1.0 g,

2.6 mmol) in toluene (5 mL) dropwise into a yellow suspension and the mixture was heated to reflux. Reflux was maintained for

1.5 hours, after which time the dark brown solution was cooled to ambient temperature.

The reaction mixture was then poured into water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to give the title compound (1.09 g, 80%) as a brown oil.

NMR (300MHz, CDCl 3) δ = 1.49-1.90 (4H, m), 2.16-2.30 (1H, m), 2.35-2.55 (4H, m), 2,622.81 (4H, m), 3.08-3.26 (2H, m), 4.18 (2H, s), 5.26 (1H, s), 5.31 (2H, s), 7.02- 7.13 (3H, m), 7.20-7.41 (10H, m), 7.81 (1H, bs).

Found: C 69.94, H 6.56, N 10.23.

^C 31 ^H 34 ^N 4 ° 2 ^S requires: C 70.7, H 6.51, N 10.64%.

(f) (R) -N-Benzyl-1- (1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl) -N-methylmethanesulfonamide

To a stirred solution of N-benzyl-1- | (R) -1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl | -1-cyano-N-methylmethanesulfonamide (from step (e)) , 29 g, 55.1 mmol) in ethanol (200 mL) at ambient temperature was added 2N potassium hydroxide solution (200 mL, 400 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hours. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined and evaporated in vacuo to give a dark brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to give the title compound (f) (24.67 g, 89%) as a brown oil.

1 H NMR (CDCl ₃ )? T = 1.54-1.98 (4H, m), 2.18-2.35 (1H, m), 2.40-2.86 (8H, m), 3.093, 30 (2H, m), 4.03 (2H, s), 4.42 (2H, s), 5.28 (2H, s), 6.99-7.44 (13H, m), 7.64 (1H, s).

Found: C 70.99, H 7.07, N 8.10.

^C 30 ^H 35 ^N 3 ° 2 ^S y ^{back 3: c} 71 »32, H 7.04, N 8.38%.

[Α] _D + 50.98 ° (c = 1.55, CH ₂ Cl ₂ ).

(G) (R) -N-Methyl- (3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl) methanesulfonamide

(R) -N-Benzyl-1- [1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-methylmethanesulfonamide solution (from step (f), 2.04) g), in tetrahydrofuran (2 mL) was added dropwise to liquid ammonia (10 mL) at -40 ° C under a nitrogen atmosphere. Sodium (about 500 mg) was then added portionwise to the colorless solution until a stable dark blue solution was obtained. The blue solution was stirred for an additional 30 minutes at -40 ° C before saturated ammonium chloride solution (5 mL) was added and the gray suspension was warmed to room temperature over an 8 hour period. The white suspension was then diluted with water (10 mL), filtered and dried under vacuum at 50 ° C to give the title compound (733 mg, 56%) as a white solid.

M.p. Mp 209-213 ° C.

NMR (300 MHz, DMSO)? F = 1.36-1.81 (4H, m), 2.04-2.17 (1H, m), 2.28-2.52 (8H, m), 2.903 10 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H, d, J = 9.7Hz), 7.15 (1H) , bs), 7.30 (1H, d, J = 9.7 Hz), 7.51 (1H, s), 10.85 (1H, bs). LRMS (thermospray): 322 (MH ⁺ ).

[α] _D + 81.08 ° (c = 0.47, DMSO).

• · <

• 0 · • ♦

Example 2 (R) -N-Methyl- [3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] methanesulfonamide (alternative route) (a) Methyl- (N-diphenylmethyl-N-methylsulfamoyl) acetate

Compound ad (a) (3.05 g, 37%) was prepared as a clear brown oil from N-methylbenzhydrylamine (prepared according to the method described by Z. Horii, T. Sakai and T. Inoi, Pharm. Bilil., 1955, 3, 159) (10.7 g, 50.7 mmol) and methyl chlorosulfonyl acetate (4.27 g, 24.7 mmol) using the method of Example 1 (a).

^{Σ Η} NMR (300 MzH, _CDCl3) <f = 2.83 (3H, s), 3.72 (3H, s), 3.82 (2H, s), 6.43 (lH, s), 7107 47 (10H, m).

Found: C 61.29, H 5.74, N 4.21.

^C 17 ^H 19 ° 4 ^NS requires C 61.24, H 5.74, N 4.20%.

(b) (N-Diphenylmethyl-N-methylsulfamoyl) acetamide

CO, Me NH ₃ (aq)

THF

AND

Compound (b) (2.62 g, 90%) was prepared as a white solid from aqueous ammonia (10 mL, rel. Density = 0.88) and methyl- (N-diphenylmethyl-N-methylsulfamoyl). ) of acetate (from step (a), 3.05 g, 9.2 mmol) by the method of example 1 (b).

M.p. Mp 110-115 ° C.

@ ¹ H NMR (300 MHz, CDCl3) .delta. = 2.80 (3H, s), 3.72 (2H, s), 5.63 (1H, bs), 6.41 (1H, s), 6, 60 (1H, bs), 7.05-7.48 (10H, m).

Found: C 60.13, H 5.67, N 8.75.

^C 16 ^H 18 ^N 2 ^O 3 requires: C 60.36, H 5.77, N 8.80%.

(c) 1-Cyano-N-diphenylmethyl-N-methylmethanesulfonamide

Compound ad (c) (0.7 g, 71%) was prepared as a beige solid from (N-diphenylmethyl-N-methylsulfamoyl) acetamide (from step (b), 1.0 g, 3.14 mmol) using of the method of Example 1 (c).

M.p. M.p. 104-107 ° C.

@ ¹ H NMR (300 MHz, CDCl3) .delta. = 2.98 (3H, s), 3.71 (2H, s), 6.39 (1H, s), 7.20-7.46 (10H, m). Found: C 63.94, H 5.38, N 9.24.

^C 16 ^H 16 ^N 2 ^O 2 ^S requires: C 63.98, H 5.37, N 9.33%.

• · · · · · · · · · · · ·

17 (d) 1 - [(R) -1-Benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (c), 18.79 g, 62.6 mmol) in a mixture of toluene (60 mL) and ethylene glycol dimethyl ether (20 mL) at 0-5 ° C sodium hydride (60% dispersion in mineral oil) (4.6 g, 115 mmol) was added portionwise under nitrogen atmosphere, maintaining the temperature below 5 ° C.

Upon completion of the addition, the dark brown solution was warmed to ambient temperature over a 30 minute period before tetrakis (triphenylphosphine) palladium (0) (3.61 g, 3.1 mmol) was added in one portion.

A solution of (R) -1-benzyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (from Example 1 (d), 19.74 g, 52 mmol) in toluene (20 mL) was then added dropwise to the brown suspension and the mixture was heated to reflux. Reflux was maintained for 2 hours, after which the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (250 mL) and extracted with ethyl acetate (3x100 mL). The organic extracts were combined and evaporated in vacuo to give a brown oil.

This was redissolved in absolute ethanol (80 mL) and stirred for 18 hours during which time precipitation occurred. The solid was filtered and dried under vacuum at 50 ° C overnight to afford compound (d) (22 g, 70%) as a cream solid.

M.p. Mp 152-155 ° C.

· · * * * * * * * * * * * * * * * * * * * * * * * * * * ·· ··· ··

- 18 ¹ H NMR (300MHz, CDCl 3)? F = 1.38-1.91 (4H, m), 2.14-2.30 (1H, m), 2.35-2.50 (4H) , m),

2.55-2.70 (1H, m), 2.78 (3H, s), 3.02-3.20 (2H, m), 4.98 (1H, s), 5.28 (2H, m, s), 6.41 (1H, s), 6.89-7.53 (18H, m), 7.60 (1H, bs). Found: C 73.70, H 6.28, N 9.26.

^ε 37 ^Η 38 ^Ν 4θ2 ^δ requires: C 73.72, H 6.35, N 9.29%.

(e) (R) -1- [1-Benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-diphenylmethyl-N-methylmethanesulfonamide

KOH (a) Ethanol, reflux

To a stirred solution of 1 - [(R) -1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (d), 1.61 g, 19.3 mmol) in ethanol (35 mL) at ambient temperature, 2N potassium hydroxide solution (35 mL, 70 mmol) was added. The dark brown solution was then brought to reflux and maintained at this temperature for 15 hours. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined and evaporated in vacuo to give the crude product as a dark brown oil. This oil was diluted with ethanol (35 mL) and stirred at ambient temperature for 12 hours, resulting in precipitation. The mixture was then filtered and the solid dried under vacuum at 50 ° C overnight to give the title compound (6.82 g, 61%) as a beige solid.

M.p. Mp 117-120 ° C.

¹ H NMR (300MHz, CDCl ₃ )

J = 1.48-1.95 (4H, m), 2.16-2.32 (1H, m), 2.39-2.70 (8H, m), 3,053.25 (2H, m), 4.24 (2H, s), 5.26 (2H, s), 6.36 (1H, s), 6.90-7.49 (19H, m).

Found: C 74.40, H 6.75, N 7.34.

^C 36 ^H 39 ^N 3 ° 2 ^S 3 ^{characterized behind ei C} 74.80, H 6.76, N 7.27%.

[σύ] ₀ = + 50.79 ° (c 8, CH ₂ C1 _2).

(f) (R) -N-Methyl- [3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] methanesulfonamide

To a stirred suspension of calcium chips (1.11 g, 27.7 mmol) in tetrahydrofuran (1.2 mL) at -40 ° C was added condensed liquid ammonia (16 mL). The blue bronze was stirred at -50 ° C to -40 ° C for an additional 15 minutes before (R) -1- [1-benzyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-solution was added dropwise. -indol-5-yl] -N-diphenylmethyl-N-methylmethanesulfonamide (from step (e), 4.0 g, 6.93 mmol) in tetrahydrofuran (10 mL) maintaining the temperature below -40 ° C. The dark blue solution was stirred at -40 ° C for an additional 30 minutes before saturated ammonium chloride solution (10 mL) was added dropwise and the gray solution was allowed to warm to ambient temperature. Water (10 mL) was then added and the white suspension was stirred for 15 minutes before being filtered under vacuum.

The solid was then dissolved in 5N HCl (12 mL) and the resulting orange solution was extracted with ethyl acetate (10 mL). The pH of the aqueous phase was then adjusted (pH = 10) with 10N NaOH, resulting in precipitation. The solid was filtered and dried under vacuum at 50 ° C overnight to give the title compound (1.54 g, 73%) as a white solid.

M.p. Mp 209-212 ° C.

¹ H NMR (300MHz, DMSO) δ = 1.36-1.81 (4H, m), 2.04-2.17 (1H, m), 2.28-2.52 (8H, m), 2.903 10 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H, d, J = 9.7Hz), 7.15 (1H) (bs), 7.30 (1H, d, J = 9.7 Hz), 7.51 (1H, s), 10.85 (1H, bs). LRMS (thermospray): 322 (MH ⁺ ).

Example 3 (R) -N-Methyl- [3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] methanesulfonamide (alternative route) (a) (N-Methylsulfamoyl) acetamide

CONH ₂

H ₂ , Pd (OH) ₂

MeOH

O ^x n ' ^s ^ ^conh *

HIM

A solution of (N-benzyl-N-methylsulfamoyl) acetamide (see Example 1 (b), 13.0 g, 50.5 mmol) in methanol (130 mL) was hydrogenated over Pearlman's catalyst (7.5 g) at 60 ° C. and 345 kPa for 24 hours. The solution was then filtered through a pad of celite (trademark), which was then washed with acetone (50 mL).

• «

• · ·

The combined filtrate was evaporated in vacuo to give a white solid, which was dried under vacuum at 50 ° C overnight to afford compound (a) (8.0 g, 98%) as a white solid.

M.p. Mp 104-108 ° C.

¹ H NMR (250MHz, DMSO) δ = 2.55-2-65 (3H, d, J = 4.9Hz), 3.85 (2H, s), 6.88-7.05 (1H, m) 7.32 (1H, bs), 7.60 (1H, bs).

LRMS (thermo-spray) 169.7 (MNH + ⁺ + * (b) 1-Cyano-N-methylmethanesulfonamide)

9.-i) (COCI) ,, DM? 0.

CONH, -►

Ii (ii) Pyridine $ o

Acetonitrile.

Compound ad (b) (0.87 g, 99%) was prepared as a beige solid from (N-methylsulfamoyl) acetamide (from step (a), 1.0 g, 6.57 mmol) following the procedure of Example 1 (c). ).

M.p. 36-39 [deg.] C.

¹ H NMR (300MHz, DMSO)

3 = 2.65 (3H, s), 4.75 (2H, s), 7.85 (1H, bs).

LRMS (thermospray) 152.0 (MH ⁺ ).

(c) N-Benzyloxymethyl-1-cyano-N-methylmethanesulfonamide

CN

i) NaH ii) BOMCI THF

O, \, S ru

Yeah

O

To a stirred solution of 1-cyano-N-methylmethanesulfonamide (from step (b), 250 mg, 1.9 mmol) in tetrahydrofuran (5 mL) at 0-5 ° C under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) in one portion. The resulting suspension was stirred at 0-5 ° C for 45 minutes before benzyloxymethyl chloride (80% purity, 0.368 g, 1.9 mmol) in tetrahydrofuran (5 mL) was added dropwise over a 15 minute period. The mixture was then allowed to warm to ambient temperature over 3 hours.

The solvent was then evaporated in vacuo and the resulting oil was purified by flash column chromatography (diethyl ether: hexanes 3: 1 as eluent) to afford compound (c) (296 mg, 61.6%) as a colorless oil.

¹ H NMR (300MHz, CDCl 3)? T = 3.19 (3H, s), 4.05 (2H, s), 4.62 (2H, s), 4.81 (2H, s), 7.297 50 (5H, m).

LRMS (thermospray) 272.3 (MNH ₄ ⁺ ).

(d) (R) -1-Benzyloxymethyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole

\

To a stirred suspension of potassium tert-butoxide (5.5 g, 45 mmol) in tetrahydrofuran (30 mL) at 0-5 ° C, under a nitrogen atmosphere, was added a solution of (R) -5-bromo-3- (1-methyl-2-). pyrrolidinylmethyl) -1H-indole (12 g, 41 mmol) in THF (40 mL) dropwise while maintaining the temperature below 10 ° C.

Upon completion of the addition, the dark brown solution was stirred at 0-5 ° C for 1 hour before benzylchloromethyl ether (80% pure, 8.8 g, 45 mmol) was added dropwise while maintaining the temperature below 5 ° C. The brown solution was then warmed to ambient temperature over a 1 hour period before being poured into water (100 mL). The mixture was then extracted with ethyl acetate (3 x 25 mL) and the combined organic phases were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: triethylamine 100: 5 as eluent) to afford compound (d) (14.1g, 83%) as a brown oil.

@ ¹ H NMR (300 MHz, CDCl3) .delta. = 1.42-1.95 (4H, m), 2.11-2.32 (1H, m), 2.32-2.65 (5H, m) 3.03.20 (2H, m), 4.36 (2H, s), 5.48 (2H, s), 7.01 (1H, s), 7.13-7.42 (7H, m) ), 7.72 (1H, s).

LRMS (thermospray): 413.3 (MH ⁺ ).

(e) N-Benzyloxymethyl-1 - [(R) -1-benzyloxymethyl-3- (1-methyl-12-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-methylmethanesulfonamide

in mineral oil, 470 mg, 11.7 mmol) and tetrakis (triphenylphosphine) palladium (0) (370 mg, 0.32 mmol) in a mixture of toluene (5 mL) and ethylene glycol dimethyl ether (1.62 mL) under a nitrogen atmosphere was a solution of N-benzyloxymethyl-1-cyano-N-methylmethanesulfonamide (from step (c), 1.62 g, 6.4 mmol) in toluene (2.2 mL) was added at 0-5 ° C.

• · · · · · · · ·

The mixture was then warmed to ambient temperature and stirred for 30 minutes before the (R) -1-benzyloxymethyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H solution was added in one portion. -indole (from step (d), 2.2 g, 5.3 mmol) in toluene (2.2 mL) and the mixture was heated to reflux. Reflux was maintained for 2 hours after which time the dark brown solution was cooled to room temperature.

The reaction mixture was then poured into water (20 mL) and extracted with ethyl acetate (3x15 mL). The organic extracts were combined and evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: triethylamine 97.5: 2.5) to afford compound (e) (2.98 g, 95%) as a brown oil.

¹ H NMR (300MHz, CDCl 3)?

1.46-1.95 (4H, m), 2.15-2.30 (1H, m), 2.37-2.75 (5H, m), 3.02 (3H, s), 3, 05-3.20 (2H, m), 4.40 (3H, s), 4.47-4.62 (4H, m), 5.31 (1H, s), 5.50 (2H, s) 7.08 (1H, s), 7.20-7.81 (13H, m).

LRMS (thermospray): 586.7 (MH ⁺ ).

(f) (R) -N-Benzyloxymethyl-1- [1-benzyloxymethyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-methylmethanesulfonamide

To a stirred solution of N-benzyloxymethyl-1 - [(R) -1-benzyloxymethyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-methylmethanesulfonamide (from step (e), 2.0 g, 3.4 mmol) in IMS (14 mL) at room temperature, 2N potassium hydroxide solution (7.0 mL, 14 mmol) was added. The dark brown solution was then brought to reflux and maintained at this temperature for 15 hours. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3x20 mL). The organic extracts were combined and evaporated in vacuo to give a dark brown oil. This was purified by flash column chromatography (ethyl acetate: triethylamine 95: 5 as eluent) to afford compound (f) (631 mg, 33%) as a brown oil.

¹ H NMR (300MHz, CDCl 3) = 1.46-1.44 (4H, m), 2.16-2.32 (1H, m), 2.37-2.75 (5H, m), 2, 89 (3H, s), 3.05-3.23 (2H, m), 4.3-4.52 (10H, m), 5.51 (2H, s), 6.937.66 (14H, m) .

LRMS (thermospray): 562.5 (MH ⁺ ).

(g) (R) -N-Methyl- [3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole

5-yl] methanesulfonamide

\

A mixture of (R) -N-benzyloxymethyl-1- [1-benzyloxymethyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-methylmethanesulfonamide (from step (f), 300 mg, 0 , 5 mmol) and methanesulfonic acid (60 mg, 0.6 mmol) in water (5 mL) were hydrogenated over Pearlman's catalyst (300 mg) at 60 ° C at 345 kPa (18 h). The solution was then filtered through a pad of celite (trademark) and the filtrate was partitioned between saturated sodium bicarbonate (25 mL) and dichloromethane (3 x 50 mL).

• · • ·

The combined organic extract was then evaporated in vacuo, the residue was dissolved in a mixture of TIIF and water (1: 1) (10 mL). A solution of Triton B (40% by weight in methanol) (0.2 mL, 0.4 mmol) was then added dropwise and the solution was then refluxed for 2 hours. Then the solution was cooled to ambient temperature before it was poured into water (10 mL) and extracted with dichloromethane (3x25 mL). The combined organic extracts were evaporated in vacuo to give a yellow film. This was then triturated by IMS (5 mL) and the solid was vacuum filtered and dried at 50 ° C overnight to give the title compound (50 mg, 29%) as a white solid.

Mp 209-231 ° C 1 H NMR (300MHz, DMSO) δ = 1.36-1.81 (4H, m), 2.04-2.17 (1H, m), 2.28-2.52 ( 8H, m), 2.90-3.09 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H, d, J = 9.7Hz), 7.15 (1H, bs), 7.30 (1H, d, J = 9.7Hz), 7.51 (1H, s), 10.85 (1H, bs). LRMS (Thermospray): 322 (MN ⁺ ).

Example 4 (R) -N-Benzyl-N-methyl-1- [3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indol-5-yl] methanesulfonamide (a) (R) -5- Bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indole

Br

i) NaH ii) ClCH ₇ OCH ₂ CH ₂ Si (CH ₃ ) ₃

THF

Si (CH3) ₃ • · · ·

To a stirred solution of (R) -5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (10 g, 34.1 mmol) in tetrahydrofuran (100 mL) at 0 ° C under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil) (1.5 g, 37.5 mmol) in portions while maintaining the temperature below 5 ° C. After the addition was complete, the dark brown solution was stirred at 0 to 5 ° C for 10 minutes before trimethylsilylethyloxymethyl chloride (6.64 mL, 37.5 mmol) was added dropwise while maintaining the temperature below 5 ° C. The brown solution was then warmed to ambient temperature over a 1 hour period before being poured into water (100 mL). The mixture was then extracted with ethyl acetate (3 x 25 mL) and the combined organic extracts were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane 1: 1 as eluent) to give ad (a) (8.96 g, 62%) as a brown oil.

¹ H NMR (300MHz, CDCl ₃ )? = -0.95 (9H, s), 0.89 (2H, t, J = 6.8Hz), 1.42-1.86 (4H, m), 2 14-2.30 (1H, m), 2.35-2.60 (5H, m), 3.05-3.18 (2H, m), 3.42 (2H, t, J = 6, 8Hz), 5.41 (2H, s), 7.31 (2H, s), 7.71 (1H, s).

LRMS (thermospray): 424.5 (MH ⁺ ).

(b) N-Benzyl-1-cyano-N-methyl-1 - [(R) -3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indol-5-yl] methanesulfonamide

Br

IN

Si (CH ₃ ) j

To a stirred solution of N-benzyl-1-cyano-N-methylmethanesulfonamide (from step (a), 1.42 g, 6.33 mmol) and tetrakis (tri).

- 28 phenylphosphine) palladium (0) (3.99 mg, 0.34 mmol) in ethylene glycol dimethyl ether (5 mL) at 0 ° C under nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil), (495 mg, 12.4 mmol) in portions, maintaining the temperature below 5 ° C. The brown solution was then warmed to ambient temperature over a 10 minute period before the (R) -5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indole solution was added dropwise (see example). 1 (c), 2.44 g, 5.8 mmol) in toluene (20 mL) and the mixture was then heated to reflux. Reflux was maintained for 1.5 hours, after which time the dark brown solution was cooled to ambient temperature.

The reaction mixture was then poured into water (50 ml) and extracted with ethyl acetate (3 x 25 ml). The organic extracts were combined and evaporated in vacuo to give a brown oil.

This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to afford compound (b) (3.25 g, 99%) as a brown oil.

¹ H NMR (300MHz, CDCl 3? F = 0.93 (9H, s), 0.88 (2H, t, J = 6.8Hz), 1.46-1.90 (3H, m), 2,152.30 (1H, m), 2.44 (3H, s), 2.60-2.76 (4H, m), 3.05-3.20 (2H, m),

3.45 (2H, t, J = 6.8 Hz), 4.20 (2H, s), 5.28 (1H, s), 5.43 (2H, s), 7.10 (1H, s) 7.22-7-43 (6H, m), 7.50-7.58 (1H, s), 7.78 (1H, s).

LRMS (thermospray): 567 (MH ⁺ ).

(c) (R) -N-Benzyl-N-methyl-1- [3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indol-5-yl] methanesulfonamide

• · · · · ·

- 29 To a stirred solution of N-benzyl-1-cyano-N-methyl-1 [(R) -3- (1-methyl-2-pyrrolidinylmethyl) -1-trimethylsilylethyloxymethyl-1H-indol-5-yl] methanesulfonamide (from step ( b),

1.56 g, 2.8 mmol) in ethanol (12 mL) at ambient temperature was added 2N potassium hydroxide solution (6.24 mL, 12.5 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hours. The oily reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined and evaporated in vacuo to give the crude product as a dark brown oil.

This was purified by flash column chromatography (ethylation tat: hexane: diethylamine 1: 1: 0.1 as eluent) to give the title compound (1.49 g, 75%) as a brown oil.

¹ H NMR (300MHz, CDCl ₃ ) (f = -0.91 (0H, s), 0.85 (2H, t, J = 6.8Hz), 1.48-1.88 (4H, m), 2.152.30 (1H, m), 2.36-2.69 (8H, m), 3.05-3.20 (2H, m), 3.45 (2H, t, J = 6.8 Hz), 4.20 (2H, s), 4.42 (2H, s), 5.42 (2H, s), 7.08 (1H, s), 7.14-7.34 (6H, m), 7 40-7.55 (1H, d), 7.56 (1H, s).

LRMS (thermospray: 542.8 (MH ⁺ )).

Example 5 (R) -1- [2-Allyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-diphenylmethyl-N-methylmethanesulfonamide (a) (R) - 1-Allyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) 1H-indole

Br

H

i) ^{L +} O Bu -> ii) ₂ CHCH ₂ is passing THF

Br \

• · · · · · · ·

To a stirred solution of (R) -5-bromo-3- (1-methyl-2-pyrrolidinylraethyl) -1H-indole (22.5 g, 76.8 mmol) in tetrahydrofuran (132 mL) at 0 ° C below. Potassium tert-butoxide (9.47 g, 84.4 mmol) was added in portions under nitrogen while maintaining the temperature below 5 ° C. After the addition was complete, the dark brown suspension was stirred at 0-5 ° C for 30 minutes before allybromide (7.3 mL, 84.3 mmol) was added dropwise while maintaining the temperature below 5 ° C. The brown solution was then warmed to ambient temperature over a 1 hour period before being cooled into water (100 mL). The mixture was then extracted with ethyl acetate (3 x 25 mL) and the combined organic extracts were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to afford compound (a) (19.94 g, 78%) as a golden oil.

@ 1 H NMR (300 MHz, CDCl3) .delta. = 1.42-1.92 (4H, m), 2.15-2.35 (1H, m), 2.38-2.64 (5H, m) ), 3.023.22 (2H, m), 4.66 (2H, d, J = 4.8Hz), 4.98-5.25 (2H, m), 5.88-6.14 (1H, m) 6.93 (1H, s), 7.15 (1H, d, J = 9.7 Hz), 7.25 (1H, d, J = 9.7 Hz), 7.72 (1H, s).

LRMS (thermospray): 333 (MH ⁺ ).

[α] _D + 62.9 ° (c = 6, CH ₂ Cl ₂ ).

(b) 1 - [(R) -1-Allyl-3- (1-methyl-5-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

O

-►

NaH, Pd (PPh ₃ ) ₄ Toluene, reflux

To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (see Example 2 (c), 1.36 g, 4.55 mmol).

- 31 in toluene (5 ml) at 0 ° C under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil) (345 mg,

8.6 mmol) portionwise while maintaining the temperature below 5 ° C. The dark brown solution was then warmed to ambient temperature over a 30 minute period before tetrakis (triphenylphosphine) palladium (0) (285 mg, 0.25 mmol) was added in one portion.

Then a solution of (R) -1-allyl-5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (from step (a), 1.37g,

4.1 mmol) in toluene (5 mL) to a yellow-green suspension and the mixture was heated to reflux. Reflux was maintained for 2 hours after which time the dark brown solution was cooled to ambient temperature.

The reaction mixture was then poured into water (50 mL) and extracted with ethyl acetate (3x25 mL). The organic extracts were combined and evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to afford compound (b) (1.81 g, 80%) as a brown oil.

^{Τ Η} NMR (300MHz, CDCl-j) d = 42-l 95 (4H, m), 2.16-2.30 (1H, m), 2.35 to 2.66 (4H, m) 2.75 (3H, s), 3.02-3.20 (2H, m), 4.66 (2H, d, J = 4.8Hz), 4.95-5.15 (3H, m) 5.16-5.25 (1H, m), 5.86-6.06 (1H, m), 6.43 (1H, s), 6.98 (1H, s),

7.10-7.50 (12H, m), 7.58 (1H, m).

LRMS (thermospray): 552.7 (MH ⁺ ).

(c) (R) -1- [1-Allyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -N-diphenylmethyl-N-methylmethanesulfonamide

• · a ·

To a stirred solution of 1 - [(R) -1-allyl-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indol-5-yl] -1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (b)) (5.11 g, 9.25 mmol) in ethanol (10.22 mL) at ambient temperature was added 2N potassium hydroxide solution (20.4 mL, 41 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 16 hours. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3 x 50 mL).

The organic extracts were combined and evaporated in vacuo to give a dark brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to give the title compound (3.7g, 76%) as a brown oil.

¹ H NMR (300MHz, CDCl 3? F = 1.42-1.93 (4H, m), 2.14-2.29 (1H, m), 2.34-2.73 (8H, m), 3.013 20 (2H, m), 4.27 (2H, s), 4.66 (2H, d, J = 4.8Hz), 4.96-5.28 (2H, m), 5.88-6 06 (1H, m), 6.38 (1H, s), 6.88-7.44 (14, m).

LRMS (thermospray): 528.9 (MH ⁺ ).

[α] _D + 52.7 ° (c = 0.88, CH ₂ Cl ₂ ).

Example 6

N-tert-Butyl-1-cyano-N-methyl-1 - [(R) -3- (1-methyl-2-pyrrolidinylmethyl-1-tosyl-1H-indol-5-yl) methanesulfonamide (a) Methyl- (N-tert-butyl-N-methylsulfamoyl) acetate

O c

,with

Cl

CO ₂ Me

NH

ch ₂ or ₂

0,

CO ₂ Me

Compound ad (a) (14.81 g, 59%) was prepared as a yellow oil from tert-butyl methyl amine (24.48 g, 0.28 mol) and methyl chlorosulfonylacetate (19.37 g, 0.11 mol), using of the method of Example 1 (a).

@ ¹ H NMR (300 MHz, CDCl3) .delta. = 1.42 (9H, s), 2.90 (3H, s), 3.77 (3H, s), 3.97 (2H, s).

Found: C 43.21, H 7.71, N 6.31.

^C 8 ^H 17 ^NO 4 ^S requires: C 43.03, H 7.67, N 6.27%.

(b) (N-tert-Butyl-N-methylsulfamoyl) acetamide

THF

Compound ad (b) (3.66g, 84%) was prepared as a white solid from aqueous ammonia (10 mL, relative density = 0.88) and methyl (N-tert-butyl-N-methylsulfamoyl) acetate ( from step (a), 4.7 g, 21 mmol) using the procedure of Example 1 (b).

M.p. 105-109 [deg.] C.

¹ H BNMR (300MHz, CDCl ₃ ) 1.47 (9H, s), 2.95 (3H, s), 3.90 (2H, s), 5.50 (1H, bs), 6.63 (1H) , bs).

Found: C 40.31, H 7.70, N 13.41.

C ₇ H ₁₅ N ₂ O ₃ S requires: C 40.37, H 7.74, N 13.45%.

(c) N-tert-Butyl-1-cyano-N-methylmethanesulfonamide,

X ^ S / ^ CONH, i) (COCl) ₂ , DMF \

CN

(ii) Pyridine Acetonitrile

Compound ad (c) (7.31 g, 96%) was prepared as a yellow oil from (N-tert-butyl-N-methylsulfamoyl) acetamide (from step (b), 8.31 g, 40 mmol) using of the method of Example 1 (c).

¹ H NMR (300MHz, CDCl 3)? = 1.49 (9H, s), 3.07 (3H, s), 3.97 (2H, s).

Found: C 44.20, H 7.51, N 14.70.

^C 7 ^H 14 ^N 2 ° 2 ^S Requires: C 44.19, H 7.42, N 14.72%.

(d) (R) -5-Bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1-tosyl-1H-indole

Br \

ch ₃ c ₆ h ₄ s ₂ ci -►

KOH, DME \

To a stirred solution of (R) -5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1H-indole (10.0 g, 34.1 mmol) in ethylene glycol dimethyl ether (50 mL) at 0 ° C under a nitrogen atmosphere potassium hydroxide flakes (9.58 g, 171 mmol) were added in one portion. Then para-toluenesulfonyl chloride (6.83 g, 35.8 mmol) was added portionwise to the brown suspension over a 5 minute period while maintaining the temperature below 5 ° C. The brown suspension was then warmed to ambient temperature and stirred for an additional 2 hours. The mixture was then filtered under vacuum and the filter cake washed with toluene (2 x 100 mL). The filtrate was then concentrated under vacuum to a volume of about 20 ml, resulting in the precipitation of a cream solid. After stirring for 2 hours, the solid was filtered and dried under vacuum at 50 ° C for 12 hours to give the title compound (9.91 g, 65%) as a beige solid.

M.p. 98-104 ° C.

- 35 ^{Χ Η} NMR (300MHz, CDCl-j)

Δ = 1.54-1.84 (4H, m), 2.15-2.28 (1H, m), 2.30-2.58 (8H, m), 2.903.15 (2H, m), 7.15-7.30 (2H, m), 7.35-7.42 (2H, m), 7.58 (1H, m),

7.65-7.9 (3 H, m).

LRMS (thermospray) ϊ 449.4 (MH ⁺ ).

[α] _D + 52.9 ° (c = 5.1, CH ₂ Cl ₂ ).

(e) N-tert-Butyl-1-cyano-N-methyl-1 - [(R) -3- (1-methyl-2-pyrrolidinylmethyl) -1-tosyl-1H-indol-5-yl] methanesulfonamide \

Sat ₂ c ₄ h ₄ ch, o

->.

NaH, Pd (PPh ₃ ) ₂ Cl ₂ , NaBH 4, DME, reflux

To a stirred suspension of dichlorobis (triphenylphosphine) palladium (II) (704 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in ethylene glycol dimethyl ether (5 mL) at ambient temperature under a nitrogen atmosphere was added sodium borohydride (38 mg,

1 mmol) of one portion. The green suspension was stirred for 5 minutes, then N-tert. butyl-1-cyano-N-methylmethanesulfonamide (from step (c), 1.04 g, 5.4 mmol) in one portion. The green suspension was then cooled to 0-5 ° C and sodium hydride (60% dispersion in mineral oil) (441 mg,

II mmol) in portions, maintaining the temperature below 5 ° C.

The brown solution was then warmed to ambient temperature over a 10 minute period before the solution of (R) -5-bromo-3- (1-methyl-2-pyrrolidinylmethyl) -1-tosyl-1H-indole (from step (d)) was added dropwise. , 2.24 g, 5 mmol) in ethylene glycol dimethyl ether (15 mL). The brown suspension was then heated to reflux.

• · ·

Reflux was maintained for 1.5 hours, after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic extracts were combined and evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to give the title compound (1.23 g, 45%) as a golden oil.

¹ H NMR (300MHz, CDCl 3? = 1.44 (9H, s), 1.54-1.84 (4H, m), 2.15-2.28 (1H, m), 2.32-2, 66 (8H, m), 2.85 (3H, s), 2.95-3.15 (2H, m), 5.15 (1H, s), 7.18-7.28 (2H, m) 7.39-7.50 (2H, m), 7.62-7.76 (3H, m), 7.96-8.05 (1H, s).

LRMS (thermospray): 557.8 (MH ⁺ ).

Example 7

3- [2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (a) 5-Bromo-N, N-dimethyl-oxo-1H-indole-3-acetamide

H

THF

To a solution of 5-bromoindole (15.85 g, 81 mmol) in tetrahydrofuran (8 mL) at 0-5 ° C under nitrogen was added oxalyl chloride (7.76 mL, 89 mmol) dropwise while maintaining the temperature below 5 Deň: 32 ° C. The cloudy solution was then warmed to ambient temperature and stirred for 30 minutes before being recooled to 0-5 ° C.

• «• ·

I · · 4

The solution was then saturated with anhydrous dimethylamine for 30 minutes, resulting in the formation of a yellow precipitate. The suspension was then warmed to room temperature and diluted with demineralized water (100ml) before being extracted with dichloromethane (3x50ml). The organic extracts were combined and evaporated in vacuo to give a white solid. This was suspended in ethyl acetate: hexane (1: 1) (40 mL) for 8 hours and then filtered in vacuo to afford compound (d) (20.28g,

%) as a white solid.

M.p. Mp 189-190 ° C.

¹ H NMR (300MHz, CDCl ₃ )

S = 2.90 (3H, s), 2.96 (3H, s), 7.35-7.55 (2H, m), 8.15 (1H, s),

8.22 (1H, d, J = 0.97Hz).

Found: C 48.71, H 3.72, N 9.41.

^c 12 ^H n ^BrN 2 ° 2 ⁱⁿ Y ^2ad 3 ^{e: c} 48.84, H 3.76, N 9.49%.

(b) 5-Bromo-3- [2- (dimethylamino) ethyl] -1H-indole

A solution of 5-bromo-N, N-dimethyl-N-oxo-1H-indole-3-acetamide (from step (a), 19.85 g, 67.3 mmol) in tetrahydrofuran (100 mL) was added dropwise to a suspension of lithium aluminum hydride (7.66 g, 0.2 mol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere while maintaining the temperature below 5 ° C.

The yellow-green suspension was then warmed to ambient temperature and then brought to moderate reflux. Reflux was maintained for 5 hours, after which the reaction mixture was cooled to 0 ° C and isopropyl alcohol (150 mL) and IMS (150 mL) were gradually added.

The gray suspension was then warmed to ambient temperature before IN NaOH (100 mL) was added. The reaction mixture was then filtered through celite (trademark) and the celite pad was washed successively with demineralized water (100 mL) and IMS (100 mL). The filtrate was then concentrated under reduced pressure until all alcohol was removed, and then the aqueous residue was extracted with ethyl acetate (2x200 mL). The combined organic extracts were then removed in vacuo to give a brown oil. This was triturated with hexane / ethyl acetate (1: 1) (30 mL) to afford compound (b) (13.4 g, 75%) as a cream solid.

M.p. Mp 82-85 ° C.

¹ H NMR (300MHz, CDCl 3)? F = 2.34 (6H, s), 2.62 (2H, t, J = 7.8Hz), 2.90 (2H, t, J = 7.8Hz) ), 7.0 (1H, s), 7.1-7.35 (2H, m), 7.72 (1H, s), 8.26 (1H, bs).

Found: C 53.94, H 5.61, N 10.40.

^{Cl H} 2 i5 ^BrN 2 requires: C 53.95, H 5.66, N 10.49%.

(c) 1-Benzyl-5-bromo-3- [2- (dimethylamino) ethyl] -1H-indole

To a stirred solution of 1-benzyl-5-bromo-3- [2- (dimethylamino) ethyl] -ΙΗ-indole (from step (b), 10.18 g, 38.1 mmol) in tetrahydrofuran (50 mL) at 0 Sodium hydride (60% dispersion) in mineral oil (1.68g, 42 mmol) was added portionwise under nitrogen atmosphere, maintaining the temperature below 5 ° C. Upon completion of the addition, the dark brown solution was stirred at 0-5 ° C for 1 hour before benzyl bromide (4.99 mL, 42 mmol) was added dropwise while maintaining

- 39 below 5 ° C. The brown solution was then warmed to ambient temperature over a 1 hour period before being poured into water (100 mL). The mixture was then extracted with ethyl acetate (3 x 25 mL) and the organic extracts were combined and evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to afford compound (c) (7.07 g, 52%) as a white solid.

M.p. Mp 49-50 ° C.

bl NMR (300MHz, CDC1 ₃₎

2.34 (6H, s), 2.60 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 7.8Hz), 5.23 (2H, s), 6, 95 (1H, s), 7.01-7.40 (7H, m), 7.72 (1H, m).

Found: C 63.69, H 5.93, N 7.76.

^C 19 ^H 21 ^{BrN 2} yžaduje: C 63.87, H 5.92, N 7.84%.

(d) 1- [1-Benzyl-3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (see Example 2 (c), 2.36 g, 7.9 mmol) in a mixture of toluene (4 mL) and ethylene glycol dimethyl ether (1 mL) at 0 to 5 Sodium hydride (60% dispersion in mineral oil (577 mg, 14.4 mmol) was added portionwise while maintaining the temperature below 5 ° C under nitrogen.

Upon completion of the addition, the dark brown solution was warmed to ambient temperature over a 30 minute period and tetrakis (triphenylphosphine) palladium (0) (529 g, 0.46 mmol) was added in one portion.

- 40 •

A solution of 1-benzyl-5-bromo-3- [2- (dimethylamino) ethyl] -1H-indole (from step (c), 2.34 g, 6.6 mmol) in toluene (2 mL) was then added dropwise into a brown suspension and the mixture was heated to reflux. Reflux was maintained for 2 hours, after which time the dark brown solution was cooled to ambient temperature.

The reaction mixture was then poured into water (25 mL) and extracted with ethyl acetate (3x15 mL). The organic extracts were combined and evaporated in vacuo to give a brown oil. This was redissolved in absolute ethanol (8 mL) and stirred for 18 hours at which time precipitation occurred. The solid was filtered and dried under vacuum at 50 ° C overnight to afford compound (d) (1.3 g, 35%) as a cream solid.

M.p. 98-100 ° C.

¹ H NMR (300MHz, CDCl ₃ )

2.30 (6H, s), 2.52 (2H, m), 2.75 (3H, s), 2.80-2.92 (2H, m), 4.96 (1H, s), 5 24 (2H, s), 6.39 (1H, s), 6.94-7.75 (19H, m). Found: C 72.56, H 6.29, N 9.31.

^C 35 ^H 36 ^N 4 ^O 2 ^{S at least} 3 ^{e: c} 72.89, H 6.29, N 9.71%.

(e) 1-f-Benzyl-3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of 1- [1-benzyl-3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] -1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (d), 3.01 g, 5.2 mmol) in IMS (15 mL) at ambient temperature was added 2N potassium hydroxide solution.

41 (15 mL, 30 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hours. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined and evaporated in vacuo to give the crude product as a dark brown oil. This was purified by flash column chromatography (ethyl acetate: hexane: diethylamine 1: 1: 0.1 as eluent) to afford compound (e) (2.14 g, 74%) as a pale yellow solid.

M.p. MP 98-100 ° C.

¹ H NMR (300MHz, CDCl 3? = 2.35 (6H, s), 2.54-2.65 (5H, m), 2.85 (2H, t, J = 8.7Hz), 4.27 ( 2H, s), 5.24 (2H, s), 6.35 (1H, s), 6.94-7.43 (99H, m).

Found: C 74.47, H 6.44, N 7.79.

^C 34 ^H 37 ^N 3 ^O 2 ^S requires: C 74.01, H 6.76, N 7.62%.

(f) 3- [2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide

Liquid ammonia (4 mL) was condensed into a stirred suspension of calcium chips (243 mg, 6 mmol) in tetrahydrofuran (4 mL) at -40 ° C. The blue bronze was stirred at -50 to -40 ° C for an additional 15 minutes before the solution was added dropwise

1- [1-benzyl-3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] -N-diphenylmethyl-N-methylmethanesulfonamide (from step (e), 836mg,

1.5 mmol) in tetrahydrofuran (2 mL) while maintaining

- 42 below -40 ° C. The dark blue solution was stirred at -40 ° C for an additional 30 minutes before saturated ammonium chloride solution (10 mL) was added dropwise and the gray solution was warmed to ambient temperature. Water (10 mL) was then added and the white suspension was stirred for 15 minutes before being filtered under vacuum. The solid was then dissolved in 5N HCl (12 mL) and the resulting orange solution was extracted with ethyl acetate (10 mL). The pH of the aqueous phase was then adjusted (pH = 10) with 10N NaOH, resulting in precipitation. The solid was filtered and dried under vacuum at 50 ° C overnight to give the title compound (250 mg, 56%) as a white solid.

M.p. Mp 159-163 ° C.

¹ H NMR (300MHz, CDCl 3)

2.22 (6H, s), 2.53-2.61 (5H, m), 2.75-2.89 (2H, m), 4.33 (2H, s), 6.75 (1H, m, q, J = 3Hz), 7.05 (1H, d, J = 4.85Hz), 7.15 (1H, s), 7.30 (1H, d, J = Hz), 7.50 (1H, s), 10.8 (1H, bs).

LRMS (thermospray): 296.4 (MH ⁺ ).

Claims (12)

- 43 PATENT CLAIMS 1. «· · ♦ A process for the preparation of a compound of formula I Wherein R and R independently represent N-protecting groups, and 3 R represents a C 1-6 alkyl group substituted with (i) 5 or a 6-membered saturated nitrogen containing heterocyclic group, which in turn may be substituted with a C 1-6 alkyl or pyrimidine ring which is itself substituted with a C 1-6 alkoxy, or (ii) di (C 1-6 alkyl). (alkyl) amino, characterized in that a compound of formula II is reacted C n) wherein Hal represents Cl, Br or I, and 2 3 R and R are as defined above, with the compound of formula III o _x RCH.N ^ Cm) wherein R is as defined above, in the presence of a strong base and a palladium (O) catalyst, at an elevated temperature in a solvent that does not adversely affect the reaction. 2. The process of claim 1 wherein the strong base is sodium hydride or potassium t-butoxide. Process according to claim 1 or 2, characterized in that the palladium (0) catalyst is tetrakis (triphenylphosphine) palladium (0). Process according to any one of the preceding claims 1 to 3, characterized in that the solvent is a mixture of toluene and ethylene glycol dimethyl ether. 5. The method of claim 1 wherein Hal is Br. A process for the preparation of a compound of formula V, wherein R is as defined in claim 1, characterized in that (i) basic hydrolysis of the cyano group of a compound of formula I as defined in claim 1 is carried out followed by decarboxylation of the resulting carboxylic acid to form a compound of formula IV R'CH, NV ^J Wherein R ¹³ is as defined in claim 1, followed by 12 (ii) replacement of R and R with hydrogen. 7. The process of claim 6 wherein step (i) is carried out using aqueous potassium hydroxide in ethanol at elevated temperature. Process according to claim 6 or 7, characterized in that step (ii) is carried out by means of hydrogenolysis. The process according to any one of the preceding claims, wherein R 1 represents benzyl, CH ₂ OCH ₂ (C 8 H 8), CH (C 8 H 3) ₂ or t-butyl. A process according to any one of the preceding claims _in 2, characterized in that R represents an N-protecting group which is stable to basic hydrolysis conditions. The process of claim 10 wherein R is benzyl or CH ₂ OCH ₂ (C 8 H 8). Process according to any one of the preceding claims 3, characterized in that R represents CH ₂ CH ₂ N (CH 2) ₂ or a group of formula Ia or 1b 13. Compound formulas 14. Compound formulas 15 Dec Compound formulas Also as defined in claim 1. III as defined in claim 1. IV as defined in claim 6. Represented by: JUDr. Ing. Milan Hořejš - 47 * to • to * to y 46 ^c 3 36 3662 * to · to · <· «· _r · ··« <»· ··· ··· - to · 1/2 CN + ³ O (III) strong base Pd (0) catalyst -► solvent, heat