A PROCESS FOR THE PREPARATION OF ELUXADOLINE

Abstract

The present invention relates to an improved process for the preparation of eluxadoline and its intermediates and that includes the use of an aqueous surfactant solution in the preparation of N.sup.2-[(benzyloxy)carbonyl]-N-(2-oxo-2-phenylethyl)-L-alaninamide, an intermediate in the preparation of eluxadoline.

Claims

1. (canceled)

2. A process for the preparation of eluxadoline of Formula I, ##STR00010## comprising: a) coupling a compound of Formula III ##STR00011## with a compound of Formula IV or a salt thereof ##STR00012## in the presence of an aqueous surfactant solution to obtain a compound of Formula II; and ##STR00013## b) converting the compound of Formula II to eluxadoline of Formula I.

4. (canceled)

5. The process according to the claim 2, wherein the coupling is carried out in the presence of a coupling agent selected from the group consisting of N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), 1,1-carbonyldiimidazole (CDI), N,N,N,N-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU), N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU).

7. The process according to the claim 2, wherein the coupling is carried out in the presence of a base selected from the group consisting of triethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisopropylamine, N,N-diisopropylethylamine, 2,4,6-trimethylpyridine, and 2,4,6-collidine.

8. The process according to claim 2, wherein the coupling is carried out in the presence of an aqueous surfactant solution prepared by contacting an anionic surfactant, a cationic surfactant, or a nonionic surfactant with water.

9. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0008] The term about, as used herein, refers to any value which lies within the range defined by a number up to +10% of the value.

[0009] The term room temperature, as used herein, refers to the temperature in the range of 25 C. to 35 C.

[0010] The term pure, as used herein, refers to N.sup.2-[(benzyloxy)carbonyl]-N-(2-oxo-2-phenylethyl)-L-alaninamide of Formula II, having a chromatographic purity of greater than or equal to about 80%, preferably, a chromatographic purity of greater than or equal to about 85%, preferably, a chromatographic purity of greater than or equal to about 95% and more preferably, a chromatographic purity of greater than or equal to about 99%.

[0011] The term nitrogen protecting group, as used herein, refers to acetyl, tert-butoxycarbonyl, trityl, p-toluenesulfonyl, benzyloxy carbonyl, or 9-fluorenylmethoxy carbonyl groups.

[0012] The term surfactant, as used herein, refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid and a liquid, or two liquids. The surfactant is a physiologically acceptable anionic, cationic, or nonionic surfactant.

[0013] Examples of anionic surfactants include, but are not limited to, sodium oleyl isethionate, sodium salt of oleyl methyl tauride, palmito nitrile sulfonate, sodium alpha naphthalene monosulfonate, sodium octahydro anthracene sulfonate, potassium dodecyl sulfate, and ammonium dodecyl sulfate.

[0014] Examples of cationic surfactants include, but are not limited to, dodecylamine acetate, octadecylamine acetate, 2-undecylimidazoline, oleylaminodiethylamine, dioctadecyl dimethyl ammonium chloride, didodecyl dimethyl ammonium chloride, dihexadecyl dimethyl ammonium chloride, beta-hydroxyethylsterarylamide, oleylbenzylaminoethylene diethylamine hydrochloride, methylheptadecyl benzimidazol hydrobromide, cetylpyridinium chloride, octadecylsulfonium methyl sulfate, and octadecylchloromethyl ether.

[0015] Examples of commercially available, nonionic surfactants include, but are not limited to, Tergitol TMN-6, Tergitol 15S40, Tergitol 15S7, Brij-35, Triton X-100, TPGS-750M, PTS-7, and SPGS-550M.

[0016] A first aspect of the present invention provides a process for the preparation of a compound of Formula II,

##STR00003##

comprising coupling a compound of Formula III

##STR00004##

with a compound of Formula IV or a salt thereof

##STR00005##

in the presence of an aqueous surfactant solution.

[0017] A second aspect of the present invention provides a process for the preparation of eluxadoline of Formula I,

##STR00006##

comprising

[0018] a) coupling a compound of Formula III

##STR00007##

[0019] with a compound of Formula IV or a salt thereof

##STR00008##

[0020] in the presence of an aqueous surfactant solution to obtain a compound of Formula II; and

##STR00009##

[0021] b) converting the compound of Formula II to eluxadoline of Formula I.

[0022] The coupling of the compound of Formula III with the compound of Formula IV or a salt thereof to obtain the compound of Formula II is carried out in the presence of an aqueous surfactant solution, a coupling agent, and a base.

[0023] The coupling agent is selected from the group consisting of N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), 1,1-carbonyldiimidazole (CDI), N,N,N,N-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU), N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU).

[0024] The base is selected from the group consisting of triethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisopropylamine, N,N-diisopropylethylamine, 2,4,6-trimethylpyridine, and 2,4,6-collidine.

[0025] The coupling of the compound of Formula III with the compound of Formula IV or a salt thereof is carried out for about 4 hours to about 15 hours, for example, from about 5 hours to about 12 hours.

[0026] The coupling of the compound of Formula III with the compound of Formula IV or a salt thereof is carried out at a temperature of from about 20 C. to about 70 C., for example, from about 25 C. to about 60 C.

[0027] The compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula II may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.

[0028] The compound of Formula II is converted to eluxadoline of Formula I by processes known in the art, for example, as disclosed in U.S. Pat. No. 7,741,356.

[0029] While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

Method

[0030] Chromatographic purity of the samples was determined by HPLC using Water Alliance HPLC system, Water 2695 separation module with 2489 UV visible detector.

[0031] The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Comparative Example: Preparation of N.SUP.2.-[(benzyloxy)carbonyl]-N-(2-oxo-2-phenylethyl)-L-alaninamide (Formula II) in the Absence of Surfactant

[0032] De-ionized water (DI water) (50 mL) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (2 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (1.98 g; a salt of Formula IV) at room temperature. N-Methylmorpholine (1.1 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0033] Yield: 1.2 g

[0034] Chromatographic purity: 57.90%

Example: Preparation of N.SUP.2.-[(benzyloxy)carbonyl]-N-(2-oxo-2-phenylethyl)-L-alaninamide (Formula II)

[0035] Method A:

[0036] An aqueous solution of Triton X-100 (5 g in 50 mL de-ionised (DI) water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0037] Yield: 4.8 g

[0038] Chromatographic purity: 95.96%

[0039] Method B:

[0040] An aqueous solution of Triton X-100 (10 g in 50 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0041] Yield: 4.3 g

[0042] Chromatographic purity: 96.10%

[0043] Method C:

[0044] An aqueous solution of Triton X-100 (20 g in 50 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0045] Yield: 3.9 g

[0046] Chromatographic purity: 96.55%

[0047] Method D:

[0048] An aqueous solution of Triton X-100 (10 g in 50 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at 50 C. to 55 C. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0049] Yield: 3.2 g

[0050] Chromatographic purity: 82.39%

[0051] Method E:

[0052] An aqueous solution of Triton X-100 (2.0 g in 10 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (1 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (0.994 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (1.4 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.8 g) was added to the reaction mixture and stirred for 10 hours to 12 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0053] Yield: 0.75 g

[0054] Chromatographic purity: 92.92%

[0055] Method F:

[0056] An aqueous solution of Brij-35 (5 g in 50 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4 g) was added to the reaction mixture and stirred for 10 hours to 12 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0057] Yield: 3 g

[0058] Chromatographic purity: 92.98%

[0059] Method G:

[0060] An aqueous solution of Brij-35 (10 g in 50 mL DI water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (5 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (4.97 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (2.78 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (4 g) was added to the reaction mixture and stirred for 6 hours to 7 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0061] Yield: 3.2 g

[0062] Chromatographic purity: 98.47%

[0063] Method H:

[0064] An aqueous solution of TPGS-750M (2 wt. % solution in 10 mL water) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (2 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (2.48 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (1.1 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g) was added to the reaction mixture and stirred for 10 hours to 12 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0065] Yield: 1.7 g

[0066] Chromatographic purity: 82.93%

[0067] Method I:

[0068] An aqueous solution of SPGS-750M (10 mL (2% w/w solution in 10 mL water)) was added to a mixture of N-[(benzyloxy)carbonyl]-L-alanine (2 g; Formula III) and 2-amino-1-phenylethanone hydrochloride (2.48 g; a salt of Formula IV) at room temperature. The reaction mixture was stirred for 10 minutes to 15 minutes. N-Methylmorpholine (1.1 g) was added to the reaction mixture over a period of 10 minutes to 15 minutes and then stirred for 10 minutes. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g) was added to the reaction mixture and stirred for 10 hours to 12 hours at room temperature. The reaction mass was filtered, washed with DI water and then dried in an air oven at 45 C. to 50 C. to obtain the title compound.

[0069] Yield: 1.5 g

[0070] Chromatographic purity: 88.46%